HALOGENOPREGNADIENES AND PROCESS FOR THE MANUFACTURE THEREOF

HALOGENOPREGNADIENES; LEUR PREPARATION SUR UNE BASE INDUSTRIELLE

English Abstract

Abstract of the Disclosure
2,9.alpha.-dichloro-paramethasone and its 21- or 17-monoesters or
17,2l-diesters possess a pronounced topical antiinflammatory
action without concomitant actions on thymus, adrenals or
body weight. They are prepared by conventional methods.

Claims

- 25 -
Claims:
1. A process for the manufacture of 2,9.alpha.-dichloro-6.alpha.
fluoro-16.alpha.-methyl-11.beta.,17,21-trihydroxy-pregna-1,4-diene-
3,30-dione compounds of the formula
<IMG> (I)
wherein each of R1 and R2 represents a free or esterified
hydroxyl group, whilst R1 and R2 together can also repre-
sent a cyclic 17,21-diester group which process comprises
(a) the addition of chlorine to the 1,2-double bond in a
compound of the formula
<IMG> (II)

- 26 -
wherein R1 and R2 are as defined in formula (I), whilst
optionally protecting the 11-hydroxyl group temporarily
beforehand, and the dehydrochlorination of the resultant
1,2-dichloro compound, or
(b) treating a compound of the general formula
<IMG> (III)
wherein R1 and R2 are as defined in formula (I), with
hypochlorous acid or with a hypochlorous acid donor, or
(c) treating a compound of the general formula
<IMG> (IV)
26

- 27 -
wherein R1 and R2 are as defined in formula (I), with
hydrogen chloride or a hydrogen chloride donor,
and/or, if desired, in compounds of the formula (I),
in which at least one of the groups R1 and R2 is esterified,
converting at least one esterified hydroxyl group into a
free hydroxyl group, or in compounds of the formula (I),
in which at least one of the groups R1 and R2 represents
a free hydroxyl group, whilst optionally protecting the
11-hydroxyl group temporarily, esterifying at least one
free hydroxyl group, and/or, if desired, converting hemi-
esters of dicarboxylic acids or of polybasic inorganic
acids into their metal salts or salts of organic bases.
2. A process according to claim 1(a), wherein the star-
ting material is treated in an inert organic solvent with
elementary chlorine.
3. A process according to claim 2, wherein a lower ali-
phatic or cyclic ether, a lower aliphatic halogenated
hydrocarbon or a lower aliphatic carboxylic acid, or a
mixture thereof, is used as inert organic solvent.
4. A process according to claim 3, wherein a solution of
the starting material in dioxane is treated with a solu-
tion of chlorine in propionic acid.
5. A process according to claim 2, wherein the reaction
is carried out at low temperature and in the dark.
6. A process according to claim 1(a), wherein the star-
ting material is treated with a mixture of two compounds
one of which yields negative chlorine and the other
positive chlorine.
27

- 28 -
7. A process according to claim 6, wherein a chlorinated
carboxamide or carboximide is used in the presence of hydro-
gen chloride or an alkali metal chloride.
8. A process according to claim 7, wherein the reaction is car-
ried out in a lower aliphatic or cyclic ether, a lower aliphatic
halogenated hydrocarbon or a lower aliphatic carboxylic
aicd, or a mixture thereof.
9. A process according to claim 1a), wherein the 11.beta.-
hydroxy group is protected by esterification with tri-
fluoroacetic acid before the addition of chlorine to the
1,2-double bond.
10. A process according to claim 4, wherein the 11.beta.-hydro-
xy group is protected by esterification with trifluoro-
acetic acid before the addition of chlorine to the 1,2-
double bond.
11. A process according to claim 1a), wherein hydrogen
chloride is split off by treatment with a base from the
1,2-dichlorosteroids obtained by the addition of chlorine.
12. A process according to claim 11, wherein a 11.beta.-tri-
fluoroacetoxy group formed before the addition of chlorine
is reconverted by hydrolysis or solvolysis into the 11-
hydroxyl group before, or simultaneously with the dehydro-
chlorination.
28

- 29 -
13. A process according to claim 12, wherein the hydro-
lysis is carried out with hydroxides, carbonates, bicar-
bonates or acetates of alkali metals or alkaline earth
metals in aqueous, alcoholic or aqueous-alcoholic solu-
tion.
14. A process according to claim 11 wherein the starting
material has been obtained by the addition of elementary
chlorine in the dark at low temperature in a solvent
selected from the group consisting of a lower aliphatic
or cyclic ether, a lower aliphatic halogenated hydrocar-
bon or a lower aliphatic carboxylic acid or a mixture
thereof.
15. A process according to claim 11, wherein the starting
material has been obtained by the addition of elementary
chlorine in the dark at low temperature in dioxane, and
chlorine is used as a solution in propionic acid.
16. A process according to claim 14, wherein the starting
material is treated with a tertiary organic base.
17. A process according to claim 15, wherein the starting
material is treated with an organic base.
18. A process according to claim 14, wherein the starting
material is treated with pyridine or a homolog thereof or
with an N, N-di - alkylaniline.
19. A process according to claim 15, wherein the starting
material is treated with pyridine or a homolog thereof or
with an N, N - dialkylaniline.
29

