GB2079755A - Androstene 17 alpha -carbonate 17 beta -carboxylates (and carbothioates) - Google Patents

Abstract

Novel anti-inflammatory agents based on a glucocortico-steroid structure having a general formula I <IMAGE> the groups R1 to R5, and Z being defined; X is O or S. One example is based on the inactive metabolite cortienic acid which is activated by the introduction of non-toxic substituents at positions 17 alpha - and 17 beta -.

Description

SPECIFICATiON Soft steroids having anti-inflammatory activity Technical Field of the Invention: The invention relates to novel soft steriods having anti-inflammatory activity, pharmaceutical compositions containing said soft steroids, novel chemical intermediates useful in the preparation of the steroids, and processes for preparing said steriods and intermediates.

Background Art: Successful predictions on a rational basis of the biological activity of compounds leading to new drugs are the main objective of drug designers. This has usually been achieved by considering a known bio-active 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 molecule which have, however, improved therapeutic and/or pharmacokinetic properties.Although "vulnerable" moieties have been identified as the ones whose role is the bioinactivation or metabolic elimination of the drug after it has performed its role, little or no attention has been paid in the drug-design process 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 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 excreted 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 quite stable structures and that, even if a drug is 95% excreted unchanged, the unaccounted small portion can, and most likely will, cause toxicity.

"Soft 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 predictable 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 advantageously employed to design especially valuable "soft drugs". 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., activation); and designing the metabololism 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., predictable metabolism). The "inactive metabolite" approach further allows controlling the rate of metabolism and pharmacokinetic properties by molecular manipulation in the activation stage.Also, if no useful inactive metabolite is known, one can be designed by the introduction of transporting groups in noncritica: structural parts.

Summary of the Invention: 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 metabolites, cortienic acid, i.e., 11 ss, 1 7a-dihydroxyandrost-4-en-3-one-1 -lP-carboxylic acid, has been used as a starting point and activated by the introduction of suitable non-toxic 1 7a- and 1 7ss-substituents, which activated derivatives will cieave in vivo, after accomplishment of their therapeutic role, to the starting inactive metabolite and other nontoxic moieties.

In accord with the foregoing, the present invention provides novel soft steroids having antiinflammatory activity, said steroids having the structural formula

wherein: R1 is C-C10 alkyl; C2-C1O (monohydroxy or polyhydroxy)aikyl; C1 -C10 (monohalo or polyhalo)alkyl; or -CH2COOR6 wherein R6 is unsubstituted or substituted C,-C10 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl or C2-C10 alkenyl, the substituents being selected from the group consisting of halo, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl,

alkyl) and

alkyl), or R6 is unsubstituted or substituted phenyl or benzyl, the substituents being selected from the group consisting of lower alkyl, lower alkoxy, halo, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(lower alkyl)amino, di(lower alkyl)amino, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl; or R1 is -CH2CONR7R8 wherein R7 and R8, which can be the same or different, are each hydrogen, lower alkyl, C3-C8 cycloalkyl, phenyl or benzyl, or R7 and R8 are combined such that -NR7R8 represents the residue of a saturated monocyclic secondary amine; or R1 is unsubstituted or substituted phenyl or benzyl, the substituents being selected from the group of phenyl and benzyl substituents defined hereinabove with respect to R6; ; or R1 is

(lower alkyl) wherein Y is -S-, -SO-, -SO2- or -O- and Rg is hydrogen, lower alkyl or phenyl, or R9 and the lower alkyl group adjacent to Y are combined so that R, is a cyclic system of the type

-CH- Y alkylene wherein Y is defined as above and the alkylene group contains 3 to 10 carbon atoms, of which at least 3 and no more than 6 are ring atoms; or R, is

wherein R6 is defined as hereinabove and R,o is hydrogen, lower alkyl, phenyl or haloalkyl; R2 is unsubstituted or substituted C,-C10 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl or C2-C10 alkenyl, the substituents being selected from the group consisting of halo, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl,

(C1-Cao alkyl) and

(C1 -C10 alkyl), or R2 is unsubstituted or substituted phenyl or benzyl, the substitutents being selected from the group consisting of lower alkyl, lower alkoxy, halo, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(lower alkyl)amino, di(lower alkyl)amino, mono(lower alkyl)carbamoyl di(lower alkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl;; R3 is hydrogen, a-hydroxy, hydroxy, methyl, methyl, = CH2, or a- or

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-; Zis carbonyl or ,B-hydroxymethylene; and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated.

A group of preferred compounds of formula (I) consists of those 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-, -SO-, -SO2- or -O-; or

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, a-hydroxy, a-methyl, methyl or

wherein R2 is identical to R2 as defined hereinabove; R4 is hydrogen or fluoro; R5 is hydrogen or fluoro; Z is ss-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 intermediates to the compounds of formula (I), e.g., the corresponding compounds wherein R1 is hydrogen, are provided also.

The soft steriods of formula (I) and quaternary ammonium salts thereof are extremely potent local anti-inflammatory agents; however, by virtue of the fact that their facile in 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 minimalor non-existent-systemic activity means that the compounds of the present invention can be used in the local (e.g., topical) treatment of inflammatory conditions without the serious systemic side effects which attend use of the known glucocorticosteroids.

Detailed Description of the Invention and the Preferred Embodiments: 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, alkenyl and alkylene groupings can be straight or branched-chain groups containing the aforementioned number of carbon atoms. Likewise, the alkyl portions of the alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkanoyloxy, haloalkyl, monoalkylamino, dialkylamino, monoalkylcarbamoyl, and dialkylcarbamoyl, 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 therein can contain 1 to 8 carbon atoms.

Specific examples of alkyl radicals encompassed by formula (I), whether as specific values for R1 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 branchedchain higher homologues in the instances where "alkyl" can contain 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, cyclopentenyl and cyclohexenyl.

The alkylene moieties are typified by trimethylene, tetramethylene and the like.

The alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkanoyloxy, monoalkylamino, dialkylamino, monoalkylcarbamoyl and dialkylcarbamoyl groupings are of the type -O-alkyl -S-alkyl -SO-alkyl -502-alkyl

-C-O-alkyl II 0 -O-C-alkyl II 0 -N H-alkyl

alkyl -N alkyl -C-N H-alkyl II 0 and alkyl -C-N 0 alkyl respectively, wherein alkyl is as hereinbefore defined and exemplified.

With respect to the structural variables encompassed by the group of preferred compounds of formula (I) identified hereinabove, the term "C1 -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-buty, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like. In addition, the term "C1 -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 monohaloalkyl and polyhaloalkyl groups include chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1-chloroethyl, 2-chloroethyl, 2,2,2-trichloroethyl, 2,2,2trifluoroethyl, 1,2-dichloroethyl, 1-chloropropyl, 3-chloropropyl, 1-chlorobutyl, 1-chloropentyl, 1chlorohexyl, 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.

When R1 in formula (I) is -CH2CONR7R8 wherein -NR7R8 represents the residue of a saturated monocyclic secondary amine, such monocycles preferably have 5 to 7 ring atoms optionally containing another hetero atom (-0-, -S- or -N-) in addition to the indicated nitrogen atom, and optionally bear one or more substituents such as phenyl, benzyl and methyl.Illustrative of residues of saturated monocyclic secondary amines which are encompassed by the -NR7R8 term are morpholino, 1-pyrrolidinyl, 4-benzyl-1 -piperazinyl, perhydro-1 ,2,4-oxathiazin-4-yl, 1- or 4piperazinyl, 4-methyl-1 -piperazinyl, piperidino, hexamethyleneimino, 4-phenylpiperidino, 2-me thyl-1-pyrazoEidinyl, 1- or 2-pyrazolidinyl, 3-methyl-l -imidazolidinyl, 1- or 3-imidazolidinyl, 4benzylpiperidino and 4-phenyl-1-piperazinyl.

Selected compounds of formula (I), i.e. compounds wherein R1 is a-haloalkyl, readily form the corresponding soft quaternary ammonium salts which are likewise useful as soft anti-inflammatory agents. Thus, for example, the selected 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 reactants are generally used in approximately equimolecular proportions and the reaction is conducted in the presence of an inert solvent (e.g., ether, acetonitrile, CH2CI2 or the like), at a temperature of from room temperature to the reflux temperature of the solvent, 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 70"C 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 expression "unsaturated amine" used above denotes N-heterocyclic unsaturated systems having 3 to 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 illustrate the scope of the defined term: l-Methylazirine

3 l=MdthylPyrrole 6) 1-Methylimida:ole l=Hethylpyrazole

Pyridine

Pyrazine

Pyr imidine

Pyridazine

2-Methylisoindole

3E-indole

Quinoline

Zsoquinoline

Phthalaz ine

Oujnoxaline

Quinazoline

Phenazine

Isotbiazole ::1 10-Methylphenothiazine e Isoxazole

Furazan

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 Nheterocyclic 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 N-substituted derivative of morpholine, pyrrolidine, imidazolidine, pyrazolidine, piperidine or piperazine, wherein the Nsubstituent can be a group such as (C,-C8)alkyl], optionally containing additional substituents such as methyl.

Preferred quaternary ammonium salts include those derived from 1,2-dimethylpyrrolidine, 3acetoxyquinuclidine, 1 -methylpyrrolidine, triethylamine and N-methylimidazole. Especially preferred are the quaternary ammonium salts derived from the reaction of the aforesaid amines with compounds of formula (I) wherein Z is ss-hydroxymethylene and Rains chloromethyl, most especially when R2 is lower alkyl.

While all of the compounds encompassed by formula (I) above essentially satisfy the - objectives of the present invention, nevertheless certain groups of compounds remain preferred.

A "first" group of preferred compounds of formula (I) has been set forth in the Summary of the Invention hereinabove.

Another preferred group of compounds consists of the compounds of formula (I) wherein Z, X, P1 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 R1 and R2 are as defined with respect to the "first" group of preferred compounds set forth hereinabove.

Another preferred group of compounds consists of the 6a- and/or 9a-fluoro and 1 6a- or 1 6ss- methyl congeners of the compounds indicated in the preceding paragraph. Within this group, the compounds wherein Z, X, R1 and R2 are defined as hereinabove and the remaining structural variables are identical to those of fludrocortisone, betamethasone and dexamethasone are particularly preferred, most especially when P1 and R2 are as defined with respect to the "first" group of preferred compounds set forth hereinabove.Other compounds of particular interest within this group are those wherein Z, X, R, and R2 are defined as hereinabove and the remaining structural variables are identical to those of triamcinolone, flumethasone, fluprednisolone or paramethasone, particularly when R, and R2 are as defined with respect to the "first" group of preferred compounds set forth hereinabove. Yet other interesting compounds are those wherein Z, X, R1 and R2 are defined as hereinabove, P3 is

and the remaining structural variables are identical to those of triamcinolone, particularly when R, 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 ss-hydroxymethylene, wherein X is oxygen, wherein R2 is C,-C6 alkyl (particularly methyl, ethyl, propyl or isopropyl), and wherein R, is C,-C6 alkyl, C,-C6 (monohalo)alkyl (particularly chloromethyl) or -CH2-Y (C,-C6 alkyl) wherein Y is defined as hereinabove (particularly when the C,-C6 alkyl group is methyl).

The compounds 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 ss-hydroxymethylene and X is oxygen utilizes steroidal starting materials of the formula

wherein R4, R5 and the dotted line in ring A are defined as before and R3' is hydrogen, a methyl, methyl, a-OH, ssOH or = CH2 (and which can be conveniently prepared by treatment of the corresponding 21 -hydroxypregnenolones of the formula

wherein R4, R5, R3@ and the dotted line in ring A are defined as above with Na 104 in a suitable organic solvent at room or elevated temperature.) According to this process of the invention, a starting material of formula (II) is reacted with R20COCI or R2OCOBr (formed by reacting R2OH with COCI2 or CO Br2, 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). Time and temperature are not critical factors; however, the reaction is conveniently carried out at a temperature between 0 C and room temperature, for about 1 to 6 hours.The resultant novel 1 7fl-carboxylic acid 1 7a-carbonate has the formula

wherein R2, R4, R5 and the dotted line in the A ring are defined as above and R3" is H, a-CH3, ss-CH3, a-OCOOR2, ss-OCOOR2 or = CH2. When R3' in the starting material of formula (II) is a OH or ss-OH, sufficient R2OCOCl or R2OCOBr is generally employed to ensure formation of the carbonate grouping at the 16-position as well as at the 1 7-position [i.e., when R3' in formula (II) is OH, R3" in the resultant intermediate of formula (III) is a- or ss-OCOOR2].

Sometimes, when a compound of formula (I) wherein R2 contains a sulfinyl or sulfonyl grouping is desired, such a grouping is not introduced via the P2OCOCI/P2OCOBr reaction, but is prepared from the corresponding thio-containing R2 derivative at a later stage in the synthetic scheme, as will be discussed in more detail below.

After the above-described introduction of the 1 7a-substituent, the resultant novel intermediate of formula (III) is converted to its corresponding metal salt of the formula

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 NH4+. 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 0 C to room temperature, for 0.5 to 4 hours.Then, the salt of formula (IV) is reacted with a compound of the formula R,-W wherein R1 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 R, grouping into the steroid, e.g., when a compound of formula (I) wherein R, is chloromethyl is desired, it has been found that the reaction proceeds well using hexamethylphosphoramide as the solvent at lower temperatures (0-1 0 C) and employing a R,-W reactant wherein W is iodine (e.g., iodochloromethane).When a non-halogen containing R, grouping is desired (e.g., R1 = alkyl or -CH2COOR6 where R6 is alkyl, etc.), no such restrictions need be placed on the R,-W reactant or on the solvent; thus, W can be any halogen, preferably chloro or bromo, and the usual organic solvents such as dimethylformamide, dichloromethane, acetonitrile, tetrahydrofuran or chloroform can, if desired, be used instead of hexamethylphosphoramide. When a compound of formula (I) wherein R, contains a sulfinyl or sulfonyl grouping is desired, such a grouping is not generally introduced via the R1-W reaction, but is subsequently prepared from the corresponding thio steroid, as described below.

The compounds of formula (I) wherein R, (or R2) 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 R, is

(lower alkyl) [wherein P9 is H, lower alkyl, or combined with the lower alkyl group adjacent to S to form a cyclic system, as described hereinabove] can be reacted with 1 equivalent of nechloroperoxybenzoic acid at 0 -25 C for 1 to 24 hours, in a suitable solvent such as chloroform, to afford the corresponding compound of formula (I) wherein R, is

(lower alkyl), or with 2 equivalents of nschloroperoxybenzoic acid to afford the corresponding compound of formula (I) wherein R1 is

(lower alkyl).

This type of reaction can also be utilised to prepare compounds of formula (I) wherein R, is -CH2COOR6 wherein R6 is substituted alkyl, cycloalkyl, cycloalkenyl, alkenyl, phenyl, or benzyl, wherein the substituent is lower alkylsulfinyl or lower alkylsulfonyl, from the corresponding lower alkylthio-substituted formula (I) steroids; to prepare compounds of formula (I) wherein R1 is lower alkylsulfinyl- or alkylsulfonyl-substituted phenyl or benzyl from the corresponding lower alkylthio-substituted formula (I) steroids; and to prepare compounds of formula (I) wherein R2 is substituted alkyl, cycloalkyl, cycloalkenyl, alkenyl, phenyl or benzyl wherein the substitutent is lower alkylsulfinyl or lower alkylsulfonyl, from the corresponding lower alkylthio-substituted formula (I) steroids.

