SK278140B6 - Androstane carbothioates and pharmaceutical agents containing thereof - Google Patents

Abstract

Androstane carbothioates of general formula I, where R1 means flouro-, -chloro- or brommethyl group or 2'-fluoroethyl group, R2 means group COR6 where R6 means C1-3 alkyl group or OR2 and R3 together created the 16 alpha 17 alpha-isopropylidendioxy group, R3 means hydrogen atom, methyl group, which can be either in alpha or in beta position or ethylene group, R4 means hydrogen atom, chloro of fluoro, R5 means hydrogen atom or fluor and symbol === means simple bond next there are described pharmaceutical agents with contents of these matters.

Description

Technical field

The invention relates to androstane-derived anti-inflammatory steroids and pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

Anti-inflammatory steroids are the most typical corticoids, i. pregnane derivatives. United Kingdom patent no. 1384372, 1438940 and 1514476 disclose esters of a particular androstane 17β-carboxylic acid having anti-inflammatory activity. European patent application no. No. 79300500.0 (Publication No. 0004741) discloses androstane 17β-carbothioic acid esters also having anti-inflammatory activity. It has now been found that certain androstane compounds containing a haloalkyl carbothioate group at the 17β position have particularly advantageous anti-inflammatory properties, as described in more detail below.

SUMMARY OF THE INVENTION

The novel androstane compounds are represented by the formula

wherein R ¹ is fluoro, chloro or bromomethyl or 2'-fluoroethyl; R ² represents a COR ⁶ group, where R ⁶ represents a C 1-6 alkyl group or OR ² and R ³ together form a 16α, 17α-isopropylidenedioxy group; R ³ is hydrogen, methyl, which may be the FA, and the β-position, or a methylene group; R ⁴ is H, Cl or F; R ⁵ represents a hydrogen or fluorine atom and the symbol .....

means a single bond.

The novel compounds of formula (I) have good anti-inflammatory activity, especially when administered topically, as demonstrated by McKenzie using patch tests, and as measured by croton oil swelling reduction when the compound was administered topically to the skin of mice and rats.

Certain compounds show good local anti-inflammatory activity in the irritation of the ear with croton oil, and the reaction is associated with minimal suppression of hypolalainopituitary-adrenal activity when administered topically in the same animal. These results show that such compounds are of great value in the topical treatment of inflammation in humans and animals with minimal incidence of adverse side effects.

Compounds of formula (I) which are preferred for their good anti-inflammatory activity include the following categories, namely a) those in which R ^{1 is} chloro- or fluoromethyl, b) those in which R ^{2 is} acetyl or propionyl, more preferably propionyl, (c) those in which R ^{4 is} fluorine;

d) those in which R ^{5 is} fluorine, e) 1,4-dienes, f) those 1,4-dienes in which R ⁴ is fluorine and R ³ is hydrogen, or β-methyl or methylene.

Compounds of formula (I) having good anti-inflammatory activity associated with minimal suppression of hypothalamo-pituitamo-adrenal activity when topically administered include 1,4-dienes wherein R ^{1 is} chloro or fluoromethyl, R ⁴ and R ⁵ are fluoro and especially those in which R ^{3 is} α-methyl.

Preferred compounds of the invention, in view of good local anti-inflammatory activity and favorable ratio of local anti-inflammatory activity to adverse events, are:

S-chloromethyl-9α-fluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-3β-thiophenol,

S-chloromethyl-9α-fluoro-11β-4β-16-π-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate,

S-fluoromethyl-6α, 9α-difluoro-11β-hydroxy-16α, 17β-isopropylidenedioxy-3-oxoandrost-1,4-diene-4-carbothioate,

S-fluoromethyl-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate,

S-fluoromethyl-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate.

The latter compound is particularly advantageous with respect to causing minimal skin atrophy.

The compounds of formula (I) may be prepared by a variety of procedures.

One such process involves the esterification of an androstane compound corresponding to formula (I) but containing a free 17β-carbothioic acid group or a functionally equivalent or free 17α-hydroxy group, R ³ is a hydrogen atom or a methyl or methylene group, other groups present in the molecule, are suitably protected as required.

For example, a salt of the original β-carbothioic acid such as an alkali metal, for example lithium, sodium or potassium, a salt or an alkylammonium, i.e. triethylammonium or tetrabutylammonium, salt may be reacted with an appropriate alkylating agent, most preferably in a polar solvent such as ketone, e.g. , dimethylacetamide or hexamethylphosphoramide, a suitable temperature is from 15 to 100 ° C. The alkylating agent may contain an appropriate dihalogen compound, ie one containing a halogen atom (bromine or iodine) in addition to the halogen atom of the desired R ¹ group. This process is particularly useful in the preparation of compounds in which R 1 is a chloromethyl group and the alkylating agent is bromochloromethane.

Alternatively, the original 16-hydrogen, methyl or methylene-17α-hydroxy-17β-carbothioate corresponding to the compound of formula (I) may be esterified at the 17α-hydroxy group. This may be accomplished by suitable techniques, for example by reacting the original 17α-hydroxy compound with a mixed anhydride of the desired carboxylic acid, which may be obtained, for example, by in situ reaction of the carboxylic acid with an appropriate anhydride such as trifluoroacetate, preferably in the presence of an acid catalyst such as ptoluenesulfonic acid. or sulfosalicyl. Advantageously, the mixed anhydride in situ may be obtained by reacting a symmetrical anhydride of the desired acid with a corresponding other acid, for example trifluoroacetyl.

SK 278140 with acid.

The reaction is conveniently carried out in an organic solvent such as benzene, methylene chloride or an excess of carboxylic acid. A suitable reaction is at 20 to 100 ° C.

Alternatively, the 17? -Hydroxy group can be esterified with the original 17? -Hydroxy compound with the appropriate acid anhydride or acid chloride, if desired, in the presence of solvents such as chloroform or methylene chloride or benzene, most preferably in the presence of a strong acid catalyst such as perchloric, p-toluenesulfonic acid. acid or in the presence of Amberlite IR 120 (the word Amberlite is a registered trademark). A suitable temperature for the reaction is from 23 to 100 ° C.

Compounds of formula (I) may also be prepared by reacting an appropriate androstane compound containing a 17β-substituent of the formula -COS / CH 2 X, Y (Y represents a translatable substituent and n is 1 or 2) with a compound serving to transfer the Y group through a halogen atom.

Thus, the compounds of formula (I) may be subjected to a halogen exchange reaction to displace the Y group. Thus, the bromomethyl, fluoromethyl and fluoroethyl 17β-carbothioate compounds may be prepared from the corresponding iodomethyl or bromomethyl-17β-carbothioate compounds using bromomethyl 17β-carbothioate compounds. corresponding fluorides, for example silver monofluoride or silver difluoride in the case of fluoromethyl or fluoromethyl-17β-carbothioate compounds. Initial iodomethyl-17β-carbothioate compounds can be prepared from the corresponding chloromethyl-17β-carbothioate compounds using, for example, alkali metals, alkaline earth metals or quaternary ammonium iodide such as sodium iodide.

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

The foregoing reactions may also be carried out with starting materials having a series of substituents and groups that are progressively converted to those substituents or groups present in the compounds of the invention.

The β-hydroxy compounds of formula (I) can also be prepared by reduction of the corresponding 11-oxo compounds, for example using alkali metals or alkaline earth metal borohydrides, for example sodium or calcium borohydride, preferably in an alcoholic or aqueous alcoholic solvent such as methanol or ethanol.

The 11-keto compound can be prepared by oxidation of the corresponding 1α-hydroxysteroid, for example using a chromic acid reagent, for example Jones reagent.

A β-hydroxy compound of formula (I) can also be obtained by deprotection of the corresponding compound having a protected hydroxyl group at the 11 β-position, for example a triC 1-6 alkylsilyloxy group such as trimethylsilyloxy or perfluoro or chloroalkanoyloxy group such as trifluoroacetoxy. Removal of the protected group may be due to hydrolysis, the trialkylsilyl group is readily removable by slightly acidic or basic hydrolysis, or particularly preferably using a fluoride, for example a hydrofluoride or ammonium fluoride. The perfluoro- or chloroalkanoyl protecting group may also be displaced by a slightly acidic or basic hydrolysis or alcoholysis, but preferably under acidic conditions when R ⁴ is a chlorine atom. Such a protected hydroxyl group may be introduced, for example, by reacting 11β-hydroxysteroid with an appropriate reagent such as a trialkylsilyl halide or perfluoro or chloroalkanoid anhydride.

Compounds of formula (I) may also be prepared by reacting an appropriate compound having a 9,11-double bond (and no substituent at position 11) with a reagent to bind the desired 9α-halo-lip-hydroxy group. This may include the initial formation of bromohydrin by reaction with an N-bromamide or an -imide such as N-bromosuccinimide followed by formation of the corresponding 9β, 11β-epoxide by treatment with a base and reaction of the epoxide with hydrofluoride or hydrochloride. Alternatively, the 9,11-olefin compound can be reacted with N-chloramide or -imide to attach the desired 9α-chloro-1β-hydroxy group directly.

Compounds Δ ⁴ with respect to the invention may conveniently be prepared by partial reduction of the corresponding ^,1,4- compound, for example by hydrogenation using a palladium catalyst, the aqueous solution being, for example, ethyl acetate, or by homogeneous hydrogenation using triphenylphosphonium sodium, preferably in a solution such as ethanol, most preferably at reflux. This reaction may be carried out on a haloalkyl ester which is sufficiently stable here or may be carried out in a previous step.

The above-mentioned compounds containing a free -COSH group at the 17β position can be prepared, for example, by aminolysis by re-treatment of a suitable 17β-β-carbamoyloxycarbonylandrostane. 17β-thiocarbamoyloxycarbonylandrostane is a mixed anhydride corresponding to β-carboxylic acid and thiocarbamic acid and is prepared by reacting salts of 17β-carboxylic acid 17α-ester or 16α, 17α-acetonide with a thiocarbamoyl halide. The thiocarbamoyl group is Ν, Ν-disubstituted, and thus may have the formula -COOCSNR ^A R ^B , wherein R ^a and R ⁸ , which may be the same or different, are alkyl groups, for example C 1 -alkyl groups or R ^A and R ⁸ together with a nitrogen atom to which they are attached in the form of a 5- to 8-membered ring which has a non-binding heteroatom separated from oxygen, nitrogen or sulfur and / or which may be non-binding substituted with one or two C 1-6 alkyl, N, N-dimethylthiocarbamoyl . The thiocarbamoyl halide is the most preferred chloride. The reaction may be accelerated by the addition of an iodide salt, preferably sodium iodide.

The initiating androstane 17β-carboxylate salt may be, for example, an alkali metal, sodium or potassium, an alkaline earth metal, for example a calcium salt or a tertiary amine salt such as triethylamine.

Aminolysis with a new treatment can be accomplished, for example, by heating the mixed anhydride to an elevated temperature, for example in the presence of ammonia, a primary amine or more preferably a secondary amine such as diethylamine or pyrrolidine. Initially, it will be appropriate to substitute the β-carboxylic acids with R ³ or -OR ² at positions 16-and 17a relative to the resulting product of formula (I).

The 17α-hydroxyandrostane compounds in a series of 16-methylenes that contain the desired 17β-carbothioic acid as described can be prepared from the corresponding 1β-methyl-16α, 17α-epoxy-17β4-4 8Γ-boxylic acid by re-treatment with a strong acid such as a strong carboxylic acid, for example trifluoroacetic acid. These 16α, 17α-epoxides can be prepared from the corresponding β-carboxylic acids by treatment with the onium salt of the 2-halo-aza-aromatic compound. This is followed by treatment of the resulting product with a hydrosulfide or salt to give a free 17β-carbothioic acid which can be alkylated as described above, most preferably in situ to obtain the desired 173-carbothioate group.

The 16α, 17α-isopropylidenedioxy compounds of formula (I) may be prepared similarly by treatment of the corresponding β-carboxylic acid with the onium salt of the 2-halo-aza-aromatic compound. This is followed by treatment of the resulting product with a hydrosulfide to give 17β-carbothioic acid, which can then be esterified.

The onium salts of the 2-halo-aza-aromatic compounds are capable of causing carboxyl activation. Such reagents include 2-halo-N-alkyl or 2-halo-N-phenyl-pyridinium or pyrimidinium salts bearing 1 or 2 additional substituents selected from phenyl or lower, for example C 1-6 alkyl groups such as methyl. The 2-halogen atoms may be fluorine, chlorine, bromine or iodine atoms. Most preferred salts are sulfonates such as tosylates, halides such as iodidates; Fluoroborates β-β-perfluoroalkyl sulfonates, the preferred salt is 2-fluoro-N-methylpyridinium tosylate or 2-chloro-N-methylbenzothiazolium trifluoromethylsulfonate.

