DK147022B - METHOD OF ANALOGUE FOR THE PREPARATION OF 11BETA, 17ALFA-DIHYDROXY-3-OXO-ANDROST-4-EN-17BETA-TIOCHARBOXYLATER - Google Patents

Description

147022 i

The present invention relates to an analogous method for the preparation of novel anti-inflammatory active steroids of the androstance series, namely, 113,17a-dihydroxy-3-oxo-androst-4-en-17e-thiocarboxylates having the generalization set forth in the preamble of claim 1. formula I wherein R, R, R, R, R and the symbol rrr have the same meanings stated. The process is peculiar to the characterizing part of claim 1.

Anti-inflammatory steroids most typically belong to the corticoid type, ie. they are pregnancy derivatives. British Patent Nos. 1,384,372, 1,438,940 and 1,514,476 disclose esters of certain andros tan-17 (3-carboxylic acids with anti-inflammatory activity. European Patent Application No. 79300500.0 (Publication No. 0004741) discloses esters of androstan-173 -carbotic acids which also have anti-inflammatory activity.

It has now been found that certain androstane compounds containing a haloalkyl carbothioate group at the 17β position have particular beneficial anti-inflammatory properties which will be discussed in greater detail later in the specification.

The compounds of general formula I have good anti-inflammatory activity, especially in topical use, as shown by McKenzie's human spot test and in measuring the reduction of croton oil-induced edema when the compounds are applied locally to the skin of mice and rats.

Some of the compounds exhibit good topical or local anti-inflammatory activity in the croton oil ear sample, combined with minimal hypothalamic-pituitary-adrenal suppressive activity after local administration in the same animal species. These results show that such compounds can be valuable in the local treatment of inflammatory conditions in humans and animals with minimal propensity to cause undesirable systemic side effects.

European Patent No. 4741 discloses anti-inflammatory active thioacetic acid derivatives of the general formula 2

ISLAND

ISR

X3 = V4> S4 5 x γ o i1 1 2 where X represents hydrogen, fluorine or chlorine, X hydrogen, fluorine, chlorine or bromine, X3 = CO, = crT ° H or, if X2 -Cl4 is chlorine, also = C ^ ^H, X hydrogen or C₂_g alkanoyl when X8 is hydrogen, or α- or B-methyl, or OX ^ and X8 together with 16α-isopropylidene dioxide, R represents C ^ g alkyl, or phenyl or benzyl optionally substituted on the phenyl ring by alkyl or alkoxy or halogen, and where. has the meaning set forth in claim 1 below.

The compounds prepared by the process of the present invention, judged by the croton oil test on the mouse ear, and as shown in the table below, have more potent anti-inflammatory effects than the compounds known from the European patent which are believed to be the most potent, viz. the compound of Example 1A, S-methyl-6a, 9a-difluoro-11B-hydroxy-16a-methyl 1- 3-oxo-17ot-propionyloxy androsta-1,4-diene-176-tiocarboxylate; this compound is the methyl analog of the compounds of Examples 5 and 19, which are S-chloromethyl and S-fluoromethyl compound, respectively.

Danish Patent Specification No. 133158 discloses anti-inflammatory active 3-oxo-17a-acyloxyandrost-4-ene-17B-carboxylic acid esters of the general formula O-X8 of 7

C

wherein X represents hydrogen, chlorine or fluorine, X oxo, 8-hydro- = 7 xy or, if X, 8-chloro, X hydrogen or C 1-4 alkyl and X8 halomethyl or fluoroethyl, and wherein R 3 alone and: -.- -. have the meanings set forth in claim 1 below. The compounds prepared by the process of the present invention, judged in the above manner and also shown in the table, have more potent effects than two of the most powerful of the compounds known from the Danish patent, namely chloromethyl and fluoromethyl-9a-fluorine. 113-hydroxy-16B-methyl-3-oxo-17cι-propionyloxyandrosta-1,4-diene-173-carboxylate (Examples 1 and 3, respectively).

In the aforementioned croton oil ear sample in mice, male mice weighing 23-28 g were used as experimental animals. Measured doses of the test steroids are dissolved in a mixture of croton oil, pyridine and ether in the amount (volume) 2:20:78.

Groups of 10 mice received 0.02 ml of the test croton oil solution containing the test steroid at the given concentration applied to the inner side of both ears of all animals in the group. In addition, a control group received croton oil solution without steroid.

Six hours later the animals were sacrificed and both ears were cut off and weighed.

A mean was calculated for each dose group and used as the response parameter; then dose response lines were constructed to determine the relative strength of the individual compounds.

The results are shown in the table below. By default, the strength of S-methyl-6a, 9a-difluoro-11B-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-178-thiocarboxylate is arbitrarily employed to 1.

147022 4

Table

Compound Compound prepared in Relative Example No. according to the invention strength 1S-chloromethyl-9a-fluoro-113-hydroxy-5,13 16 B-methyl-3-oxo-17a-prop ionyloxy-androsta-1,4-diene -173-thiocarboxylate 5S-chloromethyl-6a, 9a-difluoro-113-hydro-7.00 xy-16a-methyl-3-oxo-17a-propionyloxy-androsta-1,4-diene-17B-thiocarboxylate 7S chloromethyl-9a-fluoro-11B-hydroxy-16-5,25 methylene-3-oxo-17a-propionyloxyandrosta-1,4-diene-17 3-thiocarboxylate 8S-chloromethyl-17a-acetoxy-9a-fluorine 113- 7.38 hydroxy-163-methyl-3-oxoandrosta-1,4-diene-17β-thiocarboxylate 19 S-fluoromethyl-6a, 9a-difluoro-113-hydro-14,13 xy-16a-methyl-17a propionyloxy-3-oxo-androsta-1,4-diene-17 3-thiocarboxylate 21 S-fluoromethyl-6a, 9a-difluoro-11B-hydro-5,63 xy-16a, 17ct-isopropylidenedioxy-3-oxo-androsta-1, 4-diene-173-thiocarboxylate 24 S-fluoromethyl-113-hydroxy-± 6S-methyl-3- 6.25 oxo-17a-propionyloxyandrosta-1,4-diene-173-thiocarboxylate S-fluoromethyl-9a-chloro 113-hydroxy-163-12.50 methyl 3-oxo-17α-propionyloxyandrosta-1,4-diene-173-thiocarboxylate S-fluoromethyl-1 7a-Butyryloxy-6a, 9a-Di-6.88 fluoro-113-hydroxy-16a-methyl-3-oxoan-drosta-1,4-diene-17 3-thiocarboxylate

Table (continued)

Compound known from Example 1 of Relative European Patent No. 4741 strengths S-methyl-6a, 9a-difluoro-118-hydroxy-1,16a-methyl-3-oxo-17ct-propionyloxy-androsta-1,4-diene-17B -karbotioat

Compounds known from Examples 1 and 3 of Danish Patent No. 133,158-chloromethyl-9α-fluoro-11B-hydroxy-16B-4-methyl-3-oxo-17α-propionyloxy-andro-1,4-diene-17B-carboxylate fluoromethyl-9a-fluoro-118-hydroxy-168-2,388 methyl 3-oxo-17α-propionyloxyandrosta-1,4-diene-17B-carboxylate

The compounds of general formula I, which are preferred because of their good anti-inflammatory activity, include the following categories: (a) those compounds where 2 is chloro or fluoromethyl, (b) those where R is acetyl or propionyl, especially propionyl , (c) those where R is fluorine, (d) those where R 1 is fluorine, (e) the 1,4-dienes and (f) the 1,4-dienes 4 wherein R is fluorine and R is hydrogen, a - or 8-methyl or methylene.

Compounds of general formula I which have good antinflammatory activity combined with minimal hypothalamic mouse pituitary-adrenal suppressive activity by local application include 1,4-dienes in which R 1 is chlorine or fluorine. methyl, R and R are fluorine and especially those where R is α-methyl.

Particularly preferred compounds that can be prepared by the method of the invention are, given their good local anti-inflammatory activity and advantageous relationship between local anti-inflammatory activity and undesirable systemic activity, among other things. the following: S-chloromethyl-9a-fluoro-113-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-173-thiocarboxylic acid, S-chloromethyl-9a-fluoro-11f} -hydroxy-16 -methylene-3-oxo-176-propionyloxyandrosta-1,4-diene-17β-thiocarboxylic acid and S -fluoromethyl-6α, 9α-difluoro-113-hydroxy-16α, 17α-isopropylidene dioxy-3 -oxoandrosta-l, 4-dien-17f3-tiokarboxylsyre.

According to the invention, it is particularly convenient to prepare S-fluoromethyl-6a, 9a-difluoro-11B-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17B-thiocarboxylic acid having a particularly valuable combination of the above properties and, for the same reason, advantageously according to the invention, S-chloromethyl-6a, 9a-difluoro-11B-hydroxy-16a-methyl-3-oxo-17 α-propionyloxyandrosta-1,4-diene-17B-thiocarboxylic acid is prepared, which also causes minimal skin atrophy.