- 30 -
20. A process according to claim 14, wherein the starting
material is treated with hydroxides, carbonates, bicarbo-
nates or acetates of alkali metals or alkaline earth metals
as bases.
21. A process according to claim 15, wherein the starting
material is treated with hydroxides, carbonates, bicarbo-
nates or acetates of alkali metals of alkaline earth metals
as bases.
22. A process according to claim 1(b), wherein the star-
ting materials are treated with N-chlorocarboxamides or
N-chlorocarboximides in the presence of water and/or an
inert solvent, optionally in the presence of a strong
acid.
23. A process according to claim 1(b), wherein the star-
ting materials are treated with tert.-butylhypochlorite
in an inert solvent in the presence of perchloric acid.
24. A process according to claim 22, wherein water, a
tertiary alcohol, an ether or a ketone is used as inert
solvent.
25. A process according to claim 23, wherein a water im-
miscible solvent is used as the inert solvent.
26. A process according to claim 22, wherein a nitro -
substituted hydrocarbon is used as an inert solvent.
27. A process according to claim 23, wherein a lower
aliphatic alcohol used as the inert solvent.

- 31 -
28. A process according to claim 1(c), wherein the star-
ting materials are treated with hydrogen chloride in
aqueous medium or in an organic solvent.
29. A process according to claim 1, wherein any esterified
hydroxyl group in the 17 - position and/or 21 - position is
hydrolysed with a metal carbonate or alkali metal bicarbo-
nate in aqueous or aqueous - alcoholic solution to give the
2, 9.alpha. - dichloroparamethasone.
30. A process according to claim 1, wherein a 17, 21-
diester or a cyclic 17, 21-orthoester is hydrolysed with a
strong acid, or with a weak acid, to give a 17-monoester of the 2,9.alpha.-
dichloroparamethasone.
31. A process according to claim 1, wherein the esterification
of resultant compounds with at least one free hydroxyl group
in the 17- and 21-position is carried out by treating said
compounds with a reactive functional derivative of an
acid.
32. A process according to claim 31, wherein the 11-hydro-
xyl group is intermediately protected before the esteri-
fication by converting it into the trifluoroacetoxy group.
33. Process as claimed in claim 1, wherein starting com-
pounds are used wherein each of R1 and R2 represent hydro-
gen.
31

- 32 -
34. Process as claimed in claim 1, wherein starting com-
pounds are used wherein at least one of R1 and R2 repre-
sents a hydroxyl group esterified with a lower aliphatic
carboxylic acid having from 1 to 7 C atoms or R1 and R2
together represent a 17,21-orthoester group derived
from a lower aliphatic ortho carboxylic acid having from 1
to 7 C atoms or from carbonic acid.
35. Process as claimed in claim 1, wherein any 2-chloro
compound of formula (I) obtained which has one free hydro-
xyl group R1, and R2 can be a free hydroxyl group or a
hydroxyl group esterified with a lower aliphatic carboxylic
acid having from 1 to 7 C atoms, is treated with a reactive acid
derivative of a lower aliphatic carboxylic acid having
from 1 to 7 C atoms, in the presence of a tertiary base,
so as to give a corresponding 21 - ester, or a 2-chloro com-
pound of formula (I) in which both R1 and R2 are free
hydroxy groups, is treated with a lower aliphatic triester
of a lower aliphatic ortho carboxylic acid having from
1 to 7 C atoms in the presence of a strong acid, or a 2-
chloro compound of formula (I) in which R2 is a free
hydroxyl group and R1 can be either a free hydroxyl group
or a hydroxyl group esterified with a lower aliphatic car-
boxylic acid having from 1 to 7 C atoms, is treated with
a reactive acid derivative of a lower aliphatic acid
having from 1 to 7 C atoms in the presence of a strong
acid, optionally after having protected intermediately the
11 - hydroxyl group by esterification with trifluoroacetic
acid.
32

- 33 -
36. Process as claimed in claim 35 wherein there are
used acid chlorides or acid anhydrides as the reactive
acid derivatives and p-toluene - sulphonic acid as the
strong acid mentioned.
37. Process as claimed in claim 34, wherein a starting
compound is used so as to produce the 2, 9.alpha.-dichloro-
paramethasone 21- acetate.
38. Process as claimed in claim 34, wherein a starting
compound is used so as to produce the 2, 9.alpha.-dichloro-
paramethasone 21-pivalate.
39. Process as claimed in claim 35, wherein a starting
compound is used so as to produce the 17, 21 - ethyl-ortho-
propionate of 2, 9.alpha.-dichloroparamethasone.
40. Process as claimed in claim 35, wherein a starting
compound is used so as to produce the 17.alpha.-monopropionate
of 2, 9.alpha.-dichloroparamethasone.
41. Process as claimed in claim 35, wherein a starting
compound is used so as to produce the 17.alpha., 21 - dipro-
pionate of the 2, 9.alpha.-dichloroparamethasone.
42. Process as claimed in claim 34, wherein a starting
compound is used so as to produce the 21-valerate of 2,
9.alpha.-dichloroparamethasone.
33