The 16a, 17α-epoxy-1-methyl-17β-carboxylic acid compounds used as starting materials in the above processes can be prepared under conventional conditions, such as those disclosed in British Patent Specification No. 5,940,549. 1,517,278.

The starting materials used in the processes described below to prepare compounds of formula (I) include compounds of formula (Π).

wherein R is a radical tíokarbamoyloxykarbonylovú -COOCSNR ^a R ^b wherein R ^A and R ^B are as defined above, or a group of formula -COSR ^IA, wherein R ⁱ is a hydrogen atom or a group for R ¹ or is a group convertible to R ^1, and R ^b is an esterified hydroxyl group or R ^b and R ^c together are isopropylidene-alkoxy or R * is COSR, R ^b is optionally a hydroxyl group.

R ^c represents a hydrogen atom, a methyl group, which may be in either the α or β configuration, or a methylene group.

R ^d is hydroxy or protected hydroxy, both in the α and β or oxo configuration.

R 'represents a hydrogen, bromine, chlorine or fluorine atom, or R ^d and R' together represent an inter-carbon bond of the β-β-epoxy group in the β-configuration.

R * represents a hydrogen or fluorine atom and the symbol ..... represents a single or double bond and salts of these compounds having a free carbothioic acid group, with the exception of the compounds of formula (I) as defined above.

Where R ^d represents a protected hydroxyl group, it may be, for example, a trialkylsilyloxy group or a perfluoro- or perchloroalkanoyloxy group as defined above.

Compounds of formula (H) as defined below and processes for their preparation are described and claimed in United Kingdom Patent Application Ser. 8,325,400th

17α-hydroxy-β-carbothioic acids of formula (Π) and their salts can be converted to 17α-hydroxy-17β-carbothioates of formula (H), wherein R * is COSR ¹ as defined in formula (I) or to 17a 4-Carbothioic acid esters of formula (Π) according to the procedure described above for the preparation of compounds of formula (I). The esterification of the 17α-hydroxy group is preferably carried out with an appropriate carboxylic acid chloride in a solvent such as a halogenated hydrocarbon such as dichloromethane and preferably in the presence of a base such as triethylamine, most preferably a low temperature such as 0 ° C.

17α-hydroxy-β-carbothioic acids of formula (H) and salts thereof are particularly preferred intermediates for the preparation of androstane 17β-carbothioates of formula (I), wherein R ^c represents a hydrogen atom or a methyl group or a methylene group, R ' is H, Cl or F, R ^d is hydroxy in the configuration or preferably an oxo group. More preferred compounds or salts thereof are those wherein R ^c is a methyl group in the α or β configuration or a methylene group, R ^e is a fluorine atom, R ^d is a hydroxy group in a β-configuration or an oxo group and the symbol ..... at position 1,2, a carbon-carbon double bond.

Thus, particularly preferred compounds of formula Π include, for example, the following compounds:

9α-Fluoro-11β, 17α-dihydroxy-16β-methyl-3-oxo-androst-1,4-diene-4-carboxylic acid, 9α-fluoro-11β, 17α-dihydroxy-16α-methyl 3-oxo-androst-1,4-diene-17β-carbothioic acid, 9α-fluoro-11β, 17α-dihydroxy-16-methylene-3-oxo-androst-1,4-diene-4-carbothioic acid, 6α, 9α-difluoro-11β, 17α-dihydroxy-16α-methyl-3-oxo-androst-1,4-diene-4-carbothioic acid and the corresponding 11-ketones and their salts.

The advantage of said intermediates is that they allow direct haloalkylation to yield haloalkyl-4-carbothioates when the corresponding R'SH thiols are not available. Salts of these 17α-hydroxy-17β-carbothioic acids can be, for example, alkali metals such as lithium, sodium or potassium salts, alkaline earth metals such as calcium or magnesium salts, tertiary amine salts such as pyridinium or triethylammonium salts or quaternary ammonium salts such as tetrabutylammonium salts.

For example, 17α-hydroxy-β-carbothioic acids can be prepared by reacting a reactive derivative from the corresponding 17α-hydroxy-β-carboxylic acid with a hydrosulfide, sulfide or hydrosulfide salt. Generally, the cation of the sulfide or hydrosulfide salt may be, for example, an alkali metal salt such as sodium or potassium hydrosulfide. The above reactive derivatives are identical to compounds of formula (H) wherein R ^b is a hydroxyl group and the -COR 'group is present at the 17β position in which R ⁷ is a group of the formula

wherein X, Y and Z, which may be the same or different, are CH or N, one or two of X, Y and Z are N, the heterocyclic ring is non-bindingly substituted with at least one carbon atom for a lower alkyl group (e.g. And / or wherein the heterocyclic ring contains 2 adjacent carbon atoms, the aforementioned ring non-bindingly carrying a benzene ring fused to these adjacent carbon atoms.

The aforementioned reactive derivatives corresponding to formula (Π) are preferably prepared by reacting 17α-hydroxy-17β-carboxylic acids of formula (Π) with a symmetric or asymmetric compound of formula:

R ⁷ - W - R ⁷ (ΠΙ) where W represents a CO, CS, SO or SO ₂ group and the groups R ⁷ , which may be the same or different, have the meaning given above.

The compounds of formula (ΙΠ) are suitably symmetrical. In general, compounds of formula (ΠΙ) in which W represents CO, CS or SO will be used. Particularly preferred compounds are: N, N'-carbonyldi (1,2,4-triazole), N, N'-carbonyldibenzotriazole, N, N'-carbonyldibenzimidazole, Ν, Ν'-carbonyldi (3,5-dimethylpyrazole), Ν, Ν'-thionyl diimidazole and in particular Ν, Ν'-carbonyldiimidazole and N, N'-thiocarbonyldiimidazole.

The preparation of 17α-hydroxy-17β-carbothioic acid having the formula (Π) as defined is conveniently accomplished by reacting 17α-hydroxy-17β-carboxylic acid with a compound of formula (H1) and then reacting an intermediate having a 17β-COR ⁷ group with a hydrosulfide or salt, preferably in situ without isolation of the intermediate.

17α-acyloxy-17β-carbothioic acid of formula (H) can be obtained under similar conditions directly from the corresponding 17α-acyloxy-17β-carboxylic acid by reaction with a compound of formula (H1). 17α-acyloxy-17β-carboxylic acids can be prepared by esterifying the corresponding 17α-hydroxy-17β-carboxylic acids according to the procedures described in BP 1,384,372.

The reaction with a compound of formula (H1) is carried out under suitable conditions in the presence of an inert anhydrous solvent, for example a substituted amide solvent such as Ν, Ν-dimethylphonamide or N, N-dimethylacetamide, preferably at room or lower temperature. such as room temperature, for example at -30 ° C to +30 ° C. It is preferred to carry out the reaction under approximately neutral conditions, preferably under inert gas conditions, for example nitrogen. The same solvents and the same sieve conditions can also be used for further reactions with H ₂ S or salts thereof. Heterocyclic compounds, for example imidazole or 1,2,4-triazole, formed as a by-product, can, for example, be easily removed by extraction with water.

The foregoing reactions can be carried out with compounds having a number of different substituents or groups and which are sequentially converted, as described above, to compounds of formula (I).

The starting androstanoic 17β-carboxylic acid compounds involved in the above processes can be prepared under conventional conditions, for example by oxidation of the corresponding 21-hydroxy-20-ketopregnane, for example periodic acid in a soluble medium and most preferably at room temperature. Preferably, sodium bismuthate can be used to oxidatively remove the carbon atom 21 from the 17α-acyloxypregnate compound. It would be preferred that the starting pregnane compound had no substituent sensitive to said oxidation, such a group should be suitably removed.

The following examples illustrate the invention.

Melting points were determined in a Kofler block and are not recalculated. The stereoisomerism was determined at room temperature on solutions in dioxane.

T.l.c. (thin layer chromatography), p.l.c. (preparative chromatography) and h.p.l.c. HPLC (high performance liquid chromatography) was performed on silica gel.

The solutions were dried with magnesium sulfate unless otherwise noted.

DETAILED DESCRIPTION OF THE INVENTION

Preparation

9α-Fluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioic acid (I)

A solution of 9α-fluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carboxylic acid (5.00 g) dissolved in ethyl acetate (0.5 mol) and triethylamine ( 5.3 mL) in dichloromethane (75 mL) was mixed under nitrogen and treated with dimethylthiocarbamoyl chloride (5.071 g). After 24 hours more reagents (5.320 g) were added. After 47 hours, the mixture was diluted with ethyl acetate and washed in 1 M hydrochloric acid, 5% sodium carbonate 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 under reflux under nitrogen for 5.75 hours. The resulting brown solution was added to a mixture of concentrated hydrochloric acid (50 mL), water (250 mL) and ethyl acetate (50 mL). The products were further extracted with ethyl acetate, and the acidic products were again extracted with 5% sodium carbonate solution. The aqueous phase was acidified with 6 M hydrochloric acid (50 mL) and extracted with ethyl acetate. The extracts were washed with 1 M hydrochloric acid and water, dried and evaporated to a pale yellow solid (3.440 g). This was recrystallized from acetone to pale yellow crystals (1.980 g) of the title 17B-carbothioic acid, mp 172-173 ° C.

An analytical sample was obtained after two crystallizations from acetone as white crystals, m.p. 177 DEG-179 DEG C., [.alpha.] _D + 110 DEG (C. 1.05).

Preparation H

S-chloromethyl-9α-fluoro-16α-methyl-3,11-dioxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate (H)

N Jones reagent (1.5 mL) was added dropwise over 10 minutes to a stirred solution of the compound of Example 1 (below) (998 mg) in acetone (2 mL) and dimethylformamide (2 mL). After 30 minutes, the reacting compound was slowly diluted with water (100 mL) with stirring, and the resulting suspension was frozen for 1 hour. The precipitate was collected by filtration, washed with water, and dried to a cream solid (877 mg). Thin-layer chromatography in chloroform-acetone (10: 1)

SK 278140-6 gave a white foam (755 mg) which was crystallized twice from acetone to white needles in the title 11-ketone (523 mg). Mp 204-205 ° C, α + ₀ + 94 ° (C. 1.04).

Preparation of βΠ 17β-N, N-dimethylthiocarbamoyloxycarbonyl-9α-fluoro-11β-hydroxy-16α-methyl-17α-propionyloxyandrost-1,4-dien-3-one (ΠΙ)

A solution of 9α-fluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carboxylic acid (0.434 g) in dichloromethane (8 mL) was treated sequentially with triethylamine (0.15 g). 14 ml), dimethylthiocarbamoyl chloride (0.246 g) and sodium iodide (0.149 g) were stirred under nitrogen at 20 ° C for 6 hours. Ethyl acetate (30 mL) was then added and the total volume was reduced to half vacuum. Additional ethyl acetate (50 mL) was added and the solution was washed with water, 2 M hydrochloric acid, water, 3% sodium bicarbonate, water and saturated sodium chloride, then dried. The solution was concentrated in vacuo when the product crystallized (0.329 g). This was recrystallized from acetone (2X) to give the title anhydride as white needles, mp 191-193 ° C, [α] _D + 82 ® (c 0.57).

Preparation IV 9α-Fluoro-11β-hydroxy-10α-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioic acid (IV)

A stirred suspension of (1 H) (2.467 g) in diethylamine (25 mL) was heated under reflux under nitrogen. After 3.5 hours, poured into ice-cold 3 M hydrochloric acid (300 mL) and extracted with ethyl acetate. The combined extracts were washed with water and extracted with 5% sodium carbonate solution. The combined aqueous extracts were washed with ethyl acetate, then covered with ethyl acetate and acidified to pH 1 with hydrochloric acid. The aqueous phase was extracted with additional ethyl acetate and the combined extracts were washed with water, saturated sodium chloride solution, dried and the solvent removed in vacuo. The residue was crystallized twice to give the title compound as white needles (1.309

g), melting point 141-143 ° C, [α] + 30 ° (c.51).