The compounds of the general formula I can be prepared by several different processes.

Proceeding according to claim 1 (a), for example, a salt of the parent 17B carbothioic acid such as an alkali metal salt, e.g., lithium, sodium or potassium salt or an alkyl ammonium salt, e.g., triethylammonium or tetrabutylammonium salt, can be reacted. with a suitable alkylating agent, preferably in a polar solvent such as a ketone, for example acetone or an amide such as dimethylformamide, dimethylacetamide or hexamethylphosphoramide, suitably at a temperature of 15-100 ° C. In particular, according to the invention, one can proceed according to claim 2, wherein the alkylating agent comprises a suitable dihalogen compound, i.e. one containing an additional halogen atom, preferably a bromine or iodine atom, in addition to the halogen atom in the desired R 2 group. This process is particularly suitable for the preparation of compounds in which R 1 is a chloromethyl group and the alkylating agent is advantageously bromochloromethane.

It is also possible to subject the parent 16-hydrogen, methyl or methylene-17? -Hydroxy-17? -Thiocarboxylates corresponding to compounds of the general formula I esterification of the 17? -Hydroxy group. This can be accomplished by conventional techniques, for example, by loading the parent 17α-hydroxy compound with a mixed anhydride of the desired carboxylic acid, which can be developed, for example, by reacting the carboxylic acid with a suitable anhydride such as trifluoroacetic anhydride, preferably in the presence of an acidic catalyst such as p-toluenesulfonic acid or sulfosalicylic acid. Optionally, the mixed anhydride can also be developed in situ by reacting a symmetrical anhydride of the desired acid with a suitable other acid, for example trifluoroacetic acid.

The reaction is advantageously carried out in an organic solvent such as benzene, methylene chloride or excess of the carboxylic acid used, and the reaction is conveniently carried out at a temperature of 20-100 ° C.

It is further possible according to the invention to proceed as claimed in claim 3, i.e. esterify the 17ot hydroxy group by reacting the parent 17a-hydroxy compound with a suitable acid anhydride or acid chloride, optionally in the presence of non-hydroxylic solvents such as chloroform, methylene chloride or benzene. and preferably in the presence of a strong acid catalyst such as perchloric acid, p-toluenesulfonic acid or a strong acidic cation exchange resin, eg "Amberlite" IR 120, the reaction being conveniently carried out at a temperature of 25-100 ° C.

The compounds of general formula I may also be prepared by reacting a corresponding androstatic compound containing a 173 substituent of the formula -COS (CH2) nY, where Y is a replaceable substituent and n is the number 1 or 2, with a compound which serves to to replace the group Y with a halogen atom.

Thus, compounds of the general formula I may be prepared according to the invention according to claim 4; the starting material is subjected to a halogen exchange reaction which serves to replace the group Y, when it is a halogen atom, with another halogen substituent. Thus, bromomethyl, fluoromethyl and fluoroethyl 17β-thiocarboxylates can be prepared from the corresponding iodo-methyl or bromoethyl-17B-thiocarboxylates by means of a bromide salt such as lithium bromide in the case of bromomethyl-176-thiocarboxylates, or a suitable fluoride such as silver monofluoride or silver difluoride in the case of fluoromethyl or fluoroethyl 173-thiocarboxylates. The iodomethyl-176-thiocarboxylates used as starting materials can be prepared from the corresponding chloromethyl-17β compounds by, for example, an alkali methyl, alkaline earth methyl or quaternary ammonium iodide such as sodium iodide.

8 147022

The reaction is conveniently carried out in a solvent containing, for example, acetone, acetonitrile, methyl ethyl ketone, dimethylformamide, dimethylacetamide or ethanol.

The foregoing reactions may also be carried out on starting materials with various substituents or groups which are subsequently converted to the substituents or groups present in compounds of general formula I as defined above.

Thus, the 11β-hydroxy compounds of general formula I can be prepared by reducing a corresponding 11-oxo compound, according to the invention, conveniently by means of an alkali metal or pr alkaline earth metal borohydride (Fe sodium or calcium borohydride, suitably in an alcoholic or aqueous alcoholic solvent). such as methanol or ethanol).

Such an 11-keto compound can be prepared by oxidation of a corresponding 11a-hydroxysteroid, for example by means of a chromic acid reagent such as Jones's reagent.

A β-hydroxy compound of the general formula I may also be obtained by removing the protection from a corresponding compound containing a protected hydroxyl group at the 11β position, according to the invention particularly conveniently a tr i-C1-8 alkyls ilyloxy group (such as a trimethylsilyloxy group) or a perfluoro or chloro-alkanoyloxy group (such as the trifluoroacetoxy group). Removal of the protecting group according to the invention can be carried out by hydrolysis, the trialkylsylyl group being easily removed by mild acidic or basic hydrolysis or, particularly conveniently, by fluoride, hydrogen fluoride or an ammonium fluoride.

A perfluoro or chloroalkanoyl protecting group may also be removed by mild acidic or basic hydrolysis or alcoholysis, but preferably under acidic conditions when R 1 is a chlorine atom. Such a protected hydroxyl group may be introduced, for example, by reacting a Ιΐβ-hydroxysteroid with a suitable reagent such as a trialkylsilyl halide or a perfluoro- or chloro-alkanoic anhydride.

4

Compounds of general formula I wherein R is fluorine or chlorine can also be prepared by reacting a corresponding compound containing a 9,11 epoxy group with hydrogen fluoride or chloride. The epoxide may optionally be formed by first forming a bromohydrin by reaction with an N-bromamide or imide such as N-bromosuccinimide, followed by formation of the corresponding 90,110 epoxide and treatment with a base.

Compounds of general formula I may conveniently be prepared by partial reduction of the corresponding 1 4 Δ 'compound; According to the invention, it may be by hydrogenation by means of a palladium catalyst, conveniently in a solvent such as methyl acetate, but it may also be by homogeneous hydrogenation using, for example, tris (triphenylphosphine) rhodium chloride, conveniently in a solvent such as benzene, or by replacement hydrogenation. using, for example, the cyclohexene in the presence of a palladium catalyst in a solvent such as ethanol, preferably under reflux. This reduction may be carried out on a haloalkyl ester where it is sufficiently stable in such a reaction, or it may be carried out at an earlier step.

For example, the above compounds containing a free -COSH group at the 173 position may be prepared by amino lysis by rearrangement of a suitable 17β-thiocarbamoyloxycarbonyl androstane conveniently prepared by reacting a salt of the 173-carboxylic acid 17α ester or 16a, 17a-acetonide with a thiocarbamoyl halide, e.g., the chloride. Tiokarbamoyl-

A B AB

the group may thus have the formula -COOCSNR R, wherein R and R, which may be the same or different, are alkyl groups, for example C 1-4 alkyl groups, with the N, N-dimethylthiocarbamoyl group being preferred. The reaction can be accelerated by the addition of an iodide salt such as sodium iodide.

The original androstan-17β-carboxylate salt may be, for example, an alkali metal or alkaline earth metal salt, for example, the sodium or calcium salt, or a salt with a tertiary amine such as triethylamine.

Aminolysis during rearrangement can be carried out, for example, by heating the mixed anhydride to elevated temperature, for example in the presence of ammonia, a primary amine or more suitably a secondary amine such as diethylamine or pyrrolidine. In the starting 17B carboxylic acids, the 16 and 17a positions are conveniently substituted with the -R and -OR groups desired in the final product of the general formula I.

17α-Hydroxyandrostane compounds in the 16-methylene series containing a free 17β-thiocarboxyl group can be prepared from the corresponding 16β-methyl-16α, 17α-epoxy-173-thiocarboxylic acid, by performing a rearrangement by a strong acid, e.g. carboxylic acid such as trifluoroacetic acid. These 16a, 17a epoxides can be prepared from the corresponding 173-carboxylic acids by treatment with an onium salt of a 2-halo-aza aromatic compound, followed by treatment of the resulting product with hydrogen sulfide or a salt thereof to give the free 17β -carbothioic acid, which can then be alkylated as described above, preferably in situ to form the desired 17β-carbonate group.

The 16a-17a-Is opropylidene dioxy compound ice cream can be similarly prepared by treating a corresponding 17ficarboxylic acid with an onium salt of a 2-halo-azaaromatic compound followed by treating the resulting product with hydrogen sulfide to form the free 170-carbothioic acid which then can be esterified as described above.

Onium salts of 2-halo-azaromatic compounds have the ability to effect carboxyl activation. Examples of such reagents are 2-halo-N-alkyl or 2-halo-N-phenylpyridinium or pyrimidinium salts, and a suitable salt is 2-fluoro-N-methylpyridinium tosylate or 2-chloro-N-methyl-benzothiazolium salt. trifluormetansulfonat.

