SE452468B - ANDROSTAN CARBATIOTS, PROCEDURE FOR PREPARING THESE AND COMPOSITIONS - Google Patents

Abstract

Compounds of the formula <IMAGE> in which R<1> is a fluoro-, chloro- or bromomethyl group or a 2'-fluoroethyl group, R<2> is a group COR<6> in which R<6> is a C1-3-alkyl group, or OR<2> and R<3> together form a 16 alpha ,17 alpha -isopropylidenedioxy group; R<3> is a hydrogen atom, a methyl group (which can be present in either the alpha or the ss configuration) or a methylene group; R<4> is a hydrogen, chlorine or fluorine atom; R<5> is a hydrogen or fluorine atom, and the symbol ..... is a single or double bond. The compounds have good anti-inflammatory activity, in particular on topical application. The compounds of the formula I are prepared by esterification, halogenation, reduction, elimination of protective groups and reaction at a 9,11 double bond to form a 9 alpha -halo-11ss-hydroxy group.

Description

(I) wherein R 1 represents a fluorine, chlorine or bromomethyl group or a 2'-fluoroethyl group, R 2 represents a group COR 6 wherein R 6 is a 2 and R 3 together form a 16aV 17d isopropylidene dioxy group; R 3 represents a hydrogen atom, a methyl group, which may be in either the dr or B configuration) or a methylene group; R 4 represents a hydrogen, chlorine or fluorine atom; R5 denotes a hydrogen or fluorine atom and the symbol 17777 denotes a single or double bond.

C1-3 alkyl group or OR The new compounds of formula (I) have good anti-inflammatory activity, especially in topical application assessed by McKenzie spot test in humans and measured by the reduction of croton oil-induced edema when the compounds are applied topically to the skin of mice and rats.

Some of the compounds show good topical anti-inflammatory activity in croton oil ear test coupled with minimal hypothalamic-pituitary-adrenal-suppressive activity after topical application to the same animal species. These results show that such compounds may be of value in the local treatment of inflammation in humans and animals with minimal likelihood of causing undesirable systemic side effects.

Compounds of formula (I) which are preferred for their good anti-inflammatory activity include the following categories namely (a) those wherein R 1 is chlorine or fluoromethyl, (b) those wherein R 2 is acetyl or propionyl, preferably propionyl, (c) asssa wherein 1: 4 is fluorine, (a) dssss wherein 1: 5 is fisar, (s) 1,441-ener, and (f) 1,4-dienes wherein R4 is fluorine and R3 is hydrogen, mr or B- methyl or methylene. Compounds of formula (I) have good anti-inflammatory activity coupled with minimal hypothalamic-pituitary-adrenal-suppressive activity in topical application, including 1,4-dienes wherein R 1 is chlorine or fluoromethyl, R 4 and R 5 are fluorine and especially those wherein R 3 is d-methyl.

Particularly preferred compounds of the invention in view of their excellent topical anti-inflammatory activity and favorable ratio of topical anti-inflammatory activity to undesired systemic activity include: S-chloromethyl 9a-fluoro-11β-hydroxy-lauromethyl-3-oxo-17-urpropionyl-4-oxyandrosta-4-oxiandrosta dien ~ 17% carbothioate; S-chloromethyl 9-fluoro-11β-hydroxy-16-methylene-3-oxo-17-propionion-oxyandrosta-1,4-diene-173-carbothioate; S-fluoromethyl 6a, Cafdifluoro-115-hydroxy-16c, 17isopropylidenedioxy-3-oxoandrosta-1,4-diene-178-carbothioate; S-fluoromethyl 60,9d-difluoro-115-hydroxy-fluoromethyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17B-carbothioate; S-chloromethyl 6a, 9a-difluoro-11β-hydroxy-16d-methyl-3-oxo-17o-propionyloxyandrosta-1,4-diene-176-carbothioate. The latter compound is particularly preferred in view of its particular favorable conditions and additional minimal huàatr0fi_ The compounds of formula (I) can be prepared according to a variety of different procedures.

Such a process comprises esterifying an androstane compound corresponding to formula (I) but containing either a free 17β-carbothioic acid group (or a functionally equivalent group) or a free 16-hydroxy group (R 3 is a hydrogen atom or a methyl or methylene group with optionally other reactive groups present. in the molecule is suitably protected as desired.

For example, a salt of the starting l17β-carbothioic acid such as an alkali metal, e.g. lithium, sodium or potassium salt or an alkylammonium, e.g. triethylammonium or tetrabutylammonium salt may be reacted with a suitable alkylating agent, preferably in a polar solvent such as a ketone, e.g. acetone or an amide such as dimethylformamide, dimethylacetamide or hexamethylphosphoramide, preferably at a temperature of 15 to 100 ° C.

The alkylating agent may comprise a suitable dihalogen compound, e.g. one containing an additional halogen atom (preferably a bromine or iodine atom) in addition to the halogen atom of the desired R 1 group. This process is particularly useful for the preparation of compounds wherein R 1 is a chloromethyl group and the alkylating agent is preferably bromochloromethane.

Alternatively, starting 16-hydrogen, methyl- or methylene-17d-hydroxy-173-carbothioates corresponding to the compounds of formula I may be subjected to esterification of the 17B-hydroxyl group. This can be achieved by conventional technology, e.g. by reaction between the starting hydroxy hydroxy compound and a mixed anhydride of the required carboxylic acid, which can be generated, for example, in situ by reaction between the carboxylic acid and a suitable anhydride such as trifluoroacetic anhydride, preferably in the presence of an acid catalyst, e.g. p-toluenesulfonic acid or sulfosalicylic acid. Alternatively, the mixed anhydride may be generated in situ by reaction between a symmetrical anhydride of the required acid and a suitable additional acid, e.g. trifluoroacetic acid.

The reaction preferably takes place in an organic solvent such as benzene, methylene chloride or an excess of the carboxylic acid used, the reaction suitably taking place at a temperature of 20 to 100 ° C.

Alternatively, the hydroxy group may be esterified by reacting the starting 17α hydroxy compound with the appropriate acid anhydride or acid chloride, if desired, in the presence of a non-hydroxylic solvent, e.g. chloroform, methylene chloride or benzene, and preferably in the presence of a strong acid catalyst, e.g. perchloric acid, p-toluenesulfonic acid or a strongly acidic cation exchange resin, e.g. Amberlite IR 120, varivid the reaction suitably takes place at a temperature of 25 - 100 ° C.

The compounds of formula (I) may also be prepared by reacting the corresponding androstane compound containing a substituent of the formula -COS (CH 2) n Y (wherein Y represents a substitutable substituent and n is 1 or 2) and a compound which serves to replace the group Y with a halogen atom.

Thus, the compounds of formula (I) may be subjected to a halogen exchange reaction which serves to replace the group Y when it is halogen with another halogen substituent. Thus, the bromomethyl, fluoromethyl and fluoroethyl 173-carbothioate compounds' can be prepared from the corresponding iodomethyl or bromomethyl] carbonothioate compounds using a bromide salt such as lithium bromide in the case of the bromomethyl 17% carbothioate compounds or a suitable fluoride, e.g. silver monofluoride or silver difluoride in the case of the fluoromethyl or fluoroethyl 17B carbothioate compounds.

The starting iodomethyl-17B-carbothioate compounds can be prepared from the corresponding chloromethyl 17β-carbothioate compounds using, for example, an alkali metal, alkaline earth metal or quaternary ammonium iodide, e.g. sodium iodide.

The reaction preferably takes place in a solvent comprising, for example, acetone, acetonitrile, methyl ethyl ketone, dimethylformamide, dimethylacetamide or ethanol.

The foregoing reactions can also be performed on starting materials having a variety of substituents or groups which are subsequently converted into such substituents or groups present in the compounds of the invention as defined above. The 11β-hydroxy compounds of formula (I) may thus be prepared by reduction of a corresponding 11-oxo compound, e.g. using an alkali metal or alkaline earth metal borohydride, e.g. sodium or calcium borohydride, suitably in an alcoholic or water-alcoholic solvent such as methanol or ethanol.

Such an II-keto compound can be prepared by oxidation of the corresponding 11d-hydroxysteroid, for example, using a chromic acid reagent such as Jones' reagent. A 11β-hydroxy compound of formula (I) may also be obtained by deprotecting a corresponding compound having a protected hydroxyl group in the 115-position, for example a tri-C 1-6 alkylsilyloxy group such as the trimethylsilyloxy group or a perfluoro- or chloroalkanoyloxy group such as the trifluoroacetoxy group. The protecting group can be removed by hydrolysis, the trialkylsilyl group is easily removed by mildly acidic or basic hydrolysis or especially conveniently using fluoride, e.g. hydrogen fluoride .or an ammonium fluoride. The perfluoro- or chloroalkanoyl protecting group may also be removed by mildly acidic or basic hydrolysis or alcoholysis, preferably under acidic conditions when R 4 is a chlorine atom. A protected hydroxyl group may be introduced, for example, by reaction of an β-hydroxisteroid with a suitable reagent such as a trialkylsilyl halide or a perfluoro- or chloro-alkanoic anhydride.

The compounds of formula (I) may also be prepared by reacting a corresponding compound having 9,11-double bond (and no substituent in the 11-position) and reagents which serve to introduce the required 90-halogen-11β-hydroxy group. This may include initial formation of a bromohydrin by reaction with an N-bromamide or imide such as N-bromosuccinimide, followed by formation of the corresponding 96,113-epoxide by treatment with a base and reaction of the epoxide with hydrogen fluoride or hydrogen chloride to introduce the required the fluorohydrin or chlorohydrin group. Alternatively, the 9,11-olefin compound may be reacted with an N-chloramide or imide to introduce the required 9α-chloro-11β hydroxy group directly. The 4 compounds of the invention may conveniently be prepared by partial reduction of the corresponding 1'4 compound, for example by hydrogenation using a palladium catalyst, suitably in a solvent, e.g. ethyl acetate or by homogeneous hydrogenation using, for example, tris (triphenylphosphine) rhodium chloride, suitably in a solvent such as benzene, or by exchange hydrogenation using, for example, cyclohexene in the presence of a palladium catalyst in a solvent, e.g. . ethanol, preferably under reflux. This reduction can be carried out on a haloalkyl ester when it is sufficiently stable in such a reaction or can be achieved at an earlier stage.

The above-mentioned compounds containing a free -COSH group in the 179-position can be prepared, for example, by aminolysis with rearrangement of a suitable 17B-thiocarbamoyloxycarbonyl rostane. The 17B-thiocarbamoyloxycarbonylandrostane is a mixed anhydride of the corresponding 176-carboxylic acid and a thiourea and is conveniently prepared by reduction of a salt of the 175-carboxylic acid 1a-ester or 16c, 17u, the acetonide with a thiocarbamoyl halide. The thiocarbamoyl group is N, N-disubstituted and may thus have the formula -COOCSNRARB, wherein RA and RB, which may be the same or different, are alkyl groups, e.g. C 1-4 alkyl groups or RA and RB together with the nitrogen atom to which they are attached form a 5-8 membered ring which may optionally contain an additional heteroatom selected from oxygen, nitrogen or sulfur and / or which may optionally be substituted by one or two C 1-3 alkyl e.g. methyl groups. Preferably RA and RB are C 1-4 alkyl substituents with the N, N-dimethylthiocarbamoyl group being preferred. The thiocarbamoyl halide is preferably the chloride.

The reaction can be accelerated by the addition of an iodine salt, e.g. sodium iodide.

The initialandrostane-173-carboxylate salt may be, for example, an alkali metal, e.g. sodium or potassium, an alkaline earth metal, e.g. calcium salt or a salt of a tertiary amine, e.g. triethylamine.

Aminolysis with rearrangement can be carried out, for example, by heating the mixed anhydride to an elevated temperature, e.g. in the presence of ammonia, a primary amine or preferably a secondary amine such as diethylamine or pyrrolidine. In the starting 176 carboxylic acids, the 16 and 17a positions are suitably substituted with -R 3 and -OR 2 groups desired for the final product of formula (I).

The ibhydroxyandrostane compounds in the 16-methylene series containing the desired 175-carbothioic acid group, as described above, can be prepared from the corresponding 16-methyl-16a, 17e-epoxy-17-thiocarboxylic acid by providing a strong rearrangement with acid. .ex. a strong carboxylic acid such as trifluoroacetic acid. These 16w, 1% repoxides can be prepared from the corresponding 176-carboxylic acids by treatment with an onium salt of a 2-haloazaaromatic compound, followed by treatment of the obtained product with hydrogen sulfide or a salt thereof to give the free 17β-carbothioic acid which can be alkylated as described above, preferably in situ to give the desired 173-carbothioate group. The 16a, 17q-isopropylidene dioxy compounds of formula (I) may also be prepared by treating a corresponding 17-carboxylic acid with an onium salt of a 2-halo-azaaromatic compound following treatment of the obtained product with hydrogen sulfide to give the free the 17β-carbothioic acid which can then be esterified as described above.