When the compounds of formula (I) wherein R3 is a- or hydroxy are desired, same can be prepared by partial acid hydrolysis of the corresponding compounds of formula (I) wherein R3 is a- or fl-OCOOR2, in a suitable solvent medium. Use of a mild reagent, e.g., oxalic acid in methanol, is desirable. Alternatively, hydrolysis of the 1 6-carbonate to the 1 6-hydroxy compound could be carried out at an earlier stage in any synthetic scheme described herein after the introduction of the 1 6,1 7-carbonate groupings, e.g., selective hydrolysis of an intermediate of formula (III) having 16 and 1 7 carbonate groupings to the corresponding 1 6-hydroxy 17carbonate, followed by conversion to the corresponding compound of formula (I) as described supra.

Another process for the preparation of the compounds of formula (I) wherein Z is ss- hydroxymethylene and X is oxygen utilizes the same 1 7a-hydroxy-1 7fl-carboxylic acid starting materials of formula (II) as are employed in the synthetic scheme described supra, but involves formation of the 1 7 ss-COOR1 grouping prior to, rather than after, introduction of the 1 7a 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

wherein R3', P4, R5 and M and the dotted line in ring A are defined as above, which is then reacted with R1W wherein R1 and W are defined as above, to afford the corresponding 1 7ss- carboxylate of the formula

wherein R1, R3', R4, R5 and the dotted line in ring A are defined as above, which is in turn reacted with R2OCOCl or R2 OCOBr wherein R2 is defined as above, to afford the corresponding 1 7a-carbonate of formula (I). The various 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).

Likewise, 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 (Ill). Thus, again, when the starting material contains a 1 6-hydroxy group, the 16, 1 7-dicarbonate of formula (I) will be formed which can then be selectively hydrolyzed, if desired, to the corresponding 1 6-hydroxy1 7-carbonate of formula (I). And, again, the compounds of formula (I) in which R1 or R2 is a sulfinyl- or sulfonyl-containing grouping can be conveniently prepared by oxidation of the corresponding thio-containing compounds of formula (I) as detailed hereinabove.Alternatively, the compounds of formula (I) wherein R1 is a sulfinylor sulfonyl-containing group [e.g., when R1 is

(lower alkyl) or

(lower alkyl)] can be prepared by oxidation, preferably with nxchloroperoxybenzoic acid, of the corresponding compounds of formula (VI) in which R1 is a thio-containing group, followed by introduction of the 1 7a-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 sshydroxymethylene and X is oxygen or sulfur, utilizes the 1 7ss-carboxylic acid 1 7a-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

wherein R2, R3", R4, R5 and the dotted line in ring A are defined as above, and then with R1XM' wherein R1 and X are defined as before, and M' is hydrogen or M (M is defined as above), in an insert solvent (e.g., CHCI3, THF, acetonitrile or DMF), at a temperature between about 0 C and the boiling point of the solvent, for 1 to 6 hours, to afford the corresponding compound of formula (I). When using a compound of the formula R1XM' wherein M' is hydrogen, an acid scavenger such as triethylamine is preferably present in the reaction system.The two steps of this process can be very conveniently run in the same solvent, without isolating the acid chloride of formula (Vlil) 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 ss-hydroxymethylene and X is oxygen utilizes the 1 7a-hydroxy-1 7ss-carboxylates of formula (VI) above. According to this process, an intermediate of formula (Vl) is reacted with phosgene, in a suitable organic solvent (e.g., toluene, benzene, CH2Cl2 or acetonitrile) at a low temperature (- 20"C to room temperature, e.g., 0 C), for about 2 hours (or until the reaction is complete).

Evaporation to remove solvent and excess phosgene affords the desired novel 1 7a-chlorocarbonyloxy-1 7ss-carboxylate intermediate of the formula

wherein R1, R4, R5 and the dotted line in ring A are defined as above, R3"' is hydrogen, amethyl, methyl, a-OCOCI, ss-OCOCI 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 1 6-position as well as the 1 7-position [i.e., when R3' in formula (VI) is a-OH or ss-OH, R3"' in the resultant intermediate of formula (VII) is a- or ss-OCOCI]. The intermediate of formula (VII) is then reacted with a compound of the formula R20M' 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 P2OH, 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 R20M', the reaction conditions are described as above for conversion of compound (VII I) to compound (I). When R3"' in the formula (VII) is OCOCI, sufficient R2OM1 is generally utilized to ensure conversion of both the 16- and 1 7a-substituents to OCOOR2 groupings in the final product.And, again, the 1 6-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 1 7a-hydroxy-1 7ss- carboxylic acid starting material of formula (II) can be reacted with phosgene as described above, to afford the 1 7a-chlorocarbonyloxy-1 7fl-carboxylic acid intermediate of the formula

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 (I II) above. The novel intermediate can then be converted to a corresponding compound of formula (I) as described supra. Once again, the 1 6-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 ss- hydroxymethylene and X is oxygen utilizes the 1 7a-hydroxy-1 7ss-carboxylates of formula (VI) above. In accord with this method, and intermediate of formula (Vl) is reacted with an excess amount of a carbonate of the formula

(which can be conveniently prepared by reacting phosgene with 2 equivalents of P2OH) in the presence of an acid catalyst, to afford the corresponding compound of formula (I).Depending on the nature of the R2 grouping, the

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 hydrocarbon such as dichloromethane or chloroform).And, again, the 1 6-hydroxy and the sulfinyl and sulfonyl compound of formula (I) can conveniently be prepared as a final step in the process, although the intermediate of formula (VI) in which R1 contains a sulfur atom could be first oxidized, and the resultant sulfinyl of sulfonyl compound of formula (VI) then reacted with

Other procedures for the preparation of selected compounds of formula (I) will be apparent to those skilled in the art. By way of example, a compound of formula (I) wherein R, or R2 is halosubstituted can be subjected to a halogen exchange reaction in order to replace the halogen with a different halogen according to the order of reactivity CI < Br < l. For example, reacting a chloroalkyl 1 7ss-carboxylate of formula (I) with an alkali metal iodide, e.g., sodium iodide, will afford the corresponding iodoalkyl 1 7ss-carboxylate.Similarly, a bromide salt (e.g., lithium bromide) can be reacted with a chloroalkyl 1 7ss-carboxylate to give the corresponding bromoalkyl 1 7fl-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 1 7fl-carboxylate or an iodoalkyl 1 7fl-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 R1 is fluoromethyl or fluoroethyl.

The 21-hydroxypregnenolones from which the steroidal starting materials of formula (II) are prepared can be obtained commerically or prepared by known methods. Likewise, the nonsteroidal starting materials used in the various processes discussed above are commercially available or can be prepared by known chemical procedures.

Also, a starting material of formula (II) above can be reacted with a compound of the formula R2OCOCI or P2OCOBr wherein R2 is as defined above, to afford an intermediate of the formula

wherein R2, P R3", R4, P5 and the dotted line in ring 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 (XI). This reaction of a starting material of formula (II) with R2OCOCI or P2OCOBr can be carried out under the same conditions as the reaction of a compound of formula (II) with R20COCI or P2OCOBr as described hereinabove, except that R2OCOCI or R2OCOBr is usedin 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 (Xl) can be carried out in an inert solvent in the presence of a catalyst.Examples 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 amines such as diethylamine, dimethylamine or the like; and 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.The reaction is usually carried out a temperature of from about 0 to 100 C, preferably at room temperature to 50 C, for 1 to 48 hours, preferably for 2 to 5 hours.

In yet another aspect, the present invention provides novel compounds of the formula

wherein R1, R2, R3, R4, R5, X and the dotted line in ring A are as defined with respect to formula (I) above. The 11 -keto compounds of formula (IX) can be prepared by the procedures described hereinabove for the preparation of the corresponding 1 lfl-hydroxy compounds of formula (I).

Thus, a starting material corresponding to formula (II) but having an 11-keto group is reacted with R2OCOCl or R2OCOBr, to afford the corresponding novel intermediate corresponding to formula (III) but having an 11-keto group; that intermediate is then converted to its metal salt, which corresponds to formula (IV) except for the presence of an 1 1-keto instead of an 1 11ss- hydroxy group; and the metal salt is then reacted with R1W to afford the corresponding compound of formula (IX). All reaction conditions are as previously 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 R1 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 used for the corresponding compounds of formula (I). Further, all of the above described alternative processes for the preparation of the compounds of formula (I) are equally applicable to the preparation of the compounds of formula (IX) by simply substituting the 11-oxo starting material for the corresponding 11ss-hydroxy steroids used therein, e.g., replacing the 11-hydroxy group in formulas (V), (VI), (VII), (VIII), (X) and (XI) with an 11-oxo group and otherwise proceeding as described hereinabove for the reactions (II)#(V)#(VI)#(I); (III)#(VIII)#(I); (VI)#(VII)#(I); (II)#(X)#(I); (VI)#(I), etc.

Also, the compounds of formula (IX) can be prepared by reacting the corresponding compounds of formula (I) with an oxidizing agent. The oxidation of a 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 example, water, an organic acid (e.g. formic acid, acetic acid, trifluoroacetic acid), an alcohol (e.g. methanol, ethanol), a halogenated hydrocarbon (e.g. chloroform, dichloromethane), or the like.The oxidizing agent may also be any conventional agent which is effective for oxidizing a hydroxy group to a carbonyl group, for example, pyridinium chlorochromate, chromium trioxide in pyridine, hydrogen peroxide, dichromic acid, dichromates (e.g. sodium dichromate, potassium dichromate), permanganic acid, permanganates (e.g. sodium permanganate, potassium permanganate) or the like. The oxidizing 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 40 C, 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 1 11ss-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 11-oxo group to an a 1 lfl-hydroxy group without modifying the remainder of the steroidal starting material. Typically, microbiological reduction is advantageous 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 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 1 11ss- 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 sshydroxymethylene, namely corresponding 11-keto compounds of formula (IX). An especially preferred group of compounds of formula (IX) consists of those wherein X, R1 and R2 are defined as above with respect to formula (I) and the remaining structural 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 prednisone (i.e.R3, R4 and R5 are each hydrogen and the 1 ,2-linkage is unsaturated), or of the 6a- and/or 9a-fluoro and the 1 6a- or 1 6fl-methyl congeners thereof, particularly when R1 and R2 are as defined with respect to the "first" group of preferred compounds set forth hereinabove. Most especially preferred of these derivatives are those wherein X is oxygen, R2 is C1 -C6 alkyl and R1 is C1-C6 alkyl, C,-C6 (monohalo)alkyl [particularly chloromethyl] or -CH2-Y-(C1-C6 alkyl) [particularly -CH2-Y-CH3].

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 systemic activity/toxicity of the soft steroids of formula (I). In view of this desirable separation of local and systemic activities, the compounds of the invention can be used in the treatment of topical or other localized inflammatory conditions without causing the serious systemic side effects typically exhibited by the known natural and synthetic glucocorticosteroids such as cortisone, hydrocortisone, hydrocortisone 1 7a-butyrate, betamethasone 1 7-valerate, triamcinolone, betamethasone dipropionate and the like.

THYMUS INVOLUTION 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 microliters 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.

TABLE I Effect of topically administered soft steroids and referenca steroids on thymus weight in rats.

Amount of Total Weight Test per Rat (g) Compound Number % Test Applied of mg Thymus #SD Gain Compound ( mol) Rats 100 g Rat Starting Pinal #SD None (Control) -- 8 364#29 48.44 61.42 27#6 Hydrocortisone 0.75 8 274#45 49.44 61.15 24#7 Chloromethyl 0.75 8 347#31 48.06 62.10 29#5 11ss-hydroxy-17&alpha;methoxycarbonyloxyandrost-4-en3-one-17ss-carboxylate Chloromethyl 0.75 7 309#24 45.57 60.60 33#6 17&alpha;-ethoxycarbonyloxy-11sshydroxyandrost4-en-3-one-17sscarboxylate 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 greater 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 equal doses of representative species of the invention are much less significant, indicating those compounds have much less systemic activity than hydrocortisone.

BLANCHING STUDIES McKenzie-type human blanching studies were undertaken to study the blanching effects of a representative test compound of the invention, chloromethyl 1 7a-ethoxycarbonyloxy-1 1fl-hy- droxyandrost-4-en-3-one-1 7ss-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, O.G01 and 0.0003 M concentrations. 50 Microiiter 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 after 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 O.03M.

Further, it was noted that 0.03 M hydrocortisone caused approximately the same degree of blanching as that resulting from use of 0.001 M chloromethyl 1 7a-ethoxyearbonyloxy-1 1ss- hydroxyandrost-4-en-3-one-1 7ss-carboxylate.

EAR EDEMA TEST The test animals were Sprague/Dawley rats weighing approximately 1 50 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.

TABLE II Effect of topically applied soft steroid and reference steroids on ear swelling induced by croton oil.

Test Dosea of Test Inflamed Untreated Compound mg/kg Animals Ear Ear None (Control) 5 75.2#4.5 46.6#1.4 Chloromethyl 17a- 0.3 5 62.2+3.0* 50.8#2.4 ethoxycarbonyloxy 11f3-hydroxyandrost- 1 5 55.0#2.6** 48.4+1.0 4-en-3-one-17sscarboxylate 3 5 52.6+1.8** 51.6#3.2 Hydrocortisone 1 5 50.0+2.3** 52.0#2.5 1 7-butyrate Betamethasone 1 5 55.4+1.2* 50.4F2.0 17-valerate a : calculated values based on application of 50 yl of steroid solution.

b : 50 pl of 5% croton oil/acetone and drugs in 5% croton oil/acetons were applied to the right ear. Ear weight was measured 6 hr after topical application.

*:p < 0.05; "*p < 0.01: Significant difference from control.

TABLE II (continued) Relative Organ Weight Test (mg/100g body wt.) Compound %Increase %Inhibition Thymus Adrenals None (Control) 61.4#8.9 333#15 23.3#1.7 Chloromethyl 17a- 23.3+7.2* 62.1 290:1:25 26.0#2.5 ethoxycarbonyloxy 11ss-hydroxyandrost- 14.0#6.5** 77.2 293#21 18.7#1.4 4-en-3-one-17sscarboxylate 3.7#8.1** 94.0 288#21 20.3#0.8 Hydrocortisone -3.6#3.5** 106.0 303#21 20.2#0.7 17-butyrate Betamethasone 10.9#6.3** 82.2 267#19* 18.9#1.

17-valerate *:p < 0.05; **p < 0.01: Significant difference from control.

As can be seen from Table II above, the representative species of the present invention, namely chloromethyl 17&alpha;-ethoxycarbonyloxy-11ss-hydroxyandrost-4-en-3-one-17ss-carboxylate, substantially inhibited the swelling (and consequent increased weight) of the ear caused by croton oil, i.e., the compound exhibited substantial anti-inflammatory activity. On the other hand, in contrast to the effect caused by betametasone 1 7-valerate, the representative compound of the invention did not significantly decrease the thymus weight as compared to the control, i.e., it did not show a significant degree of systemic activity.

GRANULOMA FORMATION TEST The test compound was dissolved in acetone and aliquots of varying concentrations were injected into cotton pellets. The pellets were dried and then one pellet was implanted beneath the skin of each test rat. Six days later, the animals were sacrificed and the granulation tissue (granuloma) which formed in and around the implanted pellet was removed, dried 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 decrease in thymus weight is indicative of significant systemic activity; conversely, when a test compound does not significantly decrease thymus weight as compared to the control, such is indicative of a lack of (or very minimal) systemic side effects.