Preparation V p-hydroxy-3-oxo-17α-propionyloxyandrost-1,4-diene-17β * carboxylic acid (V)

A solution of N, 17α-dihydroxy-3-oxoandrost-1,4-diene-17β-carboxylic acid (13.5 g) and triethylamine (18 mL) in dichloromethane (500 mL) was cooled to 4 ° C and portionwise with propionyl chloride (14.2 mL) for 15 min. Stirring was continued at 4 ° C for 1 hour and the mixture was washed sequentially with 3% sodium bicarbonate, water, 2M hydrochloric acid, water, and brine, then dried and washed under reduced pressure. The residue was diluted in acetone (300 mL) and diethylamine (14.3 mL) was added with stirring. After 1 hour at 20 ° C, the solution was transferred under vacuum and the residue was diluted with water (150 mL). After acidification to pH 1 with 2M hydrochloric acid, the product was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried and then concentrated to low volume. The solid product was collected by filtration, washed with ethyl acetate and dried under vacuum at 50 ° C to give the title 17α-propionate carboxylic acid as crystals (13.309 g), [α] D + 30 ° (c.1, 10). A sample (389 mg) was recrystallized twice from methanol to an analytical sample (256 mg), mp 244-245 ° C (decop.) [A | _D + 3 '(c 0.83).

Preparation VI 6α, 9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-4-carboxylic acid (VI)

A solution of 6α, 9α-difluoro-11β, 17α-dihydroxy-16α-methyl-3-oxoandrost-1,4-diene-4-carboxylic acid (2.113 g) and triethylamine (2.5 mL) in dichloromethane (60 mL) was stirred and exposed to propionyl chloride (1.85 mL) at about 0 ° C. After 1 hour, the mixture was diluted with more solvent (50 mL) and washed sequentially with 3% sodium bicarbonate, water, 2M hydrochloric acid, water, brine, then dried and washed to give a light yellow solid. This was dissolved in acetone (50 mL) and diethylamine (2.5 mL) was added. After 1 hour at 22 ° C, the solvent was removed in vacuo and the remaining gum was dissolved in water (30 mL). Acidification to pH 1 with 2 M hydrochloric acid resulted in a solid which was washed with water and dried to give the title 17-carboxylic acid 17-propionate (2.230 g), mp 220-225 ° C, [α] _D + 4 ° (c.0) , 70).

Preparation VII 17β-N, N-Dimethylthiocarbamoyloxycarbonyl-9α-fluoro-11β-hydroxy-16α, 17α-isopropylidenedioxyandrost-1,4-dien-3-one (VII)

A solution of 9α-fluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrost-1,4-diene-17β-carboxylic acid (1000 g) in dichloromethane (15 mL) and triethylamine (0.33 mL) in an environment of nitrogen was treated with N, N-dimethylthiocarbamoyl chloride (588 mg) and the mixture was stirred at room temperature. After 68 hours of reaction, the mixture was diluted with ethyl acetate (50 mL) and washed in 1 M hydrochloric acid (2.10 mL), 5% sodium bicarbonate solution and water, dried and washed to a pale yellow crystalline solid (1.123 g). Preparative chromatography of a sample (200 mg) in chloroform-acetone (9.1) gave a white solid (161 mg) which crystallized from ethyl acetate as white needles in the title mixed anhydride (131 mg), mp 279-281 ° C, [a] o + 174 '(c 0.61, diethyl sulfoxide).

Preparation VHI 17 | _3-N> N-dimetyltiokarbamoyloxykarbonyl-6a, 9a-difluoro-11-hydroxy-Fi 16 a, 17 a-izopropylidénoxyandrost-l, 4-dien-3-one (VLH)

A solution of 6α, 9α-difluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrost-1,4-diene-17β-8β-quartic acid (4.354 g) in dichloromethane (150 mL) containing triethylamine (1.4 mL) was treated with N, N-dimethylthiocarbamoyl chloride (2.519 g), and the mixture was stirred under nitrogen at 22 ° C for 80 minutes. Ethyl acetate (500 mL) was added and the resulting solution was washed sequentially with 2 M hydrochloric acid, water, sodium bicarbonate, water and saturated sodium chloride solution and dried, and the solution was concentrated. Crystallization was performed on cooling and the solid was filtered and dried in vacuo to give the title anhydride (3.562 g) as pale yellow prisms, mp 283-287 ° C (dec), [α] D + 156 ° (c. 0.84) , dimethylsulfoxide).

Preparation IX

6α, 9α-difluoro-11β-hydroxy-16α, 17α-isopropylidenoxy-3-oxoandrost-1,4-diene-17β-carbothioic acid (IX)

A suspension of Wines (3.455 g) in diethylamine (200 mL) was heated under reflux in the presence of nitrogen for 6 hours. The initial suspension dissolved rapidly, but after 30 minutes a light brown suspension formed and remained unchanged. The cooled reaction mixture was poured into water (1.0 L), acidified with concentrated hydrochloric acid (210 mL) to pH 1 and extracted with ethyl acetate. The combined extracts were washed with water, extracted with 5% sodium carbonate solution and water, and the aqueous extracts were combined. The combined extracts were acidified with 6 M hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with water and saturated brine then dried and the solvent removed in vacuo to give a light gray solid (2.31 g). A portion of the product was crystallized from ethyl acetate to give the title carbothioic acid (0.149 g), mp 191-199 ° C, [α] _D + 124 ° (c. 1.04, dimethylsulfoxide).

Preparation X

6α-Fluoro-11β, 17α-dihydroxy-3-oxoandrost-1,4-diene-17β-carboxylic acid (X)

A solution of 6α-fluoro-predisolone (4.987 g) in tetrahydrofuran (50 mL) was stirred with a solution of periodic acid (10.0 g) in water (24 mL) at 22 ° C. After 50 minutes, the tetrahydrofuran was evaporated and the aqueous suspension was filtered. The solid product was washed with water (300 mL) and dried to a white solid (4.80 g). The title compound (271 mg) was crystallized from methanol to give the title acid (171 mg) as white needles, mp 241-248 ° C, [α] D + 54 ° (c 0.882).

Preparation XI 6α-Fluoro-11β-hydroxy-3-oxo-17β-propionyloxyandrost-1,4-diene-17β-carboxylic acid (XI)

A solution of Preparation X (4.491 g) and triethylamine (4.46 mL) in dry dichloromethane (160 mL) at 5 ° C was stirred and treated with propionyl chloride added dropwise (2.80 mL, 2.96 g) in dry dichloromethane (approximately 5 mL) for 5 minutes and below 0 ° C. After an additional 20 minutes at below 0 ° C, the reaction mixture was diluted with dichloromethane (160 mL), washed with sodium bicarbonate 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 (150 mL) was added, and the resulting solution was washed with ethyl acetate (2 x 30 mL). The aqueous phase was acidified to pH 2 with 2 M hydrochloric acid (50 mL) with stirring and the product was extracted 3 times with ethyl acetate. The extracts were combined, washed with water (50 mL), dried and evaporated to a white foam (5.819 g). A sample of the foam (304 mg) was crystallized from ethyl acetate to give the title 17-propionate (144 mg) as small slices, mp 224-227 ° C, [α] _D + 3 ° (c 0.886).

Preparation ΧΠ to ΧΧΙΠ

The following procedures are the same as described in Preparation I, but 17β-carboxylic acid corresponding to the desired 17β-carbothioate is used as the starting material (the procedure is summarized in Table I). The following compounds were prepared:

ΧΠ. 17α-acetoxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxoandrost-1,4-diene-17β-carbothioic acid Melting point 178.5-179 ° C, [α] D + 98 ° (c 1.02).

ΧΠ. 17? -Butyryloxy-9? -Fluoro-11? -Hydroxy-16? -Methyl-3-oxoandrost-1,4-diene-17? -Carbothioic acid Melting point 175-176 ° C, [α] D + 107 ° (c. 0.96).

XIV. 9? -Fluoro-11? -Hydroxy-17? -Isobutyryloxy-16? -Methyl-3-oxoandrost-1,4-diene-17? -Carbothioic acid M.p. 177-179 ° C, [α] _D + 119 ° (c.0) 90).

XV. 1β-hydroxy-3-oxo-17α-propionyloxoandrost-1,4-diene-17β-carbothioic acid

M.p. 134-138 ° C, [α] _D + 67 ° (c 0.66).

XVI. 11 β-hydroxy-16β-methyl-3-oxo-17α-propionyloxoandrost-1,4-diene-17β-carbothioic acid

Melting point 159-163 ’C, [<x) d + 113 ’(c.0,78).

XVII. 9α-Chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxoandrost-1,4-diene-17β-carbothioic acid

Mp 167-171 ° C, [α] D + 128 ° (c 0.99).

XVIII. 9α-Fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxoandrost-1,4-diene-17β-carbothioic acid

Mp 141-143 ° C, [α] D + 30 ° (c 0.51).

XIX. 6α, 9α-difluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxoandrost-1,4-diene-17β-carbothioic acid

Melting point 136-139 ° C, [α] ϋ - 30 ’(c.56).

XX. 9α-Fluoro-11β-hydroxy-16-methylene-3-oxo-17α-propionyloxoandrost-1,4-diene-17β-carbothioic acid

Melting point 236-239 ° C, [α] D - 71 ° (c 0.99).

XXI. 11P-Hydroxy-3-oxo-17α-propionyloxoandrost-4-ene-17β-carbothioic acid

Mp 176-177 ° C, [α] D + 101 ° (c 0.95).

XXII. 9? -Fluoro-11? -Hydroxy-16?, 17? -Isopropylidenedioxy-3-oxooandrost-1,4-diene-17? -Carbothioic acid M.p. 274-304 ° C (dec.), [Α] D + 121 '(c) 0.51, dimethylsulfoxide).

ΧΧΠΙ. 9? -Fluoro-11? -Hydroxy-3-oxo-17? -Propionyloxooandrost-1,4-diene-17? -Carbothioic acid M.p. 189-193 ° C (dec), [α] D + 72 '(c.0, 74).

SK 278140 Β6

Table I

Formation of mixed anhydrides

preparation 17 | Carboxylic acid input (g) C-CSNMT (G) NBt ₃ ™ solvent (CH ₂ Cl ₂ ) (ml) Reaction time (days) room temperature XII 5,000 2,940 1.66 75 5 ^la XIII 15,350 8,809 4.80 250 6 XIV 4,182 2,399 1.30 80 4 XV 7.148 4.40 2.6 150 6 ^lb XVI 6,137 3.77 2.05 140 6 ^1C XVII 5,973 3,350 1.34 100 7 xviii 4,207 2.39 1:35 80 0.67 ⁷ · ^ld XIX 2,130 1.80 0.66 50 6 ⁴ XX 5,000 2,507 1.41 75 3 XXI 1,000 2,442 1.22 15 2.7 XXII 1,000 0,588 0.33 15 2,8® XXIII 6,000 3.55 2.0 120 1.25 ¹⁰

Table I - continued

Treatment of intermediate anhydride with diethylamine

preparation NHEt ₂ (e) time (h) of the reaction under reflux product (Β) solvent XII 50 5.5 2,104 EA ^2a XIII 250 4 5,244 EA ³ XIV 60 4.5 1.00 EA XV 60 4 3.29 EA XVI 50 3.5 1,382 EA XVII 60 5.7 0,527 EA XVIII 25 4.75 1,309 A XIX 12 6 0,418 EA XX 50 3.75 1,296 EA ^2b XXI 15 4 0,397® A ⁵ XXII (a) 8 16 (a) 3 2.5 0,464 ⁹ A XXIII 60 4.5 2.88 EA - P

notes:

EA = ethyl acetate, A = acetone, P = petrol

Parts (a) 500 mg, (b) 670 mg, (c) 424 mg, (d) 171 mg of the dimethylthiocarbamide anhydride intermediate were selected for characterization.

2. Characterization was performed on a sample 2 x additionally recrystallized from ethyl acetate. Recovery (a) 84%, (b) 69%.

3. The product was released with ethyl acetate (approximately 0.2 moles).

4. The intermediate dimethylthiocarbamide anhydride (1.435 g) was crystallized from ethyl acetate. Part (95 ing) was selected for characterization.

5. Characterization was performed on a sample two more times recrystallized from acetone (recovery: 73%).

6. The product crystallized from ethyl acetate.

7. Sodium iodide (1.46 g) was also present in the reaction.

8. The intermediate dimethylthiocarbamide anhydride (1.123 g) was crystallized from ethyl acetate. The aliquot (200 mg) was chromatographed (thin layer chromatography, chloroform-acetone, 9: 1) and recrystallized from ethyl acetate (recovery 65%).

