CA1100943A - Derivatives of 9-chloroprednisolone - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
New derivatives of 9-chloroprednisolone of the formula (I) ,

Description

~ 0~3 The present inyention is concerned with new derivatives of 9-chloroprednisolone, with a process for their manufacture and with pharmaceutical preparations containing these active substances.
9-Chloroprednisolone (9~-chloro-11~,17a,21-trihydroxy-' -pregnadiene-3,20-dione) has been kno~n for a long time ~J. Amer. Chem. Soc. 77, 1955, 4181) This corticoid is unsuitable as an active substance in pharmacuetical preparations that are to be used for the topical treatment of infla~matory disorders, as it has very s-trong syste~ic effects.
It has no~ been found that hitherto unknown derivatives of 9-chloroprednisolone are systemically almost inactive, but that in topical use they surprisingly have a strong anti-inflammatory activity, which generally exceeds that of the most active commercial corticoids.
The present invention accordingly provides derivatives of 9-chloroprednisolone of the general Eormula I ~ -~[~ .
b~
E0 ~ ~ ~o ~ ~ ~
~ '~' "' : ~

in which Rl represents an alkanoyl group containing l to 8 carbon atoms or a benzoyl group and X represents a fluorine atom, a chlorine atom, a hydroxyl group, an alkanoyloxy group containing l to 8 carbon atoms or a benzoyloxy group.
As an alkanoyl group represented by Rl containing 1 to 8 carbon atoms and an alkanoyloxy group represented by X
containing l to 8 carbon atoms there is to be understood in each case a group that is derived from a straight-chained or branched ~ -2 ~ ~

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

~ -3-;)V9~3 9-Chloroprednisolone derivatives of the gener~l formula I in which X represents a hydroxyl ~roup are, for exa~ple, those listed in the following Table: -Table 2 17~-Acetoxy-9~chloro~ ,21~dihydroxy-Al'4-pregnadiene-3,20-dione, 9a-chloro-11~,21-dihydroxy-17~-propion~loxy-Al'4-pregnadiene-3,20-dione, 17~-butyryloxy-9~-chloro~ 21~dihydroxy-a ' -pre~nadiene-3,20-dione, 9~-chloro~ ,21-dihydroxy-17~-isobutyryloxy-~1'4-pregnadiene-3,20-dione, 9a-chloro-11,B, 21-dihydroxy-17c~-valeryloxy-~1 ' 4-pregnadiene-3,20-dione and 17a-benzoyloxy-9~-chloro-11~,21-dihydroxy-~1'4-pregnadiene-3,20-dione.
These compounds ~n which X of the general ~ormula I
represents a hydroxyl group are of importance not only as pharmacologically active substances. They can also be used as intermediates for the production of 9-chloroprednisolone derivatives of the general formula I in which X represents a chlorine atom, an alkanoyloxy group or a benzoyloxy group.
As 9-chloroprednisolone derivatives of the general formula I in which X represents ~n alkanoyloxy group or a benzoyloxy ~roup there are preferred those in which the groups represented by Rl and X together contain 3 to 14 carbon atoms. --Such chloroprednisolone derivatives are, for example, those listed in the followin~ Table;
Table 3 17~,21-Diacetoxy-9u-chloro~ hydroxy-al'4-pregnadiene-3,20-dione, 17~-acetoxy-9~-chloro-11~-hydroxy-21-propionyloxy-al'4-pregnadiene-3,20-dione, ~,= -4-)g~3 21-ace-toxy-9~-chloro~ hydroxy-l7a-propionyloxy-Q '4-pregna-diene-3,20~dione, 17a-acetoxy-21-butyryloxy-9~chloro~ -hydroxy-~1~4-pregnadiene-3,20-dione, 21-ace~oxy-17a-butyryloxy-9~-chloro-ll~-hydroxy~ pregnadiene-3,20-dione, 17a-acetoxy-9a-chloro-11~-hydroxy-21-isobutyryloxy-Q ' -pregna-diene-3,20~dione, . -21-acetoxy-9~-chloro-ll~-h~droxy~17~-isobutyryloxy~ 4-pre~na diene-3,20-dione~
17~-acetoxy-9~-chloro-11~-hydroxy-21-valeryloxy-Ql'4-pregnadiene-3,20-dione, ~: ~
21-acetoxy-9~-chloro-11~-hydroxy-17~-valeryloxy-~1'4-pregnadiene- ~ -3,20-dione, 17~-acetoxy-21-benzoyloxy-9~-chloro-11~-hydroxy-~ '4~pregnadiene- ~
3,20-dione, ~ :
21-acetoxy-17a-benzoyloxy-9~-chloro~ -hydroxy-~1'4-pregnadiene-3,20-aione, 9a-chloro~ hydroxy-17a,21-dipropionyloxy-~1'4-pregnadiene-3,20-dione, 17a-butyryloxy-ga-chloro-1-1~-hydroxy-21-propionyloxy-~ '4-pregnadiene-3,20-dione, 21-butyryloxy-9a-chloro~ -hydroxy-17~-propionyloxy-~l/4 pregnadiene-3,20-dione, 9a-chloro~ B-hydroxy-17a-isobutyryloxy=21-propionyloxy-~1'4-pregnadiene-3,20-dione, . . :
9a-chloro-ll~hydroxy-21-isobutyryloxy-17a-propionyloxy;~l~4 pregnadiene-3~20-dione, 9a-chloro-11~-hydroxy-17a~propionyloxy=21-valeryloxy-~ '4-pregnadiene-3,20-dione, 9a-chloro-11~-hydroxy-21-propionyloxy-17~valeryloxy~l'4-pregnadiene=3 ! 20-dione, lL~00~43 17~-benzo~loxy-9~-chloro~ hydroxy-21-propionyloxy-Al'4-pregnadiene-3,20-dione, 21-benzoyloxy-9a-chloro-ll~-hydroxy-l7~-propionyloxy~Ql~4 pregnadiene 3,20-dione, 17~,21-dibutyryloxy-9a-chloro-11~-hydroxy ~1'4-pre~nadiene-3,20-dione, 17~-butyryloxy-9~-chloro-ll~-hydroxy-2l-isobutyryloxy~ 4 pregnadiene-3,20-dione, 21-butyryloxy-9c~-chloro-ll,~-hyd:roxy~17~-isobutyryloxy-~114_ pregnadiene-3,20-dione, 17~-butyryloxy-9a-chloro-11~-hydroxy-21-valeryloxy-~'4- ~ -pregnadiene-3,20-dione, 21-butyrylQxy-9~-chloro-11~-hydroxy-17~-valeryloxy-~1'4 pregnadiene-3,20-dione, 17~-benzoyloxy-21-butyryloxy-9a-chloro-11~-hydroxy-~
pregnadiene-3,20-dione, 2l-benzoyloxy~l7~-bu~yryloxy-9a-chloro-ll,g-hydroxy ~1~4 pregnadiene=3,20~dione, ~ ;
9~-chloro-11~-hydroxy-17,21-aitsobutyryloxy-~1'4-pregnadiene- ~-3,20-dione, and ~-9a-chloro~ hydroxy-17a,21-divaleryloxy-~ '4-pregnadiene-3,20-dione. ~.
The new 9-chloroprednisolone derivatives may be prepared by the process of the present invention, as defined below.
The present invention accordingly also provides a process for the manufacture of a compound of the general formula I, wherein (a) HOCl is added on ~t the ~9'11-double bond of a compound of the general formula II :
.