The results are tabulated in Tables Ill, IV and V-a and V-b below.

TABLE Ill Effect of locally administered soft steroids and reference steroids on body weight, thymus weight, and granulation tissue formation caused by implantation of cotton pellets in rats.

Dose Number Test (mg/ of Test Body wt.

Compound pellet) Animals gain (g) None (Control) 10 40.5+0.8 Chloromethyl 17a- 0.1 8 36.0#2.8 ethoxycarbonyloxy llI3-hydroxyandrost-4-efl- 0.3 8 33.0#1.3*** 3-one-176-carboxylate 1 8 32.8i0.9*** 3 7 30.7i1.5*** Chloromethyl 11ss- 1 7 33.4+l.3*** hydroxy-17&alpha; ;-methoxy- carbonyloxyandrost-4 en-3-one-176-carboxylate Hyarocortisone 1 8 33.4#1,4*** 17-butyrate 3 8 15.9#1,4*** 10 8 4.9+1.0*** Betamethasone 1 B 16.6#1.9*** 17-valerate 3 8 14.9+1.7*** 10 8 17.0+2.1*** **+,p < 0.01 (Mean + S.E.) TAELE III Continued Effect of locally administered soft steroids and referende steroids on body weight, thymus weight and granulation tissue formation caused by implantation or cotton pellets in rats.

Granulation tissue Relative organ weight mg/100g Dry wt. body wt, (Decrease %) Test (mg/100g Inhibition Compound body wt.) (%) Thymus Adrenals Mone (Control) 43.7#4.2 326#22 23.7#1.1 Chloromethyl 17&alpha;- 34.7#4.3 20.5 282#13 22.9#2.6 ethoxycarbonyloxy- (13.5) (3.4) 11ss-hydroxyandrost-4-en- 25.3#2.3** 42.1 298#16 22.8#1.0 3-one-17ss-carboxylate (8.6) (3.8) 14.0#1.8*** 68.0 304#10 21.8#1.3 (6.7) (8.0) 18.7#2.3*** 57.2 278#21 19.6#1.1* (14.7) (17.3) Chloromethyl 11ss- 24.6#2.6** 43.7 213#15** 19.1#1.1** hydroxy-17&alpha;;-methoxy- (33.1) (19.4) carbonyloxyandrost-4an-3-one-17ss-carboxylate Hydrocortisone 32.2#5.0 26.3 73#5 *** 27.1#1.4 17-butyrate (77.6) (-14.3) 21.6#2.2** 50.6 47#3 *** 16.5#1.2*** (85.6) (30.4) 29.2#3.1* 33.2 32#3 *** 16.8#1.2*** (90.2) (29.1) Betamethasone 35.4#7.3 19.0 47#2 *** 15.5#1.3*** 17-valerate (85.6) (34.6) 31.6#2.1* 27.7 38#3 *** 13.6#0.9*** (88.3) (42.6) 40.7#2.6 6.9 43#4 *** 12.6#0.9*** (86.8) (46.8) *,p < 0.05, **, p < 0.01, ***,p < 0.001. (mean#S.E.) TABLE IV Effect of locally daministered sotf steroids and reference steroids on body weight, thymus weight and granulation tissue formation caused by implantation of cotton pellets in rats.

Dose Number of Body wt.

Test Compound ( g/pellet) Test Animals gain (g) None (Control) 10 32.4#1.4 Chloromethyl 11ss-hydroxy- 100 8 34.9#2.7 17&alpha;-isopropoxycarbonyloxy- 300 8 33.9#1.6 androst-4-en-3-one-17ss- 1000 8 34.0#2.6 carboxylate 3000 8 32.4#2.3 Chloromethyl 11ss-hydroxy- 30 8 32.4#1.2 17&alpha;-isopropoxycarbonyloxy- 100 7 35.0#1.5 androsta-1,4-dien-3-one- 300 8 34.4#1.1 17ss-carboxylate 1000 8 29.4#1.5 Chloromethyl 17&alpha;-ethoxy- 0.3 8 32.4#1.1 carbonyloxy-9&alpha;-fluoro-11ss- 1 8 37.3#1.5* hydroxy-16&alpha;-methylandrosta- 3 8 34.3#1.1 1,4-dien-3-one-17ss-carboxylate 10 8 36.1#1.1 30 8 31.3#1.4 Chloromethyl 9&alpha;-fluoro-11ss- 1 7 33.0#1.7 hydroxy-17&alpha;;-isopropoxy- 3 8 30.4#1.1 carbonyloxy-16ss-methylandrosta- 10 8 33.0#1.5 1,4-dien-3-one-17ss-carboxylate 30 8 31.8#1.7 llydrocortisone 300 6 26.2#1.7* 17-butyrate 1000 6 26.2#1.2** 3000 6 6.7#2.2*** 10000 6 -2.0#2.4*** Betamethasone 100 7 24.9#1.9** 17-valerate 300 8 22.3#1.2*** 1000 7 5.3#1.0*** 3000 8 6.6#1.4*** *,p < 0.05, **,p < 0.01, ***,p < 0.001, (Mean#S.E.) TABLE IV continued Effect of locally administered soft steroids and reference steroids on body weight, thymus weight and granulation tissue formation caused by implantation of cotton pellets in rats.

Granulation tissue Thymus wt.

Wet wt. Inhibition Dry wt. Inhibition mg (Decrease %) Test Compound (mg) (%) (mg) (%) None (Control) 566#28 81.2#6.3 445#20 Chloromethyl 11ss-hydroxy- 485#36 14.3 70.0#6.0 13.8 452#29 17&alpha;-isopropoxycarbonyloxy- 431#20** 23.9 50.9#2.8** 37.3 469#25 androst-4-en-3-one-17ss 305#16*** 46.1 24.1#2.7*** 70.3 464#30 carboxylate 292#7 *** 48.4 20.3#1.3*** 75.0 459#24 Chloromethyl 11ss-hydroxy- 432#15** 23.7 51.0#2.0** 37.2 523#26* 17&alpha;-isopropoxycarbonyloxy- 417#27** 26.3 41.1#5.8*** 49.4 537#31* androsta-1,4-dien-3-one- 369#18*** 34.8 38.1#5.9*** 53.1 525#28* 17ss-carboxylate 289#12*** 48.9 18.5#2.4*** 77.2 423#26 Chloromethyl 17&alpha;-ethoxy- 472#23* 16.6 57.3#5.0* 29.4 492#26 carbonyloxy-9&alpha;-fluoro-11ss- 388#31*** 31.4 36.4#2.4*** 55.2 519#22* hydroxy-16&alpha;;-methylandrosta- 331#11*** 41.5 27.4#2.9*** 66.3 472#16 1,4-dien-3-one-17ss- 313#13*** 44.7 22.1#3.6*** 72.8 521#35 carboxylate 290#10 48.8 20.4#2.4*** 74.9 505#26 Chloromethyl 9&alpha;-fluoro-11ss- 423#19** 25.3 44.4#5.4*** 45.3 526#30* hydroxy-17&alpha;-isopropoxy- 351#19*** 38.0 26.9#4.4*** 66.9 471#20 carbonyloxy-16ss-methyl- 362#8 *** 36.0 29.9#3.3*** 63.2 474#25 androsta-1,4-dien-3-one- 315#12*** 44.3 19.9#2.3*** 75.5 489#26 17ss-carboxylate Hydrocortisone 333#21*** 41.2 34.0#5.3*** 58.1 353#37* (20.7) 17-butyrate 366#24*** 35.3 35.3#4.2*** 56.5 99#7 *** (77.8) 329#14*** 41.9 28.0#2.7*** 65.5 58#5 *** (87.0) 311#7 *** 45.1 27.2#2.4*** 66.5 46#7 *** (89.7) Betamethasone 400#19*** 29.3 41.1#2.7*** 49.4 364#24* (18.2) 17-valerate 347#15*** 38.7 33.3#3.6*** 59.0 264#29*** (40.7) 363#28*** 35.9 38.1#4.8*** 53.1 77#5 *** (82.7) 374#15*** 33.9 43.0#4.1*** 47.0 63#3 *** (85.8) *, p < 0.05, **, p < 0.01, ***,p < 0.001. (Mean#S.E.) TABLE V -a Effect of locally administered soft steroids and reference steroids on body weight, thymus weight and granulation tissue formation caused by implantation of cotton pellets in rats.

Dose Number of Body wt.

Test Compound (@g/pellet) Test Animals gain (g) None (Control) 10 33.5#1.0 Chloromethyl 17&alpha;-ethoxy- 0.3 8 32.5#1.1 carbonyloxy-9&alpha;-fluoro- 1 8 36.3#0.9 11ss-hydroxy-16ss-methyl- 3 8 33.8#1.3 androsta-1,4-dien-3-one- 10 8 31.1#1.7 17ss-carboxylate Chloromethyl 9&alpha;-fluoro-11ss- 0.3 8 35.6#1.0 hydroxy-16&alpha;-mehyl-17&alpha;;- 1 8 31.9#0.8 propoxycarbonyloxyandrosta- 3 7 34.1#1.9 1,4-dien-3-one-17ss- 10 8 33.1#1.6 carboxylate Betamathasone 10 6 31.8#1.6 17-valerate 30 6 30.8#3.0 100 6 25.7#1.2*** Clobetasol 1 8 33.0#1.2 17-propionate 3 7 24.9#1.8*** 10 8 25.0#2.1** 30 8 24.8#1.1*** 100 8 15.9#1.0*** *, p < 0.05, **,p < 0.01, ***, p < 0.001. (Mean#S.E.) TABLE V-a (continued) Effect of locally administered soft steroids and reference steroids on body welght, thymus weight and granulation tissue formation caused by implantation of cotton pellets in rats, Granulation Tissue Thymus wt.

Wet wt. Inhibition Dry wt. Inhibition mg (Decreas@ %) Test Compound (mg) (%) (mg) (%) None (Control) 525#19 80.1#5.1 495#36 Chloromethyl 17&alpha;-ethoxy- 499#36 5.0 61.8#5.7* 22.8 501#29 carbonyloxy-9&alpha;-fluoro- 437#24* 16.8 57.0#6.2* 28.8 566#31 11ss-hydroxy-16ss-methyl- 422#32* 19.6 47.5#5.0*** 40.7 500#27 androsta-1,4-dlen-3-one- 370#21*** 29.5 34.8#5.5*** 56.6 421#30 17ss-carboxylate Chloromethyl 9&alpha;-fluoro-11ss- 454#27* 13.5 55.1#6.2** 31.2 523#28 hydroxy-16&alpha;-methyl-17&alpha; ;- 415#30** 21.0 42.9#5.1*** 46.4 453#21 propoxycarbonyloxyandrosta- 360#18*** 31.4 29.7#3.2*** 62.9 504#42 '1,4-dien-3-one-17ss- 350#13*** 33.3 28.5#2.8*** 64.4 547#26 carboxylate Betamethasone 375#19*** 28.6 38.5#6.2*** 51.9 479#25 ( 3.2) 17-valerate 412#42* 21.5 46.2#7.4** 42.3 484#23 ( 2.2) 419#20** 20.2 41.0#4.2*** 48.8 378#30* (23.6) Clobetasol 401#29** 23.6 42.0#5.8*** 47.6 478#22 ( 3.4) 17-propionate 402#40** 23.4 43.1#8.9** 46.2 449#21 ( 9.3) 364#25*** 30.7 37.9#6.8*** 52.7 322#22** (34.9) 320#10*** 39.0 25.5#2.1*** 68.2 174#26*** (64.8) 325#12*** 38.1 23.9#3.3*** 70.2 84#3 *** (83.0) *, p < 0.05, **, p < 0.01, ***,p < 0.001. (Mean#S.E.) Table V-b Effect of locally administered soft steroids on body weight, thymus weight and granulation tissue formation caused by implantation of cotton pellets in rats.

Dose Number Body wt. Dry granulation Tissue Thymus wt.

(ug/pellet) of Test gain (g) Inhibition mg mg Test Compound animals % NOne (Control) - 10 28.0#1.5 67.2#3.4 505#22 Chloromethyl 9&alpha;-fluoro-17&alpha; 1 8 28.9#1.1 59.1#5.8 12.1 441#24 -isopropoxycarbonyloxy-16ss 3 8 25.8#0.9 49.4#3.7** 26.5 519#31 -methylandrosta-1,4-dien- 10 7 28.4#0.8 51.1#5.8* 24.0 547#35 3,11-dione-17ss-carboxylate 30 8 27.4#0.9 40.6#3.6*** 39.6 536#24 Chloromethyl 17&alpha;-ethoxy- 1 7 23.7#1.5 55.3#2.6* 17.7 459#41 carbonyloxy-9&alpha;-fluoro-16&alpha;- 3 8 25.6#1.2 51.6#5.9* 38.2 467#21 methylandrosta-1,4-dien- 10 8 26.5#2.5 41.5#4.7*** 38.2 544#31 3,11-dione-17ss-carboxylate 30 8 20.3#0.9** 39.9#3.6*** 40.6 463#24 *, p 0.05, **, p 0.01 ***, p 0.001. (Mean+S.E.) Male Gprangue-Dawley rats, weighting 152-189g (mean body weight 171g), were used.

Cotton pellet weight was 30.1+0.3 mg (number of test animals 30).

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 1 7-butyrate and betamethasone 17valerate. 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 antiinflammatory agents.

Alo 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 ED80,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 1 1-hydroxy-1 7 -isopropoxycarbonyloxyandrost-4-en-3-one 7-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 ED40,s, ED50,s and ED60,s are the dosages required to achieve, respectively, 40%, 50% and 60% reduction in the weight of the granulation tissue.

TABLE VI Relative potencies of soft steroids in the local cotton pellet granuloma assay.

ED401 Relative ED502 Relative ED603 Relative ptoency potency potency Test Compound ( g/pellet) ( g/pellet) ( g/pellet) Chloromethyl 11ss-hydroxy-17&alpha;- 307 460 690 isopropoxycarbonyloxyandrost- 1 1 1 4-en-3-one-17ss-carboxylate (238-394) (360-623) (523-1023) Chloromethyl 11ss-hydroxy-17&alpha;- 47 119 301 isopropoxycarbonyloxyandrosta- 6.5 3.9 2.3 1,4-dien-3-one-17ss-carboxylate (15-85) (60-202) (178-627) Chloromethyl 17&alpha;-ethoxy- 0.47 1.07 2.44 carbonyloxy-9&alpha;-fluoro-11ss 653 430 283 hydroxy-16&alpha;-methylandrosta-1,4- (0.23-0.75) (0.66-1.59) (1.65-3.86) @ dien-3-one-17ss-carboxylate Chloromethyl 9&alpha;-fluoro-11ss 0.25 0.97 3.75 hydroxy-17&alpha;-isopropoxycarbonyloxy- 1228 474 184 16ss-methylandrosta-1,4-dien-3- (0.004-0.886) (0.08-2.31) (1.25-7.68) one-17ss-carboxylate Chloromethyl 17&alpha;-ethoxycarbonyloxy- 2.31 6.45 18.01 9&alpha;;-fluoro-11ss-hydroxy-16ss- 133 71 38 methylandrosta-1,4-dien-3-one- (1.07-6.38) (2.96-44.58), (6.47-393.8) 17ss-carboxylate Chloromethyl 9&alpha;-fluoro-11ss- 0.58 1.20 2.49 hydroxy-16&alpha;-methyl-17&alpha;- 529 383 277 propoxycarbonyloxyandrosta-1,4- (0.20-1.01) (0.67-2.88) (1.37-13.32) dien-3-one-17ss-carboxylate @lydrocortisone - - - - 1015 17-butyrate (724-26866) 0.7 Clobetasol - - > 3 - > 10 17-propionate 1 dose causing 40% inhibition of granulation tissue weight.