The onium salts of 2-halo-aza-aromatic compounds are capable of effecting carboxyl activation. Such reagents include 2-halo-N-alkyl or 2-halo-N-phenylpyridinium or pyrimidinium salts bearing 1 to 2 additional substituents selected from phenyl and lower alkyl (eg C 1-4) alkyl groups, such as methyl. The 2-halogen atoms may be fluorine, chlorine, bromine or iodine atoms. The salts are preferably sulfonates, e.g. tosylates; halides, e.g. iodides; fluoroborates or perfluoroalkylsulfonates, a suitable salt being 2-fluoro-N-methylpyridinium tosylate or 2-chloro-N-methylbenzothiazolium trifluoromethanesulfonate. The 16do-epoxy-168-methyl-17β-carboxylic acid compounds used as starting materials in the above process can be prepared in a conventional manner, e.g. as described in British patent no. l.5l7.278.

The starting materials used in the process for the precipitation of the compounds of formula XI) described herein are novel and include compounds of general formula (II) (II) wherein Ra represents a thiocarbamoyloxycarbonyl group -COOCSNRARB wherein RA and RB has the meaning given above or a group of the formula -COSR1A, wherein -RIA represents a hydrogen atom or a group as defined above for R1 or a transferable group and RB represents an esterified hydroxyl group or Rb and Rc together represent an isopropylidene dioxy group; or when Ra represents a group COSRIA, R b is optionally a hydroxyl group; Rc represents a hydrogen atom, a methyl group (which may be in either the O or B configuration) or a methylene group; Rd represents a hydroxy or protected hydroxy group (either in the Q or B configuration) or an oxo group; Re represents a hydrogen, bromine, chlorine or fluorine atom; or Rd and Re together form a carbon-carbon bond or an epoxy group in B configuration; Rf represents a hydrogen atom or a fluorine atom; and the symbol denotes a single or double bond and the salts of these compounds having a free carbothioic acid group; with the exception of the compounds of formula (I) as defined above.

When Rd represents a protected hydroxyl group, this may be, for example, a trialkylsilyloxy group or a perfluoro- or perchloroalkanoyloxy group as previously defined. The 17d-hydroxy-17B-carbothioic acids of formula (II) and the salts thereof can be converted into 17-hydroxy-176-carbothioates of formula 1 as defined in form (II) wherein Ra represents the group COSR between (I) or in 175 the carbiothioic acid ester of formula (II) according to the procedures described above for the preparation of the compounds of formula (I). The esterification of the 170-hydroxy group is preferably effected with the appropriate carboxylic acid chloride in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane and preferably in the presence of a base such as triethylamine, preferably at low temperature, e.g. OOC. The 17d-hydroxy β-carbothio acids of formula (II) and the salts thereof are thus particularly useful intermediates for the preparation of the androstane 176-carbothioates of formula (I); those in which Rc represents a hydrogen atom, an α- or β-methyl group or a methylene group, Re represents a hydrogen, chlorine or fluorine atom, R represents a hydroxy group in the β-configuration or an oxo group is preferred. Further preferred compounds and salts thereof include those compounds wherein R c represents a methyl group in the cr or β configuration or a methylene group; Re represents a fluorine atom, Rd represents a hydroxy group in the B-configuration or an oxo group and the symbol fvfff in the 1.2 position represents a carbon-carbon double bond.

Particularly preferred compounds of formula II thus include, for example, the following: 9a-fluoro-11β, 17d-dihydroxy-1GB-methyl-3-oxo-androsta-1,4-diene-175-carbothioic acid; 9d-fluoro-11β, 17-dihydroxy-16-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid; Tarfluoro-11β, 17-dihydroxy-16-methylene-3-oxoandrosta-1,4-diene-176-carbothioic acid; Ga, 9a-difluoro-11β, 17α-dihydroxy-1α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid and the corresponding II-ketones and salts thereof.

An advantage of the above-mentioned intermediates is that they allow direct haloalkylation to give haloalkyl l75 carbothioates when the corresponding thiols RISH are not available.

The salts of these 17α-hydroxy-17β-carbothio acids may be, for example, alkali metal, e.g. lithium, sodium or potassium salts; 452 468 ll. .r alkaline earth metals, e.g. calcium or magnesium salts; tertiary amine salts, e.g. pyridine or triethylammonium salts; or quaternary ammonium salts, e.g. tetrabutylammonium salts. The 176-hydroxy 176-carbothioic acids can be prepared, for example, by reacting a reactive derivative of a corresponding 17U-hydroxy-17B-carboxylic acid with hydrogen sulfide or a sulfide or hydrogen sulfide salt thereof. In general, the cation of sulfide or hydrogen sulfide salts may be, for example, an alkali metal salt such as sodium or potassium hydrogen sulfide. The above reactive derivatives correspond to the compounds of formula (II) wherein Rb is a hydroxyl-P group and the group -COR7 is present in the 17% position wherein R7 represents a group of formula 1 / ;, ¿YX \ p_¿ wherein X , Y and Z, which may be the same or different, each represent CH or N, one or two of the symbols X, Y and Z being N and the heterocyclic ring optionally substituted at at least one carbon atom having a lower alkyl group (eg having 1 to 4 carbon atoms, such as a methyl group) and / or when the heterocyclic ring contains two adjacent carbon atoms, said ring may optionally carry a benzene ring fused to said adjacent carbon atoms.

The reactive derivatives of formula (III) are preferably prepared by reacting the corresponding 170-hydroxy-17% -carboxylic acids of formula (II) with a symmetrical or asymmetrical compound of formula f R7 - w - 117 (iv) wherein W represents the group CO, CS, SO or SO 2 and the groups R 7, which may be the same or different, have the meaning given above.

Compounds of formula (III) are suitably symmetrical. In general, the compound of formula (III) wherein W represents CO, CS or SO will be used. Particularly useful compounds thus include, for example, N, N'-carbonyldi (1,2,4-triazole), N, N'-carbonyldibenzotriazole, N, N'-carbonyldibenzimidazole, N, N'-car bonyldi (3,5-dimethylpyrazole), N, N'-thionyldiimidazole and especially N, N'-carbonyldiimidazole and N, N'-thiocarbonyldiimidazole.

The preparation of a 17α-hydroxy-17% carbothioic acid of formula (II) as defined above is conveniently accomplished by reacting a 17α-hydroxy-175-carboxylic acid with a compound of formula (III) followed by reacting the intermediate with 17% -COR7- group with hydrogen sulfide or a salt thereof, preferably in situ without isolating the intermediate. The 17α-acyloxy-176-carbothioic acid of formula II can be obtained in the same manner directly from the corresponding chloroacloxy-17B-carboxylic acid by reaction with a compound of formula (III). The wyacyloxy-177-carboxylic acids can be prepared by esterification of the corresponding 10-hydroxy-17B-carboxylic acids according to the methods described in BP 1,384, “372. The reaction with the compound of formula (III) is conveniently effected in the presence of an inert anhydrous solvent, e.g. a substituted amide solvent such as N, N-dimethylformamide or N, N-dimethylacetamide, preferably in the absence of water, suitably at or below room temperature, e.g. at a temperature of from -30 ° C to f30 ° C. The reaction is conveniently effected under approximately neutral conditions, preferably in an inert atmosphere, e.g. under nitrogen. The same solvent and conditions can also be used for the subsequent reaction with H2S or a salt thereof. The heterocyclic compound, e.g. imidazole or 1,2,4-triazole, which is formed as a by-product, can be easily removed, for example, by extraction with water.

The above reactions can also be carried out on compounds having a variety of substituents or groups which are subsequently converted as previously described to compounds of formula (I).

The androstane 17β-carboxylic acid starting materials used in the above processes can be prepared in a conventional manner, e.g. by oxidation of an appropriate 21-hydroxy-20-ketopregnan, 452 468 13. .. ~ for example with periodic acid in a solvent, preferably at room temperature. Alternatively, sodium bismuthate may be used to effect the desired oxidative removal of the 21 carbon atom of the 17α-acyloxypregnane compound. It should be understood that if the parent pregnane compound contains any substituents which are sensitive to the oxidation desired above, such groups should be suitably protected.

The following examples illustrate the invention.

The melting points were determined in OC on a Kofler block and are uncorrected. Optical rotation was determined at room temperature on solutions in dioxane.

T.l.c. (Thin layer chromatography), p.l.c. (preparative layer chromatography) and h.p.l.c. (high performance liquid chromatography) was performed over silica.

The solutions were dried over magnesium sulfate unless otherwise indicated.

Preparation Example 9 9afluoro-113-hydroxy-16% -methyl-3-oxo-170-propionyloxyandrosta-1,4-diene-173-carbothioic acid (I) A solution of 9a-fluoro-1h & hydroxy-165-methyl-3-oxo- 17α-propioyl nyloxyandrosta-1,4-diene: 17 & carboxylic acid (5.00 g) solvated with ethyl acetate (1/2 mol) and triethylamine (5.3 ml) in dichloromethane (75 ml) were stirred under nitrogen and treated with dimethyl thiocarbamoyl chloride (5.07l g). After 24 hours, more reagent (5.32O 9) was added. After 47 hours, the mixture was diluted with ethyl acetate and washed with Q-hydrochloric acid, 5% sodium bicarbonate solution and water, dried and evaporated to give a viscous yellow oil (9.043 g). This was dissolved in diethylamine (50 ml), then stirred and heated to reflux under nitrogen for 5.75 hours. The resulting brown solution was added to a mixture of concentrated hydrochloric acid (50 ml), water (250 ml) and ethyl acetate (50 ml). The products were further extracted with ethyl acetate, after which the acidic products were re-extracted in 5% sodium carbonate solution. The aqueous phase was acidified with 6N-salt- [a] D + 110 ° (g 1.05). 452 # 68 I i 14. ..- acid (50 ml) and extracted with ethyl acetate. The extracts were washed with N-hydrochloric acid and water, and dried and evaporated to a pale yellow solid (3.44O g). This was recrystallized from acetone to give pale yellow crystals (1.80 g) of the title compound 17B-carbothioic acid, m.p. 172-1730.

The analytical sample was obtained after recrystallization twice from acetone as white crystals, m.p. 177 - 1790, Pregaratexemgel II S-chloromethyl 9a-fluoro-16B-methyl-3,11-dioxo-17-crionionyl-oxyanandrosta-1,4 diene-liscarbothioate (II) 8§-Jones reagent (1.5 ml) was added dropwise over 10 minutes to a stirred solution of the compound of Example 1 (described below) (998 mg) in acetone (2 ml) and dimethylformamide (2 ml). After 30 minutes, the reaction mixture was slowly diluted with water (100 ml) with stirring and the resulting suspension was cooled for one hour.

The precipitate was collected by filtration, washed with water and dried to give a cream solid (877 mg). P.l.c. in chloroform-acetone (10: 1) gave a white foam (755 mg) which was crystallized twice from acetone to give white needles of the title lacetone (523 mg) mp 2o4 - 2os °, [a1D + 94 ° ( g 1.o4).

Preparation Example III 175 N, N-dimethylthiocarbamoylcarbonyl-9m-fluoro-116-hydroxy-16n-methyl-17α-propionyloxyandrosta-1,4-dien-3-one (III).

A solution of 9m-fluoro-11β-hydroxy-16β-methyl-3-oxo-17-propionylloxyandrosta-1,4-diene-17β-carboxylic acid (0.44 g) in dichloromethane (8 ml) was successively treated with triethylamine (0.4 ml), dimethylthiocarbamoyl chloride (0.248 g) and sodium iodide (0.449) and the mixture was stirred under nitrogen at 200 for 6 hours. Ethyl acetate (30 ml) was added and the total volume was reduced to half in vacuo. Additional ethyl acetate (50 mL) was added and the solution was washed with water, 2N hydrochloric acid, water, 3% sodium bicarbonate, water and saturated sodium chloride solution and then dried. The solution was concentrated in vacuo 452 468 15 ° F when the product crystallized (0.329 g). This was recrystallized from acetone (2x) to give the title anhydride as white needles, m.p. 191 DEG-193 DEG.

Preparation Example IV 9d-fluoro-11β-hydroxy-160-methyl-3-oxo-17β-propionyloxyandrosta-1,4-diene-173-carbothioic acid (IV). A stirred suspension of (III) (2,467 g) in diethylamine (25 ml) was heated at reflux under nitrogen. After 3.5 hours, the reaction mixture was poured into iced 3N hydrochloric acid (300 ml) and the mixture was extracted with ethyl acetate. The combined extracts were washed with water and extracted with 5% sodium carbonate solution. The combined aqueous extracts were washed with ethyl acetate, then covered with ethyl acetate and acidified with hydrochloric acid to pH 1. The aqueous phase was extracted with additional ethyl acetate and the combined extracts were washed with water, saturated sodium chloride solution, dried and the solvent removed in vacuo. The residue was recrystallized twice from acetone to give the title carboxylic acid as white needles (1.309 g) mp 141 - 143 °, [øJD + 30 ° (0.51).

Preparation Example V 11β-hydroxy-3-oxo-17-arpropionyloxyandrosta-1,4-diene-17β-carboxylic acid (V).