- 34 -
43. A compound of the formula
<IMG> (I)
wherein each of R1 and R2 represents a free or esterified
hydroxyl group, whilst R1 and R2 together can represent a
cyclic 17,21-diester group and metal salts or salts of
organic bases of hemiesters of dicarboxylic acids or of
polybasic inorganic acids of these compounds, whenever pre-
pared or produced according to the process as claimed in
any one of claims 1, 34 or 35, or an obvious chemical
equivalent thereof.
44. The 2, 9.alpha.dichloroparamethasone, whenever prepared or
produced by a process as claimed in either of claims 29 or
33, or an obvious chemical equivalent thereof.
45. The 2, 9.alpha.-dichloroparamethasone 21 - acetate, whenever
prepared or produced by a process as claimed in claim 37
or an obvious chemical equivalent thereof.
46. The 2, 9.alpha.-dichloroparamethasone 21 - pivalate, when-
ever prepared or produced by the process as claimed in
claim 38 or an obvious chemical equivalent thereof.
47. The 2, 9.alpha.dichloroparamethasone 21 - valerate, whenever
prepared or produced by the process as claimed in claim 42
or by an obvious chemical equivalent thereof.
34

- 35 -
48. The 17, 21 -ethyl-ortho propionate of 2, 9.alpha.-dichloro-
paramethasone, whenever prepared or produced by the pro-
cess as claimed in claim 39 or an obvious chemical
equivalent thereof.
49. The 17.alpha.-monopropionate of 2, 9.alpha.-dichloroparamethasone,
whenever prepared or produced by the process as claimed
in claim 40 or an obvious chemical equivalent thereof.
50. The 17.alpha., 21-dipropionate of 2, 9.alpha.-dichloroparametha-
sone, whenever prepared or produced by the process as
claimed in claim 41 or an obvious chemical equivalent
thereof.

Description

32~
The invention provides 2,9~-dichloro-6a-fluoro-16~-
methyl-11~,17,21-trihydroxy-pregna-1,4-diene-3,20-dione
compounds of the formula
CH3 P.2
GO~ C~l~Rl
Cl ~ CH3
O \~ .
.
where;n each of Rl and R2 represents a free or esterified
hydroxyl group, whilst Rl and R2 together can also represent
a cyclic 17,21-diester g~oup e.g. which is derived from an
ortho-carboxylic acid or from carbonic acid, and a ~rocess for
the manufacture of these compounds~
The esterified hydroxyL groups menti~ned above are
derived from acids which are customarily suitable as esteri-
fication compounds in hydroxy~Steroids intended for
therapeutic use, for example from unsubstituted or sub~tituted
organic carboxylic acids containing 1 to 18 carbon atoms, from
sulphonic acids or ~rom inorganic acids. Preferred carboxylic
acids of the aliphatic series are in particular the lower
aliphatic mono- or dicarboxylic acids contai~n~ 1 to 7 carbon
atoms~ for exam~le acetic acid, propionic acid, the butyric
acids, the valeric acids, the caproic acids, in particular
.. . . . . ~ . ~.. .. . .. . . .

- ' -
~ ~ 7 ~ ~ Z 4
trimethylacetic acid~ n7caproic acid, dimethylethylacetic
acid, malonic acid,succinic acid, glutaric acid Suitable
higher aliphatic carboxylic acids are, for example, capric or
undecylenic acid, palmitic acid, oleic acid or stearic acid.
Examples of cycloaliphat;c or cycloaliphatic-aliphatic
monocarboxylic acids are cyclopropane-, cycLobutane_,cyclo-
pentane- and cyclohexanecarboxylic acid and cyclopropyl- or
cyclobutyl-methanecarboxylic acidl or one of the cyclopentyl-
or cyclohexyl-ethanecarboxylic acids. Preferred substituted
carboxylic acids are in particular the hydroxylated carboxylic
acids, for example the malic acids, the lactic acids3 the
citric acids, glycollic or digLyco~ic acid, or aLkoxycarboxy~ic
acids, in particular lower a~koxycarboxylic acids, such as
methoxy- or ethoxyacetic acid or methoxy- or ethoxypropionic
acid. Aromatic carboxylic acids which are particularly suitable
as esterification components are the monocycLic acids, such
as benzoic acid and the derivatives thereof, or phthalic acid,
and araliphatic carboxylic acids are monocyclic-lower
aliphatic carboxylic acids, such as phenylacetic or
phenylpropionic acid~ The esterified hydroxyl groups can
also however be derived from heterocyclic acids, for example
from nicotinic or isonicotinic acid. Suitable sulphonic acids
are chiefly methanesulphonic acid or monocyclic aromatic
sulphonic acids, for example benzene- or toluenesulphonic
acids, especially p-~oluenesulphonic acid. Finally, the esteri-
fied group can be derived from inorganic acids, in particular
sulphuric acid and ortho-, meta- or pyro-phosphoric acid.
- 3 -
. - , . ........ ,.:
, . : : , ~ .
., -, - ' ' . ~ ~` . ' ' ' ~

The esters of polybasic acids are generally in the form of
the monoesters.
The es~er g~s can also be derived from ortho-
carboxylic acids, in particular lower aliphatic ortho-carboxy-
lic acids containing l to 7 carbon atoms, such as orthoformic
acid, orthoacetic acid or orthopropionic acid, or from
carbonic acid. The esters of such acids are in the form of
cyclic 17,21-o~tho-carboxylic acid esters or cyclic
17,21-carbonates.
Water-sduble preparations.of formuLa (I) can be
obtained by advantageously preparing hemiesters of polybasic
acids, such as dicarboxylic acids, for example succinic or
phthalic acid, or of sulphuric acids or of phosphoric acids,
and then converting these into salts of organic bases, for
example of simple aliphatic amines, such as trimethylamine,
- diethylamine, ethylamine, propylamine or-isoprop~lamine, or~- -
of cyclic bases, such as piperidine, morpholine or pyrrolidine, .
or the homologues thereo~. However, for the same purpose it is
also possible to prepare esters which are derived from a
carboxylic acid which contains amino groups, for ex~mple
diethylamino-, piperidino- or morpholinoacetic acid, or any
other known amino acid, and to quaternise the amino group in
these esters, so. that the water-soluble quaternary ammonium
salts are formed.
The novel compounds of the formula ~I) enc~mpass
the free 2,9~-dichloro-6~-fluoro-16~-methyl-11~,17~,2'- ;
~- - 4 -

