CA1174667A - Soft steroids having anti-inflamatory activity - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The present invention provides compound having anti-flammtory activity selected from the group consisting of:
a compound of the formula

Description

~

The invention relates to novel sof t steroids having anti-inflammatory activity, pharmaceutical compositions con-taining said soft steroids, novel chemical intermediatesuseful in the preparation of the steroids, and processes for prepar-iny said steroids and intermediates.

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

- 2 -metabolites. The phenomenon of metabolic activation to reactive intermediates which covalently bind to tissue macromolecules is the initial step in cell damage. It is also clear that the most toxic metabolites will not survive long enough to be excre~ed and identified; thus, studies of the stable metabolites may provide misleading information.
It is clear that, in order to prevent and/or reduce toxicity problems related to drugs, the metabolic disposition of the drugs should be considered at an early stage of the drug-design process. This is true particularly when one considers that the body can attack and alter chemically ~uite stable structures and that, even if a drug is g5% excreted unchanged, the unaccounted small portion can, and most likely will, cause toxicity.
nSoft drugs" can be defined as biologically active chemical compounds (drugs) which might structurally resemble known active drugs (soft analogues) or could be entirely new types of structures, but which are all characterized by a predic~able in vivo destruction (metabolism) to nontoxic moieties, after they achieve their therapeutic role. The metabolic disposition of the soft drugs takes place with a controllable rate in a predictable manner.
The present inventor has found five major classes of soft drugs. One of the most useful classes was termed the "inactive metabolite" approach which can be adyantageously employed to design especially valuable ~soft drugsn. This approach starts with a known inactive metabolite of a drug or a drug class; followed by modifying the metabolite to resemble structurally ~isosteric and/or isoelectronic) the active drug (i.e., actiyation); and designing the metabolism of the activated species to lead to the starting inactive metabolite after achieving the desired therapeutic role, without the formation of toxic intermediates ~i.e., 1 174~67 predictable metabolism). The "inactive metabolite"
approach fur~her allows controlling the rate of metabolism and pharmacokinetic properties by molecllar manipulation in the activation stage. Also, if no S useful inactive metabolite is ~nown, one can be designed by the introduction of transporting groups in noncritical structural parts.

The present inventor has now applied his inactive metabolite approach to the case of the natural and synthetic glucocorticosteroids and has designed the soft steroidal anti-inflammatory agents of the present invention, beginning with the known inactive natural metabolites of the glucocorticosteroids. Thus, for example, in the case of hydrocortisone, one of its major, inactive met~bolites, cortienic acid, i.e., 113,17~-dihydroxyandrost-4-en-3-one-17~-carhoxylic acid, has been used as a starting point and activated by the introduction of suitable non-toxic 17a - and 17B -subs.ituents, which activated derivatives will cleave in vivo, after accomplishment of their therapeutic role, to the starting inactive metabolite and other nontoxic moieties.
~ accord with the foregoing, the present invention provides novel soft steroids having anti-inflammatory activity, said steroids having the structural form~la~

.

1 ~ 74667 l -Rl H C C=O

~ ~ 'R

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

C

`:
., 1 174~6~

A group of preferred compounds of formula (I) consists of those wherein:
R1 is Cl-C6 alkyl; Cl-C6 (monohalo or polyhalo)-alkyl; -CH2COOR6 wherein R6 is Cl-C6 alkyl; -CH2-Y-(Cl-C6 alkyl) wherein Y is -S-, -SO-, -SO2- or -O-; or I
-CH2-OCR6' wherein R6' is Cl-C6 alkyl or phenyl;
R2 is Cl-C6 alkyl, C3-C8 cycloalkyl, phenyl~
benzyl or Cl-C6 (monohalo or polyhalo)alkyl;
R3 is hydrogen, ~-hydroxy, ~-methyl, ~-methyl or ~-OCOR2 wherein R2 is identical to R2 as defined hereinabove;
R4 is hydrogen or fluoro;
R5 is hydrogen or fluoro;
Z is ~-hydroxymethylene;
and X and the dotted line in ring A are defined as hereinabove.
The invention further provides anti-inflammatory quaternary ammonium salts of selected compounds of formula (I), as discussed in further detail below. Novel inter-mediates to the compounds of formula (I), e.g, the correspond-ing compounds wherein Rl is hydrogen, are provided also.
The soft steroids of formula (I) and quaternaryammonium salts thereof are extremely potent local anti-inflammatory agents; however, by virtue of the fact that their facile ln vivo destruction leads only to the inactive steroidal metabolite, the present compounds have far less systemic activity than the known glucocorticosteroids from whose inactive metabolites they are derived. Indeed, many of the compounds of the present invention are entirely devoid of systemic activity. Such minimal -- or non-existent --systemic activity means that the compounds of the presentinvention can be used in the local (e.g., topical) treat-ment of inflammatory conditions without the serious ~ 17466~

systemic side effects which attend use of the known glucocor-ticosteroids.

With respect to the various groups encompassed by the generic terms used here and throughout this specification, the following definitions and explanations are applicable:

The alkyl, groupings can be straight or branched-chain groups containing the aforementioned number of carbon atoms.
Likewise, the alkyl portions of the haloalkyl groupings each can be straight or branched-chain. The term "lower" used in conjunction with any of those groupings or in conjunction with "alkyl" is intended to indicate that each alkyl portion there-in can contain 1 to 8 carbon atoms.
Specific examples of alkyl radicals encompassed by for-mula (I), whether as specific values for Rl or R2, or as a portion of a R1, R2, or R3 group, include methyl, ethyl propyl, butyl, pentyl, hexyl, heptyl and octyl and their branched-chain isomers, as well as their straight and branched-chain higher homologues in the instances where "alkyl" cancontain more than 8 carbon atoms. The alkenyl radicals can be exemplified by vinyl, propenyl and butenyl. Illustrative of the cycloalkyl and cycloalkenyl radicals are cyclopentyl, cyclohexyl, cyclopentyl and cyclohexenyl. The alkylene moieties are typified by trimethylene, tetramethylene and the like.

1 17466~

With respect to the structural variables encompassed by the group of preferred compounds of formula (I) identified hereinabove, the term "Cl-C6 alkyl" is used to refer to a straight or branched-chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like. In addition, the term "Cl-C6 (monohalo or polyhalo) alkyl" is used to refer to a straight or branched-chain alkyl group having 1 to 6 carbon atoms substituted with from 1 to

3 halogen atoms, the term "halogen" as used herein including a chlorine atom, a bromine atom, an iodine atom or a fluorine atom. Specific examples of the contemplated l 17466~

monohaloalkyl and polyhaloalkyl groups include chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, fluoromethyl, difuloromethyl, trifluoromethyl, l-fluoroethyl, l-chloroethyl, 2-chloroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 1,2-dichloroethyl, l-chloropropyl, 3-chloropropyl, l-chloro-butyl~ l-chloropentyl, l-chlorohexyl, 4-chlorobutyl and the like. Also the term "C3-C8 cycloalkyl" is used to refer to a cycloalkyl radical having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Selected compounds of formula (I), i.e. compounds wherein Rl is ~-haloalkyl, readily form the corresponding soft quaternary ammonium salts which are likewise useful as soft anti-inflammatory agents. Thus, for example, the selec-ted haloalkyl derivative of formula (I) can simply be reacted with a tertiary amine ~N) or an unsaturated amine (`"N) to afford the corresponding quaternary ammonium salt. The re-actants are ~l - 8 -r ~, ~
generally used in approximately equimolecular proportions and the reactlon is conducted in the presence of an inert solvent (e.g., ether, acetonitrile, C~2C12 or the like), at a temperature of from room 5 temperature to the reflux temperature of the sol~ent, for approximately 2 to 24 hours. Alternatively, the reaction can be conducted in the absence of a solvent by mixing the two reactants together and maintaining them at room temperature or between 20 to 70C for 2 to 24 hours. In either case, the crystalline salt formed can be purified by crystallization from an ether-ethanol mixture, or the like.
The exprèssion "unsaturated amine" used above denotes N-heterocyclic unsaturated systems having 3 to 15 10 members in the ring, and substituted derivatives thereof, where the unsaturation corresponds to the maximum number of non-cumulative double bonds, provided that the nitrogen atom contains no hydrogen atom as a substituent~ The following examples will sufficiently 20 illustrate the scope of the defined term:
. . .
C~3 l-Methylazirine ~
~ 3 l-Methylpyrrole l-Methylimidazole l-Methylpyrazole ~3 ¢~
Pyridine .
~', .
.
,~, .

. .
. ~'' .

CI ~~

Pyrazine ~0 Pyrimidine Pyridazine "6 2-Methylisoindole ~ N--C~3 ~ ~ .
. 3~-indole Quinoline -Iso~uino1ine Phthalazine N

10 Quinazoline ~ i;q Phenazine 1 17466~

C -~
.

Isot~iazole S~ C~3 ~ ,-1 ~ ethylphenothiazine Isoxazole 6~N
o Furazan N

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

:' :

: ' ~~
~ 17466~ .

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

:
' ' .

C '` /3 ,~

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

1 17466~

~, /'f C` ~

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

.
' ~ - .

as dichloromethane, chloroform or tetrahydrofuran, preferably in the presence of a suitable acid acceptor (e.g., triethylamine, pyridine, calcium carbonate or other appropriate base). Tlme and temperature are not critical factors; however, thé reac'ion is conveniently carried out at a temperature between 0C and room temperature, for about 1 to 6 hours. The resultant novel 17B-carboxylic acid 17~-carbonate has the formula 0~

C=O

HO ~ -OCOOR2 n (III) wherein R2, R4, R5 and the dotted line in the A ring are defined as above and R3" is H, a-C~3, ~-CH3, a-OCOOR2, B-ocooR2 or =CH2. When R3' in the starting material of formula (II) is a-OH or B-oH~ sufficient R2OCOCl or R2OCOBr is generally employed to ensure formation of the carbonate grouping at the 16-position as well as at the I7-position [i.e., when ~3' in formula (II) is OH, R3"
in the resultant intermediate of formula (III) is a- or B-ocoor~2]-., .

117466~ -. - llo Af,er the above-desc-ibed introduc_ on or the 17a-subs~ituent, the resultant novel inte~ediate or for~ul~ (III) is conve t2~ to its corresponding metal salt of the for~ula OM

C=O
~0~ --OCOOR2 wherein R2, R3", R4, R5 and the dotted line in the ring A
are defined as above, and M is a suitable metal, e.g.
alkali metal (such as sodium or potassium), alkaline earth metal/2, or thallium or MH4. The novel salt of formula (IV) is typically formed by reacting the steroid of formula (III) with a hydroxide (MOH) or alkoxide (MOR) in an appropriate organic solvent, such as ethyl ether or tetrahydrofuran, at a temperature of 0C to room temperature, for 0.5 to

4 hours. Then, the salt of formula (IV) is reacted with a compound of the formula Rl-W wherein Rl is defined as hereinabove and W is halogen, to afford the desired final product of formula (I). This step of the reaction sequence can be conveniently conducted at room temperature for about 1 to 24 hours, or at the boiling of the solvent (i.e. acetonitrile, THF, etc.) When it is desired to introduce a halo-substituted Rl grouping into the steroid, e.g., when a compound of formula (I) wherein Rl is chloromethyl is desired, it has been found that the reaction proceeds well using hexamethylphosphoramide as .

1 17466~

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

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

~ - 18 -~ 1 17466~
/q Another process for the preparation of the compounds of formula (I) wherein Z is ~-hydroxymethylene and X is oxygen utilizes the same 17-hydroxy-17~-carboxylic acid starting materials of formula (II) as are employed in the synthetic scheme described supra, but involves formation of the 17 ~-COORl grouping prior to, rather than after, introduction of the 17~-OCOOR2 substituent. Essentially, the same non-steroidal reactants, reaction conditions, etc., as described above are used for the introduction of each group. Thus, the starting material of formula (II) is first reacted with MOH or MOR to form the corresponding intermediate of the formula ~ f~
o ' ~O~--OEI
. (y ~J , I , ,~ , ~5 wherein R3', R4, R5 and M and the dotted line in ring A are defined as above, which is then reacted with RlW wherein . 15 Rl and W are defined as above, to afford the corresponding 17~-carboxylate of the formula --~` 117466~

ORl .. l`

- C=O

HO ~ ~~ (VI

.

wherein Rl, R3', R4, R5 and the dotted line in ring A are defined as above, which is in turn reacted with R20COCl or R20COBr wherein R2 is defined as above, to afford the corresponding 17a-carbonate of formula (I). The various

5 parameters of the process of converting (II) to (V) are the same as those discussed in detail above with respect to the conversion of (III) to (IV~. Like~ise, the process parameters for converting (V) to (VI) parallel those detailed above with respect to converting (IV) to (I). Similarly, the process parameters for converting (VI) to (I) are basically the same as those given above for the conversion of (II) to (III).
Thus, again, when the starting material contains a 16-hydroxy group, the 16,17-dicarbonate of formula (I) will be formed which can then be selectively hydrolyzed, if desired, to the corresponding 16-hydroxy-17-carbonate of formula (I). And, again, the compounds of formula (I) in which Rl is a sulfinyl- or sulfonyl-containing grouping can be conveniently prepared by oxidation of the corresponding thio-containing com-. pounds of formula (I) as detailed hereinabove. Alternatively, : 20 the compounds of formula (I) wherein Rl is a sulfinyl-or sulfonyl-containing group [e.g., when Rl is _CH2-So-(lower alkyl) or -CH2-SO2-(lower alkyl)] can be prepared ,~ - 20 -.

