IE51395B1 - Steroids of the androstane series - Google Patents

Abstract

The present invention relates to steroids of the androstane series and to processes for their preparation. The steroids may be used as starting materials for the preparation of androstane compounds possessing anti5 inflammatory activity, which compounds are described and claimed in the specification of our copending Irish Patent Application No. 282/81. Our above mentioned specification describes and claims iu androstane compounds represented by the formula:- wherein R^· represents a fluoro-, chloro- or bromo-methyl 2 group or a 2'-fluoroethyl group; R represents a group fi 6 2 3 COR where R ls a C, , alkyl group or OR and R 3 15 together form a 16a,17a-isopropylidenedioxy group; R represents a hydrogen atom, a methyl group (which may be in either the a- or 8- configuration) or a methylene group; A 5 R represents a hydrogen, chlorine or fluorine atom; R represents a hydrogen or fluorine atom and symbol m,r repre20 sente a single or double bond), processes for their preparation and pharmaceutical compositions containing them.

Description

The present invention relates to steroids of the androstane series and to processes for their preparation. The steroids may be used as starting materials for the preparation of androstane compounds possessing anti5 inflammatory activity, which compounds are described and claimed in the specification of our copending Irish Patent Application No. 282/81.

Our above mentioned specification describes and claims iu androstane compounds represented by the formula:- wherein R^· represents a fluoro-, chloro- or bromo-methyl 2 group or a 2'-fluoroethyl group; R represents a group fi 6 2 3 COR where R ls a C, , alkyl group or OR and R together form a 16a,17a-isopropylidenedioxy group; R represents a hydrogen atom, a methyl group (which may be in either the a- or 8- configuration) or a methylene group; Λ 5 R represents a hydrogen, chlorine or fluorine atom; R represents a hydrogen or fluorine atom and symbol m,r repre20 sente a single or double bond), processes for their preparation and pharmaceutical compositions containing them. 5139 The new compounds of formula (I) have good anti-inflammatory activity, particularly on topical application, as judged by the McKenzie patch test in man and as measured by the reduction of croton oil induced oedema when the compounds are applied topically to the skin of mice and rats.

Certain of the compounds show good topical antiinflammatory activity in the croton oil ear test coupled with minimal hypothalamus-pituitary-adrenal-suppressive activity after topical application in the same animal species. These results indicate that such compounds may be of value in the local treatment of inflammation in man and animals with minimal liability to cause undesired systemic side effects.

Compounds of formula (I) which are preferred for their good anti-inflammatory activity include the following categories namely (a) those in which R1 is chloro- or fluoromethyl (b) those in which R2 is acetyl or propionyl, preferably propionyl, (c) those in which R^ is fluorine (d) those in which R5 is fluorine (e, the 1,4-dienes, and (f) those 1,4-dienes in which R^ is fluorine and R2 is hydrogen, a- or β-methyl or methylene.

Compounds of formula (I) which have good antiinflammatory activity coupled with minimal hypothalamusX pituitary-adrenal-suppressive activity when applied topically include 1,4-dienes in which R1 is chloro- or fluoro-methyl, and are fluorine and in particular those in which R2 is a-methyl.

Especially preferred compounds of formula (z) in view of their good topical anti-inflammatory 51398 activity and favourable ratio of topical anti-inflammatory activity to undesired systemic activity include:S-chloromethy1 9a-fluoro-llg-hydroxy-16amethy1-3-oxo-17a-propionyloxyandxosta-l,4-diene-17g5 carbothioate; S-chloromethyl 9a-fluoro-llg-hydroxy-16methylene-3-oxo-l7a-propionyloxyandrosta-1,4-diene-17gcarbothioate; S-fluoromethyl 6a,9a-difluoro-llg-hydroxy-16a, l7a-isopropylidenedioxy-3-oxoandrosta-l,4-diene-17gcarbothioate; S-fIuoromethyl 6 a,9 a-di fluoro-11g-hydroxy-16amethy1-3-oxo-l7a-propionyloxyandrostsf-1,4-diene-17gcarbothioate; S-chloromethyl 6a,9a-difluoro-llg-hydroxy-16amethy1-3-oxo-l7a-propionyloxyandrosta-l,4-diene-17gcarbothioate. The last compound is especially preferred in view of its particularly favourable ratio and in addition minimal skin atrophy.

The compounds of formula (.1) may.be prepared by a variety of different processes.

One such process comprises esterifying an androstane compound corresponding to formula (I) but containing either a free 17g-carbothioic acid group (or functionally equivalent group) or a free 17ahydroxy group (R3 being a hydrogen atom or a methyl or methylene group), any other reactive groups present in the molecule being suitably protected as desired.

For example, a salt of the parent 17B-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 an appropriate alkylating agent, preferably in a polar solvent such as a ketone, e.g. acetone or an amide such as dimethylformamide, dimethylacetamide or hexamethylphosphoramide, conveniently at a temperature of 15 to 51385 100°C. The alkylating agent may comprise an appropriate dihalo compound i.e. one containing a further halogen atom (preferably a bromine or iodine atom, in addition to the halogen atom of the desired R^ group. This process ls particularly applicable to the preparation of compounds in which R1 is a choromethyl group, the alkylating agent advantageously being bromochloromethane .

Alternatively, the parent 16-hydrogen, methyl 10 or methylene-17a-hydroxy-17&-carbothioates corresponding to compounds of formula I may be subjected to esterification of the 17o-hydroxyl group. This may be effected by conventional techniques, e.g. by reacting the parent 17a-hydroxy compound with a mixed anhydride of the required carboxylic acid, which may, for example, be generated in situ by reacting the carboxylic acid with an appropriate anhydride such as trifluoroacetic anhydride, preferably in the presence of an acid catalyst, e.g. p-toluene20 sulphonic acid or sulphosalicylic acid. Alternatively, the mixed anhydride may be generated in situ by reaction of a symmetrical anhydride of the required acid with an appropriate further acid, e.g. trifluoroacetic acid.

The reaction is advantageously effected in an organic solvent medium such as benzene, methylene chloride or an excess of the carboxylic acid employed, the reaction being conveniently effected at a temperature of 20-100°C.

' Alternatively, the 17a-hydroxy group may be esterified by reaction of the parent 17a-hydroxy compound with the appropriate acid anhydride or acid chloride, if desired, in the presence of non-hydroxylie solvents, e.g. chloroform, methylene chloride or benzene, and preferably in the presence of a strong acid catalyst, e.g. perchloric acid, p-toluene sulphonic - 5 acid or a strongly acidic cation exchange resin, e.g. Amberlite IR 120 (the word 'Amberlite1 is a registered Trade Mark), tne reaction being conveniently effected at a temperature of 25 to 100°C.

The confounds of formula (I) may also be prepared by reacting a corresponding androstane compound containing a 178-substituent of fonnula -COSiCHj)^ (wherein Y represents a displaceable substituent and n is 1 or 2) with a compound serving to replace the group Y by a halogen atom.

Thus the compounds of formula XI) may be subjected to a halogen exchange reaction serving to replace the group Y where this is halogen by a.’.different halogen substituent. Thus the bromomethyi, fluoramethyl and fluoroethyl 178-carbothioate compounds may be prepared from the corresponding iodccnethyl or bromoethyl 178carbothioate compounds using a bromide salt such as lithium bromide in the case of the bromomethyi 178-carbothioate compounds or an appropriate fluoride e.g. silver mono20 fluoride or silver difluoride in the case of the fluoromethyl or fluoroethyl 178-carbothioate compounds. The starting iodomethyl 178-carbothioate compounds may be prepared frcm the corresponding chloromethyl 178-carbothioate compounds using for example, an alkali metal, alkaline earth metal or quaternary ammonium iodide e.g. sodium iodide.

The reaction is advantageously effected in a solvent medium comprising for example acetone, acetonitrile, methyl ethyl ketone, dimethylformamide, dimethylacetamide or ethanol.

The foregoing reactions may also be carried out on compounds of the present invention having a variety of substituents or groupings which are subsequently converted into those substituents or groupings which are present in the compounds of formula I defined above.

The 11β-hydroxy compounds of formula (I) may thus be prepared by reduction of a corresponding 11oxo compound, e.g. using an alkali metal or alkaline earth metal borohydride, e.g. sodium or calcium borohydride, conveniently in an alcoholic or aqueous alcoholic solvent such as methanol or ethanol.

Such an 11-keto compound may be prepared by oxidation of a corresponding lla-hydroxysteroid, for example using a chromic acid reagent such as Jones* reagent.

An 11β-hydroxy compound of formula (I) may also be obtained by deprotection of a corresponding compound having a protected hydroxyl group at the Ιΐβ-position, for example a tri C^_g alkylsilyloxy group such as the trimethylsilyloxy group or a perfluoro- or chloro-alkanoyloxy group such as the trifluoroacetoxy group. Removal of the protecting group may be effected by hydrolysis, the trialkylsilyl group being readily removed by mild acid or basic hydrolysis or particularly conveniently using fluoride e.g. hydrogen fluoride or an ammonium fluoride. The perfluoro- or chloro-alkanoyl protecting group may also be removed by mild acid or basic hydrolysis or alcoholysis, but preferably under acidic 4 conditions when R is a chlorine atom. Such a protected hydroxyl group may be introduced, for example, by reacting an 11β-hydroxy steroid with an appropriate reagent such as a trialkylsilyl halide or a perfluoroor chloro-alkanoic anhydride.

X Compounds of formula (I) may also be produced by reaction of a corresponding compound having a 9,11double bond (and no substituent in the 11-position) with reagents serving to introduce the required 9ahalo-11β-hydroxy grouping. This may involve initial formation of a bromohydrin by reaction with an Nbromo-amide or -imide such as N-bromosuccinimide, followed by formation of the corresponding 9(3,11(3epoxide by treatment with a base and reaction of the epoxide with hydrogen fluoride or hydrogen chloride to introduce the required fluorohydrin or chlorohydrin grouping respectively. Alternatively, the 9,11-olefin compound may be reacted with an N-chloro-amide or -imide to introduce the required 9a-chloro-ll(Shydroxy grouping directly.

