SOFT STEROIDS HAVING ANTI-INFLAMMATORY ACTIVITY

Abstract: Novel soft steroid anti-inflammatory agents, said agents being esters or thioesters of 17 alpha -alkoxy-11 beta -hydroxyandrost-4-en-3-one-17 beta -carboxylic acids, pharmaceutical compositions containing said agents, novel chemical intermediates useful in the preparation of said agents and methods of administering same to mammals in the treatment of inflammation. Preferred compounds are the haloalkyl esters of 17 alpha -alkoxy-11 beta -hydroxyandrost-4-en-3-one-17 beta -carboxylic acids.

Description: SOFT STEROIDS HAVING ANTI-INFLAMMATORY ACTIVITY Technical Field of the Invention; The invention relates to novel soft steroids having anti-inflammatory activity, pharmaceutical compositions containing said soft steroids, novel chemical intermediates useful in the preparation of the steroids, and methods of administering said steroids to mammals in the treatment of inflammation. 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 bioactive molecule as the basis for structural modifications, either by the group or biofunctional moieties approach or by altering the overall physical- chemical properties of the molecule. Thus, the main aim has been to design, synthesize, and test new compounds structurally analogous to the basic bioactive molecule which have, however, improved therapeutic and/or pharmacokinetic properties. Although "vulnerable" moities 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 SUBSTITUTE SHEET processes by formation of active metabolites. The phenomenon of metabolic activation to 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 (isoteric and/or isoelectronic) the active drug (i.e., activation); and designing the metabolism of the activated species to lead to the starting inactive metabolite after achieving the desired therapeutic role, without the formation of toxic intermediates (i.e., 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 noncritical 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 or analogously designed inactive natural metabolites of the glucocorticosteroids. Thus, for example, in the case of hydrocortisone, one of its major, inactive metabolites, cortienic acid, i.e., 11β, 17α- dihydroxyandrost-5-en-3-one-17β-carboxylic acid, has been used as a starting point and activated by the introduction of suitable nontoxic 17α- and 17 - substituents, which activated derivatives will cleave in vivo, at the 17β-position, and possibly also the 17 -position, after accomplishment of their nontoxic role, to predetermined or designed inactive metabolites, e.g., non-toxic moieties. SUBSTITUTE SHEET In accord with the foregoing, the present invention provides novel soft steroids having anti- inflammatory activity, said steroids having the structural formula wherein R^ is Cι-C 1Q alkyl; C2-C, Q (monohydroxy or polyhydroxy)alkyl; Cι-C, Q (monohalo or polyhalo)alkyl; or -CH2COOR6 wherein Rg is unsubstituted or substituted CJ-C- Q alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl or C2-C 10 alkenyl, the substituents being selected from the group consisting of halo, lower alkoxy, lower alkylthio, lower alkylsulfinyl, O lower alkylsulfonyl, -NHC-(Cχ-C, 0 alkyl) and -OC-(Cι-C- 0 alkyl) , or R5 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 Rj is -CH2CONR7R8 wherein R7 and RQ , which can be the same or different, are each hydrogen, lower alkyl, C3-C8 cycloalkyl, phenyl or benzyl, or R7 5 and Rs are combined such that -NR7R8 represents the residue of a saturated monocyclic secondary amine; or Rl is unsubstituted or substituted phenyl or benzyl, the substituents being selected from the group of phenyl and benzyl substituents defined hereinabove 10 with respect wherein Y is hydrogen, lower alkyl or phenyl, or Rg and the lower alkyl group adjacent to Y are combined so that Ri is a 15 cyclic system of the type -CH - Y wherein Y is defined alkylene as above and the alkylene group contains 3 to 10 carbon atoms, of which at least 3 and no more than 6 20 wherein Rg is hydrogen, lower alkyl, phenyl or haloalkyl; R2 is unsubstituted or substituted Cι~C, 0 25 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl or C2"" c ι o alkenyl, the substituents being selected from the group consisting of halo, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, 0 0 30 -NHC-(Cι-C 10 alkyl) and -OC-(Cι-C 1() alkyl) , or R 2 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, 35. monodower alkyl)amino, di(lower alkyl)amino, SUBSTITUTE SHEET mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl and lower alkylsulfony1; R3 is hydrogen, α-hydroxy, β-hydroxy, α-methyl, β-methyl, =CH2, or α- or 3-0R2 wherein R2 is identical to 2 as defined hereinabove; R4 is hydrogen, fluoro or chloro; R5 is hydrogen, fluoro, chloro or methyl; X is -0- or -S-; Z is carbonyl or β-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: Ri is Cχ-Cg alkyl; Cχ-Cg (monohalo or polyhalo)alkyl; -CI^COORg wherein Rg is Cχ-Cg alkyl; -CH2-Y-(Cχ-Cg alkyl) wherein Y is -S-, -SO-, -SO2- or 0 -0-; or -CH^-OCRg' wherein Rg • is Cχ-Cg alkyl or phenyl; R2 is Cχ-Cg alkyl, C3-C8 cycloalkyl, phenyl, benzyl or Cχ-Cg (monohalo or polyhalo)alkyl; R3 is hydrogen, os-hydroxy, o_-methyl, β-methyl or OS-OR2 wherein R2 is identical to R2 as defined hereinabove; R4 is hydrogen or fluoro; R5 is hydrogen or fluoro; Z is β-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 Rl is hydrogen, are provided also. The soft steroids of formula (I) and the quaternary ammonium salts thereof are extremely potent local antiinflammatory 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 metabo- lites they are derived. Indeed, many of the compounds of the present invention are entirely devoid of systemic activity. Such minimal — or non-existent — systemic activity means that the compounds of the present invention can be used in the local (e.g., topical) treatment of inflammatory conditions without the serious systemic side effects which attend the 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 SUBSTITUTE SHEET 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 Ri or R2, or as a portion of a Rχ 2, or R3 group, include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl and their branched-chain isomers, as well as their straight and branched-chain higher homologues in the instances where "alkyl" 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, alky1sulfony1, alkoxycarbonyl, alkanoyloxy, monoalkylamino, dialkylamino, monoalkylcarbamoyl and dialkylcarbamoyl groupings are of the type -O-alkyl -S-alkyl -SO-alkyl -S0 2 -alkyl -C-O-alkyl Mislttttlt -O-C-alkyl 0 -NH-alkyl alkyl -C-NH-alkyl δ 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 "Cχ-Cg alkyl" is used to refer to a straight or branched- chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like. In addition, the term "Cχ-Cg (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, 2,2,2-trifluoroethyl, 1,2- ~ - - * "* - -ϊ&ktmlj l dichloroethyl, 1-chloropropyl, 3-chloropropyl, 1-chlorobutyl, 1-chloropenty1, 1-chlorohexyl, 4-chlorobutyl and the like. Also, the term "C3-C8 cycloalkyl" is used to refer to a cycloalkyl radical having 3 to 20 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. When Rx in formula (I) is -CH2CONR7R8 wherein - R7R8 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-l,2,4-oxathiazin-4-yl, 1- or 4-piperazinyl, 4-methyl-1-piperazinyl, piperidino, hexamethyleneimino, 4-phenylpiperidino, 2-methyl- 1-pyrazolidinyl, 1- or 2-pyrazolidinyl, 3-methyl- 1-imidazolidinyl, 1- or 3-imidazolidinyl, 4-benzylpiperidino and 4-phenyl-l-piperazinyl. Selected compounds of formula (I), i.e., compounds wherein R^ is α-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 G= ) 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, CH3NO2, dimethylformamide, 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: 1-Methylazirine 1-Methylpyrro1e 1-Methylimidazole SUBSTITUTE SHEET 1-Methylpyrazole Pyridine ^N @ Pyrazine Pyrimidine Pyridazine 2-Methylisoindole 3H-indole 03 Quinoline Isoqumoline SUBSTITUTE SHEET Phthalazine Quinoxaline CO Qunazoline Phenazine Isothiazole 10-Methylphenothiazine Isoxazole Fur zan SUBSTITUTE SHEEt Substituted derivatives of the unsaturated amines include groups as shown above containing one or more alkyl, -COO(alkyl) or -OCO(alkyl) substituents. With respect to the expression "tertiary amine," this expression denotes amines wherein the nitrogen atom has no hydrogen atoms attached thereto and which are not among the N-heterocyclic unsaturated systems encompassed by the expression "unsaturated amine" as defined above. Typically, the term "tertiary amine" includes trialkylamines, wherein the alkyl groups, which can be the same or different, each preferably contain 1 to 8 carbon atoms; trialkoxyamines wherein the alkoxy portions each contain 1 to 8 carbon atoms; tertiary saturated cyclic amines such as quinuclidine or substituted quinuclidine (e.g., 3-acetoxyquinuclidine) ; and N-substituted derivatives of secondary saturated cyclic amines [e.g., an N-substituted derivative of morpholine, pyrrolidine, imidazolidine, pyrazolidine, piperidine or piperazine, wherein the N-substituent can be a group such as (Cχ-C8)alkyl] , optionally containing additional substituents such as methyl. Preferred quaternary ammonium salts include those derived from 1,2-dimethylpyrrolidine, 3-acetoxyquinuclidine, 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 β-hydroxymethylene and R^ is chloromethyl, most especially when R2 is lower alkyl. &:- : ■ :.% i' ~ $l°~~~ ft 'Vf , Ltϊ 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, Ri 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 R- are each a hydrogen atom and the 1,2-linkage is unsaturated) , most especially when 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 6α- and/or 9α-fluoro and 16 -or 16 -methyl congeners of the compounds indicated in the preceding paragraph. Within this group, the compounds wherein Z, X, Rx 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 Ri 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 Rj 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, 0 X, x and R2 are defined as hereinabove, R3 is α-0R2, and the remaining structural variables are identical to those of triamcinolone, particularly when Rx 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 β-hydroxymethylene, wherein X is oxygen, wherein R2 is Cχ-Cg alkyl (particularly methyl, ethyl, propyl or isopropyl) , and wherein Rx is Cχ-Cg alkyl, Cχ-Cg (monohalo)alkyl (particularly chloro ethyl) or -CH2-Y- (Cχ-Cg alkyl) wherein Y is defined as hereinabove (particularly when the Cχ-Cg 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 β-hydroxymethylene and X is oxygen utilizes steroidal starting materials of the formula OH wherein R4, R5 and the dotted line in ring A are defined as before and R3 1 is hydrogen, α-methyl, β-methyl, α-OH, β-OH or =CH2 (and which can be conveniently prepared by treatment of the corresponding 21-hydroxypregnenolones of the formula: SUBSTITUTE SHEET wherein R3' , R4 , R5 and the dotted line in ring A are defined as above with aIθ4 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 R2I and KOH, wherein 2 is defined as above, under anhydrous conditions, in an appropriate inert organic solvent such as dimethylsulfoxide (DMSO) , 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 about 0°C and room temperature, for about 1 to 6 hours. The resultant novel 17α-alkoxy 17β- carboxylate has the formula: iillii πϊ SIIEEI wherein R2, R4, R5 and the dotted line in the A ring are defined as above and R3" is H, α-CH3, β-CH3, α-OR2, β-OR2 or =CH2. When R3" in the starting material of formula (II) is α-OH or β-OH, sufficient R2I is generally employed to ensure formation of the alkoxy grouping at the 16-position as well as at the 17-position [i.e., when R3 1 in formula (II) is OH, R3 n in the resultant intermediate of formula (III) is cr or β-0R2_ . 