~ 17466~
f~ `

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

such as triethylamine is preferably present in the reaction system. The two steps of)this process can be very con-veniently run in the same solvent, without isolating the acid chloride of formula (VIII) formed in the first step.
This process is of particular value when a compound of formula (I) wherein X is S is desired.
Yet another desirable process for the preparation of the compounds of formula (I) wherein Z is ~-hydroxy-methylene and X is oxygen utilizes the 17 a-hydroxy-17~-carboxylates of formula (VI) above. According to thisprocess, an intermediate of formula (VI) is reacted with phosgene, in a suitable organic solvent (e.g., toluene, benzene, CH2C12 or acetonitrile) at a low temperature (-20C to room temperature, e.g., 0C), for about 2 hours (or until the reaction is complete). ~vaporation to remove solvent and excess phosgene affrods the desired novel 17a-chlorocarbonyloxy-17~-carboxylate intermediate of the formula ORl ~_o (VII) R

wherein Rl, R4, R5 and the dotted line in ring A are defined as above, R3"' is hydrogen, a-methyl, ~-methyl, a-OCOCl, ~-OCOCl or =CH2. When R3' in the starting material of formula (VI) is hydroxy, sufficient phosgene is generally employed to ensure formation of the chlorocarbonyloxy grouping at the 16-position as ~ as the 17-position [i.e., when 1 ~ 7 4 6 6 7 - 2~r -R3' in formula (VI) is a-OH or ~-OH, R3"' in the resultant intermediate of formula (VII) is a- or ~-OCOCl~. The inter-mediate of formula (VII) is then reacted with a compound of the formula R2OM' wherein R2 and M' are defined as above, in an inert solvent, preferably in the presence of an acid scavenger (e.g. triethylamine), to afford the corresponding compound of formula (I). When R20M' is an alcohol of the formula R2OH, the reaction is conducted under the same conditions as in the reaction for conversion of compound (II) to compound (III). On the other hand, if a compound of the formula R2OM is employed as R2OM', the reaction conditions are described as above for conversion of compound (VIII) to compound (I). When R3"' in the formula (~II) is OCOCl, sufficient R2OM' is generally utilized to ensure conversion of both the 16- and 17a-substituents to OCOOR2 groupings in the final product. And, again, the 16-hydroxy and the sulfinyl- and sulfonyl- containing compounds of formula (I) are most conveniently formed as a final step in the synthetic scheme.
As a variation of the process described immediately above, a steroidal 17a-hydroxy-17~-carboxylic acid starting material of formula (II) can be reacted with phosgene as described above, to afford the 17a-chlorocarbonyloxy-17~-carboxylic acid intermediate of the formula OIH
1=o ~ ' 1 17~667 , _ .
r ~

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

.

- C

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

.

1 17466~
<

C

.`
Also, a starting material of formula (II~ above can be reacted with a compound of the formula R2OCOCl or R2OCOBr wherein R2 is as defined above, to af ord an intzrmediate of the formula o C=O

~O ~ - OCOOR~

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

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

.
C ~.
~g the corresponding ll~-hydrc~y compounds o~ formula ~I).
Thus, a starting material correspondins to formula ~II
but having an ll-keto group is reacted with R20COCl or R20COBr, to afford the corresponding novel intermediate corresponding to formula ~III] but haYing an ll-keto group; that intermediate is then converted to its metal salt, which corresponds to formula ~IV) except for the presence of an ll-keto instead of an ll~-hydroxy group;
and the metal salt is th~n reacted with RlW to afford the corresponding compound of form~la ~IX). All reaction condi,ions are as previol~sly described with respect to the corresponding processes for preparing the corresponding compounds of formula ~I). Also, the preparation of the compounds of formula ~IX) wherein Rl is a sulfinyl- or sulfonyl- containing grouping or wherein R3 is hydroxy generally proceeds as a final step in the synthetic scheme in a manner analogous to that ~sed for the corresponding compounds of formula (I). ~urther, all of the aboYe-described alternative processes for the preparation of the compounds of formula ~I) are eq~lally applicable to the preparation of the compounds of formula (I~) by simply substituting the ll-o~o-starting material for the corresponding ll~-hydro~y steroids used therein, e.g., replacing the ll-hydrQxy group in formulas (Y~, (YI), ~VII~, ~VIII), (X) and ~I) with an ll-oxo groLp and otherwise proceeding as described hereinaboYe for the reactions (Ti) ~(V) ~YI)~ VIII)~
~ VI) )(VII) ,~I); ~II) i ~X) ~ (I); (YI3 ~ ~), etc.
Also, the compounds of formula (IX) can be prepared by reacting the corresponding compounds of formula (I) with an Qxidizing agent. The Qxidation of a 117~667 ~,2q _ j~
~` J, compound of formula (I) in order to convert it into the corresponding compound of formula (IX) is usually carried out by using an oxidizing agent in an appropriate solvent. The solvent may be any conventional solvent, for e~ample, water, an organ~c acid (e.g. formic acid, acetic acid, t~lI~ucmacetic acid), an alcohol (e.g.
methanol, ethanol),-a halogenatea hydrocarson (e.g.
chloroform, dichloromethane~, or the liXe. The oxidizing agent may also be any conventional agent which is ef ective for oxidizing a hydro~y group to a carDonyl group, for e~ample, pyridinium chlorochromata, chromium trioxide in pyridine, hydrogen peroxide, dic~romic acid, dichromates ~e.g. sodium dichr~mate, potassium dichromate), permanganic acid, permznganates ~e.g. sodium permanganate, potassium permanganate), or the lik~. The ox~dizing agent is usually used in an amount of 1 mole or more, preferably 1 to 3 mole, per mole of the compound of formula ~I). The reaction is usually carried out at a temperature of 0 to 40C, preferably at around room temperature, for about 6 to 30 hours.
The novel compounds of formula (IX) are useful as soft steroidal anti-inflammatory agents and also in vivo or in vitro precursors of the corresponding hydroxy compounds. Thus, the compounds of formula (IX) can be reduced in vitro to afford the corresponding compounds of formula ~I), using a reducing agent known to be capable of reducing the ll-oxo group to an a ll~-hydroxy group without modifying the remainder of the steroidal starting material. Typically, microbiological reduction - is advantage~us for carrying out the desired conversion, although chemical reduction also is possible. Further, the compounds of formula ~IX) may be formulated into appropriate dosage forms (e.g., retention enemas) for the .) 1 ~7466 3~

treatment of conditions such as ulcerative colitis. In such dosage forms, it is thought that the compounds of formula (IX) are microbiologically reduced by bacteria in the body (e.g. in the colon) to the highly active ll~-hydroxy steroids, which elicit the desired anti-inflammatory response.
The preferred compounds of formula (IX) are those which are precursors of the preferred compounds of formula (I) wherein Z is ~-hydroxymethylene, namely corresponding ll-keto compounds of formula (IX). An especially preferred group of compounds of formula (IX) consists of those wherein X, Rl and R2 are defined as above with respect to for~ul~ (I) and the re~aining s.ruc~ral variations are identical to those of cortisone ~i.e. R3, R4 and R5 are-each a hydrogen atom and the 1,2-linkage is saturated), of pre~nisone (i.e. R3, R4 and ~5 are each hydrogen and the 1,2-linkage is unsat~lrated), or of the 6- and/or 9a-fluoro and the 16a- or 16~-methyl congeners thereof, particularly when Rl and R2 are as defined with respect to the "first" group of preferred compounds set forth hereinabove. Most especially preferred ~f these derivatives are those wherein X is oxygen, R2 is Cl-C6aIkyl and Rl is Cl-C6 al~yl, Cl-C6 (monohalo)alkyl [particularly chloromethyll or -C~2-Y-(Cl-C6 alkyl) [particularly C~2-Y-cx3 ~
The results of various activity studies of representative species of the invention, discussed in detail below, clearly indicate the potent anti-inflammatory activity and the minimal syste.~ic activity/toxicity of the soft steroidc of formula (I). In view of this desirable separation of local and systemic activities, the compounds of the invention can be used in the treatme~t of topical or other localized inflammatory conditions without causing the serious systemic side ef~ects typically exhibited by the known natural and synthetic glucocorticost2roids such as cortisone, hydrocortisone, hydrocortisone 17a-butyrate, 1 17466~

betamethasone 17-valerate, triamcinolone, betamethasone dipropionate and the like.

T~YMUS INVO~UTIO~ TEST
The test animals were female Sprague/Dawley rats weighing approximately 40-45 grams each. One side of each ear of each rat was treated with a total of 25 microlite-s of a solution ~ethanol/isopropyl myristate or acetone/isopropyl myristate, 90/10) containing the amount of test compound indicated below. Animals which were treated identically, save for omission of the test compound, served as controls. After 24 hours, all rats were sacrificed and weighed, and their thymi were removed and weighed. The results are tabulated in Table I below, the weights of the thymi being expressed as mg/100 g of rat.

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The change in weight in the thymi is a measure of systemic activity and hence of toxicity. The lower the weight of the thymi, the greate_ the systemic activity.
As can be seen from the above data, even hydrocortisone, the natural glucocorticoid, causes a significant decrease in thymus weight compared to the control. The decreases caused by egual doses of representative species of the invention are much less significant, indicating those compounds have much l'ess systemic activity than hydrocortisone, BLANC~ING STUDIES
McKenzie-type human blanching studies were undertaken to study the blancning effects of a represent-ative test compound of the invention, chloromethyl 17~-ethoxycarbonyloxy-11~-hydroxyandrost-4-en-3-one-17~-' ' carboxylate. The ability of a compound to cause blanching ,~ in humans has been found to correlate closely with its anti-inflammatory activity.
The test compound was dissolved in ethanol/
isopropyl myristate ~90/10 or'70/30) at 0.03, 0.01, 0.003, 0.001 and 0.0003 M concentrations. 50 Microliter aliquots of each solution were applied to separate gauze portions, ' ~of a bandage of the type commonly used for allergy , testing and the bandage was applied to the forearm. After

6 hours of occlusion, the bandage was removed. After 1 to 5 hours aft^r removal of the bandage, blanching was observed even at the lowest concentrations of test compound.
When hydrocortisone was tested according to the above procedure comparing it directly to the test compound, blanching was not observed at concentrations of hydrocortisone below 0.03 M. Further, it was noted that .. -- . ~

, j ~
j ~ 1 17466~

0.03 M hydrocortisone caused approximately the same degres of blanching as that resulting from use of O.001 M cnloromethyl 17a-e~hoxycarbonyloxy-llB-hydroxyandrost-4-en-3-one-17~-carboxylate.

S EAR EDEMA TEST
The test animals were Sprague/Dawley rats weighing approximately 150 grams each. In treatment groups, selected amounts of the test compound were dissolved in acetone containing 5% croton oil and 50 microliters of the solution were applied to the inner surface of the right ear of the rats. A control group was identically treated with vehicle only, i.e. 5%
croton oil in acetone. Six hours after croton oil challenge, a constant region of each ear was removed by dissection under anesthesia. Then, 48 hours after steroid treatment, the animals were sacrificed and the thymi and adrenals were removed and weighed. The test results showing the inhibitory effect of topically applied steroids on the ear swelling induced by croton oil are summarized in Table II below.

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3 ~

As can be seen from Tahle II akove, the representative species of the present invention, namely chloromethyl 17-et.~oxycar~onyloxy~ -hydroxyandrost-4-en-3-one-17~-carbo.~ylate, s~bs~aniially inhibited the swelling (and conse uent increased weight) of the ear caused by c_oton oil, i.e., the com~ound e~nibited substanti21 anti-inflammatory act-vity. On the other hand, in contras. to the effect caused by betametasone 17-valerate, the representative compound of the invention did not significantly decrease ~he thymus weight as compared to the control, i.e., it did not show a signifi-cant degreo of syst~mic activi~x.

G ~NULOMA FOR~ION TEST
The test compound was dissolved in acetone and aliquots of varying concentrations we_e injected into cotton pellets. The pellets were dried and then one pellet was implanted beneath the skin of each test rat.
Si~ days later, the animals were sacrificed and the granulation tissue (granuloma) which formed in and around the implanted pellet was removed, aried and weighed.
In addition, the thymi and adrenals were removed and - weighed. The ability of a compound to inhibit granuloma formulation in this test is a direct indication of local - anti-inflammatory activity; thus, the lower the weight of granulation tissue, the better the anti-inflammatory activity. On the other hand, a significant dec~ease in thymus weight is indic~tive of significant systemic activity;
conversely, when a test cQmpound does not sig~ific~ntly decrease thymus weigh~ as compared to the control, such 30 i5 indicative of a lac~ of (or very minimal~ systemic side effec_s.
The results are tabulated in Tables III, IV and V-a and V-b below.

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

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1 17466~

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

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- 1 17466~
f~ '1 BLANK COTTON PELLET GRANULOMA ASSAY
A further test was undertaken to determine the thymolytic activity of a representative species of the inven-tion as compared to betamethasone 17-valerate. In this test, the drugs were administered intravenously to rats, while using a blank cotton pellet granuloma assay. Male Sprague-Dawley rats, each weighing about 185 grams (166-196 grams), were used. Two cotton pellets, each weighing 30 mg and con-taining no test compounds, were sterilized and implanted sub-cutaneously into the back of each test animal. This day wasconsidered day O of implantation. ~Test compounds suspended in 0.8%~po~yoorbatc 80~were adml~nisJtered intravenously once daily for 3 consecutive days beginning with day 1. On day 5, the animals were sacrificed and the two pellets, with their respective granulomas, were removed, dried overnight in an oven at 50C and weighed (dry granuloma weight). The thymi and final body weights were also recorded. The results are given in Table XI below.
In the foregoing tests, there was determined the deactivation of the representative species of the present soft steroids administered intravenously to rats. The ratio between the potencies of the test steroids and betamethasone 17-valerate against local anti-inflammation was 283:0.7 as seen from Table VI. This means that the test compounds exhibit a local anti-inflammatory activity which is approximately 400 times as high as the activity of the betamethasone 17-valerate.
The test compounds were administered intravenously to rats to ` check the test compounds also for systemic anti-inflammatory activity as compared to betamethasone 17-valerate. The test compounds were found lower in the inhibition of granulation tissue formation and also in the thymus involution activity than betamethasone 17-valerate. From the results of the tests, it is presumed that the compounds which will not be readily subjected to metabolism (deactivation) have a systemic anti-inflammatory activity, as is the case with betamethasone17-valerate.
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The ED50's calculated for the local cotton pellet granuloma assay ¢as shown, for example, in Table VI above) and the TED40's calc~lated on the basis of thymus inhibition testing ¢as shown, for example, in Table X above) were used to arrive at relative potency and a therapeutic index for representative species of the invention as compared to prior art steroids. See Table XII below, which clearly shows the potent anti-inflammatory activity and minimal systemic toxicity of the compounds of the present invention.