A solution of 11β, 170-dihydroxy-3-oxoandrosta-1,4-diene-17β-carboxylic acid (1.3 g), and triethylamine (18 ml) in dichloromethane (500 ml) was cooled to 4 ° C and treated. portionwise over 15 minutes with propionyl chloride (14.2 ml). stirring was continued at 4 ° C for a total of one hour and the mixture was washed successively with 3% sodium bicarbonate, water, 2D hydrochloric acid, water and saturated brine, then dried and evaporated under reduced pressure. The residue was dissolved in acetone (300 ml) and diethylamine (13.3 ml) was added with stirring. After 1 hour at 20 DEG C., the solvent was removed under reduced pressure and the residue was dissolved in water (150 ml). After acidification to pH 1 with 2D hydrochloric acid, the product was extracted with ethyl acetate. The combined extracts were washed with water and saturated brine, dried and then concentrated to a small volume. The solid product 452 4682 16. .f I was collected by filtration, washed with ethyl acetate and dried in vacuo at 500 to give the title l] orpropionate carboxylic acid as crystals (13,309,9), [α] D + 2 ° (E l.10.). A portion (389 mg) was recrystallized twice from methanol to give an analytical sample (256 mg), m.p. 244-2450 (dec.), Number + 3 ° (0.83). Preparation Example 6 6a, Cordifluoro-11β-hydroxy-160-methyl-3-oxo-17-arpropionyl-oxyandrosta-1,4-diene-175-carboxylic acid (VI).

A solution of 6d, β-difluoro-118,17-dihydroxy-1-Gormethyl-3-oxo-androsta-1,4-diene-176-carboxylic acid (2.113 g) and triethylamine (2.5 ml) in dichloromethane (60 ml) was stirred and was treated at about 0 ° C with propionyl chloride (1.85 mL). After one hour, the mixture was diluted with more solvent (50 ml) and washed successively with 3% sodium bicarbonate, water, 2D hydrochloric acid, water, saturated brine, then dried and evaporated to a pale yellow solid. This was dissolved in acetone (50 ml) and; diethylamine (2.5 ml) was added. After 1 hour at 22 ° C, the solvent was removed in vacuo and the remaining adhesive was dissolved in water (30 ml). Acidification to pH 1 with 2-hydrochloric acid precipitated a solid, which was collected, washed with water, and dried to give the title carboxylic acid 17u-propionate (2.23O g), mp 220-222 °, Iain + 4 ° (3 ° C). 7o). Preparation Example VII 173-N, N-dimethylthiocarbamoyloxycarbonyl-Cofluoro-118-hydroxy-solder, 17d-isopropylidene dioxiandrosta-1,4-dien-3-one (VII).

A solution of Qarfluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrosta-1,4-diene-176-carboxylic acid (100 g) in dichloromethane (15 ml) and triethylamine (0.33 ml) under nitrogen was treated with N, N-dimethylthiocarbamoyl chloride (588 mg) and the mixture was stirred at room temperature. After 68 hours, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with N-hydrochloric acid (2.10 mL), 5% sodium bicarbonate solution and water, dried and evaporated to a light yellow crystalline solid (1.123 g).

P.1.c. of a portion (200 mg) in chloroform acetone (9: 1) gave a off-white solid (161 mg) which was crystallized from ethyl acetate as white needles of the mixed title anhydride (131 mg), melting point 279 - 2s1 °, (all) + 174 ° (go, s1, acetylsulfoxide).

Pregaratexemgel VIII 175-N, N-dimethylthiocarbamoyloxycarbonyl-6a, 9d-difluoro-115-hydroxy-16d, 17d-isopropylidenedioxiandrosta-1,4-dien-3-one (VIII).

A solution of 6a, 9a-difluoro-11B-hydroxy-16a, 17urisopropylidenedioxy-3-oxoandrosta-1,4-diene-178-carboxylic acid (4,354 g) in dichloromethane (150 ml) containing triethylamine (1.4 ml) was treated with N, N-dimethylthiocarbamoyl chloride (2.519 g) and the reaction mixture was stirred under a nitrogen atmosphere at 220 for 80 minutes.

Ethyl acetate (500 ml) was added and the resulting solution was washed successively with 2N hydrochloric acid, water, sodium bicarbonate solution, water and saturated sodium chloride solution and dried and the solution was concentrated. on cooling, crystallization took place and the solid was filtered and dried in vacuo to give the title anhydride (3,562 g) as light yellow prisms, m.p. 283-2870 (dec.), [.alpha.] D @ 156 DEG (E 0.84, dimethylsulfoxide).

Pregaratexemgel IX 6a, 9d-difluoro-111-hydroxy-16a, 17orisopropylidenedioxy-3-oxoanedrosta-1,4-diene-175-carbothioic acid (IX).

A suspension of VIII (3,455 g) in diethylamine (200 ml) is heated under reflux under nitrogen for 6 hours. The initial suspension dissolved rapidly but a light brown suspension formed after 30 minutes and remained unchanged. The cooled reaction mixture was poured into water (1.0 L), acidified with concentrated hydrochloric acid (210 ml) to pH 1 and extracted with ethyl acetate. The combined extracts were washed with water and extracted with 5% sodium carbonate solution and water and the aqueous extracts were combined. The combined extracts were acidified with 6N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were diluted with water and saturated sodium chloride solution, then dried and the solvent evaporated in vacuo to give a light gray solid (2.3l g).

Portions of the product (0.408 g) were crystallized from ethyl acetate to give the title carbothioic acid (0.149 g), mp 191-1990, 452 468 la 2 ..f [a] D + 124 ° (3 1, o4, dimethylsulfoxy).

Pregaratexemgel X 6a-fluoro-11β, 17α-dihydroxy-3-oxoandrosta-1,4-diene-17β-carboxylic acid (X).

A solution of paraffluoroprednisolone (4.987 g) in tetrahydrofuran (SO ml) was stirred with a solution of periodic acid (10.0 g) in water (24 ml) at 220 DEG-50 DEG C. After 50 minutes, the tetrahydrofuran was evaporated and the aqueous suspension was filtered. The solid product was washed with water (300 ml) and dried to give a white solid (4.80 g). A portion (271 mg) was crystallized from methanol to give the title acid (171 mg) as white needles, mp 241 - 24a °, [q] D + s4 ° (5 o.s25>.

Pregaratexemgel XI 6a-fluoro-11β-hydroxy-3-oxo-17α-propionyloxyandrosta-1,4-diene-173-carboxylic acid (XI) - A solution of X (4.49lg) and triethylamine (4.46ml) in dry dichloromethane (160 ml) at -50 was stirred and treated dropwise with propionyl chloride (2.80 ml, 2.96 g) in dry dichloromethane (ga. 5 ml) for 5 minutes below 0 °. After a further 20 minutes below 0 °, the reaction mixture was diluted with dichloromethane (160 ml), washed with sodium bicarbonate solution, water, dried and evaporated to give a white solid (S. 70l g).

This was stirred with diethylamine (4.60 ml, 3.24 g) in acetone (30 ml) to give a clear yellow solution. After 30 minutes, the solution was concentrated, water was added (150 ml) and the resulting solution was washed with ethyl acetate (2 x 30 ml). The aqueous phase was acidified to pH 2 using 2N hydrochloric acid (50 ml) with stirring and the product was extracted three times with ethyl acetate. The extracts were combined, washed with water (50 ml), dried and evaporated to give a white foam (5.8l9 g). A portion of the foam (304 mg) was crystallized from ethyl acetate to give the title 17u-propionate (144 mg) as small plates, mp 224-2270, [d] D +30 tg 0.886). 452 468 19 ~ = _9 Preparation Examples XII - XXIII Following the same procedure as described in Preparation Example I, but using as starting material the 178-carboxylic acid corresponding to the desired 176-carbothioate (the procedure details are summarized in Table 1 below), the following compounds were prepared.

XII. 17-Acetoxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diamine-176-carbothioic acid, m.p. 178.5 DEG-179 DEG, number + 9a DEG (g'l.02).

XIII. 17-Carbutyryloxy-Fluoro-11β-hydroxy-165-methyl-3-oxoandrostate-1,4-diene-175-carbothioic acid, m.p. 175 DEG-176 DEG, [m] D + 107 DEG (3.96).

XIV. Sa-fluoro-115-hydroxy-17α-isobutyryloxy-solvent-methyl-3-oxoanedrosta-1,4-diene-175-carbothioic acid, m.p. 177-179, [α] D + 119 ° (E 0.90 ).

XV. 188-hydroxy-3-oxo-17α-propionyloxyandrosta-1,4-diene-175-carbothioic acid, m.p.

XVI. 11B-hydroxy-165-methyl-3-oxo-17c-propionyloxyandrosta-1,4-diene-175-carbothioic acid, m.p. 159-163 °, [m] D + 113 ° (g 0.78).

XVII. Chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-175-carbothioic acid, m.p. 167-171, [α] D + 128 °, (δ 0.99). XVIII.Carfluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionionyloxy-drosta-1,4-diene-17β-carbothioic acid, m.p. 141 DEG-143 DEG, [.alpha.] D @ +30 (2 0.51).

O XIX. 6d, Qm-fluoro-11β-hydroxy-16n-methyl-3-oxo-17H-propionyloxy-androsta-1,4-diene-175-carbothioic acid, m.p. 136 DEG-1390 DEG-13 DEG C. (g 0.56).

XX. 9α-fluoro-11β-hydroxy-16-methylene-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioic acid, m.p. 236-2390, [α] D -71 ° (δ 0.99) .

XXI. 11β-hydroxy-3-oxo-17α-propionyloxyandrosta-4-ene β-17% carboxylic acid, m.p. 176 DEG-177 DEG, IQJD + 110 DEG.

XXII. 9a-fluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoanarosta-1,4-alien-175-carbouioic acid, m.p. 274 DEG-30 DEG C. (decomposition), [c] D + 122 ° (2 0.51, dimethyl sulfoxide).

XXIII.Saffluoro-11β-hydroxy-3-oxo-17α-propionyloxyandrosta-1,4-diene-170-carbothioic acid, m.p. 189-193 °, [0] D + 7z ° (δ 0.74).

TABLE I Formation of the mixed anhydrides Preparation Example 17 8- cl-csnme NE: I fi ïäïíngs -Éïäktionsu 3 3 :::: ° :::; .. 2 Hc fl z fl z »03969 v1d rums ~ (9) (9) (ml) (ml) (ml ) temperature xx: 5.000 2.940 1.66 75 beat x111 15.354 6.609 4.8 2504 6 ~ x1v 4.182 2.399 1.3 so 4 xv 7.143 4.40 2.6 150 _ elb xvz a 6.137 3.77 2.05 140 _ 6l ° xv11 5.973 Å 3.350 1.34 100 7 xv111 4.207 2.39 1.35 so 0.677'ld xxx 2.130 1.60 0.66 50 64 xx 5.000 2.507 1.41 75 3 xx: 1.000 2.442 1.22 15 2.7 xxx: 1.000 0.500 0.33 15 2.08 xx111 6.000 3.55 '2.0 120 1.251 ° 452 468 21 TABLE I (continued) Treatment of the mixed anhydride intermediate with diethylamine.

.P fiämæa fl æ fi mpel NHEt2 Ræktkxst Produkt d Product Crystallization (ml) (t) (gl Solvent at reflux de xn so s. S 2.104 zAza 3 XIII 250 4 5.244 EA XIV 50 4.5 l.0Û EA XV 60 4 3.29 EA xv: so 3.5 1.382 xvn so 5.7 0.527 13A XVIII 25 4.75 1.309 A XIX 12 6 0.418 EA xx so 3.75 1.296 _ EAZb xx: 15 4 o.3976 A5 XXI1 (a) 8 (a) 3 9 bus XXIII G0 4.5 2.88 EA-P Remarks: EA = ethyl acetate, A = acetone, P = petrol boiling point 60 - 800 l. Aliquots (of 500 mg, (b) 670 mg, (c) 424 mg, (d) 171 mg of the starting dimethylthiocarbamic anhydride were removed 452 468 "22 for characterization Characterization was performed on samples recrystallized two more times from ethyl acetate.

Yields (a) 84 percent (b) 69 percent. 3. The product was solvated with ethyl acetate (about 0.2 mol). The starting dimethylthiocarbamic anhydride (1.435 g) was crystallized from ethyl acetate. One portion (95 mg) was removed for characterization. 5. Characterization was performed on a sample recrystallized twice more from acetone (recovery: 73 percent). 6. The product was crystallized from ethyl acetate. Sodium iodide (1.46 g) was also present in the reaction. 8. The starting dimethylthiocarbamic anhydride (1123 g) was crystallized from ethyl acetate. One portion (200 mg) was chromatographed (p.l.c., chloroform acetone, 9: 1) and crystallized from ethyl acetate (recovery 65 percent). 9. The reaction was carried out on 781 mg of anhydride. Sodium iodide (2.13 g) was also present in the reaction.

Pregaratexemgel XXIV 9a-chloro-11β-hydroxy-16β-methyl-3-oxo-17β-propionyloxyandrosta-1,4-diene-178-carbothioic acid and 9B, 11β-epoxy-16β-methyl-3-oxo-17α-propionyloxyandros dien-17B-carbothioic acid (XXIV).

A solution of 175-N, N-dimethylthiocarbamoyloxycarbonyl-9c-chloro-11β-hydroxy-165-methyl-17-propionyloxyandrosta-1,4-dien-3-one (5,586 g), in diethylamine (60 ml) was refluxed under nitrogen for 5 hours. hours 40 minutes. The reaction was poured into water (450 ml), acidified to pH 10 with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 60 ml). The combined extracts were washed with water, then extracted with aqueous sodium carbonate solution (4 x 50 ml). The aqueous extracts were acidified with 6N hydrochloric acid to pH 1 and extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with water and saturated sodium chloride solution and dried, and the solvent was removed in vacuo to give a colorless foam (2,834 g). Crystallization twice of the mixture from ethyl acetate gave 9α-chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioic acid (0.527 g) as white prisms, m.p. 167-1710, [a] D + 1280 (E 0.99). The mother liquors from the crystallizations contained an additional amount of the above 9u-chloro-11β-hydroxy-carbothioic acid together with 9β, 11β-eEoxy- 16B-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β- karbo- tiosxra.