The Δ 4-compounds according to the invention 10 can conveniently be prepared by partial reduction of the corresponding Δ1'^-compound, for example, by hydrogenation using a palladium catalyst, conveniently in a solvent e.g. ethyl acetate or by homogeneous hydrogenation using for example tris(triphenylphosphine) rhodium chloride, conveniently 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 may be carried out on a haloalkyl ester where this is sufficiently stable in such a reaction or may be effected at an earlier stage.

The above mentioned compounds containing a free -COSH group in the 17(3-position may be prepared for example by aminolysis with rearrangement of a suitable l7(S-thiocarbamoyloxycarbonyl androstane. The 17(3thiocarbamoyloxycarbonyl androstane is a mixed anhydride of the corresponding 17β-carboxylie acid and a thiocarbamic acid and is conveniently prepared by reaction of a salt of the 17(3-carboxylie acid 17a30 ester or 16a, 17a-acetonide.with a thiocarbamoyl ha'lide. The thiocarbamoyl group is Ν,Ν-disubstituted, and may thus have the formula -COOCSNR^R3, where n and R, which may be the same or different, are alkyl A B groups, e.g. alkyl groups or R and R together 51398 with the nitrogen atom to which they are attached form a 5-8 membered ring which may optionally contain an additional hetero atom selected from oxygen, nitrogen and sulphur and/or which may optionally be substituted by one or two Cj_2 alkyl e.g. methyl groups. Ν,Ν-dimethylthiocarbamoyl group being preferred. The thiocarbamoyl halide is preferably the chloride. The reaction may be accelerated by the addition of an iodide salt e.g. sodium iodide.

The Initial androstane 178-carboxylate salt may be for example, an alkali metal, e.g. sodium or potassium, alkaline earth metal, e.g. calcium, salt or a salt of a tertiary amine, e.g. triethylamine.

Aminolysis with rearrangement may. 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 more preferably a secondary amine such as diethylamine or pyrrolidine. In the starting 178-carboxylic acids, the 16- and 17a-positions will 2 conveniently be substituted by the -R and -OR groupings desired for the final product of formula (I). 17a-Hydroxy androstane compounds in the 16methylene series which contain the desired 178carbothioic acid grouping, as described above, may be prepared from the corresponding l68-njeth.yl-16a, 17a-epoxy 178thiocarboxyllc acid, by effecting a rearrangement using a strong acid e.g. a strong carboxylic acid such as trifluoroacetic acid. These 16a,17a-epoxides may be prepared from the corresponding 178-carboxylic acids by treatment with an onium salt of a 2-halo-azaaromatic compound, followed by treatment of the resulting product with hydrogen sulphide or a 3alt thereof to give the free 178-carbothloic acid which may be alkylated as described above, preferably in situ to give the desired 17β-oarbothioate group. 16a,l7a-lsopropylidenedioxy compounds of formula (I) may similarly be prepared by treating a corresponding 170-carboxylic acid with an onium salt of a 2-halo-azaaromatic compound followed by treatment of the resulting product with hydrogen sulphide to give the free 178carbothioic acid which may then be esterified as described above.

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-phenyl-pyridinium or pyrimidinium salts carrying 1 to 2 further substituents selected from phenyl and lower (e.g. C^_4) alkyl groups, such as methyl. The 2-halogen atoms can be fluorine, chlorine, bromine or iodine atoms. The salts are pre15 ferably sulphonates, e.g. tosylates; halides e.g. iodides; fluoroborates or perfluoroalkylsulphonates, a convenient salt being 2-fluoro-N-methylpyridinium tosylate or 2chloro-N-methylbenzothiazolium trifluoromethanesulphonate.

The 16α,17a-epoxy-16 8-methyl-l7(5-carboxylic acid compounds used as starting materials in the above process may be prepared in conventional manner, e.g. as described in British Patent Specification No. 1,517,278.

The present invention relates to starting materials employed in the process described herein for the preparation of compounds of formula (I, which starting materials are new.

Thus according to one feature of the present invention there are provided compounds of the general formula (II) 51385 - 10 [wherein Ra represents a thiocarbamoyloxycarbonyl group -COOCSNRARB (where RA and RB, which may be a the same or different, are alkyl groups or R and D R together with the nitrogen atom to which they are attached form a 5-8 membered ring which may optionally contain an additional hetero atom selected from oxygen, nitrogen and sulphur and/or which may be optionally substituted by one or two C. , alkyl IA1-J groups) or a group of the formula -COSR (where R^a represents a hydrogen atom or is a group as defined below for R3 or is the group -(CH2)nY in which n is 1 or 2 and Y represents a displaceable substituent) and Rb represents an esterified hydroxyl group or Rb and Rc together represent an isopropylidenedioxy group; or where Ra represents a group COSR3A, Rb is optionally a hydroxyl group; Rc represents a hydrogen atom, a methyl group (which may be in either the a- or Β-configuration) or a methylene group; Ra represents a hydroxy or protected hydroxy group (in either the a- or β-configuration) or an oxo group; Rc represents a hydrogen, bromine, chlorine d β or fluorine atom; or R and R together represent a carbon-carbon bond or an epoxy group in the β-configuration; R^ represents a hydrogen or a fluorine atom; and the symbol u s. 11 represents a single or double bond] and salts of those compounds which have a free carbothioic acid group; with the exclusion of compounds of the formulas51395 wherein R^ represents a fluoro-, chloro- or brorao2 methyl group or a 2'-fluoroethyl group, R represents β β 2 a group COR where R is a C. , alkyl group or OR 3 and R together form a 16ot,17a-isopropylidenedioxy group; R^ represents a hydrogen atom, a methyl group (which may be in either the a- or B-configuration, or a methylene group; R represents a hydrogen, chlorine or fluorine atom; R^ represents a hydrogen or fluorine atom and the symbol »t r-.·. represents a single or double bond.

Where Rd represents a protected hydroxyl group, this may, for example be a trialkylsilyloxy group or a perfluoro- or perchloro-alkanoyloxy group as defined previously.

The 17a-hydroxy 176-carbothioic acids of formula (II) and salts thereof may be converted into the 17ahySroxy 17f5~carbothioates of formula (II) where Ra represents the group COSR* as defined in formula (I) or into the 176-carbothioic acid 17a-esters of formula (II) by the processes described above for preparing the compounds of formula (I). The esterification of the 17a-hydroxy group is preferably effected with the appropriate carboxylic acid chloride in a solvent such as a halogenated hydrocarbon S13SS - 1·2 e.g. dichloromethane, and advantageously In the presence of a base such as triethylamine, preferably at a low temperature e.g. 0°C.

The 17ct-hydroxy 178-carbothioic acids of formula (II) and salts thereof are thus particularly useful intermediates for preparing the androstane 176-carbothioates of formula (I) ? those in which Re represents a hydrogen atom, an a- or 8-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 being preferred. More preferred compounds and salts thereof include those compounds in which Rc represents a methyl group in the a- or 8-configuration or a methylene group? Re represents a fluorine atom, Rd represents a hydroxy group in the Β-configuration or an oxo group and the symbol -πτπ· in the 1,2 position represents a carbon-carbon double bond.

Especially preferred compounds of formula II thus include, for example, the following: 9a-fluoro-118,17a-dihydroxy-168-methy1-3-oxoandrosta-1,4-diene-178-carbothioic acid? 9 One advantage of the above Intermediates is that they permit direct haloalkylation to give haloalkyl 17βcarbothioates when the corresponding thiols R2SH are not available. The salts of these 17a-hydroxy 176-carbothioic acids may, for example be alkali metal, e.g. lithium, sodium or potassium salts? alkaline earth metal, e.g. calcium or magnesium salts? tertiary amine salts, e.g. pyridinium or triethylammonium salts? or quaternary ammonium salts, e.g. tetrabutylammonium salts.

The 17a-hydroxy 178-carbothioic acids may, for - 13 example, be prepared by reaction of a reactive derivative of a corresponding 17ct-hydroxy-17B-carboxylic acid with hydrogen sulphide or a sulphide or hydrosulphide salt thereof.

Xn general, the cation of the sulphide or hydrosulphide salt may be for example an alkali metal salt such as sodium or potassium hydrogen sulphide. The above-mentioned reactive derivatives correspond to compounds of formula (II) where Rb is a hydroxyl group and the group -COR7 is present at the 178-position wherein R represents a group of the formula in which X, Y and Z, which may be the same or different, each represent CH or N, one or two of X, Y and Z being N, the heterocyclic ring optionally being substituted on at least one carbon atom by a C-j_4 alkyl group (such as e.g. a methyl group) and/or where the heterocyclic ring contains two adjacent carbon atoms, the said ring optionally carrying a benzene ring fused to the' said adjacent carbon atoms.

The-above mentioned reactive derivatives corresponding to fonnula II are preferably prepared by reacting corresponding 17a-hydroxy-17Bcarboxylic acids of formula (II) with a symmetric or asymmetric compound of the formula: R7 - W - R7 (III) wherein W represents the group CO, CS, SO or SO- and the 7 2 groups R , which may be the same or different, have the above meanings.

The compounds of formula (III) are conveniently symmetric. In general, compounds of formula (III) in which W represents CO, CS or SO will be used. Thus, for example, especially useful compounds include N,N'carbonyldi(1,2,4-triazole), N,N'-carbonyldibenzotriazole, Ν,Ν'-carbonyldibenzimidazole, N,N’-carbonyldi(3,5-dimethylpyrazole), N,N'-thionyldiimidazole and especially N,N'carbonyldiimidazole and Ν,Ν'-thiocarbonyldiimidazole. 51385 - 14 The preparation of a 17a-hydroxy 176-carbothioic acid having the formula (II) as herein defined is conveniently effected by reaction of a 17a-hydroxy 176-carboxylic acid with a compound of formula (III) followed by reaction of the intermediate product having the 176-COR grouping with hydrogen sulphide or a salt thereof preferably in situ without isolation of the intermediate.