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 R2I 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 17 - and 17 -substituents, the resultant novel steroid of formula (III) is converted to its corresponding 17β-carboxylic acid of the formula: _ 't ~ v _■ i s^i ~ ~Tca '-" "(Jj/ifc su wherein R2, R4 , R5 and the dotted line in the A ring are defined as above and R3" is H. The novel steroid (IV) is typically formed by reacting the steroid of (III) with KOH, under anhydrous conditions, in an appropriate inert organic solvent such as dimethylsulfoxide (DMSO) , dichloromethane, chloroform or tetrahydrofuran. After the above-described preparation of the novel steroid of formula (IV), the formula (IV) is converted to its corresponding metal salt of the formula: whύiil lt ζki 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 (V) is typically formed by reacting the steroid of formula (IV) 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 (V) is reacted with a compound of the formula Rχ-W wherein Rx 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 point of the solvent (i.e., acetonitrile, tetrahydrofuran, etc.) When it is desired to introduce a halosubstituted Rx grouping into the steroid, e.g., when a compound of formula (I) wherein Rx is chloromethyl is desired, it has been found that the reaction proceeds well using hexamethylphosphoramide as the solvent at lower temperatures (0-10°C) and employing a Rχ-W reactant wherein W is iodine (e.g., iodochloromethane) . When a non-halogen containing R grouping is desired (e.g., Rl = alkyl or -CH2COOR where Rg is alkyl, etc.), no such restrictions need be placed on the R^- 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 Rx contains a sulfinyl or sulfonyl grouping is desired, such a , -. s -~r.---'-- ~ t ~ ' PUCE" SiiBSUKϋ ii: aHtfc grouping is not generally introduced via the Rχ-W reaction, but is subsequently prepared from the corresponding thio steroid, as described below. The compounds of formula (I) wherein Rx (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 Rx is -CH-S-(lower alkyl) [wherein R9 is Rg 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 m-chloroperoxy-benzoic 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 Rx is -CH-SO-(lower alkyl), or Rg with 2 equivalents of m-chloroperoxybenzoic acid to afford the corresponding compound of formula (I) wherein Rx is -CH-SO2(lower alkyl). This type of Rg reaction can also be utilized to prepare compounds of formula (I) wherein Rx is -CH2COOR wherein Rg 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 Rx 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 substituent is lower alkylsulfinyl or lower alkylsulfonyl, from the ■ • * - _ "^ ϊ 'τ ,, ' ri r f ■■ ___■______■ corresponding lower alkylthio-substituted formula (I) steroids. When the compounds of formula (I) wherein R3 is α- or β-hydroxy are desired, same can be prepared by partial acid hydrolysis of the corresponding compounds of formula (I) wherein R3 is α- or -0R2, in a suitable solvent medium. Use of a mild reagent, e.g., oxalic acid in methanol, is desirable. Alternatively, hydrolysis of the 16-alkoxy to the 16- hydroxy compound could be carried out at an earlier stage in any synthetic scheme described herein after the introduction of the 16,17α-alkoxy, 17β-σarboxylate groupings, e.g., selective hydrolysis of an intermediate of formula (III) having 16 and 17α-alkoxy groupings to the corresponding 16-hydroxy 17α-alkoxy, followed by a two-step conversion to the corresponding compound of formula (I) as described supra. Another process for the preparation of the compounds formula (I) wherein Z is β-hydroxymethylene and X is oxygen utilizes the same 17α-hydroxy-17β- carboxylic acid starting materials of formula (II) as are employed in the synthetic scheme supra, but involves formation of the 17β-COORχ grouping prior to introduction of the 17α-0R2 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 KOH in ROH to form the corresponding novel steroid of the formula: ~ rr ϋvϋw i_- .HEEΪ wherein Rx, R3' , R4, R5 and the dotted line in ring A are defined as above, which is in turn reacted with R2I wherein R2 is defined above, to afford the corresponding 17 -alkoxy-17β-carboxylate of formula (I) . Thus, again, when the starting material contains a 16-hydroxy group, the 16-alkoxy-17β-carboxylate of formula (I) will be formed which can then be selectively hydrolyzed, " if desired, to the corresponding 16-hydroxy-17 -carboxylate of formula (I). After the above-described introduction of the 17 β-carboxylate substituent, the resultant novel steroid of formula (VI) is converted to its corresponding 3-(l' ,3'-dioxacyclopent-2'-yl) of the formula: HEX wherein Rx, R3' , R4 and R5 and the dotted line are defined as above and R3' is H. The novel steroid (VII) is typically formed by reacting the steroid of (VI) with ethylene glycol in a solvent such as g ^ -toluenesulfonic acid. After the above-described introduction of the heterocyclic group at the 3-position, the resultant novel steroid of formula (VII) is converted to its corresponding 17 -alkoxy compound of the formula: Silfttillbi ' MEET wherein Rχ R2, R4, and R5 and the dotted line are defined as above and R3 1 is H. The novel steroid (VIII) is typically formed by reacting the steroid of (VII) with OH, under anhydrous conditions, in an appropriate inert organic solvent such as dimethylsulfoxide, dichloromethane, chloroform or tetrahydrofuran. After the above-described introduction of the 17α-alkoxy substituent, the resultant novel steroid of formula (VIII) is converted to the corresponding 3- oxo-17β-carboxylic acid of formula (IV) as previously described: SUBSTITUTE SiEEI wherein 2, R3' , R4, R5 and the dotted line are defined as above and R3* is H. The novel steroid of formula (IV) is typically formed by reacting the steroid of formula (VIII) with KOH, under anhydrous conditions, in an appropriate inert organic solvent such as dimethylsulfoxide, dichloromethane, chloroform or tetrahydrofuran. The reaction conditions used to convert III to IV are substantially the same as those used to convert VIII to IV. After the above-described conversion of the 17 -carboxylate to the 17 -carboxylic acid moiety and conversion of the heterocyclic substituent to the oxo substituent at the 3-position, the resultant novel steroid of formula (IV) is reacted with MOH or MOR to form the corresponding intermediate of the formula (V) as previously described: SHEET wherein R2, R3, R4, R5 and M and the dotted line in ring A are defined as above, which is then reacted with RxW wherein Rx and W are defined as above, to afford the corresponding 17β-carboxylate of the formula: tϋiϋiffi)!£ SHEET wherein x, R2, R3' , R4, R5 and the dotted line in ring A are as defined above. Thus, again, when the starting material contains a 16-hydroxy group, the 16- alkoxy-17 -carboxylate of formula (I) will be formed which can then be selectively hydrolyzed, if desired, to the corresponding 16-hydroxy-l7 -carboxylate of formula (I) . And, again, the compounds of formula (I) in which Rx 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 Rx is a sulfinyl- or sulfonyl-containing group [e.g., when Rx is -CH-SO- (lower alkyl) or -CH-SO2- (lower Rg Rg alkyl) ] can be prepared by oxidation, preferably with m-chloroperoxybenzoiσ acid, of the corresponding compounds of formula (I) in which Rx is a thio- containing group. Ϊ? F* { flTBϊE SjSEEI 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 Rx or R2 is halo- substituted can be subjected to a halogen exchange reaction in order to replace the halogen with a different halogen according to the order of reactivity Cl<Br<I. For example, reacting a chloroalkyl 17 - carboxylate of formula (I) with an alkali metal iodide, e.g., sodium iodide, will afford the corresponding iodoalkyl 17β-carboxylate. Similarly, a bromide salt (e.g., lithium bromide) can be reacted with a chloroalkyl 17 -carboxylate to give the corresponding bromoalkyl 17β-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 17β-carboxylate or an iodoalkyl 17β- 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 R is fluoromethyl or fluoroethyl. The 21-hydroxypregnenolones from which the steroidal starting materials of formula (II) are prepared can be obtained commercially or prepared by known methods. Likewise, the nonsteroidal starting syesϊiTiiE S EL materials used in the various processes discussed above are commercially available or can be prepared by known chemical procedures. In yet another aspect, the present invention provides novel compounds of the formula: wherein x, 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 llβ-hydroxy compounds of formula (I) . Thus, a starting material corresponding to formula (II) but having an 11-keto group is reacted with R2I, to afford the corresponding novel intermediate corresponding to formula (III) but having an 11-keto group; that intermediate is then SHEET. converted to the corresponding novel intermediate corresponding to formula (IV); that intermediate is then converted to its metal salt, which corresponds to formula (V) except for the presence of an 11-keto instead of an llβ-hydroxy group; and the metal salt is then reacted with RxW to afford 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 Rx 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 llβ-hydroxy steroids used therein, e.g., replacing the 11-hydroxy group in formulas (VI) , (VII) and (VIII) with an 11- oxo group and otherwise proceeding as described hereinabove for the reactions (II)—=» (VI)— - ~~ (VII)— ■ * (VIII )→a (IV)-» (V)—* (I) . 