~078B24
trihydroxy-pregna-1,4-diene-3,20-dione ~2, 9a - di chloropara-
methasone), the 17a- and 21-monoester and the 17~,21-diPster
thereof, in particular also the cyclic 17,21-diesters. These
- compounds possess valuable pharmacological properti~s. By way
of example, they have in particular a pronounced antiinflamma-
tory action, as can be demonstrated in animal tests, for
example on rats in the foreign body granuloma test. For example,
when applied locally in the dosage range between 0.003 mg per
cotton wool peLle~ and 0.03 mg per cotton wool pellet they
exhibit a marked antiinflar~matory action. An action on the
thymus is observed in this mode of administration only from
0.03 mg per cotton wool pellet and action on adrenals and body
weight oco~s only at doses from 0.3 mg per cotton wool pellet.
For example, in the indicated mode of administration and in the
above mentioned test on rats, both 2,9a-dichloroparam2thasone-21-
pivalat~ and 2,9a-dichloroparamethaso~17,21-dipropionate
exhibit an ED20-5o from ~.001 mg per co~Dn wool pellet.
The novel compounds can therefore be used as antiinflammatory
agents, in particular in de~matology. However, they are also
valuable intermediates for obtaining other useful substances,
especially pharmacologically active compounds.
The compounds of the above formula (I) can be
obtained in a manner known per se. In particular, they can be
obtained by
~ _
- - , . . .
.
- ~ .

~.07~
(a) the addition of chlorine to the 1,2-double bond in a
compound of the formula
~10 CU3 ~2
~IrcO--~n2- R
~/` (Il)
0~
F
wherein Rl and R2 are as defined in formula (I), whilst
optionally protecting the ll-hydroxy group temporarily
beforehand, and the dehydrochlorination of the resultant
1,2-dichloro compound, or
(b) treating a compound of the general formula
.- - - ~ . - - .
~ . 1 3
CO~CH2 P~
Cl ~ ~ ~ CH3 (III)
O ~ ~ :
F
wherein Rl and R2 are as defined in formula (I), with
- . . . .

~ 0~88 ~ 4
.
hypochlorous acid or with a hypochlorous acid donor, or
(c) treating a compound of the general formula
C1~3 ~2
~CO~ 2--R
O
- ' :'' ' ''
'
wherein Rl and R2 are as defined in formula (I), with
hydrogen chloride or a hydrogen chloride donor,
and/or, if desired, in compounds o the formula (I),
in which at least one of the~groups Rl and R~ is esterified,
converting at least one esterified hydroxyl group into a free
hydroxyl group, or in compounds of the formula (I), in which
àt leas~ one of the groups Rl and R2 represents a free
hydroxyl group, whilst optionally protecting the ll-hydroxyl
group temporarily, esterifiying at least one free hydroxyl
group, and/ora if desired, converting hemiesters of dicarboxy-
lic acids or of polybasic inorganic acids into their metal
salts or salts of organic bases.
According to method (a~, chlorine is added to the
1,2-double bond in a manner known per se, To this end,
~ 7

07&~3~ 4
preferably elementary chlorine is used and the chlorination is
carried out in an inert solvent, for example an ether~ such as
dioxane or tetrahydrofurane, a halogenated hydrocarbon, for
example methylene chloride, or a carboxylic acid, in particular
a lower aliphatic carboxylic acid, such as acetic acid or
propionic acid. Instead of using carboxylic acids it is also
possib~e to use derivatives thereof, such as acid amides 5 for
example dimethyl ormamide, or nitriles, such as lower alkylnit
riles, for example acetonitrile. Advantageously~ mixtures of
these solvents can also be used, in particular a mixture of
an ether, such as dioxane, with one of the above mentioned
lower aliphatic carboxylic acids. The process can be carried
out with chlorine in an amount substantially in excess of ~he
theoretical amount; but preferably the stoichiometric amount
of chlorine is used. The chlorination is advantageously
carried out at low temperature, approx. between -50 and ~3Q~
for example between -20 and ~10C, and in the dark. The
reaction time is normally sev~al hours or days, for example
up to 7 days. In a particularly preferred embodiment of the
process, the starting steroid is dissolved in one of the
solvents mentioned above, for example dioxane, and treated
with a solution of the chlorinating agent, for example
chlorine, in a lower aliphatic carboxylic acid, for example
propionic acid, and this solution is then allowed to stand at
the given temperature for several days.
~ 8 -
. . - . ~ ,
- - ~ , , . . ." . .....