The 17a-acyloxy 176-carbothioic acid of formula II may be obtained in a similar manner directly from the corresponding 17a-acyloxy 176-carboxylic acid by reaction with a compound of formula (III).The 17a-acyloxy 176-carboxylic acids may be prepared by esterification of the corresponding 17a-hydroxy 176-carboxylic acids by 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 Ν,Νdimethylformamide or Ν,Ν-dimethylacetamide, desirably in the absence of water, advantageously at or below ambient temperature e.g. at a temperature of from -30°C to +30°C.

The reaction is conveniently effected under approximately neutral conditions, advantageously in an inert atmosphere, e.g. under nitrogen. The same solvents and conditions are also applicable to the subsequent reaction with H2S or a salt thereof. The heterocyclic compound e.g. imidazole or 1,2,4-triazole formed as a by-product may, for example, be readily removed by extraction with water.

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

The androstane 176-carboxylic acid starting materials employed in the above processes may be prepared in conventional manner, e.g. by oxidation of an appropriate - 15 21-hydroxy-20-keto pregnane for example with periodic acid, in a solvent medium and preferably at room temperature. Alternatively, sodium bismuthate may be employed to effect the desired oxidative removal of the 21-carbon atom of a 17u-acyloxy pregnane compound. As will be appreciated should the starting pregnane compound contain any substituent sensitive to the above desired oxidation, such a group should be suitably protected.

The following Examples illustrate the invention.

Melting points were determined in °C on a Kofler block and are uncorrected. Optical rotations were determined at room temperature on solutions in dioxan.

T.l.c. (Thin layer chromatography), p.l.c.

(Preparative layer chromatography) and h.p.l.c. (High performance liquid chromatography) were carried out over silica.

Solutions were dried over magnesium sulphate unless stated otherwise.

Preparation A lip-Hydroxy-3-Qxo-17a-propionyloxyandrosta-l,4-diene-17gcarboxylic acid (A) A solution of 116,17a-dihydroxy-3-oxoandrosta-l,4diene-176-carboxylic acid (13.5 g), and triethylamine (18 ml) in dichloromethane (500 ml) was cooled to 4°C and treated portionwise during 15 minutes with propionyl chloride (14.2 ml). Stirring was continued at 4°C for a total time of 1 h and the mixture was washed successively with 3% sodium hydrogen carbonate, water,2N-hydrochloric acid, water and saturated brine, then dried and evaporated under reduced pressure. The residue was dissolved in acetone (300 ml) and diethylamine (14.3 ml) was added with stirring. After 1 h at 20°C the solvent was removed under reduced pressure, and the residue was dissolved in water (150 ml). After acidification to pH 1 with 2N-hydrochloric acid the product was ex35 tracted with ethyl acetate. The combined extracts were - 16 washed with water and saturated brine, dried and then concentrated to a low volume. The solid product was collected by filtration, washed with ethyl acetate and dried in vacuo at 50° to give the title 17a-propionate carboxylic acid as crystals (13.309 g), [a]D +2° (c 1.10,). A portion (389 mg) was recrystallised twice from methanol to give an analytical sample (256 mg) m.p. 244-245° (decomp), [a]D +3° (c 0.83). Preparation B 6tt,9tt-Dlfluoro-118-hydroxy-16a-methy1-3-oxo-17tt-propionyloxyandrosta-l,4-diene-17B-carboxylic acid (b ) A solution of 6a,9a-difluoro-llB,17a-dihydroxy-16amethy1-3-oxoandrosta-l,4-diene-178-carboxylie acid (2.113 g) and triethylamine (2.5 ml) in dichloromethane (60 ml) was stirred and treated at ca 0°C with propionyl chloride (1.85 ml). After 1 h the mixture was diluted with more solvent (50 ml) and washed successively with 3% sodium hydrogen carbonate, water, 2N-hydrochloric acid, water, saturated brine, then dried and evaporated to a buff solid. This was dissolved in acetone (50 ml) and diethylamine (2.5 ml) was added. After 1 h at 22°C the solvent was removed in vacuo and the residual gum was dissolved in water (30 ml). Acidification to pH 1 with 2N-hydrochloric acid precipitated a solid,which was collected, washed with water, and dried to give the title carboxylic acid 17t»-proplonate (2.230 g), m.p. 220-225°, [a]D +4° (c 0.70).

Preparation C 6q-Fluoro-118,17tt-dlhydroxy-3-oxoandrosta-l,4-diene-17gcarboxylic acid (C) A solution of 6a-fluoroprednisolone (4.987 g) in tetrahydrofuran (50 ml) was stirred with a solution of periodic acid (10.0 g) in water (24 ml) at 22°. After 50 mins the tetrahydrofuran was evaporated and the aqueous suspension was filtered. The solid product was washed with water (300 ral) and dried to give a white solid (4.80 g). A portion (271 mg) was crystallised from methanol to give the title acid (171 mg) as white needles, m.p. 241 - 248°, [a]D +54° (c 0.825). ’ S139S - 17 Preparation β z 6a-Fluoro-llg-hydroxy-3-oxo-17a-propionyloxyandrosfca-l,4dlene-17g-carboxyllc acid (D) A solution of C (4.491 g) and triethylamine (4.46 ml) in dry dichloromethane (160 ml) at - 5° was stirred and treated dropwise with propionyl chloride (2.80 ml., 2.96 g) in dry dichloromethane (ca. 5 ml.) during 5 min at below 0°. After a further 20 min below 0° the reaction mixture was diluted with dichloromethane (160 ml), washed with sodium hydrogen carbonate solution, water, 'dried and evaporated to a white solid (5.701 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 pH2 using 2N-hydrochloric acid (50 ml) with stirring and the product extracted with ethyl acetate three times. The extracts were combined, washed with water (50 ml), dried and evaporated to give a white foam (5.819 g). A portion of the foam (304 mg) was crystallised from ethyl acetate to give the title 17apropionate (144 mg) as small plates, m.p. 224 - 227°, [aJD + 3° (c 0.861) .

Preparation E 16a,17a-Epoxy-9a-fluoro-llg-hydroxy-16g-methyl-3-oxoandrostal,4-diene-17g-carbothioic acid (E ) A mixture of 16a,17a-epoxy-9a-fluoro-llg-hydroxy-16gmethyi-3-oxoandrosta-l,4-diene-17g-carboxylic acid (377 mg) and 2-fluoro-1-methylpyridinium tosylate (340 mg) in dry di30 chloromethane (7 ml) was stirred, cooled in ice, and treated during 1 min with triethylamine (0.42 ml). After 1 h, hydrogen sulphide was passed through the mixture for 30 mire bo give a yellow solution. T.l.c. (chloroformacetone-acetic acid, 30:8:1) showed a major less polar 81398 - 18 product had formed. After being allowed to warm to room temperature during 1 h the mixture was treated with 2Nhydrochloric 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 agueous extracts were combined and acidified with 6N-hydrochloric acid, 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 16α,17a-epoxy-9a-fluoro-llfS-hydroxy-166-methyl-3-oxoandrosta-l,4-diene-17g-carbothioic acid (no starting oxyacid present) as judged by t.l.c. (chloroform-acetone-acetic acid 30:8:1, Rp ca 0.7).

Preparation F S-Chloromethyl 16a,17a-epoxy-9a-fluoro-llg-hydroxy-16gmethyl-3-oxoandrosta-l,4-diene-17g-carbothioate (f) Method A A suspension of 16a,17a-epoxy-9a-fluoro-llg-hydroxy16g-methyl-3-oxoandrosta-l,4-diene-17g-carboxylic acid (753 mg) and 2-fluoro-1-methylpyridinium tosylate (680 mg) in dichloromethane (7 ml) was treated dropwise at 0°C with triethylamine (1.39 ml), and then stirred at 0°C for 1 h. Hydrogen sulphide was then passed through the mixture for 15 min and then the resulting solution was stirred at 0°C for a further 1 h. Bromochloromethane (0.26ml) was then added and the mixture was stirred and allowed to warm to room temperature. After a further 1.5 h the reaction mixture was diluted with ethyl acetate (250 ml) and-washed successively with 2N-hydrochlorice acid, 5% sodium hydrogen carbonate solution and water, dried and evaporated to a pale yellow solid (818 mg). The solid was subjected to p.l.c. in chloroform-acetone (9:1) (two runs). The major band (515 mg) was crystallised from acetone to give white needles of the title S-chloromethyl ester epoxide (447 mg), m.p. 246-251°, [aJD +131° (c 0.67). - 19 Method B A suspension of 16a,17a-epoxy-9a-fluoro-118-hydroxy16(2-methyl-3-oxoandrosta-l,4-diene-178-carboxylic acid (376 mg) and 2-chloro-N-methylbenzothiazolium trifluoro5 methane sulphonate (400 mg) in dichloromethane was treated dropwise at 0°C with triethylamine (0.7 ml). The resulting solution was stirred at 0°C for 1.25 h and then hydrogen sulphide was passed through the mixture for 10 minAfter a further 1 h at 0°C bromochloromethane (0.13 ml) was added and the mixture was stirred at room temperature. Two more portions of broraochloromethane (0.13 ml) were then added after a further 1,5 h and 1.8 h. Fifteen min. after the final addition the reaction mixture was diluted with ethyl acetate (200 ml) and washed successively with 2N-hydrochloric acid, 5% sodium hydrogen carbonate 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 pale pink solid, the title S-chloromethyl ester (134 mg)., identical to an authentic sample on t.l.c.