16 α-17α-Epoxy-16 β-methyl-1,173-carboxylic acid compounds used as starting materials in the aforementioned process / can be prepared in a conventional manner, for example, as described in British Patent No. 1,517,278.

17α-Hydroxy-17β-carbothioic acids corresponding to compounds of the general formula I and their salts can be converted to the corresponding 17α-hydroxy-17β-carbothioates or 17β-αΛοΉο acid-17α-esters by the processes described above to 147022 11 preparation of compounds of general formula I.

For example, 17α-Hydroxy-17β-carbothioic acids can be prepared by reacting a reactive derivative of a corresponding 17α-hydroxy-17β-carboxylic acid with hydrogen sulfide or a sulfide or hydrosulfide salt thereof. Generally, for example, the cation in the sulfide or the hydrosulfide salt may be an alkali metal salt such as sodium or potassium hydrosulfide.

The reactive derivatives are preferably prepared by reacting a corresponding 17α-hydroxy-17β-carboxylic acid with N, N'-carbonyldi- (1,2,4-triazole), N, N'-carbonyldibenzotriazole, N, N'-carbonyldibenzimidazole, N , N'-carbonyldi (3,5-dimethyl-pyrazole), K1 N'-thionyl diimidazole or, in particular, Ν, Ν'-carbonyl-diimidazole or Ν, Ν'-thiocarbonyldiimidazole. The reaction is conveniently carried out in the presence of an inactive anhydrous solvent such as a substituted amide solvent such as Ν, Ν-dimethylformamide or Ν, Ν-dimethylacetamide, conveniently in the absence of water and advantageously at or below room temperature, e.g. + 30 ° C. The reaction is conveniently carried out under substantially neutral conditions, advantageously in an inert atmosphere, for example under nitrogen. The same solvents and conditions are also applicable to the substituent reaction with H 2 S 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 foregoing reactions may also be carried out on compounds having different substituents or groups which are subsequently converted as described above into compounds of general formula I.

The androstane-17β-carboxylic acid starting materials used in the above processes can be prepared in a conventional manner, for example, by oxidation of a suitable 21-hydroxy-20-ketopregan, e.g., with periodic acid, in a solution medium and preferably at room temperature. It is also possible to use sodium bismuthate to perform the desired oxidative removal of the 21-carbon atom from a 17α-acyloxypregnan compound. It will be appreciated that if the precursor contains any substituent which is sensitive to the desired oxidation described above, such a group must be suitably protected.

Some examples serve to elucidate the method of the invention. Melting points were determined on a Kofler block and are uncorrected. Optical rotations were determined at room temperature on solutions in dioxane.

T.I.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.

Before the actual examples of the process according to the invention, some examples of preparation of starting materials are given.

Starting material 19a-Fluoro-11B-hydroxy-163-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17B-carboxylic acid (I)

A solution of 5.00 g of 9α-fluoro-lip-hydroxy-16S-methyl-3-oxo-17α-propionyloxyandrost α-1,4-diene-17β-carboxylic acid, solvated with 1/2 mol of ethyl acetate, and 5 3 ml of triethylamine in 75 ml of dichloromethane was stirred under nitrogen and treated with 5.071 g of dimethylthiocarbamoyl chloride. After 24 hours, an additional 5.320 g of reagent was added. After 47 hours, the mixture was diluted with ethyl acetate and washed with N-hydrochloric acid, 5% sodium bicarbonate solution and water, dried and evaporated to 9.043 g of a viscous yellow oil. This was dissolved in 50 ml of diethylamine and then stirred and refluxed under nitrogen for 5.75 hours. The resulting brown solution was added to a mixture of 50 ml of concentrated hydrochloric acid, 250 ml of water and 50 ml of ethyl acetate. The products were further extracted with ethyl acetate and the acidic products were back extracted in 5% sodium carbonate solution. The aqueous phase was acidified with 50 ml of 6N hydrochloric acid and extracted with ethyl acetate. The extracts were washed with N hydrochloric acid and water, dried and evaporated to 3,440 g of tan solid. This recrystallized from acetone to give 1.980 g of light brown crystals of the title 173-carbothioic acid, m.p. 172-173 ° C.

The assay was won after two recrystallizations from acetone as white crystals with m.p. 177-179 ° C, [α] β = + 110 ° (c = 1.05).

Starting material 2 (a) S-Chloromethyl-9a-fluoro-16β-methyl-3,11-dioxo-17a-propionyloxy-androsta-1,4-diene-173-thiocarboxylate (II) reagent was added dropwise over 10 minutes to a stirred solution of 998 mg of the compound of Example 1 in 2 ml of acetone and 2 ml of dimethylformamide. After 30 minutes, the reaction mixture was slowly diluted with 100 ml of water with stirring and the resulting suspension was refrigerated for 1 hour. The precipitate was collected by filtration, washed with water and dried to 877 mg of cream colored solid. P.l.c. in chloroform / acetone 10: 1 gave a white foam in an amount of 755 mg? it was crystallized twice from acetone to give 523 mg of white needles of the title 11 ketone, m.p. 204-205 ° C, [α] D = + 94 ° (c - 1.04).

Starting material 3 17 β-β, N-Dimethylthiocarb amoyloxycarbonyl-9α-fluoro-1β-hydroxy-16α-methyl-17α-proplonyloxyandrosta-1,4-dien-3-one (III)

A solution of 0.434 g of 9α-fluoro-113-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-170-carboxylic acid in 8 ml of dichloromethane was treated successively with 0.14 ml of triethylamine, 0.248 g of dimethylthiocarbamoyl chloride and 0.149 g of sodium iodide, and the mixture was stirred under nitrogen at 20 ° C for 6 hours.

30 ml of ethyl acetate was added and the whole volume reduced by half in vacuo. An additional 50 ml of ethyl acetate 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 to crystallize the product in an amount of 0.329 g. It was recrystallized twice from acetone to give the title anhydride as white needles, m.p.

191-193 ° C, [<x] D = + 82 ° (c = 0.57).

Starting material 499-Fluoro-11 & hydroxy-16a-methyl-3-oxo-17a-propionyloxy-androsta-1,4-diene-17g-thiocarbocyl acid (IV)

A stirred suspension of 2.467 g of (III) in 25 ml of diethylamine was heated to reflux under nitrogen. After 3.5 hours, the reaction mixture was poured into 300 ml of ice-cooled 3N hydrochloric acid 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 and 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 and saturated sodium chloride solution and dried and the solvent removed in vacuo. The residue was crystallized twice from acetone to give 1.309 g of the title carbothioic acid as white needles, m.p. 141-143 ° C, [α] D = + 30 ° (c = 0.51).

Starting material 5 118-Hydroxy-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carboxylic acid (V)

A solution of 13.5 g of 11 (1,17a-dihydroxy-3-oxoandrosta-1,4-diene-17 (3-carboxylic acid and 18 ml of triethylamine in 500 ml of dichloromethane) was cooled to 4 ° C and treated portionwise over time. of 15 minutes with 14.2 ml of propionyl chloride The stirring was continued at 4 ° C for a total of 1 hour and the mixture was washed successively with 3% sodium bicarbonate, water, 2N hydrochloric acid, water and saturated brine, then dried and evaporated under reduced pressure. in 300 ml of acetone and 14.3 ml of diethylamine were added with stirring. After 1 hour at 20 ° C, the solvent was removed under reduced pressure and the residue was dissolved in 150 ml of water. After acidification to pH 1 with 2N hydrochloric acid, the product was extracted with ethyl acetate. extracts were washed with water and saturated brine, dried and then concentrated to low volume.The solid product was collected by filtration, washed with ethyl acetate and dried in vacuo at 50 ° C to give the title 17α-propionate. vessel boxylic acid as 13,309 g of crystals with [a] jj = + 2 ° (c = 1.10). A 389 mg aliquot was recrystallized twice from methanol for a 256 mg assay; it had m.p. 244-245 ° C (dec.), [Α] D = + 3 ° (c = 0.83).

Starting material 6,69,9-Difluoro-113-hydroxy-16a-methyl-3-oxo-17a-propionyloxy-androsta-1,4-diene-17β-carboxylic acid (VI)

A solution of 2,113 g of 6a, 9a-difluoro-110,17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-173-carboxylic acid and 2.5 ml of triethylamine in 60 ml of dichloromethane was stirred and treated at ca. 0 ° C with 1.85 ml of propionyl chloride. After 1 hour, the mixture was diluted with an additional 50 ml of solvent and washed successively with 3% sodium bicarbonate, water, 2N hydrochloric acid, water and saturated brine, then dried and evaporated to a tan solid. This was dissolved in 50 ml of acetone and 2.5 ml of diethylamine was added. After 1 hour at 22 ° C, the solvent was removed in vacuo and the remaining gum was dissolved in 30 ml of water. Acidification to pH 1 with 2N hydrochloric acid precipitated a solid which was collected, washed with water and dried to 2,230 g of the title carboxylic acid 17α propionate, m.p. 220-225 ° C, [α] D = + 4 ° (c = 0.70).