9. The reaction was carried out on 781 mg of anhydride.

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

Preparation XXIV

9α-chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioic acid and 9β, 11β-epoxy-16β-methyl-3-oxo-17α-propionyloxyandrost- 1,4-diene-17β-carbothioic acid (XXIV)

A solution of 17β-N, N-dimethylthiocarbamoyloxycarbonyl-9α-chloro-11β-hydroxy-16β-methyl-17α-propionyloxyandrost-1,4-dien-3-one (5.586 g) in diethylamine (60 mL) was refluxed under nitrogen. for 5 hours and 40 minutes. The mixture was poured into water (450 mL), acidified to pH 1 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 to pH 1 with 6 M hydrochloric acid and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water and saturated with sodium chloride, dried and the solvent removed in vacuo to give a colorless foam (2.834 g).

Two crystallizations of the mixture from ethyl acetate gave 9α-chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxy-androst-1,4-diene-17β-carbothioic acid (0.527 g) as white prisms, temperature mp 167-171 ° C, [α] _D + 128 ° (c. 0.99).

The mother liquors from crystallization contained an additional amount of the above 9α-chloro-1β-hydroxycarbothioic acid together with 9β, 1β-epoxy-16β-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioic acid.

Preparation XXV S-Iodomethyl-9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate (XXV)

A solution of the compound of Example 1 (500 mg) and sodium iodide (1.874 g) in acetone (15 mL) was stirred and heated under reflux for 6.5 hours. Ethyl acetate (75 mL) was then added and the compound was washed sequentially with water, 10% sodium thiosulfate solution, 5% sodium bicarbonate solution and water, dried and evaporated to a faded foam (525 mg). Preparative chromatography in chloroform-acetone (6: 1) gave a faded foam (478 mg) which was crystallized twice from acetone without heating at about room temperature to give colorless crystals of the title ester (241 mg), m.p. 197 ° C, [α] D -32 '(c. 1.01).

Preparation XXVI to XXXVII

The following procedures are the same as those described in Preparation XXV, but S-chloromethyl-4-carbothioate corresponding to the desired products was used as starting material (the procedure is described in more detail in Table Π). The following compounds were prepared: XXVI. S-iodomethyl-17α-acetoxy-9α-fluoro-11β-hydroxy-16β-π-1-3-οχοβη (1α-8ΐ-1,4-diene-17β4: α> οίίοέΙ Melting point 204-205 ° C, [α] ] _D -29 '(c 0.98).

XXVII. S-iodomethyl-1 H -hydroxy-3-oxo-17α-propionyl-oxoandrost-1,4-diene-4-carbothioate [α] _D + 26 ° (c 0.47).

XXVni. S-iodomethyl-11β-hydroxy-16β-methyl-3β-β-17α-propionyloxoandrost-1,4-diene-17β-carbothioate [α] _D + 5 '(c. 0.74).

XXIX. S-iodomethyl-9α-chloro-11β-hydroxy-β-hydroxy-3-oxo-17α-propionyloxoandrost-1,4-diene-173-carbothioate [α] η + 7 ° (c 0.36).

XXX. S-iodomethyl-9α-fluoro-1H-hydroxy-16α-methyl-3-oxo-17α-propionyloxoandrost-1,4-diene-17β-carbothioate [α] _D + 85 '(c 0.55).

XXXI. S-iodomethyl-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-οχο-17α-propionyloxoandrost-1,4-diene-17β-carbothioate

ΧΧΧΠ. S-iodomethyl-9α-fluoro-1H-hydroxy-16-methylene-3-oxo-17α-propionyloxoandrost-1,4-diene-17β-carbothioate

Mp 191-199 ° C, [α] _D - 31 ° (c 0.99).

ΧΧΧΙΠ. S-iodomethyl-9α-fluoro-1H-hydroxy-3-oxo-17α-propionyloxoandrost-1,4-diene-4-carbothioate m.p. 175-178 ° C, [α] D + 4 '(c.0, 50).

XXXIV. S-iodomethyl-6α-fluoro-1 H -hydroxy-3-oxo-17α-propionyloxoandrost-1,4-diene-17βΛατΙχύίοέί Mp 195-197 ° C, [α] D + 18 ° (c.0.64) .

XXXV. S-iodomethyl-17-acetoxy-6a, 9a-difluoro-11β-hydroxy-16-methyl-3-oxoandrost-1,4-diene-17.beta.-carbothioate

Mp 241-243 ° C, [α] _D + 78 '(c 0.78).

XXXVI. S-iodomethyl-17α-butyryloxy-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrost-1,4-diene-17β-carbothioate

Melting point 210 DEG-212 DEG C., [.alpha.] + 89 DEG (c 0.90).

XXXVH. S-iodomethyl-9α-fluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrost-1,4-diene-17β-carbothioate

Melting point: 261 to 270 ° C (dec.), [Α] D + 97 ° (c.48 dimethylsulfoxide).

Table Π

Halogen exchange on S-haloalkyl-17α-acyloxyandrostane-17β-carbothioethers

Pripra- NaJ input- Rozpúšťad- time silicone Kryätal. pro- va mg you are- lo reactive CHCl-i- rozpúš- Dukt no. roid acetone cie Tadla entry h. Me ₂ C0 halogen ml reflux mg

XXVI 6632 Cl 1715 20 3.5 - EA 216 ¹ XXVII 3800 Cl 925 10 4 - - 1084 XXVIII 3260 Cl 840 10 3 - - - 969 XXIX 1995 Cl 536 20 5.5 - - 591 XXX 2160 Cl 580 10 3 - - 685 XXXI 1200 Cl 303 30 5 - - 317 ³ XXXII 7361 Cl 1953 23 6 19: 1 A 296 ² XXXIII 5500 Cl. 1300 35 4 - M 1250® XXXIV R400 Cl 2000 54 4.5 - EA-P 1800 XXXV 19000 Cl 4750 200 5 - EA 4620 ^S XXXVI 6500 Cl 1620 70 5.5 - EA 1610 ⁴ XXXVII 5491 Cl 1419 20 24 9: 1 A 224 ⁷

EA = ethyl acetate A = acetone M = methanol P = petrol, boiling point 60 to 80 ´C Notes: 5

1. Obtained from part (300 mg) of crude product (2,024 B) ·

2. Obtained in part (400 mg) of the crude product (2.058)

8) ·

3. The product was used directly to prepare the corresponding fluorophenyl 17β-carbothioate.

4. Solvent 0.5 H ₂ O.

5. Solvent 0.1 EA.

6. Solvent 0.2 EA + 0.5 H ₂ O.

7. Partial product (300 mg) of crude crystalline product 15 (1.611 g).

Preparation XXXVHI S-iodomethyl-6α, 9α-difluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrost-1,4-diene-17β-carbothioate 20 (XXX in m)

A solution of Example 4 (0.795 g) in acetone (50 mL) was heated to reflux with sodium iodide (2.960 mg) for 5.5 hours. Ethyl acetate (75 mL) was added and the solution was washed successively with water, sodium metabisulfite solution 25, then dried and the solvent removed in vacuo to give a faded solid (0.893 g). A portion (0.205 g) was crystallized twice from ethyl acetate to give the title S-iodomethylthioester (0.105 g) as a white prism, m.p. 260 DEG-262 DEG C. (dec.), [.Alpha.] D + 81 ' (c.6, dimethylsulfide).

Preparation XXXIX

S-2-bromo-ethyl-9-fluoro-I, β-hydroxy-16β-ιηοΙγ1-3 οχο- ^17a-3 propionyloxoandrost-1,4-diene-17β-carbothioate (XXXIX)

Iodine (0.5 g) was reacted as described for the S-chloromethyl ester, Example 1, Procedure A, but 1,2-dibromoethane was used to give colorless crystals of the title S-2'-bromomethyl ester (0.409 g). mp 174-175 ° C, [α] _D + 120 ° (c. 1.04).

Preparation XL

16α, 17α-epoxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxoandrost-1,4-diene-4-carbothioic acid (XL)

A mixture of 16α, 17α-epoxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxoandrost-1,4-diene-17β-carboxylic acid (377 mg) and 2-fluoro-1-methylpyridinium tosylate ( 340 mg) in dry dichloromethane (7 ml) was stirred, cooled on ice, and subjected to triethylamine (0.42 ml) for 1 minute. After 1 hour, the hydrosulfide was passed through the mixture for 30 minutes to give a yellow compound. Thin layer chromatography (chloroform-acetone-acetic acid, 30: 8: 1) showed that a much less polar product was formed. After 1 h, warm to room temperature and treat with 2 M hydrochloric acid (30 mL), extract the product with ethyl acetate (3 x 20 mL). The acidic product was extracted from the organic phase with 5% sodium carbonate, the aqueous extracts were combined and acidified with 6 M 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, faded crystals (274 mg) probably quite unstable 16α, 17α-epoxy-9α-fluoro-11β-hydroxy-1β-methyl 1-3- oxoandrost-1,4-diene-17β-carbothioic acid (without starting oxyacid) as judged by thin layer chromatography (chloroform-acetone-acetic acid, 30: 8: 1, R f is about 0.7).

Preparation XLI S-Chloromethyl-16α, 17α-epoxy-9α-fluoro-11β-hydroxy-16β-π-1-3-ηχ-8η <1το8ΐ-1,4-diene-173-carbothioate (XLI)

SK 278140 Β6

Procedure

A suspension of 16α, 17α-epoxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxoandrost-1,4-diene-17β-carboxylic acid (753 mg) and 2-fluoro-1-methylpyridinium tosylate (680 mg) in dichloromethane (7 mL) was treated with triethylamine (1.39 mL) added dropwise. It was then stirred for 1 hour. The hydrosulfide was passed through the mixture for 15 minutes and the resulting solution was stirred at 0 ° C for an additional hour. Bromochloromethane (0.26 mL) was then added, the mixture was stirred and allowed to warm to room temperature. After an additional 1.5 hours, the mixture was diluted with ethyl acetate (250 mL), washed sequentially with 2 M hydrochloric acid, 5% sodium bicarbonate solution and water, dried and evaporated to a light yellow solid (818 mg). The material was subjected to preparative chromatography (9: 1) (2x). The larger band (513 mg) was crystallized from acetone to white needles in the title S-chloromethyl ester epoxide (447 mg), mp 246-251 ° C, [α] D + 13 '(c.0.67).

Procedure B

A suspension of 16α, 17α-epoxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxoandrost-1,4-diene-17β-carboxylic acid (376 mg) and 2-chloro-N-methylbenzothiazolium trifluoromethylsulfonate (400 mg) in dichloromethane, was treated with triethylamine (0.7 mL) added dropwise at 0 ° C. The resulting solution was stirred at 0 ° C for 1.25 hours and then hydrosulfide was passed through it for 10 minutes. After an additional hour at 0 ° C, bromochloromethane (0.13 mL) was added and the mixture was stirred at room temperature. After another 1.5 to

Two more portions of bromochloromethane (0.13 mL) were added at 1.8 hr. 15 minutes after the last addition, the reaction mixture was diluted with ethyl acetate (200 mL), washed sequentially with 2 M hydrochloric acid, 5% sodium bicarbonate solution and water, dried and evaporated to a red crystalline solid. The material was subjected to preparative chromatography in chloroform-acetone (19: 1) (3x). The multi-polar band gave a light pink substance, the title S-chloromethyl ester (134 mg), identical to an authentic sample by thin layer chromatography.

Preparation of XLH

S-chloromethyl-9α-fluoro-11β, 17α-dihydroxy-16-methylene-3-oxoandrost-1,4-diene-17D-carbothioate (XLD)

A solution of Preparation XLI (400 mg) in trifluoroacetic acid (16 mL) was stirred at room temperature. After 5.5 hours, the reaction mixture was evaporated and the residue was diluted with ethyl acetate (100 mL). The solution was washed with 5% sodium bicarbonate, water, dried and evaporated to a yellow-green foam (466 mg). The foam was subjected to preparative chromatography in chloroform-acetone (9: 1) (3x). A portion (80 mg) of the larger band was crystallized twice from acetone to white crystals of the title 16-methylene-17d-alcohol (48 mg), mp 242-243 ° C, (<x] _D + 36 '(c.0) , 50).