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1 174~67 b The compounds of formula ~I) can be combined with suitable non-toxic pharmaceutically acceptable carriers to provide pharmaceutical compositions for use in the treatment of topical or other localized inflammation. Obviously, in vie~ of their lac~ o~
systemic activity, the compounds-of the present invention are not intended for treatment of conditions where systemic adrenocortical therapy is indicated, e~g., adrenocortical insufficiency. As examples of inflammatory conditions which can be treated with'pharmaceutical compositions containing at least one'compound of the invention and one or more pharmaceutical carriers, the following can be mentioned: dermatological disorders such'as atopic dermatitis, acne, psoriasis or contact dermatitis; allergic states such as bronchial asthma;
' 'ophthalmic and otic diseases involving acute and chronic allergic and inflammatory reactions; respiratory diseases;
ulcerative cclitis; and anorectal inflammation, pruritus and pain associated with hemorrhoids, proctitis, cryptitis, fissures, postoperative pain and pruritus ani. Such compositions may also be applied locally as a prophylactic measure against the inflammation and tissue rejection which arise in connection with transplants.
' Obviously, the choice of carrier~s) and dosage forms will vary with-the particular condition for which the'composition is to be administered.
Examples of various types of prepàrations for topical/local administration include ointments, lotions, creams, powders, drops, ~e.g. eye or ear drops), sprays, ~e.g. for the nose or throat), suppositories, retention enemas, chewable or suckable'tablets or pellets ~e.g. for the'treatment of aphthous ulcers) and aerosols. Ointments and creams may, for example, be formulated with an aqueous 1 17d~67 ~ 5~
_~ _ or oily base with the addition of suitable thickening and/or gelling agents and/or glycols. Such base may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a glycolic sol~ent such as propylene glycol or 1,3-butanediol. Thic~ening agents which may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, woolfat, hydrogenated lanolin and beeswax and/or glyceryl monostearate and/or non-ionic emulsifying agents.
The solubility of the steroid in the ointment or cream may ben enhanced ~y incorporation of an aromatic alcohol such as benzyl alcohol, phenylethyl alcohol or phenoxyethyl alcohol.
Lotions may be formulated with an aqueous or oily base and will in general also include one or more of the following, namely, emulsifying agents, dispersing agents, suspending agents, thickening agents, solvents, coloring agents and perfumes. Powders may be formed with the aid of any suitable powder base e.g. talc, lactose or starch. Drops may be formulated with an aqueous base also comprising one or more dispersing agents, suspending agents or solubilizing agents, etc. Spray compositions ~ay, or example, be formulated as ~erosols with the use of a suitable propellane, e.g., dichlorodifluoromethane or trichlorofluoromethane.
The proportion of active ingredient in the compositions according to the invention will vary with the precise compound used, the type of formulation prepared and the particular condition for which the composition is to be administered. The formulation will generally contain from about 0.0001 to about 5.0% by weight of the compound of formula ~I). Topical .

.
s~

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

~ ~ 17 466~
s~

Another e~ample of a pharmaceutical com~osition according to the invention is a foam suitable f,or trea~ment of a wide variety o' inflammatory anorectal disorders, to be applied anally or perianally, comprising 0.1% of a compound of formula ~I~ such'as chloromethyl 17a-ethoxycarbonyloxy-11~-hydroxyandr~s.:-4-en-3-one-17B-,carboxylate, and 1% of a local anaesthe~ic such as pramoxine hydrochloride, in a mucoadhesive foam base of propylene glycol, ethoxylated stearyl alcohol, ,10 polyoxyethylene-10-stearyl ether, cetyl alcohol, methyl paraben, propyl paraben, triethanolamine, and water, with inert propellents. ~nen a more potent compound of the invention is employed, less active ingredient generally is used, e.g. 0.05% of chloromethyl 9a-fluoro~ -hydroxy-17a-methoxycarbonyloxy-16a-methylandrosta-1,4-dien-3-one-17~-carboxylate.
Yet another pharmaceutical formulation according to the invention is a solution or suspension suitable for use as a retention enema, a single dose of which typically contains 40 milligrams of a compound o' the invention such as chloromethy~ 17a-ethoxycarbonyloxy-11~-hydroxyandrost-4-en-3-one-17~-carboxylate ~or 20 milligrams of a more potent compound of the invention such as chloromethyl 9a-fluoro~ -hydroxy-17a~isopropoxycarbonyloxy-16~-25 ~ethylandrosta~1,4,-dien-3-one-17~-carboxylate or chloro-methyl'9a-fluoro-11~-hydroxy-16a-methyl-17a-propoxy-carbonyloxyandrosta-1,4-dien-3-Qn,e-17~-c,arboxy,late) k~
rDlusO~bc~ atr6~ ma~ J
, together with sodium chloride, po~yLorbato 80~and from 1 ; to 6 ounces of water (the water being added shortly before use). The suspension can be administered as a retention enema or by continuous drip several times weekly in the treatment of ulcerative colitis.
Other pharmaceutical formulations according to , tL 174667 ,~
~ 6 ,,~

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

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

C=O
HO ~ - - OH
~ .
,~

To a cold solution of 1~,17a-dihydroxyandrost-4-en-3-one-17~-carboxylic acid (5%
weigh~/vo1ume: 1 mol) end triethylamine (4 =ol~ in .

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dicholormethane is added a 50~ ~weight/Yolume) solution of methyl cnloroformat~ ~3.9 mol) in dichloromethane.
The reaction mixture is allowed to warm to room temper-ature over a 2 hour period. The triethylamine hydro-chloride precipitate whic~ forms; is removed ~y filtrationand the filtrate is wasned successively with 3~ sodium bicarbonate, dilute (-1~) hydrochloric acid and water.
The organic layer is separated, dried with magnesium sulfa.e, and filtered. The filtrate is concentrated in 1~ vac-lo to a foam. The foæm is used in the next step te.g., E~ample 3 below) or chromatographed and crystal-lized for analysis. The product, ll~-hydroxy-17a-methoxycarDonyloxyandrost-4-en-3-one-17~-car~oxylic acid, melts at 198-204C after chrom2tosraphy and 15crys.allization; ir ~KBr) 3000-2800 ~C-H), 1750, 1735, 1720 ~C-O), 1650, 1640 CC=C-C=O)cm 1, The product can be represented by the structural formula OH

~ ~ 3 0~
Substitution of an equi~alent quantity of ethyl chloroformate for the methyl chIoroformate employed a~ove and substantial repetition of the for~going procedure af,ords 17G-ethoxycarbonyloxy-ll~-hydr~Yyandrost-4-en-3-one-17~-carbo~ylic acid, melting at 192-195C after chromatography and crystallization; ir tKBr) 3500 (ll~-O_H), 3000-2800 (C-H), 1740(C=O), 1630_ ~ 174667 ~C=C-C-O)cm l; nmr(C3C13) ~6.4~1, b, CCOH), 5.67(1,s, ~_C~), 4.43 (l,b, C~O~), 4.13 ~2, ~, J=7.5~z, OC~2C~3);
Anal. calcd. for C23~3207: C, 6;.69; ~, 7.67. Found: C, 6;.76; H, 7.74.
In a similar manner, substitution of an equivalent quantity of butyl chloroformate for the methyl chloroformate employed in the first paragraph of this ex2mple and substantial repetition of the procedure there detailed affords 17-butoxycarbonyloxy-11~-hydroxyandrost-4-en-3-one-17~-carboxylic acid. The final product, after crystallization from tetrahydrofuran-hexane, melts at 164-166C.
Similarly, substituting an equivalent amount of isopropyl chlorofo-rmate f~r the methyl chloroformate used in the first paragraph of this example and repeating the procedure there detailed affords ll~-hydroxy-17a-isopropoxycarbonyloxyandrost-4-en-3-one-17~-carboxylic acid. The final product, after crystallization from tetrahydrofuran-hexane, melts at 144.5-146.5C.

EXAM~LE 3 ll~ ydroxy-17a-methoxycarbonyloxyandrost-4-en-3-one-17B-carboxylic acid is combined with an e~uivalent amount of lN sodium hydroxide in methanol and that soiution is diluted to 100 times the original volume with ethyl ether. The suspension which results is refrigerated for 1 hour. Then, the crystals which form are removed by filtration, dried in an evacuated desiccator, and dissolved in hexamethylphosphoramide ~10~ weight/volume).
A portion of the resultant solution containing 1 mole of the acid salt, i.e. of sodium 11~-hydroxy-17a-metho~ycarbonyloxyandrost-4-en-3-one-17B-carbo~ylate, is combined with 4 moles of chloromethyl iodide. The reaction mixture is maintained at room temperature for 3 hours, then is diluted to 10 times the original ~olume with ethyl acetate. The diluted reaction mixture is washed successively with 5% sodium t~iosulfate, 3% sodium 5 bicarbonate, and water. The organic layer is separated, dried with magnesium sulfate and filtered. The filtrate is concentrated in vacuo to a foam. The foam is purified by crystallization from a suitable solvent (ethyl ether or tetrahydrofuran/hexane). There is thus obtained 10 chloromethyl 11~-hydroxy-17a-methoxycarbonyloxyandrost-4-en-3-one-17~-car~oxylate, melting at 171-173C after crystallization; ir(XBr) 3000-2800tC-H), 1760, 1748(C-O), 1650~C=C-C-O)cm l; nmr (CDC13)~ 5.67~s,~1, C=CH), 5.82, 5.62 (ABq, J=5.5Hz, 2, OC~2Cl), 4.47(b, l,:C~OH); Anal.
15 calcd. for C23H31ClO: C, 60.72; H, 6.87; Cl, 7.79.
Found: C, 60.50; H, 7.06; Cl, 7.50. The product is characterized by the structural formula C=O

~O ~ - -O~O~3 Substitution of an equiYalent quantity of 17a-20 ethoxycarbonylaxy~ hydroxyandrost-4-en-3-one-17g-carbo~ylic acid for the steroidal acid employed abo~e and substantial repetition of the foregoing procedure affords, as t~e intermediate salt, sodium 17a-ethoxycarbonyloxy-.; - .

~, 11~4B6 .. 6~

llB-hydroxyandrost-4-en-3-one-17B-carboxylate, and, as the final product, chloromethyl 17a-ethoxycarbonylo~y-llB-hydroxyandrost-4-en-3-one-17B-car~o~ylate, melting at 197-200C after crystallization; ir ~KBr) 3600-3200 ~O--d), 3000-2800(C-H), 1763, 1740~C-O), 1650(C=C-C_O)cm l;
S nmr (CDC13)~ 5.7(s, 1, C=C~), 5.81, 5.62 (ABq, J=5~z, 2, -OCH2Cl); Anal calcd. for C2aH33C1O7: C, 61.46; H,

7.09. Found: C, 61.58; H, 7.08.
In a similar manner, substitution of an equivalent quantity of 17-butoxycarbonyloxy-llB-hydroxyandrost-4-en-3-one-17~-carboxylic acid for the steroidal acid em?loyed in the first paragraph of this example and subs.antial repetition of the procedure there detailed affords, as the intermediate salt, sodium 17-butoxycarbonyloxy-llB-hydroxyandrost-4-en-3-one-17~-carboxylate, and, as the final product, chloromethyl17~-butoxycarbonyloxy-11~-hydroxyandrost-4-en-3-one-17B-carboxylate, melting at 98-100C after crystallization;
ir(KBr) 3600-3300 (O-H), 3000-2800 ~C-H~, 1765 (O2C-O), 1735 (OC-O), 1650 (C=C-C=O)cm l; nmr~CDC13)~5.80, ~5.60 ~2,ABq, J=4.5Hz, -OCH2Cl), 5.67 (1, s, C=C~), 4.45 ~1, b, C~O~), 4.08 ~2, t, J=6Hz, O2COC~2-C~2); Anal calcd. for C26H37ClO7: C, 62.77; H, 7.44; Cl, 7.14. Found: C, 62.88; H, 7.23; Cl, 7.30.
Similarly, substituting an e~uivalent amount of llg-hydroxy-17a-isopropoxycarbonyloxyandrost-4-en-3-one-17~-carboxylic acid for the steroidal acid employed in the first paragraph of this e~ample and substantial repetition of the procedure there detailed affords, as the intermediate salt, sodium llB-hydroxy-17a-isopropoxycarbonyloxyandrost-4-en-3-one-17~-carboxylate, and, as the final product, chloromethyl ll~-hydroxy-17a-isopropoxycarbonyloxyandrost-4-en-3-one-17~-carboxylate, melting at 183.5-184.5C after recrystallization from tet=ahydrofuran-hexane.

:' .
. .

1 17466~

In a similar manner, an equivalent quantîty of 17~-ethoxycarbonyloxy~ -hydro~yandrost-4-en-3-one-17B-carboxylic acid is substituted for the steroidal acid and an equi~alent quantity of ~utyl chloride is substituted for the chlorGmethyl iodide employed in the first paragraph of this example; and the procedure there detailed is substantially repeated, except that the step of washing with 5~ sodium thiosulfate is eliminated.
Obtained in this manner are the intermediate salt, sodium 17-ethoxycarbonyloxy-llB-hydroxyandrost-4-en-3-one-17B-carboxylate, and the final product, butyl 17~-ethoxycarbonyloxy-llB-hydrQxycmdrost-4-en-3-one-17~-carboxylate. The final product after crystallization from acetone melts at 148-149C; after chromatography and crystallization, ir ~Br) 3600-3200~0-H), 3000-2800 ~C-H), 1750 (2 C-O), 1670 ~C=C-C--O)cm l; nmr ~CDC13) ~5.64(s, 1, -C=CH), 4.46 Ub, l, CHOH), 4.32-4.95 ~m, 4, COOC~2CX3+, COOCH2C~2-); Anal. calcd.
for C27H40O7: C, 67.99; H, 8.39. Found: C, 67.76;
~, 7.74.