~8824
However, the chlorination of the 1,2-double bond
can also be effected with mLxtures of two different chlorine-
containing compounds one of which yields positive and the
other negative chlorine. Examples of suitable reagents which
are able to set free positive chlorine are chlorinated acid
amides or acid imides, such as chlorosuccinimide or chloro-
acetamide, and reagents which yield negative chlorine are,
for example, hydrogen chloride and alkali metal chlorides. The
above mentioned solvents can also be used for the addition of
chlorine wi~h these reagents.
I~ desired, the ll-hydroxyl group can be protected
before the chlorination, preferably by esterification with
trifluoroacetic acid. The trifluoroacetates are obtai~ed by -
reacting the starting materials with trifluoroacetic ch~oride
or anhydride in a manner known per se. It is known that this
ester can be easily split of again by hydrolysis or
solvolysis, for example by treatment with hydroxides,
carbonates, bicarbonates or acetates of alkali metals or
alkaline earth metals, for example in alcoholic or aqueous-
alcoholic solution, for example in methanolic solution, or
with alcohols alone. A particular method of carrying out the
solvolysis of the ll-trifluoroacetate group is that
described in German patent speciication 1~593~519, which is
chiefly suitable whenever it is a question of le~ving the
ester groups in 17- and/or 21-position intact. This method
comprises treating the ll-ester in a lower alcohol with a
_ 9 _
... . ...... ~ - . .. .
~ . . .
:- , . ;
.~-
.. .. .

8~3Z~L
~alt of an acid whose pKa-value is in the range between about
2 3 and abo-ut 7.3, such as sodium or po~assium azide or
sodium or potassium formiate. If appropriate, this salt
can also only be used in catalytic amounts Furthermore, the
~ydrolysis of the ll-trifluoroacetate group can also be
effected by treatment wi~h other basic reagents, for example
with amines3 in particular heterocyclic bases, such as pyridine
or collidine. Finally, the saponification by treatment with
silica gel according to the process described in DT-OS
2,144,405 is also possible.
The ll-hydroxyl protective group can be removed
immediately after the addition of chlorine to the 1,2-double
bond or, if appropriate, simultaneously~with dehydrochlorination -
by treatment with a base to be carried out, according to the
process, after the chlorination. However, if desired, the
protective group can be removed not until after the removal
of hydrogen chloride by treatment with a base.
The dehydrochlorinatio~ of the 1,2-dichloro compounds
obtained by the addition of chlorine in the 1,2-double bond
can advantageously be accomplished with a base. Suitable bases
are, for example, tertiary organic nitrogen bases, such as
the lower aliphatic amines, for example triethylamine, or
heterocyclic bases, such as pyridine and homologues thereof,
for example collidine, or aromatic bases, such as N,N-dialkyl-
aniline, However, it is also possible to use inorganic bases,
: ,,
- 10 -
- : - . . : , -
. ~ .
- . -
. -

- ~L0'7~2a~
such as in particular the alkali metal and alka~ine earth
metal salts also used for removing the above mentioned
~ hydroxyl protective group, for example potassium or sodium
acetate or potassium or sodium bicarbonate, in aque~us-
alcoholic solution, and the corresponding hydroxides. The
dehydrohalogenation is preferably carried out in the
temperature range between approx 20 and 100C and over the
course of half an hour up to approx. 30 hours, depending on
whether the reaction is carried out at elevated or low
temperature. Preferably, an excess of the dehydrohalogenating
agent is used.
According to method (b), the elements of hypochlor-
ous acid are added in a manner known peri se to the
9,11-double bond of the compounds of the formula (III) by,
for example, treatment with aqueous hypochlorous acid or with
hypochlorous acid donors, such as N-chlorocarboxamides or
N-chlorocarboximides (cf. US patent specification 3,057,886),
in the presence of water and/or an inert solven~ such as a
tertiary alcohol, for axample butanol, an ether, for example
diethyl ether, methyl isopropyl ether, dioxane, or a ketone,
such as acetone~ optionally in the presence of a strong acid.
An advantageous method of carrying out this process is the
reaction with tert.-butylhypochlorite in an inert water-
immiscible solvent, for example a nitro-substituted hydro-
carbon, in the presence of perchloric acid (cf. German patent
specification 2,011,559).
.
- " ~

:~07~
According to method (c), the 9~ oxido group of
the starting compounds of the formula (IV) is treated in a
manner known per se with hydrogen chloride and the process
can be carried out in aqueous medium or in an inert organic
solvent.
According to the process, esterified hydroxyl
groups in the 17- and/or 21-position can, if desired, be con-
verted into free hydroxyl groups. This conversion can be
accomplished in a manner known per se, for example preferably
by alkaline saponification with the hydroxides, carbonates or
bicarbonates o alkali metals, in particular of sodium or
potassium, for example in aqueous or aqueous-alcoholic
solution. The use of an aqueous solution of sodium bicarbonate
in methanol ~ ethanol is preferred.
The selective saponification of the 21-ester group
in 17,21-esters can be ~ffected in-a manner known per se by,
ior example, treating these esters with a soLution of a strong
acid, such as perchloric acid, in an alcohol, for example
methanol, preferably at room temperature, to yield in this
way the 17-monoesters. Another method of obtaining 17-mono-
esters comprises treating the cyclic 17,21-orthoesters o~
a carboxylic acid with a weak organic acid, for example
oxalic acid.
If desired, according to the process of this
invention free hydroxyl groups can be esterified in the 17-
- 12 -
- .. . .. - , .
. ~ ,,, , ... - ,., , , . :