Preparation of XLHI

9α-Fluoro-17α-hydroxy-16β-methyl-3,11-dioxoandrost-1,4-diene-17β-carboxylic acid (XLHI)

A stirred suspension of 9α-fluoro-17,21-dihydroxy-16β-methylpregna-1,4-diene-3,11,20-trione (4,842 g) in tetrahydrofuran (50 mL) was cooled on ice and dropped over 5 minutes a solution of periodic acid (4.255 g) in water (15 mL). The mixture was mixed for 2.25 hours at 22 ° C when most of the suspension dissolved. The solvent was removed in vacuo, with periodic addition of water to maintain the original volume. The resulting precipitate was filtered, washed with water, air dried and vacuum dried to give the title carboxylic acid as cream prunes (4.55 g), mp 270-272 ° C, [α] D + 136 ° (c. 1, 04, dimethylsulfoxide).

Preparation of XLIV 9α-Fluoro-11β, 17α-dihydroxy-16β-methyl-3-oxoandrost-1,4-diene-17β-carbothioic acid (XLIV)

A stirred solution of 9α-fluoro-lip, 17α-dihydroxy-16β-methyl-3-oxoandrost-1,4-diene-17β-carboxylic acid (0.502 g) in dry N, N-dimethylformamide (15 mL) was cooled to -5 '. C under nitrogen and treated with N, N-carbonyldiimidazole (0.435 g) and the mixture was stirred at -5 ° C for 18 hours. Gaseous hydrosulfide was bubbled through the mixture for 20 minutes and the solution was stirred for an additional 4 hours and gradually allowed to warm to 22 ° C. The mixture was poured into ethyl acetate and the resulting solution was washed with 2 M hydrochloric acid and water, then extracted with 2 M sodium carbonate solution (3 x 50 mL). The combined extracts were washed with ethyl acetate (60 mL) then covered again with additional ethyl acetate (100 mL) and acidified to pH 1.0 with hydrochloric acid. The aqueous layer was extracted with more ethyl acetate and the extracts were washed with water and saturated brine, then dried and solvent removed Vacuum yielded a white solid which was crystallized twice from ethyl acetate to give the title carbothioic acid (0.315 g), m.p. 198 DEG-201 DEG C., [.alpha.] D + 189 DEG (c 0.71).

Preparation of XLV 9α-Fluoro-17α-hydroxy-16β-methyl-3,11-dioxoandrost-1,4-diene-17β-carbothioic acid (XLV)

A stirred compound of Preparation XLE (5.587 g) in dry N, N-dimethylphonaniamide (150 mL) at 20 ° C under nitrogen was treated with N, N-carbonyldiimidazole (4.847 g) and stirred at 20 ° C for 4 hours. hours. Gaseous hydrosulfide was bubbled through the mixture for 10 minutes and the solution was stirred for an additional hour. The compound was poured onto ice (300 mL) and 2 M hydrochloric acid to give a light yellow precipitate. This was filtered, air dried overnight (6.268 g) and crystallized from ethyl acetate to give the title carbothioic acid (3.761 g) as a white prism, mp 215-218 ° C, [α] D + 143 ° (c. 0.88, dimethylformamide).

Preparation of XLVI

9α-Fluoro-17α-hydroxy-16β-methyl-3,11-dioxoandrost-1,4-diene-17β-carbothioic acid (XLVI)

A stirred solution of Preparation XLIU (1.059 g) in dry Ν, Ν-dimethylformainide (50 mL) at 20 ° C under nitrogen was treated with N, N-thiocarbonyldiimidazole (1.368 g) and stirred at 20 ° C for 4 hours. hours. Gaseous hydrosulfide was bubbled through the mixture for 5 minutes and the solution was stirred for an additional hour. The reaction was partitioned between ethyl acetate (100 mL) and 2 M hydrochloric acid (100 mL), and the organic phase was washed with 2 M hydrochloric acid and water (2 x 100 mL) and extracted with 2 M sodium carbonate solution (2 x 75 mL). The combined extracts were for

Washed with ethyl acetate (50 ml), then covered with ethyl acetate (100 ml) and acidified to pH 1 with hydrochloric acid. The aqueous layer was extracted with additional ethyl acetate (50 ml) and the combined extracts were washed with water, saturated sodium chloride solution, dried and solvent. was removed under vacuum. The residue was crystallized from ethyl acetate to give the title carbothioic acid (0.559), mp 212-219 ° C, [α] _D + 145 (c 0.81, dimethylformamide).

Preparation of XLVU

S-chloromethyl-9α-fluoro-11β, 17α-dihydroxy-16β-methyl-3-oxoandrost-1,4-diene-4-carbothioate (XLVU)

A stirred solution of Preparation XLIV (0.169 g) and sodium bicarbonate (0.040 g) in N, N-dimethylformamide (6 mL) was combined with bromochloromethane (0.1 mL) and stirring was continued at 22 ° C for 1 hour. The reaction mixture was diluted with ethyl acetate (100 mL) and the solution was washed sequentially with 2 M hydrochloric acid, water, 2 M sodium carbonate solution, water and saturated brine, then dried and the solvent was removed in vacuo. The residue was crystallized twice from ethyl acetate to give the title S-chloromethylthioester (0.193 g) as white petals soluble in ethyl acetate, mp 126-130 ° C, [α] _D + 147.5 * (c 0.64).

Preparation of XLVUI 9α-Fluoro-16β-methyl-3,11-dioxoandrost-1,4-diene-17β-carbothioic acid (XLVIII)

A stirred solution of Preparation XLV (0.485 g) and triethylamine (0.57 mL) in dichloromethane was cooled to an ice salt, treated with propionyl chloride (0.43 mL), and the mixture was stirred at 0 ° C for 1.5 hours. The mixture was partitioned between ethyl acetate (75 mL) and 2 N sodium carbonate (75 mL), and the organic layer was washed successively with another 2 N sodium carbonate solution, water and 2 M hydrochloric acid, water, and saturated brine, then dried and removed The solvent was 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 mixture was stirred at 22 ° C for 1.25 hours. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (30 mL) and 2 M hydrochloric acid (30 mL). The ethyl acetate layer was washed with water and extracted with 2 N sodium carbonate solution (2 x 30 mL). The combined extracts were washed with ethyl acetate (30 mL) and overlaid with ethyl acetate (60 mL) and acidified to pH 1.0 with hydrochloric acid. The ethyl acetate layer was washed with water and saturated brine, then dried and the solvent removed in vacuo to give a white solid which was crystallized twice from ethyl acetate to give the title ester (0.290 g), mp 173-180 ° C, (a] _D + 148 DEG (c, 1.03).

Preparation XLIX S-chloromethyl-9α-fluoro-17α-hydroxy-16β-π-1-3,11-dioxoandrost-1,4-diene-17β-carbothioate (XLDC)

A solution of Preparation XLV (5.006 g) and sodium carbonate (1.612 g) in N, N-dimethylacetamide (50 mL) was treated with bromochloromethane (1.24 mL) and the mixture was stirred at 22 ° C for 3.3 hours . The solution was diluted with ethyl acetate (70 mL) and washed sequentially with 2 M hydrochloric acid, water, sodium metabisulfite solution, water, and the solution was saturated with brine, then dried, and the solvent was removed by vacuum removal of the cream (3.638 g). An analytical sample was obtained after preparative thin layer chromatography (silica gel, chloroform-acetone, 9: 1) and crystallized from ethyl acetate as colorless prisms in the title ester (0.262 g), mp 223-228 ° C, [α] D + 251 ° (c. 1.2).

Preparation L 9α-Fluoro-1H-hydroxy-4-methyl-3-oxo-17α-propionyloxoandrost-1,4-diene-4-carbothioic acid (L)

A stirred solution of Preparation XLTV (0.511 g) in dichloromethane (20 mL) containing triethylamine (0.6 mL) was cooled to 2 ° C and treated with propionyl chloride (0.45 mL), and the mixture was further stirred at 2 ° C for 2.5 hours. The mixture was partitioned between ethyl acetate and sodium bicarbonate, and the organic phase was washed with water, 2M hydrochloric acid, water and saturated brine, dried and the solvent was removed in vacuo to give a colorless solid (0.634 g). This was dissolved in acetone (30 mL) at 22 ° C for 55 minutes. The mixture was diluted with ethyl acetate (50 mL) and washed with 2 M hydrochloric acid and water, then extracted with 5% sodium carbonate solution. The combined extracts were acidified to pH 1 with 2M hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water and saturated brine, dried, and the solvent removed to give a colorless foam (0.522 g) which crystallized from ethyl acetate to the title ester as colorless prisms (0.307 g), mp 174-179 ° C; ] d + 107 '(c. 1.0).

Preparation of LI 9α-Fluoro-11β, 17α-Dihydroxy-16-methylene-3-oxoandrost-1,4-diene-4-carbothioic acid (LI)

A solution of 9α-fluoro-11β, 17α-β-β-1-α-16-methyl-3-oxoandrost-1,4-diene-17β-β-α-1-acid (0.218 g) in dry Ν, Ν-dimethylformamide (10 mL) ) at 22 ° C under nitrogen was reacted with Ν, Ν'-carbonyldiimidazole (0.254 g) and the reaction was stirred at 22 ° C for 4 hours. Gaseous hydrosulfide was bubbled through the mixture for 5 minutes and the mixture, now light green, was stirred at 22 ° C for 1 hour. The mixture was diluted with ethyl acetate (150 mL) and washed with 2N hydrochloric acid, water and saturated brine, dried and removed of solvent in vacuo gave a yellow foam (0.222 g) which crystallized twice from ethyl acetate to the title carbothioic acid (0.078 g) as white prisms, decomposed at about 250 ° C without melting, [α] D +117 '(c. 0.32) .

Preparation of LII

9α-Fluoro-1β, 17α-dihydroxy-3-oxoandrost-1,4-diene-4-carboxylic acid (LII)

A suspension of 9α-fluoro-predisolone (10 g) in dry tetrahydrofuran (55 ml) was stirred and reacted with a solution of periodic acid (9.0 g) in water (90 ml) and stirred at 22 ° C for 2 hours then The mixture was poured into ice water (about 400 mL) and after stirring for 15 minutes, the solid product was washed with water and dried to give the title acid as a solid (9.42 g). A portion recrystallized from ethanol had a melting point of 289-293 CC, [cc] d + 66 ((c.0.73, methanol).

Preparation of LIRA

9α-Fluoro-11β, 17α-dihydroxy-3-oxoandrost-1,4-diene-17β-carbothioic acid (LRI)

A solution of 9α-fluoro-11β, 17α-dihydroxy-3-oxoandrost-1,4-diene-17β-carboxylic acid (4.5 g) in dry dimethylformamide (100 mL) was stirred under nitrogen for 4 hours at 22 ° C. 1 C with N, N'-carbonyldiimidazole (4.04 g). Hydrosulfide was bubbled through the mixture for 30 minutes and then left for a further 15 minutes. The mixture was poured into a mixture of 2 M hydrochloric acid (230 mL) and ice (approximately 100 g) and the resulting precipitate was collected, washed with water and dried to a white solid (4.56 g). A portion (120 mg) was recrystallized from ethanol to the title thioacid, as colorless crystals (70 mg), m.p. 222 DEG-225 DEG C., [.alpha.] _D + 116 DEG (c 0.57).

Preparation of L1V 6α, 9α-difluoro-11β, 17α-dihydroxy-16α-methyl-3-oxoandrost-1,4-diene-17β-carbothioic acid (LIV)

A solution of 6α, 9α-difluoro-lip, 17α-dihydroxy-16α-methyl-3-oxoandrost-1,4-diene-17β-carboxylic acid (12.0 g) in dry dimethylformamide (250 mL) was stirred and reacted with N, N'-carbonyldiimidazolone (9.94 g) under nitrogen at room temperature. After 4 hours, the hydrosulfide was bubbled through the mixture for 0.3 hours and the mixture was left for a further 0.5 hours. The reaction mixture was poured into 2 M hydrochloric acid (500 mL) containing ice (approximately 250 g). The resulting precipitate was collected, washed with water and vacuum dried to give the title thioacid as a white solid (11.47 g), mp 230-232 ° C [α] D + 94 ° (c.0, 91).