:., :: :, -C~
OE~

. O

.in which ~1 and X have the meanings given above, or (b) the epox.ide ring of a compound of the general formula III

.- ~0 OX
~

~;, f .f' ` ' -, ~
in which Rl and X have the meanings given above, is opened up with hydrogen chloride, or tc) when X represents a hydroxyl group or a fluorine or chlorine atom, an ortho-ester o~ the general formula I~ ;

a-o / \ ~ ~

.1 ~i ,.

in which R3 represents a hydrogen atom, an alkyl group containing ~ -7-9~3 l to 7 carbon atoms or a phenyl group and R2 represents an alkyl group containin~ 1 to 4 carbon atoms, is hydrolysed or reacted with trimethylsilyl fluoride or chloride or triphenylmethyl fluoride or chlorlde, or (d) when X represents a chlorine atom, an alkanoyloxy group or a benzoyloxy group, a 9-chloro-derivative of the general formula Ia a~2o~ , C-O

~ (Ja), , f in which Rl has the meaning gi~en above, is chlorinated or esterified at the 21-position. -Each of the variants of the process of the presentinvention may be carried out in a manner known per se. The process ~ariants (a), (b) and (d) may be carried out under the conditions descrlbed in United States Patent Specification Nos.
3,678,034, 3,718,671 and 3,828,083. The process of the present invention in accordance with process variant (c) may be carried out under the conditions described in United States ~ ;
Patent No. 3,152,154 and in ~erman Offenlegungsschriften Nos.
26 13 875 and 24 36 747.
The starting compounds for the process of the present invention can be preparea, as ls known, ln a simple manner and in high yields from prednisolone, which ltself can be synthesized relatively easily from diosgenin. The consequence of this is that the compounds of the present invention can be prepared from diosgenin with relatively lTttle expenditure in a total yield of about 15%. On the other hand, the syntheses of known highly ~ -8-~vg43 active corticoids from dios~enin are considerably more expensive - and the total yields obtained are si~nificantl~v smaller (about 0.5 to 5%). This is not without importance in view of the increastng difficulties in procuring suf~icient quantities of starting materials suitable for the syntheses of corticoids, and having regard to the hi~h costs of the active substances with which medicinal specialties containing corticoids are encumbered.
The compounds o~ the present invention possess, as has ~lready been stated, a strong anti inflammatory activity in topical applicatlon, but they are only very weakly active in systemic appllca-tion.
The pharmacological properties of the compounds have been determined by the following tests: -(A) The inflammation-inhibiting activity in local application to the ears of rats:
The substance to be tested was dissolved in an irritant ronsisting of 4 parts of pyridine, 1 part of-distilled water, 5 parts o~ ether and 10 parts of an ethereal soluti~n of 4~
strength of croton oil Str;ps of felt, which were attached to the inner sides of a microscope slide forceps, were impregnated with this test solution, and were pressed with light pressure for 15 seconds on the right ear of male rats wei~hing 100 to 160 grams. The left ear remained untreated and served for comparison.
Three hours after the application tha animals were killed and -discs having a size of 9 mm were stamped out of their ears. The difference in weight between the discs of the right and that of the left ear w~s a measure of ~he pedema formed.
The dose of test substance was determined at which after three h~urs a 50~ inhibitlon ~f the f~rmatlon of oedema was observed.
(B) The inflammatlon-inhibiting activity ln subcutaneous application to the pa~ of rats:

_.
_g_ ~

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

943 : ^
The xesults obtained in these tests are given in the ~:
following Table;

N ~ _ . ~ _ `

~ ~ ~D O U~ ~ a;
10 ` c~ ' o, o ~ .

~a _ _~ _ _~ ~ `:
C ,¢ o ~) ~ o A o o Is`) o A .

o r~ ~ ~ _ ~ ~:

~+) ~r' u~' ~, ~, u~ ~' u~ ~
' ~_ .-1 o o o ~
. .. ,: : . : .

x ~ r ~ o ~: o ~ x ~ ~

~ X c F Y ~c c 2 C I ~D ~ ~r r h ` ~ rD o r~ ~ r~ o ~ N h h h O ~ 5~ ` ~ ~ ~ 'I O I ~ Q~ I ~i .
~ 1 ~ ~ ~ I~r ~: ~ z~ I ~:

CQ ~ I .Q) ~ X . ~ rl ~ ~ I a 1--à X O

0 v ~ O ~ ~ u I O N ~ N ~ N

. :S ~ ~1 ,la. ~ ~ ~5 ~,i ;~ ,~
_ ~

Z H H H H ~ H H H

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

~ -12-)943 Furt}len~ore, tne new compounds of the gene~al formula I
are also well suited for the production of inhalant preparations, if desire~ in combination witil the usual carrier substances and auxiliary substanc~s, wllich preparations can be used for tlle thera~y of allergic disorders of the respiratory system, for example broncllial asthma or rhinitis.
The following Examples illustrate tlle invention. Examples `1 to 3~ illustrate t.he manufacture of compounds of tlle general formula I and Examples 40 and 41 illustrate pharmaceutical preparations contailling such compounds.
Example 1 .
(a) 5.0 gms of 9~-chloro~ , 17~, 21-trihydroxy-~ pregnaaiene-3,20-dione were mixea with 500 ml of benzene, 40 ml of dimethyl-formamide and 500 my of absolute pyridine tosylate. The mixture - was heated, 50 ml of the solvent were distilled off at a bath temperature of 130C, 60 ml of ortho-benzoic acid trietllyl ester were aadea and tlle residual benzene was distilled off during the course of 2 1/2 hours. 2.4 ml of pyriaine were added to the residue, tlle mixture was concentrated in vacuo and 17~,21-(1-ethoxy-~enzylidenedioxy)-9~-chloro-11~-hydroxy-Al'4-pregnadiene-3,20-dione was o~tained in tlle form of an oily crude product.
(~, The crude product so obtained was mixed with 150 nl of methanol, 54 ml of O.lN-aqueous acetic acid and 6 ml of an O.lN-aqueous solution of sodium acetate and the mixture was heated under refl:~x for 90 minutes. The reaction mixture was then concentrated in vacuo, water was added to the residue and the mixture was extracted with eth~l acetate. The organic phase was washed with water, concentrated in vacuo, the residue was purified by chromatography over a column of silica gel and recrystallized from acetone-hexane and there were obtained 3.7 gms of 17~-benzoyloxy-9Q-chloro-ll~ aihydroxy-~1'4-pregnadient-3,20-dione melting at 216C (with aecomposition).

,~ ;,. .

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

9~3 Example 5

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

-- 1~ --... ....

" 11()~943 Example 9 -:
2.3 ~ms of 17c~-~enzoyloxy-9c~-chloro-11~,21~dillydroxy-Q ' - pregnadiene-3,2ù-dione were mixed with 5û ml of pyridine and 2û ml of isovaleric acid chloride and the w~ole was stirred for 2 hours at 0C. The reaction mixture was worked up as des-cribed in Example 3 and 2.1 gms of 17c~-benzoyloxy-9~-chloro-ll~-hydroxy-21-isovaleryloxy-~1'4-pregnadiene-3,2û-dione melting at 197C were obtained.
Example 10 lQ 2.3 gms of 17a-benzoyloxy-9c~ chloro~ ,21-dihydroxy-Ql'4-pregnadiene-3,20-dione were mixed with 50 ml of pyridine and 30 ml of oenanthic anliydride and the whole was stirred for 16 hours at room temperature. The reaction mixture was poured into ice-water and heated and the excess of oenanthic acid was removed ;~
by steam distillation. The mixture was extracted with dichloro-methane, the organic phase was worl~ed up as described in Example

3 and 2.03 gms of 17~-benzoyloxy-9o~-chlorc~21 he~tanoyloxy~
hydroxy-~l' -pregriadiene-3~20-dione were obtained in the form of an oily product.
la]D = ~64 (Ch1OrOfOrm~ ;
Example 11 2.3 gms of 17c~-benzoyloxy-9a-chloro-ll,B,21-dlllydroxy-Q '4-pregnadiene-3,2()-dione were stirred with 45 ml of pyridine and 1 ml of benzoyl chloride for one hour at room temperature.
The reaction mixture was worked up as descri}~ed in Example 3 and there were obtained 2.5 gms of 17~,21-dibenzoyloxy-9~-chloro-11 hydroxy-Ql'4-pregnadiene-3,20-dione melting at 221C.
Example 12 (a) Under tlle conditions described in Example l(a) 7.5 gms of 9~-chloro~ ,17 a,21-trillydroxy-â '4-pregnadiene-3,20-dione , -16~
,,~

)0~43 were reacted with ortho-acetic acid triethyl es-ter and worked up. There was obtained 17~,21-(1-ethoxy-ethylidenedioxy)-9~-chloro~ hydroxy-~l'4-pregnadiene-3,20-dione in the form of an oily crude product.
(b) The crude product so obtained was reacted under the con-ditions described in Example l(b) and worked up, and 5.2 gms of 17a-acetoxy-9~-chloro-11~,21-dihydroxy-~1~4-pregnadiene-3,20-dione melting at 205C (with decomposition) were obtained.
Example 13 1.0 gm of 17a-acetoxy-9a-chloro-11~,21-dil1ydroxy-~l'4-pregnadiene-3,20-dione was mixed with 20 ml of pyridine and 5 ml o~ acetic anllydride and the whole was stirred for one hour at room temperature. The reaction mixture was then poured into ice-water, the product that separated was filtered off with suction and dissolved in dichloromethane and the organic phase was washed and concentrated _ vacuo. The residue was recrystallized from acetone-hexane and there were obtained 860 mg of 17~,21-diacetoxy-9a-chloro~ -hydroxy-~1'4-pregnadiene-3,20-dione melting at 222C
(with decomposition).
Example 14 Under the conditions described in Example 4, 1.0 gms of 17a-acetoxy-9~-chloro-11~,21-dihydroxy-~1'4-pregnadiene-3,20-dione was reacted with propionic anhydride and worked up, and there were obtained 940 mg of 17a-acetoxy-9a-chloro-11~-hydroxy-21-~ropionyloxy-~1'4-pregnadiene-3,20-dione melting at 219C ~ -(with decomposition).
Example 15 Under the conditions described in Example 6, 1.0 gm of 17~-acetoxy-9a-chloro-11~,21-dihyroxy-~1'4-pregnadiene-3,20-dione was reacted with valeric anhydride and worked up, and therewere obtained 660 mg of 17a-acetoxy-9~-chloro-11~-hydroxy-21 valeryloxy-~l'4-pregnadiene-3,20-dione melting at 220C (with , , , .- , .
-.-, , 1~00943 decomposition).
Example 16 (a) Under the conditions described in Example l(a) 7 gms of 9~-chloro~ ,17~,21-trihydroxy-~1'4-pregnadiene-3,20-dione were reacted with ortno-propionic acid trietilyl ester and worked up, and 17~,21-(1-ethoxy-propylidenedioxy)-9~-chloro~ -hydroxy-'4-pregnadiene-3,20-dione was obtained in the form of a crude product.
(b) The crude ~roduct so ohtained was react~d under the con-ditions described in Example l(b) and worked up, and there were obtained 2.9 gms of 9a-chloro-11~,21-dihydroxy-17a-propionyloxy-~ '4-pregnadiene-3,20-dione melting at 181C (with decomposition).
Example 17 Under the conditions described in Example 2, 1.2 gms of 9~-cnloro-11~,21-dihydroxy-17a-propionyloxy-Al'4-pregnadiene-3,20-dione were reacted with formic acid and worked up, and there were obtained 400 mg of oily 9u-chloro-21-formyloxy-11~-hydroxy-17~-propionyloxy~l'4-pregnadiene-3,20-dione. [~]~5 = +67 (chloroform).
Example 18 700 mg of 9a-chloro-11~,21-dihydroxy-17~-propionyloxy-~ '4-pregnadiene-3,20-dione were reacted with acetic anhydride as aescribed in Example 3 and worked up and there were obtained 320 mg of 21-acetoxy-9~-chloro~ -hydroxy-li~-propionyloxy-~
pregnadiene-3,20-dione meltins at 210C (with decomposition).
Example 19 700 mg of 9a-chloro~ ,21-dihydroxy-17a propionyloxy-~1~ -pregnadiene-3,20-dione were reacted with propionic anhydride under the conditions described in Example 4 and worked up, and there were obtained 420 mg of 9~-chloro-11~-hydroxy-17a,21-dipropionyloxy-~l'4-pregnadiene-3,20-dione melting at 215C
(with decomposition).