Pregaratexemgel XXVV §; Iodomethyl-9urfluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate (XXV) A solution of the compound of Example 1 (described below) ( S50 mg) and sodium iodide (1,874 g) in acetone (15 ml) Stirred and heated under reflux for 6.5 hours. Ethyl acetate (75 ml) was then added and the solution was washed successively with water, 10% sodium thiosulphate solution, 5% sodium bicarbonate solution and water, dried and evaporated to give an off-white foam (525 mg). P.l.c. in chloroform-acetone (6: 1) gave an off-white foam (478 mg), which crystallized twice from acetone without heating above room temperature to give colorless crystals of the title S-iodomethyl ester (241 mg), m.p. 197 °, [α] D -32 ° (g 1.01).

Preparation Examples XXVI - XXXVII Following the same general procedure as described in Preparation Example 25, but using the S-chloromethyl-17B-carbothioate corresponding to the desired product as starting material (procedure details summarized in Table II below), the following compounds were prepared.

XXVI. S-iodomethyl-17α-acetoxy-9α-fluoro-11β-hydroxy-16β-methyl--3-oxoandrosta-1,4-diene-176-carbothioate, m.p. 04 - 2050, [α] D -29 ° (9 0.98).

XXVII. S-iodomethyl-11β-hydroxy-3-oxo-17α-propionyloxyandrosta-1,4-diem-iva-carbothioate, crude + 2e ° (9 0.47).

XXVIII. S-iodomethyl-11β-hydroxy-166-methyl-3-oxo-17α-propionyl-oxyanarosta-1,4-alien-113-carbothioate,: α1 + 5 °, <5 0.74). _ ._ ._ -..___.-...__: _______.___. ..__ 4__._.-.__.:____é 452 468 24. S-iodomethyl-9α-chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate, [α] D +70 (E 0, 36).

XXX. S-iodomethyl-9Q-fluoro-11β-hydroxy-16u-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate, [α] D + 85 ° (3 0.55).

XXXI. S-iodomethyl-Ga, 9a-difluoro-11β-hydroxy-16α-methyl-3-oxo-17β-propionionyloxyandrosta-1,4-diene-17β-carbothioate.

XXXII. S-iodomethyl-9α-fluoro-11β-hydroxy-16-methylene-3-oxo-17α-propionyloxyandrosta-1,4-diene-175-carbothioate, m.p. 191 DEG-199 DEG-31 DEG C.

XXXIII. S-iodomethyl-9arfluoro-11B-hydroxy-3-oxo-17α-propionyloxy-androsta-1,4-diene-176-carbothioate, m.p. 175 - 1780, Iain + 4 ° (δ 0.50).

XXXIV. S-iodomethyl-6a-fluoro-11B-hydroxy-3-oxo-17a-propionyloxyandrosta-1,4-diene-175-carbothioate, m.p. 195 - 1970, [u] D + 1s ° (3 0.64) .

XXXV. S-iodomethyl-17α-acetoxy-6α, 9α-difluoro-11β-hydroxy-1Gα-methyl-3-oxoandrosta-1,4-diene-176-carbothioate, m.p. 241 DEG-243 DEG, IQJD + 7 DEG. , 78).

XXXVI. S-iodomethyl-17-carbutyryloxy-6q, 9a-difluoro-11B-hydroxy-β-dimethyl-3-oxoandrosta-1,4-diene-17β-carbothioate, m.p. 210 DEG-12 DEG. 90).

XXXVII. S-iodomethyl-9a-fluoro-11β-hydroxy-16α, 17α-isopropylidene dioxide-3-oxoandrosta-1,4-diene-176-carbothioate, m.p. 261 DEG-27 DEG C. (decomposition>, IQJD + 97 ° <90 °, 48, AIMETY SULFOXIA> 452 46 8. TABLE II - Halogen substitutions on S-haloalkyl-17α-acyloxy-androstane-17β-carbothioates _ _ L ïPreParat ~ NaI Starting solution Reactionf-PLc: xr1sta1- Product 'Example mg) steroid (acetone) time (t) (silica) lysation (mg) no halide (ml) at recycled CHCl 3 solution (m9) flow Me2CO'_ agent__ xxvï 6632 c1 1115 20 3.5 - BA 2161 XXVII 3800 Cl 925 10 4 - - 1084 XXXVIII 3260 Cl 840 10 3 - - 969 XXIX 1995 Cl 536 20 6.5 - - 591 XXX 2160 Cl 580 10 3 - - 685 .xxxz 1200 c1 303 30 s - - 3173 xxxzz 7361 c1 1953 23 6 19 : 1 _A 2962 xxxzxz 5500 c1 1300 as 4 - M 12507 XXXIV 8400 Cl 2000 54 4.5 ~ EA ~ P 1800 xxxv 1900: c1 4750 200 s - EA 46206 XXXVI 6500 Cl 1620 70 5.5 - EA 16105 xxxvzx 5491 c1 1419 20 24 9 = 1 A 2248 A = acetone M = methanol P = petrol boiling point eo - s0 ° Remarks: 1. Obtained from a portion (300 mg) of the crude product (2.024 g). 2. Obtained from a portion (400 mg) of the crude product (2.058 g). 3. The product was used directly to prepare the corresponding fluoromethyl-17B-carbothioate.

Solvated with 0.5 H 2 O. 452 468 26 5. Solvated with 0.1 EA * 6. Solvated with 0.2 EA + 0.5 H 2 O. 7. Obtain a portion (300 mg) of the crude crystalline product (1.611 g).

Preparation Example XXXVIII S-Iodomethyl-6a, 9a-difluoro-11β-hydroxy-16a, 17c-isopropylidenedioxy-3-oxoandrosta-1,4-diene-17β-carbothioate (XXXVIII) A solution of the compound of Example 4 described below (0.705 g) in acetone (50 ml) was heated under reflux with sodium iodide (2.969 g) for 5.5 hours. Ethyl acetate (75 ml) was added and the solution was washed successively with water, sodium metabisulfite solution, then dried and the solvent was evaporated in vacuo to give an off-white solid (0.893 g).

A portion (0.205 g) of this was crystallized twice from ethyl acetate to give the title S-iodomethylthioester (0.15 g) as white prisms, mp 260-2620 (dec.), [Α] D + 81 ° (g 0.6, dimethyl sulfoxide).

Preparation XXXIX S-2'-bromomethyl-9a-fluoro-115-hydroxy-160-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-176-carbothioate (XXXIX) I (0.5 g) was treated as described for the S-chloromethyl ester (Example 1 Method A described below), but using 1,2-dibromoethane to give colorless crystals of the title S-2'-bromoethyl ester (0.440 g), m.p. 14s °, lalD + 120 ° (g 1.04).

Preparation Example XL 16d, 17α-Epoxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid (XL) A mixture of 16α, 17α-epoxy-9α-fluoro- 11β-hydroxy-16B-methyl--3-oxoandrosta-1,4-diene-17B-carboxylic acid (377 mg) and 2-fluoro-1-methylpyridinium tosylate (340 mg) in dry dichloromethane (7 ml) were stirred. was cooled on ice and treated for 1 minute with triethylamine (0.42 ml). After 1 hour, hydrogen sulfide was passed through the mixture for 30 minutes to give a yellow solution. T.l.cv (chloroform-acetone-acetic acid, 30: 8: 1) showed that a major amount of less polar product was formed. After being allowed to warm to room temperature for 1 hour, the mixture was treated with 2N hydrochloric acid (30 ml), and the product was extracted with ethyl acetate (3 x 20 ml). The acidic product was extracted from the organic phase with 5% sodium carbonate, the aqueous extracts were combined and acidified with 6N hydrochloric acid and then extracted with ethyl acetate. The combined acidic extracts were washed with water, dried and concentrated under reduced pressure to give, after filtration, off-white crystals (274 mg), probably largely the unstable 166, 17α-epoxy-9α-fluoro-11β-hydroxy-166- methyl 3-oxoandrosta-1,4-diene-17B-carbothioic acid (no starting oxyacid present) as assessed by tlc (chloroform-acetone-acetic acid, 30: 8: 1, RF ca. 0.7).

Preparation Example XLI S-Chloromethyl-16d, 17a-epoxy-9a-fluoro-11B-hydroxy-16B-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate (XLI) Method A w A suspension of 16a, 17a -epoxy-9d-fluoro-11β-hydroxy-16β-methyl--3-oxoandrosta-1,4-diene-176-carboxylic acid (753 mg) and 2-fluoro-1-methylpyridinium tosylate (680 mg) in dichloromethane (7 ml) was treated dropwise at 0 ° with triethylamine (1.39 ml), and then stirred at 0 ° C for 1 hour. Hydrogen sulfide was then passed through the mixture for 15 minutes, and the resulting solution was stirred at 0 ° C for an additional 1 hour. Bromochloromethane - (0.26 ml) was then added and the mixture was stirred and allowed to warm to room temperature. After an additional 1.5 hours, the reaction mixture was diluted with ethyl acetate (250 mL) and washed successively with 2N hydrochloric acid, 5% sodium bicarbonate solution and water, dried and evaporated to a light yellow solid (818 mg). The solid was subjected to p.l.c. in chloroform-acetone (9: 1) (two runs). The headband (515 mg) was crystallized from acetone to give white needles of the title S-chloromethyl ester epoxide (447 mg), mp 246-2510, IQJD + 131 ° (5o, e1>).

Method B.

A suspension of 16α, 17α-epoxy-9-fluoro-111-hydroxy-16β-methyl--3-oxoandrosta-1,4-diene-176-carboxylic acid (376 mg) and 2-chloro-452 468 'v. 28 -N-Methylbenzothiazolium trifluoromethanesulfonate (400 mg) in dichloromethane was treated dropwise at 0 DEG C. with triethylamine (0.7 ml).

The resulting solution was stirred at 0 DEG for 1.2 hours and then hydrogen sulfide was passed through the mixture for 10 minutes. After a further 1 hour at 0 °, bromochloromethane (0.1 ml) was added and the mixture was stirred at room temperature.

Two additional portions of bromochloromethane (0.1 ml) were added after an additional 1.5, and 1.8 hours. Fifteen minutes after the final addition, the reaction mixture was diluted with ethyl acetate (200 ml) and washed successively with 2N hydrochloric acid, 5% sodium bicarbonate solution and water, dried and evaporated to a red crystalline solid. The solid was subjected to p.l.c. in chloroform-acetone (19: 1) (three runs).

The more polar band gave a light cut solid, the title S-chloromethyl ester (134 mg), identical to an authentic sample of t.l.c. Preparation Example XLII S-Chloromethyl-9α-fluoro-11β, 17α-dihydroxy-16-methylene-3-oxoandrosta-1,4-diene-17β-carbothioate (XLII) A solution of XLI (400 mg) in trifluoroacetic acid (16 ml ) was stirred at room temperature. After 5.5 hours, the reaction mixture was evaporated to near dryness, and the residue was dissolved in ethyl acetate (100 ml). The solution was washed with 5% sodium bicarbonate solution and water, dried and evaporated to a yellowish-green foam (466 mg). The foam was subjected to p.l.c. in chloroform-acetone (9: 1) (three runs). One portion (80 mg) of the headband (315 mg) was crystallized twice from acetone to give white crystals of the title 16-methylene-17d-alcohol (48 mg), m.p. 242 DEG-243 DEG., , 50).

Preparation Example XLIII 9α-fluoro-17α-hydroxy-163-methyl-3,11-dioxoandrosta-1,4-diene-17β-carboxylic acid (XLIII) A stirred suspension of 9α-fluoro-17,211-dihydroxy-16β-methyl pregna-1,4-diene-3,11,20-trione (4, B42 g) in tetrahydrofuran (50 ml) was cooled in ice and treated dropwise over 5 minutes with a solution of periodic acid (4.255 g) in water (1.5 ml). The reaction mixture was stirred at 220 for 2.25 hours, when most of the suspension had dissolved. The solvent was removed in vacuo with periodic addition of water to maintain the original volume.

The resulting precipitate was filtered off, washed with water and dried in air and in vacuo to give the title carboxylic acid as cream prisms (4.55 g), m.p. 270 DEG-2720 (dec.): [Α] D + 136 ° (3 1 , 04, dimethylsulfoxide).