EXAMpT~ 4 17-EthQxycarbonyloxy-ll~-hydroxyandrost-4-en-3-one-17~-carboxy-ic acid ~3 grams, 7.13 mmol) is treated with 7.13 milliliters of lM methanolic sodium hydroxide solution, and 500 milliliters of ethyl ether are then added to effect precipitation. The precipitate is separated by filtration and dried in an evacuated dessicator overnight to afford 2.71 grams (6.12 mmol) of the desired salt, i.e. sodium 17~-etho_ycarbonyloxy-llB-hydroxyandrost-4-en-3-one-17B-carboxylate, as a yellow powder. The salt is dissolYed in 40 milliliters of hexamethylphosphoramide and chloromethyl methyl sulfide ~2.36 grams, 24.5 mmol) is added slowly. A precipitate C. 6f/

of sodium chloride forms in the reaction mixture within 1 minute. The reaction mixture is stirred at room temperature for 1 hour, then is diluted with ethyl acetate to a total ~olume of 200 milliliters and washed successiYely with 3% sodium bicarbonate and water. The organic layer is separated, dried with magnesium sulfate and filtered. The filtrate is concentrated in vacuo to an oil, and the oil is chromatographed from silica gel, using ethyl acetate, chloroform and acetic acid as eluants. The chromatographed product is crystallized from a mixture of ethyl ether and hexane to give white powdery crystals of methylthiomethyl 17G-ethoxycarbonyloxy-ll~-hydroxyandrost-4-en-3-one-17~-carboxylate, melting at 133-136C. That product is characterized by the structural formula IC~2SC~3 C=O
~30 ~- -O~OC2115 o~ V

T~ a solution of methylthiome~yl 17a-ethoxycar~onylo~y-ll~-hydroxyandrost-4-en-3-one-17B-c-~rboxylato ~0.48 gram,l mmol) in 2 millilite-s of dichloromethane is added m-chloroperoxybenzoic acid ~0.4 gram o 0~34 gram of peracid, 2 mmol). An exothermic react~on ensues, ~hich subsides quic~ly. The reaction mi~ture is stirred at room temperature for 1 hour. The r ' .

~ 174667 ;`.
,. 6g precipitate which forms is removed by filtration and the .... .
filtrate is concentrated in vacuo to afford~ as a white foam, methylsulfonylmethyl 17~-ethoxycarbonyloxy-llg-hydroxyandrost-4-en-3-one-17~-carboxylate. That product has the structural formula ~CH2S02CH3 C=O
HO ~ - -O~OC2H5 ~ .
0~

NMR ~CDC13): ~5.07 (s, 2, OCH2S02), 2.~7 (s, ~, S02CH3).
Repetition of the procedure described in the preceding paragraph, but using only 1 mmol of m-chloroperoxybenzoic acid, affords methylsulfinylmethyl 17~-ethoxycarbonyloxy-11~-hydrQ~yandrost-4-en-3-one-17B-carboxylate.

ExAMæLE 5A
Substitution of an e~uivalent quantity of one of the starting materials listed below for the hydrocortisone used in Example 1 and substantial repetition of the procedure there detailed affords the indicated products:

; . ' :

1 17~667 , ' C i 6~
_ ~ _ STARTING MATERIAL PROD~CT
fludrocortisone 9-fl~oro~ ,17~-dihydroxy-androst-4-en-3-one-17~-car~oxylic acid, m.p. 250-253~C
betamethasone 9a-fluoro-11~,17~-dihydroxy-16~-methylandrosta-1,4-dien-3-one-173-car~oxylic acid, m.p. 248-249~C
dexamethasone 9a-fluoro-11~,17-dihydroxy-16a-methylandrosta-1,4-dien-3-one-17~-carboxylic acid, m.p. 275-278~C

Substitution of an equivalent quantity of one of the starting materials listed below for the hydrocortisone used in Example 1 and s~bstantial repetition of the procedure there detailed affords the indicated products:
STARTING MATERIAL PRODUCT
cortisone 17 ~hydroxyandrost-4-en-3,11-dione-17B-car~oxylic acld chloroprednisone 6a-chloro-17a-hydroxyandrosta-1,4-dien-3,11-dione-17~-` 25 . carboxylic acid flumethasone 6a~9a-difluoro-ll~ll7a-dihydroxy-16a-methylandrosta-1,4-dien-3-one-17~-carboxylic acid fluprednisolone 6a-fluoro-11~,17a-dihydroxy-androsta-1,4-dien-3-one-17~-carboxylic acid meprednisone 17a-hydroxy-16~-methylandrosta-1,4-dien-3,11-dione-17~-; carh~Yylic acid methyl prednisolone 11~,17a-dihydroxy-6a-methyl-androsta-1,4-dien-3-one-17~-carboxylic acid ' " :

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

H

C=O
'~,e= ~COOR~

1 17466~

,i, I ~/

~ ~U~ U~ U ~D

'~1 ~r ~r ~. ~i _i' ~r ~_~ ~ ~_1` ~ . _1' ~1 S PC j\U, \~,~' I \U~ - ~ ~ / lO\~u\F ~F -o\ ,: \u~ ~u~

, ~;1 ~: ss ~ ~ ~ ~ 5 ~, :C : :
: ~t :~ ~ ~ ~ ~ s ~ c ~ ~ ~
~ ~ ~.- ~, ~ ~ ~U` ~ ~u~
i ~ ~ ' ,~ C ~s .

-1~
.~g .

~ ~,~ ~,~
~1 ~ x co x x ~ ~ x ~1 u~ ~ ,, ~ I h G~ ~
~ ~ ~ ~ a~

5~1~ 0\~5 ~U~

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

.: .
, ~

. . , ... ..
i~
. ~

f ~ ~OOR2 o R

Com~ound No. R R R R Z
q ~ - 1 ~ , 6B-l C2H5 ~ - ~ ~ ,C - O 4 6B-2 CH3 H. H H ,C - O 4 6B-3 CH3 H F H ,C~ 4 6B-4. C2H5 ~ -CH3 F F C ~ 1,4 `H

6B-5 C2H5 B H F ,C~ 1,4 6B-Ç C2H5 ~-C~3 ~ . `C - O 1,4 6B-7 CH2CC13 ~ ~ E ,C ~ 4 6B-8 C2~5 -C~3. H F ,C ~ 1,4 OH
; 6B-9. C2H5 H ~ ~ 1,4 6B-lQ C2H5 ~ ~ ~ `C = O 1,4 - ...

' ' .

., ~

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

r ~,~ rj~?

EXAMP~E 7A
Following the general proc dure of Example 3 and substituti~g therein the appropriate reactants affords the following compounds:

IR

,~ OCOOR2 S ~ 3 O

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

~ 174667 .
.. . ~iY
_ .~

. ~cmcound No. ~ ~ ~ R~ R Z -- m.p. , 7~r16* C~3iso-C ~ ~ H H~ 4 181-182.5C
. G~:l . ~ ~I~IF/~) . .... 1 3 ... ¦ i~o-c ~ . .. ~..... H H ,~ 4 195-200C
,. . .... . ~ 1: . .,. . . . .. I ~ ...... ~
.. 7A D ~2CI~2C2~5-- E U C~ 4 ____ 7A-18* 1 3 iso-C ~ ~-C~3 F H ,C~ 1,4 167.5~169C
C~Cl 'H ~IffF/kexane) c~3 ~ ~a l iso-C ~ ~-C~3 F H ~ 1,4 163-164C
. ........ '~C~ . .... .. . I ~ .......... (IXF/~ne) 7A-l9 ~ ~-C~3 F H - 1,4 ~00-2 C
. . ... . _ _ _ PrCpyl et~r 7~,20 C~2Cl C2H5 ~-C~3 F H ~ 1,4 138-140C
1 ether ~ _ P~Y
7A-21 a2Cl C~ ~-C~ F H C~ 1,4 260-263C
3 3 . ' ~H (T~F/hexane) 7A-22 C ~ iso-C3H7 H ~ H ,C~c~ 4 2a7.5-210C
. ~a (T~F/h~ ne) 7A-23 C~2Cl n-C ~ o-Ca3 F ~ H - -ca 1,4 176-177C
. ..... _ ~ ~l~F~hexzne) .
7A-24 2 1 C ~ ~ H F C~ 1,4 15~-154 ~ I , ~ (q~l?/~ex~ne) : . ...... ... .. .. C2H
. ~A,25 . . ~ . C2 ~ ~ F H ; ~ 1,4 ~239-240.5C .
................. ...... ~...... ~F~e) 7Ar26 2CCOC~3 C2~ ~ H H ,C~ 4 N~M5.R(6C~s,~) . OC~2O), 2.01 . ::.. . . . .......... _ ~s-,3~ COC~3) * ~ias~ ,, `` 1 174667 t~, Compourld Rl ~ R2 ~ R3 ¦

\ /OH
7A-27 CH2Cl C2H5 -CH3 F F C 1,4 195-197C
_ / ~H (THF/hexane) \ /OH
7A-28 CH2CH2Cl C2H5 a-CH3 F H C 1,4 243 245C
/ ~H (THF/hexane) .';',~; _ \/~ _ I 7A-29 CH C2H5 a-CH3 F H C 1,4 258.5-262.5C
3 _ _ / ~H (THF/hexane) 7A-30 CH2CH2Cl iso-C H H H H C 4 188.5-189.5C
3 7 _ / ~H = (THF/hexane) .

7~67 - c The foregoing compounds can be named as follows:
7A-l: chloromethyl 17a-ethoxycarbonylQxy-9a-fluoro-llB-hydroxyandrost-4-en-3-one-17B-carboxylate 7A-2: chloromethyl 17a-ethoxycarbonylQxy-9a-fluoro~
hydroxy-16~-methylandrosta-1,4-dien-3-one-17~-carboxylate 7A-3: chlom methyl 17a-ethoxycarbonyloxy-9a-fluoro-11~-hydroxy-16a-methylandrosta-1,4-dien-3-one-17~-carboxylate 10 7A-4: chloromethyl 17a-ethoxycarbonyloxy-11~-hydroxy-androsta-1,4-dien-3-one-17~-carboxylate 7A-5: chloromethyl 11~-hydroxy-17a-isopropoxycarbonyloxy-androsta-1,4-dien-3-one-17~-carboxylate 7A-6: chloromethyl 17a-ethoxycarbonyloxy-9a-fluoro-11~-hydroxyandrosta-1,4-dien-3-one-17~-carboxylate 7A-7: chloromethyl 9a-fluoro-11~-hydroxy-17a-isopropoxycarbonyloxy-16a-methylandrosta-1,4-dien-3-one-17~-carboxylate 7A-8: chloromethyl 9a-fluoro-11~-hydroxy-17a-isopropoxy-carbonyloXy-16~-methylandrosta-1,4-dien--3-one-17~-carboxylate 7A-9: chloromethyl 11~-hydroxy-17a-isobutoxycarbonyloxy-androst-4-en-3-one-17~-carboxylate 7A-10: chloromethyl 17a-cyclohexyloxycarbonyloxy-11~-hydroxyandrost-4-en-3-one-17~-carboxylate 7A-ll: chloromethyl ll~-hydroxy-17a-propoxycarbonyloxy-androst-4-en-3-one-17~-carboxylate 7A-12: chloromethyl 9a-fluoro-ll~-hydroxy-l6a-methyl-l7a propoxycarbonyloxyandrosta-1,4-dien-3-one-17~-carboxylate 7A-13: methyl 11~-hydroxy-17a-isopropoxycarbonyloxyandrost-4-en-3-one-1.7~-.~arbo~ylate 7A-14: ethoxymethyl 11~-hydro~y-17a-isopropoxycarbonyloxyandrost-4-en-3-one-17~-carboxylate 7A-15: chloromethyl 17-benzyloxycarbonyloxy-llB-hydroxyandrost-4-en-3-one-17~-carboxylate 7A-16: l-chloroethyl 11~-hydroxy-17a-isopropoxycarbonyloxy-: androst-4-en-3-one-17B-carboxylate 7A-17: ethoxycarbonylmethyl 11~-hydro~y-17a-isopropoxy-carbonylQxyandrost-4-en-3-one-17~-carboxylate 1 17~667 7A-18: l-chloroethyl 9a-fluoro-11~-hydroxv-17a-isopropo~ycarbonyloxy-16B-methylandrosta-1,4 -dien-3-one-17B-carbQxylate 7A-~l9: chloromethyl 9a-fluoro-17a-isopropoxycarbonyloxy-16~-methylandrosta-1,4~dien-3,11-dione-17 -carboxylate 7A-20: chloromethyl 9a-fluoro-17a-isopropoxycarbonyloxy-16~-methylandrosta-1,4-dlen-3,11-dione-17 -carboxylate 10 7A-21: chloromethyl 9a-fluoro-11~-hydroxy-17a-methoxycarbonylo~y-16a-methylandrosta-1,4-dien-3-one-17~-carboxylate 7A-22: fluoromethyl llB-hydroxy-17a-isopropoxycarbonyl-oxyandrost-4-en-3-one-17~-carboxylate 15 7A-23: chloromethyl 9a-fluoro-llB-hydroxy-16a-methyl-17a-pentyloxycarbonylo~yandros~a-1,4-dien-3-one-17~-carboxylate 7A-24: chloromethyl 16a,17-di~ethoxycarbonyloxy)-6a-fluoro-ll~-hydroxyandrosta-1,4-dien-3-one-17B-carboxylate 7A-25: fluoromethyl 17a-ethoxycarbonyloxy-9a-fluoro- 11~-hydroxy-16a-methylandrosta-1,4-dien-3-one-17B-carboxylate 7A-26: acetoxymethyi 17a-ethoxycarbonyloxy-11~-hydroxy-androst-4-en-3-one-17B-carboxylate 7A-27: chloromethyl 17a-ethoxycarbonyloxy-6,9a-difluoro-llB-hydroxy-16a-methylandrosta-1,4-dien-3-one-17~-carboxylate 7A-28: 2-chloroethyl 17a-ethoxycarbonyloxy-ga-fluoro-llB
hydroxy-l6a-methylandrosta-l~4-dien-3-one-l7B
carboxylate 7A-29: methyl 17a-ethoxycarbonyloxy-9a-fluoro-11~-hydroxy-16a-methylandrosta-1,4-dien-3-one-17~-carboxylate 7A-30: 2-chloroethyl 17a-isopropoxycarbonyloxy-11~-hydroxy-androst-4-en-3-one-17~-carboxylate f~ ` 1 1746~7`

, Following the gene~al procPdure of ExamDles 3 or 4 and subs~ituting therein the appropriate reactants affords the following compounds:
OR
I

H3C f -~ OCOOR2 ~ R3 .. .. . ... , . , _ . .. .. . ... . . ....
.. . . . .. ... ....