9~3 Example 20 650 mg of 9a-chloro~ ,21-dihydroxy-17~-propionyloxy-~ ' -pre~nadiene-3,20-dione were reacted with butyric anhydride under the conditions described in Example 5 and worked up, and there were obtained 360 mg of 21-butyryloxy-9~-chloro-11~-hydroxy-17a-propionyloxy-~1'4-pregnadiene-3,20-dione melting at 208C twith decomposition~.
Example 21 Under the conditions described in Example 6, 700 mg of 9~-chloro-11~,21-dihydroxy-17a-propionyloxy-~1'4-pregnadiene-3,20-dione were reacted with valeric anhydride and ~orked up, and there were obtained 520 mg of 9a-chloro-11~-hydroxy-17a-propiony-loxy-21-valeryloxy-~1'4-pregnadiene-3,20-dione melting at 210C
(with decomposition).
Example 22 3.0 gms of 9~-chloro~ ,21-dihydroxy-17a-propionyloxy-' -pregnadiene-3,20-dione were mixed with 30 ml of pyridine and 15 ml of caproic anhydride and the whole was stirred for 90 minutes at room temperature. The reaction mixture was worked up as described in Example 3 and there were obtained 2.6 gms of 9a-chloro-21;hexanoyloxy~ hydroxy-17a-propionyloxy-~1'4-preg-nadiene-3,20-dione. ;
Example 23 UndQr the conditions described in Example 10, 2.1 gms of 9~-chloro-11~,21-dihydroxy-17~-propionyloxy-~ '4-pregnadiene-3,20-dione were reacted with oenanthic anhydride and worked up, and there were obtained 1.02 gms of 9a-chloro-21-lleptanoyloxy-ll~-hydroxy-17~-propionyloxy-~1'4-pregnadiene-3,20-dione.
Example 24 Under the conditions described in Example 7, 1.4 gms of 9a-chloro-11~,21-dihydroxy-17a-propionyloxy-~ '4-pregnadiene-3,20-dione were reacted with trimethylacetic anhydride and worked f: 19 , , , `943 up, and 670 mg of 9~-chloro-11~-hydroxy-17~-propionyloxy-21-trimethylacetoxy-~l'4-pregnadiene-3,20-dione were o~tained.
~xample 25 (a) Under the conditions described in Example 20, 25 gms of 11~-17~,21-trihydroxy-~1'4-pregnadiene-3,20-dione were reacted with butyric anhydride and worked up, and 23.1 gms of 21-butyryloxy-11~,17 ~dihydroxy-~1'4-pregnadiene-3,20dione were obtained.
tb) Into a suspension of 24 gms of cooper-(l) chloride in 480 ml of absolute tetrahydrofuran were introduced dropwise under 1~ argon at 0C 100 ml of an ethereal solution of 5~ strength of lithium methyl. The mixture was then cooled to -30C and a solution of 22.3 gms of 21-butyryloxy-11~,17~-dillydroxy-~1'4-pregrandiene-3,20-dione was added. The mixture was stirred for

4 hours until the primarily formed ll~-hydroxy 17a,21-(1-hydroxy-butylidenedioxy)_~l'4-pregnadiene-3,20-dione had been rearranged. An a~ueous solution of ammonium chloride was then added to the reaction mixture, extraction was carried out with methylene chloride, the organic phase was washed and concentrated in vacuo and 20.3 gms of 17a-butryrloxy-11~21-dillydroxy-~ '4-pregnadiene-3,20-dione were obtained in the form of a crude product.
(c) Under the conditions described in Example 3, 20 gms of the crude product so obtained were reacted with acetic anhydride and worked up, and there were obtained 14.2 gms of 21-acetoxy-17~- -butyryloxy-ll~ ydroxy-~l'4-pregnadiene-3,20-dione.
(d) 5.4 ml of metllane sulphonic acid chloride were introduced dropwise at room temperature into a solution of 10 gms of 21-acetoxy-17a-butyryloxy-11~-hydroxy-~1' -pregnadiene-3,20-dione in 50 ml of dimethylformamide and 11 ml of pyridine. The reaction mixture was stirred for two hours at 85C, poured, after cooling, into ice-water and wor~ed up as described in Example 3, and 6.5 gms of 2l-acetoxy-l7~-butyryloxy-~l~4~9(ll) ~ - 20 -, . , ~ . - .