Preparation G 9a-Fluoro-17g-hydroxy-166-methyl-3 ,ll-dioxoandrosta-l,4dlene-178-carboxylic acid (G) A stirred suspension of 9a-fluoro 17,21-dihydroxy25 168-methylpregna-l,4-diene-3,11,20-trione (4.842 g) in tetrahydrofuran (50 ml) was cooled in ice and treated dropwise over 5 min with a solution of periodic acid (4.255 g) in water (15 ml). The reaction was stirred at 22° for 2.25 h, when most of the suspension had dissolved. The sol30 vent 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) mp 270 - 272° (dec), [o]D +136° (c 1.04, dimethyl35 sulphoxide). ei 38S - 20 Preparation Η 9a-Fluoro-llB,17a-dlhydroxy-3-oxoandrosta-l,4-dlene-17gcarboxyllc acid (H) A suspension of 9a-fluoroprednisdone (10 g) in dry 5 tetrahydrofuran (55 mi) was stirred and treated with a solution of periodic acid (9.0 g) in water (90 ml) and the mixture was stirred at 22°C for 2 h. It was then poured into iced-water (ca 400 ml) and, after being stirred for 15 min., the solid product was collected, washed with water, and dried to give the title acid as a solid (9.42 g). A portion recrystallised from ethanol had m.p. 289-293° [tx ] D +66° (c 0.73, methanol).

S1395 - 21 Example I 9a-Fluoro-llg-hydroxy-16g-methyl-3-oxo-17ct-propionyloxyandrosta-l,4-diene-178-carbothioic acid (I) A solution of 9a-fluoro-llf3-hydroxy-16fJ-methyl-35 oxo-17a-propionyloxyandrosta-l,4-diene-17(3-carboxylie acid (5.00 g) solvated with ethyl acetate (1/2 mole) and triethylamine (5.3 ml) in dichloromethane (75 ml) was stirred under nitrogen and treated with dimethylthiocarbamoyl chloride (5.071 g). After 24 h more reagent (5.320 g) was added. After 47 h the mixture was diluted with ethyl acetate and washed with N-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 at reflux under nitrogen for 5.-75 h. The resulting brown solution was added to a mixture of concentrated hydrochloric acid (50ml), water (250 ml) and ethyl acetate (50 ml). The products were further extracted with ethyl acetate, then the acid products were back-extracted into 5% sodium carbonate solution. The acqueous phase was acidified with 6N-hydrochloric acid (50 ml) and extracted with ethyl acetate. The extracts were washed with N-hydrochloric acid and water, dried and evaporated to a buff solid (3.440 g). This was recrystallised from acetone to give pale buff crystals (1.980 g) of the title 17β25 carbothioic acid, m.p. 172-173°.

The analytical sample was obtained after two recrystallizations from acetone as white crystals, m.p. 177-179°, [D +110° (c 1.05).

Example II S-Chloromethyl 9a-fluoro-16B-methy1-3,ll-dloxo-17a-propionyloxyandrosta-1,4-dlene-17B-earbothloate (II) 8N-Jones reagent (1.5 ml) was added dropwise over 10 mins to a stirred solution of S-chloromethyl 9 2,088,877)) (998 mg) in acetone (2 ml) and di5139s - 22 methylformamide (2 ml). After 30 mins the reaction mixture was slowly diluted with water (100 ml) with stirring, and the resulting suspension was refrigerated for 1 h.

The precipitate was collected by filtration, washed with water and dried to give a cream coloured solid (877 mg).

P.l.c. in chloroform-acetone (10:1) gave a white foam (755 mg) which was crystallised twice from acetone to give white needles of the title 11-ketone (523 mg) m.p. 204-205°, [0 +94° (c 1.04).

Example III 178-N,N-Blmethylthiocarbamoyloxycarbonyl-9a-fluoro-118hydroxy-16a-methyl-17a-propionyloxyandrosta-l,4-dlene-3one (III) A solution of 9a-fluoro-116-hydroxy-16a-methyl-3-oxo15 17a-propionyloxyandrosta-l,4-diene-178-carboxylic acid (0.434 g) in dichloromethane (8 ml) was treated successively with triethylamine (0.14 ml), dimethylthiocarbamoyl chloride (0.248 g), and sodium iodide (0.149 g) and the mixture was stirred under nitrogen at 20°C for 6 h. Ethyl acetate (30 ml) was added and the total volume was reduced by half In vacuo. Further ethyl acetate (50 ml) was added and the solution was washed with water, 2N-hydrochloric acid, water, 3% sodium hydrogen carbonate, water and saturated sodium chloride solution then dried. The solution was concentrated in vacuo when the product crystallised (0.329 g). This was recrystallised from acetone (2 x) to give the title anhydride as white needles, m.p. 191-193°, [o]p +82°(c0.57). Example IV 9a-Fluoro-llg-hydroxy-16a-methyl-3-oxo-17a-proplonyloxygn androsta-1,4-diene-178-carbothloic acid (IV) A stirred suspension of (III) (2.467 g) in diethylamine (25 ml) was heated at reflux under nitrogen. After 3. ί-h. the reaction was poured into iced 3N hydrochloric acid (300 ml) and the mixture was extracted with ethyl 35acetate. The combined extracts were washed with water and were extracted with 5* sodium carbonate solution. The com5A39S - 23 bined 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 further ethyl acetate and the combined extracts were washed with water, saturated sodium chloride solution, dried and the solvent was removed in vacuo. The residue was crystallised twice from acetone to give the title carbothioic acid as white needles (1.309 g) m.p. 141-143°, [g]D +30° (c 0.51). Example V 17g-N,N-Dimethylthiocarbamoyloxycarbonyl-9g-fiuoro-llghydroxy-16a,17a-isopropylldenedioxyandrosta-1,4-diene-3one (V) A solution of 9a-fluoro-llg-hydroxy-16a,17g-isopropylidenedioxy-3-oxoandrosta-l,4-diene-17g-carboxylic acid (1.000 g) in dichloromethane (15 ml) and triethylamine (0.33 ml) under nitrogen was treated with Ν,Ν-dimethylthiocarbamoyl chloride (588 mg) and the mixture was stirred at room temperature. After 68 h the reaction mixture was diluted with ethyl acetate (50 ml) and washed with N-hydrochloric acid (2.10 ml), 5% sodium hydrogen carbonate solution and water, dried and evaporated to a pale yellow crystalline solid (1.123 g) . P.l.c. of a porticn (200 mg) in chloroformacetone (it: 1) gave an off-white solid (.161 mg) which crystallised from ethyl acetate as white needles of the title mixed anhydride (131 mg), m.p. 279-281°, [α]ρ +174° (c 0.61, dimethylsulphoxide)..

Example VI 17g'-N,N-Dimethylthlocarbamoyloxycarbonyl-6q,9g-difiuoro-llghydroxy-16a,17g-isopropylidenedioxyandrosta-l,4-diene-330 one (VI) A solution of 6o,9a-difluoro-llg-hydroxy-16g,17gisopropylidenedioxy-3-oxoandrosta-l,4-diene-178-carboxylic acid (4.354 g) in dichloromethane (150 ml) containing triethylamine (1.4 ml), was treated with N,N-dimethylthiocar35 bamoyl chloride (2.519 g) and the reaction was stirred under nitrogen at 22° for 80 min. Ethyl acetate (500 ml) was added and the resulting solution was successively washed with 2N-hydrochloric acid, water, sodium hydrogen carbonate solution, water and saturated sodium chloride solution and dried and the solution was concentrated. On cooling, crystallisation occurred and the solid was filtered and dried in vacuo to give the title anhydride (3.562 g) as pale yellow prisms, m.p. 283 - 287° (dec), [olD +156° Cc. 0.84, dimethylsulphoxide).

Example VII 6a,9a-Difluoro-llg-hydroxy-16a,17a-isopropylldenedloxy-3oxoandrosta-l,4-dlene-17g-carbothiolc acid (VII) A suspension of VI (3.455 g) in diethylamine (200 ml) was heated under reflux under nitrogen for 6 h.

The initial suspension quickly dissolved, but a pale brown suspension formed after 30 min and remained unchanged. The cooled reaction mixture was poured into water (1.0 1), 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 washed with water and saturated sodium chloride solution, then dried, and the solvent was removed in vacuo to give a pale grey solid (2.31 g).

Part of the product (0.408 g) was crystallised from ethyl acetate to give the title carbothloic acid (0.149 g), m.p. 191 - 199°, t«»iD +124° (c 1.04, dimethylsulphoxide).

Example VIII - XIX Following the same general procedure as described in Example i but using as starting material the 17gcarboxylic acid corresponding to the desired 17βcarbothioate (process details being summarised in Table 1 below), the following compounds were prepared:VIII. 17a-Acetoxy-9a-fluoro-llg-hydroxy-16g-methyl-3-oxo- 25 androsta-1,4-diene-176-carbothioic acid, m.p. 178.5-179°, [e]D +98° (c 1.02).

IX. 17a-Butyryloxy-9a-fluoro-ll{5-hydroxy-166-methy1-3oxoandrosta-l,4-diene- 176-carbothioic acid, m.p. 175-176°, [a]n +107° (c 0.96) .

X. 9a-Fluoro-116-hydroxy-17a-isobutyryloxy-168-methyl3-oxoandrosta-l,4-diene-176-carbothioic acid, m.p. 177-179, [a]D +119° (c 0.90).

XI. 116-Hydroxy-3-oxo-17a~propionyloxyandrosta-l,4diene-176-carbothioic acid, m.p. 134-138°, [a)D +67° (c 0.66) .

XII. 116-Hydroxy-166-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-176-carbothioic acid, m.p. 159-163°, [a)D +113° (c 0.78) .

XIII. 9a-Chloro-118-hydroxy-16B-methyl-3-oxo-17a-propionyl oxyandrosta-l,4-diene-17B-carbothioic acid, m.p. 167-171, [a) +128° (c 0.99) .

XIV. 9a-Fluoro-116-hydroxy-16a-methyl-3-oxo-17a-propionyl oxyandrosta-l,4-diene-17B-carbothioic acid, m.p. 141-143°, [β]θ +30° (c 0.51).

XV. 6a,9a-Difluoro-116-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-176-carbothioic acid, m.p. 136-139°, [a)D -30° (c 0.56).

XVI. 9a-Fluoro-118-hydroxy-16-methylene-3-oxo-17a-propionyloxyandrosta-1,4-diene-176-carbothioic acid, m.p. 236-239°, [a)D -71° (c 0.99).