Pregaratexemgel XLIV 9α-fluoro-11β, 17α-dihydroxy-163-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid (XLIV) A stirred solution of 9α-fluoro-11β, 17α-dihydroxy-16β-methyl -3-Oxo-androsta-1,4-diene-175-carboxylic acid (0.502 g) in dry N, N-dimethylformamide (15 ml) was cooled at -50 under nitrogen and treated with N, N'-carbonyldiimidazole (0.435 g). g), and the reaction mixture was stirred at -SO for 18 hours. Hydrogen sulphide gas was bubbled into the reaction mixture for 20 minutes and the solution was stirred for a further 4 hours and gradually heated to 220. The reaction mixture was poured into ethyl acetate and the resulting solution was washed with 2N hydrochloric acid and water and then extracted with 2N sodium carbonate solution (3 x 50 ml). The combined extracts were washed with ethyl acetate (60 ml), then covered with additional ethyl acetate (100 ml) and acidified with hydrochloric acid to pH 1.0. The aqueous layer was extracted with additional ethyl acetate, and the extracts were washed with water and saturated sodium chloride solution, then dried and the solvent removed in vacuo to give a white solid which crystallized twice from ethyl acetate to give the title carbothioic acid (0.315 g), m.p. 198 - 2o1 ° (solar eclipse). MID + 1a9 ° (3 0.71).

Pregaratexemgel XLV 9Q-fluoro-17α-hydroxy-16B-methyl-3,11-dioxoandrosta-1,4-diene-17B- -carbothioic acid (XLV) A stirred solution of XLIII (5,587 9) in dry N, N-dimethylformamide ( 150 ml) at 200 under nitrogen was treated with N, N'-carbonyldiimidazole (4.847 g), and the reaction mixture was stirred at 200 for 4 hours. Hydrogen sulphide gas was bubbled into the reaction mixture for 10 minutes, and the solution was stirred for an additional 1 hour. The solution was poured onto ice (300 ml) and 2N hydrochloric acid (100 ml) to give a pale yellow precipitate. This was filtered off, air dried overnight (6.268 g) and crystallized from ethyl acetate to give the title carbothioic acid (3.76l g) as white prisms, m.p. 215 DEG-25 DEG C., tqln + 143 DEG (90 DEG C., ethyl acetate).

Pregaratexemgel XLVI 9cfluoro-17α-hydroxy-16β-methyl-3,11-dioxoandrosta-1,4-diene-17β- -carbothioic acid (XLVI) A stirred solution of XLIII (1,059 g) in dry N, N-dimethylformamide ( 50 ml) at 20 ° under nitrogen was treated with N, N'-thiocarbonyl-diimidazole (1,368 g) and the reaction mixture was stirred at 200 for 4 hours. Hydrogen sulphide gas was bubbled into the reaction mixture for 5 minutes, and the solution was stirred for an additional 1 hour.

The reaction mixture was partitioned between ethyl acetate (100 ml) and 2N hydrochloric acid (100 ml), and the organic phase was washed with 2N hydrochloric acid (100 ml) and water (2 x 100 ml) and extracted with 2N sodium carbonate solution (2 x 75 ml). The combined extracts were washed with ethyl acetate (50 ml), then covered with ethyl acetate (100 ml) and acidified with hydrochloric acid to pH 1. The aqueous layer was extracted with additional ethyl acetate (50 ml), and the combined extracts were washed. with water, saturated sodium chloride solution, dried, and the solvent was removed in vacuo. The residue was crystallized from ethyl acetate to give the title carbothioic acid (o, ss9), mp 212 - 219 °, [α] D + 145 ° (δ 0.81, methyl ethyl formamide).

Preparation XLVII S-Chloromethyl-9α-fluoro-11β, 17α-dihydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate (XLVII) A stirred solution of XLIV (0.69 g) and sodium bicarbonate (0.040 g) in N, N-dimethylformamide (6 ml) was treated with bromochloromethane (0.1 ml) and stirring was continued at 22 ° for 1 hour.

The reaction mixture was diluted with ethyl acetate (100 mL), and the solution was washed successively with 2N hydrochloric acid, water, 2N sodium carbonate solution, water and saturated sodium chloride solution, then dried and the solvent removed in vacuo. The residue was crystallized twice from ethyl acetate to give the title S-chloromethylthiol ester (0.13 g) as white plates solvated with ethyl acetate (1 moi), m.p. 126 DEG-130 DEG, [.alpha.] D @ 147, 5 ° (δ 0.64).

Preparation XLVIII 9α-fluoro-16β-methyl-3,11-dioxo-17H-propionyloxyandrosta-1,4-diene-173-carbothioic acid (XLVIII) A stirred solution of XLV (0.485 g) and triethylamine (0.57 ml) in dichloromethane was cooled in ice-salt, treated with propionyl chloride (0.43 ml), and the reaction mixture was stirred at 0 DEG for 1.5 hours. The mixture was partitioned between ethyl acetate (75 ml) and 2N sodium carbonate solution (75 ml), and the organic layer was washed successively with additional 2N sodium carbonate solution, water, 2N hydrochloric acid, water and saturated sodium chloride solution, then dried and the solvent removed in vacuo gave a yellow crystalline solid (0.562 g). This was dissolved in acetone (10 ml), diethylamine (1.0 ml) was added and the reaction mixture was stirred at 220 for 1.25 hours. The solvents were removed in vacuo and the residue partitioned between ethyl acetate (30 ml) and 2N hydrochloric acid (30 ml). The ethyl acetate layer was washed with water and extracted with 2N sodium carbonate solution (2 x 30 ml).

The combined extracts were washed with ethyl acetate (30 ml) and covered with ethyl acetate (60 ml) and acidified to pH 1.0 with hydrochloric acid. The ethyl acetate layer was washed with water and saturated sodium chloride solution, then dried and the solvent removed in vacuo to give a white solid which crystallized twice from ethyl acetate to give the title ester (0.290 g), mp 173-150 °, [alm + 14s ° (9 1.03).

Pregaratexemgel XLIX S-chloromethyl-90-fluoro-17-hydroxy-16B-methyl-3,11-dioxoandrosta-1,4-diene-17β-carbothioate (XLIX) A solution gave XLV (5.006 g) and sodium bicarbonate (1.612 g) in N, N-dimethylacetamide (50 ml) was treated with bromochloromethane (1.24 ml) and the reaction mixture was stirred at 22 ° for 3.3 hours. The solution was diluted with ethyl acetate (70 mL) and washed successively with 2N hydrochloric acid, water, sodium metabisulfite solution, water and saturated sodium chloride solution, then dried and the solvent removed in vacuo to give a cream solid 452 468 o a 32. .. ~ 'substance (3.638 g). The analytical sample was obtained after preparation t.l.c. (silica gel, developed with chloroform: acetone = 9: 1) and crystallized from ethyl acetate as colorless prisms of the title ester (0.262 g), mp 223-2280, [c] D + 251 ° (E 1.2).

Pregaratexemgel L 9d-fluoro-11B-hydroxy-16B-methyl-3-oxo-17d-propionyloxyandrosta-II, 4-diene-176-carbothioic acid (L) A stirred solution of XLIV (0.5 μl g) in dichloromethane ( 20 ml) containing triethylamine (0.6 ml) was cooled to 2 ° and treated with propionyl chloride (0.45 ml), and the reaction mixture was stirred at 2 ° for 2.5 hours. The reaction mixture was partitioned between ethyl acetate and sodium bicarbonate and the organic phase was washed with water, 2N hydrochloric acid, water and saturated sodium chloride solution, dried, and the solvent was removed in vacuo to give a colorless solid (0.634 g). This was dissolved in acetone (30 ml), diethylamine (1.5 ml) was added and the clear solution was stirred at 220 for 55 minutes. The reaction mixture was diluted with ethyl acetate (50 ml) for 55 minutes and washed with 2N hydrochloric acid and water and then extracted with 5% sodium carbonate solution. The combined extracts were acidified with 2N hydrochloric acid to pH 1 and extracted with ethyl acetate. The combined extracts were washed with water and saturated sodium chloride solution and dried, and the solvent was removed to give a colorless foam (0.522 g), which was crystallized from ethyl acetate to give the title ester as colorless prisms (0.307 g), m.p. 1799, (all) + 10 ° (5 1.0).

Pregaratexemgel L1 Burfluoro-11β, 17α-dihydroxy-16-methylene-3-oxoandrosta-1,4-diene-17β-carbothioic acid (II) A solution of 9α-fluoro-11β, 17α-dihydroxy-16-methylene-3- oxoandrosta-1,4-diene-17B-carboxylic acid (0.218 g) in dry (N, N-dimethylformamide (10 ml) at 220 under nitrogen was treated with N, N'-carbonyldiimidazole (0.254 g) and the reaction mixture was stirred at 220 for 4 hours. Hydrogen sulfide was bubbled into the reaction mixture for 5 minutes and the mixture, now pale green, was stirred for 1 hour at 22 °. The mixture was diluted with ethyl acetate (10 ml) and the solution was washed with 2N hydrochloric acid, water and saturated sodium chloride solution, dried, and the solvent was removed in vacuo to give a yellow foam (0.222 g), which was crystallized twice from ethyl acetate to give the title carbothioic acid (0.0789) as white prisms, which decomposed at ca. 250 ° without melting, [α] D + 117 ° (C 0.32).

Pregaratexemgel LII 9a-fluoro-11β, 17α-dihydroxy-3-oxoandrosta-1,4-diene-17β-carboxylic acid (LII) A suspension of 9d-fluoroprednisolone (10 g) in dry tetrahydrofuran (55 ml) was stirred and treated with a solution of periodic acid (9.0 g) in water (90 ml), and the mixture was stirred at 220 for 2 hours. The mixture was then poured into iced water (about 400 ml) and, after stirring for 15 minutes, the solid product was collected, washed with water and dried to give the title acid as a solid (9.42 g). A portion recrystallized from ethanol having a melting point of 289-2930, [α] D + 66O (g 0.73, methanol).

Pregaratexemgel LIII 9d-fluoro-11β, 17α-dihydroxy-3-oxoandrosta-1,4-diene-17β-carbothioic acid (LIII) - A solution of 9u-fluoro-11β, 17α-dihydroxy-3-oxoandrosta-1,1 4-Diene-17β-carboxylic acid (4.5 g) in dry dimethylformamide (100 ml) was stirred under nitrogen with N, N'-carbonyldiimidazole (4.04 g) at 220 for 4 hours. Hydrogen sulfide was passed through the solution for 30 minutes and held for another 15 minutes. The mixture was poured into a mixture of 2N hydrochloric acid (250 ml) and ice (ca. 100 g), and the precipitate obtained was collected, washed with water and dried to give a white solid (4.56 g). A portion (120 mg) was recrystallized from ethanol to give the title thioacid as colorless crystals (70 mg), m.p. 222 DEG-25 DEG. 452 468 34 Preparation Example LIV 6d, 9u-difluoro-11β, 17α-dihydroxy-16D-methyl-3-oxoandrosta-1,4-diene-176-carbothioic acid (LIV) A solution of 6d, 9α-difluoro-11β, 17d- Dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-176-carboxylic acid (1.2 g) in dry dimethylformamide (250 ml) was stirred and treated with N, N'-carbonyl-diimidazole (9.94 g) under nitrogen at room temperature. After 4 hours, hydrogen sulfide was passed through the solution for 0.5 hours and the mixture was kept for another 0.5 hours. The reaction mixture was poured into 2N hydrochloric acid (500 ml) containing ice (ca. 250 g).

The resulting precipitate was collected, washed with water and dried in vacuo to give the title thioacid as a white solid (II, 47 g), mp 230-2320, [d] D + 94 ° (c 0.91).

Preparation Example LV 17α-Acetoxy-Gu, 9α-difluoro-11B-hydroxyalkyl-6-methyl-3-oxoandrosta-1,4-diene-17B-harbothioic acid (LV) 'A solution of LIV (1.625 g) and triethylamine (2, 0 ml) in dichloromethane (75 ml) was stirred at approx. Oo, was treated dropwise with acetyl chloride (1.275 ml), then stirred at this temperature for 1.25 hours. The mixture was washed with 2N sodium carbonate (50 ml), water, 2N hydrochloric acid (50 ml), water (3 x 50 ml), brine (50 ml), then dried and evaporated. a white solid (1.91 g). This was dissolved in acetone (40 ml) and stirred with diethylamine (4 ml) at 270 for 45 minutes.

The mixture was concentrated to about 25 ml and poured into 2N hydrochloric acid (100 ml) containing ice (about 100 g): after stirring, the resulting precipitate was collected, washed with water and dried to give a solid (1.685 g). A portion (400 mg) was recrystallized from ethyl acetate to give the title 17α-acetate (z 50 mg), mp 175-177 °. <452 468 35 V --- Preparation Example LVI 17u-butyryloxy-6a, 9a-difluoro-11β-hydroxy-solder-methyl-3-oxo-androsta-1,4-diene-176-carbothioic acid (LVI) Using the same procedure such as those described in Preparative Example LV, LIV (2.0 g) was transferred with butyryl chloride (1.5 ml) instead of acetyl chloride to the title 17a-butyrate (2.08 g). A portion recrystallized from ethyl acetate had melting point lss - 1s7 °.

Preparation Example LVII 9a-Fluoro-11B-hydroxy-3-oxo-17a-propionyloxyandrosta-1,4-diene-17B-carbothioic acid (LVII) Using the same procedure as that described in Preparation Example LV, LIII (3.8 g) was transferred. using propionyl chloride (3.9 ml) instead of acetyl chloride and after aminolysis of the intermediate with diethylamine (10.35 ml) in the title 17a-propionate (4.1 g). One portion (350 mg) recrystallized from ethyl acetate gave colorless crystals (165 mg), mp 135-13a °, [α] D + 1z ° (C 0.92).