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 St acid (e.g. formic acid, acetic acid, trifluoroacetic acid) , an alcohol (e.g. methanol, ethanol) , a halogenated hydrocarbon (e.g. chloroform, dichloro¬ methane) , 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 moles, per mole of the compound of formula (I) . The reaction is usually carried out at a temperature of 0° to 40°C, preferably at about 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 llβ-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 llβ-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 r dlllU l-. ώ SlHlEET thought that the compounds of formula (IX) are microbiologically reduced by bacteria in the body (e.g. in the colon) to the highly active ll -hydroxy steroids, which elicit the desired anti-inflammatory response. The preferred compounds of formula (IX) are those which are precursors of the preferred compounds of formula (I) wherein Z is β-hydroxymethylene, namely corresponding 11-keto compounds of formula (IX) . An especially preferred group of compounds of formula (IX) consists of those wherein X, Rx 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 6 - and/or 9 - fluoro and the 16α- or 16β-methyl congeners thereof, particularly when Rx 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 Cχ-Cg alkyl and Rx is Cχ-Cg alkyl, Cχ-Cg (monohalo)alkyl [particularly chloromethyl] or -CH2-Y-(Cχ-Cgalkyl) [particularly -CH2-Y-CH3] . Under oxidation conditions, it is important to protect the 11-hydroxy group when preparing the compounds of the present invention since it is known that the mixture of dimethylsulfoxide and acetic anhydride has oxidative properties with respect to primary and secondary alcohols. Therefore, it is possible to prepare a 17 β-methylthiomethyl ether derivative having the formula TiTii t (. ' ffl wherein R3, R4, R5, Z and the dotted line in ring A are as previously defined, from the compound of formula (I) using triethyla ine and chloromethylmethylsulfide (CICH2SCH3) . The methylthiomethyl ester of formula (X) is then treated with trifluoroacetic anhydride and pyridine at about -15°C to give mainly the desired 11 -trifluoroacetate derivative having the formula wherein R3, R4, R5 and the dotted line in ring A are as previously defined. The 11 -trifluoroacetate of formula (XI) is then transformed to the 17c. - methylthiomethyl ester of formula (XII) using dimethyl sulfoxide and acetic anhydride under the same conditions as previously described. OCH 2 SCH 3 ' mmmi SHEET wherein R3, R4, R5 and the dotted line in ring A are as previously defined. The compound of formula (XII) is then reacted with triethylamine and methanol in a sodium bicarbonate and water solution to form a compound having the formula OCH-S E, I 2 3 c=o wherein R3, R4, R5 and the dotted line in ring A are as previously defined. Dexamethasone-type compounds having the structure: *!_!!_ K' 6 ' i mi (XIV) may be prepared in a manner well-known to those of average skill in the art. For instance, a suitable starting material may be __!___?I wherein R3 is as previously defined. The compound of formula (XIII) is reacted with KOH in methanol and the potassium salt of tertiary butyl hydroxide in tetrahydrofuran. The novel steroid formed has the formula: OH C=0 wherein R3 is as previously defined. The resultant novel steroid of formula (XV) is then converted to its corresponding chloromethyl ester of the formula: SOBSTilile SHEET wherein R3 is as previously defined. The novel steroid (XIV) is typically formed by reacting the steroid of (XV) with KOH and chloromethylmethyl chlorosulfate (ClCH2gθ2Cl) under phase transfer conditions. The article "Chlorosulfates as Reagants in the Synthesis of Carboxylic Acid Esters Under Phase-Transfer Conditions" by Binderup E. and Hansen E.T., in Synthetic Communications, 14(9), 857-864 (1984) discloses the use of chloromethyl chlorosulfate in the synthesis of chloromethyl esters of sensitive carboxylic acids under phase transfer conditions, which synthesis is applicable hereto. 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, 17α-butyrate, betamethasone 17-valerate, triamcinolone, betamethasone dipropionate and the like. TOPICAL VASOCONSTRICTION TEST A topical vasoconstriction test was conducted using the general method of McKenzie, A.W. and R.B. Stoughton, Arch. Dermatol, 86, (1962), 608-10. The topical vasoconstriction test was done in order to røϊ£7? ϊiϊ. evaluate the anti-inflammatory potency of the novel compounds of the present invention. A 0.03M solution of the test compound in acetone/isopropylmyristate 90:10 volume/volume was prepared. An aliquot of 0.05 milliliter was applied to a circular patch, one centimeter in diameter, which was in turn applied against the skin of the flexor surface of the forearm (previously cleansed with ethanol 95% and dried) . This application was occluded with a water-impervious film. The patch was removed after about six hours and the blanching score was evaluated one hour later. Two control compounds were used at the same time and under the same conditions. The control compounds were hydrocortisone 17-valerate and cortienic acid 17- ethylcarbonate chloromethylester. The experiment was made in duplicate and the average estimation values for the blanching activity are reported in Table I. The left column of Table I indicates the 17α- substituent of the structure: Cl OR. TABLE I BLANCHING STUDIES * The 17-methoxy homologue was determined in a previous study to have low activity. ** Simple study - duplicate experiment not conducted. 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 pharmaceu¬ tical 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; SUBSTITUTE SHEET 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, aluminum 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 phenoxyethyl alcohol. suBSTjiiiTE SUET Lotions may be formulated with an aqueous or oily base and will in general also include one or more of the following, namely, emulsifying agents, dispersing agents, suspending agents, thickening agents, solvents, coloring agents and perfumes. Powders may be formed with the aid of any suitable 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 suitable propellant, e.g, dichlorodifluoromethane or trichlorofluoromethane. The proportion of active ingredient in the compositions according to the invention will vary with the precise compound used, the type of formulation prepared and the particular condition for which the composition is to be administered. The formulation will generally contain from about 0.0001 to about 5.0% by weight of the compound of formula (I) . Topical 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 -fc SiiEfcT 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 chloromethyl 17α-methoxy-llβ-hydroxyandrost-4-en-3- one-17 β-σarboxylate, 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., trichloro- fluoromethane 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 17α-methoxy-9α -fluoro-11 β-hydroxy-16α- methylandrosta-l,4-dien-3-one-l7 -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 17α-ethoxy-llβ - hydroxyandrost-4-en-3-one 17 -carboxylate, and 1% of a local anaesthetic such as pramoxine hydrochloride, in a mucoadhesive foam base of propylene glycol, ethoxylated stearyl alcohol, polyoxyethylene-10- suBsπππt .EEET stearyl ether, cetyl alcohol, methyl paraben, propyl paraben, triethanolamine, and water, with inert propellents. When a more potent compound of the invention is employed, a less active ingredient generally is used, e.g. 0.05% of chloromethyl 9α- fluoro-llβ -hydroxy-17α-methoxy-16α-methylandrosta- l,4-dien-3-one-17β-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 chlomethyl 17α- ethoxy-llβ -hydroxyandrost-4-en-3-one-l7β-carboxylate (or 20 milligrams of a more potent compound of the invention such as chloromethyl 9α-fluoro-llβ-hydroxy- 17α-isopropoxy-16j_.-methylandrosta-l,4-dien-3-one-17 - carboxylate or chloromethyl 9α-fluoro-ll -hydroxy-16α -methyl-17α-propoxy androsta-1,4-dien-3-one-l7β- 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 si i 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 β C for 3 hours. The product, ll ,17α-dihydroxyandrost-4-en-3-one 17β- 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 1. TU ' I£ EXAMPLE 2 To a solution of powdered potassium hydroxide (2.14 grams) in dimethylsulfoxide (10 milliliters) was added 11β,17α-dihydroxyandrost-4-en-3-one-17β- carboxylic acid (1.7 gram; 4.88 millimoles) . The mixture was stirred for five minutes and immediately followed by addition of methyliodide (1.22 milliliters; 19.5 millimoles). After stirring for one hour and fifteen minutes at 25°C, the mixture was diluted with 100 ml of ethylacetate. The mixture was then washed successively with 10 milliliters water, 10 milliliters a2S2θ3 (5% weight/volume) , 10 milliliters NaHCθ3 (5% weight/volume) and then three additional times with 10 milliliters water. The organic solution was then dried over gSθ4 and evaporated under partial pressure. The white crystalline crude product weighed 1.73 gram (94% theoretical) and had a melting point of 195°C to 201°C. Crystallization from CH2Cl2/Pentane raised the melting point to 215°C to 217°C then 217°C to 218.5°C. Elemental analysis: Required C70.18; H8.57; Found C70.16; H8.62. I.R. (KBr) 3500, 1725, 1655, 1210, CM "2 , H n r (CDCI3) : 0.93 (S,3,18CH j ); 1.43 (S,3,19CH3); 3.10 (S,3,170CH3) ; 5:65 (S,1,C=CH). The product, methyl llβ-hydroxy-17α-methoxyandrost-4- en-3-one-17β-carboxylate, can be represented by the structural formula: EXAMPLE 3 The methyl 11 -hydroxy-17α-methoxyandrost-4-en-3-one- 17β -carboxylate (3.76 grams; 10 millimoles) was stirred overnight (16 hours) at 50°C, under nitrogen in a mixture of powdered potassium hydroxide (4.50 grams) in 15 milliliters dimethylsulfoxide. The reaction mixture was then diluted with 200 milliliters water, acidified with dilute HC1, stirred 30 minutes and extracted with several portions of ethylacetate. The organic layer was then washed with 30 milliliters water, evaporated and taken up into 150 milliliters NaHC03 solution (5% weight/volume) . The aqueous solution was then washed with 30 milliliters methylene chloride, acidified with diluted HC1, filtered, and the residue was dried in vacuo at 40°C overnight. The crude, yellow, pseudocrystalline product, llβ-hydroxy- 17α-methoxyandrost-4-en-3-one-17β-carboxylic acid, weighed 3.05 grains (84% theoretical) H nmr (DMSOdg) : 0.92 (S,3,18CH3); 1.38 (S,3,19CH3); 3.04 (S,3,0CH3); 5.50 (S,1,C=CH); 8.28 (S, <- 1,C00H) . The product can be represented by the structural formula SUBSTITUTE SHET EXAMPLE 4 A 1 normal solution of KOH (3.62 milligrams; 1 millimole) in methanol was added dropwise to the llβ -hydroxy-17 -methoxyandrost-4-en-3-one-l7β-carboxylic acid at 0°C in an ice bath. The