Preparation of LV

17.alpha.-acetoxy-6.alpha., 9.alpha.-difluoro-11.beta.-1 (3-oxoandrost-1,4-diene-173-carbothioic acid (LV))

A solution of Preparation LIV (1.625 g) and triethylamine (2.0 mL) in dichloromethane (75 mL) was stirred at 0 ° C and treated with acetyl chloride (1.275 mL) dropwise and then stirred at 0 ° C for 1 h. , 25 hours. Wash the mixture with 2 N sodium carbonate (50 mL), water, 2 M hydrochloric acid (50 mL), water (3 x 50 mL), brine (50 mL), then dry and evaporate to a white solid (1 mL). 91 g). This was dissolved in acetone (40 mL), stirred with diethylamine (4 mL) at 27 ° C for 43 minutes. The mixture was concentrated to about 25 mL and poured into 2 M hydrochloric acid (100 mL) containing ice (about 100 g), after stirring, the resulting precipitate was collected, washed with water and dried to a solid (1.685 g). A portion (400 mg) was recrystallized from ethyl acetate to give the title 17α-acetate (280 mg), mp 175-177 ° C.

Preparation of LVI

17α-butyryloxy-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrost-1,4-diene-4-carbothioic acid (LVI)

Using a general procedure as described in Preparation LV, the compound of Preparation LIV (2.0 g) was converted with butyryl chloride (1.5 mL) instead of acetyl chloride to give the title 17α-butyrate (2.08 g). A portion recrystallized from ethyl acetate had a melting point of 155-157 ° C.

Preparation L VR 9α-Fluoro-11β-1β (1αθχγ-3-οχο-17α-propionyloxoandrost-1,4-diene-17β-carbothioic acid (LVH)

Using the general procedure described in Preparation LV, the compound of Preparation LII (3.8 g) was converted with propionyl chloride (3.9 mL) instead of acetyl chloride, and after aminolysis of the intermediate with diethylamine (10.35 mL), the title 17α-propionate was obtained. (4.17 g). A portion (350 mg) was recrystallized from ethyl acetate to give colorless crystals (165 mg), mp 135-138 ° C, [α] _D + 72 ° (c 0.92).

Preparation L VRI 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxoandrost-1,4-diene-17β-carbothioic acid (LVHI)

A solution of Preparation LIV (5.0 g) and triethylamine (6.15 mL) in dichloromethane (140 mL) was cooled to an ice salt and treated with propionyl chloride (4.74 mL) dropwise. The reaction mixture was stirred at 0 ° C for an additional 0.75 hours, then washed sequentially with 2 N sodium carbonate, water, 2 M hydrochloric acid, water, and brine. Drying by solvent removal gave a white solid (6.35 g). This was dissolved in acetone (120 mL) and diethylamine (12.5 mL). After stirring the solution for 1 hour at room temperature, the volume was reduced to approximately 75 mL. The solution was poured into 2 M hydrochloric acid (200 mL) containing ice (approximately 300 g) and the resulting precipitate was collected, washed with water and dried in vacuo to a white solid (5.17 g), mp 152-155 ° C. Recrystallization of a portion (400 mg) from ethyl acetate gave the analytically pure title 17α-propionate as colorless crystals (290 mg), mp 161-164 ° C, [α] D -27 '(c. 0.95), which were solid the state in the infrared spectrum showed a different crystalline form from the sample obtained in preparation XIX.

Preparation LIX

S-chloromethyl-9α-fluoro-16β-methyl-3,11-dioxo-17α-propionyloxoandrost-1,4-diene-17β-carbothioate (LIX)

A solution of Preparation XLIX (409 mg) in propionic acid (5 mL), trifluoroacetic anhydride (2 mL) and toluene-p-sulfonic acid (0.1 mL dry chloroform, 80 mg / mL) was stirred at 22 ° C for 2.75 days. Non-acidic products were isolated by extraction with ethyl acetate after pouring into saturated sodium bicarbonate. The crude material was chromatographed on silica gel in chloroform-acetone (14: 1) and crystallized from ethyl acetate-gasoline (bp 60-80 ° C) to give the title 17α-propionate as colorless crystals, mp 205-206 ° C, [ α] ο + 95 '(c.1, 15).

Preparation of LX S-chloromethyl-9α-fluoro-11β, 17α-dihydroxy-16β-methyl-3-oxoandrost-1,4-diene-17β-carbothioate (LX)

A suspension of Preparation XLIX (102 g) in ethanol (2.5 mL) was stirred with sodium borohydride (10 mg) at 22 ° C for 1 hour. The reaction mixture was treated with acetone (5 mL), then concentrated to near dryness, the residue was diluted in ethyl acetate (25 mL), washed with 1 M hydrochloric acid, water, and brine. After drying, the organic solvent was removed and the title compound was formed

It was passed through 1 β-alcohol as a colorless foam (103 mg), the only major component of which was an equipolane with an authentic sample on comparative thin layer chromatography (silica gel, chloroform-acetone, 9: 1).

Preparation of LXI 9α-Fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxoandrost-1,4-diene-17β-carbothioic acid (LXI)

Procedure

A solution of 9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxoandrost-1,4-diene-17β-carboxylic acid (603 mg) and N, N-carbonyldi (1,2,4-triazole) (0.997 mg) in dry dimethylformamide (45 mL) was stirred under nitrogen at about 22 ° C for 18.5 hours. A prepared solution (15 mL) of sodium hydride (305 mg) in dimethylformamide by saturation with hydrosulfide was added to the reaction mixture and the stirring was continued at room temperature for 3 days. The reaction mixture was poured into 2 M hydrochloric acid (200 mL) and the product was extracted with ethyl acetate (3x). The organic extracts were combined, washed with water and extracted again with 5% sodium carbonate solution. The alkaline extracts were acidified with hydrochloric acid and extracted with ethyl acetate (3x). After washing with water and brine, the organic extracts were dried and concentrated to low volume. The title thioacid was formed, separated as cream crystals (101 mg), the only major component of which was identified by comparison with an authentic sample by thin layer chromatography (silica gel, chloroform-acetone, 4: 1).

Procedure B

A solution of 9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxoandrost-1,4-diene-17β-carboxylic acid (701 mg) and N, N'-carbonyldiimidazole (473 mg) in dry dimethylformamide (26 mg) was stirred under nitrogen at about 22 ° C for 19.5 hours, then reacted with a solution (10 mL) of sodium hydride (60% dispersion in oil, 233 mg) in dimethylformamide (10 mL) saturated hydrosulfide. The resulting mixture was stirred at room temperature for 5.3 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 2 M hydrochloric acid, water and brine, then dried and evaporated to a foam (186 mg). The title thioacid was presented as a major component of the product by thin layer chromatography (silica gel, chloroform-acetone, 4: 1 and chloroform-acetone-acetic acid, 30: 8: 1) compared to an authentic sample.

Method C

In almost the same reaction as described in Method A, the carboxylic acid was reacted with 1,1'-carbonyldibenzotriazole (1.587 g) instead of N, h -carbonyldi- (L2,4-triazole) at room temperature for 6 hours. After addition of the solution obtained from hydrosulfide and sodium hydride in dimethylformamide, the reaction was continued for 41.5 hours. The crude product was obtained as a foam. Thin-layer chromatography (silica gel, chloroform-acetone, 4: 1 and chloroform-acetone-acetic acid, 30: 8: 1) indicated the title thioacid as the main component compared to an authentic sample.

Preparation of LXII

S-chloromethyl-6α, 9α-difluoro-16α-methyl-3-oxo-17α-for pionyloxy-11β-β-β-β-β-β-β-α ((1το5ΐ-1,4 β-β-17β-carbothioate) (LXII)

A solution of Example 5 (100 mg) in dry tetrahydrofuran (2 mL) and pyridine (0.1 mL) was treated with trifluoroacetic anhydride (0.05 mL) and the mixture was left at room temperature for half an hour. The reaction mixture was poured into water and the product was extracted with ethyl acetate (3x). The organic extracts were washed with water, dried and evaporated to give the homogeneous title tri-trifluoroacetate (116 mg) according to spectroscopy (singlet at 8.59, 19 protons, in deuterochloroform) and thin layer chromatography on silica gel (acetone-petrol boiling point 40-60 ° C). , 1: 3). An analytical sample of etherpentane had a melting point of 158-162 ° C, {a] _D + 56 '(c 0.23).

Example 1

S-chloromethyl-9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate

Procedure

A mixture of Preparation I (2.115 g) in dimethylacetamide (7 mL) was treated with sodium bicarbonate (592 mg) and bromochloromethane (0.46 mL) and the mixture was stirred at room temperature. After 2 hours, the reaction mixture was diluted with ethyl acetate (500 mL) and washed with 5% sodium bicarbonate solution and water, dried and evaporated to an orange foam (1.560 g). Preparative chromatography in chloroform-acetone (19: 1) gave a faded foam (803 mg) which crystallized 2 times from methanol to faded needles in the title S-chloromethyl ester (668 mg), mp 212-214 ° C, [α] ϋ + 4 '(c, 1.06).

Procedure B

The title compound was prepared similarly using chloroiodomethane instead of bromochloromethane.

Procedure C

Sodium borohydride (19 mg) was added to the compound of Preparation Π (230 mg) in ethanol (3.5 mL) and the mixture was stirred at room temperature. After 20 minutes, acetone (1 mL) was added and the mixture was concentrated to approximately 1/4 volume. After addition of ethyl acetate (30 mL), the mixture was washed with 1 M hydrochloric acid and water, dried in vacuo to a white foam (239 mg). Preparative chromatography in chloroform-acetone (19: 1) gave a white foam (188 mg) which was crystallized twice from methanol to white needles in the title S-chloromethyl ester (158 mg), mp 210-212 ° C, [a] _D + 44 (c, 1.07).

Example 2

S-Chloromethyl-9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate

The compound of Preparation IV (0.927 g) in dimethylacetamide (4 ml) was treated with sodium bicarbonate (0.256 g) and bromochloromethane (0.20 ml) and the mixture was stirred at 22 ° C for 2 hours. The reaction mixture was partitioned between ethyl acetate (100 mL) and 2 M hydrochloric acid (20 mL) and the aqueous layer was further extracted with ethyl acetate. The combined extracts were washed sequentially with 2 M hydrochloric acid, water, 3% sodium bicarbonate, water and saturated saline. After drying, the solvent was removed and the crude product (757 mg) was crystallized twice from acetone and the title chloromethylthioester (0.367 g), mp 247-250 ° C, [α] _D + 50.5 ° (c. 0, 63).

Example 3

S-chloromethyl-11β-hydroxy-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate

A solution of the crude product of Preparation XV (2.366 g) in dimethylformamide (10 ml) was treated with sodium bicarbonate (756 mg) and bromochloromethane (0.59 ml) at 22 ° C for 16 hours. The mixture was partitioned between ethyl acetate and 2M hydrochloric acid and the aqueous layer was further extracted with ethyl acetate. The combined organic phases were washed successively with 2M hydrochloric acid, water, sodium bicarbonate, water, saturated saline, then dried and the solvent removed to give a yellow foam. The neutral product was purified by preparative high performance liquid chromatography on silica gel (15µ) in 7% acetone in chloroform and the major product crystallized in acetone to give the title chloromethylthioester (0.511 g), mp 117-120 ° C, [α] _D + 56 ° (c. 1.3).

Example 4 S-Chloromethyl-6α, 9α-Difluoro-lip-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrost-1,4-diene-17β-carbothioate

A stirred solution of Preparation IX (1.360 g) in N, N'-dimethylacetamide (10 mL) was treated with sodium bicarbonate (0.377 g) and bromochloromethane (0.3 mL) and stirring was continued for 1.5 hours. Ethyl acetate (100 mL) was then added and the resulting solution was washed sequentially with 2 M hydrochloric acid, water, sodium metabisulfite solution, water, sodium carbonate solution, water and saturated sodium chloride solution, then dried and concentrated to crystallize. . The crystallized product (0.765 g) was purified by preparative silica gel chromatography using chloroform-acetone (9: 1). The main band was leached with ethyl acetate and crystallization from ethyl acetate gave the title S-chloromethylthioester (0.475 g) as white prisms, mp 271-278 ° C, [α] D + 116 ° (c 0.96 dimethylsulfoxide).

Example 5

S-Chloroethyl-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate

A solution of Preparation XIX (0.546 g) in dimethylacetamide (3 mL) was treated with sodium bicarbonate (202 mg) and bromochloromethane (0.16 mL) at 22 ° C for 3 hours. The mixture was washed with 2 M hydrochloric acid (50 mL) and the product was extracted with ethyl acetate. The extracts were combined and washed sequentially with 2 M hydrochloric acid, water, saturated saline, dried and the solvent was removed. Two crystallizations from ethyl acetate gave the title chloromethylthioester (0.404 g), mp 272-275 ° C, [α] _D + 49 '(c 0.35).