1 17466~ .
.. ~3 ,~ _ - R~ R; _ ~-- ~H ~--. 7B-1 C2H5 2 5 H H . `~ 4 .

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

~,,., ~_ ~mDol~nd Nb. R~ R_ R~ R R_ z 1 ~ _ ~
7B~16 CH2S32CH3 C2~ H F H `,C ~ 4 " .............. .... : : , . ' 7B-17 CH2SCH3 C2H5 B-C~3 F H ,C ~ 1,4-. .......................... . . - . H
7B-18 CH2SO2CH3 C2H5 3 F H ,C~ ~1,4 .

7B~l9 CH2Cl C2H5 H H Cl ,C = O ¦1,4 .
7B-20 2 3 C2H5 H H Cl ~C = O I .1,4 .. : . .
7B-2L CH2902CH3 C2H5 H H Cl ,C = O L,4 . OH
7B-22 CH2SCH3 ~ 5 F H ,C~ 1,4 7B-23 CHzS02CH3 C2H5 1 3 F H ~ ~ ~ 1,4 7B-24 CH2Cl C2H5 I--C~3 F F ~C ~ 1,4 7B-25 CH2SCH3 C2H5 I-C;33 F F ,C~ 1,4 7B~26 2 2 3 C2H5 1 3 F F ,C ~ 1,4.

7D~n CHzCl CZ 5 3 H F ~ ~ 3 L,4 .
7B-28 CH2SCH3 C2H5 H H F ,C~ 1,4 7E-29 CH2S02CH3 C2 5 H F ~C ~ 1,4 ... ....... .. .. . .... .... . . ...... . . . H ..
7B-30 CH2Cl C H ~-CH3 H H ,C = O 1,4 .. . . . ... 2.5 ........ .._ .
7B-31....... C~2CCH3 ... C2H5 ~ 3 H .. H ,C = O . 1,4 .
_ 7B~32 . CzH B-CH H H ~ _ o 1,4 ... . .
- 2.. . ~ 3. I l . ~ , , .

-- 117466~

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

1 17i~667 . Ccm~ound No. Rl I R~ R, R~ R, Z _ ~ ~OH
7E-51 C4Hg CH2CC13 H H H ~C~H 4 OH
7E-52 CH2OON(CZH5)2 C2H5 H H H ,C~ 4 __ _ O~I
7B-53 CH2CON CH3 H _ H ,C~ 4 .

. 7B~54 C6H5 C2H5 H H H ~C ~ 4 . _ OH _ .
7B-55 CH2C6H5 CH3 H H H ~C~H 4 S OE~ .
7B~56 ~ C2H5 H H H `,C~ H 4 OH
7B-57 CH2Cl' ~ H H _ ~C ~ 4 7B~58 CH2Cl CH=CH2 H H H `C ~HH 4 OH
7B-59 CH2Cl CH2CCH3 HH H ~ ~H 4 . . - OH
7B-60 CH2Cl CH2CH2NHCocH3 H H H ,C ~ 4 OH
7B~61 CH2ClCH2cH2ococH3 H H H ,C ~H 4 . _ OH
¦ 7B~62 j 2 3 C2H5 H H H ,C~' 4 '. 1 . .

- ` (~ ` ~ 17466 g7 I a3~ound No ~ j _ _ ~ Z ~

2C~ c 2502C~3 1~ ~ ~¦
7B--64 l CE2Cl CH2~X~3* I ~ H ¦~ ¦ ~C~

* prepared from Example 6B-24 and 6B~25 respectively by reaction with ClC~2I, or from Example 7B-7 by reaction with m-chloroperbenzoic acid.

. .

8~ _ An equivalent quantity of 11~,17-dihydroxy-androst-4-en-3-one-17B-carboxylic acid is s~bstit1lted for the ll~-hydroxy-17a-methoxycarbonyloxyandrost-4-~n-3-one-17~-carboxylic acid starting material employed in Example 3, and the procedure of the first paragraph of that example is substantially repeated. There are thus obtained, as the intermediate salt, sodium llB,17a-dihydroxyandrost-4-en-3-one-17B-carboxylate, and, as the final product, chloromethyl 11~,17a-dihydroxyandrost-4-en-3-one-17~-carboxylate, melting at 184-186C ~recrystallization from tetrahydrofuran-ether-hexane).

An equivalent quantity of llB,17a-dihydro~y-androst-4-en-3-one-17B-carboxylic acid is substituted for the 17a-ethoxycarbonyloxy~ -hydrQxyandrost-4-en-3-one-17B-carboxylic acid starting material employed in Example 4, and the procedure of the first paragraph of that example is substantially repeated. There are thus obtained, as the intermediate salt, soaium 11~,17a-dihydroxyandrost-4-en-3-one-17B-carboxylate, and,as the final product, methylthiomethyl llB,17a-dihydroxyandrost-4-en-3-one-17~-carboxylate.
Substitution of an equi~alent quantity of methylthiomethyl llB,17a-dihydroxyandrost-4-en-3-one-17B-carboxylate for the methylthiomethyl 17a-ethoxycarbonyloxy-ilB-hydroxyandrost-4-en-3-one-17B-carboxylate used in the second paragraph of Example 4 and substantial repetition of the procedure there detailed affords methylsulfonylmethyl llB,17a-dihydroxyanarost-4-en-3-one-17B-carbo~ylate.

- -" 1 174667 ., ~

EXA~D?LE lOA
The procedure of each paragraph of Example 2 is substantially repeated, substituting an equiYalent quantity of each of the following starting materials for the steroids 5 employed therein: chloromethyl 11~ ,17~-dihydroxyandrost-4-en-3-one-17~-carboxylate; and methylthiomethyl 11~, 17~-dihydroxyandrost-4-en-3-one-17 ~carboxylate. The following soft anti-inflammatory agents of formula ~I) are obtained:
0~

~R2 ~5~ "

10o~d No. R, I m.p.
lOA-l CH2Cl CH3 171-173C

10A-2 C~I2Cl C2H5 197-200C~l~/h~ane) , . .
10A-3 C~2SCH3 C2H5 137.5-138C(etherh~re) -4 ~ jC4H9 I 99.5-102C(l~F/h~e) i 1aA-5 CE~2Cl 13 7 183.5-184.5C(~IF/h~e) , _ .
j 10A-6 * CH2Cl iso C~g 1140-141C~?/isopropyl ether) *utilizing isobutyl chloroformate as the alkyl chloroformate reactant ........ ~ .. _ _ . .. _ _ .. . . . . .

.

, I 17466~

C ,9~

EXAMPLE lOB
_ _ The procedure of each paragraph of Example 2 is substantially repeated, substituting an equivalent quantity of each of the following starting materials for the steroids employed therein: methylthiomethyl 11~,17a-dihydroxyandrost-4-en-3-one-17~-carboxylate; and methylsulfonylmethyl 11~,17-dihydroxyandrost-4-en-3-one-17~-carboxylate. The following soft anti-inflammatory agents of formula (I) are obtained.
~Rl HO ~ - OCOR2 H3C l O
~/

0~ J

Co pound No. R~_ lOB-l CH2SCH3 CH3 lOB-2 CH2SCH3 C4Hg _ lOB-3 CH2SCH3 3 7 . , lOB-4 - CH2SO2CH3 CH3 . ._ lOB-5 CH2SO2CH3 C2H5 .
lOB-6 CH2SO2CH3 C4Hg _ .___ ._ . lQB-7 CH2502CH3 i-C3H7 - ~ j 1 17466~
ql Other representatiye speci.es, e.g. compounds of Examples 7A and 7B, can likewise be prepared according to the procedures of Examples 8 throl~gh l0.

The products of Example 2 and Example 6A-4 are each allowed to react, first with. diethylchlorophosphate and then with C~3SNa in chloroform for approximately 6 hours. The following intermediates are obtained in the first step: . 71 10 ~J~,`D`3 R~ R3 R~ ___~ _ CH3 H . H 4 _ _ _ C2H5 H ~ 4 . . _ i C4Hg H _ 4 i-C3H7 H .~ 4 . . a-CH3 F 1,4 1 17~667 ,~

and the ollo~ing compounds of formula ¢I) are obtained in the second step:

H ~ R3~R2 0~

R~ R3 R1 .

C4Hg H H 4 i-C3H7 H 4 ~ _ ~-CH3 F 1,4 ; 5 When the remaining products of Example 6A
and those of Example 6B are treated according to the above procedure, the corresponding compounds of the formula .

~ .
~'.',, , , , 1 17466~
' .1 ~ ~
.. . I
IC~3 ~3C f=o ~ OCOOR2 o~

wherein the various structural parameters represented by R2, R3, R4, R5, Z and the dotted line are identical to those of compounds 6Al-6A3, 6A5-6All, and..6B]..-6B25 of Examples 6A and 6B are obtained.

Chloromethyl 11~, 17-dihydroxyandrost-4-en-3-one-17~-carboxylate (3.01 mol) is dissolved in toluene (100 milliliters) and the solution is cooled to approximately 0C. Phosgene is then bubbled into the solution, while maintaining the reaction mixture at low temperature, until the reaction is complete ~approximately 2 hours). The solvent and excess phosgene are removed by evaporation to leave the crude 17~-chlorocarbonyloxy compound of the formula OC~2Cl I

C

O

. . _ .

.

- 1 17466~
C

9~f ,~ _ The intermediate (0.01 mol) obtained above is then combined with ethanol (0.02 mol) containing 2,6 -dimethylpyridine (0.01 mol) and allowed to react at room temperature for 6 hours. At the end of that time, the desired chloromethyl 17~-ethoxycarbonyloxy-11~-hydroxyandrost-4-en-3-one-17~-carboxylate is isolated from the reaction mixture. The compound melts at 197-200C, after crystallization.
Substitution of an equivalent quantity of

10 methylthiomethyl 11~,17a-dihydroxyandrost-4-en-3-one-17~-carboxylate for the chloromethyl 11~,17a-dihydroxyandrost-4-en-3-one-17~-carboxylate used above and substantial repetition of the foregoing procedure affords methylthio-methyl 17~-ethoxycarbonyloxy-llB-hydroxyandrost-4-en-3-15 one-17~-carboxylate, melting at 133-136C, after crystallization. That compound can then, if desired, be converted to the corresponding sulfonyl or sulfinyl compound as described in Example 4.
Other representative species, e.g., the compounds 20 of Example 3, paragraphs 1, 3, 4 and 5, and the compounds of Examples 7A and 7B can be prepared in li~e manner from reaction of the corresponding 17a-hydroxy 17~-carboxylates with the appropriate alcohols, including, when appropriate, subsequent treatment with m-chloroperoxybenzoic acid as in Example 4.

The procedure of the first paragraph of Example 12 is repeated, except that an equivalent quantity of

11~,17~-dihydroxyandrost-4-en-3-one-17B-carboxylic acid is used in place of the chloromethyl llB,17a-dihydroxyandrost-4-en-3-one-17B-carboxylate. The crude intermediate thus obtained has the formula , . . .
.
~' . .
. .
., :

:

.: ' ..... . .

` `- 1 17466~
~s 9,~ _ OH
I

C=o ~ _ollcl That intermediate is then subjected to the procedure of the second paragraph of Example 12, to afford 17a-ethoxycarbonyloxy-11~-hydroxyandrost-4-en-3-one-17B-carboxylic acid, identical to the product of Example 2, paragraph 2.
The other compounds of Examples 2, 6~and ~æ can be prepared using the same general procedure.

Chloromethyl 1~17a-dihydroXyandrOSt-4-en-3-one-17~-carboxylate (0.02 mol) is combined with diethylcarbonate (0.2 mol) containing 20 mg of p-toluenesulfonic acid. The reaction mixture is maintained at room temperature for 4 hours, then h-eated to about 80 to 85C; the remaining ethanol which forms is removed by distillation under reduced pressure. Obtained as the residue is crude chloromethyl 17a-ethoxycarbonyloxy-llg-hydroxyandrost-4-en-3-one-17B-carboxylate, melting at 197-200C, after crystallization.
Substitution of an equivalent quantity of methylthiomethyl llg,17~-dihydroxyandrost-4-en-3-one-17~-carboxylate for the chloromethyl 11~,17a-dihydroxyandrost-4-en-3-one-17g-carboxylate used above and substantial repetition of the foregoing procedure affords methylthiomethyl 17a-ethoxycarbonyloxy-11~-hydroxyandrost-. . .
, ' ' ' ' . .

:. , ' ., ,'; ' '' ' ' :, . . .
.`, , ~, . .. .

~, ~

1 17466~

4-en-3-one-17~-carboxylate, melting at 133-136C. That compound can then, if desired, be converted to the cor-responding sulfonyl or sulfinyl compound as described in Example 4.
Other representative species, e.g., the com-pounds of Example 3, paragraphs 1, 3; 4 and 5, and the compounds of Examples 7A and 7B, can be prepared in like manner from reaction of the corresponding 17~-hydroxy-17~-carboxylates with the appropriate carbonates of the type R20~0R2 (including, when appropriate, subsequent treatment with m-chloroperoxybenzoic acid as in Example 4).

. _ To a solution of 8.7 grams of 11~,17~-dihydroxy-androst-4-en-3-one-17~-carboxylic acid and 9.6 milliliters of triethylamine in 100 milliliters of dry dichloromethane, is added 10 grams ofethyl chloroformate, dropwise at 0 to 5C. The reaction mixture is gradually allowed to warm to room temperature and the insoluble material is removed by filtration. The filtrate is washed successively with 3% aqueous sodium bicarbonate, 1~
-hydrochloric acid, and water, then is dried over anhydrous magnesium sulfate. The solvent is concentrated under reduced pressure and the residue is crystallized to give 10.5 grams of ethoxycarbonyl 17~-ethoxycarbonyloxy-11~-hydroxyandrost-4-en-3-one-17~-carboxylate, melting at 158-159C.

Following the general method described in Example 15 and substituting therein the appropriate reactants affords the following additional compounds:

:
.