~L0~18;Z4
andlor 21-position. The esterification is again carried out
in a manner known per se, for example by treating the steroid
alcohol with a reactive derivative of the acid in question,
for example an organic acid, in particular a carboxylic acid.
In particular the chlorides or the anhydrides of these acids
are used, preferably in the presence of a tertiary base,
such as pyrldine or collidine. If it is desired to esterify
both groups in 17,21-dihydroxy compounds, or also the 17a~
hydroxy group in 21-esters~ then acylation is carr~ out with
the indicated reactive functional acid derivatives in the
presence of a strong acid, in particular an aromatic sulphonic
acid, for example p-toluenesulphonic acid, which ac~s as
cataiyst~ It is advantageous to protect the ll-hydroxyl group
temporarily before these esterification reactions, for example
by conversion into the tri~oroacetate, because under the
conditions in which the 17-hydroxy group is esteriEied, the
ll-hydroxyl group is also easily acylated. As described above,
the trifluoroacetoxy group can be selectively reconverted
into the free hydroxyl group. It is known that ortho- -
esters can be obtained advantageously by reacting a 17,21-
steroid-diol with an orthoester of the R'-C(OR")3 type,
wherein R' represents a hydrogen atom or an alkyl group, in
the presence of a strong acid, for example p-toluenesulphonic
acid, in an inert organic solvent, for example an aromatic
hydrocarbon, such as benzene or homologues thereof. Chiefly
- 13 -
.. .
:..
, . . .

or~hoacetates and orthopropionates are prepared.
The starting materials necessary for carrying out the
above process methods are known or they can be obtained in a
manner known per se.
The invention also relates to those embodiments of
the process in which a compound obtainable in any stage of
the process is used as starting material and the missing steps
are carried out, or the process is in~errupted at any stage,
or in which a starting material is formed under the reaction
conditions.
The present invention also provides pharmaceutical
preparations which contain as active ingredient a compound
according to the invention of the formula (I) or a sa~Lt of
such a compound with salt-forming properties, and a process
for the manufacture of such pharmaceutical preparations.
Suitable pharmaceuticaL preparations are primarily
ones for topical application, such as creams, ointments,
pastes, foams, tinctures and solutions, which contain approx.
0.005% to approx. 0.1% of active compound, and also
preparations for oral administration, for example tablets,
coated tablets and capsules, and those for parenteral
administration.
Creams are oil-in-water emulsions which contain more
than 50% of water. Fatty alcohols are chiefly used as
oleaginous base, for example lauryl, cetyl or stearyl alcohol,
fatty acids, for example palmitic or stearic acid, liquid to
- 14 -

~7882~
solid waxes, for example isopropyl myristate, wool wax or
bees-wax, and/or hydrocarbons, for example petroleum
jelly (petrolatum) or paraffin oil. Suitable emulsifiers
are surface-active substances wlth primarily hydrophilic
properties, such as corresponding non-ionic emulsifiers,
for example fatty acid esters of polyalcohols or ethylene
oxide adducts thereof, such as polyglycerol fatty acid
esters or polyoxyethylene sorbitan fatty acid esters
(Tweens-Trade-mark); polyoxyethylene fatty alcohol ethers
or esters, or corresponding ionic emulsifiers, such as
alkali metal salts of fatty alcohol sulphates, for example
sodium lauryl suIphate ! sodium cetyl suIphate or sodium
stearyl sulphate, which are customarily used in the
presence of fatty alcohols, for example cetyl alcohol or
stearyl alcohol. Additives to the water phase include
agents which reduce water loss through evaporation, for
example polyalcohols, such as glycerol, sorbitol, propylene
glycol and/or polyethylene glycols, as well as preserva-
tives, perfumes etc.
Ointments are water-in-oil emulsions which contain
up to 70 %, preferably however approx. 20 % to about 50
of water or aqueous phase. The oleaginous phase comprises
chiefly hydrocarbons, for example petroleum jelly, paraffin
oil and/or hard paraffins, which contain preferably
hydroxy compounds suitable for improving the water-absorp-
tion, such as fatty alcohols or esters thereof, for example
cetyl alcohol or wool wax alcohols, or wool wax. Emulsi-
fiers are corresponding lipophilic substances, such as
.
-.
,~ . ;
- ' ' `' .. ~' .

-
~L~78824
`sorbitan fatty acid esters (Spans-Trade-mark), ~or
example sorbitan oleate and/or sorbitan isostearate.
Additives to the water phase include humectants, such as
polyalcohols, for example glycerol, propylene glycol,
sorbitol and/or polyethylene glycol, and preservatives,
perfumes etc.
Greasy ointments are anhydrou~ and contain as base
in particular hydrocarbons, for example parafin,
petroleum jelly and/or llquid paraffins, furthermore
natural or par~ially synthetic fa~, for example coconut
fatty acid triglycerides, or preferably hardened oils,
or example hydrated ground nut or castor oil, and also
fatty acid partial esters of glycerol, for example
glycerol mono- and distearate, and, for example, the
fatty alcohols, emulsifiers and/or additives for
increasing the water-absorption mentioned in connection
with the ointments.
Pastes are creams and ointments containing powdered
ingredients which absorb secretions, such as metal oxides,
for example titanium oxide or zinc oxide, and talc and/or
aluminium silicates whose purpose it is to bind moisture
or secretion present.
Foams are administered from pressurised dispensers
and are liquid oil-in-water emulsions in aerosol form,
with halogenated hydrocarbons, such as chlorofluoro-lower
alkanes, for example dichlorodifluoromethane and dichloro-
tetrafluoroethane being used as propellants. For the
oleaginous phase there are used, inter alia, hydrocarbons,
- 16 -
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., .: ' : . . ~ . '