solution was evaporated under vacuo and dried thoroughly. The resulting potassium salt was mixed with 10 milliliters dimethylsulfoxide and 4 millimoles chloroiodomethane. After stirring for seven hours at room temperature (24°C) , the mixture contained a precipitate of potassium iodide. The mixture was then diluted with 100 milliliters ethylacetate and washed successively with 18 milliliters water, 10 milliliters Na 2 S2θ3 (5% weight/volume) , 10 milliliters NaHCθ3 and three times with 10 milliliters water. The product was dried over MgSθ4 and evaporated under partial pressure. The dried product was purified by column chromatography from 12 grams of Silica gel (100-200 mesh type 60A special), eluted with EtOAc/CHCl3 20:80 and crystallized from ethylacetate/ether to give a final product that melted at 195°C-196°C and 1H n r (CDC1 3 ) : 0.95 (S,3,18CH3); 1.43 (S,3,19CH3) 3.12 (S,3,0CH3); 5.60 (S,1,C=CH); 5.75 (S,2,COOCH2Cl) . IR (KBr) : 3400, 1755, 1655, 1205, 1110 (ether) cm -1 . Elemental analysis: Required: C64.30; H760; C18.63; Found: C64.16; H7.63; C18.63. The product, chloromethyl llβ -hydroxy-17α-methoxyandrost-4-en-3-one-l7β- carboxylate, can be represented by the structural formula: siπm SHET EXAMPLE 5 llβ, 17α-Dihydroxyandrost-4-en-3-one-17β - carboxylic acid (3.484 grams; 10 millimoles) was dissolved into methylalcohol. A 10 milliliter solution of 1 normal KOH in methanol was added dropwise to the cold mixture. The solution was evaporated under vacuo and the residue was dried thoroughly and taken up into 20 milliliters dimethylsulfoxide and 2.5 milliliters methyliodide (48 millimoles) . After stirring overnight at room temperature, the mixture was diluted with 150 milliliters ethylacetate and washed successively with 50 milliliters NaHCθ3 (3% weight/volume) , 50 milliliters Na2S2θ3 (5% weight/volume) and three additional times with 50 milliliters water. The mixture was dried over MgSθ4 and evaporated. The product crystallized from the ethylacetate, and 3 crops gave 3.31 grams (92%) of white crystals melting at 206°C to 207°C (little at 207°C to 208°C) . 1H nmr (CDC1 3 ) : 0.98 (S,3,18CH3); 1.45(S,3,I9CH3) ; 3.75 (S,3,COOCH_3) ; 5.67 (S,1,C=CH). The product, methyl BSΠΠΠE sf E ll ,17α-dihydroxyandrost-4-en-3-one-l7 -carboxylate, can be represented by the structural formula: EXAMPLE 6 The methyl llβ-17α-dihydroxyandrost-4-en-3- one-17 -carboxylate (10.332 grams; 22.5 millimoles) was taken into 178 milliliters of ethylene glycol, then 85 milligrams of p-toluenesulfonic acid (anhydrous, crystallized from benzene) was added. The solvent was slowly distilled off at 0.3-1 mm Hg for two hours. The distillation head was 60°C to 70°C and the mixture turned red after about 30 minutes when the compound started to precipitate. The suspension was neutralized with NaHCθ3 (the mixture turned colorless) , then the suspension was poured into 200 milliliters of cold water and stirred for at least 30 minutes. The white precipitate was isolated by filtration, washed with water and dried in a freeze dryer. Thin layer chromotography showed a small amount of starting material and a few percent of a product that was identified as the Δg.ll 3,3' cyclic ketal. Triturating the product with a few milliliters of ether yielded white crystals of melting point 204°C to 205°C that had satisfactory elemental analysis. Required: C67.96; H8.43; Found: C67.71; H8.47. *H nmr (CDCI3) : 0.93 (S,3,18CH3); 1.27 (S,3,19CH3) 3.70 (S,3,COOCH_3) ; 3.90 (S,4,OCH2CH2O) ; 5.12 (S,1,C=CH). The product, methyl ll ,17α-dihydroxyandrost-5-en-3- (1' ,3'-dioxacyclopent-2'-yl)-17β-carboxylate, can be represented by the structural formula: EXAMPLE 7 Powdered KOH (1.2 grams) was stirred 5 minutes into 15 milliliters dimethylsulfoxide, then 2.15 grams methyl llβ ,17α-dihydroxyandrost-5-en-3- (1* ,3*-dioxacyclopent-2*-yl)-17 -carboxylate (5.3 millimoles was added. This was immediately followed by the addition of 1.7 milliliters iodoethane (21.2 millimoles) and the mixture was stirred at 25°C for 23 hours. The reaction mixture was then diluted with 158 milliliters ethylacetate and washed successively with 50 milliliters Na2S2θ3 (5% weight/volume) , and three times with 50 milliliters water. The mixture was then dried over MgSθ4 and evaporated to give 1.92 grams of a crude product (83% theoretical) . Some product had been extracted in the aqueous phase and was identified UTE SiEEI as cortienic acid-3,3'cyclic ketal. Purification from 45 grams of silica gel, eluting with benzene/EtOAc 80:20 yielded 1.1 gram of a white compound. IR (KBr) : 3500, 1725, 1215, 1110, 1085 cm "1 . H nmr 0.90 (S,3,18CH3); 1.10 (T,3,J=7Hz,OCH 2 CH3) ; 1.28 (S,3,19CH3); 3.32 (M,2,0CH2CH 3 ) 3.70 (S,3,C00CH3) ; 3.95 (S,4,OCH2CH θ) ; 5.15(S,1,C=CH) . The product, methyl 11 -hydroxy-17α-ethoxyandrost-5-en-3-(1* ,3'- dioxacyclopent-2*-yl)-17β-carboxylate, can be represented by the structural formula: Substitution of an equivalent quantity of iodopropane for iodoethane employed above and substantial repetition of the foregoing procedure afforded methyl llβ-hydroxy-17α-propoxy-androst-4-en- 3-(1' ,3'-dioxacyclopent-2'-yl)-17β-carboxylate, having an identical H nmr spectrum to that presented above without the triplet of 1.10 ppm. Substitution of bromobutane for iodoethane at a ratio of 4 parts bromobutane per part methyl llβ,17α-dihydroxyandrost-5-en-3-(1' ,3'-dioxacyclopent- 2*-yl)-17β-carboxylate and substantial repetition of S J : JBSΠΠΠE SJEEI the foregoing procedure while allowing the reaction to proceed for three days afforded methyl ll -hydroxy-17 - butoxyandrost-5-en-3-(l' ,3'-dioxacyclopent-2'-yl)-17β- carboxylate. The crude product was a mixture of the methyl and butyl ester. EXAMPLE 8 The methyl ll -hydroxy-17 -ethoxyandrost-4- en-3 (1* ,3'-dioxacyclopent-2*-yl)-17β-carboxylate (1.1 grams, 2.5 millimoles), the first product described in Example 7, was stirred for 17 hours under nitrogen at 60°C in 5 milliliters dimethyl sulfoxide containing 0.5 grams of powdered KOH. The reaction was then taken up into 150 milliliters of water, acidified slowly with dilute HC1 to pH 1.2, stirred for fifteen minutes and extracted four times with 80 milliliters EtOAc. The mixture was dried over MgSθ4 and evaporated. The crude product was dissolved in NaHCθ3 (3% weight/volume) , washed with EtOAc and acidified. Drying gave 669 milligrams (64%) of acid (11) . IR (KBr) : 3500, 1715, 1670, 1085 cm "1 . H nmr (DMSOdg) : 0.92 (S,3,18CH3); 1.05 (T,3,J=7H z ,OCH 2 CH3) ; 1.37 (S,3,19CH3); 3.28 (M,2,OCH2CH3) ; 5.55 (S,1,C=CH). The product, llβ-hydroxy-17α-ethoxyandrost-4-en-3-one-17β- carboxylic acid, can be represented by the structural formula: TE S EEX Likewise, the second and third products described in Example 7 were subjected to substantially the same procedure described above. The products obtained were llβ-hydroxy-17α propoxyandrost-4-en-3- one-17 -carboxylic acid and llβ-hydroxy-17α- butoxyandrost-4-en-3-one-l7β-carboxylic acid, respectively. EXAMPLE 9 The potassium salt of the first product of Example 8, llβ-hydroxy-17α-ethoxyandrost-4-en-3-one- 17β-carboxylic acid (1.58 millimole) was prepared in substantially the same manner as the potassium salt of Example 4. That is, the first product of Example 8 was stirred at room temperature for eight hours in 10 milliliters dimethylsulfoxide containing 1.25 milliliters chloroiodomethane. The work-up described in Example 4 was followed and 0.594 gram of a crude product was obtained that was chromatographed on 15 grams silica gel, eluting with Hexane/EtOAc 80:20 then 70:30. Crystallization from CH2Cl2/Pentane gave white crystals melting at 203°C to 205°C. IR (KBr) : 3400, 1750, 1650, 1205, 1110, 1060 cm -1 H nmr (CDCI3) : 0.95 (S,3,18CH j ); 1.13 (T, 3 , J-7H z ;OCH 2 CH3) ; 1.43 (S,3,19CH3); 3.38 (M,2, OCH CH3) ; 5.65 (S,1,C=CH); 5.77 (S,2,COOCH_?Cl) . Elemental analysis: Required: C65:08; H7.83; C18.34 Found: C64.86, H7.84; C18.32. The product, chloromethyl 11 β-hydroxy-17 α- ethoxyandrost-4-en-3-one-l 7 β-carboxylate, can be represented by the structural formula: OCH^Cl Likewise, the second and third products described in Example 8 were subjected to substantially the same procedure described above. The product, chloromethyl llβ-hydroxy-17α - propoxyandrost-4-en-3-one-17 -carboxylate, had a melting point of 194°C to 195°C. IR(KBr) : 3400; 1750, 1650, 1205, 1110, 1060, 1030 cm "1 H nmr (CDCI3) : 0.88 (T,3,J=7H z ,OCH 2 CH 2 CH3) ; 0.98 (S,3,18CH j ); 1.42 (S,3,19CH3); 3.18 (M,2,OCH2CH2CH3) ; 5.65 (S,1,C=CH); 5.77 (S,2,COOCH2Cl) . Elemental analysis: Required: C65.66; H8.04; C18.08; Found: C65.78; H8.09; C18.14. TIΠE HEET The product, chloromethyl llβ-hydroxy-17α- butoxyandrost-4-en-3-one-l7β-carboxylate, had a melting point of 150°C to 151°C IR(KBr) : 3400, 1750, 1645, 1200, lllθ(ether), 1070(llβ0H) H nmr (CDC1 3 ) : 0.98 (S,3,18CH3); 1.45 (S,3,19CH_3); 3.28(M, 2,0CH_2CH2CH2CH3) ; 5.65 (S,1,C=CH); 5.77 (9,2,COOCH_2Cl) . EXAMPLE 10 Methoxy ll ,17 -dihydroxy-l,4-diene-3-one-17 - carboxylate (prednisolone) (30 grams; 0.08 moles) was placed in a solution of tetrahydrofuran and methanol. A warm water solution of 53 grams NaIθ4 was added dropwise. The reaction mixture was stirred for two hours at room temperature, then while the stirring was continued, ice water was added to obtain crystalline materials. The crude crystals were washed with water then stirred and suspended in 800 milliliters of water for 30 minutes. The crystals were filtered, washed with water and dried. The colorless crystal product weighed 27 grams (77 millimoles) which represents a 97% yield and had a melting point of 236°C to 238°C. The product, ll ,17α-dihydroxy-l,4-diene-3-one-17β- carboxylic acid, can be represented by the formula: EXAMPLE 11 To an ice cooled mixture of llβ,17c - dihydroxy-l,4-diene-3-one-17 -carboxylic acid (5.2 grams; 15 millimoles) as prepared in Example 10 and KOH (6.7 grams; 12 moles) in 30 milliliters of dimethylsulfoxide was added 3.7 milliliters methyliodide (60 millimoles) under nitrogen. The mixture was stirred for 5 hours at room temperature. The reaction mixture was diluted with ethyl acetate. The organic phase was separated and washed successively with water, Na2S2θ3 solution, NaHCθ3 solution and finally with water. The mixture was dried over gSθ4 and the solvent was evaporated. The resulting crystalline material was recrystallized from CH2CI2 hexane to afford colorless prisms. The " product weighed 2.7 grams (7.2 millimoles) which represents an 83% yield and had a melting point of 241°C to 246°C. C 22 N 30°5 374 * 47ϊ Theoretical: H 8.07; C 70.56; Found: H 8.13; C 70.54. The product, methyl llβ- hydroxy-17 -methoxy-3-oxo-androsta-l,4-diene-l7β- carboxylate, can be represented by the formula: irø Tim SHEET In a similar manner, substitution of an equivalent quantity