~ i 9 1 1 17466~
~ .

f-~}-OR2 C=O o ~3~
HO ~ - - OCOR2 i3 G~ouna No. R~ _ R~ _ ~ ~Elting point 16-A -C~2C~3 HF H 4 llO-111C (T~F-isopr~Fyl ethe~) _ _ _ .
16-B i~C ~ H H H 4 200-203C
_ . .
16-C -CH2C~2C~3 H _ H 4 142-143~C (TffF) .
.... .. .. . . .

To a solution of 9.8 grams of ethoxycarbonyl 17~
ethoxycarbonyloxy-11~-hydroxyandrost-4-en-3-one-17~-carboxylate in 100 milliliters of tetrahydrofuran and l20 milliliters of ethanol are added 42 milliliters of 5% aqueous sodium bicarbonate. The mixture is stirred at room temperature for about 30 hours and adjusted to pH 2 to 3 by adding lN hydro-chloric acid. The insoluble material is isolated by filtra-tion. Recrystallization from a mixture of tetrahydrofuran and n-hexane gives 6 grams of 17a-ethoxycarbonyloxy-11~-hydroxyandrost-4-en-3-one-17B-carboxylic acid having a melting point of 192-195C.
The compound obtained in Example 2, first paragraph, and the compounds of Example 6A can be prepared, ; following the same procedure as above and substituting therein appropriate reactants.

qg _, 5~

ExAMæLE 18 Following the general method described in Example 17 and substituting therein the appropriate reactants affords the following compounds:

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

.
- . ~' ' ' ' ' ~

.

4~67 - ~

gives 10.; grams of propoxycarbonyl 11~-hydroxy-17a-propoxycarbonyloxyandrost-4-en-3-one-17~-carboxylate, which is dissolved in 40 milliliters of pyridine'. To that solution, 300 milliliters of water are added dropwise over a 1 to 1.5 hour period. The mixture is stirred for one hour and adjusted to pH 2 to 2.5 by adding concentrated ~ydrochloric acid with ice-cooling. The mixture is then extracted with chloroform, washed successively with lN hydrochloric acid and water, and then dried over sodium sulfate. The solvent is concentrated under reduced pressure, and the residue is recrystallized from a mixture of acetone and tetrahydra-furan to give 7.7 grams of 11~-hydroxy-17~-propoxycarbonyloxyandrost-4-en-3-ene-17~-carDoxylic acid, melting at 1~6-157C.

Following the general procedure detailed in Exam le 19, but utilizing the appropriate starting materials and reaction conditions, affords the remaining compounds of Example 6A.

EXAMPLæ 21 Chloromethyl 17a-ethOxycarbonyloxy-9a-fluoro-ll~-hydroxy-16a-methylandrosta-1,4-dien-3-one-17~-carboxylate (2 grams) is dissolved .n anhydrous dichloromethane [200 millil'iters) and pyri~;n;um ~ Qnx~x~ ' mate (3.5 grams) is added at room'temperature, with stirring. ~he resultant mixture is ~tirred for 24 hours, then the solvent is conc~ntrated under reducod pressure at about 10 to 20~C. The residue is subjected to column chromatography on silica gel ~Riesel gel 60), using chloroform as an eluting solvent, followed by recrystallization from a mixture of tetrahydrofuran and 1 1746~

...~.., ~0 isopropyl ether to give chlorome~hyl 17a-ethoxycarbonyloxy-9a-fluoro-16a-methylandrosta-1,4-dien-3,11-dione-L7~-carboxylate, in the yield of 1.7 gr~ms, melting at 138-140C.

By a method similar to that described in Example 21, there is obtained chloromethyl 9-fluoro-17a-isopropoxycarbonyloxy-16~-methylandrosta-1,4-dien-3,11-dione-17B-carboxylate, melting at 200-201C.

Utilizing the general procedure of Example 3, but substituting the appropriate reactantsA therein, affords methyl 17a-~2-chloroethoxyjcarbonyloxy-9a-fluoro-llB-hydroxy-16a-methylandrosta-1,4-dien-3-one-17~-carboxylate. That product, after recrystallization from isopropanol, melts at 223-227C.

In the same general manner as in Example 3, there is obtained 2-chloroethyl 17a-ethoxycarbonyloxy-9~-fluoro-11~-hydroxy-16~-methylandrosta-1,4-dien-3-one-17B-carboxylate. That product, after recrystallization from tetrahydrofuraa-hexane, mel~s at 243-245C.

.

.

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

l 17466~
o ~
--`~3 --N ' C~3 ~3~ ~ 3 i-C3~7 N(C2~5)3 C

C2~5 . H3C~

C2115 N~OCOC~3 C2~5 N(C2~5)3 ' . C2~5 ' . ~

.: - .
- Ointment Compound of formula (I), 0.2% w/w e.g. chloromethyl 17-ethoxycar~onyloxy-ll~-: hydroxyandrost-4-en-3-one-17~-car~oxylate or chloromethyl 11 ~hydroxy-l-.~..isopropoxycar~onyl-oxyandrost-4-en-3-one-17~-carboxylate Liquid paraffin 10.0% ~/w ~hite soft paraffin89.8% w/w ~ . .

.. _ .. . . . _ _ __ . . ,_ . _ __ . __ .. ... _ .. _ . . . _ . . .. . . . . .. . .

... . . .

.

1 17~6 -;

~V~ .
~_ APhthous Ulcer Pellet -Compound of formula (I), . 0.25 mg as above Lactose 69.90 mg Acacia 3.00 mg Magnesium stearate 0.75 mg Retention Enema Compound of formula (I), 0.001% w/v as above Tween 80 0.05% w/v Ethanol 0.015% w/v Propylparaben ~ 0.02~ w/v Methylparaben ~ 0.08% w/v Distilled water q.s. 100 volumes Eye Drops Compound of formula (I), 0.1% w/v as above ~ .
~ Tween 80 ~ 2.5% w/v Ethanol 0.75% w/v Benzalkonium chloride 0.02% w/v Phenyl ethanol 0.25% w/v Sodium chloride 0.60% w/v 20 . Water for injection q.s. 100 volumes ~ ( a ~ mcll k) ; "' ' 1 17466~ -C,, ~tS~

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

.. ..
. . ~

. . , :
:.
~ . ~
, ~ 17466~
I S

Retention Enema Compound of formula (I), 0.001% w/v e.g. chloromethyl llB-hydroxy-17a-isopropoxycarbonyloxy-androsta-1,4-dien-3-one-17~-carboxylate or chloromethyl 9a-fluoro-llB-hydroxy-17a- ~-isopropoxycarbonyloxy-16B-methylandrosta-1,4-dien-3-one-17B-carboxylate Tween 80 ~ 0.05~ w/v Ethanol 0.015% w/v Propylparaben ~ 0.02% w/v Methylparaben 0.08~ w/v Distilled water q.s. 100 volumes .

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

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

r --~ 117466~

SUPPLEMENTARY DISCLOSURE

. E~AMæLE 6C

Following the ge~eral procedure or Example 2 and substituting therei~ the appropriate reactants af_ords the following novel intermediates of the present invention:.
OE~
C=O ' .

Z~OC00~2 ~ ~ 3 o~ ' ' . ' - .

,.~
,~.1 C

~ 174687 ~ t,= ~ t~ ~
C~l X C~ o ,, . ~ ~ o o ~ o U~ C ~ C
E ,~ c~ u~ 0 ~4 0 t`~ 9 - S

~ ~ ~ ' . ~

'~
.

,. , ~; . ' '., ' :
.'', ' .

., ' ' ~, ' '. ', 1 1746~

C C C C ~x ~x' . O ~ O a) O ~ O ~ O ~ O a.a:~ ~~ c~l~ ~.- O ~ ! ~O
. o, U~ ~ ~, CO ~ 0, U~ ~E ~ c ~ c ,~ c , , ~ c U~ ~ o ~ C~ _ ~ ~ C~l ~ ~ E~ ~ E~ ~ E~ ~ E~ ~ E~

_ ~ ~ r_ _ _ ~ C _ _ ~
C~l /~;~ o~,~ o~"~ /~\ o~,~ /~'\

. . .~ .

~ -~ ~5~ ~ 5~

..

. ' , 8--¦ ¦ o K
~ r ~ C
~o = ~ =

S= o_ o ~ ~ ' :' , .

`
. ~

r~~
~ 17~667 The foregoing compounds can be named as follows:
6C-1: 17a-allyloxycarbonyloxy-9a-fluoro-11~-hydroxy-16a-methylandrosta-1,4-dien-3-one-17~-carboxylic acid 6C-2: 17a-n-propoxycarbonyloxy-6a,9a_difluoro-11~-hydroxy-16a-methylandrosta-1,4-dien-3-one-17~-carboxylic acid 6C-3: 17a-isopropoxycarbonyloxy-6a,9a-difluoro-11~-hydroxy-16a-methylandrosta-1,4-dien-3-one-17~-carboxylic acid ///
.~
~t 466~

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

.: .

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

~ ~7~667`

E2A~E 7C

Following the general proceduIe of E~zm~le 3 and cUbstituti~g therein the appropriate reactants ar ords the ~ollowing compounds:

. IRl C=O

: R5 -- ,La~ --r~ ., , 1 17466~

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

~ ~ ~ 5~ 0~ ~
. C~c~
~:~ ~ ~ ~ ~C~
C~ ~ C~

_ .~ _ 1 ~7~667 C~- . ,7_ _ ~_ o ~ U U o ~ ~ o ~
U~ C . C' U " U U~ C C U~ C
~ X u~ ~ ~D ~ ~ X ~ X u~ X
u~ ~ ~ c~ c~ a~ ~ o ~ .
_~5 a~ ~a ~ 5 _1 ~ c c~ -U~ C U~ ~ U~ U~ ~: C`J C U~ C
~r~ r-. S ~ 5 o ~ u~ ~ `* ~
~~ a~ u c~ co _. ~ ~ _ ~
. ~ ' a~ ~ ~ ~ ~ E~ c~ c`l E~

~ -o~ _ _ _ _ o~- o _ 0~"~

~ ~ ~ ~ _ .~ k ~5 _ r~ _ _ 5 5 C~

_ "~ ~ 5 . ~ '~ '~'`1 3'`' ~,~ C5~ 'c~

~ ,~i /~6 ....
;
- . .: .

:

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

-~ 17466~

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

' . ' ~ . .

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

1 ~7466~

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

.~
:. , ' ' . : . . . ' ' 1 17466~

Exam~le 28 To a solution of 3 grams of chloromethyl 113-hydroxy-17a-isopropoxycarbonyloxyandrost-4-en-3-one-l7B-carboxylate in 100 ml of acetonitrile, 7.9 grams (10 times moles) of AgF
is added, and the mixture is stirred at room temperature for

12 days while shading the reaction syste~ from light~
Thereafter the reaction mixture is filtered, and the solid on the filter is fully washed with ethyl acetate. The filtrate and the ethyl acetate solution are combined, and the mix~ure is washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvents are distilled off, giving 2 grams of crude crystalline product.
The product is subjected to preparative thin-layer chromatography ~Silica Gel 60F254, Merc~), using a mix~ure of chloroform and methanol (15:1) as an eluting solvent. Then the product is recrystallized from a mixture of tetrahydrofuran and n-hexane to give 180 mg of fluoromethyl l~ -hydroxy-17~-isopropoxy-carbonyloxyandrost-4-en-3-one-17~-carboxylate as colorless needles, melting at 207.5-210C.

_ ~_ /0~/
;

. ......

... .

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

¦ OCOOR~

~ .

.'` ' ' ' .

~, .

1 174~67.

~,~, C~

C~
c~

/~ / \

.
.
. .
.. `.. - . ~ . . .