Starting material 7 17 | 3-N, N-Dimethylthiocarbamoyloxycarbonyl-6a, 9a-difluoro-β-hydroxy-16a, 17a-isopropylidene dioxyandrosta-1,4-dien-3-one (VII)

A solution of 4,354 g of 6α, 9α-difluoro-11β-hydroxy-16α, 17β-isopropylidenedioxy-3-oxoandrosta-1,4-diene-178-carboxylic acid in 150 ml of dichloromethane containing 1.4 ml of triethylamine was treated with 2,519 g The Ν, Ν-dimethylthiocarbamoyl chloride and the reaction mixture were stirred under nitrogen at 22 ° C 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, then dried and the solution concentrated. On cooling, crystallization occurred and the solid was filtered off and dried in vacuo to 3.562 g of the title anhydride as pale yellow prisms with m.p. 283-287 ° C (dec.), [Α] β = + 156 ° (c = 0.84 in dimethyl sulfoxide).

Starting material 8 6a, 9a-Difluoro-113-hydroxy-16a, 17a-isopropylidene dioxy-3-oxo-androsta-1,4-diene-173-thiocarbocylic acid (VIII)

A suspension of 3.455 g (VII) in 200 ml of diethylamine was heated under reflux under nitrogen for 6 hours. The first suspension formed dissolved rapidly, but after 30 minutes a light brown suspension formed which remained unchanged. The cooled reaction mixture was poured into 1.0 ml of water, acidified with 210 ml of concentrated hydrochloric acid to pH 1 and extracted with ethyl acetate. The combined extracts were washed with water, extracted with 5% sodium carbonate solution and with 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 washed with water and saturated sodium chloride solution, then dried and the solvent removed in vacuo to give 2.31 g of light gray solid. Part of the product, 0.408 g, was crystallized from ethyl acetate to give 0.149 g of the title acid with m.p. 191-199 ° C, [α] β = + 124 ° (c 1.04 in dimethyl sulfoxide).

Starting material 9 6a-Fluoro-113,17a-dihydroxy-3-axyandrosta-1,4-diene-173-carboxylic acid (IX)

A solution of 4,967 g of 6α-fluoroprednisolone in 50 ml of tetrahydrofuran was stirred with a solution of 10.0 g of periodic acid in 24 ml of water at 22 ° C. After 50 minutes, the tetrahydrofuran was evaporated and the aqueous suspension was filtered. The solid product was washed with 300 ml of water and dried to 4.80 g of white solid. A 271 mg portion thereof was crystallized from methanol to give 171 mg of the title acid as white needles, m.p. 241-248 ° C, [α] D = + 54 ° (c = 0.825).

Starting material 10 6 α-Fluoro-1β-hydroxy-3-oxo-17 α-propionyloxyandrose ta-1,4-diene-17g-carboxylic acid (X)

A solution of 4.491 g (IX) and 4.46 ml of triethylamine in 160 ml of dry dichloromethane at -5 ° C was stirred and treated dropwise with 2.80 ml (2.96 g) of propionyl chloride for approx. 5 ml of dry dichloromethane over 5 minutes at a temperature below 0 ° C.

After a further 20 minutes below 0 ° C, the reaction mixture was diluted with 160 ml of dichloromethane, washed with sodium hydrogencarbonate solution and water, dried and evaporated to 5.701 g of white solid. This was stirred with 4.60 ml (3.24 g) of diethylamine in 30 ml of acetone to give a clear yellow solution. After 30 minutes, the solution was concentrated, 150 ml of water was added and the resulting solution washed with 2 x 30 ml of ethyl acetate. The aqueous phase was acidified to pH 2 with 50 ml of 2N hydrochloric acid with stirring and the product was extracted with ethyl acetate 3 times. The extracts were combined, washed with 50 ml of water, dried and evaporated to 5.819 g of white foam. A 304 mg portion of this foam was crystallized from ethyl acetate to give 144 mg of the title 177 propionate as small plates, m.p. 224-227 ° C, [α] D = + 3 ° (c = 0.861).

Starting Materials 11-20

By the same general procedure as described in starting material 1, but using starting material of the 17β-carboxylic acid corresponding to the desired 17β-carbothioate (the details of the process being summarized in Table 1 below), the following compounds were prepared: (XI ) 17α-Acetoxy-9α-fluoro-113-hydroxy-163-methyl-3-oxoandrosta-1,4-diene-173 “thiocarboxylic acid with m.p. 178.5-179 ° C, [alpha = + 98 ° (c = 1.02).

(XII) 17α-Butyryloxy-9α-fluoro-lip-hydroxy-16β-methyl-3-oxo-androsta-1,4-diene-173-thiocarboxylic acid with srrp. 175-176 ° C, α3D = + 107 ° (c = 0.96).

(XIII) 9α-Fluoro-11β-hydroxy-17α-isobutyryloxy-163-methyl-3-oxoandrosta-1,4-diene-173-iocarbaxyl acid with snp. . 177-179 ° C, [α] D = + 119 ° (c = 0.90).

(XIV) 11f} -Hydroxy-3-oxo-17a-propionyloxyandrosta-1,4-diene-170-carbothioic acid, m.p. 134-138 ° C, α] D = + 67 ° (c = 0.66).

(XV) 11 (3-Hydroxy-163-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-iocarboxylic acid, mp 159-163 ° C, [α] + = + 113 ° (c = 0.78).

(XVI) 9α-Chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-173-thiocarboxylic acid with soap. 167-171 ° C, [α] β = + 128 ° (c = 0.99).

(XVII) 9α-Fluoro-lip-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-thiocarboxylic acid down snp. 141-143 ° C, [α] D = + 30 ° (c = 0.51).

(XVIII) 6α, 9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propio-nyloxyandrosta-1,4-diene-17β-thiocarboxylic acid with snp. 136-139 ° C, [α] d = -30 ° (c * 0.56).

(XIX) 9a-Fluoro-11B-hydroxy-16-methylene-3-oxo-17a-propionyl-oxyandrosta-1,4-diene-17B-thiocarboxylic acid, m.p. 236-239 ° C, [α] D = -71 ° (c = 0.99).

(XX) 6a-Fluoro-11B-hydroxy-3-oxo-17a-propionyloxyandrosta-1,4-diene-173-thiocarboxylic acid, m.p. 189-193 ° C, [α] D = + 72 ° (c = 0.74).

147022 19

Table 1

Formation of the mixed anhydrides.

Starting 17β-carb-Cl-SCNMe "NEt_ Solution-Reaction-Material Oxoic Acid. . . mean time (decrease input (g) IgJ (CH Cl2) ge) at (ml) room temp.

(XI) 5,000 2,940 1.66 75 5la (XII) 15,354 8,809 4.8 250 6 (XIII) 4,182 2,399 1.3 80 4 (XIV) 7,148 4.40 2.6 150 6lb (XV) 6,137 3.77 2 05 140 6lc (XVI) 5,973 3,350 1,34 100 7 (XVII) 4,207 2,39 1,35 80 0,671'ld (XVIII) 2,130 1,80 0,66 50 64 (XIX) 5,000 2,507 1,41 75 3 (XX) 6,000 3.55 2.0 120 1.225

Table 1 (continued)

Treatment of the mixed anhydride intermediates with diethylamine.

Initial NHEt2 Reaction Product Crystallization Matter, Time (h) at (g) Solvent Lezonate (XI) 50 5.5 2,104 EA2a (XII) 250 4 5.24 EA3

(XIII) 60 4.5 1.00 EA

(XIV) 60 4 3.29 EA

(XV) 50 3.5 1,382 EA

(XVI) 60 5.7 0.527 EA

(XVII) 25 4.75 1.309 A

(XVIII) 12 6 0.418 EA

(XIX) 50 3.75 1.296 EA2b

(XX) 60 4.5 2.88 EA / P

notes; 2 EA = ethyl acetate A = acetone P = petroleum ether with boiling range 60-80 ° C.

1. Portions of (a) 500 mg, (b) 670 mg, (c) 424 mg, (d) 171 mg of the dimethylthiourea anhydride formed as intermediate were taken out for characterization.

2. The characterization was performed on a sample which was recrystallized two more times from ethyl acetate; yields (a) 84%, (b) 69%.

3. The product was solvated with approx. 0.2 mole of ethyl acetate.

4. The dimethylthiocarbamic acid anhydride obtained as an intermediate (1.435 g) was crystallized from ethyl acetate; a portion of 95 mg was taken for characterization.

5. Also 1.46 g of sodium iodide was present in the reaction mixture.

6. 2.13 g of sodium iodide was also present in the reaction mixture.