1~L()~9~3 dione were obtained in the form of a crude product.
(e) 6 gms of the crude product so obtained were suspended in 80 ml of dioxane and 5.6 gms of N-chlorosuccinimide were added.
There were then introduced dropwise into the mixture during the course of 10 minutes at 20C, 42 ml of an a~ueous solution of ld~ strength of perchloric acid, and the mixture was stirred for 3 hours at 20C and was then poured into a solution of 2.5 gms of sodium hydrogen sulphlte in 400 ml of water. The product that separated was filtered off with suction and worked up as described in Example 3, and 3.1 gms of 21-acetoxy-17a~butyryloxy-9~-chloro-11~-hydroxy-~1'4-pregnadiene-3,2-dione melting at 215C
were obtained.
Example 26 (a) 9.5 gms of 17~-butyryloxy~ ,21-dihydroxy-~1'4-pregnadiene-3,20-dione prepared as a crude product in accordance with Example 25~b) were reacted under the conditions described in Example 7 with trimethylacetic anhydride and worked up, and 6.3 gms of i7~-~utyryloxy-11~-hydroxy-21-trimethylacetoxy-~1'4- pregnadiene 3,20-dione were obtained.
(b) 6.0 gms of 17a-butyryloxy-11~-hydroxy-21-trimethylacetoxy-~ ' -pregnadiene-3,20--dione were reacted with methane sulphonic acid chloride under the conditions described in Example 25(d) and ~-~
wor~ed up, and there were obtained 3.4 gms of 17a-butyryloxy- -21~trimethylacetoxy-~1'4-pregnatrienen-3,20-dione in the form of - a crude product.
(c) 3.0 gms of ~he crude product so obtained were reacted under the conditions described in Example 25(e) and worked up, and there were obtained l.i gms o~ 17~-butyryloxy-9~-chloro-11~-hydroxy-21-trimeth~lacetoxy-~l'4-pregnadiene-3,20-dione melting at 259C.
Example 27 (a) 14.1 gms of 17~-butyryloxy-11~,21-dihydroxy-~1'4-pregnadiene-3,20-dione, prepared as a crude product in accordancP with ~xample -~l~()094~3 25(b), were reacted under the conditions described in Example 10 with oenanthic anhydride and worked up, and there were obtained 8.2 gms of 17a-butyryloxy-21-heptanoyloxy-11~-hydroxy~
pre~nadiene-3,20-dione.
(b) 7.6 gms of 17a-butyryloxy-21-heptanoyloxy-11~ ydroxy-~pregnadiene-3,20-dione were reacted under the conditions described in Example 25(d) and worked up, and 3.9 gms of 17a-bu~yryloxy-21-heptanoyloxy-~1'4-pre~natriene-3,20-dione were obtained as a crude product.
(c) 3 gms of tne crude product so obtained were reacted with N-chlorosuccinimide under tl~e conditions described in Example 25 (e) and worked up, and 950 mg of 17a-butyryloxy-9a-chloro-21-heptanoyloxy-ll~-hydroxy-~l'4-pregnadiene-3,20-dione were obtained.
~xample 28 .
(a) Under the conditions described in ~xample 25(b) 20 gms of 11~,17a-dihydroxy-21-valeryloxy-Ql'4-pregnadiene-3,20-dione were reacted with lithium dimethyl cuprate and worked up, and 18.6 gms of 11~,21-dihydroxy-17a-valeryloxy-~1'4-pre~nadiene-3,20-dione were obtained in the form of a crude product.
(b) 18 gms of the crude product so obtained were reacted with propionic anhydride under the conditions described in Example 4 and worked up, and 10.8 gms of 11~-hydroxy-21-propionyloxy-17a-valeryloxy-~l'4-pregnadiene-3,20-dione were obtained.
(c) 9 gms of 11~-hydroxy-21-propionyloxy-17a-valeryloxy-~1'4-pregnadiene-3,20-dione were reacted with methane sulphonic acid chloride under the conditions described in Example 25(d) and worked up, and 4.9 gms of 21-propionyloxy-17~-valeryloxy-~1'4'9(11)-pregnatriene-3,20-dione were obtained in the form of a crude product.
(d) 4.0 gms of the crude product so obtained were reacted under the conditions described in Example 25(e) and worked up, and 1.4 gms of 9a-chloro-11~-hydroxy-21-propionyloxy-17a-valeryloxy-~ ' -22 ... !

,~ " ~ : .

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

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

- ~4 -~ ;-:

The yield was 1.24 gms of 9~-chloro-21-fluoro~ ydroxy-17~-propionyloxy-~ '4-pregnadiene-3,20-dione. Melting point 221C.
(with decomposition). [~]25 = +48~ (cllloroform).
UV: 239 = 15,500 (methanol) Example 35 1.5 gms of 17~-butyryloxy-21-fluoro-~ i ~ ( )-preg-natriene-3,20-dione, prepared from 21-fluoro-17~-hydroxy-A ,4,9(11) pregnatriene-3,20-dione and butyric anhydride in a manner analo-gous to that described in Example 33(a), were treated with N-clllorosuccinimide in a manner analogous to that described inExample 25(ej. Purification of the crude product was carried out over 1~0 gms of silica gel with a methylene chloride-acetone gradient (60-10~ of acetone). The yield was 840 mg of 17~-~utyryloxy-9o-chloro-21-fluoro-11~- hydroxy-~l'4-pregnadiene- -3,20-dione.
~xample 36 1 gm of 17~,21-(1-ethoxy-benzylidenedioxy)-9~-chloro-ll~-hydroxy-~l'4-pregnadiene-3,20 dione prepared in a manner analogous to that described in Example l(a) was stirred in 40 ml of dimet}lylformamide with 4 ml of trimethylsilyl fluoride for 2 hours at room temperature. After precipitation in ice-water and the usual workiny up, evaporation in vacuo was carried out. Tile crude product was purified over 120 gms of silica gel with a methylene chloride-acetone gradient (0-10~ of acetone).
The yield was 240 mg of 17~-benzoyloxy-9~-cllloro-21-fluoro-~ hydroxy-~l'4-pregnadiene-3,20-dione.
Example 37 In a manner analogous to that described in Example 33(a) tllere were prepared from 5 gms of 21-fluoro-17~-hydroxy-~1'4'9(11)-3V pregnatriene-3,20-dione and iso~utyric anhydride 4.8 gms of 21-fluoro-17~-isobutyryloxy-~1'4'9~11)-pregnatriene--3,20-dione, which were reacted with N-chlorosuccinimide under the conditions , _ 9~3 descri~ed in Example 25(e). The crude product was purified over 350 gms of silica gel with a methylene chloride-acetone gradient (0-10~ of acetone). The yield was 3.5 gms of 9~chloro-21-fluoro~ hydroxy-17a-isobutyryloxy-~1'4-pregnadiene-3,20-dione.
Example 38