XVII. 116-Hydroxy-3-oxo-17a-propionyloxyandrosta-4-ene-176carbothioic acid, m.p. 176-177°, [α]β +101° (c 0.96).

XVIII. 9a-Fluoro-116-hydroxy-16a,17a-isopropylidenedioxy-3oxoandro3ta-l,4-diene-17f5-carbothfi.oic acid, m.p. 274-304° (dec.), [a)D +121° (c 0.51, dimethylsulphoxide).

XIX. 6a-Fluoro-116-hydroxy-3-oxo-17a-propionyloxyandrosta1,4-diene-176-carbothioic acid, m.p. 189-193°, [α]θ +72° (c 0.74). 51388 - 26 TABLE I Formation of the mixed anhydrides Preparation 176- carboxylic acid Input (g) Cl-CSNMe2 ig) NEt3 (ml) Solvent (CH2C12) (ml) Reaction Time (days) at room temperature VIII 5.000 2.940 1.66 755la IX 15.354 8.809 4.8 250 6 X 4.182 2.399 1.3 80 4 XI 7.148 4.40 2.6 150 6lb XII 6.137 3.77 2.05 140 6lc XIII 5.973 3.350 1.34 100 7 XIV 4.207 2.39 1.35 80 0.677,ld XV 2.130 1.80 0.66 50 64 XVI 5.000 2.507 1.41 75 3 XVII 1.000 2.442 1.22 15 2.7 XVIII 1.000 0.588 0.33 15 CO co CM XIX 6.000 3.55 2.0 120 1.251° 513SS - 27 TABLE I(Continued) Treatment of the mixed anhydride intermediates with diethylamine Preparation NHEt_ (ml) 2 Reaction Time (h) at reflux Product (g) Crystallisation Solvent VIII 50 5.5 2.104 EA2a IX 250 4 5.244 EA3 X 60 4.5 1.00 EA XI 60 4 3.29 EA XII 50 3.5 1.382 EA XIII 60 5.7 0.527 EA XIV 25 4.75 1.309 A XV 12 6 0.418 EA XVI 50 3.75 1.296 EA2b XVII 15 4 0.3976 A5 XVIII (a) 8 b) 16 (a) 3 (b) 2.5 0.4649 A XIX 60 4.5 2.88 EA-P Notes : EA - ethyl acetate. A = acetone. P=petrol b.p. 60-80° 1. Portions (a) 500 mg, (b) 670 mg, (c) 424 mg, (d) 171 mg. of the intermediate dimethylthiocarbamic 51398 - 28 anhydride were removed for characterisation. 2. Characterisation was carried out on a sample recrystallised twice more from ethyl acetate.

Recoveries (a) 84% (b) 69%. 3. Product was solvated with ethyl acetate (ca 0.2 mol). 4. The Intermediate dimethylthiocarbamic anhydride (1.435 g) crystallised from ethyl acetate. A portion (95 mg) was removed for characterisation.

. Characterisation was carried out on a sample recrystallised twice more from acetone (recovery : 73%). 6. Product crystallised from ethyl acetate. 7. Sodium iodide (1.46 g) was also present in the reaction. 8. The intermediate dimethylthiocarbamic anhydride (1.123 g) crystallised from ethyl acetate. A portion (200 mg) was chromatographed (p.l.c., chloroform-acetone, 9si) and recrystallised frcm ethyl acetate (recovery 65%). 9. Reaction carried out on 781 mg of anhydride,.

. Sodium iodide (2.13 g) was also present in the reaction.

Example XX 9a-Chloro-116-hydroxy-16B-methyl-3-oxo-17a-proplonyloxyandrosta-l,4-diene-178-carbothloic acid and 9β,118-epoxy-16g-methyl-3-oxo-17tt-propionyloxyandrosta-l,4diene-17g-carbothioic acid (XX) A solution of 17g-N,N-dimethylthiocarbamoyloxycarbonyl-9a-chlorο-ΙΙβ-hydroxy-16g-methyl-17a-propionyloxyandrosta—l,4-diene-3-one (5.586 g,) in diethylamine (60 ml) was-refluxed under nitrogen for 5 h 40 min. 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 - 29 (3 χ 50 ml). The combined extracts were washed with water and saturated sodium chloride solution and dried and the solvent removed in vacuo to give a colourless froth (2.834 g).

Two crystallisations of the mixture from ethyl acetate gave 9g-chloro-118-hydroxy-16g-methyl-3-oxo-17apropionyloxyandrosta-l>4-diene-17g-carbothiolc acid (0.527 g) as white prisms, m.p. 167 to 171°, [α]θ + 128° (c 0.99).

The mother liquors from the crystallisations contained an additional quantity of the above 9a-chloro-118-hydroxycarbothioic acid together with 98,118~epoxy-168-methyl-3oxo—17g—propionyloxyandrosta—1,4—diene—17g—carbothioic acid.

Example XXI S-Iodomethyl 9a-fluoro-118-hydroxy-168-methyl-3-oxo-17n15 propionyloxyandrosta-1,4-diene-178-carbothioate (XXX) A solution of S-chloromethyl 9a-fluoro-118-hydroxy168-methyl-3-oxo-17a-propionyloxyandrosta-l,4-diene-178_ carbothioate (see Example 1 of our copending British Patent Application No. 8104496 (Serial No. 2,088,877)) (500 mg) and sodiim iodide (1.874 g) in acetone (15 ml) was stirred and heated under reflux for 6.5 h. Ethyl acetate (75 ml) was then added and the solution was washed successively with water, 10% sodium thiosulphate solution, 5% sodium hydrogen carbonate 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 was crystallised twice from acetone without being heated above room temperature to give colourless crystals of the title S-iodomethyl ester (241 mg) m.p. 196-197°, [a]D -32° (c 1.01).

Examples XXII - XXXIII Following the same general· procedure as described in Preparation XXI but using as starting material the Schloromethyl 178-carbothioate corresponding to the desired product (process details being summarised in Table II below), the following compounds were prepared. The starting 51398 - 30 materials were prepared as described in our copending British Patent Application No. 8104496 (Serial No. 2,088,877).

XXII. S-Iodomethyl 17a-acetoxy-9a-£luoro-llg-hydroxy-16gmethy1-3-oxoandrosta-1,4-diene-17g-carbothioate, m.p. 204-205°, [a)D -29° (c 0.98).

XXIII. S-Iodomethyl llg-hydroxy-3-oxo-17a-propionyloxyandros ta-1, 4-diene- 17 6-carbothioate, [a)D +26° (c0.47).

XXXV. S-Iodanethyl llg-hydroxy-16g-methyl-3-oxo-17apropionyloxyandrosta-l,4-diene-178_carbothioate, [a)D +5° (c 0.74).

XXV. S-Iodomethyl 9a-chloro-llg-hydroxy-16g-methyl-3oxo-17a-propionyloxyandrosta-l,4-diene-17g-carbothioate, [a]D +7° (c 0.36).

XXVI. S-Iodomethyl 9a-fluoro-llg-hydroxy-16a-methyl-3oxo-17a-propionyloxyandrosta-l,4-diene-178-carbothioate, [a]D +85° (c 0.55).

XXVII. S-Iodomethyl 6a,9a-difluoro-llg-hydroxy-16a-methyl3-oxo-17u-propionyloxyandrosta-l,4-diene-176-carbothioate. XXVIII. S-Iodomethyl 9a-fluoro-llg-hydroxy-16-methylene-3oxo-17a-propionyloxyandros ta-1,4-dlene-17 g-carbothioate, m.p. 191-199°, [α]θ -31° (c 0.99).

XXIX. S-Iodomethyl 9a-fluoro-llg-hydroxy-3-oxo-17apropionyloxyandros ta-1,4-diene-17g-carbothioate, m.p. 175-178°, [a)D +4° (c 0.50).

XXX. S-Iodomethyl 6a-fluoro-llg-hydroxy-3-oxo-17apropionyloxyandros ta-1,4-d iene-17 g-carbothioate, m.p. 195-197°, [o]D +18° (c 0.64).

XXXI. S-Iodomethyl 17a-acetoxy-6a, 9a-difluoro-llghydroxy-16a-methy1-3-oxoandrosta-l,4-diene-176-carbothioate, m.p. 241-243°, [«1D +78° (c 0.78).

XXXII. S-Iodomethyl 17a-butyryloxy-6a,9a-difluoro-llghydroxy-16o-methy1-3-oxoandrosta-1,4-diene-17g-carbothioate, m.p. 210-212°, [a)D +89° (c 0.90). - 31 XXXIII. S-iodomethyl 9a-fluoro-110-hydroxy-16o,17a-isopropylidenedioxy— 3—oxoandrosta-1,4-diene-17f5-carbothioate, m.p. 261-270° (dec.), [α]ρ +97° (c 0.48, dimethylsulphoxide).

TABLE II Halogen Exchanges on S-haloalkyl 17a-acyloxyandrostane-17 β-carbothioates Example No. Nal (mg) STARTING STEROID SOLVENT (acetone (ml) REACTIO! TIME (h) (at reflux] PLC (Silica CHC1-- Me2C0 2RYSTAL- ]5ISATIOt SOLVENT PRODUCT (mg) HALIDE INPU1 (mg) XXII 663; Cl 1715 20 3.5 - EA 2161 XXIII 3800 Cl 925 10 4 - - 1084 XXIV 3260 Cl 840 10 3 - - 969 XXV 1995 Cl 536 20 6.5 - - 591 XXVI 2160 Cl 580 10 3 - - 685 XXVII 1200 Cl 303 30 5 - - 3173 XXVIII 7361 Cl 1953 23 6 19:1 A 2962 XXIX 5500 Cl 1300 35 4 - M 12506 XXX 8400 Cl 2000 54 4.5 EA-P 1800 XXXI L900C Cl 4750 200 5 EA 46205 XXX n 6500 Cl 1620 70 5.5 - EA 16104 XXX HI 5491 Cl 1419 20 24 9:1 A 2247 EA = ethyl acetate A = acetone M = methanol n P = petrol b.p. 60-80u Notes 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 for the preparation of the corresponding fluoromethyl 178-carbothioate. 4. Solvated with 0.5 H^O. 31395 - 32 5. Solvated with 0.1 EA.