Preparation Example LVIII 6α, 9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioic acid (LVIII).

A solution of LIV (5.0 g) and triethylamine (6.15 ml) in dichloromethane (140 ml) was cooled with ice salt and treated dropwise with propionyl chloride (4.74 ml). The reaction mixture was further stirred at approx. 00 for 0.75 hours, then washed successively with 2N sodium carbonate, water, 2N hydrochloric acid, water, brine. After drying, solvent was removed to give a white solid (6.35 g). This was redissolved in acetone (120 ml) and diethylamine (1.2.5 ml): after stirring at room temperature for 1 hour, the volume was reduced to about 75 ml.

The solution was poured into 2N hydrochloric acid (200 ml) containing ice (ca. 300 g) and the resulting precipitate was collected, washed with water and dried in vacuo to give a white solid (5.17 g), m.p. 152-1550. Recrystallization of a portion (400 mg) of ethyl acetate gave the analytically pure title 452 468 36. .- thioacid-17a-propionate as colorless crystals (290 mg), m.p. 161 - 1e4 °, mn -21 ° (co, 9s>, whose solid-state infrared spectrum (in Nujol) showed a crystalline form other than samples obtained in Preparation Example XIX.

Pregaratexemgel LIX S-chloromethyl-9a-fluoro-166-methyl-3,11-dioxo-17u-propionyloxy-diandrostyl, 4-diene-17B-carbothioate (LIX) A solution of XLIX (409 mg) in propionic acid (5 ml), trifluoroacetic anhydride (2 ml) and toluene-p-sulfonic acid (0.1 ml in dry chloroform solution, 80 mg / ml) were stirred at 22 ° for 2.75 days. The non-acidic product was isolated by extraction with ethyl acetate after pouring into saturated sodium bicarbonate. The crude material was chromatographed on silica in chloroform-acetone (14: 1) and crystallized from ethyl acetate-gasoline (b.p. 60-800) to give the title 17a-propionate as colorless crystals, m.p. ° (c 1.15).

Pregaratexemgel LX S-chloromethyl-9a-fluoro-11β, 17β-dihydroxy-16β-methyl-3-oxo-androsta-1,4-diene-176-carbothioate (LX) A suspension of XLIX (102 mg) in ethanol (2 (5 ml) was stirred with sodium borohydride (10 mg) at 220 [mu] l hour. The reaction mixture was treated with acetone (5 ml), then concentrated to near dryness: the residue was dissolved in ethyl acetate (25 ml), washed with N-hydrochloric acid, water and brine. After drying, the organic solvent was removed to give the title IIs alcohol as a colorless foam (103 mg) whose only major component was equipolar with an authentic sample by t.l.c. comparison (silica, chloroform-acetone, 9: 1).

Preparation Example LXI 9d-fluoro-116-hydroxy-16β-methyl-3-oxo-17-dipropionyloxyandrosta-1,4-diene-176-carbothioic acid (LX1) Method A A solution of 9d-fluoro-11B-hydroxy-16B-methyl-3 -oxo-17d-propionyloxyandrosta-1,4-diene-178-carboxylic acid (603 mg, 0.75 mol of ethyl acetate solvate) and N, N'-carbonyldi (1,2,4-triazole) - (0,997 mg) in dry dimethylformamide (45 ml) was stirred under nitrogen at ca. 220 for 18.5 hours. A solution (15 ml) prepared from sodium hydride (305 mg) in dimethylformamide by saturation with hydrogen sulfide was added and stirring was continued at room temperature for 3 days. The reaction mixture was poured into 2N hydrochloric acid (200 ml) and the product was extracted with ethyl acetate (3x). The organic extracts were combined, washed with water and re-extracted with 5% sodium carbonate solution: the alkaline extracts were acidified with hydrochloric acid and extracted with ethyl acetate (3x). After washing with water and brine, the organic extracts were dried and concentrated to a small volume: the title thioacid was separated as cream crystals (101 mg), the only major component of which was identified by comparison with an authentic sample according to 1 H nmr and t.l.c. (silica, chloroform-acetone 4: 1).

Method B A solution of 9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-176-carboxylic acid (701 mg, 0.75 mol of ethyl acetate solvate) and N, N'- carbonyldiimidazole (473 mg) in dry dimethylformamide (26 mg) was treated under nitrogen at ca. 220 for 19.5 hours, then treated with a solution (10 ml) of sodium hydride (60% dispersion in oil, 233 mg) in dimethylformamide (10 ml) saturated with hydrogen sulfide. The resulting mixture was then stirred at room temperature for 5.5 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with ZN hydrochloric acid, water and brine, then dried and evaporated to a foam (186 mg). The title thio acid was shown to be the major component of the product according to 1 H nmr and according to t.l.c. (silica, chloroform-acetone [4: 1] and chloroform-acetone-acetic acid [30: 8: 1] compared to an authentic sample.

Method CI an almost identical reaction to that described in Method A, the carboxylic acid was treated with 1,1'-carbonyl-dibenzotriazole (1,587 g) instead of N, N'-carbonyl di (1,2,4-triazole), at room temperature for 6 hours. After the addition of the solution obtained from hydrogen sulfide and sodium hydride in dimethylformamide, the reaction was continued for 41.5 hours. The crude product was obtained as a foam; t.l.c. (silica, chloroform-acetone, 4: 1; and chloroform-acetone-acetic acid 30: 8: 1) showed that the title thioacid was present as a major component compared to an authentic sample.

Pregaratexemgel LXII S-Chloromethyl-Ga, 9d-difhxyl-16d-methyl-3-oxo-17d-propionyloxy-11β-trifluoroacetoxyandrosta-1,4, diene-176-carbothioate (LXII) A solution of the compound of Example 5 (described below) ( 100 mg) in dry tetrahydrofuran (2 ml) and pyridine (0.1 ml) were treated with trifluoroacetic anhydride (0.05 ml) and the mixture was kept at room temperature for 0.5 hours. The reaction mixture was poured into water and the product was extracted with ethyl acetate (3x). The organic extracts were washed with water, dried and evaporated to give the homogeneous title trifluoroacetate (116 mg) by 1 H nmr spectroscopy (singlet at 8,591, 19-protons in deuterio-chloroform) and t.l.c. on silica (acetone-gasoline, b.p. 40-600, 1: 3). An analytical sample of ether pentane had a melting point of 158 DEG-1620 DEG [56 DEG] + 56 DEG (c 0.23).

Example 1 S-Chloromethyl-9d-fluoro-11β-hydroxy-16β-methyl-3-oxo-17D-propionyloxyandrosta-1,4-diene-176-carbothioate Method A A solution of the product of Preparation Example I (2,115 g) In dimethylacetamide (7 ml), 452 468 39 2-- was treated with sodium bicarbonate (592 mg) and bromochloromethane (0.46 ml) and the mixture was stirred at room temperature. After 2 hours, the reaction mixture was diluted with ethyl acetate (500 mL) and washed with 5% sodium bicarbonate solution and water, dried and evaporated to give an orange foam (1.560 g). P.l.c. in chloroform-acetone (19: 1) gave an off-white foam (803 mg) which was crystallized twice from methanol to give off-white needles of the title S-chloromethyl ester (668 mg), m.p. 212-214 °, [a1D +44 ° (C 1.06).

Method B The title compound was prepared in the same manner using chloroiodomethane instead of bromochloromethane.

Method C. Sodium borohydride (19 mg) was added to a solution of II (230 mg) in ethanol (3.5 ml) and the solution was stirred at room temperature.

After 20 minutes, acetone (1 ml) was added and the solution was concentrated to ca. l / 4 volume. Ethyl acetate (30 ml) was then added and the solution was washed with N-hydrochloric acid and water, dried and evaporated to give a white foam (239 mg). P.l.c. in chloroform-acetone (19: 1) gave a white foam (188 mg) which was crystallized twice from methanol to give white needles of the title S-chloromethyl ester (158 mg), m.p. 210-2120, [α1D + 44 ° (C 1.07).

Example 2 S-chloromethyl-9α-fluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate A solution of IV (0.927 g) in dimethylacetamide (4 ml ) was treated with sodium bicarbonate (0.256 g) and bromochloromethane (0.2 ml). and the mixture was stirred at 22 ° for 2 hours. The reaction mixture was partitioned between ethyl acetate (100 ml) and 2N hydrochloric acid (20 ml) and the aqueous layer was further extracted with ethyl acetate. The combined extracts were washed successively with 2N hydrochloric acid, water, 3% sodium bicarbonate, water and saturated brine. After drying, the solvent was removed and the crude product (757 mg) was crystallized twice from acetone to give the title chloromethyl thiol ester (0.367 g), m.p. 247 DEG-250 DEG., [.Alpha. 63).

Example 3 S-chloromethyl-11β-hydroxy-3-oxo-17α-propionyloxyandrosta-1,4, diene-176-carbothioate A solution of crude XV (2.366 g) in dimethylacetamide (10 ml) was treated with sodium bicarbonate (756 mg) and bromochloromethane (0.5 ml) at 220 for 16 hours. It was partitioned between ethyl acetate and 2N hydrochloric acid and the aqueous layer was further extracted with ethyl acetate. The combined organic phases were washed successively with 2N hydrochloric acid, water, sodium bicarbonate, water, saturated brine, then dried and the solvent was removed to give a yellow foam. The neutral product was purified by preparative h.p.l.c. on silica (15u) in 7% acetone in chloroform and the main product was crystallized from acetone to give the title chloromethyl-thiol ester (0.511 g), m.p. 117 DEG-120 DEG, [.alpha.

Example 4 S-chloromethyl-6a, 9c-difluoro-111-hydroxy-16d, 17d-isopropylidenedioxy-3-oxoandrosta-1,4-diene-17β-carbothioate A stirred solution of IX (1.36O g) in N , N-dimethylacetamide (10 ml) was treated with sodium bicarbonate (0.377 g) and bromochloromethane (0.3 ml) and stirring was continued for 1 hour.

Ethyl acetate (100 ml) was added and the resulting solution was washed successively with 2N hydrochloric acid, water, sodium metabisulfite solution, water, sodium bicarbonate solution, water and saturated sodium chloride solution, then dried and the solution was concentrated, whereupon crystallization took place. The crystallized product (0.765 g) was purified by p.l.c. on silica gel, developed with chloroform: acetone (9: 1). The headband was eluted with ethyl acetate and crystallized from ethyl acetate to give the title S-chloromethyl-thioester (0.475 g) as a white prism, m.p. 271 DEG-21 DEG, [.alpha. + D @ 20], (C10.9, ethylethylsulfoxy).

Example 5 S-chloromethyl-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate A solution of XIX (0.546 g) in dimethylacetamide (3 ml ) was treated with sodium bicarbonate (202 mg) and bromochloromethane (0.6 ml) at 220 for 3 hours. The mixture was treated with 2N hydrochloric acid (50 ml) and the product was extracted with ethyl acetate.

The extracts were combined and washed successively with 2N hydrochloric acid, water, saturated brine, dried and the solvent was removed. Two crystallizations from ethyl acetate gave the title chloromethyl thiol ester (0.404 g), m.p. 272-2750, [α] D + 49 ° (C 0.35).

Example Gel 6 - 15 Following the same general procedure as in Example 1 (Method A) but using as starting material the 17β-carbothioic acid corresponding to the desired 176-carbothioate (procedure details are summarized in Table III below) the following compounds were prepared: 6. S-chloromethyl-11β-hydroxy-16β-methyl-3-oxo-17d-propionyloxy-androsta-1,4-diene-17β-carbothioate, m.p. 192 - 1930, n [a1 + es ° læ1, osL _221 [α] D -56 7. S-chloromethyl-9d-fluoro-11β-hydroxy-16-methylene-3-oxo-17α-propionyloxyandrosta-1,4-diene-176-carbothioate, m.p. 212 DEG-0 DEG C. ). 8. S-chloromethyl-17α-acetoxy-9d-fluoro-IIβ-hydroxy-16β-methyl-3-452 468 42 --- oxoandrosta-1,4-diene-17β-carbothioate, m.p. 220 DEG-223 DEG. D + 39.5 ° (C 1.06). 9. S-chloromethyl-17α-butyryloxy-9α-fluoro-11β-hydroxy-16H-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, m.p. 172 DEG-17 DEG, [.alpha. , 10). 10. S-chloromethyl-9α-fluoro-1,1B-hydroxy-17α-isobutyryloxy-166-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, m.p. 234-2-239 °, [α] + 43 ° ( C 1, oo) .- ll. S-chloromethyl-9-fluoro-1,1B-hydroxy-3-oxo-17U-propionyloxy-androsta-1,4-diene-175-carbothioate, m.p. 196-190, [α] D + 38 ° (Q 0.97). 12. S-chloromethyl-Gu-fluoro-11β-hydroxy-3-oxo-17α-propionyloxy-anarosta-1,4-alien-17s-carbothioate, melting point las - 191 °, ( . 13. S-chloromethyl-17α-acetoxy-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-176-carbothioate, m.p. 280 - zs3 °, [@ 1D + 4s ° (C o, so). 14. S-chloromethyl-17U-butyryloxy-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, m.p. 235 DEG-23 DEG, [.alpha. (co, ss). 15. S-chloromethyl-9a-fluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrosta-1,4-diene-176-carbothioate, m.p. 276 DEG-50 DEG (sonication), [u] D + 121 ° (C o, s1, aimecylsulfoxia). 43 Table III 452 468 l Ex Reagent NêHC03 Steroid L3sning¿Reaktions-1 Plç __ íäââšâlli 'Pr ° dukt 4- 01 »w» gnfffd mfdel, 1:13 4: 1- W mg EMA t 3 nædel> a¶xxaüu _ m ) 144200 6 Bzcxzu 300 .. 981 s 3 - EA 026 (0.2s) 7 ar <142c1 749 2000 11 1.5 19 = 1 EA '201 (0.58) s. 141014201 565 1955 7 2.0 - EA 307 * (0.44) 9 afcnzcs . 421 1501 10 1.0 14 = 1 m4 071 (032) “10 0100201 121 sas 3 2.75 - EA 255 (0004) 11 mca2c1 1100 2750 20 1.25 fm 1600 (0.90) 12 arc fi zcl 1000 2740 20 2 - EA-P 2460. (006 ) 13 nfcxzcl 2500 6600 40 1.75 - A 5410 (2.00> 14 mca2c1 1600 4600 46 2 - A 2140 (1.40) 15 s = cn2c1 615 1600 12 1.5 4 = 1 A 2444 * (040) 452 468 44. = Remarks: EA = ethyl acetate A = acetone M = methanol P = petrol boiling point 60 - 800 * Obtained from a portion (400 mg) of the crude product l (2,35 9) Ä ** Obtained from a portion (300 mg) of the crude product (1.72 g).