of propyl iodide (5.8 milliliters; 60 millimoles) for the methyl iodide employed in the first part of this example and substantial repetition of the procedure there detailed affords 1.9 gram propyl llβ-hydroxy-17α-propoxy-androsta-l,4-diene-3- one-17β-carboxylate (4.4 moles; 29% yield). The final product, after crystallization from CH2CI2 hexane, melts at 189°C to 190°C. C 2g H 38 0 5 430.58: Theoretical: H 8.99; C 72.53; Found: H 9.04; C 72.26. EXAMPLE 12 A mixture of 5.4 grams KOH (9 millimoles) and 4.5 grams methyl llβ-hydroxy-17α-methoxy-androsta- l,4-diene-3-one-17 -carboxylate in 20 milliliters dimethylsulfoxide was stirred under nitrogen for five hours at 50°C. Water was added to the reaction mixture and the mixture was then acidified with 10% HC1. The reaction mixture was stirred for 30 minutes. The ethylacetate extract was washed with water and the solvent was evaporated. The residual solid was neutralized with sodium bicarbonate solution and the mixture was washed with dichloromethane. The aqueous phase was acidified with 10% HC1 and the deposited crystalline material was filtered under suction. The dried crude crystals were washed with water and dried. The crude product was subjected to silica gel chromatograph eOH/CH2Cl2)=1/200-1/50. The product so obtained was recrystallized from methanol. The colorless prism product was 2.3 grams (6.4 millimoles) which represents yield of 53% and had a melting point of about 256°C to 257°C. c χ H 28°5 : 360 « 44: Theoretical: H 7.83; C 69.98; Found: H 8.02; C 70.01. SlSTiTlTE SHEET The product, llβ-hydroxy-17α-methoxy-androsta-l,4- diene-3-one-17β-carboxylic acid, can be represented by the formula: OH I C=0 OCH. I .n a a similar y manner, the second product of Example 11, propyl llβ-hydroxy-17α-propoxy-androsta- l,4-diene-3-one-17β-carboxylate (1.6 gram; 3.7 millimoles) and 1.8 gram KOH (32 millimoles) in 20 milliliters dimethylsulfoxide was heated at 50°C under stirring in nitrogen for 20 hours. The crude acid was worked up and chromatographically purified ( eOH/CH2Cl2= 1/500-1/30) . Recrystallization from ether afforded 0.62 grams llβ-hydroxy-17α-propoxy- androsta-1,4-diene-3-one-17β-carboxylic acid representing a 43% yield and had a melting point of 223°C to 225°C. C 2 3 H 2°5 : 388.50: Theoretical: H 8.30; C 71.11; Found: H 8.74; C 71.05. Sπf.ΦTϋT.iS *3 r_~ <:*•_ * =•-. EXAMPLE 13 To 5 milliliters of 1 normal KOH/MeOH solution which was cooled with ice, was added 1.8 gram ll -hydroxy-17α-methoxy-androsta-l,4-diene-3-one-17β- carboxylic acid. The mixture was worked up to dryness under vacuum. The dried mixture was dissolved in 5 milliliters dimethylsulfoxide then 3.6 grams chloroiodomethane (20 millimoles) was added. The reaction mixture was stirred at room temperature for six hours. The ethylacetate extract was washed with water, sodium thiosulfate solution, sodium bicarbonate solution and finally with water. The solution was dried over MgSθ4 and the solvent was evaporated. After silica column chromatography (MeOH/CH2Cl2=250- 1/100) , the product was recrystallized from ethylacetate. The colorless prism product was 0.46 gram (1.1 millimoles) representing a yield of 22% and had a melting point of 217°C to 218°C. C22H29CIO5: 408.92: Theoretical: H 7.15; C 64.62; Found: H 7.24; C 64.48. The product, chloromethyl llβ- hydroxy-17α-methoxy-androsta-1,4-diene-3-one-l7β- carboxylate, can be represented by the formula: In a similar manner, the second product of Example 12, 11β-hydroxy-17α-propoxy-androsta-l,4- diene-3-one-l7β-carboxylic acid (0.55 gram; 1.4 millimole) was heated at the same manner to the first part of this example. Substantial repetition of the procedure there detailed afforded 34 milligrams chloromethyl 11 -hydroxy-17α-propoxy-androsta-1,4- diene-3-one-l7 -carboxylate (0.08 millimoles) which represents a yield of 6% and a melting point of 184°C to 187°C. C 24 H 33 C10 5 :436.97: Theoretical: H 7..61; C 65.97; Found: H 7.74; C 65.65. SUBSTITUTE SHEET EXAMPLE 14 To a suspension of 11β,17α-dihydroxyandrost- 4-en-3-one 17β-carboxylic acid (cortienic acid; 3.0 grams) in acetonitrile (30 milliliters) was added triethylamine (1.2 milliliters) followed by chloromethylmethylsulfide (CICH2SCH3) . The resulting solution was refluxed overnight. After cooling at room temperature, the solvent was evaporated and the residue was triturated with tetrahydrofuran (30 milliliters) . The precipitate was filtered off and washed with additional tetrahydrofuran. The filtrates were combined and evaporated under reduced pressure to obtain 3.0 grams of product having the following: H nmr (CDCI3) : 1.06 (s, 3, I8CH3) ; 1.47 (s, 3, I9CH3) ; 2.30 (s, 3, SCH3) ; 4.52 (m, 1, 11CH) ; 5.27 (s, 2, OCH2SCH3); 5.73 (s, 1, C=CH) . The product, methylthiomethyl llβ,17α-dihydroxyandrost-4- en-3-one-l7β-carboxylate, can be represented by the structural formula: SUBSTITUTE SHEET EXAMPLE 15 The methylthiomethyl llβ,17α- dihydroxyandrost-4-en-3-one-l7β-carboxylate (0.817 gram) was stirred for 10 minutes in pyridine (10 ml) at -15°C and trifluoroacetic anhydride (1.1 equivalent) was added dropwise. After stirring for 15 minutes at -15°C, the cold bath was removed and the solution was allowed to slowly warm up to room temperature and poured into cold brine (100 milliliters) . The resulting precipitate was stirred for 30 minutes and filtered off, washed with water and dried. The dried product was purified from 30 grams of silica gel and eluted with EtOAc/Hexane 20 to 60% and gave 0.75 gram of final product having the following elemental analysis: H nmr (CDCI3) : 0.92 (s, 3, I8CH3) ; 1.29 (s, 3, I9CH3) ; 2.24 (s, 3, SCH3) ; 5.24 (ABq,Δv=0.13 ppm; J AB =12Hz, CH2SCH3O) ; 5.71 ( , 1, 11CH) ; 5.76 (s, 1, C=CH) . IR (CDCI3) : 3400, 1780, 1730, 1670cm . The product, methylthiomethyl 17α- hydroxy-11 -trifluoroacetoxyandrost-4-en-3-one-l7β- carboxylate, can be represented by the structural formula: SUET EXAMPLE 16 The methylthiomethyl 17α-hydroxy-ll - trifluoro-acetoxyandrost-4-en-3-one-l7β-carboxylate (0.75 gram) was dissolved in 20 milliliters of a mixture containing equal parts (volume/volume) of dimethylsulfoxide and acetic anhydride. The solution was stirred for two days at room temperature under an atmosphere of nitrogen, concentrated under vacuo (1-2 mm Hg) and poured into a saturated NaHCθ3 solution (200 milliliters) . After stirring an additional hour, the precipitate was filtered off, washed with water and dried to obtain 0.744 gram of product having the following elemental analysis: H nmr (CDCI3) : 0.90 (s, 3, I8CH3); 1.30 (s, 3, I9CH3); 2.18 (s, 3, SCH3) ; 2..24 (s, 3, SCH3); 4.44 (ABq, Δv=0.07ppm, J Aβ =12Hz, OCH2SCH3) ; 5.22 (ABq, Δv=0.29ppm, J Aβ =12Hz, COOCH2SCH3) . IR(KBr): 1780, 1730, 1670cm "1 . The product, methylthiomethyl 17α-methylthiomethyloxy-llβ- trifluoroacetoxyandrost-4-en-3-one-17β-carboxylate, can be represented by the structural formula: 0CH 2 SCH 3 C=0 SUBSTITUTE SHEET EXAMPLE 17 The methylthiomethyl 17α-methylthiomethyloxy- 11 -trifluoroacetoxyandrost-4-en-3-one-l7β- carboxylate (0.677 grams) was refluxed for four hours in wet methanol (10 milliliters) containing sodium bicarbonate (150 milligrams) . The solution was then poured into cold stirring water (100 milliliters) and stirred another 30 minutes. The precipitate was filtered off, washed with water and dried. The pure final product, from silica gel chromatography (17 g) , eluting with EtOAc/Hexane 30:70 and crystallization from CH2Cl2/Pentane, had a melting point of 195°C to 196 e C. H nmr (CDCI3) : 1.01 (s, 3, I8CH3); 1.46 (s, 3, I9CH3); 2.19 (s, 3, SCH3) ; 2.41 (s, 3, SCH3); 4.44 ( , 3, OCH2S and 11CH) ; 5.21 (ABq, Δv=0.06 ppm, J Aβ =12Hz, COOCH2S) ; 5.71 (s, 1, C=CH) . IR (KBr) : 3400, 1730, 1655cm "1 . The product, methylthiomethyl 11β-hydroxy-17 -methylthiomethyl- oxyandrost-4-en-3-one-17β-carboxylate, can be represented by the structural formula: SUBSTITUTE SHEET EXAMPLE 18 ll ,17α-dihydroxyandrost-4-en-3-one-17β- carboxylic acid (cortienic acid; 3.48 grams was suspended in methanol (10 milliliters) and a 1 normal solution of KOH in methanol (10 milliliters) was added dropwise. After concentration under vacuo and drying, the potassium salt was taken up into dimethylsulfoxide (10 milliliters) and treated with chloroiodomethane (1.5 milliliters). The reaction mixture was stirred at room temperature for five hours, partitioned between CH2CI2 (100 milliliters) and water 100 milliliters) . The organic layer was washed successively with 50 milliliters a2S2θ3 (5% weight/volume) , 50 milliliters of 5% NaHCθ3 and twice with 50 milliliters water. The product was dried over MgS04, filtered and evaporated, giving a mixture containing the desired product plus a compound which was a dimer of the starting material. The pure compound had a melting point of 100°C to 192°C. The product, chloromethyl llβ ,17 -dihydroxyandrost-4-en- 3-one-17β-carboxylate, can be represented by the structural formula: EXAMPLE 19 Chloromethyl 11β,17α-dihydroxyandrost-4-en- 3-one-l7 -carboxylate (3.48 grams) was reacted following the same procedure as in Example 15. Analysis: H nmr (CDCI3) : 0.91 (s, 3, I8CH3) ; 1.30 (s, 3, I9CH3); 5.73 (m, 4, C=CH plus 11CH plus COOCH2CI) . The product, chloromethyl 17α-hydroxy-ll -trifluoroacetoxyandrost-4-en-3-one-l7β-carboxylate, can be represented by the structural formula: SUBSTITUTE SHEET EXAMPLE 20 Chloromethyl 17α-hydroxy-11β- trifluoroacetoxyandrost-4-en-3-one-l7β-carboxylate (3.48 grams) was reacted following the same procedure in Example 16. The final product had the following elemental analysis: H nmr (CDCI3) : 0.90 (s, 3, I8CH3); 1.33 (s, 3, 19CHj); 2.24 (s, 3, SCH3) ; 4.43 (ABq, Δv=0.11ppm, J^llHz, OCH2S) ; 5.74 (m, 4, C=CH plus 11CH plus COOCH2CI) . The product, chloromethyl 17α-methyIthiomethyloxy-11 -trifluoroacetoxyandrost-4- en-3-one-l7β-carboxylate, can be represented by the structural formula: IΠE liEET -72- EXAMPLE 22 Powdered potassium hydroxide (2.14 grams) was stirred for five minutes into dimethylsulfoxide (10 milliliters) . llβ-17α-Dihydroxyandrost-4-en-3-one-17β -carboxylic acid (cortienic acid; 1.7 grams; 4.88 millimoles) was immediately added followed by methyliodide (1.22 milliliters; 19.5 millimoles). After stirring for one hour and 15 minutes at 25°C, the mixture was diluted with ethylacetate (100 milliliters) and washed successively with 10 milliliters water, 10 milliliters Na2S2θ3 (5% weight/volume), 10 milliliters NaHCθ3 (5% weight/volume) and three more times with 10 milliliters water. The organic solution was then dried over MgSθ4 and evaporated under partial pressuree The white, crystalline, crude product weighed 1.73 grams (94% theoretical) and had a melting point of 195°C to 201°C. Crystallization from CH2Cl2/Pentane raised the melting point to 215°C to 217°C, then 217°C to 