. Solvated with 0.2 EA + 0.5 HjO. 7. Obtained from a portion (300 mg) of the crude crystalline product (1.611g,.

Example XXXIV S-Iodomethyl 6ct,9 A solution of S-chloromethyl 6a,9a-difluoro-118hydroxy-16a,17a-isopropylidenedioxy-3-oxoandrosta-l,4diene-17B-carbothioate (see Example 4 of our copending British Patent Application No. 8104496 (Serial No. 2,088,877)) (0.795 g) in acetone (50 ml) was heated under reflux with sodium iodide (2.969 g) for 5.5 h. Ethyl acetate (75 ml) was added and the solution was washed successively with water, sodium metabisulphite solution, then dried and the solvent removed ln vacuo to give an off-white solid (0.893 g). Part (0.205 g) of this was crystallised twice from ethyl acetate to give the title S-iodomethylthioester (0.105 g) as white prisms, m.p. 260-262° (dec.)., [a]Q +81° (c 0.6, dimethylsulphoxide).

Example XXXV S-2'-Bromoethyl 9a-fluoro-118-hydroxy-168-methyl-3-oxo-17apropionyloxyandrosta-l,4-dlene-178~carbothloate (XXXV) I (0.5 g) was treated as described for the S-chloromethyl ester (see Example 1 Method A of our copending British Patent Application No. 8104496 (Serial No. 2,088,877)) but using 1,2-dibromoethane to give colourless crystals of the title S-2'-bromoethyl ester (0.409 g), m.p. 174-145°, [a]D +120° (o 1.04) . - 33 Example XXXVI S-Chloromethyl 9a-fluoro-llg,17a-dlhydroxy-16-methylene-3oxoandrosta-l,4-diene-17g-carbothioate (XXXVI) A solution of F (400 mg) in trifluoroacetic acid (16 ml) was stirred at room temperature. After 5.5 h the reaction mixture was evaporated to near dryness and the residue dissolved in ethyl acetate (100 ml). The solution was washed with 5% sodium hydrogen carbonate solution and water, dried and evaporated to a yellowish-green foam 3-q (4^6 mg). The foam was subjected to p.l.c. in chloroformacetone (9:1) (three runs). A portion (80 mg) of the major band (315 mg) was crystallised twice from acetone to give white crystals of the title 16-roethylene 17ct-alcohol (48 mg), m.p. 242-243°, (a)D +36° (c 0.50).

Example XXXVII 9a-Fluoro-llg,17a-dlhydroxy-16g-methyl-3-oxoandrosta-l,4diene-17g-carbothioic acid (XXXVII) A stirred solution of 9a-fluoro-llg,17a-dihydroxy16g-methyl-3-oxoandrosta-l,4-diene-17g-carboxylic acid (0.502 g) in dry Ν,Ν-dimethylformamide (15 ml) was cooled at -5° under nitrogen and treated with Ν,Ν'-carbonyldiimidazole (0.435 g) and the reaction was stirred at -5° for 18 h. Hydrogen sulphide gas was bubbled into the reaction for 20 min and the solution was stirred for a further 4 h, gradually being allowed to warm to 22°. The reaction was poured into ethyl acetate and the resulting solution was washed with 2Nhydrochloric acid and water, then extracted with 2N-sodium carbonate solution (3 x 50 ml). The combined extracts were washed with ethyl acetate (60 ml) then covered with further ethyl acetate (100 ml) and acidified with hydrochloric acid to pH 1.0. The aqueous layer was extracted with further ethyl acetate and the extracts were washed with water and saturated sodium chloride solution, then dried and the solvent was removed in vacuo to give a white solid which was crystallised twice from ethyl acetate to give the title carbothiolc acid (0.315 g) m.p. 198 - 201° (dec), [a)D+189° (c 0.71). - 34 Example XXXVIII 9a-Fluoro-17a-hydroxy-16B-methyl-3,ll-dioxoandrosta-l,4diene-17g-carbothloic acid (XXXVIII, A stirred solution of G (5.587 g) in dry N,N-di5 methylformamide (150 ml) at 20° under nitrogen was treated with Ν,Ν'-carbonyldiimidazole (4.847 g) and the reaction was stirred at 20° for 4 h. Hydrogen sulphide gas was bubbled into the reaction for 10 min and the solution was stirred for a further hour. The solution was poured onto ice (300 ml) and 2N-hydrochloric acid (100 ml) to give a buff precipitate. This was filtered off, air-dried overnight (6.268 g) and crystallised fran ethyl acetate to give the title carbothioic acid (3.761 g) as white prisms, m.p. 215 - 218°, [e]p +143° (c 0.88, dimethylformamide).

Example XXXIX 9a-Fluoro-17tt-hydroxy-16g-methyl-3,ll-dioxoandrosta-l,4diene-178-carbothiolc acid (XXXIX) A stirred solution of G (1.059 g) in dry Ν,Ν-dimethylformamide (50 ml) at 20° under nitrogen was treated with Ν,Ν'-thiocarbonyldiimldazole (1.368 g) and the reaction was stirred at 20° for 4 h. Hydrogen sulphide gas was bubbled into the reaction for 5 min and the solution was stirred for a further hour. The reaction 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 was 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 pHl. The aqueous layer was extracted with further 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 crystallised from ethyl acetate to give the title carbothioic acid (0.559), m.p. 212 - 219°, [α]β +145° (c 0.81, dimethylformamide). - 35 Example XL S-Chloromethyl 9a-fluoro-ΙΙβ,17a-dihydroxy-16β-methy1-3oxoandrosta-l ,4-diene-17g-carbothioate (XL) A stirred solution ofXXXVH (0.169 g) and sodium hydrogen carbonate (0.040 g) in Ν,Ν-dimethylformamide (6 ml) was treated with bromochloromethane (0.1 ml) and stirring was continued at 22° for 1 h. The reaction mixture was diluted with ethyl acetate (100 ml) and the solution was successively washed with 2N-hydrochloric acid, water, 2N-sodium carbonate solution, water and saturated sodium chloride solution, then dried and the solvent was removed in vacuo. The residue was crystallised twice from ethyl acetate to give the title S-chloromethylthiolester (0.193 g) as white plates solvated with ethyl acetate (1 mol), m.p. 126 - 130°, [α]θ +147.5° (c 0.64).

Example XLI 9a-Fluoro-16B-methyl-3,ll-dloxo-17ct-propionyloxyandrostal,4-diene-17g-carbothioic acid (XLI) A stirred solution ofXXXVOTp.485 g) and triethylamine (0.57 ml) in dichloromethane was cooled in ice-salt, treated with propionyl chloride (0.43 ml) and the reaction was stirred at 0° for 1.5 h. The mixture was partitioned between ethyl acetate (75 ml) and 2N-sodium carbonate solution (75 ml) and the organic layer was successively used with further 2N-sodium carbonate solution, water, 2N-hydrochloric acid, water, and saturated sodium chloride solution, then dried and the solvent removed in vacuo to give a yellow crystalline solid (0.562 g). This was dissolved in acetone (10 ml), diethylamine (1.0 ml) was added and the reaction was stirred at 22° for 1.25 h. The solvents were removed in vacuo and the residue was 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 - 36 hydrochloric acid. The ethyl acetate layer was washed with water and saturated sodium chloride solution, then dried and the solvent was removed In vacuo to give a white solid which was crystallised twice from ethyl acetate to give the title ester (0.290 g), m.p. 173 " 180°, [α]θ+148° (c 1.03).

Exanple XLII S-Chloromethyl 9ct-fluoro-17ct-hydroxy-16g-methy 1-3,11dioxoandrosta-1,4-diene-17g-carbothioate (XLII) A solution of XXXVIII(5.006 g), and sodium bicarbonate (1.612 g) in Ν,Ν-dimethylacetamide (50 ml) was treated with bromochloromethane (1.24 ml) and the reaction was stirred at 22° for 3.3 h. The solution was diluted with ethyl acetate (70 ml) and washed successively with 2N-hydrochloric acid, water, sodium metabisulphite solution, water and saturated sodium chloride solution, then dried and the solvent was removed in vacuo to give a cream solid (3.638 g).

The analytical sample was obtained after preparative t.l.c. (silica gel, developed with chloroform’.acetone = 9.1), and crystallised from ethyl acetate as colourless prisms of the title ester (0.262 g), m.p. 223 - 228°, [α]β +251° (c 1.2).’ Example XLIII ga-Fluoro-lIB-hydroxy-ieg-methyl-S-oxo-lIa-proplonyloxyandrosta-l,4-dlene-17g-carbothlolc acid (XLIII) A stirred solution ofXXXVII (0.511 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 was stirred at 2° for 2.5 h. The reaction was partitioned between ethyl acetate and sodium hydrogen carbonate and the organic phase was washed with water, 2N-hydrochloric acid, water and saturated sodium chloride solution, dried and the solvent removed in vacuo to give a colourless solid (0.634 g,. This was dissolved in acetone (30 ml), at 22° for 55 min. The reaction was diluted with ethyl acetate (50 ml) and was washed with 2N-hydrochloric acid and water then - 37 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 solu5 tion and dried and the solvent removed to give a colourless froth (0.522 g) which was crystallised from ethyl acetate to give the title ester as colourless prisms (0.307 g) m.p. 174 - 179°, [a]Q +107 °(c 1.0).