Example 16 S-chloromethyl-9α-chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-175-carbothioate and S-chloromethyl-9β, 11β-egoxy-16β- Methyl 3-oxo-17α-propionyloxyandrosta-1,4-diene-17B-carbothioate A solution of mixture XXIV (1.032 g) in dimethylacetamide (5 ml) was treated with sodium bicarbonate (0.203 g) followed by bromochloromethane (0.2 ml). ml) and the reaction mixture was stirred at 220 for 1.5 hours, then partitioned between ethyl acetate (50 ml) and 2N hydrochloric acid (35 ml). The aqueous phase was extracted with additional ethyl acetate (2 x 30 ml) and the combined extracts were washed with ZN hydrochloric acid, water, saturated sodium bicarbonate solution, water, saturated sodium chloride solution and dried, and the solvent was removed in vacuo to give a cream foam. 0.856 g) containing a mixture of the title S-chloromethyl esters.

These were separated by p.l.c. on such, developed with chloroform: acetone (19: 1). The more polar component (0.306 g) was crystallized twice from ethyl acetate to give S-chloromethyl-9d-chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxoandrosta-1,4-diene-17β-carbothioate (0.232 g) as white plates, melting point 222 - 229 °, mn + 70 ° (c 1,23). The less polar component (0.210 g) was crystallized from acetone-gasoline to give S-chloromethyl-95,115-epoxy-16B-methyl-3-oxo-17U-propionyloxyandrosta-1,4-diene 17β-carbothioate (0.065 g), m.p. 169 DEG-173 DEG, [QJD +49? (c o, so).

Example 17 S-fluoromethyl-9c-fluoro-11B-hydroxy-16B-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate XXV (660 mg) Stirred with a suspension of silver fluoride (1,442l g) in acetonitrile (8.5 ml) in the dark at room temperature.

After 72 hours, the reaction mixture was diluted with ethyl acetate (200 mL) and filtered through a bed of kieselguhr. The filtrate was washed with water, dried and evaporated to give a white foam (517 mg). P.l.c. in chloroform-cyclohexane (19: 1) and chloroform gave an off-white foam (270 mg) which was crystallized from methanol, then methanol-diethyl ether to give the title S-fluoromethyl ester (176 mg), mp 241-242 °, [ a] D + 97.5 ° (c 0.98).

Example 18 S-fluoromethyl-9d-fluoro-11B-hydroxy-16u-methyl-3-oxo-17u-propionyloxyandrosta-1,4-diene-175-carbothioate A solution of XXX (0.64O g) in acetonitrile (8 ml ) was treated with dry silver fluoride (1.5 μl g) and stirred in the dark at 220 for 46.5 hours. The mixture was diluted with ethyl acetate (200 ml) and filtered through kieselguhr. The solution was washed with 2N hydrochloric acid, water and saturated sodium chloride solution, and the solvent was removed in vacuo to give a light yellow foam (0.504 g). This was chromatographed (p.l.c.) on silica gel, developed with 5% acetone in chloroform. The headband was eluted with ethyl acetate and crystallized twice from acetone to give: ite1-fluoromecyl-cioester (0.244 g), mp 242-243 ° (dec.), [Α] D + 37 ° (c 0.75). 452_4es s Example 19 S-Fluoromethyl-6α, 9α-difluoro-11B-hydroxy-16u-methyl-17H-propionyloxy-3-oxoandrosta-1,4-diene-17B-carbothioate A solution of XXXI (310 mg) in acetonitrile ( 10 ml) was stirred with silver fluoride (947 mg) for 3 days at room temperature in the dark.

Ethyl ether (100 ml) was added and the mixture was filtered through kieselguhr. The filtrate was washed successively with 2N hydrochloric acid, water, saturated brine and then dried. The solvent was removed and the residue was exposed to p.l.c. in chloroform then chloroform-acetone (19: 1). The product was eluted with ethyl acetate and crystallized at concentration of the solution to give the title fluoromethyl thiol ester (0.075 g), mp 272-2730 (dec.), [Α] D + 30 ° (c 0.35).

Example 20 S-Fluoromethyl-9u-fluoro-116-hydroxy-16a, 17a-isopropylidene dioxy-3-oxoandrosta-1,4-diene-17B-carbothioate A suspension of XXXVII (1.2O g) in acetonitrile (20 ml) stirred was diluted with silver (I) fluoride (2.842 g) at room temperature in the dark.

After 11 days (no starting iodide left, tlc (chloroform, six runs), the reaction mixture was diluted with ethyl acetate (400 ml) and filtered through diatomaceous earth. The filtrate was evaporated to a light yellow crystalline solid (726 mg) and the diatomaceous earth was continuously extracted with ethyl acetate. a Soxhlet apparatus to give a yellow solid (197 mg) The solid from the filtrate was suspended in chloroform-methanol (10: 1) and the insoluble fraction (203 mg) was collected.

This was combined with the solid from the Soxhlet extraction in ethyl acetate (300 ml) and filtered through a silica column (Merck Kiselgel 60) (50 q). The eluate containing the product (t.l.c.) was combined, washed with water, dried under co-treatment with charcoal and concentrated to a small volume. The resulting white solid (276 mg) was collected and recrystallized from ethyl acetate to give colorless crystals of tite1-S-fluoromethyl. ester (231 mg), m.p. 320 DEG-322 DEG (sonar), [.alpha.] D @ 20 + 132 DEG (C 0.22, methyl ethyl sulfoxide).

Example gel Z1 S-fluoromethyl-6a, 9d-difluoro-111-hydroxy-16a, 17a-isopropylidenedioxy-3-oxoandrosta-1,4-diene-176-carbothioate A solution of XXXVIII (0.804 g) in acetonitrile (60 ml ) was treated with silver fluoride (1.82l g) and the reaction mixture was stirred in the dark for 18 hours. The reaction was diluted with ethyl acetate and filtered through kieselguhr. The filtrate was washed with water and saturated sodium chloride solution, then dried and the solvent removed in vacuo to give a light cream solid (0.636 g). This was purified by p.l.c. on silica gel, developed twice with chloroform: acetone (14: 1).

The headband was diluted with ethyl acetate and crystallized five times from ethyl acetate to give the title S-fluoromethyl-thioester (0.11s9) as a white prism, mp 305-311 °, [α] D + 12s ° (c 0.73, dimethylsulfoxide).

Example 22 - 30 Following the same general procedure as in Example 17 using as starting material the S-iodomethyl-176-carbothioate corresponding to the desired product (process details summarized in Table IV below) the following compounds were prepared: 22. S-fluoromethyl- 17α-acetoxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carbotloate, m.p. 248 DEG-249 DEG, [.alpha.] D @ 20 +1 ° (C1, os>. -fluoromethyl-11B-hydroxy-3-oxo-17α-propionyloxyandrosta-1,4-alien-11β-carbothioate, m.p. 112-117 °, [α] D + s1 ° (c 0.76) .452 468 48 ~ - 24. S-fluoromethyl-11β-hydroxy-16β-methyl-3-oxo-17β-propionyloxy-androsta-1,4-diene-17β-carbothioate, m.p. 223-222, [α] D + 10 ° (C 0.38). -fluoromethyl-9α-chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate, m.p. 182 DEG-193 DEG, [α] D + 116 ° (C0, 7s) 26. S-Fluoromethyl-9a-fluoro-11B-hydroxy-16-methylene-3-oxo-17a-propionyloxyandrosta-1,4-diene-17B-carbothioate, m.p. 205 DEG-31 DEG, [.alpha. z1s °, [u1D -ss ° (C1, 00). 27. S-Fluoromethyl-9α-fluoro-11β-hydroxy-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate, m.p. 207 DEG-211 DEG, [.alpha. . 28. S-fluoromethyl-6u-fluoro-116-hydroxy-3-oxo-17α-propionyloxyanarosta-1,4-alien-17β-carbothioate, m.p. 224 DEG-22 DEG, [.alpha. 29. S-fluoromethyl-17u-acetoxy-Gu, 9u-difluoro-11B-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-176-carbothioate, m.p. 308 DEG-0 DEG C. (C10, ao) 30. S-fluoromethyl-17α-butyryloxy-6n, 9α-difluoro-1,1'-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-176-carbothioate, m.p. 249-2.5 °, [α] D + 32 ° (c 1.05). 452 468 49 Sf fluoromethyl- 17cx-acyloxyandros ta-Uß-carbothioates via halogen exchange Table IV Ex. Ag E 'Starting Steroid Solution - Reaction- PLC KfiStallï- "Pl-'Odllkt Ill-_ (mg) I means rgäš- (å RE): gšåâggs- (IT19) ïalogerm (ï fi âq) tanperaüm Me zCà means 22 3745 I 1702 22 202 '24: l A 477 '23 2071 I 1034 10 26 l9: l EA 585 * 24 1945 I 850 6 26 l9: l EA 166 25 ll6l I 550 8 23.5 1921 M 106 26 3574 I 1658 25 24 l9: l A 300 27 700 I 1000 50 3 - M 470 28 462 I 700 35 2 - EA-P 350 29 2600 I 4000 200 0.75 ~ EA; 2280 30 7 ao I 1 2 oo 6 ol - EA 755 EA = ethyl acetate A = acetone = meta zero petrol boiling point 60 - 800 'U ll * Purity approx. 95% 452 468 50 - Exemgel 31 S-bromomethyl-9G-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate A solution of XXV (660 mg) in acetone (20 ml) was stirred with lithium bromide (972 mg) at room temperature for 5 days. The reaction mixture was diluted with ethyl acetate (150 mL) and then washed successively with 10% sodium thiosulfate solution, water and brine, dried and evaporated to a off-white foam (624 mg). This was crystallized twice from acetone-petroleum ether (m.p. 40-60 °) to give colorless crystals of the title S-bromomethyl ester (499 mg), m.p. 186.5-187 °, [α] D + 2 ° ( c 0.99).

Bxemgel 32 S-bromomethyl-6u, 9u-difluoro-11E-hydroxy-16a-methyl-3-oxo-17u-propionyloxyandrosta-1,4-diene-17B-carbothioate A solution of XXXI (850 mg) in acetone (25 ml ) was stirred with lithium bromide (1.2l g) at ca. 220 for 5 days. The product was isolated as described for Example 31 and recrystallized twice from ethyl acetate to give colorless crystals (690 mg).

These were re-treated under the same reaction conditions for a further 4 days to give the pure title S-bromomethyl ester (600 mg), colorless crystals of ethyl acetate, m.p. 255 DEG-27 DEG, [.alpha.

Example 33 S-2'-Fluoroethyl-9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate A solution of XXXIX (910 mg) in acetonitrile (20 ml) was stirred with silver (I) fluoride (2.07l g) at room temperature in the dark. After 6 days, the reaction mixture was diluted with ethyl acetate (150 mL). and filtered through diatomaceous earth. The filtrate was diluted with more ethyl acetate (150 ml) and washed with water, dried and evaporated to a white foam (704 mg). P.l.c. in chloroform-acetone (9: 1) gave a less polar product, such as a yellow foam (431 mg), which was crystallized twice from methanol to give the title S-2'-fluoroethyl ester (253 mg), m.p. 1340, mn + 1o4, s ° (c 0.98).

Example 34 S-Chloromethyl-9a-fluoro-11B-hydroxy-16-methylene-3-oxo-177 propionyloxyandrosta-1,4-diene-176-carbothioate A suspension of XLII (227 mg) in propionic acid (2.2 ml) and trifluoroacetic anhydride (0.7 ml) were treated with a dry chloroform solution of toluene-p-sulfonic acid (0.044 ml, c about 80 mg / ml) and then stirred at room temperature for 6 hours * and then at 30 in 16 ml. ,5 hours. The reaction mixture was diluted with 5% sodium bicarbonate solution (75 ml) and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried and evaporated to a brown adhesive (254 mg). The adhesive was subjected to p.l.c. in chloroform-acetone (19: 1) (three runs). The headband (152 mg) was crystallized twice from ethanol to give white crystals (30 mg) of the title S-chloromethyl ester-17α-propionate contaminated with S-chloromethylf9c-fluoro-17α-hydroxy-16-methylene-3-oxo -11β-propionyloxyandrosta-1,4-diene-175-carbothioate as shown by 1Hnmr spectroscopy.