218.5°C. Elemental analysis: required C70.18; H8.57; found C70.16; H8.62. IR (KBr) : 3500, 1725, 1655, 1210 cm "1 , H nmr (CDCI3) : 0.93 (s, 3, I8CH3); 1.43 (s, 3, I9CH3) ; 3.10 (s, 3, I7OCH3); 3.72 (s, 3, COOCH); 5.65 (s, 1, C=CH) . The product, methyl llβ-hydroxy-17α-methoxyandrost-4-en- 3-one-l7β-carboxylate, can be represented by the structural formula: SUBSTITUTE SHEET -71- EXAMPLE 21 The chloromethyl 17α-methylthiomethyloxy-llβ -trifluoroacetoxyandrost-4-en-3-one-l7β-carboxylate, was reacted following the same procedure as Example 17. The final product had the following elemental analysis: H nmr (CDCI3) : 1.00 (s, 3, I8CH3) ; 1.30 (s, 3, I9CH3) ; 2.18 (s, 3 SCH3) ; 4.41 (ABq, Δv=0.06ppm; J AR =6Hz; OCH2S); 4.44 (m, 1, 11CH) ; 5.67 (s, 1, C=CH) ; 5.77 (ABq, Δv=0.06ppm, J Aβ =6Hz; COOCH2CI) . The product, chloromethyl llβ-hydroxy-17α- methylthiomethyloxyandrost-4-en-3-one-17β-carboxylate, can be represented by the structural formula: SUBSTITUTE SHEET EXAMPLE 23 The methyl llβ-hydroxy-17α-methoxyandrost-4- en-3-one-17β-carboxylate, (3.76 grams; 10 millimoles), was stirred overnight (16 hours) at 50°C, under nitrogen, in a mixture compound of powdered potassium hydroxide (4.50 grams) and dimethylsulfoxide (15 milliliters) . The reaction mixture is then diluted into water (200 milliliters) , acidified with HC1, stirred 30 minutes and extracted with several portions of ethyl acetate. The organic layer was then washed with water (30 milliliters) , evaporated and taken up into 150 milliliters of NaHCθ3 solution (5% weight/volume) . This aqueous solution was washed with 30 ml of methylene chloride, acidified with diluted HC1, filtered, and the residue is dried in vacuo at 40°C overnight. The yellow, pseudocrystalline, crude product weighed 3.05 g (84% theor.). Elemental analysis: 1-H nmr (DMSOdg) : 0.92 (s, 3, I8CH3) ; 1.38 (s, 3, I9CH3); 3.04 (s, 3, OCH3); 5.50 (s, 1, C=CH) ; 8.28 (s, <1, COOH) . Purification from Silica gel (CCI4) , eluting with EtOAc/Hexane 50:50 and crystallization from acetone gave a compound melting at 214°C to 216°C, with satisfactory elemental ύ miϊπiHt SHEET analysis. The product, 11 -hydroxy-17α- methoxyandrost-4-en-3-one-l7 -carboxylic acid, can be represented by the structural formula: EXAMPLE 24 The llβ-hydroxy-17α-methoxyandrost-4-en-3- one-17β-carboxylic acid, (1 millimole) was suspended in methanol (5 milliliters) and a 1 normal solution of KOH in methanol (1 milliliter) was added dropwise at 0°C (ice bath) . The solution was evaporated under vacuo, dried thoroughly, and the resulting potassium salt was mixed with dimethylsulfoxide (10 milliliters) and chloroiodomethane (4 millimoles) . After stirring for 7 hours at room temperature (24°C) , the mixture (containing a precipitate of potassium iodide) was diluted with ethylacetate (100 milliliters) and washed successively with 10 milliliters water, 10 milliliters Na 2 s 2°3 ( % weight/volume) , 10 milliliters NaHCθ3 and 3 times with water (10 milliliters) and dried over MgSθ4 and evaporated under partial pressure. Purification by column chromatography from 12 grams of Silica gel (100-200 mesh type 60A) eluting with SHEET EtOAc/CHCl3 20:80 and crystallization from ethylacetate/ether gave a product that melts at 195° to 196°C. 1 E nmr (CDC1 3 ) : 0.95 (s, 3, I8CH ) ; 1.43 (s, 3, 19CH j ) ; 3.12 (s, 3, OCH3) ; 5.60 (s, 1, C=CH) ; 5.75 (s, 2, COOCH2CI) . IR (KBr) : 3400, 1755, 1655, 1205, 2110 (ether) cm " . Elemental analysis: Required: C64.30; H7.60; C18.63; Found: C64.16; H7.63; C18.63. The product, chloromethyl llβ-hydroxy- 17 -methoxyandrost-4-en-3-one-l7β-carboxylate, can be represented by the formula: EXAMPLE 25 11β,17 -Dihydroxyandrost-4-en-3-one-17β- carboxylic acid (cortienic acid; 3.434 grams; 10 millimoles) was dissolved in methylalcohol, then a 1 normal solution of KOH in MeOH (10 milliliters) was added dropwise in the cold. The solution was evaporated under vacuo and the residue was dried thoroughly and taken up into dimethylsulfoxide (20 milliliters) and methyliodide (2.5 milliliters; 40 millimoles) . After stirring overnight at room temperature, the mixture was diluted with ethylacetate (15 milliliters) and washed successively with 50 HEET milliliters NaHCθ3 (3% weight/volume) , 50 milliliters Na 2 s 2°3 (5% weight/volume) and three times with 50 milliliters water, dried over MgSθ4, and evaporated. The product crystallized from ethylacetate, and 3 crops gave 3.31 g (92%) of white crystals melting at 206°C to 207°C (litt. 207°C to 208°C) . 1 E nmr (CDC1 3 ) : 0.98 (s, 3, I8CH3); 1.45 (s, 3, I9CH3) ; 3.75 (s, 3, COOCH3); 5.67 (s, 1, C=CH) . The product, methyl llβ,17α-dihydroxyandrost-4-en-3-one-17β- carboxylate, can be represented by the structural formula: EXAMPLE 26 The methyl llβ,17α-dihydroxyandrost-4-en-3- one-17 -carboxylate, (10.32 grams; 22.5 millimoles), was taken up into ethylene glycol (170 milliliters) and p-toluenesulfonic acid (anhydrous, crystallized from benzene; 85 milligrams) was added. The solvent was slowly distilled off at 0.3-1 mm Hg for 2 hours. The distillation lead was 60°C to 70°C and the mixture turned red after about 30 minutes. The suspension was neutralized with aHCθ3 (the mixture turned colorless) , poured into cold water (200 milliliters) SUBSTITUTE SHEET and stirred for at least 30 minutes. The white precipitate was isolated by filtration, washed with water and dried in the freeze dryer. Thin layer chromatography showed a small amount of starting material and a few percent of a product identified as the Δ 9'11 3,3' cyclic ketal. Triturating the product with a few milliliters of ether yielded white crystals having a melting point of 204°C to 205°C with satis¬ factory elemental analysis. Theoretical: C67.96; H8.43; Found: C67.71; H8.47. ^-H nmr (CDCI3) : 0.93 (s, 3, I8CH3); 1.27 (s, 3, I9CH3); 3.70 (s, 3, COOCH 3 ); 3.90 (s, 4, OCH2CH2O); 5.12 (s, 3, I9CH3) ; 3.70 (s, 3, COOCH3); 3.90 (s, 4, OCH2CH O) ; 5.12 (s, 1, C=CH) . The product, methyl 3-(1* ,3'-dioxacycloperit-2'-yl)- llβ,17α-dihydroxyandrost-5-en-3-one-17β-carboxylate, can be represented by the structural formula: SUBSTITUTE SHEET EXAMPLE 27 Powdered KOH (1.2 grams) was stirred for five minutes into dimethylsulfoxide (15 milliliters) , then the methyl 3-(l' ,3 « -dioxacyclopent-2'-yl)-llβ,17α- dihydroxyandrost-5-en-3-one-17β-carboxylate (2.15 grams; 5.3 millimoles) was added, immediately followed by iodoethane (1.7 milliliters, 21.2 millimoles) and the mixture was stirred at 25°C for 23 hours. The reaction was then diluted with ethylacetate (150 milliliters) and washed successively with 50 milliliters Na2S2θ3 (5% weight/volume) and three times with 50 milliliters water, dried over MgSθ4 and evaporated to give 1.92 grams of crude product (83% theoretical) . Some product was extracted with the aqueous phase and was identified as cortienic acid- 3,3' cyclic ketal. Purification from 45 grams of silica gel and eluting with benzene/EtOAc 80:20 yielded 1.1 g of a white compound. IR (KBr) : 3500, 1725, 1215, 1110, 1085 cm "1 . H nmr 0.90 (s, 3, I8CH3) ; 1.10 (t,3, J=7Hz, OCH2CH3) ; 1.28 (s, 3, I9CH3); 3.32 (m, 2, OCH2CH3) 3.70 (s, 3, COOCH3) ; 3.95 (s, 4, OCH2CH2O) ; 5.15 (s, 1, C=CH) . The product, methyl 3-(1' ,3'-dioxacyclopent-2*-yl)-17α-ethoxy-llβ- hydroxyandrost-5-en-3-one-l7β-carboxylate, can be represented by the structural formula: EXAMPLE 28 The methyl 3-(1* ,3'-dioxacyclopent-2'-yl)- 11β,17α-dihydroxyandrost-5-en-3-one-l7β-carboxylate and iodopropane were reacted following the same procedure in Example 27. The H nmr spectrum was identical (without the triplet at 1.10 ppm) . The product, methyl 3-(l* ,3'-dioxacyclopent-2'-yl)-llβ- hydroxy-17α-propoxyandrost-5-en-3-one-17β- carboxylate, can be represented by the following structural formula: EXAMPLE 29 The methyl 3-(1*3'-dioxacyclopent-2'-yl)- 11 β,17α-dihydroxyandrost-5-en-3-one-l7β-carboxylate and bromobutane were reacted following the same procedure in Example 25 except that a ratio of 4:1 of bromobutane to the 17o-hydroxy compound was used and the reaction was allowed to proceed for three days. The crude product was a mixture of the methyl and butyl ester. The butyl ester, methyl 3-(l',3'- dioxacyclopent-2'-yl)-17α-butoxy-llβ-hydroxyandrost- 5-en-3-one-17β-carboxylate, can be represented by the structural formula: SUET EXAMPLE 30 The chloromethyl 11β-hydroxy-17 - methylthiomethyloxyandrost-4-en-3-one-17β-carboxylate (1.1 grams; 2.5 millimoles) was stirred for 17 hours under nitrogen at 60°C in dimethylsulfoxide (5 milliliters) containing powdered KOH (0.5 gram). The reaction was then taken up into water (150 milliliters) , acidified slowly with dilute HCl to pH 1-2, stirred for 15 minutes and extracted four times with EtOAc (80 milliliters) , dried over MgSθ4 and evaporated. The crude product was dissolved into NaHCC"3 (13% weight/volume) , washed with EtOAc and acidified. Drying gave 669 mg (64%) of product. IR (KBR) : 3500, 1715, 1670, 1085 cm "1 . H nmr (DMSOdg) : 0.92 (s, 3, I8CH3); 1.05 (t, 3, J=7H z ,OCH CH3) ; 1.37 (s, 3, I9CH3); 3.28 ( , 2, OCH2CH3) ; 5.55 (s, 1, C=CH) . Purification from CCI4 silica gel and crystallization from acetone gave a compound melting at 236°C to 240°C with satisfactory elemental analysis. The product, 17α-ethoxy-llβ- hydroxyandrost-4-en-3-one-17β-carboxylic acid, can be represented by the structural formula: EXAMPLE 31 llβ-Hydroxy-17α-propoxyandrost-4-en-3-one-17 -carboxylic acid and 17α-butoxy-llβ-hydroxyandrost-4- en-3-one-l7 -carboxylic acid were prepared following a similar procedure to Example 30 and gave satisfactory elemental analysis. EXAMPLE 32 The 17α-ethoxy-llβ-hydroxyandrost-4-en-3- one-17 -carboxylic acid (1.58 millimoles) was converted to the potassium salt following the same procedure as Example 24. The potassium salt was stirred at room temperature for eight hours in dimethylsulfoxide (10 milliliters) containing chloroiodomethane (1.25 milliliters). After the work- up used in Example 24, 0.594 grams of crude product was obtained which was chromatographed on 15 grams silica gel, eluted with Hexane/EtOAc 80:20 then 70:30. Crystallization from CH2Cl2/ entane gave white crystals melting at 203°C to 205°C. IR (KBr) : 3400, 1750, 1650, 1205, 1110, 1060 cm "1 . H nmr (CDCI3) : 0.95 (s, 3, I8CH3); 1.13 (t, 3, J=7H Z ; OCH2CH3) ; 1.43 . ■ >- c-*r.-- •" 5< ~ ~" __-* ~ f ~~ ~ ~ - ι~~ -"' cff^'ϋϊ ύft .i.jft?ϊ- .' rul!. l'ti< 5fEf0. ^ OSi IlEΪ (s, 3, I9CH3); 3.38 (m, 2, OCH2CH3) ; 5.65 (s, 1, C=CH) ; 5.77 (s, 2, COOCH2CI) . Elemental analysis: Required: C65.08; H7.83; C18.34; Found: C64.86; H7.84; C18.32. The product, chloromethyl 17α-ethoxy llβ-hydroxyandrost-4-en-3-one-17β-carboxylate, can be represented by the structural formula: EXAMPLE 33 Chloromethyl 11 -hydroxy-17α-propoxyandrost- 4-en-3-one-17β-carboxylate was prepared following a similar procedure as Example 32 and had a melting point of 194°C to 195°C. IR (KBr) : 3400; 1750, 1650, 1205, 1110, cm -1 ; H nmr (CDCI3) : 0.88 (t, 3,J=7H Z , OCH2CH2CH3). 