Examples 6 to 15

The following are general procedures as in Example 1 (Procedure A), but 17β-carbothioic acid corresponding to the desired 17β-carbothioate was used as the starting product (the procedure is more fully evaluated in Table ΠΙ). The following compounds were prepared:

6. S-Chloromethyl-1β-hydroxy-16β-methyl-3-oxo-7α-propionyloxyandrost-1,4-diene-17β-carbothioate Melting point 192-193 ° C, [α] _D + 65 ° (c. 05).

7. S-Chloromethyl-9α-fluoro-11β-hydroxy-16-methylene-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate

Mp 212-221 ° C, [α] _D - 56 ° (c 0.99).

8. S-Chloromethyl-17.alpha.-acetoxy-9.alpha.-fluoro-11.beta.-hydroxy-16.beta.-methyl-3-oxoandrost-1,4-diene-17.beta.-carbothioate Melting point 220 DEG-223 DEG C. [α] ο + 39.5 ° (c, 1.06).

9. S-Chloromethyl-17.alpha.-butyryloxy-9.alpha.-fluoro-11.beta.-hydroxy-16.beta.-methyl-3-oxoandrost-1,4-diene-17.beta.-carbothioate [.alpha.] _D + 46 (c, 1.10).

10. S-Chloromethyl-9α-fluoro-11β-hydroxy-17α-isobutyryloxy-16β-methyl-3-oxoandrost-1,4-diene-17β-carbothioate

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

11. S-Chloromethyl-9α-fluoro-11β-hydroxy-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate

Melting point 196-199 C C, []] + 38 ((c.0.97).

12. S-Chloromethyl-6α-fluoro-1β-hydroxy-3-oxo-17α-propionyloxyandrost-1,4-diene-17β 178τΙχ> ΙίοόΙ

Melting point 188-191 C C, +48 ((c0.91).

13. S-Chloromethyl-17α-acetoxy-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrost-1,4-diene-17β-thioate

Melting point 280-283 ° C, [α] + 45 ° (c.0.80).

14. S-Chloromethyl-17α-butyryloxy-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrost-1,4-diene-17β-carbothioate

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

15. S-Chloromethyl-9α-fluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrost-1,4-diene-17β-carbothioate Melting point 276-280 ° C, [afo + 127 ° (c. 0.51, dimethylsulfoxide).

Table m

SK 278140 Β6

Pr. NaHCO 3 Reagent Sternide Time PLC Crystal. pro- no. ml mg mg ml of reagents. NC. Dukt labor. CHCl g repl. Mejc

6 BrCHjCl (0.25) 300 7 BrCHjCl (00:58) 749 8 BrCK ₂ Cl (0.45) 565 9 BrCH ₂ Cl (0.33) 421 10 BrCH ₂ Cl (0.085) 121 11 BrCH ₂ Cl (0.90) 1100 12 BrCH ₂ Cl (0.87) 1080 13 BrCH ₂ Cl 2500 14 BrCH ₂ Cl (1.40) 1600 15 BrCH ₂ Cl (0.49) 615

981 5 3 2000 11 1.5 1955 7 2.0 1501 10 1.8 385 3 2.75 2730 20 1.25 2740 20 2 6600 40 1.75 4600 46 2 1600 12 1 .5

EA 826 19: 1 EA 201 - EA 307 * 14: 1 EA 871 - EA 235 - M 1600 - EA-P 2460 - A 5410 - A 2140 4: 1 A 244 '

Remarks: EA = ethyl acetate A = acetone M = methanol P = petrol (boiling point 60 to 80 ° C) 5 * Obtained in part (400 mg) crude product (2,35 g) ”Obtained in part (300 mg) crude product (1.72 g).

Example 16 S-Chloromethyl-9α-Chloro-11β-hydroxy-16β-methyl-3-oxo-10

-17α-propionyloxyandrost-1,4-diene-17β-carbothioate and S-chloromethyl-9β, 11β-epoxy-16β-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate

A solution of the mixture of Preparation XXTV (1.032 g) in dimethylacetamide (5 ml) was treated with sodium carbonate (0.203 g) followed by bromochloromethane (0.2 ml) and the mixture was stirred at 22 ° C for 1 hour. 5 hours at which time it was partitioned between ethyl acetate (50 mL) and 2 M hydrochloric acid (35 mL). The aqueous phase was extracted with additional ethyl acetate (2 x 30 mL) and the combined 20 extracts were washed with 2 M hydrochloric acid, water, saturated sodium carbonate solution, water, saturated sodium chloride solution, dried and the solvent removed to leave a creamy foam (0.856 g). a mixture of the title S-chloromethyl esters.

These were separated by preparative chromatography on silica gel, induced by chloroform-acetone (19: 1). The more polar component (0.306 g) was crystallized twice from ethyl acetate to give S-chloromethyl-9α-chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate (0.232 g) as 222 DEG-229 DEG C., [.alpha.] _D + 70 DEG (c. 1, 23).

The less polar component (0.210 g) crystallized from acetone-benzene to S-chloromethyls 1-9β, 11 β-epoxy-16β-methyl-3-οχο-17α-propions loxyandrost-1,4-diene-17β-carbothioate (0.065 g) mp 169-173 ° C, [α] _D + 49 '(c 0.60).

Example 17

S-fluoromethyl-9α-fluoro-11β-hydroxy-16β-methyl-3-oxo16

17a-propionyloxyandrost-1,4-diene-17.beta.-carbothioate

The compound of Preparation XXV (660 mg) was stirred with a suspension of silver fluoride (1.421 g) in acetonitrile (8.5 mL) in the dark at room temperature. After 72 hours, the reaction mixture was partitioned with ethyl acetate (200 mL) and filtered. The filtrate was washed with water, dried and evaporated to a white foam (517 mg). Preparative chromatography in chloroform-cyclohexane (19: 1) and chloroform gave a faded foam (270 mg) which crystallized from methanol, then from methanol-diethyl ether to the title S-fluoromethyl ester (176 mg), m.p. α] _D + 97.5 '(c 0.98).

Example 18

S-fluoromethyl-9α-fluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate

A solution of Preparation XXX (0.640 g) in acetonitrile (8 mL) was treated with dry silver fluoride (1.511 g) and stirred in the dark at 22 ° C for 46.5 hours. The mixture was diluted with ethyl acetate (200 mL) and filtered. The solution was washed with 2M hydrochloric acid, water and saturated sodium chloride solution and removal of the solvent in vacuo gave a light yellow foam (0.504 g). This was chromatographed (preparative chromatography) on silica gel, using 5% acetone in chloroform. The main band was leached with ethyl acetate and crystallized twice from acetone to the title fluoromethylthioester (0.244 g), mp 242-243 ° C, [α] _D + 37 '(c 0.75).

Example 19 S-Fluoromethyl-6α, 9α-difluoro-1H-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-3-oxoandrost-1,4-diene-17β-carbothioate

A solution of Preparation XXXI (310 mg) in acetonitrile (10 mL) was stirred with silver fluoride (947 mg) for 3 days at room temperature in the dark. After addition of ethyl acetate (100 mL), the mixture was filtered. The filtrate was washed successively with 2 M hydrochloric acid, water, saturated saline, and then dried. The solvent was removed and the residue was subjected to preparative chromatography in chloroform, then chloroform

acetone (19: 1). The product was extracted with ethyl acetate and crystallized to the title fluoromethylthioester. Melting point 272-273 CC, []] + 30 ’(c.0.35).

Example 20

S-fluoromethyl-9α-fluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrost-1,4-diene-17β-carbothioate

A suspension of Preparation XXXVII (1.290 g) in acetonitrile (20 mL) was stirred with silver fluoride I (2.842 g) at room temperature in the dark. After 11 days (no iodide input, chloroform thin layer chromatography, 6X), the reaction mixture was diluted with ethyl acetate (400 mL) and filtered. The filtrate was evaporated to a pale yellow crystalline solid (726 mg) and the diatomaceous earth was continuously extracted with ethyl acetate in a Soxhlet apparatus to give a yellow solid (197 mg). The solid obtained by filtration was suspended in chloroform

methanol (10: 1) and the insoluble fraction (203 mg) were combined. This was combined with a solid from Soxhlet extraction in ethyl acetate (300 mL) and filtered through a silica gel column (Merck Kieselgel 60, the word Merck is a registered trademark) (50 g). The product-containing extract (thin layer chromatography) was combined, washed with water, dried by simultaneous treatment with charcoal and concentrated to low volume.

The resulting white solid (276 mg) was recrystallized from ethyl acetate to give the colorless crystals of the title S-fluoromethyl ester (231 mg), mp 320-322 ° C, + 132 ° (c 0.22, dimethylsulfoxide).

Example 21

S-fluoromethyl-6α, 9α-difluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrost-1,4-diene-17β-carbothioate

A solution of Preparation XXXVm (0.804 g) in acetonitrile (60 mL) was treated with silver fluoride (1.821 g and stirred for 18 hours in the dark. The mixture was diluted with ethyl acetate and filtered through diatomaceous earth .The filtrate was washed with water and saturated sodium chloride solution. This was purified by preparative chromatography on silica gel twice eluted with chloroform-acetone (14: 1). The main band was leached with ethyl acetate and crystallized 5 times from ethyl acetate to give the title S-, m.p. fluoromethylthioester (0.118 g) as white prisms, m.p. 305 DEG-311 DEG C., [.alpha.] D + 125 DEG (c 0.73, dimethylsulfoxide).

Examples 22-30

The following general procedures follow as in Example 17, but using the starting material S-iodomethyl-4-carbothioate corresponding to the desired product (the procedure is reviewed in detail in Table IV). The following compounds were prepared:

22. S-fluoromethyl-17α-acetoxy-9α-fluoro-1β-hydroxy-16β-β-γ-3-ω-α-β-1,4-1,4-β-β-17β-4 β-β-hydroxy-16β-β 101 '(c, 1.08).

23. S-Fluoromethyl-1H-hydroxy-3-oxo-17α-propionyloxyandrost-1,4-diene-17 [] carbothioate

Melting point 112-117 ° C, [α] D + 67 ° (c 0.76).

24. S-fluoromethyl-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate M.p. 223-225 ° C, [α] D + 103 ° (c. 0.38).

25. S-fluoromethyl-9α-chloro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate

Melting point 182-193 CC, [a] D +116 ’(c.0.75).

26. S-fluoromethyl-9α-fluoro-11β-hydroxy-16-methylene-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate M.p. 205-215 ° C, [α] D-58 ° (c. 1.00).

27. S-fluoromethyl-9α-fluoro-11β-hydroxy-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate Melting point 207 DEG-211 DEG C., [.alpha.] D + 70 DEG (c. 0.88).

28. S-fluoromethyl-6α-fluoro-11β-hydroxy-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate M.p. 224-225 ° C, [α] D + 70 ° (c. 0.79).

29. S-Fluoromethyl-17α-acetoxy-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrost-1,4-diene-17β-carbothioate

Melting point 308-310 C, []] + 29 (c0.80).

30. S-Fluoromethyl-17α-butyryloxy-6α, 9α-difluoro-11β17

hydroxy-16α-methyl-3-oxoandrost-1,4-diene-17β-carbothioate

Mp 249-252 ° C, [α] _D + 32 '(c, 1.05).

Table IV

Halogen exchange of S-fluoromethyl-17α-acyloxyandrostane-17β-carbothioates

Pr. no. AgF mg Input steroid halogen input NC. MeCN ml Laboratory reaction time temperature (h) Preparations. Oh, silicone. CHCl 3 - Me ₂ CO Quartz crystal Product mg 22 3745 I 1702 22 20 24: 1 A 477 23 2071 I 1034 10 26 19: 1 EA 585 ' 24 1945 I 850 6 26 19: 1 EA 166 25 1161 I 550 8 23.5 19: 1 M 106 26 3574 I 1658 26 24 19: 1 A 300 27 700 I 1000 50 3 - M 470 28 462 l 700 35 2 - EA-P 350 29 2600 I 4000 200 0.75 - EA 2280 30 780 T 1200 60 L BA 755

A = acetone M = methanol P = petrol, boiling point 60 to 80 ° C 5 * Purity approximately 95%.

Example 31

S-Bromomethyl-9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate 10

A solution of Preparation XXV (660 mg) in acetone (20 mL) was stirred with lithium bromide (972 mg) at room temperature for 5 days. The reaction mixture was diluted with ethyl acetate (150 mL) and then washed sequentially with 10% sodium thiosulfate solution, water and brine, dried and evaporated to give a faded foam (624 mg). This crystallized twice from acetone-petroleum ether (melting point 40-60 ° C (499 mg), melting point 186.5-187 ° C, [a] p + 2 "(c.99).