Starting material 21 9a-Chloro-lip-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17B-thiocarboxylic acid (XXI) and 9β, 118-epoxy-163-methyl-3-oxo 17a-propionyloxyandrosta-1,4-diene-17ft-_

A solution of 5.586 g of 178-N, N-dimethylthiocarbamoyloxy-carbonyl-9α-chloro-β-hydroxy-16β-methyl-17α-propionyloxyandrosta-1,4-dien-3-one in 60 ml of diethylamine was refluxed 5 hours and 40 minutes under nitrogen. The reaction mixture was poured into 450 ml of water, acidified to pH 10 with concentrated hydrochloric acid and extracted with 3 x 60 ml of ethyl acetate. The combined extracts were washed with water and then extracted with 4 x 50 ml aqueous sodium carbonate solution. The aqueous extracts were acidified with 6N hydrochloric acid to pH 1 and extracted with 3 x 50 ml of ethyl acetate. The combined extracts were washed with water and saturated sodium chloride solution and dried and the solvent removed in vacuo to give 2.834 g of colorless foam.

Two crystallizations of the mixture from ethyl acetate gave 0.527 g of 9α-chloro-1β-hydroxy-168-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-173-thiocarboxylic acid with white prisms with m.p. 167-171 ° C, [α] β = + 128 ° (c = 0.99). The mother liquors from the crystals contained an additional amount of the above 9α-chloro-113-hydroxycarbothioic acid together with 9β> 11β-εροχγ-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-thiocarbocyl -acid.

Starting material 22 S-Iodomethyl-9α-fluoro-1β-hydroxy-16B-methyl-3-oxo-17α-propionyl-oxyandrosta-1,4-diene-17β-thiocarboxylate (XXII)

A solution of 500 mg of the compound of Example 1 and 1.874 g of sodium iodide in 15 ml of acetone was stirred and heated under reflux for 6.5 hours. Then 75 ml of ethyl acetate was added and the solution was washed successively with water, 10% s sodium thiosulfate solution, 5% s sodium hydrogen carbonate solution and water, dried and evaporated to 525 mg of sooty foam. P.l.c. in chloroform / acetone 6: 1 gave 478 mg of dirt-white foam which was recrystallized twice from acetone without being heated to above room temperature, and 241 mg of colorless crystals of the title S iodine methyl ester were obtained which had m.p. 196-197 ° C, [α] D = -32 ° (c = 1.01).

Starting material 23-33

By the same general procedure as described in starting material 23, but using as starting material of the S-chloromethyl-170 thioesters corresponding to the desired product (process details are summarized in subsequent Table 2), the following compounds were prepared: (XXIII) Iodomethyl-17α-acetoxy-9α-fluoro-β-hydroxy-16 (3-methyl-3-oxoandrosta-1,4-diene-170-thiocarbaxylate, mp 204-205 ° C, [α] D = -29 ° (c = 0.98).

(XXIV) S-Iodomethyl-118-hydroxy-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-thiocarboxylate [α] D = + 26 ° (c = 0.47).

(XXV) S-Iodomethyl-118-hydroxy-168-methyl-3-oxo-17α-propionyl-oxyandrosta-1,4-diene-17β-thiocarboxylate [α] D = + 5 ° (c = 0.74).

(XXVI) S-Iodomethyl-9α-chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4 ^ϊθη-17β - δ <3τΕοχγΐ3 ^ [a] D = + 7 ° (c = 0.36).

(XXVII) S-Iodomethyl-9a-fluoro-110-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-170-thiocarboxylate, [a] D = + 85 ° (c = 0.55).

(XXVIII) S-Iodomethyl-6a, 9a-difluoro-110-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-170-thiocarbylcylate.

(XXIX) S-Iodomethyl-9a-fluoro-110-hydroxy-16-methylene-3-oxo-17a-propionyloxyandrosta-1,4-diene-170-thiocarbyl oxylate, m.p. 191-199 ° C, [α] D = -31 ° (c = 0.99).

(XXX) S-Iodomethyl-9a-fluoro-110-hydroxy-3-oxo-17a-propionyloxy-androsta-1,4-diene-170-thioalkyl: boxylate, mp 175-178 ° C, [α] β = + 4 ° (c = 0.50).

(XXXI) S-Iodomethyl-6a-fluoro-110-hydroxy-3-oxo-17a-propionyloxy-androsta-1,4-diene-170-tickarbaxylate with snp. 195-197 ° C, [α] D = + 18 ° (c = 0.64).

(XXXII) 'S-Iodomethyl-17α-acetoxy-6α, 9α-difluoro-110-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-170-thiocarboxylate, m.p. 241-243 ° C, [α ] D = + 78 ° (c = 0.78).

(XXXIII) S-Iodomethyl-17α-butyryloxy-6α, 9α-difluoro-110-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-170-thiocarboxylate

210-212 ° C, [α] D = + 89 ° (c = 0.90).

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Notes: 1. Recovered from a 300 mg portion of the crude product (2.024 g).

2. Recovered from a 400 mg portion of the crude product (2.058 g).

5 3. The product was used directly to prepare the corresponding fluorine type 1-17 β-1 iocarboxylate.

4. Lithium chloride was used instead of sodium iodide.

5. Solvated with 0.5 ϊ ^ Ο.

6. Solvated with 0.1 EA.

7. Solvated with 0.2 EA + 0.5 I ^ O.

Starting material 34 S-Iodomethyl-6a, 9a-difluoro-113-hydroxy-16a, 17a-isopropylidenedioxy-3-oxoandrosta-1,4-diene-17S-thiocarboxylic acid (XXXIV)

A solution of 0.795 g of the compound of Example 4 according to the above Example 4 in 50 ml of acetone was heated under reflux with 2.969 g of sodium iodide for 5.5 hours. 75 ml of ethyl acetate was added and the solution was washed successively with water and sodium metabisulphite solution and dried, then the solvent was removed in vacuo to give 0.893 g of sooty white solid. A portion of 0.205 g of this was crystallized twice from ethyl acetate to give 0.105 g of the title S-iodomethylthioester as white prizes with m.p. 260-262 ° C (dec.), [A) D = + 81 ° (c = 0.6 in dimethyl sulfoxide).

Starting material 35 S-21-Bromoethyl-9α-fluoro-118-hydroxy-163-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ft-thiocarboxylate (XXXV) - 0.5 g (I) ) was treated as described for the S-chloromethyl ester (about Example 1, Method A), but using 1,2-dibromo-methane to give colorless crystals of the title S-2 * -bromoethyl ester in an amount of 0.409 g, m.p. 174-145 ° C, [α] D = + 120 ° (c = 1.04).

147022 25

Starting material 36 S-Chloromethyl-16α, 17α-epoxy-9α-fluoro-11β-hydroxy-160-methyl-3-oxoandrosta-1,4-diene 17β-thiocarboxylate (XXXVI)

Method A

A suspension of 753 mg of 16a, 17α-epoxy-9α-fluoro-11β-hydroxy-168-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid and 680 mg of 2-fluoro-1-methylpyridinium tosylate in 7 ml of dichloromethane were treated dropwise at 0 ° C with 1.39 mg triethylamine and then stirred at 0 ° C for 1 hour. Hydrogen sulfide 10 was then passed through the mixture for 15 minutes and the resulting solution was stirred at 0 ° C for an additional 1 hour. 0.26 ml of bromochloromethane 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 250 ml of ethyl acetate and washed successively with 2N hydrochloric acid, 5% sodium bicarbonate solution and water, dried and evaporated to 818 mg pale yellow solid. The solid was subjected to p.c. in chloroform / acetone 9: 1 (twice). The main band (515 mg) was crystallized from acetone to give 447 mg of white needles of the title 20 S-chloromethyl ester epoxide, m.p. 246-251 ° C, [α] β = + 131 ° (c = 0.67).

Method B

A suspension of 376 mg of 16a, 17a-epoxy-9a-fluoro-11 [3-hydroxy-16-methylene-3-oxoandrosta-1,4-diene-173-carboxylic acid 25 and 400 mg of 2-chloro-N-methylbenzothiazolium trifluoromethanesulfonate in dichloromethane was treated dropwise at 0 ° C with 0.7 ml of triethylamine. The resulting solution was stirred at 0 ° C for 1.25 hours and then hydrogen sulfide was passed through the mixture for 10 minutes. After an additional 1 hour at 0 ° C, 0.13 ml of bromochloromethane was added and the mixture was stirred at room temperature. After an additional 1.5 hours and 1.8 hours, two additional portions of 0.13 ml of bromochloromethane were added each. 15 minutes after the final addition, the reaction mixture was diluted with 200 ml of ethyl acetate 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 26 p.l.c. in chloroform / acetone 19: 1 (3 times). The most polar band yielded a pink solid constituted by the S-chloromethyl ester (134 mg) which at t.l.c. proved identical to authentic sample.