5 gms of crude 17~,21-(1-ethoxy-ethylidenedioxy)-9a-chloro-ll~- hydroxy-~l'4-pregnadiene-3,20-dione, prepared from ~ -chloroprednisolone and ortho-acetic acid triethyl ester in a manner analogous to that described in Example l(a), were refluxed under nitrogen for one hour in 30 ml of methylene chloride with 3 gm~ of triphenyl-metllyl chloride. The solvent was distilled off and the residue was purified over 350 gms o~
silica gel with a methylene chloride-acetone gradient (0-15 of acetone)O The yield was 1.3 gms of 17a-acetoxy-9~,21-dichloro-ll~-hydroxy-A '4-pregnadiene-3,20-dione. Melting point: 222C (with decomposition). [~]25 = +124 , (pyridine). UV: E239 = 15,200 (methanol).
Example ~9 2 gms of crude 17a,21-(1-ethoxypropylidenedioxy)-9~ -~
chloro-11~-hydroxy-~1'4~pregnadiene-3,20-dione, prepared from 9 -chloroprednisolone and ortho-propionic acid triethyl ester in a manner analogous to that described in Example l(a), were stirred in 50 ml of dimethylformamide with 5 ml of trimethylsilyl chloride for 2-hours at room temperature. After precipitation in --ice-water and the usual working up, 1.4 gms of 9a,21-dichloro-ll~-hydroxy-17~-propionyloxy-~1'4-pregnadiene-3,20-dione were isolated, which was purified by recrystalli~ation from acetone/
hexane. Melting point: 232C. [~]D = +78 (chloroform) UV:~239 = 15,200 (methanol).
Example 40 The composition of a salve.
: .
- 2~ -, , ~ ILOV943 O.Q3~ of 21-acetoxy-9a-chloro~ -hydroxy-17~-propionyloxy-~l~4-pregnadiene-3l2o-dione 2.50% of Allereur hexaehlorophenate, micronized, particle size about 8~ (Allercur = Registered Trade Mark for l-para-chloro-benzyl-2-pyrrolidyl-methyl-benzimidazole)

6.00% of Hostaphat KW 340(R) (tertiary ester of O~phosphoric acid and wax alcohol tetra-ylycol ether) 0.10% of sorbic aeid 10.00% of neutral oil (Migloyol 8.2(R)) 3.50% of stearyl aleohol 1.50% of wool fat, anhydrou~ DAB 6 76.36% of desalted water.
"DAB 6" is an abbreviation for Deutsches Arzneibuch, 6th edition. -Example 41 The manufacture of an inhalant preparation.
1.000 gms of micronized 21-acetoxy-9a-ehloro-11~ ydroxy-17a-propionyloxy-~1' -pregnadiene-3,20-dione (average partiele ~ ;
size smaller than 7~) and 39.000 gms of ground lactose were mixed together. A dose of 20 mg of inhalant preparation, per inhalation is used.

~ - G7 -

Claims (79)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the manufacture of a compound of the general formula I

(I) , in which R1 represents an alkanoyl group containing 1 to 8 carbon atoms or a benzoyl group and X represents a fluorine atom, a chlorine atom, a hydroxyl group, an alkanoyloxy group containing 1 to 8 carbon atoms or a benzoyloxy group, which comprises (a) adding HOCl at the .DELTA.9,11-double bond of a compound of the general formula II

(II) , in which R1 and X have the meanings given above, or (b) opening up the epoxide ring of a compound of the general formula III

(III) , in which R1 and X have the meanings given above, with hydrogen chloride, or (c) X represents a hydroxyl group or a fluorine or chlorine atom, an ortho-ester of the general formula IV

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

2. A compound of the general formula I

(I) in which R1 represents an alkanoyl group containing 1 to 8 carbon atoms or a benzoyl group and X represents a fluorine atom, a chlorine atom, a hydroxyl group, an alkanoyloxy group containing 1 to 8 carbon atoms or a benzoyloxy group when prepared by the process as claimed in claim 1 or an obvious chemical equivalent thereof.

3. A process as claimed in claim 1, in which in the reactants R1 is an alkanoyl group having 2 to 6 carbon atoms.

4. A compound of formula I given in claim 1, wherein R1 represents an alkanoyl group containing 2 to 6 carbon atoms when prepared by the process as claimed in claim 3 or an obvious chemical equivalent thereof.

5. A process as claimed in claim 3, in which in the reactants X is an alkanoyloxy group having from 2 to 6 carbon atoms.

6. A process as claimed in claim 1, which comprises refluxing 17.alpha.,21-(1-ethoxybenzylidenedioxy)-9.alpha.-chloro-11.beta.-hydroxy-.DELTA.1,4-pregnadiene-3,20-dione in a mixture of methanol, acetic acid and sodium acetate.

7. 17.alpha.-Benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 6 or an obvious chemical equivalent thereof.

8. A process as claimed in claim 6, in which the 17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadien-3,20-dione so obtained is treated with formic acid.

9. 17.alpha.-Benzoyloxy-9.alpha.-chloro-21-formyloxy-11.beta.-hydroxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 8 or an obvious chemical equivalent thereof.

10. A process as claimed in claim 6, in which the 17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with acetic anhydride in pyridine.

11. 21-Acetoxy-17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.-hydroxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 10 or an obvious chemical equivalent thereof.