Example XLIV 9α-ηυοΓθ-11β,17a-dihydroxy-16-methylene-3-oxoandrosta-l,4diene-178-carbothioic acid (XLIV) A solution of 9ot-fluoro-118,17o-dihydroxy-16methylene-3-oxoandrosta-l,4-diene-178-carboxylic acid (0.218 g) in dry Ν,Ν-dimethylformamide (10 ml) at 22° under nitrogen was treated with N,Ν'-carbonyldiimidazole (0.254 g) and the reaction was stirred at 22° for 4 h. Hydrogen sulphide gas was bubbled into the reaction for 5 min and the mixture, now pale green, was stirred for 1 h at 22°. The mixture was diluted with ethyl acetate (150 ml) and the solu tion was washed with 2N-hydrochloric acid, water and saturated sodium chloride solution, dried and the solvent removed in vacuo to give a yellow froth (0.222 g) which was crystallised twice from ethyl acetate to give the title carbothioic acid (0.078 g) as white prisms, decomposed at ca. 250° with25 out melting, [a]Q +117° (c 0.32). - 38 Example XLV 9ct-Fluoro-llg , 17a-dihydroxy-3-oxoandrosta-1,4-diene- 17βcarbothioic acid (XLV) A solution of 9a-fluoro-ΙΙβ,17a-dihydroxy-3-oxoandrosta-1,4-diene-17g-carboxylic acid (4.5 g) in dry dimethylformamide (100 ml) was stirred under nitrogen with Ν,Ν'-carbonyldiimidazole (4.04 g) at 22°C for 4 h. Hydrogen sulphide was then passed through the solution for 30 min and then kept for a further 15 min. The mixture was poured into a mixture of 2N-hydrochloric acid (250 ml) and ice (ca 100 g) and the resulting precipitate was collected, washed with water and dried to give a white solid (4.56 g). A portion (120 mg) was recrystallised from ethanol to give the title thloacid as colourless crystals (70 mg), m.p. 222 - 225°, [a]D +116° (c 0.57).

Example XLVI 6α,9a-Dlliuoro-llg,17a-dihydroxy-16a-methyl-3-oxoandrostal,4-diene-17g-carbothlolc acid (XLVI) A solution of 6a ,9a-difluoro-llg,17a-dihydroxy-16amethy1-3-oxoandrosta-l,4-diene-17g-carboxylic acid (12.0 g) in dry dimethylformamide (250 ml) was stirred and treated with N,N'-carbonyldiimidazole (9.94 g) under nitrogen at room temperature. After 4 h, hydrogen sulphide was passed through the solution for 0.5 h and the mixture was kept for a further 0.5 h. The reaction mixture was poured into 2Nhydrochloric 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 (11.47 g,, m.p. 230 - 232°, [αίθ +94° (c 0.91).

Example XLVII 17a-Acetoxy-6a,9a-dlfluoro-llB-hydroxy-16a-methy1-3-oxoandrosta-l, 4-dlene-17g-carbothioic acid (XLVII) A solution of XLVI (1.625 g) and triethylamine (2.0 ml) in dichloromethane (75 ml) was stirred at ca 0°C, treated dropwise with acetyl chloride (1.275 ml), then stirred at this temperature for 1.25 h. The mixture was washed with - 39 2N-sodium carbonate (50 ml), water, 2N-hydrochloric acid (50 ml), water (3 x 50 ml), brine (50 ml), then dried and evaporated to a white solid (1.91 g). This was dissolved in acetone (40 ml) and stirred with diethylamine (4 ml) at 27°C for 45 min. The mixture was concentrated to ca 25 ml and poured into 2N-hydrochloric acid (100 ml) containing ice (ca 100 g): after being stirred the resulting precipitate was collected, washed with water and dried to give a solid (1.685 g). A portion (400 mg) was recrystallised from ethyl acetate to give the title 17ot-acetate (280 mg), m.p. 175 177°.

Example XLVIII 17a-Butyryloxy-6a,9a-difluoro-llg-hydroxy-16a-methy1-3-oxoandrosta-l,4-diene-17B-carbothioic acid (XLVIII) Using a similar procedure to that described in Example XLVII, XLVI (2.0 g) was converted, with butyryl chloride (1.5 ml) instead of acetyl chloride, to the title 17g-butvrate (2.08 g). A portion recrystallised from ethyl acetate had m.p. 155 - 157°.

Example XLIX 9a-Fluoro-llB-hydroxy-3-oxo-17g-propionyloxyandrosta-l,4diene-17g-carbothioic acid (XLIX) Using a similar procedure to that described in Example XLVII, XLVI (3.8 g) was converted, using propionyl 25 chloride (3.9 ml) instead of acetyl chloride and after aminolysis of the intermediate with diethylamine (10.35 ml), into the title 17g-propionate (4.17 g). A portion (350 mg) recrystallised from ethyl acetate gave colourless crystals (165 mg), m.p. 135 - 138°, [α]β +72° (c 0.92).

Example L 6a,9a-Difluoro-llg-hydroxy-16a-methyl-3-oxo-I7a-propionyloxyandrosta-l,4-diene-17g-carbothioic acid (L) A solution of XLVI(5.0 g) and triethylamine (6.15 ml) in dichloromethane (140 ml) was cooled with ice-salt and 35 treated dropwise with propionyl chloride (4.74 ml). The reaction mixture was stirred further at ca 0°C for 0.75 h 5139S - 40 then washed successively with 2N-sodium carbonate, water, 2N-hydrochloric acid, water and brine. After being dried, solvent was removed to give a white solid (6.35 g). This was redissolved in acetone (120 ml) and diethylamine (12.5 ml): after being stirred at room temperature for 1 h the volume was reduced to ca 75 ml. The solution was poured into 2N-hydrochloric acid (200 ml) containing ice (ca 300g) and the resulting precipitate was collected, washed with water and dried in vacuo to a white solid (5.17 g) m.p. 152155°. Recrystallisation of a portion (400 mg) from ethyl acetate gave the analytically pure title thloacid 17aproplonate as colourless crystals (290 mg), m.p. 161 - 164°, [a)D -27° (c 0.95), whose solid-state infrared spectrum (in Nujol) shewed a different crystalline form from the sample obtained in Example XV.

Example LI S-Chloromethyl 9a-fluoro-166-methyl-3,ll-dioxo-17aproplonyloxyandrosta-1,4-dlene-17g-carbothioate (LI ) A solution of XLH (409 mg) in propionic acid (5 ml), trifluoroacetic anhydride (2 ml) and toluene p-sulphonic acid (0.1 ml of dry chloroform solution, 80 mg/ml) was stirred at 22°C for 2.75 days. The non-acidic product was isolated by extraction with ethyl acetate after being poured into saturated sodium hydrogen carbonate. The crude material was chromatographed on silica in chloroform-acetone (14:1) and crystallised from ethyl acetate-petrol (b,p.60-80°C) to give the title 17a-propionate as colourless crystals, m.p. 205-206°, [α]θ +95° (c 1.15), Example LII S-chloromethyl 9a-fluoro-HB, 17a-dihydroxy-16g-methyl-3oxoandrosta-1,4-diene-17B-carbothioate (LII) A suspension of XLII (102 mg) in ethanol (2.5 ml) was stirred with sodium borohydride (10 mg) at 22°C for 1 h.

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 being dried the organic solvent was - 41 removed to give the title HB-alcohol as a colourless foam (103 mg) whose sole major component was equipolar with an authentic specimen on t.l.c. comparison (silica, chloroformacetone, 9:1).

Example LIII 9a-Fluoro-llB-hydroxy-I6g-methyl-3-oxo-17a-propionyloxyandrosta-l,4-diene-17B~carbothioic acid (iJii) Method A A solution of 9a-fluoro-Ιΐβ-hydroxy-16B~methy1-3-oxo10 17a-propionyloxyandrosta-l,4-diene-178-carboxylic acid (603 mg, 0.75 mol ethyl acetate solvate) and Ν,Ν'-carbonyldi(1,2,4-triazole) (0.997 mg) in dry dimethylformamide (45 ml) was stirred under nitrogen at ca 22°C for 18.5 h.

A solution (15 ml) prepared from sodium hydride (305 mg) in dimethylformamide by saturating with hydrogen sulphide, was added and stirring was continued at ambient 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 back extracted with 5% sodium carbonate solution : the alkaline extracts were acidified with hydrochloric acid and extracted with ethyl acetate (3x). After being washed with water and brine the organic extracts were dried and concentrated to low volume: the title thioacid separated as cream crystals (101 mg), whose sole major component was identified by comparison with an authentic specimen by XH nmr and by t.l.c. (silica, chloroform-acetone 4:1).

Method B > A solution of 9o-fluoro-118-hydroxy-168-methyl-3-oxo17a-propionyloxyandrosta-l,4-diene-178-carboxylic acid (701 mg, 0.75 mol ethyl acetate solvate) and N,N'-carbonyldiimidazole (473 mg) in dry dimethylformamide (26 mg) was stirred under nitrogen at ca 22°C for 19.5 h., then treated with a solution (10 ml) of sodium hydride (60% dispersion in oil, 233 mg) in dimethylformamide (10 ml) saturated with hydrogen sulphide. The resulting mixture was then stirred 51398 - 42 «♦λΜΜ·' at ambient temperature for 5.5 h. The reaction mixture was diluted with ethyl acetate (100ml) and washed with 2N-hydi-cj" chloric acid, water and brine, then dried and evaporated to a froth (186 mg). The title thioacid was shown to be the major component in the product by nmr and by t.l.c. (silica, chloroform-acetone [4:1], and chloroform-acetoneacetic acid [30:8:1]) comparison with an authentic specimen. Method C In an almost identical reaction to that described in 10 Method A the carboxylic acid was treated with l,l'-carbonyldibenzotriazole (1.587 g) instead of Ν,Ν’-carbonyldi(1,2,4triazole), at room temperature for 6 h. After the addition of the solution obtained from hydrogen sulphide and sodium hydride in dimethylformamide, reaction was continued for 41.5 h. The crude product was obtained as a foam; t.l.c. (silica, chloroform-acetone, 4:1; and chloroform-acetoneacetic acid 30:8:1) showed the title thioacid was present as a major component by comparison with an authentic specimen. Example LIV S-Chloromethyl 6a,9a-difluoro-16a-methyl-3-oxo-17aproplonyloxy-118-trlfluoroacetoxyandrosta-1,4-diene-178carbothioate (LIV) A solution of S-chloromethyl 6a,9a-difluoro-118hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-l,425 diene-17B-carbothioate (see Example 5 of our copending British Patent Application No. 8104496 (Serial No, 2,088,877)) (100 mg) in dry tetrahydrofuran (2ml) and pyridine (0.1ml) was treated with trifluoroacetic anhydride (0.05 ml) and the mixture was kept at room temperature for 0.5 h. 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 homogenous title trlfluoroacetate (116 mg) according to nmr spectroscopy (singlet at 8.59t, 19-protons, in deuterio35 chloroform) and t.l.c. on silica (acetone-petrol, b.p. 40-60 C, 1:3). An analytical sample frcm ether-pentane had m.p. 158-162°, [α]β +56° (c 0.23).