0.98 (s, 3, I8CH3); 1.42 (s, 3, I9CH3) ; 3.18 (m, 2, OCH2CH2CH3); 5.65 (s, 1, C=CH) ; 5.77 (s, 2, COOCH2CI) . Elemental analysis: Theoretical: C65.65; H8.04; C18.08; Found: C65.78; H8.09; C18.14. i Z r~ _ -_ ~~ -_ _*!'"- i i v- " ". --~ -- -ύ iy EXAMPLE 34 Chloromethyl 17 -butoxy-llβ-hydroxyandrost- 4-eri-3-one-l7 -carboxylate was prepared following a similar procedure as Example 32 and had a melting point of 100°C to 151°C. IR (KBr) 3400, 1750, 1645, 1200, 1110 H nmr (CDCI3) : 0.98 (s, 3, I8CH3) ; 1.45 (s, 3, I9CH3) ; 3.28 (m, 2, OCH CH2CH3) ; 5.65 (s, 1, C- CH); 5.77 (s, 2, COOCH2CI) . EXAMPLE 35 The chloromethyl ll ,17α-dihydroxyandrost-4- en-3-one-l7β-carboxylate was treated under the same conditions as Example 20. IR (KBr): 1755, 1705, 1660 cm "1 . H nmr (CDCI3) : 0.67 (s, 3, I8CH3) ; 1.40 (s, 3, I9CH3); 2.09 and 2.23 (2s, I2CH ) , 2.19 (s, 3, SCH3) ; 4.45 (ABq, Δv=0.06 ppm, J Aβ =12Hz, OCH2S) ; 5.71 (s, 1, C=CH) ; 5.87 (s, 2, OCH2CI) . The product, chloromethyl-17α-methylthio-methyloxyandrost-4-en- 3,ll-dione-17β-carboxylate, can be represented by the structural formula: _¥ H uiEE"Γ EXAMPLE 36 The chloromethyl ll ,17α-dihydroxyandrost-4- en-3-one-17β-carboxylate (80 milligrams), was taken up into dry CH2CI2 (5 milliliters) and methylal (2 milliliters) . A mixture of P20s/silica gel 1:2 (100 milligrams) was added, while stirring. After stirring 7 hours at room temperature, the mixture was filtered, the silica gel was washed with CH2CI2. The organic extracts were washed with concentrated NaHC03 solution and water. H nmr (CDCI3) : 0.83 (s, 3, I8CH3) ; 1.41 (s, 3, I9CH3) ; 3.40 (s, 3, OCH3) ; 4.6 (2ABq, llβ and 17α-0CH2θ) ; 5.66 (s, 1, C=CH); 5.76 (ABq, Δv=0.27 ppm; J ==6Hz; OCH2CI) . The product, chloromethyl llβ,17 α - di(methoxymethoxy)androst-4-en-3-one-17β-carboxylate, can be represented by the structural formula: EXAMPLE 37 The chloromethyl llβ ,17 -dihydroxyandrost-4- en-3-one-l7β-carboxylate was treated at -78°C according to the procedure of Example 15 to obtain 2.44 grams of methyl-17α-hydroxy-llβ- trifluoroacetoxyandrost-4-en-3-one-l7β-carboxylate and r <-i,z_ ' _ i n '•' ' ' ~~ H h I 350 milligrams of the d.isubstituted side product, methyl 11β,17α-trifluoroacetoxyandrost-4-en-3-one-17β -carboxylate. The product is easily separated by chromatography on 60 grams silica gel, eluting with EtOAc/Hexane 50:50. H nmr (CDCI3) : 0.82 (s, 3, I8CH3); 1.27 (s, 3, 19CH j ; 3.70 (s, 3, COOCH3) ; 5.69 (M, 2, C=CH and 11CH) . IR (KBr): 1780; 1730; 1660 cm " . Elemental analysis: Required: C 60.25, H 6.38; Found: C 60.43, H 6.49. The product can be represented by the structural formula: The side product can be easily hydrolyzed to the product, methyl llβ ,17α-dihydroxyandrost-4-en-3-one- 17β-carboxylate, by refluxing in MeOH/H2θ/NaHCθ3 following the procedure of Example 17. EXAMPLE 38 The methyl 17α-hydroxy-llβ- trifluoroacetoxyandrost-4-en-3-one-17β -carboxylate (3.0 grams) was treated following the procedure of Example 16 to obtain 3.1 grams of product. H nmr (CDCI3) : 0.80 (s, 3, I8CH3) ; 1.26 (s, 3, I9CH3) ; 2.14 v.'. s S? " ^ s k ~ _ ■ _ \t ϊ y * -ύ ' sjuaiti __■ IϊEET (s, 3, SCH3); 3.70 (s, 3, COOCH3); 4.37 (ABq, Δv=0.1 ppm; J AB =10Hz, OCH2S) ; 5.70 (m, 2, 11CH and C=CH) . The product, methyl 17α-methylthiomethyloxy-llβ- trifluoroacetoxyandrost-4-en-3-one-17β-carboxylate, can be represented by the structural formula: EXAMPLE 39 The methyl 17α-hydroxy-llβ- trifluoroacetoxyandrost-4-en-3-one-17β-carboxylate (5.43 grams) in dry CH2CI2 (50 milliliters) and methylal (50 milliliters) was treated with a mixture of P2O5 (6 grams) and silica gel (12 grams) at 0°C. After stirring for seven hours at 0°C, the mixture was filtered and the residue washed with CH2CI2. The organic phase was then washed with saturated NaHCθ3 -solution and water, dried over MgSθ4 and concentrated in vacuo. Column chromatography on 200 g silica gel, eluting with CH2Cl2/EtOAc 90:10 yielded 4.0 g of product and 0.7 g of a compound identified as the 6 methylene derivative (by nmr and uv) . H nmr (CDCI3) : 0.80 (s, 3, I8CH3); 1.26 (s, 3, I9CH3) ; 3.31 (s, 3, OCH3) ; 3.68 (s, 3, COOCH3) ; 4.60 (ABq, Δv=0.18 ppm, J AB =7Hz; OCH2O) ; 5.70 (m, 2, 11CH andC^CH) . The SUBSTITUTE SHEET product, methyl 17α-methoxymethoxy-llβ- trifluoroacetoxyandrost-4-en-3-one-l7β-carboxylate, can be represented by the structural formula: EXAMPLE 40 The methyl 17α-methoxymethoxy-11β- trifluoroacetoxyandrost-4-en-3-one-17β-carboxylate was treated following the procedure of Example 17. H nmr (CDC1 3 ) : 0.96 (s, 3, I8CH3); 1.44 (S, 3, I9CH3; 3.31 (s, 3, OCH3); 3.70 (s, 3, COOCH3); 4.46 (m, 1, 11CH) ; 4.61 (ABq, Δv=0.16 ppm, J Aβ =7Hz, OCH O) ; 5.68 (s, 1, C=CH) . The product, methyl ll -hydroxy-17α- methoxymethoxyandrost-4-en-3-one-l7β-carboxylate, can be represented by the structural formula: OCH. C=0 EXAMPLE 41 The methyl 17α-methylthiomethyloxy-llβ- trifluoroacetoxyandrost-4-en-3-one-l7β-carboxylate was treated following the procedure of Example 17. The product was methyl ll -hydroxy-17α-methylthio- methyloxyandrost-4-en-3-one-l7β-carboxylate. EXAMPLE 42 The methyl ll -hydroxy-17α- methylthiomethyloxyandrost-4-en-3-one-17 - carboxylate, (882 milligrams) was treated at room temperature with a 1 normal solution of potassium tertiobutoxide in dimethylsulfoxide (5 milliliters) . After 45 minutes under nitrogen, the mixture was poured into water (50 milliliters) and extracted with CH2CI2. The aqueous layer was then combined with EtOAc (50 milliliters) and acidified slowly with 1 normal HCl while stirring. After extracting several times with EtOAc, the organic layers were dried over MgS04 and concentrated in vacuo. H nmr (DMSOdg) 0.94 (s, 3, 18 CH3); 2.10 (s, 3, SCH3); 4.26 (m, 1, HCH) ; 4.37 (ABq, Δv=0.13 ppm, J AB =llHz, CH2SCH3) ; 5.56 (s, 1, C=CH) . The product, llβ-hydroxy-17α- methylthiomethyloxyandrost-4-en-3-one-17β-carboxylic acid, can be represented by the structural formula: SUBSTITUTE SHE EXAMPLE 43 The methyl llβ-hydroxy-17α- methoxymethoxyandrost-4-en-3-one-l7 -carboxylate was reacted following the procedure of Example 42. H nmr (DMSOdg): 0.94 (s, 3, I8CH3) ; 1.39 (s, 3, I9CH3) ; 3.24 (s, 3, OCH3) ; 4.56 (ABq, Δv=0.08 ppm, J Aβ =7Hz, OCH O); 4.26 (m, 1, 11CH); 5.56 (s, 1, C=CH) . m.p. 207-209°C. The product is 1lβ-hydroxy-17α-methoxy- methoxyandrost-4-en-3-one-17β-carboxylic acid. EXAMPLE 44 The llβ-hydroxy-17 -methoxymethoxyandrost-4- en-3-one-17β-carboxylic acid was introduced into a mixture composed of water (20 milliliters) , CH2CI2 (10 milliliters) and NaHCθ3 (1.60 grams), then tetrabutylammonium hydrogen sulfate (0.105 grams) was added. After stirring for five minutes, a mixture of chloromethyl chlorosulfate (1.1 equivalent) in CH2CI2 (10 milliliters) was slowly added over a period of 30 minutes. The mixture was then stirred an additional 30 minutes. The organic phase was separated, dried over a2Sθ4 and concentrated in vacuo, to give the product in yield. H nmr (CDCI3) : 1.02 (s, 3, I8CH3) ; 3.33 (s, 3, OCH3); 4.43 (m, 1, 11CH) ; 4.62 (ABq, Δv=0.17 ppm, J AB =7Hz, OCH2O) ; 5.67 (s, 1, C=CH) ; 5.74 (ABq, Δv=0.14 ppm, J ==6Hz, OCH2CI) . The product, chloromethyl llβ-hydroxy-17α-methoxymethoxyandrost-4- en-3-one-17β-carboxylate, can be represented by the structural formula: SUBSTITUTE SHEET From the foregoing description, one of ordinary skill in the art can readily ascertain the essential characteristics of the present invention and, without departing from the spirit and scope thereof, can make various changes 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. .x>! <E-^π e ~ . ~ t ~~ ~~ γ SϋESTi ' I ii i UUM

Claims: WHAT IS CLAIMED IS: 1. A compound selected from the group consisting of: (a) a compound of the formula wherein: RX is Cχ-C 1Q alkyl; C 2 -C, Q (monohydroxy or polyhydroxy) alkyl; C -C. 0 (monohalo or polyhalo)alkyl; or -OH^COORg wherein Rg is unsubstituted or substituted C--C, Q alkyl, C3-C3 cycloalkyl, C3-C8 cycloalkenyl or C 2 -C-, 0 alkenyl, the substituents being selected from the group consisting of halo, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, alkyl), or Rg is unsubstituted or substituted phenyl or benzyl, the substituents being selected from the group consisting of lower alkyl, lower alkoxy, halo, carbamoyl, lower * •« ■ !• w& SUBSTiT u 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 Rx is -C^CONR Rg wherein R7 and Rg, which can be the same or different, are each hydrogen, lower alkyl, C3-C8 cycloalkyl, phenyl or benzyl, or R7 and Rg are combined such that -NRyRg represents the residue of a saturated monocyclic secondary amine; or Rx is unsubstituted or substituted phenyl or benzyl, the substituents being selected from the group of phenyl and benzyl substituents defined hereinabove with respect alkyl) wherein Y is -S-, hydrogen, lower alkyl or phenyl, or Rg and the lower alkyl group adjacent to Y are combined so that Rx is a cyclic system of the type - CH - Y wherein Y is alkylene 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 Rx is Rg is defined as hereinabove and lower alkyl, phenyl or halophenyl; R2 is unsubstituted or substituted C.-C. Q alkyl, C3-C8 cycloalkyl, C3-Cg cycloalkenyl or C 2 -C, Q alkenyl, the substituents being selected from the group consisting of halo, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, O O -NHC-(C^C^ alkyl) and -OC-(C 1 -C- L0 alkyl), or R2 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. ono(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, α-hydroxy, β-hydroxy, α-methyl, β-methyl, =CH2, or a,- or β-OR2 wherein R2 is identical to R2 as defined hereinabove; R4 is hydrogen, fluoro or chloro; R5 is hydrogen, fluoro, chloro or methyl; X is -0- or -S-; and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated; (b) a quaternary ammonium salt of a compound of formula (I) wherein at least one of Rx and R2 is a halo-substituted alkyl group; (c) a compound of the formula wherein R2, R3, R4, R5, and the dotted line in ring A are as defined in (a) above, Z is carbonyl or - hydroxymethylene and R3 is hydrogen, α-methyl, β- SOESTITISTE SHE methyl, =CH2 or α- or β-OR2 wherein R2 is identical to 2 above; (d) a compound of the formula wherein R2, R4, R5, and the dotted line in ring A are as defined in (a) above, Z is carbonyl or β- hydroxymeth lene and R3 is hydrogen, α-methyl, β- methyl, =CH 2 or α- or -OR2 wherein R2 is identical to R2 above; (e) a compound of the formula wherein M is alkali metal, thallium, alkaline earth metal/2 or NH4 and 2, R3, R4, R5, Z and the dotted line in ring A are as defined in (a) and (d) above; f) a compound of the formula where R3 is hydrogen, α-methyl, β-methyl, α-0&2 or β-OR2, and Rχ f R4 and R5 are as defined in (a) above; (g) A compound of the formula SUBSTITUTE SHER wherein R3 is hydrogen, α-methyl, β-methyl, α-OR2 or β-OR2, and Rχ f R2, R4 and R5 are as defined in (a) above; (h) a compound of the formula wherein Rx, R2, R3, R4, R5, X and the dotted line in ring A are as defined in (g) above. 