Starting material 37 S-Chloromethyl-9α-fluoro-β, 17α-dihydroxy-16-methylene-3-oxoandrosta-1,4-diene-17β-thiocarboxylate (XXXVII)

A solution of 400 mg (XXXVI) in 16 ml of trifluoroacetic acid was stirred at room temperature. After 5.5 hours, the reaction mixture was evaporated to near dryness and the residue dissolved in 100 ml of ethyl acetate. The solution was washed with 5% sodium hydrogen carbonate solution and water, dried and evaporated to 466 mg of yellow-green foam. The foam was subjected to p.c. in chloroform / acetone 9: 1 (3 times). An 80 mg portion of the headband (315 mg) was twice crystallized from acetone to give 48 mg of white crystals of the title 16-methylene-17a alcohol, m.p. 242-243 ° C, [α] D = + 36 ° (c = 0.50).

Starting material 38 6a, 9a-Difluoro-ΙΙβ, 17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17β-thiocarboxylic acid (XXXVIII)

A solution of 12.0 g of 6α, 9α-difluoro-β, 17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid in 250 ml of dry dimethylformamide was stirred and treated with 9.94 g of N , N'-Carbonyldiimidazole under nitrogen at room temperature. After 4 hours, hydrogen sulfide was passed through the solution for 1/2 hour and the mixture was allowed to stand for another 1/2 hour. The reaction mixture was poured into 500 ml of 2N hydrochloric acid containing ca. 250 g is. The resulting precipitate was collected, washed with water and dried in vacuo to give the title thio acid as a white solid in an amount of 11.47 g, m.p. 230-232 ° C, [α] D = + 94 ° (c = 0.91).

27 14702.2

Starting material 39 17a-Acetoxy-6a, 9a-difluoro-113-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17g-thiocarboxylic acid (XXXIX)

A solution of 1.625 g (XXXVIII) and 2.0 ml of triethylamine in 75 ml of dichloromethane was stirred at ca. 0 ° C, treated dropwise with 1,275 ml of acetyl chloride and then stirred at this temperature for 1 1/4 hour. The mixture was washed with 50 ml of 2N sodium carbonate, water, 50 ml of 2N hydrochloric acid, 3 x 50 ml of water and 50 ml of brine and then dried and evaporated to 1.91 g of white solid. This was dissolved in 40 ml of acetone and stirred with 4 ml of diethylamine at 27 ° C for 45 minutes. The mixture was concentrated to ca. 25 ml and poured into 100 ml of 2N hydrochloric acid containing approx. 100 g is; after stirring, the resulting precipitate was collected and washed with water and dried to 1.685 g of solid. A 400 mg portion was recrystallized from ethyl acetate to give 280 mg of the title 17α-acetate, m.p. 175-177 ° C.

Starting material 40 17a-Butyryloxy-6a, 9a-difluoro-113-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17g-thiocarbaxyl acid (XL) - In the same manner as described in starting material 39, 2, 0 g (xxxvill) with 1.5 ml of butyryl chloride instead of acetyl chloride to 2.08 g of the title 17α-butyrate. A portion of recrystallized from ethyl acetate had m.p. 155-157 ° C.

Starting material 41 S-Chloromethyl-6a, 9a-difluoro-16a-methyl-3-oxo-17a-propionyloxy-β-trifluoroacetoxyandrosta-1,4-diene-17β-thiocarboxylate (XLI)

A solution of 100 mg of the compound prepared according to Example 5 in 2 ml of dry tetrahydrofuran and 0.1 ml of pyridine was treated with 0.05 ml of trifluoroacetic anhydride and the mixture was kept at room temperature for 1/2 hour. The reaction mixture was poured into water and the product extracted 3 times with ethyl acetate. The organic extracts were washed with water, dried and evaporated to 116 mg of the title trifluoroacetate, homogeneous by nmr spectroscopy (singlet at 8.59 τ, 19 protons, in deuteriochloroform) and t.l.c. on silica (acetone / petroleum ether (bp 40-60 ° C) 1: 3). An ether / pentane assay sample had m.p. 158-162 ° C, [α] D = + 56 ° (c = 0.23).

Example 1 S-Chloromethyl-9a-fluoro-11 (3-hydroxy-168-methyl-3-oxo-17a-propionylloxyandrosta-1,4-diene-17 & -thiocarboxyate)

Method A

A solution of 2.115 g (I) in 7 ml of dimethylacetamide was treated with 592 mg of sodium bicarbonate and 0.46 ml of bromochloromethane, and the mixture was stirred at room temperature. After 2 hours, the reaction mixture was diluted with 500 ml of ethyl acetate and washed with 5% sodium bicarbonate solution and water, dried and evaporated to 1.560 g of an orange foam.

P.l.c. in chloroform / acetone 19: 1 gave 803 mg of dirt-white foam which was crystallized twice from methanol to give 668 mg of dirt-white needles of the title S-chloro methyl ester with m.p. 212-214 ° C, [α] D = + 44 ° (c = 1.06).

Method B

The title compound was similarly prepared by chloro-iodomethane instead of bromochloromethane.

Method C

19 mg of sodium borohydride was added to a solution of 230 mg (II) in 3.5 ml of ethanol and the solution was stirred at room temperature. After 20 minutes, 1 ml of acetone was added and the solution concentrated to ca. 1/4 of the volume. Then 30 ml of ethyl acetate was added and the solution washed with N-hydrochloric acid and water, dried and evaporated to 239 mg white foam. P.l.c. in chloroform / acetone 19: 1 gave a white foam in an amount of 188 mg and it was crystallized twice from methanol to white needles of the title S-chloromethyl ester in an amount of 158 mg, m.p. 210-212 ° C, ta] D = + 44 ° (c = 1.07).

Example 2 S-Chloromethyl-9a-fluoro-113-hydroxy-16a-methyl-3-oxo-17a-propionyl-oxyandrosta-1,4-diene-173-thiocarboxylate

A solution of 0.927 g (IV) in 4 ml of dimethylacetamide was treated with 0.256 g of sodium bicarbonate and 0.20 ml of bromochloromethane, and the mixture was stirred at 22 ° C for 2 hours. The reaction mixture was partitioned between 100 ml of ethyl acetate and 20 ml of 2N hydrochloric acid and the aqueous layer was further extracted with ethyl acetate. The combined extracts were washed successively with 2N hydrochloric acid, water, 3S sodium bicarbonate, water and saturated brine. After drying, the solvent and crude product, 757 mg, were twice crystallized from acetone to give 0.367 g of the title chloromethyl thiol ester with m.p. 247-250 ° C, [α] D = + 50.5 ° (c = 0.63).

Example 3 S-Chloromethyl-113-hydroxy-3-oxo-17a-propionyloxyandrosta-1,4-one-17,3-thiocarboxylate

Prepared similarly using compound (XIV). It had m.p. 117-120 ° C, [α] D = + 56 ° (c = 1.3).

Example 4 S-Chloromethyl-6a, 9a-difluoro-113-hydroxy-16a, 17a-isopropylidene-dioxy-3-oxoandrosta-1,4-diene-173-thiocarboxylate

A stirred solution of 1.360 g (VIII) in 10 ml of N, N-dimethylacetamide was treated with 0.377 g of sodium bicarbonate and 0.3 ml of bromochloromethane and stirring was continued for 1 1/2 hours.

100 ml of ethyl acetate was added and the resulting solution was washed successively with 2N hydrochloric acid, water, sodium metabisulphite solution, water, sodium bicarbonate solution, water and saturated sodium chloride solution and then dried, the solution concentrated and crystallization began. The crystallized product, 0.765 g, was purified by p.l.c. on silica gel and developed with chloroform / acetone 9: 1. The main band was eluted with ethyl acetate and crystallized from ethyl acetate to give 0.475 g of the title S-chloromethylthioester as white prisms with m.p. 271-278 ° C, [α] β = + 116 ° (c = 0.96 in dimethyl sulfoxide).

Example 5 S-Chloromethyl-6a, 9a-difluoro-113-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-173-thiocarboxylic acid

A solution of 0.546 g (XVIII) in 3 ml of dimethylacetamide was treated with 202 mg of sodium bicarbonate and 0.16 ml of bromochloromethane at 22 ° C for 3 hours. The mixture was treated with 50 ml of 2N hydrochloric acid and the product extracted with ethyl acetate. The extracts were combined and washed successively with 2N hydrochloric acid, water and saturated brine, and dried, and the solvent was removed. Two crystallizations from ethyl acetate gave 0.404 g of the title chloromethyl thiol ester with m.p. 272-275 ° C, [α] D = + 49 ° (c = 0.35).

Examples 6-15

By proceeding generally in the same manner as described in Example 1 (Method A), but using starting material of the 17 (3-thiocarboxylic acid corresponding to the desired 173-thio carboxylate (the details of the process are summarized in Table 3)) , the following compounds were prepared: 6. S-Chloromethyl-113-hydroxy-163-methyl-3-oxo-17a-propionyl-oxyandrosta-1,4-diene-173-thiocarboxylate, mp 192-193 ° C, [a] D = + 65 ° (c = 1.05).

7. S-Chloromethyl-9a-fluoro-113-hydroxy-16-methylene-3-oxo-17a-propionyloxyandrosta-1,4-diene-173-tidecarbonylate, m.p. 212-221 ° C, α] D = -56 ° (c = 0.99).