12. A process as claimed in claim 6, in which the 17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with propionic anhydride in pyridine.

13. 17.alpha.-Benzoyloxy-9.alpha.-chloro-11.beta.-hydroxy-21-propionyl-oxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 12 or an obvious chemical equivalent thereof.

14. A process as claimed in claim 6, in which the 17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with butyric anhydride in pyridine.

15. 17.alpha.-Benzoyloxy-21-butyryloxy-9.alpha.-chloro-11.beta.-hydroxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 14 or an obvious chemical equivalent thereof.

16. A process as claimed in claim 6, in which the 17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with valeric anhydride in pyridine.

17. 17.alpha.-Benzoyloxy-9.alpha.-chloro-11.beta.-hydroxy-21-valeryloxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 16 or an obvious chemical equivalent thereof.

18. A process as claimed in claim 6, in which the 17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with trimethyl acetic anhydride in pyridine.

19. 17.alpha.-Benzoyloxy-9.alpha.-chloro-11.beta.-hydroxy-21-trimethyl-acetoxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 18 or an obvious chemical equivalent thereof.

20. A process as claimed in claim 6, in which the 17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with isobutyric anhydride in pyridine.

21. 17.alpha.-Benzoyloxy-9.alpha.-chloro-11.beta.-hydroxy-21-isobutyryl-oxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 20 or an obvious chemical equivalent thereof.

22. A process as claimed in claim 6, in which the 17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with isovaleric acid chloride in pyridine.

23. 17.alpha.-Benzoyloxy-9.alpha.-chloro-11.beta.-hydroxy-21-isovaleryl-oxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 22 or an obvious chemical equivalent thereof.

24. A process as claimed in claim 6, in which the 17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with oenanthic anhydride in pyridine.

25. 17.alpha.-Benzoyloxy-9.alpha.-chloro-21-heptanoyloxy-11.beta.-hydroxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 24 or an obvious chemical equivalent thereof.

26. A process as claimed in claim 6, in which the 17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with benzoyl chloride in pyridine.

27. 17.alpha.,21-Dibenzoyloxy-9.alpha.-chloro-11.beta.-hydroxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 26 or an obvious chemical equivalent thereof.

28. A process as claimed in claim 1, which comprises refluxing 17.alpha.,21-(1-ethoxy-ethylidenedioxy)-9.alpha.-chloro-11.beta.-hydroxy-1,4-pregnadiene-3,20-dione in a mixture of methanol, acetic acid and sodium acetate.

29. 17.alpha.-Acetoxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadien-3,20-dione when prepared by the process as claimed in claim 28 or an obvious chemical equivalent thereof.

30. A process as claimed in claim 28, in which the 17.alpha.-acetoxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with acetic anhydride in pyridine.

31. 17.alpha.,21-Diacetoxy-9.alpha.-chloro-11.beta.-hydroxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 30 or an obvious chemical equivalent thereof.

32. A process as claimed in claim 28, in which the 17.alpha.-acetoxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with propionic anhydride in pyridine.

33. 17.alpha.-Acetoxy-9.alpha.-chloro-11.beta.-hydroxy-21-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 32 or an obvious chemical equivalent thereof.

34. A process as claimed in claim 28, in which the 17.alpha.-acetoxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with valeric anhydride in pyridine.

35. 17.alpha.-Acetoxy-9.alpha.-chloro-11.beta.-hydroxy-21-valeryloxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 34 or an obvious chemical equivalent thereof.

36. A process as claimed in claim 1, which comprises refluxing 17.alpha.,21-(1-ethoxy-propylidene-dioxy)-9.alpha.-chloro-11.beta.-hydroxy-.DELTA.1,4-pregnadiene-3,20-dione in a mixture of methanol, acetic acid and sodium acetate.

37. 9.alpha.-Chloro-11.alpha.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 36 or an obvious chemical equivalent thereof.

38. A process as claimed in claim 36, in which the 9.alpha.-chloro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with formic acid.

39. 9.alpha.-Chloro-21-formyloxy-11.beta.-hydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 38 or an obvious chemical equivalent thereof.

40. A process as claimed in claim 36, in which the 9.alpha.-chloro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with acetic anhydride in pyridine.

41. 21-Acetoxy-9.alpha.-chloro-11.beta.-hydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 40 or an obvious chemical equivalent thereof.

42. A process as claimed in claim 36, in which the 9.alpha.-chloro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with propionic anhydride in pyridine.

43. 9.alpha.-Chloro-11.beta.-hydroxy-17.alpha.,21-dipropionyloxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 42 or an obvious chemical equivalent thereof.

44. A process as claimed in claim 36, in which the 9.alpha.-chloro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with butyric anhydride in pyridine.

45. 21-Butyryloxy-9.alpha.-chloro-11.beta.-hydroxy-17.alpha.-propionyl-oxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 44 or an obvious chemical equivalent thereof.

46. A process as claimed in claim 36, in which the 9.alpha.-chloro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with valeric anhydride in pyridine.

47. 9.alpha.-Chloro-11.beta.-hydroxy-17.alpha.-propionyloxy-21-valeryloxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 46 or an obvious chemical equivalent thereof.

48. A process as claimed in claim 36, in which the 9.alpha.-chloro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with caproic anhydride in pyridine.

49. 9.alpha.-Chloro-21-hexanoyloxy-11.beta.-hydroxy-17.alpha.-propionyl-oxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 48 or an obvious chemical equivalent thereof.

50. A process as claimed in claim 36, in which the 9.alpha.-chloro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with oenanthic anhydride in pyridine.

51. 9.alpha.-Chloro-21-heptanoyloxy-11.beta.-hydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 50 or an obvious chemical equivalent thereof.

52. A process as claimed in claim 36, in which the 9.alpha.-chloro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with trimethylacetic anhydride in pyridine.

53. 9.alpha.-Chloro-11.beta.-hydroxy-17.alpha.-propionyloxy-21-trimethyl-acetoxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 52 or an obvious chemical equivalent thereof.