2. A compound selected from the group consisting of: (a) a compound of the formula wherein: RX is Cχ-Cg alkyl; Cχ-Cg (monohalo or polyhalo) alkyl; -CH2COOR wherein Rg is Cχ-Cg alkyl; -CH2-Y- (Cχ-Cg alkyl) wherein Y is -S-, -SO-, -SO2- or p -0-; or -CH2θdRg' wherein Rg ' is Cχ-Cg alkyl or phenyl; R2 is Cχ-Cg alkyl, C3~C cycloalkyl, phenyl, benzyl or Cχ-Cg (monohalo or polyhalo) alkyl; R3 is hydrogen, q-hydroxy, α-methyl, β-methyl 0 or α-OR2 wherein R2 is identical to R2 as defined hereinabove; R4 is hydrogen or fluoro; R5 is hydrogen or fluoro; X is -0- or -S-; and the dotted line in ring A indicates that the 1,2-linkage is saturated or unsaturated; (b) a quaternary ammonium salt of a compound of formula (I) wherein at least one of Rx and 2 is a halo-substituted alkyl group; (c) a compound of the formula wherein 2, R3, R4, R5, and the dotted line is ring A are as defined in (a) above, Z is carbonyl or β- hydroxymethylene and R3 is hydrogen, α-methyl, β- methyl, =CH2 or α- or -OR2 wherein 2 is identical to R2 above; (d) a compound of the formula wherein R2, R4, R5, and the dotted line in ring A are as defined in (a) above, Z is carbonyl or β- hydroxyme hylene and R3 is hydrogen, α-methyl, β- methyl, =CH2 or α- or -OR2 wherein R2 is identical to R2 above; (e) a compound of the formula SUBSTITUTE SiET wherein M is alkali metal, thallium, alkaline earth metal/2 or NH4 and R2, R3, R4, R5, Z and the dotted line in ring A are as defined in (a) and (d) above; (f) compound of the formula wherein R3 is hydrogen, α-methyl, β-methyl, α-OR2 or -0R2, and R , R4 and R5 are as defined in (a) above; (g) a compound of the formula SUBSTITUTE SHEI wherein R3 is hydrogen, α-methyl, β-methyl, α-0R2 or -OR2r and Rχ r R2, R4 and R5 are as defined in (a) above; (h) a compound of the formula X-R η wherein Rx, R2, R3, R4, R5, X and the dotted line in ring A are as defined in (g) above. 3. A compound of Claim 1 or 2, said compound having the structural formula (I) . 4. A compound of Claim 1 or 2, said compound being a quaternary ammonium salt of a compound of formula (I) wherein at least one of Rx and R2 is a halo-substituted alkyl group. 5. A compound of Claim 1 or 2, said compound having the structural formula (III) . 6. A compound of Claim 1 or 2, said compound having the structural formula (IV) . 7. A compound of Claim 1 or 2, said compound having the structural formula (V) . 8. A compound of Claim 1 or 2, said compound having the structural formula (VII) . 5 9. A compound of Claim 1 or 2, said compound having the structural formula (VIII) . 10. A compound of Claim 1 or 2, said compound having the structural formula (IX) . X0 11. A compound of Claim 1, said compound having the structural formula (I) wherein R3 is hydrogen, α-methyl, β-methyl, =CH2, -OR2 or β-OR2. 12. A compound of Claim 1 or 2, said compound having the structural formula (I) wherein Rx 5 is Cχ-Cg alkyl. 13. A compound of Claim 1 or 2, said compound having the structural formula (I) wherein R is Cι~Cg (monohalo or polyhalo)alkyl. 14. A compound of Claim 13 wherein Cχ-Cg 0 (monohalo or polyhalo)alkyl is Cχ-Cg monohaloalkyl. 15. A compound of Claim 14, wherein Cχ-Cg monohaloalkyl is Cχ-Cg monochloroalkyl. 16. A compound of Claim 13 wherein Cχ-Cg monochloroalkyl is chloromethyl. 5 17. A compound of Claim 12 wherein R2 is Cχ-Cg alkyl or Cχ-Cg monohaloalkyl. 18. A compound of Claim 13 wherein R2 is Cχ-Cg alkyl. 19. A compound of Claim 14 wherein R2 is 0 Cχ-Cg alkyl. iϋiSTiTUTE smπ 20. A compound of Claim 15 wherein R2 is Cχ-Cg alkyl. 21. A compound of Claim 16 wherein R2 is Cχ-Cg alkyl. 22. A compound of Claim 12 wherein R2 is C3-C8 cycloalkyl, phenyl, benzyl or Cχ-Cg (monohalo or polyhalo) lkyl. 23. A compound of Claim 13 wherein R2 is C3-C8 cycloalkyl, phenyl, benzyl or Cχ-Cg (monohalo or polyhalo)alkyl. 24. A compound of Claim 14 wherein R2 is C3~C cycloalkyl, phenyl, benzyl or Cχ-Cg (monohalo or polyhalo)alkyl. 25. A compound of Claim 15 wherein R2 is c 3~ c 8 cycloalkyl, phenyl, benzyl or Cχ-Cg (monohalo or polyhalo)alkyl. 26. A compound of Claim 16 wherein R2 is c 3~ c 8 cycloalkyl, phenyl, benzyl or Cχ-Cg (monohalo or polyhalo)alkyl. 27. A compound of Claim 1 or 2, said compound having the structural formula (I) wherein X 28. A compound of Claim 13 wherein X is -0-. 29. A compound of Claim 14 wherein X is -0-. 30. A compound of Claim 15 wherein X is -0-. 31. A compound of Claim 27 wherein R4 and R5 are hydrogen. 32. A compound of Claim 28 wherein R4 and R5 are hydrogen. STO UTE SUET 33. A compound of Claim 29 wherein R4 and R5 are hydrogen. 34. A compound of Claim 30 wherein R4 and R5 are hydrogen. 35. A compound of Claim 27 wherein at least one of R4 and R5 is fluoro. 36. A compound of Claim 28 wherein at least one of R4 and R5 is fluoro. 37. A compound of Claim 29 wherein at least one of R4 and R5 is fluoro. 38. A compound of Claim 30 wherein at least one of R4 and R5 is fluoro. 39. A compound of Claim 27 wherein R4 is fluoro and R5 is hydrogen. 40. A compound of Claim 28 wherein R4 is fluoro and R5 is hydrogen. 41. A compound of Claim 29 wherein R4 is fluoro and R5 is hydrogen. 42. A compound of Claim 30 wherein R4 is fluoro and R 5 is hydrogen. 43. A compound of Claim 36 wherein R3 is α-methyl or β-methyl. 44. A compound of Claim 38 wherein R3 is α-methyl or β-methyl. 45. A compound of Claim 40 wherein R3 is α-methyl or β-methyl. 46. A compound of Claim 42 wherein R3 is α-methyl or β-methyl. SBSΠΠΠE SHEET 47. A compound of Claim 1 or 2, said compound having the structural formula (I) wherein R 9 is -CH 2 COORg, -CH 2 -Y-(Cχ-Cg alkyl) or -C^-OCRg'. 48. A compound of Claim 1, said compound having the structural formula (I) wherein Rx is -CH 2 CONR7R . 49. A compound of Claim 48 wherein at least one of Ry and Rg is hydrogen or Cχ-Cg alkyl. 50. A compound of Claim 48 wherein R7 and Rg are combined so that -NRyRg represents the residue of a saturated monocyclic secondary amine containing 5 to 7 carbon atoms. 51. A compound of Claim 50 wherein -NR7Rg represents morpholino, 1-pyrrolidinyl, 4-benzyl-l- piperazinyl, perhydro-l,2,4-oxathiazin-4-yl, 1- or 4-piperazinyl, 4-methyl-l-piperazinyl, piperidino, hexamethyleneimino, 4-phenylpiperidino, 2-methyl- 1-pyrazolidinyl, 1- or 2-pyrazolidinyl, 3-methyl- 1-imidazolidinyl, 1- or 3-imidazolidinyl, 4-benzylpiperidino or 4-phenyl-1-piperazinyl. 52. A compound of Claim 1, said compound having the structural formula (I) wherein Rx is -CH-Y-(lower alkyl) wherein Rg is hydrogen or methyl, R9 or wherein Rg and the lower alkyl group adjacent to Y are combined so that Rx is -CH Y wherein Y is alkylene -S-, -SO-, -SO2 - or -0- and the alkylene group contains 3 to 10 carbon atoms, of which at least 3 and no more than 6 are ring atoms. NBSTITIΠE spx 53. A compound of Claim 1 or 2, said compound having the structural formula (I) wherein the R3, R4 and R5 groupings and the 1,2-linkage are identical to those of a glucocorticosteroid selected from the group consisting of hydrocortisone and prednisolone. 54. A compound of Claim 1 or 2, said compound having the structural formula (I) wherein the R3, R4 and R5 groupings and the 1,2-linkage are identical to those of a glucocorticosteroid selected from the group consisting of fludrocortisone, betamethasone and dexamethasone. 55. A compound of Claim 1 or 2, said compound having the structural formula (I) wherein the R3, R4 and R- groupings and the 1,2-linkage are identical to those of a glucocorticosteroid selected from the group consisting of flumethasone, fluprednisolone, methyl prednisolone and paramethasone. 56. A compound of Claim 1 or 2, said compound having the structural formula (I) wherein R3 is α-0R2, and wherein the R4 and R5 groupings and the 1,2-linkage are identical to those of triamcinolone. 57. A compound of Claim 1 or 2, said compound having the structural formula (III) wherein Z is β-hydroxymethylene and R2 is Cχ-Cg alkyl. 58. A compound of Claim 1 or 2, said compound having the structural formula (IV) wherein Z is β-hydroxymethylene and R2 is Cχ-Cg alkyl. SUBSTITUTE SHEET 59. A compound of Claim 1 or 2, said compound having the structural formula (VII) wherein Z is β-hydroxymethylene and Rx is Cχ-Cg alkyl or Cχ-Cg monohaloalkyl. 60. A compound of Claim 1 or 2, said compound having the structural formula (VIII) wherein Z is β-hydroxymethylene and R2 is Cχ-Cg alkyl. 61. A compound of Claim 1 or 2, said compound having the structural formula (IX) wherein Rx is Cχ-Cg (monohalo or polyhalo)alkyl. 62. A compound of Claim 61 wherein Cχ-Cg (monohalo or polyhalo)alkyl is Cχ-Cg monohaloalkyl. 63. A compound of Claim 62 wherein R2 is Cχ~ Cg alkyl. 64. A compound of Claim 1 or 2, said compound having the structural formula (IX) wherein Rx is Cχ-Cg alkyl or Cχ-Cg monohaloalkyl, R2 is Cχ-Cg alkyl or Cχ-Cg monohaloalkyl and X is -0-. 65. A compound of Claim 64 wherein the R3, R4 and R5 groupings and the 1,2-linkage are identical to those of a glucocorticosteroid selected from the group consisting of cortisone, prednisone, chloroprednisone and meprednisone. 66. A pharmaceutical composition of matter comprising an anti-inflammatory effective amount of a compound of Claim 1 or 2 having the structural formula (I) , in combination with a non-toxic pharmaceutically acceptable carrier therefor suitable for topical or other local application. SUBSTITUTE SHEET 67. A method for alleviating inflammation in or on a warm-blooded animal exhibiting a topical inflammatory response, which comprises topically administering thereto an anti-inflammatory effective amount of a composition of Claim 66. 68. A method for alleviating inflammation in or on a warm-blooded animal exhibiting a localized inflammatory response, which comprises locally administering thereto an anti-inflammatory effective amount of a composition of Claim 66. 69. A method for alleviating inflammation in or on a warm-blooded animal exhibiting a topical inflammatory response, which comprises topically administering thereto an anti-inflammatory effective amount of a composition of Claim 1. 70. A method for alleviating inflammation in or on a warm-blooded animal exhibiting a localized inflammatory response, which comprises locally administering thereto an anti-inflammatory effective amount of a composition of Claim 1. SUBSTITUTE SHE!

Inventors: BODOR NICHOLAS S, BODOR, NICHOLAS, S.
Applicants: BODOR NICHOLAS S, BODOR, NICHOLAS, S.
Application year: 1987
Main classification: C07J1
IPC codes: C07J3, C07J21, C07J31