8. S-Chloromethyl-17a-acetoxy-9a-fluoro-113-hydroxy-163-methyl-3-oxoandrosta-1,4-diene-173-thiocarbonyl oxylate, m.p. 220-223 ° C, [α] D = + 39.5 ° (c = 1.06).

9. S-Chloromethyl-17α-butyryloxy-9α-fluoro-113-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-1733 thiocarboxylate with snp. 172-175 ° C, [α] D = + 46 ° (c = 1.10).

10. S-Chloromethyl-9a-fluoro-113-hydroxy-17a-isobutyryloxy-163-methyl-3-oxoandrosta-1,4-diene-173-thiocarboxylate, m.p.

234 - 239 ° C, [α] D = + 43 ° (c = 1.00).

11. S-Chloromethyl-9a-fluoro-113-hydroxy-3-oxo-17a-propionyl-oxyandrosta-1,4-diene-173 · thiocarboxylate, m.p. 196-199 ° C, [α] D = + 38 ° (c = 0.97).

12. S-Chloromethyl-6α-fluoro-113 “hydroxy-3-oxo-17α-propionyl-oxyandrosta-1,4-diene-173-thiocarboxylate, m.p. 188-191 ° C, [α] D = + 48 ° (c = 0.91).

13. S-Chloromethyl-17a-acetoxy-6a, 9a-difluoro-113-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-173 "thiocarboxylate, mp 280-283 ° C, [a] D = + 45 ° (c = 0.80).

14. S-Chloromethyl-17a-butyryloxy-6a, 9a-difluoro-113-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-173 * -thiocarboxylate with srtp.

235 - 238 ° C, [α] D = + 49 ° (c = 0.65).

15. S-Clomethyl-9a-fluoro ~ 113 ~ hydroxy-16a, 17a-isopropylidene-dioxy-3-oxoandrosta-1,4-diene-173 ”thiocarboxylate with snp. 276-280 ° C (dec.), [Α] D = + 127 ° (c = 0.51 in dimethyl sulfoxide).

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Example 16 33 S-Chloromethyl-9a-chloro-lip-hydroxy-163-methyl-3-oxo-17a-propionyl-oxyandrosta-1,4-diene-17β-thiolerboxylate and S-chloromethyl-9 [3,113-epoxy-16 | 3-Methyl 1-3-oxo-17α-propionyloxy androse ta-1,4-diene-17β-thiocarboxylate

A solution of 1.032 g of the mixture (χχι) in 5 ml of dimethyl acetamide was treated with 0.203 g of sodium bicarbonate followed by 0.2 ml of bromochloromethane and then the reaction mixture was stirred at 22 ° C for 1 1/2 hour, then partitioned between 50 ml ethyl acetate and 35 ml of 2N hydrochloric acid. The aqueous phase was extracted with an additional 2 x 30 ml of ethyl acetate and the combined extracts were washed with 2N hydrochloric acid, water, saturated sodium bicarbonate solution, water and saturated sodium chloride solution and dried, and the solvent was removed in vacuo to give 0.856 g of cream colored foam containing a mixing the title S-chloro methyl esters.

These were separated by p.l.c. on silica under development with chloroform / acetone 19: 1. The most polar component, 0.306 g, was crystallized twice from ethyl acetate to give 0.232 g of S-chloro-methyl-9α-chloro-113-hydroxy-16β-methyl-3-oxo-17α-propionyloxy-androsta-1,4 -diene-17 & -thiocarboxylate as white sheets with m.p.

222-229 ° C, [α] D = + 70 ° (c = 1.23).

The least polar component, 0.210 g, was crystallized from acetone / petroleum ether to give S-chloromethyl-93,11 & epoxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-173-thiocarboxylate in an amount of 0.065 g, m.p. 169-173 ° C, [α] D = + 49 ° (c = 0.60).

Example 17 S-Fluoromethyl-9α-fluoro-113-hydroxy-16β-methyl-3-oxo-17α-propionyl-oxyandrose ta-1,4-diene-17β-thiocarboxylate 660 mg (xxii) was stirred with a suspension of 1.421 g of silver fluoride in 8.5 ml of acetonitrile in the dark at room temperature.

After 72 hours, the reaction mixture was diluted with 200 ml of ethyl acetate and filtered through a silica pad. The filtrate was washed with water, dried and evaporated to 517 mg white foam. P.l.c. in chloroform / cyclohexane 19: 1 and chloroform afforded 270 mg of sooty foam which crystallized from methanol and then from methanol / diethyl ether to give 176 mg of the title S-fluoromethyl ester with a snip.

241-242 ° C, [α] D = + 97.5 ° (c = 0.98).

Example 18 S-Fluoromethyl-9a-fluoro-113-hydroxy-16a-methyl-3-oxo-17a-propionic loxyandrose ta-1,4-diene-17ft-fluoro-thoroxylate

A solution of 0.640 g (xxvii) in 8 ml of acetonitrile was treated with 1.511 g of dry silver fluoride and stirred in the dark at 22 ° C for 46.5 hours. The mixture was diluted with 200 ml of ethyl acetate and filtered through diatomaceous earth. The solution was washed with 2N hydrochloric acid, water and saturated sodium chloride solution and the solvent removed in vacuo to give 0.504 g of a pale yellow foam. This was chromatographed (p.l.c.) on silica gel and developed with 5% acetone in chloroform. The headband was eluted with ethyl acetate and crystallized twice from acetone to give 0.244 g of the title fluoromethyl thioester, m.p. 242-243 ° C (dec.), [Α] p = + 37 ° (c = 0.75).

Example 19 S-Fluoromethyl-6a, 9a-difluoro-II3-hydroxy-16a-methyl-17a-propionyl-oxy-3-oxoandrosta-1,4-diene-173-thiocarboxylate

A solution of 310 mg (XXVIII) in 10 ml of acetonitrile was stirred with 947 mg of silver fluoride for 3 days at room temperature in the dark.

100 ml of ethyl acetate was added and the mixture was filtered through diatomaceous earth. The filtrate was washed successively with 2N hydrochloric acid, water and saturated brine and dried. The solvent was removed and the residue was subjected to p.c. in chloroform and then chloroform / acetone 19: 1. The product was eluted with ethyl acetate and crystallized after concentration of the solution to give 0.075 g of the title fluoromethyl thiol ester with m.p. 272-273 ° C (dec.), [Α] D = + 30 ° (c = 0.35).

Example 20 S-Fluoromethyl-6a, 9a-difluoro-113-hydroxy-16a, 17a-isopropylidene-dioxy-3-oxoandrosta-1,4-diene-173-thiocarboxylate

A solution of 0.804 g (XXXIV) in 60 ml of acetonitrile was treated with 1.821 g of silver fluoride and the reaction mixture was stirred in the dark for 18 hours. The reaction was diluted with ethyl acetate and filtered through diatomaceous earth. The filtrate was washed with water and saturated sodium chloride solution and then dried and the solvent removed in vacuo to give 0.636 g of light cream solid. This was purified by p.l.c. on silica gel during induction twice with chloroform / acetone 14: 1. The main binder was eluted with ethyl acetate and crystallized five times from ethyl acetate to give 0.118 g of the title S-fluoromethyl thioester as white prisms with m.p. 305-311 ° C, [α] β = + 125 ° (c = 0.73 in dimethyl sulfoxide).

Examples 21-29

Using the same general procedure as in Example 17, but using as starting material for the desired product corresponding to the desired iodine methyl-173 carbothioate (process details are summarized in Table 4), the following compounds were prepared: 21. S-Fluoromethyl -17a-acetoxy-Sa-fluoro-113-hydroxy-163-methyl-3-oxoandrosta-1,4-diene-173-thiocarboxylate, m.p. 248-249 ° C, [α] D = + 101 ° (c = 1.08).

22. S-Fluoromethyl 1,11 (3-hydroxy-3-oxo-17α-propionyloxy andros waist 4-diene-173 ~ thiocarboxy lat, mp 112-117 ° C, [α] D = + 67 ° ( c = 0.76).

23. S-Fluoromethyl-113-hydroxy-163-methyl-3-oxo-17a-propionyl-oxyandrosta-1,4-diene-173-thiocarboxylate, m.p. 223-225 ° C, [α] D = + 103 ° (c = 0.38).

24. S-Fluoromethyl-9α-chloro-11B-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17 (3-thiocarboxylate, mp 182-193 °, [α] D = + 116 ° (c = 0.75).

25. S-Fluoromethyl-9α-fluoro-11β-hydroxy-16-methylene-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-thiocarbaxylate with syrup.

205-215 ° C, [α] D = -58 ° (c = 1.00).

S-Fluoromethyl-9a-fluoro-113-hydroxy-3-oxo-17a-propionyl-oxyandrosta-1,4-diene-173-thiocarboxylate, dec. 207-211 ° C, [α] D = + 70 ° (c = 0.88).