Example 35 S-Chloromethyl-166-hydroxy-16B-methyl-3-oxo-17α-propionyloxy-androst-4-ene-17β-carbothioate Catalytic reduction of the compound of Example 6 (0.517 g). in the presence of tris (triphenylphosphine) -chloro fl x fl ion fl) (497 mg) in benzene (50 ml) for 22 hours gave, after chromatography (plc) 452 468 52 -f - on silica in chloroform (four runs), elution with ethyl acetate and crystallization twice from ethyl acetate the title A4-3 ketone (0, 13o 9), m.p. 176 - 177 °, [q1D + 7s ° (C o, so).

Example Gel 36 S-Chloromethyl-9a-fluoro-11B-hydroxy-16B-methyl-3-oxo-17a-propipnyloxyandrost-4-ene-17B-carbothioate Catalytic reduction of the compound of Example 1 (0.664 g) with tris (triphenylphosphine ) chlorohodium (I) (800 mg) in benzene (100 ml) for 21.5 hours gave, after chromatography on silica in chloroform-acetone (9: 1) and two crystallizations from acetone, the title chloromethyl-thiol ester (0.142 g) as white needles, melting point 217 - 22s °, [a1D + s4 ° (C o, e3).

Example Gel 37 S-Fluoromethyl-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrost-4-ene-178-carbotate Catalytic reduction of the compound of Example 24 (0.413 mg) in the presence of tris (triphenylphosphine ) chlorohodium (I) (432 mg) in benzene (60 ml) at 220 for 24 hours gave, after multiple chromatography on silica in chloroform-acetone mixtures and crystallization from acetone the title A4-3 ketone (0.16 g ), melting point 174 - 177 °, [@] D + 12s ° (C o, ss.

Example 38 S-chloromethyl-9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-178-carbothioate S-chloromethyl-95,11β-epoxy-16β-methyl-3 -Oxo-17α-propionyloxyandrosta-1,4-diene-175-carbothioate (ca. 0.9 mg) from Example 16 was treated with hydrogen fluoride-urea complex (ca. 1 ml) and stirred for a total of 24 hours at room temperature. The mixture was treated with sodium bicarbonate and the product was extracted twice with ethyl acetate: the extracts were washed twice with water, dried and evaporated. The product obtained was displayed according to t.l.c. on silica in three different solvent systems (acetone-petrol, boiling point 40 - 600, 1: 2; chloroform-acetone, 9: 1; ethyl acetate-petrol, boiling point 40-600, 1: 2, two runs) contain the title fluorohydrin by comparison with an authentic sample.

Example 39 S-Chloromethyl-6α, 9α-fluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-176-carbothioate A solution of LXII (29 mg) 1 methanol (2 ml ) was kept at room temperature for 3 hours. The mixture was evaporated to dryness to give the title 11B alcohol (25 mg) identified by comparison with its 1 H nmr spectrum (in deuteriodimethyl sulfoxide) and t.l.c. the same properties (silica, acetone-petrol, boiling point 40 - 600, 1: 3) as those according to an authentic sample.

The invention also relates to pharmaceutical compositions intended for use in anti-inflammatory therapy, comprising at least one androstane compound of formula (I) (as defined above) together with one or more pharmaceutical carriers or excipients. Such compositions may be in forms adapted for topical or internal administration.

The active androstane compounds can preferably be formulated in conventional manner in preparations suitable for topical administration by means of a topical vehicle therefor. The term topical administration in this context includes insufflation and inhalation. Examples of different types of preparations for topical administration include ointments, lotions, creams, powders, drops (eg eye or ear drops), sprays, I (eg for the nose, throat, lungs or skin), suppositories, retention enemas, chewable or absorbent tablets or 452,468 pills (eg for the treatment of aphthous ulcers), capsules or cartridges for use in an inhaler or insufflator and aerosols (for example for the nose, throat or lungs).

Ointments and creams can be prepared, for example, with a water or oil base with the addition of suitable thickening and / or gelling agents and / or solvents. Such a base may, for example, comprise water and / or an oil such as liquid paraffin or a vegetable oil such as acarid oil or castor oil or a solvent such as polyethylene glycol having an average molecular weight in the order of 200-600. Thickeners which may be used according to the nature of the base include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycols with an average molecular weight in the order of 4000 - 6000, wool grease and beeswax and / or glyceryl monostearate and / or non-ionic emulsifiers.

Spray compositions may, for example, be prepared as aqueous solutions or suspensions or aerosols using a suitable tear agent, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or another suitable gas.

Capsules and cartridges intended for use in an inhaler or insufflator of e.g. gelatin can be prepared containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch. Each capsule or cartridge may generally contain between 20 pg - 10 mg of the active androstane compound.

The amount of the active androstane compound in the topical compositions of the invention depends on the exact type of preparation to be prepared but is generally in the order of 0.001 to 5.0% by weight. However, for most preparation types, the amount used should preferably be in the order of 0.005 to 0.5% and preferably - 0.01 to 0.25%. However, with powder for inhalation or insufflation 452 468 ss _ - the amounts used must be in the order of 0.1 - 2%.

The above preparations for topical application to the skin can be used for the treatment of inflammatory dermatoses in humans and animals, for example eczema, which normally respond to corticosteroid therapy and even less susceptible to conditions such as psoriasis in humans.

The broads for administration by inhalation or insufflation are intended for prophylaxis administration in people suffering from allergic and / or inflammatory conditions of the nose, throat or lungs such as asthma and rhinitis including hay fever. The aerosol formulations are preferably arranged so that each metered dose or "puff" of aerosol contains 20 pg - 1000 pg, preferably about 50 g - 100 g of a compound of the invention. The administration can be several times daily, for example 2, 3, 4 or 8 times and give for example 1, 2 or 3 doses each time. The total daily dose of an aerosol should be in the order of 100 ng - 10 mg, preferably 200 μg - 100 pg. The total daily dose of the measured dose given by capsules and cartridges in an inhaler or insufflator is generally twice as large as the aerosol formulations.

Topical preparations can be administered by one or more applications per day in the affected area; over the skin areas, closing bandages can often be used successfully.

For internal administration, the novel compounds of the invention may be prepared, for example, by conventional means for oral, parenteral or rectal administration. For oral administration, syrups, elixirs, powders and granules may be used which may be prepared in a conventional manner. However, dosage unit forms are exemplified as described below.

Preferred dosage forms for internal administration are 452 468 ss g. - unit forms, e.g. tablets and capsules. Said dosage unit forms contain 0.1 mg to 20 mg, preferably 2.5 to 10 mg of the active steroid.

The compounds of the invention may generally be administered by internal administration when systemic adrenocortical therapy is indicated.

Generally speaking, preparations for internal administration may contain 0.05 to 10% of the active ingredient depending on the type of preparation used. The daily dose may vary from 0.1 mg to 60 mg, e.g. 5 - 30 mg, depending on the condition to be treated and the desired treatment time.

Exemgel (A) Ointment active ingredient 0.1% w / w liquid paraffin B.P. 10% w / w white soft paraffin to produce 100 parts by weight The active ingredient is ball milled with a small amount of the liquid paraffin until the particle size is reduced to 95% is less than Sp, the paste is diluted and the mill is rinsed with the remaining liquid paraffin, mixed and the suspension is added to the molten white soft paraffin at 50 ° C. The mixture is stirred until cold and gives a homogeneous ointment. 452 468 57 _ _ _ »- Exemgel (BL Cream §__y¿! Active ingredient 0.1 cetostearyl alcohol 10.0 cetamacrogbl 1,000 2.5 white soft paraffin 10.0 liquid paraffin _ 10.0 chlorocresol 0.1 sodium acid phosphate 0.5 purified water to 100.0 Preparation Chlorocresol and sodium acid phosphate are dissolved in water at about 70-75 ° C. The waxes melt together at about 65-70 ° C and are added with stirring to the aqueous phase when cooled to 65-70 ° C. The steroid is micronized. (particle size as defined in BPC 1973 page 911 for ultrafine powder) and dispersed in a portion of liquid paraffin. The steroid suspension and the rest of the liquid paraffin are added to the base with stirring at 60-6500. The preparation is cooled with stirring to room temperature.

Exemgel (C) Measured dose aerosol formulation gives dose% w¿w active ingredient 0.05 mg 0.059 fluorotrichloromethane 25.5 mg 30.0 dichlorodifluoromethane to 85.0 mg to 100.0 The active ingredient is micronized (particle size as defined in BPC 1973 page 911 for ultrafine powder) and dispersed in fluorotrichloromethane. This suspension is filled into an aluminum aerosol container, the main area is rinsed with gaseous dichlorodifluoromethane to exclude air and a dosing v. 452 468 aerosol valve is crimped into position on the container. Liquid dichlorodifluoromethane is pumped through the metering valve under pressure to the intended weight.

Exemgel (D) Inhalation capsule (100 g / dose) per capsule% w / w active ingredient 0.1 mg 0.4 lactose to 25.0 mg to 100.0 The active ingredient is micronized (particle size as defined in BPC 1973 page 911 for ultrafine powder) and mixed with lactose in the proportions given in the above preparation. The steroid lactose mixture is filled into hard gelatin capsules for administration by an inhaler.

Claims (11)

452 468 51 _ - PATENT REQUIREMENTS Compounds of formula (I) wherein R 1 represents a fluorine, chlorine or bromomethyl group or a 2'-fluoroethyl group PP, R 2 represents a group COR 6 wherein R 6 is a C 1-3 alkyl group or OR 2 and together form a 16d, 17d, isopropylideneoxy group; R represents a hydrogen atom, a methyl group (which may be either in the d- or ß -configuration) or a methylene group; R 4 represents a hydrogen, chlorine or fluorine atom; R 5 denotes a hydrogen or fluorine atom and the symbol fffffv denotes a single or double bond. Compounds according to claim 1, characterized in that R1 is a chloromethyl or fluoromethyl group. Compounds according to claim 1 or 2, characterized in that R 4 is fluorine. Compounds according to any one of claims 1 to 3, characterized in that they are 1,4-dienes. Compounds according to claim 2, characterized in that these are 1,4-dienes wherein R 4 and R 5 are fluorine and R 3 is (- or β-methyl or methylene. Compounds according to claim 5, characterized in that 452 468 "c and g in that R 3 is a d-methyl group. Compounds according to Claim 1, characterized in that they are S-chloromethyl-9d-fluoro-11β-hydroxy-1G-dimethyl-G-oxo-17-propionion-oxyandrosta-1,4-diene-17β-carbothioate; 1S-Chloromethyl-ed-fluoro-1ip-nyaroxy-is-methylene-α-oxo-iveopropionyloxyandrosta-1,4-diene-1,7-carbothioate and S-fluoromethyl-61.9K-difluoro-11β-hydroxy- 16qßl7d% isopropylidenedioxy-3-oxoandrosta-1,4-diene-17§-carbothioate. A compound according to claim 1, characterized in that it is S-fluoromethyl-6m, quinodifluoro-11β-hydroxy-16-methylmethyl-3-oxo-1β-propionyloxyandrosta-1,4-diene-1β-carbothioate. A compound according to claim 1, characterized in that it is S-chloromethyl-6m, 9drdifluoro-Ig-hydroxy-16d-methyl-3-oxo-17M-propionyloxyandrosta-1,4-diene-light-carbothioate. 10. A process for the preparation of compounds according to claim 1, characterized in that I (a) a compound corresponding to formula 1 as defined in claim 1 but containing either a free 17β-carbothioic acid group or a functionally equivalent group) or a free 17d-hydroxy group (R 3 is a hydrogen atom or a methyl or methylene group), or that another reactive group present is optionally in protected form, is subjected to esterification; (b) a compound corresponding to formula I as defined in claim 1 but containing a 17 P substituent of the formula -COS (CH 2) n Y (wherein Y represents a substitutable substituent and n is 1 or 2) may react with a compound which serves to: replacing the group Y with a halogen atom to form a compound of formula I according to claim 1; (c) a compound of formula I as defined in claim 1 but containing an 11-oxo group is subjected to 452,468 ål r - reduction to form the required 11β-hydroxy-androstane; (d) a compound corresponding to formula I as defined in claim 1 but containing a protected 11α-hydroxy group is subjected to deprotection; (e) a compound of formula I as defined in claim 1 but containing a 9,11 double bond (and no substituent in the 11-position) is reacted with one or more reagents which serve to introduce the desired 9-dihalo-11β the hydroxy group. (f) a compound corresponding to formula I as defined in claim 1 wherein fwwwww represents a double bond is subjected to partial reduction to produce a corresponding compound wherein fffffv represents a single bond. A pharmaceutical composition for use in anti-inflammatory therapy, comprising at least one androstane compound of formula I as defined in claim 1 together with one or more pharmaceutical carriers or excipients. A composition according to claim 1f, characterized in that it is in a form suitable for topical administration.