2 dose causing 50% inhibition of granulation tissue weight. ( ) = 95% confidence limits 3 dose causing 60% inhibition of granulation tissue weight.

THYMUS INHIBITION TESTING Several further studies were undertaken to determine the effects 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% CMC (carboxymethylcellulose) and injected subcutaneously once daily for three days. On the fifth day (48 hours following the last treatment), 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 Viol, VIII and IX below. The TED40,s, TED50,s (thymolytic 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 1 7-valerate has each been assigned a value of 1, and the potencies of the other compounds are expressed relative thereto. It is evident that the higher the inhibition of thymus activity at a given dose, the more toxic the compound is.

TABLE VII Effects of systemically administered (s.c.) soft steroids and reference steroids on body weight and thy@@@@ weight in rats.

Dose Number of Body weight Thymus Inhibition Test Compound (mg/kg/day) Test Animals gain (g) (mg) (%) None (Control) 9 18.3#0.7 471#21 Chloromethyl 11ss-hydroxy- 3 9 14.7#0.6** 439#18 6.8 17&alpha;-isopropoxycarbonyloxy- 10 10 10.2#0.7*** 386#17** 18.0 androst-4-en-3-one-17ss- 30 10 6.8#2.1*** 291#22*** 38.2 carboxylate 100 10 2.8#1.8*** 185#17*** 60.7 Chloromethyl 11ss-hydroxy- 3 9 9.0#0.9*** 377#16** 20.0 17&alpha;-isopropoxycarbonyl- 10 9 6.2#0.7*** 312#23*** 33.8 oxyandrosta-1,4-dien-3- 30 10 4.8#1.4*** 257#24*** 45.4 one-17ss-carboxylate 100 10 0.3#1.6*** 161#19*** 65.8 Chloromethyl 17&alpha;-ethoxy- 1 10 13.1#1.0*** 428#20 9.1 carbonyloxy-9&alpha;-fluoro- 3 9 12.7#1.4** 412#20 12.5 11ss-hydroxy-16&alpha; ;-methyl- 10 10 9.7#1.3*** 405#21* 14.0 androsta-1,4-dien-3-one- 30 10 4.4#0.7*** 292#15*** 38.0 17ss-carboxylate Hydrocortisone 0.3 10 17.0#0.8 441#27 6.4 17-butyrate 1 10 11.8#0.8*** 323#16*** 31.4 3 10 7.3#0.5*** 166#5 *** 64.8 10 10 -5.0#1.1 *** 65#5 *** 86.2 Betamethasone 0.1 10 15.5#0.9* 362#16*** 23.1 17-valerate 0.3 10 12.4#0.9*** 276#11*** 41.4 1 10 13.0#1.1*** 200#14*** 57.5 3 10 9.9#1.3*** 119#7*** 74.7 *,p < 0.05, **,p < 0.01, ***,p < 0.001 (Mean#S.E.) Male Sprague-Dawley rats, weighting 149-168g, were used.

TABLE VIII Effects of systemically administered (s.c.) soft steroids and reference steroids on body weight and thymus weight in rats.

Dose Number of Body weight Thymus wt. Inhibicion Test Compound (mg/kg/day) Test Animals gain (g) (mg) (%) None (Control) 10 18.9#0.6 550#24 Chloromethyl 17&alpha;-ethoxycarbonyloxy- 10 7 14.2#1.9 533#31 3.1 @9&alpha;-fluoro-11ss-hydroxy-16&alpha;-methylandrosta-1,4-dien-3-one-17sscarboxylate Chloromethyl 9&alpha;-fluoro-11ss-hydroxy- 10 7 2.7#1.9*** 234#31*** 57.5 17&alpha;-isopropoxycarbonyloxy-16&alpha;methylandrosta-1,4-dien-3-one-17sscarboxylate Chloromethyl 9&alpha;-fluoro-11ss-hydroxy- 10 7 5.3#1.4*** 260#26*** 52.7 17&alpha;-isopropoxycarbonyloxy-16ssmthylandrosta-1,4-dien-3-one-17sscarboxylate Chloromehyl 17&alpha;-ethoxycarbonyloxy- 10 7 2.4#1.8*** 266#20*** 51.6 9&alpha;-fluoro-11ss-hydroxy-16ssmethylandrosta-1,4-dien-3-one-17sscarboxylate Chloromethyl 9&alpha;-fluoro-11ss-hydroxy- 10 7 2.7#1.7*** 277#25*** 49.6 16&alpha;-methyl-17&alpha;;-propoxycarbonyloxyandrosta-1,4-dien-3-one-17ss-carboxylate Clobetasol 0.003 8 18.2#0.6 537#28 2.4 17-propionate 0.01 8 15.5#1.1* 498#15 9.5 0.03 8 12.3#1.3** 363#22*** 34.0 0.1 8 -0.4#1.3*** 149#9 *** 72.9 0.3 8 -14.3#1.3*** 63#3 *** 88.5 *,p < 0.05, ** p < 0.01, ***, p < 0.001. (mean#S.E.) Male Sprague-Dawley rats, weighing about 185g (162-209g), were used.

TABLE IX Effects of systemically administered (s.c.) soft steroids on body weight and thymus weight in rats.

Dose Number of Body weight Thymus wt. Decrease Test Compound (mg/kg/day) Test Animals gain (g) (mg) (%) None (Control) 10 21.2#0.9 426#17 Chloromethyl 9&alpha;-fluoro-11ss- 3 7 18.8#1.4 426#19 0.0 hydroxy-17&alpha;-methoxycarbonyloxy- 10 7 13.8#1.6*** 354#8 ** 16.9 16&alpha;-methylandrosta-1,4-dien-3- 30 7 12.0#0.8*** 282#11*** 33.8 one-17ss-carboxylate 100 7 9.8#1.3*** 206#15*** 51.6 Chloromethyl 9&alpha;-fluoro-11ss- 1 7 18.0#1.5 387#23 9.2 hydroxy-16&alpha;-methyl-17&alpha;- 3 7 15.6#1.3** 347#15** 18.5 pentyloxycarbonyloxyandrosta- 10 7 17.4#1.5* 357#22* 16.2 1,4-dien-3-one-17ss-carboxylate 30 7 13.5#1.0*** 335#17** 21.4 *,p < 0.05, **, p < 0.01, ***,p < 0.001 (Mean#S.E.) Male Spraque-Dawley rats, weighing 91-112g, were used.

TABLE X Thymolytic activities of soft steroids administered subcutaneously to rats.

TED Relative TED Relative Compound 40 50 (mg) Potency (mg) Potency Chloromethyl 11ss-hydroxy- 31.0 58.5 17&alpha;-isopropoxycarbonyloxyandrost- 0.01 0.01 4-en-3-one-17ss-carboxylate (23.9-41.9) (43.1-87.1) Chloromethyl 11ss-hydroxy-17&alpha;- 16.2 35.3 isopropoxycarbonyloxyandrosta- 0.02 0.02 1,4-dien-3-one-17ss-carboxylate (11.2-23.2) (24.6-57.5) Chloromethyl 17&alpha;-ethoxycarbonyloxy- 51.5 > 51.5a 9&alpha;-fluoro-11ss-hydroxy-16&alpha;- 0.0058 < 0.011 methylandrosta-1,4-dien-3-one- (26.5-290.0) 17ss-carboxylate Hydrocortisone 1.3 2.0 0.23 0.29 17-butyrate (1.1-1.5) (1.7-2.3) Betamethasone 0.30 0.58 1 1 17-valerate (0.24-0.36) (0.49-0.69) Clobetasol 0.035 0.052 8.6 11.2 17-propionate (0.030-0.039) (0.046-0.059) a Even at a dosage level of 100 mg/kg/day, 50% reduction in thymus weight could not be achieved.

BLANK COTTON PELLET GRANULOMA ASSAY A further test was undertaken to determine the thymolytic activity of a representative species of the invention as compared to betamethasone 1 7-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 containing no test compounds, were sterilized and implanted subcutaneously into the back of each test animal. This day was considered day 0 of implantation. Test compounds suspended in 0.8% polysorbate 80 were administered 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 50"C and weighed (dry granuloma weight). The thymi and final body weights were also recorded. The results are given in Table Xl below.

In the foregoing tests, there was determined the deactivation of representative species of present soft steriods administered intravenously to rats. The ratio between the potencies of the test steroids and betamethasone 1 7-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 17valerate. The test compounds were administered intravenously to rats to check the test compounds also for systemic anti-inflammatory activity as compared to betamethasone 17valerate. The test compounds were found lower in the inhibition of granulation tissue formation and also in the thymus involution activity than betamethasone 1 7-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 betamethasone 17valerate.

TABLE XI @hymolytic activities of test steroids administered intravenously to rats in the 'blank cotton pellet granuloma assay.

Dose Number of Body wt. Dry granuloma Inhibition Thymus wt. Decrease Test Compound (mg/kg/day) Test Animals gain (g) wt. (mg) (%) (mg) (%) None (Control) 7 21.4#1.3 62.7#6.1 422#27 Chloromethyl 17&alpha;- 1 7 14.1#1.4** 50.1#6.9 20.1 373#25 11.6 athoxycarbonyloxy-9&alpha;- 3 6 14.2#1.3** 49.3#5.1 21.4 338#20* 19.9 fluoro-11ss-hydroxy- 10 6 0.3#1.7*** 45.7#4.6 27.1 209#31*** 50.5 16&alpha;;-methylandrosta- 30 6 -18.5#2.3*** 32.7#3.0** 47.8 71#4 *** 83.2 1,4-dien-3-one-17sscarboxylate Betamethasone 0.1 7 14.4#1.6** 49.3#3.9 21.4 305#14** 27.7 17-valerate 0.3 5 12.2#1.1*** 44.4#2.8* 29.2 288#27** 31.8 1 7 12.9#1.1*** 46.1#4.3* 26.5 233#15*** 44.8 3 7 13.0#2.5* 47.3#2.7 24.6 167#22*** 60.4 *,p < 0.05, **,p < 0.01, ***,p < 0.001. (Mean#S.E.) The ED50,s calculated for the local cotton pellet granuloma assay (as shown, for example, in Table VI above) and the TED40,s calculated 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.

TABLE XII Therapeutic Indices of representative species of the invention as compared to prior art steroids.

Relative Relative therapeutic Compound, ED50a TED40b Potency Potency Indexc Chloromethyl 11ss-hydroxy-17&alpha;- 460 1 31.0 1/24 24 isopropoxycarbonyloxyandrost-4- (360-623) (23.9-41.9) en-3-one-17ss-carboxylate Chloromethyl 11ss-hydroxy-17&alpha;- 119 4 16.2 1/12 48 isopropoxycarbonyloxyandrosta- (60-202) (11.2-23.2) 1,4-dien-3-one-17ss-carboxylate Chloromethyl 17&alpha;-ethoxycarbonyloxy- 1.07 450 51.5 1/40 18000 9&alpha;-fluoro-11ss-hydroxy-16&alpha;- (0.66-1.59) (26.5-290.0) methylandrosta-1,4-dien-3-one17ss-carboxylate Chloromethyl 9&alpha;-fluoro-11ss-hydroxy- 2.38 202 46.0 1/36 7270 17&alpha;-methoxycarbonyloxy-16&alpha;;- (1.60-3.78) (36.0-62.1) methylandrosta-1,4-dien-3-one17ss-carboxylate Hydrocortisone 480 1.3 1 1 1 17-butyrate (313-892) (1.1-1.5) @ Betamethasone 100 0.3 4 1 5 17-valerate (0.24-0.36) a for the anti-inflammatory effect in cotton pellet granuloma ( g/pellet) b for the thymus inhibition effect required subcutaneously (mg/kg) c the ratio of the relative potency for the ED50 to the relative potency for the TED40; hydrocortisone 17-butyrate has been assigned a value of one 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 view of their lack of 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 colitis; 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 preparations 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 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 solvent such as propylene glycol or 1,3-butanediol.Thickening 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 be enhanced by incorporation of an aromatic alcohol such as benzyl alcohol, phenylethyl alcohol or phebnoxyethyle alcohol.

Lotions may be formulated with an aqueous or oily base and will in general also include one or more of the following, namely, emulsifyin agents, dispensing agents, suspending agents, thickening agents, solvents, coloring agents and perfumes. Powders may be formed with the aidof 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 may, for example, be formulated as aerosols with the use of a suitablepropellane, e.g., dichlorodifluromethane 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 preparations will generally contain 0.0001 to 2.5%, preferably 0.01 to 0.5%, and will be administered once daily, or as needed.Also, generally speaking, the compounds of the invention can be incorporated into topical and other local compositions formulated substantially as are such presently available types of compositions containing known glucocorticosteroids, at approximately the same (or 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 beclomethasone 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 prepared as a metered-dose aerosol unit containing a representative species of the invention such as ch loromethyl 1 7a-ethoxycarbonyloxy-1 fl-hydroxyandrost-4-en-3-one- 1 7ss-ethoxycarbo- nyloxy-1 1ss-hydroxyandrost-4-en-3-one-1 7ss-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 dichlorodifluoromethane), with oleic acid or other suitable dispersing agent.Each unit typically 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 1 7a-ethoxycarbonyloxy-9a-fluoro-1 1ss-hydroxy-1 6amethylandrosta-1 ,4-dien-3-one-1 7fl-carboxylate, is employed, each unit typically contains 1 milligram of the active ingredient and releases approximately 5 micrograms at each actuation.

Another example of a pharmaceutical composition according to the invention is a foam suitable for treatment of a wide variety of inflammatory anorectal disorders, to be applied anally or perianally, comprising 0. 1% of a compound of formula (I) such as chloromethyl 1 7aethoxycarbonyloxy-1 1ss-hydroxyandrost-4-en-3-one-1 7ss-carboxylate, and 1% of a local anaesthetic such as pramoxine hydrochloride, in a mucoadhesive foam base of propylene glycol, ethoxylated stearyl alcohol, polyoxyethylene-10-stearyl ether, cetyl alcohol, methyl paraben, propyl paraben, triethanolamine, and water, with inert propellents.When a more potent compound of the invention is employed, less active ingredient generally is used, e.g. 0.05% of chloromethyl 9a-fluoro-1 1ss-hydroxy-1 7a-methoxycarbonyloxy-1 6a-methylandrosta- 1 ,4-dien-3 one 1 7fl-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 of the invention such as chloromethyl 1 7a-ethoxycarbonyloxy-1 1ss-hydroxyandrost- 4-en-3-one-1 7ss-carboxylate (or 20 milligrams of a more potent compound of the invention such as chloromethyl 9a-fluoro-1 1 fl-hydrnxy-1 7a-isopropoxycarbonyloxy-1 6fl-methylandrosta-1 4- dien-3-one-1 7ss-carboxylate or chloromethyl 9a-fluoro-1 1ss-hydroxy-1 6a-methyl-1 7a-propoxy-car- bonyloxyandrosta-1 ,4-dien-3-one-1 7ss-carboxylate) together with sodium chloride, polysorbate 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 the invention are illustrated in the examples which follow.

Without further elaboration, 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 examples are to be construed as merely illustrative and not limitative of the remainder of the specification and claims in any way whatsoever.