.` :

``` l 17466~

The foregoing compounds can be named as follows:

¢ /L~
C 29-1: fluoromethyl 17a-ethoxycarbonyloxy-9- louro--ll~-hydroxy-16-methylandrosta-1,4-dien-3-one-17~-carboxylate 29-2: fluoromethyl 17a-n-propoxycarbonyloxy-9-fluoro-11~-hydroxy-16-methylandrosta-1,4-dien-3-one-17~-carboxylate _ ,~
: a~
; , . . ~

.~ .

Claims (115)

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

1. A process for preparing a compound represented by the formula wherein R1 is a C1-C10 alkyl; Cl-C10 (monohalo or polyhalo)-alkyl; or -CH2COOR6 wherein R6 is C1-C10 alkyl, or R1 is -CH2-Y-(lower alkyl) wherein Y is -S-, SO, SO2 or -O-, or R1 is -CH2-O?R6 wherein R6 is C1-C10 alkyl or phenyl, R2 is C1-C10 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or C1-C10 (monohalo or polyhalo) alkyl, R3 is hydrogen, .alpha.-hydroxy, .beta.-hydroxy, a-methyl, .beta.-methyl, =CH2, or .alpha.- or .beta.-O?OR2 wherein R2 is identical to R2 as defined hereinabove; R4 is hydrogen, fluoro or chloro; R5 is hydrogen, fluoro, chloro or methyl; X is -O- or -S-; Z is carbonyl or .beta.-hydroxymethylene;
and the dotted line in ring A indicates that the 1,2 linkage is saturated or unsaturated; and a pharmaceutically accep-table quaternary ammonium salt of the compound represented by said formula wherein at least one of R1 and R2 is a halo-substituted alkyl group; comprising the steps of (a) reacting a compound represented by the formula wherein R2, R3, R4, R5, Z and the dotted line in ring A are defined as above, and M is alkali metal, alkaline earth metal/2, thallium or NH4 with a compound represented by the formula wherein R1 is defined as above, and wherein R3 is .alpha.- or .beta. --O?OR2 and when R3 is required to be hydroxy selectively hydrolyzing the product obtained, (b)reacting a compound represented by the formula wherein R2, R4, R5, Z and the dotted line in ring A are de-fined as above, and R3" is hydrogen, a-methyl, .beta.-methyl, =CH2 or .alpha.or.beta.- -O?-OR2, with a compound represented by the formula RlXM' wherein Rl and X are as defined above, and M' is hydrogen or M wherein M is as defined above, and wherein R3 is .alpha. or .beta. --O?OR2 and when R3 is required to be hydroxy selectively hydrolyzing th8 product obtained, (c) reacting a compound represented by the formula wherein R1, R4, R5, Z and the dotted line in ring A are defined as above, and R3" is hydrogen, a-methyl, .beta.-methyl, =CH2, .alpha.-OCOCl or .beta.-OCOCl with a compound represented by the formula R2OM' wherein R2 is as defined above, and M' is as defined above, and wherein R3 is .alpha.-or, .beta. -O?OR2 and when R3 is required to be hydroxy selectively hydrolyzing the product obtained, (d) reacting a compound represented by the formula wherein R1, R4, R5, Z and the dotted line in ring A are defined as above, and R3 is hydrogen, .alpha.-methyl, .beta.-methyl, =CH2, .alpha.-OH or .beta.-OH with a compound represented by the formula R2OCOX' or R2O?OR2 wherein R2 is as defined above, and X' is chloro or bromo, and wherein R3 is .alpha.-or .beta. -O?OR2 and when R3 is required to be hydroxy selectively hydrolyzing the product obtained, (e) oxidizing a compound represented by the formula wherein R1, R2, R3, R4, R5, X, Z and the dotted line in ring A
are as defined above, with the proviso that R1 is a sulfur-containing group, (f) reducing a compound represented by the formula wherein R1, R2, R3, R4, R5, X and the dotted line in ring A

are as defined above, or (g) oxidizing a compound represented by the formula wherein Rl, R2, R3, R4, R5, X and the dotted line in ring A are as defined above, and when the quaternary ammonia compound is required, reacting the compound obtained in which at least one of R1 and R2 in a halo substituted alkyl group with a amine or an unsaturated amine.

2. A compound represented by the formula wherein R1 is C1-C10 alkyl; C1-C10 (monohalo or polyhalo)-alkyl; or -CH2COOR6 wherein R6 is C1-C10 alkyl or R1 is -CH2-Y-(lower alkyl) wherein Y is -S-, SO, SO2 or -O-, or R1 is -CH2-O?R6 wherein R6 is C1-C10 alkyl or phenyl, R2 is C1-C10 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or C1-C10 (monohalo or polyhalo) alkyl, R3 is hydrogen, .alpha.-hydroxy, .beta.-hydroxy, .alpha.-methyl, .beta.-methyl, =CH2, or .alpha.- or .beta.-O?OR2 wherein R2 is identical to R2 as defined hereinabove; R4 is hydrogen, fluoro or chloro; R5 is hydrogen, fluoro, chloro or methyl; X is -O- or -S-; Z is carbonyl or .beta.-hydroxymethylene; and the dotted line in ring A
indicates that the 1,2 linkage is saturated or unsaturated;
and a pharmaceutically acceptable quaternary ammonium salt of the compound represented by said formula wherein at least one of R1 and R2 is a halo-substituted alkyl group, whenever prepared by the process or produced by the process as claimed in claim 1, or an obvious chemical equivalent thereof.

3. A process for preparing a compound represented by the formula:

wherein R1, R2, R3, R4, R5, z and the dotted line in ring A
are as defined in claim 1, a pharmaceutically acceptable quaternary ammonium salt thereof, comprising reacting a compound represented by the formula:

wherein R2, R3, R4, R5, Z and the dotted line in ring A are defined as above, and M is alkali metal, alkaline earth metal/2, thallium or NH4 with a compound represented by the formula wherein R1 is defined as above, and W is halogen, and wherein R3 is .alpha.- or .beta. -O?OR2 and when R3 is required to be hydroxy selectively hydrolysing the product obtained, and when required reacting the compound obtained wherein at least one of R1 and R2 is a halo-substituted alkyl group with a tertiary amine or an unsaturated amine.

4. A compound represented by the formula:

wherein R1 is C1-C10 alkyl; C1-C10 (monohalo or polyhalo)alkyl;
or -CH2COOR6 wherein R6 is C1-C10 alkyl, or R1 is -CH2-Y-(lower alkyl) wherein Y is -S- or -O-, or R1 is -CH2-O?R6 wherein R6 is C1-C10 alkyl or phenyl, R2 is C1-C10 alkyl, C3-C8 cyclo-alkyl, phenyl, benzyl or C1-C10 (monohalo or polyhalo)alkyl, R3 is hydrogen, .alpha.-hydroxy, .beta.-hydroxy, .alpha.-methyl, .beta.-methyl, =CH2, or .alpha.- or .beta.-O?OR2 wherein R2 is identical to R2 as defined hereinabove; R4 is hydrogen, fluoro or chloro; R5 is hydrogen, fluoro, chloro or methyl; Z is carbonyl or .beta.-hydroxymethylene;
and the dotted line in ring A indicates that the 1,2 linkage is saturated or unsaturated; and a pharmaceutically acceptable quaternary ammonium salt of the compound represented by said formula wherein at least one of R1 and R2 as a halo-substituted alkyl group; whenever prepared or produced by the process as claimed in claim 3, or an obvious chemical equivalent thereof.

5. A process for preparing a compound represented by the formula:

wherein R1, R2, R3, R4, R5, X, Z and the dotted line in ring A are as defined in claim 1, and a pharmaceutically acceptable quaternary ammonium salt thereof, the process comprising reacting a compound represented by the formula:

wherein R2, R4, R5, Z and the dotted line in ring A are defined as above and R3" is hydrogen, .alpha.-methyl, .beta.-methyl, =CH2 or .alpha.- or .beta. -OC?-OR2, with a compound represented by the formula:

R1XM' wherein R1 and X are as defined above, and M' is hydrogen or M wherein M is as defined in claim 1, and wherein R3 is .alpha.-or .beta. -O?OR2 and when R3 is required to be hydroxy selectively hydro-lyzing the product obtained, and, when required, reacting the compound obtained wherein at least one of R1 and R2 is a halo-substituted alkyl group with a tertiary amine or an unsat-urated amine.

6. A compound represented by the formula:

wherein R1, R2 R3, R4, R5, X, Z and the dotted line in ring A are as defined in claim 1,and a pharmaceutically acceptable quaternary ammonium salt thereof, whenever prepared or produced by the process as claimed in claim 5, or an obvious chemical equivalent thereof.

7. A process for preparing a compound represented by the formula:

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

8. A compound represented by the formula:

wherein R1, R2, R3, R4, R5, X, Z and the dotted line in ring A are as defined in claim 1, and a pharmaceutically acceptable quaternary ammonium salt thereof, whenever prepared or produced by the process as claimed in claim 7, or an obvious chemical equivalent thereof.

9. A process for preparing a compound represented by the formula:

wherein R1, R2, R3, R4, R5, Z and the dotted line in ring A are as defined in claim 1, and a pharmaceutically acceptable quat-ernary ammonium salt thereof, the process comprising reacting a compound represented by the formula:

wherein R1, R4, R5, Z and the dotted line in ring A are defined as above, and R3 is hydrogen, .alpha.-methyl, .beta.-methyl, =CH2 .alpha.-OH or .beta.-OH with a compound represented by the formula:

R2OCOX' or R2O?OR2 wherein R2 is as defined above, and X' is chloro or bromo, and wherein R3 is .alpha.-or .beta. -O?OR2 and when R3 is required to be hydroxy selectively hydrolyzing the product obtained, and, when required, reacting the compound obtained above wherein at least one of R1 and R2 is a halo-substituted alkyl group with a tertiary amine or an unsaturated amine.

10. A compound represented by the formula:

wherein R1, R2, R3, R4, R5, Z and the dotted line in ring A are as defined in claim 1, and a pharmaceutically accpetable quaternary ammonium salt thereof, whenever prepared or produced by the process as claimed in claim 9, or an obvious chemical equivalent thereof.

11. A process for preparing a compound represented by the formula:

wherein R1, R2, R3, R4, R5, X, Z and the dotted line in ring A are as defined in claim 1, with the proviso that R1 is a sulfinyl- or sulfonyl-containing group, the process comprising the step of oxidizing a compound represented by the formula:

wherein R1, R2, R3, R4, R5, X, Z and the dotted line in ring A are as defined above, with the proviso that R1 is a sulfur-containing group.

12. A compound represented by the formula wherein R1, R2, R3, R4, R5, X, Z and the dotted line in ring A are as defined in claim 1, with the proviso that R1 is a sulfinyl- or sulfonyl- containing group, whenever prepared or produced by the process as claimed in claim 11, or an obvious chemical eqivalent thereof.

13. A process for preparing a compound represented by the formula wherein R1, R2, R3, R4, R5, X and the dotted line in ring A are as defined in claim 1, and a pharmaceutically acceptable quaternary ammonium salt thereof, the process comprising reducing a compound represented by the formula:

wherein R1, R2, R3, R4, R5, X and the dotted line in ring A
are as defined above, and, when required, reacting the compound obtained above wherein at least one of R1 and R2 is a halo-substituted alkyl group with a tertiary amine or an unsaturated amine.

14. A compound represented by the formula:

wherein R1, R2, R3, R4, R5, X and the dotted line in ring A
are as defined in claim 1, and a pharmaceutically acceptable quaternary ammonium salt thereof, whenever prepared or produced by the process as claimed in claim 13, or an obvious chemical equivalent thereof.

15. A process for preparing a compound represented by the formula wherein R1, R2, R3, R4, R5, X and the dotted line in ring A are as defined in claim 1, the process comprising the step of oxi-dizing a compound represented by the formula:

wherein R1, R2, R3, R4, R5, X and the dotted line in ring A are as defined above.

16. A compound represented by the formula;

wherein R1, R2, R3, R4, R5, X and the dotted line in ring A
are as defined in claim 1, whenever prepared or produced by the process as claimed in claim 15, or an obvious chemical equivalent thereof.

17. A process as claimed in claim 3, wherein R1 is C1-C6 alkyl; C1-C6 (monohalo or polyhalo)alkyl; -CH2COOR6"
wherein R6' is C1-C6 alkyl; -CH2-Y-(C1-C6 alkyl) wherein Y
is -S- or -O-; or -CH2-O?R6" wherein R6" is C1-C6 alkyl or phenyl; R2 is C1-C6 alkyl; C3-C8 cycloalkyl; phenyl, benzyl or C1-C6 (monohalo or polyhalo)alkyl; R3 is hydrogen; .alpha.-hydroxy;
.alpha.-methyl; .beta.-methyl or .alpha.-O?OR2 wherein R2 is as defined above R4 is hydrogen or fluoro; and R5 is hydrogen or fluoro.

18. A compound of the formula given in claim 4, or a pharmaceutically acceptable quaternary ammonium salt thereof, wherein Z is as in claim 1 and R1, R2, R3, R4 and R5 are as in claim 17, whenever prepared or produced by the process as claimed in claim 17, or an obvious chemical equivalent thereof.

19. A process as claimed in claim 17, wherein Z is .beta.-hydroxymethylene.

20. A compound of the formula given in claim 4, wherein Z is as in claim 19, and R1, R2, R3, R4 and R5 are as in claim 17, or a pharmaceutically acceptable quaternary ammonium salt thereof whenever prepared or produced by the process as claimed in claim 19, or an obvious chemical equivalent thereof.

21. A process as claimed in claim 19, wherein R1 is C1-C6 (monohalo or polyhalo)alkyl.

22. A compound of the formula given in claim 4, wherein R2, R3, R4 and R5 are as in claim 17, Z is .beta.-hydroxymethylene and R1 is as in claim 21, or a pharmaceutically acceptable quaternary ammonium salt thereof, whenever prepared or produced by the process as claimed in claim 21, or an obvious chemical equivalent thereof.

23. A process as claimed in claim 21, wherein R2 is C1-C6 alkyl.

24. A compound of the formula given in claim 4, wherein R3, R4, and R5 are as in claim 17, Z is .beta.-hydroxymethylene, R1 is C1-C6 (monohalo or polyhalo)alkyl and R2 is as in claim 23, whenever prepared or produced by the process as claimed in claim 23, or an obvious chemical equivalent thereof.

25. A process as claimed in claim 21, wherein R2 is C3-C8 cycloalkyl, phenyl, benzyl or C1-C6 (monohalo or poly-halolalkyl.

26. A compound of the formula given in claim 4, wherein R3, R4 and R5 are as in claim 17, Z is .beta. -hydroxymethylene, R1 is C1-C6 (monohalo or polyhalo)alkyl and R2 is as in claim 25, or a pharmaceutically acceptable quaternary ammonium salt thereof, whenever prepared or produced by the process as claimed in claim 25, or an obvious chemical equivalent thereof.

27. A process of claim 23, wherein R4 and R5 are hydrogen.

28. A compound of the formula given in claim 4, wherein R3 is as in claim 17, Z is .beta.-hydxoxymethylene, R1 is C1-C6 (monohalo or polyhalo)alkyl, R2 is C1-C6 alkyl and R4 and R5 are as in claim 27, or a pharmaceutically acceptable quaternary ammonium salt thereof, whenever prepared or produced by the process as claimed in claim 27, or an obvious chemical equivalent thereof.

29. A process of claim 25, wherein R4 and R5 are hydrogen.

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

31. A process as claimed in claim 23, wherein R4 is fluoro and R5 is hydrogen.

32. A compound of the formula given in claim 4, wherein R3 is as in claim 17, Z is .beta.-hydroxymethylene, R1 is C1-C6 tmonohalo or polyhalo)alkyl, R2 is C1-C6 alkyl and R4 and R5 are as in claim 31, or a pharmaceutically acceptable quaternary ammonium salt thereof, whenever prepared or produced by the process as claimed in claim 31, or an obvious chemical equivalent thereof.

33. A process as claimed in claim 25, wherein R4 is fluoro and R5 is hydrogen.

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

35. A process as claimed in claim 31, wherein R3 is .alpha.-methyl or .beta.-methyl.

36. A compound of the formula given in claim 4, wherein Z is .beta.-hydroxymethylene, R1 is C1-C6 (monohalo or polyhalo)alkyl, R2 is C1-C6 alkyl, R4 and R5 are as in claim 31, and R3 is as in claim 35, or a pharmaceutically acceptable quaternary ammonium salt thereof, whenever prepared or produced by the process as claimed in claim 35, or an obvious chemical equivalent thereof.

37. A process as claimed in claim 33, wherein R3 is .alpha.-methyl or .beta.-methyl.