1~7~8Z~
for example paraffin oil, fatty alcohols, for example
cetyl alcohol, fatty acid esters, for example isopropyl
myristate, and/or other waxes. As emulsifiers there
are used, inter alia, mixtures of those emuIsifiers with
primarily hydrophilic properties, such as polyoxyethylene
sorbitan fatty acid esters ~Tweens-Trade-mark), and
those with primarily lipophilic properties, such as
sorbitan fatty acid esters ~Spans-Trade-mark). In
addition, the conven~ional additives are used, such as
preservatives etc.
Tinctures and solutions generally have an aqueous
ethanolic base to which are added, inter alia, poly-`
alcohols, or example glycerol, glycols, and/or poly-
ethylene glycol, as humectants for reducin~ water loss,
and fat-restoring substances, such as fatty acid esters
with lower polyethylene glycols, i.e. lipophilic
substances which are soluble in the aqueous mixture as
substitute for fatty substances which are taken from
the skin wtth the ethanol, and if necessary, other
assistants and additives.
The pharmaceutical preparations for topical applicat-
ion are obtained in known manner, for example by
dissolving or suspending the active substance in the
base or in a part thereof, if necessary. When processing
the active substance in the form of a solution, it
is usually dissolved in one of the two phases before
the emulsification, and when processlng the active
substance in the form of a suspension, it is mixed with
- 17 -
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. .
.
-

7~
a part of the base before the emulsification and then added
to the remainder of the formulation.
Besides the pharmaceutical preparations which can be
applied topically, other suitable preparations are those
for enteral, ~or example oral, and parenteral adminis~ration to
warm-~oded animals and which contain the pharmacologically
active substance as sole ingredient or together with a pharma~
ceutica~ly acceptable carrier. These pharmaceutical preparations
contain about 0.01% to about 10% of active substance and are
in dosage unit form, such as coated tablets, tablets, capsules,
suppositories or ampoules. They are obtained in known manner,
for example by con~entional mixing, gran~ating, coating,
dissolving or l~ophilising methods
The dosage of active substance depends on the
species of warm-blooded animal, the age, and the individual
condition as well as on the mode of application.
The present invention also relates to the use of the
novel compounds of the formula I and of ~he salts of such
compounds wlth salt-forming properties, preferably for
treating inflammations, chiefly as an~.iinflammatory
glucocorticoids for local application, normally in the form
of pharmaceutical preparations, especially in the form of
pharmaceutical preparations for topical application.
The compounds of the ~sent invention can also be
used as additives to animal feeds.
The following Examples describe the invention in
more detail. - 18 - ~
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78~24
- xample 1
700 ml of tert.-butyl alcohol are poured over
34 57 g of 2-chloro-6~-fluoro-16~-methyl-17~,21-dihydroxy-
pregna-1,4,9-triene-3,20-dione-21-acetate in a flask of 2000 ml
capacity and, under nitrogen and with stirring, 35 ml of
a 10% solu~ion of perchloric acid and finally 10 ml of tert.
butylhypochlor~e are added thereto. The steroid has completely
dis~olved after stirring for a urther 2 hours; but after
S hours, a crystalline material precipitates again Then 360 ml
of water are added, stirring is continued for a time, and ~hen
the precipitate is collected by filtration with suction~ The
~ilter cake is washed firstly w~th 200 ml of methanol water
(1:1) and then thoroughly with water and dried in vacuo. The
concentrated mother liquors are extracted with ethyl acetate
and the extract is dried over sodium sulphate. The dry product
is dissolved in acetone and tr~ated at elevated temperature
with animal charcoal. Toluene is then added ~o the filtered
solution and the ace~one is evaporated in vac~o. The precipi-
tated crystals are collected with suction,washed with toleuene
nnd dried in a vacuum exsiccator. The product is 2,9a-di-
chloro~6a-fluoro-16~-methyl~ ,17~,21-trihydroxy-pregna-1,4-
diene-3,20-dione-21-acetate (2~9~-dichloroparamethasone~
acetate), which melts at 124C. UV absorption spectrum 3~ maxO
249 nm (~ = 12952)o
The starting material can be prepared as follows:
- 19 -

~ ~ 8 ~ ~ ~
35 g of 2-chloroparam~thason~21-acetate are dissolv-
ed in 70 ml of pyridine and 210 ml of dimethyl formamide. The
solution is cooled to -15 to -20 C and treated dropwise
with stirring in the course of approx. 15 minutes, at a
temperature of -10 to -15C, w;th 22 ml of a soLution
prepared from 3 g of sulphur dioxide and 90.4 g of mesyl
chloride (me~hanesulphonyl chloride). The mixture is stirred
for a further 20 minutes a~ the same temperature and then
water is added dropwise with caution (especially a~ the start),
while the temperature is kept at 0 to -5C The mixture is
then poured into 1500 ml o~ water and stirred for 30 minu~es.
After this time, the precipitate which has formed is collected
with suction and washed with water. The filter cake is then
dissolved in 700 ml of boiling methanol and, at boiling
temperature, 210 ml of water are added5 whereupon a thick
crystalline precipitate falls out o~ the solution. Ater
cooling to 0C~ the precipitated crystals are collected with
suction, washed with methanol/water (1:1) and dried in an
exsiccator. The product is 2-chloro-6a-fluoro-16a-methyl-17a,21-
dihydroxy-pregna-1,4,9-triene-3,20-dione 21-acetate, which
melts at 130-148C .
Example 2
10 g of 2a9a-dichloro-paramethasone-21-acetate
(2,9a-dichloro-6a-fluoro-16a-methyl-11~,17a-21-trihydroxy-
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;