54. A process as claimed in claim 1, which comprises treating 21-acetoxy-17.alpha.-butyryloxy-.DELTA.1,4,9(11)-pregnatriene-3,20-dione in dioxane with N-chloro-succinimide treating the product obtained with an aqueous solution of perchloric acid and the mixture so obtained poured into an aqueous solution of sodium hydrogen sulphate.

55. 21-Acetoxy-17.alpha.-butyryloxy-9.alpha.-chloro-11.beta.-hydroxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 54 or an obvious chemical equivalent thereof.

56. A process as claimed in claim 1, which comprises treating 17.alpha.-butyryloxy-21-trimethylacetoxy-.DELTA.1,4,9(11)-pregnatriene-3,20-dione in dioxane with N-chloro-succinimide treating the product obtained with an aqueous solution of perchloric acid and the mixture so obtained poured into an aqueous solution of sodium hydrogen sulphate.

57. 17.alpha.-Butyryloxy-9.alpha.-chloro-11.beta.-hydroxy-21-trimethyl-acetoxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 56 or an obvious chemical equivalent thereof.

58. A process as claimed in claim 1, which comprises treating 17.alpha.-butyryloxy-21-heptanoyloxy-.DELTA.1,4,9(11)-pregnatriene-3,20-dione in dioxane with N-chloro-succinimide treating the product obtained with an aqueous solution of perchloric acid and the mixture so obtained poured into an aqueous solution of sodium hydrogen sulphate.

59. 17.alpha.-Butyryloxy-9.alpha.-chloro-21-heptanoyloxy-11.beta.-hydroxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 58 or an obvious chemical equivalent thereof.

60. A process as claimed in claim 1, which comprises treating 21-propionyloxy-l7.alpha.-valeryloxy-.DELTA.1,4,9(11)-pregnatriene-3,20-dione in dioxane with N-chloro-succinimide treating the product obtained with an aqueous solution of perchloric acid and the mixture so obtained poured into an aqueous solution of sodium hydrogen sulphate.

61. 9.alpha.-Chloro-11.beta.-hydroxy-21-propionyloxy-17.alpha.-valeryloxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 60 or an obvious chemical equivalent thereof.

62. A process as claimed in claim 1, which comprises treating 17.alpha.,21-divaleryloxy-.DELTA.1,4,9(11)-pregnatriene-3,20-dione in dioxane with N-chloro-succinimlde treating the product obtained with an aqueous solution ofperchloric acid and the mixture so obtained poured into an aqueous solution of sodium hydrogen sulphate.

63. 9.alpha.-Chloro-11.beta.-hydroxy-17.alpha.,21-divaleryloxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 62 or an obvious chemical equivalent thereof.

64. A process as claimed in claim 28 in which the 17.alpha.-acetoxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadien-3,20-dione so obtained is treated with a mixture of hexamethyl phosphoric acid triamide and thionyl chloride.

65. 17.alpha.-Acetoxy-9.alpha.,21-dichloro-11.beta.-hydroxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 64 or an obvious chemical equivalent thereof.

66. A process as claimed in claim 36, in which the 9.alpha.-chloro-11.beta.,21-dihydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with a mixture of hexamethyl phosphoric acid triamide and thionyl chloride.

67. 9.alpha.,21-Dichloro-11.beta.-hydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadien-3,20-dione when prepared by the process as claimed in claim 66 or an obvious chemical equivalent thereof.

68. A process as claimed in claim 6, in which the 17.alpha.-benzoyloxy-9.alpha.-chloro-11.beta.,21-dihydroxy-.DELTA.1,4-pregnadiene-3,20-dione so obtained is treated with a mixture of hexamethyl phosphoric acid triamide and thionyl chloride.

69. 17.alpha.-Benzoyloxy-9.alpha.,21-dichloro-11.beta.-hydroxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 68 or an obvious chemical equivalent thereof.

70. A process as claimed in claim 1, which comprises treating 17.alpha.-acetoxy-21-fluoro-.DELTA.1,4,9(11)-pregnatriene-3,20-dione in dioxane with N-chlorosuccinimide and the product obtained treated with perchloric acid and then sodium hydrogen sulphate.

71. 17.alpha.-Acetoxy-9.alpha.-chloro-21-fluoro-11.beta.-hydroxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 70 or an obvious chemical equivalent thereof.

72. A process as claimed in claim 1, which comprises treating 21-fluoro-17.alpha.-propionyloxy-.DELTA.1,4,9(11)-pregnatriene-3,20-dione in dioxane with N-chlorosuccinimide and the product obtained treated with perchloric acid and then sodium hydrogen sulphate.

73. 9.alpha.-Chloro-21-fluoro-11.beta.-hydroxy-17.alpha.-propionyloxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 72 or an obvious chemical equivalent thereof.

74. A process as claimed in claim 1, which comprises treating 17.alpha.-butyryloxy-21-fluoro-.DELTA.1,4,9(11)-pregnatriene-3,20-dione in dioxane with N-chlorosuccinimide and the product obtained treated with perchloric acid and then sodium hydrogen sulphate.

75. 17.alpha.-Butyryloxy-9.alpha.-chloro-21-fluoro-11.beta.-hydroxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 74 or an obvious chemical equivalent thereof.

76. A process as claimed in claim 1, which comprises reacting 17.alpha.,21-(1-ethoxy-benzylidenedioxy)-9.alpha.-chloro-11.beta.-hydroxy-.DELTA.1,4-pregnadiene-3,20-dione with trimethyl silyl fluoride in dimethyl formamide.

77. 17.alpha.-Benzoyloxy-9.alpha.-chloro-21-fluoro-11.beta.-hydroxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 76 or an obvious chemical equivalent thereof.

78. A process as claimed in claim 1, which comprises treating 21-fluoro-17.alpha.-isobutyryloxy-.DELTA.1,4,9(11)-pregnatriene-3,20-dione in dioxane with N-chlorosuccinimide and the product obtained treated with perchloric acid and then sodium hydrogen sulphate.

79. 9.alpha.-Chloro-21-fluoro-11.beta.-hydroxy-17.alpha.-isobutyryloxy-.DELTA.1,4-pregnadiene-3,20-dione when prepared by the process as claimed in claim 78 or an obvious chemical equivalent thereof.