38. A compound of the formula given in claim 4, wherein Z is B-hydroxymethylene, R1 is C1-C6 (monohalo or polyhalo)alkyl, R2 is C3-C8 cycloalkyl, phenyl, benzyl or C1-C6 (monohalo or polyhalo)alkyl, R4 and R5 are as in claim 33, and R3 is as in claim 37, or a pharmaceutically acceptable quaternary ammonium salt thereof, whenever prepared or produced by the process as claimed in claim 37, or an obvious chemical equivalent thereof.

39. A process as claimed in claim 17, wherein Z is carbonyl.

40. A compound of the formula given in claim 4, wherein Z is as in claim 39 and R1, R2, R3, R4 and R5 are as in claim 17, or a pharmaceutically acceptable quaternary ammonium salt thereof, whenever prepared or produced by the process as claimed in claim 39, or an obvious chemical equivalent thereof.

41. A process as claimed in claim 1, in which R1 is a C1-C6 alkyl; C1-C6 (monohalo or polyhalo)alkyl; -CH2COOR6 wherein R6 is C1-C6 alkyl; -CH2-Y-(C1-C6 alkyl) wherein Y is -S-, -SO-, -SO2-, or -O-; or -CH2-O?R6' wherein R6' is C1-C6 alkyl or phenyl; R2 is C1-C6 alkyl, C3-C8 cycloalkyl, phenyl benzyl or C1-C6 (monohalo or polyhalo)alkyl; R3 is hydrogen, .alpha.-hydroxy, .alpha.-methyl, .beta.-methyl or .alpha.-OCR2 wherein R2 is identical to R2 as defined hereinabove; R4 is hydrogen or fluoro; R5 is hydrogen or fluoro; Z is .beta.-hydroxymethylene; and X and the dotted line in ring A are as inclaim 1.

42. A compound of the formula given in claim 4, or a pharmaceutically acceptable quaternary ammonium salt thereof, wherein R1, R2, R3, R4, R5, X, Z and the dotted line in ring A are as in claim 41, whenever prepared or produced by the process as claimed in claim 41, or an obvious chemical equivalent thereof.

43. A processs as claimed in claim 41, in which X
is oxygen; R2 is C1-C6 alkyl, R1 is C1-C6 alkyl, C1-C6 monohalo alkyl CH2-Y(C1-C6) alkyl where Y is as in claim 41.

44. A compound of the formula given in claim 4 or a pharmaceutically acceptable quaternary ammonium salt thereof, wherein X, R1 and R2 are as in calim 43 and R3, R4 and R5 are as in claim 41, whenever prepared or produced by the process as claimed in claim 43, or an obvious chemical equivalent thereof.

45. A process as claimed in claim 43, in which R2 is methyl, ethyl, propyl, or isopropyl, and R1 is C1-C6 alkyl chloromethyl, or CH2Y- methyl where Y is as in claim 43.

46. A compound of the formula given in claim 4 or a pharmaceutically acceptable quaternary ammonium salt thereof wherein R1 and R2 are as in claim 45, X is oxygen, and R3, R4 and R5 are as in claim 41, whenever prepared or produced by the process as claimed in claim 45, or an obvious chemical equivalent thereof.

47. A process as claimed in claim 3, which comprises reacting sodium 11.beta.-hydroxy-17.alpha.-methoxycaxbonyloxyandrost-4-en-3-one-17.alpha.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

48. Chloromethyl 11.beta.-hydroxy-17.alpha.-methoxycarbonyloxyan-drost-4-en-3-one-17.alpha.-carboxylate, whenever prepared or produced by the process as claimed in claim 47, or an obvious chemical equivalent thereof.

49. A process as claimed in claim 3, which comprises reacting sodium 17.alpha.-ethoxycarbonyloxy-11.beta.-hydroxyandrost-4-en-3-one-17.alpha.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

50. Chloromethyl 17.alpha.-ethoxycarbonyloxy-11.beta.-hydroxyand-rost-4-en-3-one-17.alpha.-carboxylate, whenever prepared or produced by the process as claimed in claim 49, or an obvious chemical equivalent thereof.

51. A process as claimed in claim 3, which comprises reacting sodium 17.alpha.-buoxycarbonoyloxy-11.beta.-hydroxyandrost-4-en-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

52. Chloromethyl 17.alpha.-butoxycarbonyloxy-11.beta.-hydroxy-androst-4-en-3-one-17.beta.-caxboxylate, whenever prepared or produced by the process as claimed in claim 51, or an obvious chemical equivalent thereof.

53. A process as claimed in claim 3, which comprises reacting sodium 11.beta.-hydroxy-17.alpha.-isopropoxycarbonyloxyandrost-4-en-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

54. Chloromethyl 11.beta.-hydroxy-17.alpha.-isopropoxycarbonyl-oxyandrost-4-en-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 53, or an obvious chemical equivalent thereof.

55. A process as claimed in claim 3, which comprises acting sodium 17.alpha.-ethoxycarbonyloxy-11.beta.-hydroxyandrosta-1,4-dien-3-one 17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

56. Chloromethyl 17.alpha.-ethoxycarbonyloxy-11.beta.-hydroxyand-rosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 55, or an obvious chemical equivalent thereof.

57. A process as claimed in claim 3, which comprises reacting sodium 11.beta.-hydroxy-17.alpha.-isopropoxycarbonyloxyandrosta-1,4-dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

58. Chloromethyl 11.beta.-hydroxy-17.alpha.-isopropoxycarbonyl-oxyandrosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 57, or an obvious chemical equivalent thereof.

59. A process as claimed in claim 3, which comprises reacting sodium 11.beta.-hydroxy-17.alpha.-isopropoxycarbonyloxyandrosta-1,4-dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

60. 1-Chloroethyl 11.beta.-hydroxy-17.alpha.-isopropoxycarbonyl-oxyandrost-4-en-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 59, or an obvious chemical equivalent thereof.

61. A process as claimed in claim 3, which comprises reacting sodium 17.alpha.-ethoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

62. Chloromethyl 17.alpha.-ethoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.beta.-methylandrosta-1,4-diene-3-One-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 61, or an obvious chemical equivalent thereof.

63. A process as claimed in claim 3, which comprises reacting sodium 9 -fluoro-11 -hydroxy-16 -methyl-17 -propoxycarbonyloxyandrosta-1,4-dien-3-one-17 -carboxylate in hexamethyl phosphoramide with chloromethyl iodide.
64. Chloromethyl 9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methyl-17.alpha.-propoxycarbonyloxyandrosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in

claim 64, or an obvious chemical equivalent thereof.

65. A process as claimed in claim 3, which comprises reacting sodium 17 -ethoxycarbonyloxy-9 -fluoro-11 -hydroxyandrosta-1,4-dien-3-one-17 -carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

66. Chloromethyl 17.alpha.-ethoxycarbonyloxy 9.alpha.-fluoro-11.beta.-hydroxyandrosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 65, or an obvious chemical equivalent thereof.

67. A process as claimed in claim 3, which comprises reacting sodium 17.alpha.-ethoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

68. Chloromethyl 17.alpha.-ethoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-diene-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 67, or an obvlous chemical equivalent thereof.

69. A process as claimed in claim 3, which comprises reacting sodium 9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-isopropoxycarbonyloxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

70. Chloromethyl 9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-isopro-poxycarbonyloxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxyl-ate, whenever prepared or produced by the process as claimed in claim 69, or an obvious chemical equivalent thereof.

71. A prooess as claimed in claim 3, which comprises reacting sodium 9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-isopropoxycarbonyloxy-16.alpha.-methylandrosta-1,4 dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

72. Chloromethyl 9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-isopropoxy-carbonyloxy-16.beta.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 71, or an obvious chemical equivalent thereof.

73. A process as claimed in claim 3, which comprises reacting sodium 9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxycarbonyloxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

74. Chloromethyl 9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxy-carbonoyxloxy-1.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 73, or an obvious chemical equivalent thereof.

75. A process as claimed in claim 3, which comrises reacting sodium 9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-isopropoxycarbonyloxy-16.beta.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with .beta.-chloromethyl iodide.

76. 1-Chloroethyl 9.alpha.r-fluoro-11.beta.-hydroxy-17.alpha.-iso-propoxycarbonyloxy-16.beta.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 75, or an obvious chemical equivalent thereof.

77. A process as claimed in claim 3, which comprises reacting sodium 17.alpha.-ethoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with fluoromethyl iodide.

78. Fluoromethyl 17.alpha.-ethoxycarbonyloxy-9.alpha.fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 77, or an obvious chemical equivalent thereof.

79. A process as claimed in claim 3, which comprises reacting sodium 17.alpha.-chloroethoxy)carboyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-diene-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with methyl iodide.

80. Methyl 17.alpha.-(2-chloroethoxy)carbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 79, or an obvious chemical equivalent thereof.

81. A process as claimed in claim 1, in which R2 is ethyl, R4 is fluorine, z is .beta.-hydroxymethylene, R5 is hydrogen, R3 is .alpha.-methyl, R1 is chloromethyl, X is oxygen and the 1,2 linkage is unsaturated.

82. A process as claimed in claim 3, which comprises reacting sodium 17.alpha.-ethoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate with chloromethyl iodide.

83. Chloromethyl 17.alpha.-ethoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 81 or 82, or an obvious chemical equivalent thereof.

CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE

84. A process as claimed in claim 3, which comprises reacting sodium 17.alpha.-isopropoxycarbonyloxy-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methylandrosta,1,4-dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

85. Chloromethyl 17.alpha.-isopropoxycarbonyloxy-6.alpha.,9.alpha.-di-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxy-late, whenever prepared or produced by the process as claimed in claim 84, or an obvious chemical equivalent thereof.

86. A process as claimed in claim 3, which comprises reacting sodium 17 .alpha.-n-propoxycarbonyloxy-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

87. Chloromethyl 17.alpha.-n-propoxycarbonyloxy-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 86, or an obvious chemical equivalent thereof.

88. A process as claimed in claim 3, which comprises reacting sodium 17.alpha.-ethoxycarbonyloxy-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one 17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

89. Chloromethyl 17.alpha.-ethoxycarbonyloxy-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 88, or an obvious chemical equivalent thereof.

90. A process as claimed in claim 3, which comprises reacting sodium 17.alpha.-n-propoxycarbonyloxy-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17-carboxyalte in hexamethyl phosphoramide with chloromethyl iodide.

91. Chloromethyl 17.alpha.-n-propoxycarbonyloxy-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-caxboxylate, whenever prepared or produced by the process as claimed in claim 90, or an obvious, chemical equivalent thereof.

22. A process as claimed in claim 3, which comprises reacting sodium 17.alpha.-isopropoxycarbonyloxy-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta. carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

93. Chloromethyl 17.alpha.-isopropoxycarbonyl9xy-6a-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 92, or an obvious chemical equivalent thereof.

94. A process as claimed in claim 3, which comprises reacting sodium 17.alpha.-n-propoxycarbonyloxy-11.beta.-hydroxy-androsta-1,4-dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

95. Chloromethyl 17.alpha.-n-propoxycarbonyloxy-11.beta.-hydroxy-androsta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 94, or an obvious chemical equivalent thereof.

96. A process as claimed in claim 3, which comprises reacting sodium 17.alpha.-methoxycarbonyloxy-11.beta.-hydroxy-androsta-1,4-dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

97. Chloromethyl 17.alpha.-methoxycarbonyloxy-11.beta.-hydroxy-androsta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 96, or an obvious chemical equivalent thereof.

98. A process as claimed in claim 3, which comprises reacting sodium 17.alpha.-methoxycarbonyloxy-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl-iodide.

99. Chloromethyl 17.alpha.-methoxycarbonyloxy-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta 1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 98, or an obvious chemical equivalent thereof.

100. A process as claimed in claim 3, which comprises reacting sodium 17.alpha.-methoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

101. Chloromethyl 17.alpha.-methoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydxoxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 100, or an obvious chemical equivalent thereof.

102. A process as claimed in claim 3, which comprises reacting sodium 17.alpha.-n-propoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with chloromethyl iodide.

103. Chloromethyl 17.alpha.-n-propoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.beta.-methylandrosta-1,4-dien-3-on3-17.beta.-carboxylate.
whenever prepared or produced by the process as claimed in claim 102, or an obvious chemical equivalent thereof.

104. A process as claimed in claim 3, which comprises reacting sodium 17.alpha.-n-propoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with fluoromethyl iodide.

105. Fluoromethyl 17.alpha.-n-propoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 104, or an obvious chemical equivalent thereof.

106. A process as claimed in claim 3, which comprises reacting sodium 17.alpha.-isopropoxycarbonyloxy-11.beta.-hydroxy-androsta-1,4-dien-3-one 17 -carbaxylate in hexamethyl phosphoramide with .beta.-chloromethyl iodide.

107. 2-Chloroethyl 17.alpha.-isopropoxycarbonyloxy-11.beta.-hydroxy-androsta-1,4-dien-3-one-16.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 106, or an obvious chemical equivalent thereof.

108. A process as claimed in claim 3, which comprises reacting sodium 17.alpha.-(2-chloroethoxy)carbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate in hexamethyl phosphoramide with methyl iodide.

109. Methyl 17.alpha.-(2-chloroethoxy)carbonyloxy09.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 108, or an obvious chemical equivalent thereof.

110. A process as claimed in claim 51, in which the chloromethyl 11.beta.-hydroxy-17.alpha.-isopropoxycarbonyloxyandrost-4-en-3-one-17.beta.-carboxylate obtained is reacted in acetonitrile with silver fluoride at room temperature.

111. Fluoromethyl 11.beta.-hydroxy-17.alpha.-isopropoxy-carbonyl-oxyandrost-4-en-3-one-17.beta.-carboxylate, whenever prepared or pro-duced by the process as claimed in claim 110, or an obvious chemical equivalent thereof.

112. A process as claimed in claim 67, in which the 17.alpha.-ethoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate, obtained is reacted in aceto-nitrile with silver fluoride at room temperature.

113. Fluoromethyl 17.alpha.-ethoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-on3-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 112, or an obvious chemical equivalent thereof.

114. A process as claimed in claim 63, in which the 17.alpha.-n-propoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate obtained is reacted in aceto -nitrile with silver fluoride at room temperature.

115. Fluoromethyl 17.alpha.-n-propoxycarbonyloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17.beta.-carboxylate, whenever prepared or produced by the process as claimed in claim 114, or an obvious chemical equivalent thereof.