27. S-Fluoromethyl-6a-fluoro-118-hydroxy-3-oxo-17a-propionyl xy androsene-1,4-diene-17β-thiocarboxylate, m.p. 224-225 ° C, [α] D = + 70 ° (c = 0.79).

28. S-Fluoromethyl-17a-acetoxy-6a, 9a-difluoro-113-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-173-thiocarboxylate, m.p. 308-310 ° C, [α] D = + 29 ° (c = 0.80).

29. S-Fluoromethyl-17α-butyryloxy-6α, 9α-difluoro-113 ~-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-173-thiocarboxylate with snip, 249-252 ° C, [αID » + 32 ° (c = 1.05).

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Example 30 S-Bromomethyl-9a-fluoro-113-hydroxy-163-methyl-3-oxo-17a-propionylloxyandrosta-1,4-diene-17β-thiocarboxylate

A solution of 660 mg (QCII) in 20 ml of acetone was stirred with 972 mg of lithium bromide at room temperature for 5 days. The reaction mixture was diluted with 150 ml of ethyl acetate and then washed successively with 10% sodium thiosulfate solution, water and brine, dried and evaporated to 624 mg of sooty foam. This was crystallized twice from acetone / petroleum ether (mp 40-60 ° C) to give 499 mg of colorless crystals of the title S-bromomethyl ester with m.p. 186.5-187 ° C, [α] D = + 2 ° (c = 0.99).

Example 31 S-2'-Fluoroethyl-9a-fluoro-113-hydroxy-163-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17β-thiocarboxylate

A solution of 910 mg (XXXV) in 20 ml of acetonitrile was stirred with 2.071 g of silver (I) fluoride at room temperature in the dark.

After 6 days, the reaction mixture was diluted with 150 ml of ethyl acetate and filtered through diatomaceous earth. The filtrate was diluted with additional ethyl acetate (150 ml) and washed with water, dried and evaporated to a white foam in an amount of 704 mg. P.l.c. in chloroform / acetone 9: 1 gave the least polar product as 431 mg of yellow foam; it was recrystallized twice from methanol to give 253 mg of the titled S-2'-fluoroethyl ester with m.p. 133-134 ° C, [α] D = + 104.5 ° (c = 0.98).

Example 32 S-Chloromethyl-9α-fluoro-11B-hydroxy-16-methylene-3-oxo-17α-propionyloxy and other α-1,4-diene-17β-thiocarboxylate

A suspension of 227 mg (XXXVII) in 2.2 ml of propionic acid and 0.7 ml of trifluoroacetic anhydride was treated with a dry chloroform solution of toluene-p-sulfonic acid (0.044 ml, c.

80 mg / ml) and then stirred at room temperature for 6 hours and then stirred at 3 ° C for 16 1/2 hours. The reaction mixture was diluted with 75 ml of 5% sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried and evaporated to 254 mg of brown gum. The rubber was subjected to pl.c. in chloroform / acetone 19: 1 (3 times). The main band, 152 mg, was crystallized twice from ethanol to give 30 mg of white crystals of the title S-chloromethyl ester 17a propionate contaminated with S-chloromethyl-9a-fluoro-17a-hydroxy-16-methylene-3-oxo -lip-propionyloxyandrosta-1,4-diene-17 (3-thiocarboxylate as evidenced by nmr spectroscopy.

Example 33 S-Chloromethyl-9α-fluoro-113-hydroxy-16β-methyl-3-oxo-17α-propionyl oxyandrost-4-ene-17β-thiocarboxylate

Catalytic reduction of 0.646 of the compound of Example 1 with 800 mg of tris (triphenylphosphine) chlorrodium (I) in 100 ml of benzene for 21.5 hours after chromatography on silica in chloroform / acetone 9: 1 and two crystallisations from acetone the title chloromethyl thiol ester in the amount of 0.142 g as white needles, m.p. 217-225 ° C, [α] D = + 54 ° (c = 0.83).

Example 34 S-Fluoromethyl-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyanostrost-4-ene-17ft-thiocarboxylate Similarly, catalytic reduction of the compound of Example 23 gave 432 mg of the catalyst for 60 ml of benzene at 22 ° C for 24 hours and after repeated chromatography on silica in chloroform yields the title A4-3 ketone of 0.106 g, m.p. 174-177 ° C, [α] D = + 123 ° (c = 0.55).

Example 35 S-Chloromethyl-9a-fluoro-113-hydroxy-16β-methyl-3-oxo-17a-propionyl-oxyandrose ta-1,4-dlene-17β-thiocarboxylate .........

Ca. 0.9 mg of S-chloromethyl-9β, lip-epoxy-163-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate from Example 16 were treated with ca. 1 ml of hydrogen fluoride-urea complex 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 resulting product was detected by tlc on silica in three different solvent systems (acetone / petroleum ether (bp 40-60 ° C) 1: 2; chloroform / acetone 9: 1; ethyl acetate / petroleum ether (same) 1: 2, two - times) to contain the title fluorohydrin, the detection being made by comparison with an authentic sample.

Example 36 S-Chloromethyl-6α, 9α-difluoro-11α-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrose ta-1,4-diene-17β-thiocarboxylate

A solution of 29 mg (XLI) in 2 ml of methanol was kept at room temperature for 3 hours. The mixture was evaporated to dryness to give 25 mg of the title Ιΐβ alcohol, identified by comparison of its H nmr spectrum (in deuteriodimethylsulfoxide) and t.c. properties (silica, acetone / petroleum ether b.p. 40-60 ° C, 1: 3) with the corresponding properties of an authentic sample.

The active androstane compounds can advantageously be worked up in conventional manner for compositions suitable for local use by means of a topically applicable carrier material therefor. By the term topical or local application, in this specification is meant also administration by insufflation and inhalation.

Said preparations for topical application to the skin can be used to treat inflammatory dermatoses in humans and animals, e.g., eczema that usually respond to corticosteroid therapy, and also to less treatable conditions such as psoriasis in humans.

For internal administration, the novel compounds of the present invention may be prepared, for example, by conventional means for oral, parenteral or rectal administration.

Claims (8)

147022 An analogous process for the preparation of 11,17a-dihydroxy-3-oxo-androst-4-ene-17β-thiocarboxylates of the general formula COSR1 '5 R ° wherein is a fluorine, chlorine or bromomethyl group or a 2 a fluoroethyl group, R 2 is a group COR 1, where R 6 is a C 1-3 alkyl group and R 3 is a hydrogen atom, an α or β methyl group or a methylene group, or wherein CR 2 and R 3 collectively are a 16a, 17a isopropylidene dioxide group and R4 is a hydrogen, chloro-fluorine atom, R is a hydrogen or fluorine atom and the symbol - a single or double bond, characterized in that one a) esterifies a compound similar to compound I but containing a 173-thiocarboxyl group or a functionally equivalent group, or a free 17α-hydroxy group, in which case R is hydrogen, methyl or methylene and wherein all other reactive groups present are, if desired, in a protected state, with an esterifying agent corresponding to the group R or the group R, respectively. or b) translates a connection response end of Formula I, but containing a 17β substituent of the formula -COS (CEL) Y, wherein Y 1 chlorine or bromine atom if n is the number 1 and with a fluorine atom if n is the number 2, or c) reduce a compound of formula I but containing an 11-oxo group to give the desired 11 (3-hydroxyandrostane, or 147022) d) removing the protection from a compound of formula I but containing a protected hydroxyl group, or 4 e) forming a compound of formula I wherein R is fluorine or chlorine, reacting a compound of formula 1. but with a 9,11 epoxy group, with hydrogen fluoride or hydrogen chloride, or f) subject to a compound similar to the general formula I wherein ..... denotes a double bond partial reduction to produce a corresponding compound wherein. an affords a single bond. A process according to claim 1 (a), characterized in that a compound corresponding to formula I but containing a free 17B-thiocarboxyl group or a functionally equivalent group is esterified by reaction with a dihaloalkylating agent of the general formula R an interchangeable halogen atom. Process according to claim 1 (a), characterized in that a compound corresponding to formula I but containing a free 17a hydroxy group is esterified by reaction with an anhydride or acid chloride to form a compound of formula I as defined in claim 1. first Process according to claim 1 (b), characterized in that a compound of formula I is used but containing a 170 substituent of formula -COS (CH 2) Y, where 2 n Y is an interchangeable halogen atom. Process according to claim 1 (c), characterized in that the reduction is carried out by means of an alkali metal or alkaline earth metal borohydride. Process according to claim 1 (d), characterized in that a compound of formula I is used, but with a 116-tri-C 1-6 alkylsilyloxy group or an HB-perfluoro or chloroalkanoyloxy group. Process according to claim 1 (d) or claim 6, characterized in that the protective removal takes place by hydrolysis. Process according to claim 1 (f), characterized in that the partial reduction is carried out by hydrogenation with a palladium catalyst.