EXAMPLE 1 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 50 C) 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 of water, separated by filtration, washed with water and dried in vacuo at 50 C for 3 hours.The product, 1 1fl, 1 7a-dihydroxyandrost-4-en-3-one-1 7ss-carboxylic acid (i.e., cortienic acid), melts at 231-234 C, is obtained in approximately 96% yield (13.76 grams), and can be represented by the structural formula

EXAMPLE 2 To a cold solution of 1 11ss, 17&alpha;-dihydroxyandrost-4-en-3-one-17ss-carboxylic acid (5% weight/volume; 1 mol) and triethylamine (4 mol) in dichloromethane is added a 50% (weight/volume) solution of methyl chloroformate (3.9 mol) in dichloromethane. The reaction mixture is allowed to warm to room temperature over a 2 hour period. The triethylamine hydrochloride precipitate which forms is removed by filtration and the filtrate is washed successively with 3% sodium bicarbonate, dilute (- 1%) hydrochloric acid 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 used in the next step (e.g., Example 3 below) or chromatographed and crystallized for analysis. The product, 1 1fl-hydroxy-1 7a-methoxycarbony- loxyandrost-4en-3-one-1 7fl-carboxylic acid, melts at 1 98-204 C after chromatography and crystallization; ir (KBr) 3000-2800 (C-b), 1750, 1735, 1720 (C = 2, 1650, 1640 (C = C-C O)cm-'. The product can be represented by the structural formula

Substitution of an equivalent quantity of ethyl chloroformate for the methyl chloroformate employed above and substantial repetition of the foregoing procedure affords 1 7a-ethoxycarbo- nyloxy-1 1ss-hydroxyandrost-4-en-3-one-1 7ss-carboxylic acid, melting at 192-1 95 C after chromatography and crystallization; ir(KBr) 3500 (11ss-O-H), 3000-2800 (C-H), 1740 (C=O), 1630 (C = C-C = O)cm-1; nmr (CDCl3) .4(1, b, COOH), 5.67(1 ,s,C = CH), 4.43 (1 ,b, CHOH), 4.13 (2, q, J = 7.5Hz, OCH2CH3); Anal. calcd. for C23H32O7: C, 65.69; H, 7.67. Found: C, 65.76; 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 example and substantial repetition of the procedure there detailed affords 1 7a-butoxycarbonyloxy- 11 ss-hydroxyandrost-4-en-3-one- 1 7ss-carboxylic acid. The final product, after crystallization from tetrahydrofuran-hexane, melts at 164-166 C, Similarly, substituting an equivalent amount of isopropyl chloroformate for the methyl chloroformate used in the first paragraph of this example and repeating the procedure there detailled affords 11ss-hydroxy-17&alpha;-isopropoxycarbonyloxyandrost-4-en-3one-17ss-carboxylic acid.

The final product, after crystallization from tetrahydrofuran-hexane, melts at 144.5-146.5 C, EXAMPLE 3 11ss-hydroxy-1 7a-methoxycarbonyloxyandrost-4-en-3-one- 1 7fl-carboxylic acid is combined with an equivalent amount of 1 N sodium hydroxide in methanol and that solution 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 1 1ss-hydroxy-1 7amethoxycarbonyloxyandrost-4-en-3-one-1 7ss-carboxylate, 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 volume with ethyl acetate. The diluted reaction mixture is washed successively with 5% sodium thiosulfate, 3% sodium 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 chloromethyl 1 1sshydroxy-1 7a-methoxycarbonyloxyandrost- 4-en-3-one-1 7ss-carboxylate, melting at 171-1 73'C after crystallization; ir (KBr) 3000-2800 (C-h), 1760, 1748 (C=0), 1650 (C-C-C-O)cm-1; nmr (CDCl3) # 5.67 (s, 1, C=Ch), 5.82, 5.62 (ABq, J = 5.5Hz, 2, OCH2CI), 4.47 (b, 1, CHOH); Anal. 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

Substitution of an equivalent quantity of 1 7a-ethoxycarbonyloxy-1 1fl-hydroxyandrost-4.en-3- one-1 7ss-carboxylic acid for the steroidal acid employed above and substantial repetition of the foregoing procedure affords, as the intermediate salt, sodium 1 7a-ethoxycarbonyloxy-1 1ss- hydroxyandrost-4-en-3-one-1 7ss-carboxylate, and, as the final product, chloromethyl 1 7a-ethoxycarbonyloxy-11ss-hydroxyandrost-4-en-3-one-17ss-carboxylate, melting at 197-200 C after crystallization; ir (KBr) 3600-3200 (O-H), 3000-2800 (C-1), 1763, 1740 (C = O), 1650 (C = C-C = 0) cm-l; nmr (CDCl3)# 5.7 (s, 1, C=CH), 5.81, 5.62 (ABq, J = 5Hz, 2, -OCH2Cl); Anal calcd. for C24H33CI07: C, 61.46; H, 7.09. Found: C, 61.58; H, 7.08.

In a similar manner, substitution of an equivalent quantity of 1 7a-butoxycarbonyloxy-1 1ss- hydroxyandrost-4-en-3-one-1 7ss-carboxylic acid for the steroidal acid employed in the first paragraph of this example and substantial repetition of the procedure there detailed affords, as the intermediate salt, sodium 1 7a-butoxycarbonyloxy-1 1 ss-hydroxyandrost-4-en-3-one-1 7ss-car- boxylate, and, as the final product, chloromethyl 1 7&alpha;-butoxycarbonyloxy-11 fl-hydroxyandrost-4- en-3-one-1 7fl-carboxylate, melting at 98-100 C after crystallization; ir(KBr) 3600-3300 (0-H) 3000-2800 (C-H), 1765 (02C=O), 1735 (OC=O), 1650 (C = C-C = O)cm-1; nmr (CDCl3) #5.80, 85.60 (2, ABq, J = 4.5Hz, -OCH2CI), 5.67 (1, s, C = CH), 4.45 (1, b, CHOH), 4.08 (2, t, J = 6Hz, 02COCH2-CH2); Anal calcd. for C26H37CI07: C, 62.77; H, 7.44; Cl, 7.14. Found: C, 62.88; H, 7.23; Cl, 7.30.

Similarly, substituting an equivalent amount of 11 fl-hydroxy-1 7a-isopropoxycarbonyloxyandrost-4-en-3-one-1 7fl-carboxylic acid for the steroidal acid employed in the first paragraph of this example and substantial repetition of the procedure there detailed affords, as the intermediate salt, sodium 11ss-hydroxy-17&alpha;-isopropoxycarbonyloxyandrost-4-en-3-one-17ss-car- boxylate, and, as the final product, chloromethyl 1 1fl-hydroxy-1 7a-isoprnpoxycarbonyloxyan- drost-4-en-3-one-l 7P-carboxylate, melting at 183.5-184.5 C after recrystallization from tetrahydrofuran-hexane.

In a similar manner, an equivalent quantity of 1 7a-ethoxycarbonyloxy-1 1ss-hydroxyandrost-4- en-3-one-1 7ss-carboxylic acid is substituted for the steroidal acid and an equivalent quantity of butyl chloride is substituted for the chloromethyl 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 1 7a-ethoxycarbonyloxy-1 1 ss-hydroxyandrost-4-en-3-one-1 7fl.carboxylate, and the final product, butyl 1 7a-ethoxycarbonyloxy-1 1 ss-hydroxyandrost-4-en-3-one-1 7ss-carboxylate.The final product after crystallization from acetone melts at 148-149 C; after chromatography and crystallization, ir(KBr) 3600-3200 (O-H), 3000-2800 (C-H), 1750 (2 C=0), 1670 (C-C-C=O)cm-1; nmr (CDCl3) 85.64 (s, 1, -C = CH), 4.46 (b, 1, CHOH), 4.32-4.95 (m, 4, COOCH2CH3+, COOCH2CH2-); Anal. calcd. for C27H4007: C, 67.99; H, 8.39. Found: C, 67.76; H, 7.74.

EXAMPLE 4 1 7a-Ethoxycarbonyloxy-1 1 ss-hydroxyandrost-4-en-3-one-1 7ss-carboxylic acid (3 grams, 7.1 3 mmol) is treated with 7.13 milliliters of 1 M 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 1 7a-ethoxycarbonyloxy- 11 ss-hydroxyandrost-4-en-3-one-1 7ss-car- boxylate, as a yellow powder. The salt is dissolved in 40 milliliters of hexamethylphospheramide and chloromethyl methyl sulfide (2.36 grams, 24.5 mmol) is added slowly. A precipitate 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 volume of 200 milliliters and washed successively 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 1 7a-ethoxycarbonyloxy-1 1ss-hydroxy- androst-4-en-3-one-1 7ss-carboxylate, melting at 133-1 36 C. That product is characterized by the structural formula

To a solution of methylthiomethyl 1 7a-ethoxycarbonyloxy-1 1 ss-hydroxyandrost-4-en-3-one- 1 7fl-carboxylate (0.48 gram, 1 mmol) in 2 milliliters of dichloromethane is added m chloroperoxybenzoic acid (0.4 gram = 0.34 gram of peracid, 2 mmol). An exothermic reaction ensues, which subsides quickly. The reaction mixture is stirred at room temperature for 1 hour.

The precipitate which forms is removed by filtration and the filtrate is concentrated in vacuo to afford, as a white foam, methylsulfonylmethyl 1 7a-ethoxycarbonyloxy-1 1 fl-hydroxyandrost-4-en- 3-one-1 7fl.carboxylate. That product has the structural formula

NMR (CDCI3): 65.07 (s, 2, OCH2SO2), 2.97 (s, 3, SO2CH3).

Repetition of the procedure described in the preceding paragraph, but using only 1 mmol of m-chloroperoxybenzoic acid, affords methylsulfinyl methyl 1 7&alpha;-ethoxycarbonyloxy-11ss-hydroxy- endrost-4-en-3-one-17ss-carboxylate.

EXAMPLE 5A Substitution of an equivalent 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: Starting material Product fludrocortisone 9a-fluoro-1 1ss,1 7a-dihydroxy androst-4-en-3-one-1 7fl- carboxylic acid, m.p. 250-253 C betamethasone 9a-fluoro- 1ss,1 7a-dihydroxy-.

16ss-methylandrosta-1,4-dien 3-one-17ss-carboxylic acid, m.p. 248-249 C dexamethasone 9&alpha;-fluoro-11ss,17&alpha;-dihydroxy-16&alpha;- methylandrosta-1 ,4-dien-3-one 17ss-carboxylic acid, m.p. 275-278.5 C EXAMPLE 5B Substitution of an equivalent 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:

: Starting Material Product cortisone 17&alpha;-hydroxyandrost-4-en-3,11- dione-17ss-carboxylic acid chloroprednisone 6&alpha;-chloro-17&alpha;-hydroxyandrosta- 1,4-dien-3,11-dione-17ss carboxylic acid flumethasone 6a, 9a-difluorn-1 1ss, i 7a-dihydroxy- 1 6a-methylandrosta-1 ,4-dien-3-one 17ss-carboxylic acid fluprednisolone 6&alpha;-fluoro-11ss,17&alpha;-dihydroxy- androsta-1 ,4-dien-3-one-1 7fl- carboxylic acid meprednisone 17&alpha;-hydroxy-16ss-methylandrosta- 1,4-dien-3,11-dione-17ss carboxylic acid methyl prednisolone 11ss,17&alpha;-dihydroxy-6&alpha;;-methyl- androsta-1 ,4-dien-3-one-1 7fl- carboxylic acid paramethasone 6&alpha;-fluoro-11ss,17&alpha;-dihydroxy-16&alpha;- Methylandrosta-1 ,4-dien-3-one 17ss-carboxylic acid prednisolone 1 1ss,1 7a-dihydroxyandrosta-1 ,4 dien-3-one-17ss-carboxylic acid prednisone 1 7&alpha;-hydroxyandrosta-1 ,4-dien 3,11-dione-17ss-carboxylic acid triamcinolone 9&alpha;-fluoro-11ss,16&alpha;-,17&alpha;-trihydroxy- androsta-1 ,4-dien-3-one-1 7fl- carboxylic acid EXAMPLE 6A Following the general procedure of Example 2 and substituting therein the appropriate reactants affords the following novel intermediates of the present invention:

Compound No. R2 R3 R4 R5 Z # m.p.

183-1B40C 6A-1 CH2C6H5 H H H s C/ I 4 183-1840C / (ethanol) ",,011 6A-2 C2H5 H F 8 IC/OII 4 190-l91-C (TIIF/hexane) 6A-3 C2H5 ss-CH3 F H or11 128-129 C H 1,4 (TllP/hexane) 6A-4 C2H5 a-CH3 P H CZ 1,4 143-144.5 C / 11 (TllF/hexane) 6A-5 iso-C3H7 a-cH3 F 8 Cvz 1,4 154. 5-156iC I,a 154.5-1560C "H isa-CaHg H B B )C/011 (TIlF/hexane) 6A-6 iso-C II H II H 4 iEIo-C4B 9 11 Cs 4 125-1260C H (TllF/hexane) ^11 6A-7 iso-C3H7 ss-CH3 p g Cz 1,4 171.5-172.5-C B n-CH7 H II H: k (TIIF/hexane) 6A-8 n C3H7 H 11 H C/ 4 156-157-C 156-157C 11 n-C3H7 (TllF/hexane) 6A-9 n C3H7 a-C113 F H CZ 1 4 157-158iC > TllF/hexane) 6A-10 -Q H H Cs 4 /011 156-157,5-C "H a-3 F H /HzI (ether/hexane) 6A-11 C113 a-CH3 F H 1,4 180-1820C H (ethyl acetate) 6A-12 n-C5H11 a-CH3 F H \ ,OH 1,4 138.5-139.50C C (THF/hexane) H 6A-13 C2H5 -CH3 F F \ 10H 1,4 157-158 C (decomp.) C (THF/hexane) / "H 6A-14 C6H5 a-CH3 F H \ zOH 1,4 246-248"C C6H5 C (THF/hexane) H 6A-15 CH2ClI2Cl a-CH3 F H \ /OH 4 93-940C C (THF/hexane) / "H Compounds 6A-1 to 6A-15 above can be named as follows: 6A-1: 17&alpha;-benzyloxycarbonyloxy-11ss-hydroxyandrost-4-en-3-one-17ss-carboxylic acid 6A-2: 17&alpha;-ethoxycarbonyloxy-9&alpha;-fluoro-11ss-hydroxyandrost-4-en-3-one-17ss-carboxylic acid 6A-3: 17&alpha;-ethoxycarbonyloxy-9&alpha;-fluoro-11ss-hydroxy-16ss-emthylandrosta-1,4-dien-3-one- 1 7ss-carboxylic acid 6A-4: 1 7&alpha;-ethoxycarbonyloxy-9&alpha;-fluoro-11 fl.hydroxy-1 fia-methylandrnsta- 1 ,4-dien-3-one- 1 7ss-carboxylic acid 6A-5: 9a-fluoro-1 1 1ss-hydroxy-1 7a-isopropoxycarbonyloxy-1 6a-methylandrosta-1 ,4-dien-3 one-1 7ss-carboxylic acid 6A-6: 11ss-hydroxy-17&alpha;-isobutoxycarbonyloxyandrost-4-en-3-one-17ss-carboxylic acid 6A-7: 9&alpha;-fluoro-11ss-hydroxy-17&alpha;-isopropoxycarbonyloxy-16ss-emthylandrosta-1,4-dien-3- one-1 7ss-carboxylic acid 6A-8: 11ss-hydroxy-17&alpha;-propoxycarbonyloxyandrost-4-en-3-one-17ss-carboxylic acid 6A-9: 9a-fluoro-1 1 ss-hydroxy-1 6ez-methyl-1 7a-propoxycarbonyloxyandrosta-1 ,4-dien-3-one 17ss-carboxylic acid 6A-10:: 17&alpha;-cyclohexyloxycarbonyloxy-11ss-hydroxyandrost-4-en-3-one-17ss-carboxylic acid 6A-11: 9&alpha;-fluoro-11ss-hydroxy-17&alpha;-methoxycarbonyloxy-16&alpha;-methylandrosta-1,4-dien-3-one- 1 7ss-carboxylic acid 6A-1 2: 1 7&alpha;-n-pentyloxycarbonyloxy-9&alpha;-fluoro-1 1ss-hydroxy-1 6a-methylandrosta-1 ,4-dien-3 one-17ss-carboxylic acid 6A-13: 17&alpha;-ethoxycarbonyloxy-6&alpha;-,9&alpha;-difluoro-11ss-hydroxy-16&alpha;-methylandrosta-1,4-dien-3- one-17ss-carboxylic acid 6A-14: 17&alpha;-phenoxycarbonyloxy-9&alpha;-fluoro-11ss-hydroxy-16&alpha;-methylandrosta-1,4-dien-3-one- 17ss-carboxylic acid 6A-15: : 17&alpha;-(2-chloroethoxycarbonyloxy)-9&alpha;-fluoro-11ss-hydroxy-16&alpha;-methylandrosta-1,4-dien- 3-one-17ss-carboxylic acid EXAMPLE 6B Following the general procedure of Example 2 and substituting therein the appropriate reactants affords the following novel intermediates of the present invention:

Compound No.R2 R3 R4 R5 Z #

6B-1 C2H5 H H H ,'C = 0 4 6B-2 CH3 H H H ,C = 0 4 OH 63-3 CH3 H F H Cs 4 63-4 C2H5 a-CH3 F F s OH 1,4 H OH 63-5 C235 H H F ,C/ 1,4 6B-6 C2H5 B CH3 H H ,'c = 0 1,4 OH 6B-7 CH2CC13 H H H ,Cz 4 63-8 C2H5 a aCR3 H F , > H OH 6B-9. C2H5 H H H " 1,4 "H 68-10 C2H5 H H H ,'C = 0 1,4 Compound No. R2 R3 R4 R5 Z A

OH 63-11 C2H5 a-OCOOC2H5 F H tCasa 1,4 65-12 \/OH CH2Cl a-CE3 P H sCoHH 1,4 H OH 6By13 CH2CH2cl a-CE3 F 3 1,4 H 6By14 C2H5 H H C1 ,C = 1,4 68-15 6B15 C6H5 H H H oC 4 a 6B-16 88 H H 3 OH .3 6B-17 < H H H OH 7 OH 65-18 CH=CH2 H H H A 4 OH 63-1S CH2OCH3 H H H 4 OH 6By20 CH2SCH3 H H H oC 4 OH 63-21 CH2CH2NHcocH3 H H H oC 4 OH 63-22 CH2CH2OCOCH3 H H H 'C"' OH 63-23 C2H5 H H CH3 oCo 1,4 OH 6B24 CH2so2CH3* H H H sCz 4 OH 63-25 CH2SOCH3 * H 3 H ,,'C"' 4 '3 *prepared from 6B-20 by subsequent reaction with m-chloroperbenzoic acid.

EXAMPLE 7A Following the general procedure of Example 3 and substituting therein the appropriate reactants affords the following compounds:

o=oaz. -: --- A in.D. 6 r w 24 7A1 ChC1 ht5 8 F 8 ,CZ 4 22s-229ec ..... , -: ,\ ~ -{59F*) - -r -rCI1,4 12b2210C 7A-2 ChC1 Cffl5 B.< F H a 22 > n1 'H OIZC1 7A-3 C 2C1 C2Hg C2B5 aT F H- ,,,'C"' 1, 230-235eC ~ /a ( ) /CH' 7A4 c,g c~u, 8 a H x 1,4 220.5-223.50C 4 ;R vg H - CE 7 > 5 CE2C1 w3N H H B I 1, 197-1990C H a 7A-6 CNC1 C2H5 H F 8 ,,C% 1,4 245-2480C ~ ~ H ~ (lEF/h2=Q) Q 7A-7 CE2U bC3B7 a F B ,Co 1 4 1S4.1e60C '.3 IDCJS QCij - ' I --- (F/}A::n) CE 7A-8 GI zU iC3 EI7 3 H B 1,4 174-175 . 5C 'H (THF) CE oIC1 i4H9 isrrCqH a H ,Cs 4 14 > 141-C nisaprcpyl et . 7A-10 -C5C1 H H H H 4 148-19-C - s~ e E tisceawl - - hExE' CE 7A-l1 . ... . CZLLQ Jz-Efi K K K. =C/CL 4 191-1820C 'H CR 1,4 2CI- - fizz F H ,C/ . . 1,4 17y176. sec * &commat; E w 7at13 , isot; 8 H H H 4 211.21350C . . . . .3 . ,J,J > ' aF ) 7A-14 al2CC2S5 tec B. B 8 SY 4 137138eC 4 .. ........ ...... .... . .ta , 137-1l0C .a -- -nn%eJEne Cl '.-CH . . . - - H H EI ~ 1L 182-1S30C' 'H '(ethaaol)

id-. d- No. R, ' R, R; 'R' R Z z - m p. 7S,16* zCK3 iso S H H 4 lel-192.S0c nRm . t (EF~=e) P4 .ieaa.. lal I ca tl: . a-. H E . . Pl9Fhse) cH 7R17 c02C2H 1'so-Ck 8 H H ,C 4 *3-*1 (i:s:ii,,1 - - ethaz,) ~ ~ ca 'et:her:) . 7A-lS* lea3 4 oC3B7 ss43 F H ,Co 1,4 167. 5169 ec CHCl 'L (59Fheme) cL a I J w7 3 F 8 sK 1,4 163-164iC CEE X ,ae) - f * 7219 ca2cl C83 F H > 1,4 200-2010C - 3 (s?/m 1 ~ propyl ether 7per20 CC1 C2H5 43 F H > 1,4 U8-1400C (PIP/Fs 1 ether 1,4 26263'C 7An21 cH2,C1 3 i F H , (IEF > ) . CE 7A-22 CNF ie7 EI H z ,c' 4 2O7.52100C (,nF'he"ne) 7A23 ceC1 * < 3 F H 1,4 1 t 4 176-1770C - (HFThexsse) 7A24 CS2C1 3 8 8 F ,C* 1, 4 154 7An24 M2Q cm 83 8 F 1,4 - -7R25 G2F C2z5 aT;3 F H 1,4 29-240.50C . ..... ., . , ~ ~~ ' (Ae) "Cs 7ZZ6 ca2m3 C2Ei5 H H H tS 4 65K. 7C6 (sE, 2) ld5.76(s,L, i . (5,3, oCcE3)

*diastere@mers

Compound RI R2 - R4 R5 Z A m.p.

No.

\ P wOE 7A-27 CH2C1 C2H5 a"CE13 F F C 1, 4 195197 ec / ll (THF/hexane) - ,OH 7A28 H5 CH C1 C2H5 aCH3 F H C 1,4 243-2450C CH2CH2CI C2 CH3 I n (THFlhexane) (THF/hexane) 7A-29 CH3 C2H5 CH3 F H C 'oH 1,4 258.5-262.5 C 3 2 5 C' 'H (THF/hexane) \ wOE 7A-30 CH2CH2Cliso-C3Hj H H H C 4 188.5-189.50C CH2cH2Cl / 'H . (THF/hexane) The foregoing compounds can be named as follows: 7A-1: chloromethyl 1 7a-ethoxycarbonyloxy-9a-fluoro-1 1ss-hydroxyandrost-4-en-3-one-1 7fl- carboxylate 7A-2: chloromethyl 17&alpha;-ethoxycarbonyloxy-9&alpha;-fluoro-11ss-hydroxy-16ss-methylandrosta-1,4- dien-3-one-17ss-carboxylate 7A-3: chloromethyl 17&alpha;-ethoxycarbonyloxy-9&alpha;-fluoro-11ss-hydroxy-16&alpha;-methylandrosta-1,4- dien-3-one-17ss-carboxylate 7A-4: chloromethyl 1 7a-ethoxycarbonyloxy- 11 ss-hydroxy-androsta-1 4-dien-3-one-1 7ss-car- boxylate 7A-5: chloromethyl 11ss-hydroxy-1 7a-isopropoxycarbonyloxy-androsta- 1,4-dien-3-one-l 7ss- carboxylate 7A-6: chloromethyl 17&alpha;-ethoxycarbonyloxy-9&alpha;-fluoro-11ss-hydroxyandrosta-1,4-dien-3-one- 17ss-carboxylate 7A-7: chloromethyl 9&alpha;-fluoro-11ss-hydroxy-17&alpha;-isopropoxycarbonyloxy-16&alpha;-methylandrosta- 1,4-dien-3-one-17ss-carboxylate 7A-8: chloromethyl 9&alpha;-11ss-hydroxy-17&alpha;-isopropoxycarbonyloxy-16ss-methylandrosta- 1,4-dien-3-oen-17ss-carboxylate 7A-9: chloromethyl 11ss-hydroxy-17&alpha;-isobutoxycarbonyloxyandrost-4-en-3-one-17ss-carboxy- late 7A-10: chloromethyl 17&alpha;-cyclohexyloxycarbonyloxy-11ss-hydroxyandrost-4-en-3-one-17ss-car- boxylate 7A-11: chloromethyl 11ss-hydroxy-17&alpha;-propoxycarbonyloxyandrost-4-en-3-one-17ss-carboxy- late 7A-12: chloromethyl 9&alpha;-fluoro-11ss-hydroxy-16&alpha;-methyl-17&alpha;-propoxycarbonyloxyandrosta-1,4- dien-3-one-17ss-carboxylate 7A-13: methyl 11ss-hydroxy-17&alpha;-isopropoxycarbonyloxyandrost-4-en-3-one-17ss-carboxylate 7A-14: ethoxymethyl 11ss-hydroxy-17&alpha;-isopropoxycarbonyloxyandrost-4-en-3-one-17ss-car- boxylate 7A- 1 5: chloromethyl 1 7a-benzyloxycarbonyloxy-1 1 P-hyd roxyan d rost-4-en-3-one- 1 7ss-carboxy- late 7A-16: 1-chloroethyl 11ss-hydroxy-17&alpha;-isopropoxycarbonyloxyandrost-4-en-3-one-17ss-car- boxylate 7A-17: ethoxycarbonylmethyl 11ss-hydroxy-17&alpha;-isopropoxycarbonyloxyandrost-4-en-3-one- 17ss-carboxylate 7A-18: 1-chloroethyl 9&alpha;-fluoro-11ss-hydroxy-17&alpha;-isopropoxycarbonyloxy-16ss-methylandrosta- 1,4-dien-3-one-17ss-carboxylate 7A-19: chloromethyl 9a-fl uoro- 1 7a-isopropoxycarbonyloxy- 1 6ss-methylandrosta- 1 ,4-d ien 3,1 1-dione-1 7-carboxylate 7A-20: chloromethyl 9&alpha;-fluoro-17&alpha;-isopropoxycarbonyloxy-16&alpha;-methylandrosta-1,4-dien-3,11- dione-17-carboxylate 7A-21: chloromethyl 9a-fluoro-1 1fl-hydroxy-1 7a-methoxycarbonyloxy-1 6a-methylandrnsta- 1,4-dien-3-one-17ss-carboxylate 7A-22: fluoromethyl 11ss-hydroxy-17&alpha;-isopropoxycarbonyloxyandrost-4-en-3-one-17ss-carboxy- late 7A-23: chloromethyl 9&alpha;-fluoro-11ss-hydroxy-16&alpha;-methyl-17&alpha;-pentyloxycarbonyloxyandrosta- 1,4-dien-3-one-17ss-carboxylate 7A-24: chloromethyl 16&alpha;,17&alpha;-di(ethoxycarbonyloxy)-6&alpha;-fluoro-11ss-hydroxyandrosta-1,4-dien- 3-one-17ss-carboxylate 7A-25: fluoromethyl 17&alpha;-ethoxycarbonyloxy-9&alpha;-flouro-11ss-hydroxy-16&alpha;-methylandrosta-1,4- dien-3-one-17ss-carboxylate 7A-26: acetoxymethyl 17&alpha;-ethoxycarbonyloxy-11ss-hydroxyandrost-4-en-3-one-17ss-carboxy- late 7A-27: chloromethyl 1 7&alpha;-ethoxycarbonyloxy-6&alpha;,9&alpha;-difluoro-1 1 fl-hydroxy-1 6a-methylandrnsta- 1,4-dien-3-one-17ss-carboxylate 7A-28: 2-chloroethyl 17&alpha;-ethoxycarbonyloxy-9&alpha;-fluoro-11ss-hydroxy-16&alpha;-methylandrosta-1,4- dien-3-one-17ss-carboxylate 7A-29: methyl 17&alpha;-ethoxycarbonyloxy-9&alpha;-fluoro-11ss-hydroxy-16&alpha;-methylandrosta-1,4-dien-3- one-17ss-carboxylate 7A-30: 2-chloroethyl 17&alpha;-isopropoxycarbonyloxy-11ss-hydroxyandrost-4-en-3-one-17ss-car boxylate EXAMPLE 7B Following the general procedure of Examples 3 or 4 and substituting therein the appropriate reactants affords the following compounds:

=mono. Rn R, e Z Z d C2H5 - C2H5 ,C2BS H H H "C 4 CE C4H9 C4Rs CH2C6H5 H H H ff 22 4 7 & 3 Cg2U2H 5 C225 H H 8 "cm 4 'H 7 > 4 C32no23 C2E5 H a s ',C 4 4 7Bw5 C82C1 C6H5 H H H tCs vH n oCH 78-6 CH2Cl d tor H z g Fv g 4 'H 2 CH2SCH3 H H H 'C 4 'H C4H9 C4Hg C2H5 H H ,'C = 0 4 7Be9 CE2Cl 033 H H H 6'C = 0 4 78-10 CEI2C1 CE5 H H H =C = O 4 78-11 CE25CEI3 C2Es H H H ,C 8 0 o 4 > 12 . .. Cg2S02CS3 C2B5 H H H rO 4 v we b e 78-13 CS,2o zCZSCC C2H5 H H 'C rO 4 7 > 14 ClI2e3 H.. B F E vB 4 "H 78-15 a ----F- ,,e,, Cs ,,4, H "'c"H . b

H X - S X I~R rz II .Z A - cH 7816 cE2502CH3 CzEts X F H 8 ::C/Ct 4 OH 72 17 C2H5, B-3 F H oC/s 1,4 'H CE 7B=18 CR2S02CH3 C2H5 ss < B3 F H B-CEI3 1,4 'H 7819 CH2C1 C2E5 H H C1 ;;C S O 1,4 7829 Oi2SCH3 C2H5 H H Cl ,'C-o .1,4 78-21 ChS02CW3 C2 H H C1 'c= 0 1,4 - C 1,4 7822 CE2SCH3 C2H5 a-CH3 P H oCr/sH 1, OH 78-23 M2902CE3 C a3 F H -" 1,4 H 7824 CH2C1 C2H5 rCB3 F P 'H 1,4 7emu25 CH2SCH3 C2H5 aT3 F F "-CE 1,4 H 7 & 6 CH2S02CE3 C H5 XT3 F F - - aH - OH 1,4 27 O3C1 C2E5 H H F 'H OH 7828 C 2SUCH C2H5 H H F ,Cso 1,4 'H OH 7829 7 > 29 CH2502CH3 C2H5 H H F ,C / 1,4 7830 ,C,E2C1 C2H5 ss < 3 H H ,C = O 1,4 7831 CH2SCH3 C2H5 a3 H a ',C= O 1,4 7 & 2 CH2S02CH3 , C2g5 BCH3 H H )C = 1) .1,4