Claims (31)

1. Compounds of the general formula (II) [wherein R a represents a thiocarbamoyloxycacbonyl S group -COOCSNR A R B (where R A and R B , which may be a the same or different, are alkyl groups or R and o R together with the nitrogen atom to which they are attached form a 5-8 membered ring which may optionally contain an additional hetero atom selected lo from oxygen, nitrogen and sulphur and/or which may be optionally substituted by one or two C, , alkyl Τ'/ J groups) or a group of the formula -COSR (where R 1A represents a hydrogen atom or is a group as defined below for R 1 or is the group -(CH 2 > n Y in which n IS is 1 or 2 and Y represents a displaceable substituent) and R b represents an esterified hydroxyl group or R b and R c together represent an isopropylidenedioxy group; or where R a represents a group COSR 1A , R b is optionally a hydroxyl group; R C represents a hydrogen atom, a methyl group (which may be in either the a- or 0-configuration, or a methylene group; - 44 R^ represents a hydroxy or protected hydroxy group (in either the n- ot β-configuration) or an oxo group; R e represents a hydrogen, bromine, chlorine ¢3 θ 5 or fluorine atom; or R and R together represent a carbon-carbon bond or an epoxy group in the β-configuration; l/ represents a hydrogen or a fluorine atom; and the symbol -m-r-r-r represents a single or double IQ bond] and salts of those compounds which have a free carbothioic acid group; with the exclusion of compounds of the formula:- wherein R 1 represents a fluoro-, chloro- or bromo2 15 methyl group or a 2'-fluoroethyl group, R represents 6 6 2 a group COR where R is a C, , alkyl group or OR and R together form a 16a,17a-isopropylidenedioxy group; R 2 represents a hydrogen atom, a methyl group (which may be in either the a- or β-configuration) 3.0 or a methylene group; R^ represents a hydrogen, chlorine or fluorine atom; R 2 represents a hydrogen or fluorine atom and the symbol mm represents a single or double bond.

2. Compounds as claimed in claim i wherein R a 35 represents -COSH and R b represents a hydroxy group. - 45 ΙΑ

3. Compounds as claimed in claim 1 wherein R represents a chloromethyl or fluoromethyl group.

4. Compounds as claimed in claim 1 wherein R b represents an acetoxy or propionyloxy group. S

5. Compounds as claimed in claim 4 wherein R b represents a propionyloxy group.

6. Compounds as claimed in any one of the preceding claims wherein R e represents a fluorine atom.

7. Compounds as claimed in any one of the preceding io claims wherein R f represents a fluorine atom.

8. Compounds as claimed in any one of the preceding claims which are 1,4-dienes.

9. Compounds as claimed in claim 8 wherein R represents a fluorine atom and R C represents a hydrogen IS atom, or an a- or β-methyl or methylene group. IA

10. Compounds as claimed in claim 8 wherein R θ represents a chloro- or fluoro-methyl group and R and each represents a fluorine atom.

11. Compounds as claimed in claim 10 wherein R □.o represents an α-methyl group.

12. Compounds as claimed in any one of claims 1 to 5, 7 d e and 8 wherein R and R together represent an epoxy group.

13. Compounds as claimed in claim 1 in which R a 3-S represents -COSH, R b represents a hydroxyl group, R c represents a hydrogen atom, an a- or β-methyl group or a methylene group, R e represents a hydrogen, chlorine or fluorine atom, and R d represents a hydroxyl group in the β-configuration or an oxo group.

14. Compounds as claimed in claim 2 wherein R c represents a methyl group in the a- orβ-configuration or a methylene group; R e represents a fluorine atom, R d represents a hydroxy group in the β-configuration or an oxo group and the symbol π .-..- in the 1,2is position represents a carbon-carbon double bond. 51398 -4615. 9a-Fluoro-lie,17a-dihydroxy-168-methy1-3-oxoandrosta-l, 4-diene-17B-carbothioic acid and the salts thereof.

15. 16. 9a-Fluoro-17a-hydroxy-168-methyl-3,11-dioxoand5 rosta-1,4-diene-17B-carbothioic acid and the salts thereof.

16. 17. 9a-Fluoro-116,17a-dihydroxy-16a-methyl -3-oxoandrosta-l,4-diene-17B-carbothioic acid and the salts thereof.

17. 18. 9a-Fluoro-17a-hydroxy-16a-methyl-3,11-dioxoand»O rosta-1,4-diene-17B-cacbothioic acid and the salts thereof.

18. 19. 9o-Fluoro-llB,17a-dihydroxy-16-methylene-3oxoandrosta-1,4-diene-17B-carbothioic acid and the salts thereof and

19. 20. 9a-Fluoro-17e-hydroxy-16-methylene-3,11-dioxo16 androsta-1,4-diene-17B-carbothioic acid and the salts thereof

20. 21. 6a,9a-Difluoro-116,17o-dihydroxy-16a-methyl3-oxoandrosta-l,4-diene-17B-carbothioic acid and the salts thereof.

21. 22. •6a,9a-Difluoco-17a-hydroxy-16a-methyl-3 ,11lo dioxoandrosta-1,4-diene-17B-carbothioic acid and the salts thereof.

22. 23. A process for the preparation of compounds as claimed in claim 1 carrying a free -COSH group in the 17B-position wherein a compound as claimed 'X in claim 1 carrying a thiocarbamoyloxycarbonyl group in the 17B-position is subjected to aminolysis with rearrangement.

23. 24. A process for the preparation of compounds as claimed in claim 1 carrying a 16-methylene group and a free -COSH group in the 178-position wherein a compound corresponding to formula II as claimed in claim 1 carrying a 16P-methyl and a 16α,17a-epoxy group but having a 17g-carboxyl group or a salt thereof is reacted with an onium salt of a 2haloaza-aromatic compound followed by hydrogen sulphide and 35 the 16^-methyl-l6o,l7a-epoxy 17f-thiooarboxylic acid product thus obtained is subjected to rearrangement with a strong acid followed, if desired, by esterification of the 17 513 9 3' -4725. A process for the preparation of compounds as claimed in claim 1 carrying a 16o(,1 -isopropylidenedioxy group and a free -COSH group in the 17β-position wherein a compound corresponding to formula II as claimed in claim 1 carrying S' a 1 6

24. 26. A process for the preparation of compounds Ό as claimed in claim 1 carrying a free -COSH group in the 178-position wherein a compound corresponding tb formula II as claimed in claim 1 in which R is a hydroxy group but carrying at the 178-position 7 . 7 a group -COR in which R represents Y= X IS the group -N | (in which X, Y and Z, which may be the same or different each represent CH or N, one or two of X, Y and Z being N, the heterocyclic ring optionally being substituted on at least one carbon atom by a C^_ 4 alkyl group and/or where 2o the heterocyclic ring contains two adjacent carbon atoms, the said ring optionally carrying a benzene ring fused to the said adjacent carbon atoms) is reacted with hydrogen sulphide or a sulphide or hydrosulphide salt thereof. OS 27. A process as claimed in claim 26 wherein the said compound corresponding to formula II but carrying the group -COR 9 at the 178 - position is first prepared by reaction of a compound corresponding to formula II but carrying a carboxylic acid group at the 178 3o - position with a symmetric or asymmetric compound of the formula: R 7 - W - R 7 m wherein W represents the group CO, CS, SO or SO, and the groups R , which may be the same or different, 3>S are as defined in claim 26. 5139 - 48 23. A process according to claim 27 wherein a compound of formula III is used in which W represents the group CO,CS or SO.

25. 29. A process according to claim 28 wherein the S' compound of formula III used is Ν,Ν'-carbonyldi (1,2,4triazole), N,N’-carbonyldibenzotriazole, Ν,Ν'-carbonyldibenzimidazole, Ν,Ν'-carbonyldi(3,5-dimethylpyrazole), Ν,Η'-thiocarbonyldiimidazole or Ν,Ν'-thionyldiimidazole.

26. 30. A process according to claim 28 wherein the io compound of formula III used is N,N'carbonyldiimidazole

27. 31 . A process according to claim 27 wherein reaction of a compound corresponding to a compound of formula II, but carrying a 17B-carboxylic acid group with a compound of formula III is followed in situ by reaction '5 of the compound corresponding to formula II,but carrying the group -COR 7 at the 17B-position,thus obtained, with hydrogen sulphide or a sulphide or hydrosulpbide salt without isolation of the compound corresponding to formula II, but carrying the group -COR 7 at the 2.0 176-position.

28. 32. a process for the preparation of a compound I. of formula II wherein R represents a hydroxy group and R a represents the group-COSR 1 in which R 1 is as defined in claim 1 which comprises esterifying -15 a'·compound of formula II in which R b represents a hydroxy group and R a represents the group -COSH.

29. 33. A process for the preparation of a compound of formula II wherein R a represents the group -COSH and R b represents an esterified hydroxyl group which 3o comprises esterifying a compound of formula II in which R b represents a hydroxy group and R a represents the group -COSH. - 49

30. 34, A process for preparing a compound as defined in claim 1, substantially as described with reference to the Examples.

31. 35. A compound whenever prepared by a process as claimed 5 in any one of claims 24 to 34.