~ll078824
pregnadiene-3,20-dione-21-acetate) are dissolved in 250 ml of
me~anol and the solution is cooled to 0 C under nitrogen. To
this solution is added dropwise at 0C and in the course of
15 minutes a solution prepared from 5 g of potassium carbonate,
70 ml of water and 70 ml of methanol and which has been freed
from oxygen by introducing nitrogen. The mixture is then
stirred for 45 minutes at 0 C. The solution is then adjusted
with 10 ml oE 50% acetic acid to a slighly acid reaction.
The methanol is evaporated completelv in vacuo and the
resultant suspension is filtered with suction. The filter cake
is washed with water and then sharply filtered with suction.
The residue is dissolved in acetone and the solution is con
centrated in vacuo and the res~ue dried to constant weight.
Crystallisation from acetone-toluene yields pure 2,~u-dichloro~
paramethasone, which melts at 240-250C ~with decomposition).
Example 3
With stirring, 2 g of 2j9a-dichloroparamethasone
are d~olved in 10 ml of pyridine and the solution is
treated with a solution obtained by mixing 4 ml of trimethylace~l-
chloride and 10 ml of pyridine at 0C. The mixture is then
allowed to stand for 1 hour at 20C. After addition of ice,
the mixture is extracted with ethyl acetate and the extract
is washed with 2N hydrochloric acid and then with water, dried
and concentrated. The res~ue is filtered through a column of
30 g of aluminium oxide of activity II and the residue obtained
- 21
: .

2 ~
from the filtrate is recrystallised ~rom methanol/water to
yield 2~9a-dich~roparamethaso~21-pivalate (trime~hylacetate),
which melts at 261 -262 C with decomposition.
Example 4
11,92 g of 2,9~-dichloroparamethasone ~e dissolved
in 50 ml of tetrahydro~urane and the solution is treated at
20C with L2 ml of triethyl orthopropionate and 500 mg o
p-toluenesulphonic acid and allowed to stand for 1 hour a~
20C. Then 4 ml of pyridine are added, the batch is slightly
concentrated in vacuo and the reaction product is taken up in
ethyl acetate. The ethyL acetate extract is washed 5 times
w~h water, dried and concentrated. The re~due is then dissol~ed
in approx. 150 ml of methylene chloride, freshly distilled
isopropyl ether is added and the mixture is concentrated to
some extent by heating. As the batdh cools, the ethyl-17~,21-
ortho propionate of 2,9~-dichloroparame~hasoneprecipitates,
is collected with suction, washed with isopropyl ether, and
dried. Melting point: 223-237 C (with decomposition).
'
Example 5
A solution of 1.5 g of 2,9~-dichloroparamethasone-
17-propionate in 10 ml of pyridine is treated at 0C with 5 ml
of propionic anhydride and the mixture is allowed to stand for
1 hour at 0C. After this time ice is added and the mixture
is again allowed to stand for 1 hour and then extracted with
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.. .. . ~ . ~ . . . -- : -

37~8~4
ethyl acetate. The extract is washed with 2N hydrochloric
acid, water, potassium hydro~en carbonate and water, dried and
concentrated.
The residue is crystallised from methanol to yield
2,9a-dichloroparamethasone-17~21-dipropionate, which is still
further purified as follows:
The obtained amount of ester is chromatographed
through a column of 50 g of silica gel wi~h methylene chloride
as eluant, Fractions 4-13 are combined and recrys~allised from
acetone-methanol~ The purified ester melts at 135 C.
The starting material can be prepared as follows:
A solution of 5 g of 2,9~-dichloro paramethason~l7,21-
ethyl-ortho-propionate in 220 ml oE methanol and a solution of
1.4 g of oxalic acid (dihydrate) in 12 ml of water are stirred
at 50C and after 5 minutes a clear solution results. After
1 hour water is added~ and the mixture is concentrated in
vacuo and extracted with 500 ml of ethyl acetate. The extract
is washed twice with 100 ml of 2N potassium hydrogen carbonate
and three times with water, dried and concentr~ted. T~le residue
is dissolved in acetone and ~oluene is added ~o the solution.
The mixture is heated, so that the acetone distiLls of, then
cooled to yield 2,9a-dichloroparamethason~17-propionate, which
melts at 239-248C (with decomposition).
~,
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.:
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78~324
Example 6
A solution, cooled to 0 C, of 1 g of 2,9~-dichloro-
6a-fluoro-16a-methyl-11~,17a,21-trihydroxy-pregna-1,4-diene-
3,20-dione in 5 ml of pyridine is treated with 2 ml of
valeric anhydride and the reaction mixture is allowed to .
stand for 2 hours at 0C. After addition of ice, the mixture
is s~ood for 15 minutes at 20 C and extracted with ethyl
ace~ate. The combined ethyl acetate extracts are washed with
2N hydrochloric acid and water, dried, and filtered through
a column of 30 g of aluminium oxide of activit~ II and washed.
The residue of the evapora~d filtrate is recrystallised from
acetone-isopropyl ether to yield the 21-valerate of 2,9a-
dichloro-6a-fluoro-16OE-methyl~ ,17a,21-trihydroxy-p~egna-
1,4-diene-3,20-dione (2,9a-dichloroparamethasone~21-vale~ate),
which melts at 188-191C.
- 2
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..
.. . . . . .