=,Di No. S F, R Z z A CE.2C1.. . , .8 E H H.; ,Cv 1,4 6 oS 7By34 af2sctS CE H . E 3 1,4 .2 CRZS02M3 .3 B -a C2H H H 1,4 7 > 35 C ---- -S- ,C2E5 B H CH3 CE 3 C?I2C1 ,,,, 0-213 8 F 1,4 H 7B-36 CH2C1 C2H5 %Oi3 H F 1,A 23 H5 H F 1,4 OH OH 3B CE2502CE3 C2H5 "CH3 H F 1,4 39 CI2SCH3 CH5 H 8 I 8 7B-39 CH25CH3 C2H5 H E Cv xH 1, 4 4O aiso2CE3 C2H5 H H H 1,4 78-41 C62Cl i C28s 8 8 8 ::C 0 1,4 7B-41 cg2Cl C2H5 H H H zC = O 1,4 7B-42 CH25CH3 C2H5 H H H ,CO 1,4 CE2502CE3 C2H5 H H H ,'c = 0 1,4 OH 7B 44 CH2C1 H5 a{MmOc2H5 F H ,C or 1,4 . C82SCII3 a2 c-a3DCZBg * 'H O5CH3 CH2503 3 C2H5 aT OC2E5 F H Cvs | 1,4 H OH 7B-46 CH2502CE3 C2H5 a < CzZ5 F H ,C/ 1,4 7B-47 ";C-k 1.4 ,,,""','z- .1,4 'H c;2c1 e aT3 o-CI, P H ""'OH 1,4 OH ,7B 9 ca2cl CE2CH2.C1 ax, F H \j:/QEI 1,4 5O OC1 CA i3, F H 1,4

Around No. Rt R x R X Z A 7 & 1 C4H9 Char3 H H H sCZ 4 "' 'H OH 7B-52 CH2a tcz35) C2H5 H H H \ C 2 4 The53 C 2( CH3 H H H oC > /s 4 7B-53 OH 7 & 4 C6H5 C5 H H H oC/ 4 -'H OH 7B-55 CE2C5 CH3 H H H > ,C */ 4 ""'H 7By56 CH5 H H H ",,C"",OH 'H 7B-57 CH2C1 . H H H 4 ""'H OH 7 & 8 ca2Cl CH=CH2 H H H "C,"" 4 'H 7B-59 C & C1 arz0ar H fl H 4 761 Cg2C1 ca2C CSO;0;H3 H H H o svH 4 'H OH 62 cH2 CH5 H 'H H EI -4

catw9otrd N5. . Re R1 L S R Z A 7B-63 CH2C1 CH25 2CH3* H H H z - 4 OH 7B-64 ca2Cl CH2SOI3* a H 8 ,C/8H 4 'H

prepared from Example 6B-24 and 6B-25 respectively by reaction with ClCH2l, or from Example 7B-7 by reaction with m-chloroperbenzoic acid.

EXAMPLE 8 An equivalent quantity of 1 1ss,1 7a-dihydroxyandrost-4-en-3-one-1 7fl-carboxylic acid is substituted for the 11ss-hydroxy-17&alpha;-methoxycarbonyloxyandrost-4-en-3-one-17ss-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 1 1ss, 1 7a dihydroxyandrost-4-en-3-one-1 7ss-carboxylate, and, as the final product, chloromethyl 11ss,17&alpha;- dihydroxyandrost-4-en-3-one-1 7ss-carboxylate, melting at 184-1 86 C (recrystallization from tetrahydrofuran-etherhexane).

EXAMPLE 9 An equivalent quantity of 11ss,1 7a-dihydroxyandrost-4-en-3-one-1 7ss-carboxylic acid is substituted for the 1 7a-ethoxycarbonyloxy-1 1 ss-hydroxyandrost-4-en-3-one-1 7ss-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, sodium 1 1ss,17&alpha;- dihydroxyandrost-4-en-3-one-1 7fl-carboxylate, and as the final product, methylthiomethyl 11ss,17&alpha;-dihydroxyandrost-4-en-3-one-17ss-carboxylate.

Substitution of an equivalent quantity of methylthiomethyl 11ss,1 7a-dihydroxyandrost-4-en-3 one 1 7ss-carboxylate for the methylthiomethyl 1 7&alpha;-ethoxycarbonyloxy-11 fl-hydroxyandrost-4-en- 3-one-1 7ss-carboxylate used in the second paragraph of Example 4 and substantial repetition of the procedure there detailed affords methylsulfonylmethyl 11ss,1 7a-dihydroxyandrost-4-en-3one-17ss-carboxylate.

EXAMPLE 10A The procedure of each paragraph of Example 2 is substantially repeated, substituting an equivalent quantity of each of the following starting materials for the steriods employed therein: chloromethyl 11ss,17&alpha;-dihydroxyandrost-4-en-3-one-17ss-carboxylate; and methylthiomethyl 11ss,17&alpha;-dihydroxyandrost-4-en-3-one-17ss-carboxylate. The following soft anti-inflammatory agents of formula (I) are obtained:

Compound No. R1 R2 m.p.

10A-1 CH2CI CH3 171-173 C 10A-2 CH2CI C2H 197-200 C (THF/hexane) 10A-3 CH2SCH3 QH5 137.5-138 C (ether/hexane) 10A-4 CH2CI C4H9 99.5-102'C (THF/hexane) 10A-5 CH2CI iso-C3H7 183.5-184.5 C (THF/hexane) 10A-6* CH2CI iso-C4Hg 140-141 'C (THF/isopropyl ether) utilizing isobutyl chloroformate as the alkyl chloroformate reactant EXAMPLE 10B 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 11ss,17&alpha;-dihydroxyandrost-4-en-3-one-17ss-carboxylate; and methylsulfonylmethyl 11ss,1 7a-dihydroxyandrost-4-en-3-one-1 7ss-carboxylate.The following soft anti-inflammatory agents of formula (I) are obtained.

Compound No. R, R2 10B-1 CH2SCH3 CH3 10B-2 CH2SCH3 C4H9 10B-3 CH2SCH3 i-C3H7 10B-4 CH2SO2CH3 CH3 1OB-5 CH2SO2CH3 C2H5 10B-6 CH2SO2CH3 C4H9 10B-7 CH2SO2CH3 i-C3H7 Other representative species, e.g. compounds of Examples 7A and 7B, can likewise be prepared according to the procedures of Examples 8 through 10.

EXAMPLE 11 The products of Example 2 and Example 6A-4 are each allowed to react, first with diethylchlorophosphate and then with CH3SNa in chloroform for approximately 6 hours. The following intermediates are obtained in the first step:

R2 R3 R4 A CH3 H H 4 C2H5 H H 4 C4H9 H H 4 i-C3H7 H H 4 C2H5 a-CH3 F 1,4 and the following compounds of formula (I) are obtained in the second step::

R2 R3 R4 CH3 H H 4 QH H H 4 C4H9 H H 4 i-C3H? H H 4 C2H5 aCH3 F 1,4 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

wherein the various structural parameters represented by R2, R3, R4, R5, Z and the dotted line are identical to those of compounds 6A1-6A3, 6A5-6A11, and 6B1-6B25 of Examples 6A and 6B are obtained.

EXAMPLE 12 Chloromethyl 11ss,17&alpha;-dihydroxyandrost-4-en-3-one-17ss-carboxylate (0.01 mol) is dissolved in toluene (100 milliters) and the solution is cooled to approximately 0 C. 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 1 7a-chlorocarbonyloxy compound of the formula

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 1 7a-ethoxycarbonyloxy-1 1ss-hydroxyan- drost-4-en-3-one-1 7ss-carboxylate is isolated from the reaction mixture.The compound melts at 1 97-200 C, after crystallization.

Substitution of an equivalent quantity of methylthiomethyl 11ss,1 7a-dihydroxyandrost-4-en-3one-1 7fl-carboxylate for the chloromethyl 11 ss, 1 7a-dihydroxyandrost-4-en-3-one-1 7ss-carboxylate used above and substantial repetition of the foregoing procedure affords methylthiomethyl 1 7aethoxycarbonyloxy-11ss-hydroxyandrost-4-en-3-one-17ss-carboxylate, melting at 133-136 C, after crystallization. That compound can then, if desired, be converted to the corresponding sulfonyl or sulfinyl compounds as described in Example 4.

Other representative species, e.g., the compounds 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 1 7oi-hydroxy 1 7ss-carboxylates with the appropriate alcohols, including, when appropriate, subsequent treatment with nxchloroperoxybenzoic acid as in Example 4.

EXAMPLE 13 The procedure of the first paragraph of Example 12 is repeated, except that an equivalent quantity of 1 1ss,1 7&alpha;-dihydroxyandrost-4-en-3-one-1 7fl-carboxylic acid is used in place of the chloromethyl 11P,1 7a-dihydroxyandrost-4-en-3-one- 17P-carboxylate. The crude intermediate thus obtained has the formula

That intermediate is then subjected to the procedure of the second paragraph of Example 12, to afford 1 7a-ethoxycarbonyloxy-1 1 ss-hydroxyandrost-4-en-3-one-1 7ss-carboxylic acid, identical to the product of Example 2, paragraph 2.

The other compounds of Examples 2, 6A and 6B can be prepared using the same general procedure.

EXAMPLE 14 Chloromethyl 1 1ss,1 7a-dihydroxyandrost-4-en-3-one-1 7fl-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 heated to about 80 to 85 C; the remaining ethanol which forms is removed by distillation under reduced pressure. Obtained as the residue is crude chloromethyl 1 7a-ethoxycarbonyloxy-1 1ss-hydroxyandrost-4-en-3-one-1 7ss- carboxylate, melting at 1 97-200 C, after crystallization.

Substitution of an equivalent quantity of methylthiomethyl 11 fl, 1 7a-dihydroxyandrost-4-en-3one-17ss-carboxylate for the chloromethyl 11ss,17&alpha;-dihydroxyandrost-4-en-3-one-17ss-carboxylate used above and substantial repetition of the foregoing procedure affords methylthiomethyl 1 7aethoxycarbonyloxy-1 1ss-hydroxyandrost-4-en-3-one-1 7ss-carboxylate, melting at 133-1 36 C.

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 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 1 7oi-hydroxy-1 7ss-carboxylates with the appropriate carbonates of the type

(including, when appropriate, subsequent treatment with m-chloroperoxybenzoic acid as in Example 4).

EXAMPLE 15 To a solution of 8.7 grams of 11ss,17&alpha;-dihydroxyandrost-4-en-3-one-17ss-carboxylic acid and 9.6 milliliters of triethylamine in 100 milliliters of dry dichloromethane, is added 10 grams of ethyl chloroformate, dropwise at 0 to 5 C. 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 1 7a-ethoxycarbonyloxy 11 ss-hydroxyandrost-4-en-3-one-1 7ss-carboxylate, melting at 1 58-1 59'C.

EXAMPLE 16 Following the general method described in Example 15 and substituting therein the appropriate reactants affords the following additional compounds:

Compound No. R2 R3 R4 R5 A melting point 16-A -CH2CH3 H F H 4 110-111'C(THF- isopropyl ether) 16-B iso-C3H7 H H H 4 200-203 C 16-C -CH2CH2CH3 H H H 4 142-143'C(THF) EXAMPLE 17 To a solution of 9.8 grams of ethoxycarbonyl 17&alpha;-ethoxycarbonyloxy-11ss-hydroxyandrost-4- en-3-one-17ss-carboxylate in 100 milliliters of tetrahydrofuran and 120 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 1 N hydrochloric acid. The insoluble material is isolated by filtration.Recrystallization from a mixture of tetrahydrofuran and n-hexane gives 6 grams of 1 7a-ethoxycarbonyloxy-1 1 fl-hydroxyandrost-4-en-3-one-1 7ss-carboxy- lic acid having a melting point of 192-195 C.

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.

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

Compound No. R melting point 18-A

144.5-1 46.5'C (THF/hexane) 18-B -(CH2)3CH3 164-166 C (THF/hexane) EXAMPLE 19 To a solution of 8.7 grams of 11P,1 7ar-dihydroxyandrost-4-en-3-one-1 7P-carboxylic acid and 10 grams of triethylamine in 100 milliliters of dichloromethane, a solution of 13.2 grams of npropyl chloroformate in 200 milliliters of dichloromethane is added dropwise over 1-1.5 hours with ice-cooling. The reaction mixture is allowed to warm to room temperature over a 2 hour period, then is washed successively with 3% aqueous sodium bicarbonate, 1 N hydrochloric acid, and water and dried over anhydrous sodium sulfate.The solvent is concentrated under reduced pressure. Crystallization from a mixture of ether and n-hexane gives 10.5 grams of propoxycarbonyl 11ss-hydroxy-1 7&alpha;-propoxycarbonyloxyandrost-4-en-3-one-1 7ss-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 hydrochloric acid with ice-cooling. The mixture is then extracted with chloroform, washed successively with 1 N 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 tetrahydrafuran to give 7.7 grams of 1 11ss- hydroxy-17&alpha;-propoxycarbonyloxyandrost-4-en-3-one-17ss-carboxylic acid, melting at 156-1 57'C.

EXAMPLE 20 Following the general procedure detailed in Example 19, but ulitizing the appropriate starting materials and reaction conditions, affords the remaining compounds of Example 6A.

EXAMPLE 21 Chloromethyl 1 7&alpha;-ethoxycarbonyloxy-9&alpha;-fluoro-1 1 fl-hydroxy-1 6a-methylandrnsta.1 ,4-dien-3one-1 7ss-carboxylate (2 grams) is dissolved in anhydrous dichloromethane (200 milliliters) and pyridinium chlorochromate (3.5 grams) is added at room temperature, with stirring. The resultant mixture is stirred for 24 hours, then the solvent is concentrated under reduced pressure at about 10 to 20 C.The residue is subjected to column chromatography on silica gel (Kiesel gel 60), using chloroform as an eluting solvent, followed by recrystallization form a mixture of tetrahydrofuran and isopropyl ether to give chloromethyl 1 7a-ethoxycarbonyloxy-9afluoro-1 6a-methylandrosta-1 ,4-dien-3, 1 1-dione-1 7fl-carboxylate, in the yield of 1.7 grams, melting at 138-140 C.

EXAMPLE 22 By a method similar to that described in Example 21, there is obtained chloromethyl 9a fluoro-17&alpha;-isopropoxycarbonyloxy-16ss-methylandrosta-1,4-dien-3,11-dione-17ss-carboxylate, melting at 200-201 C.

EXAMPLE 23 Utilizing the general procedure of Example 3, but substituting the appropriate reactants therein, affords methyl 1 7&alpha;-(2-chloroethoxy)carbonyloxy-9&alpha;-fluoro- 1 fl-hydroxy- 1 6a-methylan drosta- 1 ,4-dien-3-one-1 7ss-carboxylate. That product, after recrystallization from isopropanol, melts at 223-227"C.

EXAMPLE 24 In the same general manner as in Example 3, there is obtained 2-chloroethyl 1 7a ethoxycarbonyloxy-9a-fluoro- 11 ss-hydroxy-1 6a-methylandrosta- 1 , 4-dien-3-one- 1 7ss-carboxylate.

That product, after recrystallization from tetrahydrofuran-hexane, melts at 243-245"C.

EXAMPLE 25 Chloromethyl 1 7a-ethoxycarbonyloxy-1 1 1ss-hydroxyandrost-4-en-3-one-17ss-carboxylate (0.01 mol) and 1,2-dimethylpyrrolidine (0.01 mol) 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 affording the desired quaternary ammonium salt of the formula

In analogous fashion, use of the appropriate steroidal and amine starting materials in the foregoing general procedure affords the following additional quaternary ammonium salts of the invention

N cS H3 3 i-C3H7 ' N(C2H5)3 C4H9 E34NC C2S5 E3RC C2H5 tOCOC33 C2E5 N(C2H5)3 C2H5 H39 EXAMPLE 26 Ointment Compound of formula (I), e.g. chloromethyl 17a- ethoxycarbonyloxy-1 1ss- hydroxyandrost-4-en 3-one-17ss-carboxylate or chloromethyl 11ss-hydroxy 1 7a-isopropoxycarbonyl- oxyandrost-4-en-3-one 1 7ss-carboxylate 0.2% w/w Liquid paraffin 10.0% w/w White soft paraffin 89.8% w/w Aphthous Ulcer Pellet Compound of formula (1), as above 0.25 mg Lactose 69.90 mg Acacia 3.00 mg Magnesium stearate 0.75 mg Retention Enema Compound of formula (I), as above 0.001% w/v 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), as above 0. 1% w/v 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 Water for injection q.s. 100 volumes EXAMPLE 27 Ointment Compound of formula (I), e.g. chloromethyl 1 7a ethoxycarbonyloxy-9oe- fluoro-11ss-hydroxy-16&alpha;- methylandrosta-1 4-dien 3-one-1 7ss-carboxylate or chloromethyl 9&alpha;-fluoro- 1 1ss-hydroxy-1 7a- methoxycarbonyloxy-1 6a- methylandrosta-1 ,4-dien 3-one-1 7ss-carboxylate 0.025% w/w Liquid paraffin 10.175% w/w White soft paraffin 89.8% w/w Aphthous Ulcer Pellet Compound of formula (I) e.g. chloromethyl 9a4luoro- 1 1fl-hydroxy-1 7a isopropoxycarbonyloxy- 1 6fl- methylandrosta-1 ,4-dien-3 one-1 7ss-carboxylate or chloromethyl 1 7a ethoxyca rbonyloxy-9a-fl uoro- 11ss-hydroxy-16&alpha;;- methylandrosta-1 ,4-dien-3 one-1 7ss-carboxylate 0.1 mg Lactose 69.90 mg Acacia 3.0 mg Magnesium stearate 0.75 mg Retention Enema Compound of formula (I), e.g. chloromethyl 1 1ss- hydroxy-1 7a isopropoxycarbonyloxy androsta-1 ,4-dien-3-one 1 7fl-carboxylate or chloromethyl 9a-fluoro 11ss-hydroxy-17&alpha;;- isopropoxycarbonyloxy 16ss-methylandrosta-1,4 dien-3-one-1 7ss-carboxylate 0.001% w/v Tween 80 0.05% w/v Ethanol 0.01 5% w/v Propylparaben 0.02% w/v Methylparaben 0.08% w/v Distilled water q.s. 100 volumes Eye Drops Compound of formula (I), e.g. chloromethyl 9a fluoro-1 1 ss-hydroxy-1 6a methyl 7a-propoxy carbonyloxyandrosta-1 ,4 dien-3-one-17ss-carboxylate or chloromethyl 9a-fluoro 11ss-hydroxy-17&alpha; ;-methoxy- carbonyloxy-1 6a-methyl androsta-1,4-dien-3-one 1 7ss-carboxylate 0.025% w/v 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 Water for injection q.s. 100 volumes Frnrn 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.

Claims (22)

1. A compound selected from the group consisting of: (a) a compound of the formula

wherein: R1 is C1-C10 alkyl; C2-C,O (monohydroxy or polyhydroxy)alkyl; C1 -C10 (monohalo or polyhalo)alkyl; or -CH2COOR6 wherein R6 is unsubstituted or substituted C1 -C10 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl or C2-C10 alkenyl, the substituents being selected from the group consisting of halo, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl,

(C,-C,O alkyl) and

(C,-C,O alkyl), or R6 is unsubstituted or substituted phenyl or benzyl, the substituents being selected from the group consisting of lower alkyl, lower alkoxy, halo, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(lower alkyl)amino, di(lower alkyl)amino, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl; or R, is -CH2CONR7R8 wherein R7 and R8, which can be the same or different, are each hydrogen, lower alkyl, C3-C8 cycloalkyl, phenyl or benzyl, or R7 and R8 are combined such that -NR7R8 represents the residue of a saturated monocyclic secondary amine; or R, is unsubstituted or substituted phenyl or benzyl, the substituents being selected from the group of phenyl and benzyl substituents defined hereinabove with respect to R6; or R, is

(lower alkyl) wherein Y is -S-, -50-, 502 or -0- and P9 is hydrogen, lower alkyl or phenyl, or P9 and the lower alkyl group adjacent to Y are combined so that R, is a cyclic system of the type

-CH Y alkylene wherein Y is defined as above and the alkylene group contains 3 to 10 carbon atoms, of which at least 3 and no more than 6 are ring atoms; or R, is

wherein R6 is defined as hereinabove and R10 is hydrogen, lower alkyl, phenyl or halophenyl; R2 is unsubstituted or substituted C1 -C10 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl or C2-C10 alkenyl, the substituents being selected from the group consisting of halo, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl,

(C1-C10 alkyl) and

(C,-C,O alkyl), or R2 is unsubstituted or sub - stituted phenyl or benzyl, the substituents being selected from the group consisting of lower alkyl, lower alkoxy, halo, carbamoyl, lower alkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(lower alkyl)amino, di(lower alkyl)amino, mono(lower alkyl)carbamoyl, di(lower alkyl)carba moyl, lower alkylthio, lower alkylsulfinyl and lower alkylsulfonyl; R2 is hydrogen, a-hydroxy, hydroxy, a-methyl, methyl, = CH2, or a- or

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 fl-hydroxymethylene; and the dotted line in ring A indicates that the 1,2 linkage is saturated or unsaturated; and a quaternary ammonium salt of the compound represented by said formula wherein at least one of R, and R2 is a halo-substituted alkyl group; and (b) a compound of the formula

wherein: R2, R4, R5, Z and the dotted line in ring A are as defined above; R is hydroxy; chloro;OM wherein M is alkali metal, alkaline earth metal/2, thallium or NH4; or OR, wherein R, is as defined above; R' is R3" or R3"', R3" being hydrogen, a-methyl, methyl, =CH2,

or

wherein R2 is as defined above, and R3"' being hydrogen, a-methyl, methyl, = CH2, a-OCOCI or ssOCOCI; when R' is R3", R is hydroxy, chloro or OM, and when R' is R3"', R is OR1.

2. A compound of claim 1, said compound having the structural formula as described in (a).

3. A compound of claim 2 wherein R, is C,-C6 alkyl; C,-C6 (monohalo or polyhalo)alkyl; -CH2COOR6' wherein R6' is C,-C6 alkyl; -CH2-Y- (C1-C6 alkyl) wherein Y is -S-, -SO-, -SO2- or -O-; or

wherein R6" is C,-C6 alkyl or phenyl; R2 is C,-C6 alkyl; C3-C8 cycloalkyl; phenyl; benzyl or C1-C6 (monohalo or polyhalo)-alkyl; R3 is hydrogen; a-hydroxy; a-methyl; methyl or

wherein R2 is as defined above; R4 is hydrogen or fluoro; and R5 is hydrogen or fluoro.

4. A compound of claim 3 wherein Z is fl-hydroxymethylene.

5. A compound of claim 4 wherein R1 is C1-C6 (monohalo or polyhalo)alkyl.

6. A compound of claim 5 wherein R2 is C1-C6 alkyl.

7. A compound of claim 5 wherein R2 is C3-C8 cycloalkyl, phenyl, benzyl or C,-C6 (monohalo or polyhalo)-alkyl.

8. A compound of claim 6 or 7 wherein X is -O-.

9. A compound of claim 8 wherein R4 and R5 are hydrogen.

10. A compound of claim 8 wherein R4 is fluoro and R5 is hydrogen.

11. A compound of claim 10 wherein R3 is a-methyl or methyl.

12. A compound of claim 3 wherein Z is carbonyl.

13. A compound of claim 4, said compound being selected from the group consisting of chloromethyl 11ss-hydroxy-1 7a-methoxycarbonyloxyandrost-4-en-3-one- 1 7fl-carboxylate, chloromethyl 17&alpha;-ethoxycarbonyloxy-11ss-hydroxyandrost-4-en-3-one-17ss-carboxylate, chloromethyl 17&alpha;-butoxycarbonyloxy-11ss-hydroxyandrost-4-en-3-one-17ss-carboxylate, chloromethyl 11ss-hy droxy-17&alpha;-isopropoxycarbonyloxyandrost-4-en-3-one-17ss-carboxylate, 1-chloroethyl 11ss-hydroxy-1 7a-isopropoxycarbonyloxyandrost-4-en-3-one-1 7ss-carboxylate, chloromethyl 1 7a-ethoxycarbonyloxy-1 1 ss-hydroxyandrosta-1 ,4-dien-3-one-1 7ss-carboxylate and chloromethyl 11 ss-hy droxy-17&alpha;-isopropoxycarbonyloxyandrosta-1,4-dien-3-one-17ss-carboxylate.

14. A compound of claim 4, said compound being selected from the group consisting of chloromethyl 17&alpha;-ethoxycarbonyloxy-9&alpha;-fluoro-11ss-hydroxy-16ss-methylandrosta-1,4-dien-3-one- 17ss-carboxylate, chloromethyl 9&alpha;-fluoro-11ss-hydroxy-16&alpha;-methyl-17&alpha;-propoxycarbonyloxyan- drosta-1,4-dien-3-one-17ss-carboxylate, 1-chloroethyl 9&alpha;-fluoro-11ss-hydroxy-17&alpha;-isopropoxycar- bonyloxy-16ss-methylandrosta-1,4-dien-3-one-17ss-carboxylate, chloromethyl 17&alpha;-ethoxy-carbo- nyloxy-9&alpha;-fluoro-11ss-hydroxyandrosta-1,4-dien-3-one-17ss-carboxylate, chloromethyl 17&alpha;- ethoxycarbonyloxy-9&alpha;-fluoro-11ss-hydroxy-16&alpha;;-methylandrosta-1,4-dien-3-one-17ss-carboxylate, chloromethyl 9&alpha;-fluoro-11ss-hydroxy-17&alpha;-isopropoxycarbonyloxy-16&alpha;-emthylandrosta-1,4-dien-3- one-17ss-carboxylate, chloromethyl 9&alpha;-fluoro-11ss-hydroxy-17&alpha;-isopropxycarbonyloxy-16ss-me- thylandrosta-1,4-dien-3-one-17ss-carboxylate, chloromethyl 9&alpha;-fluoro-11ss-hydroxy-17&alpha;-methoxy- carbonyloxy-16&alpha;-methylandrosta-1,4-dien-3-one-17ss-carboxylate, chloromethyl 9&alpha;-fluoro-11ss- hydroxy- 1 6a-methyl- 1 7a-pentyloxycarbonyloxyandrosta- 1 ,4-dien-3-one- 1 7ss-carboxylate, fluoromethyl 17&alpha;-ethoxycarbonyloxy-9&alpha;-fluoro-11ss-hydroxy-16&alpha; ;-methylandrosta-1,4-dien-3-one-17ss- carboxylate and methyl 1 7&alpha;-(2-chloroethoxy)carbonyloxy-9&alpha;-fluoro-11ss-hydroxy-1 6a-methylan drosta- 1 , 4-dien-3-one- 1 7fl.carboxylate.

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

wherein P1, R2, R3", R4, R5, Z and the dotted line in ring A are as defined in claim 1, (a), with the proviso that R, and R2 is not a sulfinyl-or sulfonyl- containing group, and a quaternary ammonium salt thereof, comprising reacting a compound represented by the formula

wherein R2, R3", R4, R,, Z and the dotted line in ring A are defined as above, and M is alkali metal, alkaline earth metal/2, tallium or NH4 with a compound represented by the formula R1W wherein R, is defined as above, and W is halogen, and, if desired, reacting the compound obtained above wherein at least one of R, and R2 is a halo-substituted alkyl group with a tertiary amine or an unsaturated amine.

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

wherein P1, R2, R3", R4, R5, Z and the dotted line in ring A are as defined in claim 15, and X is -O- or -S-, and a quaternary ammonium salt thereof, the process 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, with a compound represented by the formula R,XM' wherein R, and X are as defined above, and M' is hydrogen or M wherein M is as defined in claim 1, (a), and, if desired, reacting the compound obtained above wherein at least one of R, and R2 is a halo-substituted alkyl group with a tertiary amine or an unsaturated amine.

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

wherein P1, R2, R4, R5, Z and the dotted line in ring A are as defined in claim 15, and X and R' are as defined in claim 1, (a), and a quaternary ammonium salt thereof, the process comprising reacting a compound represented by the formula

wherein P1, R4, R5, Z and the dotted line in ring A are defined as above, and R3"' is as defined in claim 1 with a compound represented by the formula R2OM1 wherein R2 is as defined above, and M' is as defined in claim 16, and, if desired, reacting the compound obtained above wherein at least one of R, and R2 is a halo-substituted alkyl group with a tertiary amine or an unsaturated amine.

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

wherein P1, R2, R4, R5, Z and the dotted line in ring A are as defined in claim 15, and R3 is as defined in claim 1, (a), and a quaternary 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, amethyl, methyl, = CH2, a-OH or ss-OH with a compound represented by the formula R2OCOX1 or

wherein R2 is as defined above, X' is chloro or bromo, and, if desired, 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.

1 9. A process for a 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, (a), with the proviso that at least one of R1 and R2 is a sulfinyl- or sulfonyl-containing group, the process comprising the step of oxidizing a compound represented by the formula

wherein R3, R4, R5, X, Z and the dotted line in ring A are as defined above, and R1 and R2 are as defined in claim 1, (a), with the proviso that at least one of R1 and R2 is a sulfur-containing group.

20. A process for preparing a compound represented by the formula

wherein R,, R2, R3, R4, R5, X and the dotted line in ring A are as defined in claim 1, (a), and a quaternary ammonium salt thereof, the process comprising reducing a compound represented by the formula

wherein P1, R2, R3, R4, R5, X and the dotted line in ring A are as defined above, and, if desired, reacting the compound obtained above wherein at least one of R, and R2 is a halo-substituted alkyl group with a tertiary amine or an unsaturated amine.

21. A process for preparing a compound represented by the formula

wherein P1, R2, R3, R4, R,, X and the dotted line in ring A are as defined in claim 1, (a), the process comprising the step of oxidizing a compound represented by the formula

wherein P1, R2, R3, R4, R5, X and the dotted line in ring A are as defined above.

22. A pharmaceutical composition of matter comprising an anti-inflammatory effective amount of a compound represented by the formula

wherein P1, R2, R3, R4, R5, X, Z and the dotted line in ring A are as defined in claim 1, (a), in combination with a non-toxic pharmaceutically acceptable carrier therefor suitable for topical or other local application.