Example 32

S-Bromomethyl-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-173-carbothioate

A solution of Preparation (850 mg) in acetone was stirred with lithium bromide (1.21 g) at about 22 ²⁵ ° C 5 days. The product was isolated as described in Example 31 and recrystallized twice from ethyl acetate to give colorless crystals (690 mg). These were reprocessed under the same conditions for an additional 4 days to give the pure S-bromomethyl ester (600 mg), colorless crystals of ethyl acetate, mp 255-257 ° C, [α] _D + 62 '(c.0.82) ).

Example 33

S-2'-Fluoroethyl-9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate

A solution of Preparation XXXIX (910 mg) in acetonitrile (20 mL) was stirred with silver fluoride (I) (2.071 g) at room temperature in the dark. After 6 days, the reaction mixture was diluted with ethyl acetate (150 mL) and filtered. The filtrate was diluted with additional ethyl acetate (150 mL) and washed with water, dried and evaporated to a white foam (704 mg). Preparative chromatography in chloroform-acetone (9: 1) gave a less polar product than a yellow foam (431 mg), which crystallized twice from methanol to the title S-2'-fluoroethyl ester (253 mg), mp 133-134 1 C, [α] _D + 104.5 (c 0.98).

Example 34

S-Chloromethyl-9α-fluoro-11β-hydroxy-16-methylene-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate

A suspension of the preparation of XLH (227 mg) in propionic acid (2.2 mL) and trifluoroacetic anhydride (0.7 mL) was treated with a dry solution of chloroform and toluene-p-sulfonic acid (0.044 mL, approximately 80 mg / mL) and then stirred for 6 hours at room temperature, stirring was continued at 3 ° C for 16.5 hours. The reaction mixture was diluted with 5% sodium bicarbonate solution (75 mL) and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried and evaporated to a brown gum (254 mg). The gum was subjected to preparative chromatography in chloroform-acetone (19: 1) (3x). The main band (152 mg) was crystallized twice from ethanol to white crystals (30 mg) in the title S-chloromethyl ester of 17α-propionate contaminated with S-chloromethyl-9α-fluoro-17α-hydroxy-16-methylene-3-oxo-11β -propionyloxyandrost-1,4-diene-17β-carbothioate as shown by spectroscopy.

Example 35

S-Chloromethyl-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandroso-17β-carbothioate

Catalytic reduction of the compound of Example 6 (0.517 g) in the presence of tris (triphenylphosphine) chlorodiode (I) (497 mg) in benzene (50 mL) for 22 hours afforded, after chromatography (preparative chromatography) on silica gel in chloroform (4x). elution with ethyl acetate and double crystallization from ethyl acetate, Δ ⁴ -3-ketone (0.130 g), m.p. 176-177 ° C, [α] D + 78 ° (c 0.80).

Example 36

S-Chloromethyl-9α-fluoro-11β-hydroxy-16β-η-γ-3-ω-17α-propionyloxyandrost-4-en-17β-carbothioate Catalytic reduction of the compound of Example 1 (0.646 g) in the presence of tris (triphenylphosphine) chlorodi (I) (800 mg) in benzene (100 mL) over 21.5 hours gave, after chromatography on silica gel in chloroform-acetone (9: 1) and two acetone crystallizations, the title chloromethylthioester (0.142 g) as white needles. mp 217-255 ° C, [α] _D + 54 ° (c 0.83).

Example 37

S-fluoromethyl-11β-hydroxy-16β-γηεγγ-3-οχο-17α-propionyloxyandrost-4-en-17β-carbothioate

Catalytic reduction of the compound of Example 24 (0.413 g) in the presence of tris (triphenylphosphine) chloro (I) (432 mg) in benzene (60 mL) for 24 hours at 22 ° C afforded, after several chromatographies on silica gel in chloroform-acetone. and crystallization from acetone, the title A ⁴ -3-ketone (0.106 g), mp 174-177 ° C, [α] _D + 123 '(c 0.55).

Example 38

S-Chloromethyl-9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate S-chloromethyl-9β, 11β-epoxy-16β-methyl- The 3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate (about 0.9 mg) from Example 16 was treated with the hydrofluoride complex (about 1 mL) and stirred for 24 hours at room temperature. The mixture was subjected to sodium bicarbonate and the product was extracted twice with ethyl acetate. The extracts were washed twice with water, dried and evaporated. Thin-layer chromatography on silica gel in three different systems (acetone-petrol, boiling point 40-60 ° C, 1: 2, chloroform-acetone, 9: 1, ethyl acetate-petrol, bath temperature 40-60 ° C, 1: 2, two) The product was shown to give the fluorohydrin in the final product by comparison with an authentic test sample.

Example 39

S-chloromethyl-6α, 9α-fluoro-11β-hydroxy-16α-methyl 1-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate

A solution of the preparation of LXD (29 mg) in methanol (2 mL) was left at room temperature for 3 hours. The mixture was evaporated to dryness to give the title 11Balcohol (25 mg) identified by comparing its Ή NMR spectrum (in deuteriodimethylsulfoxide) and its properties in thin layer chromatography (silica gel, acetone gasoline, bp 40-60 ° C, 1: 3) with those of the authentic of the test sample.

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

The active androstane mixtures may advantageously be formulated in conventional manner into preparations suitable for topical administration by means of topical administration. Topical administration also involves administration by inhalation and insufflation. Examples of various types of topical preparations include ointments, solutions, creams, powders, drops (e.g., eye or ear drops), sprays (e.g., nasal, throat, lung, or skin), suppositories, retention enemas, chewable or succulent tablets or beads (e.g. for treatment of aphthous ulcers), capsules or cartridges for use in an inhaler or insufflator, and aerosols (e.g., nasal, throat, or pulmonary).

Ointments or creams may, for example, be formulated with an aqueous or oily base by the addition of a suitable enhancer and / or gelling agent and / or solvent. Such a base may, for example, include water and / or oil such as liquid paraffin or vegetable oil such as peanut oil or castor oil or solvent such as polyethylene glycol having an average molecular weight in the range of 200 to 600. Enhancers which may be used due to the nature of the base include fine paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycols having an average molecular weight in the range of 4000-6000, wool fat and bee fat. wax and / or glyceryl monostearate and / or nonionic emulsifying agents.

Spray mixtures can be formed, for example, as aqueous solutions or suspensions or as aerosols using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases.

Capsules or cartridges for use in an inhaler or insufflator, for example of gelatin, may be formulated containing a powder mix of the compound of the invention and a suitable powder base such as lactose or starch. Each capsule or cartridge may generally contain 20 µg to 10 mg of the active androstane mixture.

The amount of active androstane mixture in the topical compound with respect to the invention depends on the exact type of sample to be prepared, but will generally range from 0.001 to 5.0% by weight. In general, however, most types of formulations will be in the range of from 0.005 to 0.5%, most preferably from 0.01 to 0.25%. For inhalation or insufflation, the dose will be used together with the buffers in the range of 0.1 to 2%.

Previous formulations for topical use on the skin may be used to treat inflammatory dermatoses in humans or animals, for example eczema, which normally

They respond to corticosteroid therapy and also in less sensitive cases than psoriasis in humans.

Samples for inhalation or insufflation are also contemplated for prophylactic administration in subjects suffering from allergies and / or inflammatory infections of the nose, throat, lungs such as asthma and rhinitis as well as hay fever. Aerosol preparations are formulated so that each metered dose or each aerosol tap contains 20 mg to 1000 pg, most preferably about 50 pg to 100 pg of the composition of the invention. Administration can be several times a day, for example 2,3,4 or 8x, each time for example 1,2 or 3 doses can be given. The all-day dose for aerosol administration will be in the region of 100 pg to 10 mg, most preferably 200 pg to 1000 pg. The daily dose and the measured dose obtained when administered by capsules and cartridges in an inhaler or insufflator will generally be twice as much as by aerosol administration.

Topical formulations may be applied to the affected areas one or more times per day, occlusive wraps may be applied to the skin as appropriate.

For internal administration, the novel compounds of the invention may be formulated, for example, by conventional means suitable for oral, parenteral or rectal administration. For oral administration, syrups, elixirs, powders and granules may be formulated under conventional conditions. The most preferred dosage units are given below.

The most preferred forms of oral preparations are tablets and capsules. One such dosage form contains from 0.1 mg to 20 mg, most preferably 2.5 to 10 mg of active steroid.

The compounds of the invention can generally be used for internal administration where adrenocortical therapy is indicated.

Under general conditions, the formulations for internal administration may contain from 0.05 to 10%, depending on the type of formulation desired. The daily dose may vary from 0.1 mg to 60 mg, for example 5 to 30 mg, depending on the treatment conditions and the desired duration of treatment.

Example (A) Ointment Active substance 0.1% v / v

Liquid paraffin 10% v / v

White fine paraffin up to 100

Crush the active ingredient with a small amount of liquid paraffin until the particle size is 95% reduced to below 5 µ. Dilute the paste and rinse the grinder with the remaining liquid paraffin, mix and add the suspension to the melting white fine paraffin at 50 ° C. Stir until cooled until homogeneous ointment.

Example (B)% v / v cream

Active substance0,1

Cetostearylalkohol10,0

Cetamacrogol 1.0002,5

White fine paraffin10,0

Liquid paraffin10,0

Chlórkrezol0,1

Sodium phosphate0,5

Purified water up to 100.0

Method of preparation

Chlorocresol and dicalcium phosphate are dissolved in water at a temperature of about 70-75 ° C. The waxes are melted at a temperature of about 65 to 70 ° C together and added while stirring to the aqueous phase which has been cooled to a temperature of about 65 to 70 ° C. The steroid is micronized (particle size as defined in BPC 1973 p. 911 for ultra fine powder) and dispersed in a portion of liquid paraffin. The steroid suspension and the remainder of the liquid paraffin are added with stirring at 60-65 ° C to the base. During stirring, the formulation is cooled to room temperature.

Example (C) Formulation of a measured aerosol dispenser dosage _____% v / v

Active Ingredient 0.05 mg 0.059

Fluorotrichloromethane 25.5 mg 30.0

Dichlorodifluoromethane to 85.0 mg to 100.0

The active ingredient is micronized (particle size as defined in BPC 1973 p. 911 for ultra fine powder) and dispersed in fluorotrichloromethane. This suspension is filled into an aluminum aerosol container, the upper part is purged with gaseous dichlorodifluoromethane to eliminate air, and the aerosol dispensing valve is turned to the correct position on the container. The liquid dichlorodifluoromethane is pumped through the metering valve under pressure to the correct weight.

Example (D)

Capsules for inhalation (100 g / dose) per capsule _______% v / v

Active ingredient 0,1 mg 0,4

Lactose up to 25.0 mg up to 100.0

The active ingredient is micronized (particle size as defined in BPC 1973 p. 911 for ultra fine powder) and is mixed with lactose in the amount shown in the above example. The lactose steroid mixture is filled into hard gelatin capsules to be administered with an inhalation agent.

Claims (24)

PATENT CLAIMS An androstane carbothioate of the general formula I wherein R ¹ represents a fluoro, chloro or bromomethyl group or a 2'-fluoroethyl group; R ² represents a COR ⁶ group, where R ⁶ represents a C 1-6 alkyl group or OR ² and R ³ together form a 16α, 17α-isopropylidenedioxy group; R ³ represents a hydrogen atom, a methyl group, which may be in either the β or the β position, or a methylene group; R ⁴ is H, Cl or F; R ⁵ represents a hydrogen or fluorine atom and the symbol ..... represents a single bond. Compounds according to claim 1, wherein R ¹ is a chloromethyl or fluoromethyl group. Compounds according to claim 1 or 2, wherein R ² is acetyl or propionyl. Compounds according to claim 3, wherein R ² is propionyl. Compounds according to any one of claims 1 to 4, wherein R ⁴ is fluoro. Compounds according to any one of claims 1 to 5, wherein R ⁵ is fluoro. Compounds according to any one of claims 1 to 6, which are 1,4-dienes. Compounds according to claim 7, wherein R ⁴ is fluoro and R ³ is hydrogen, alpha or beta-methyl or methylene. Compounds according to claim 2, namely 1,4-dienes, in which R ⁴ and R ³ are fluorine atoms and R ³ is an alpha- or betamethyl or methylene group. Compounds according to claim 9, wherein R ³ is alphamethyl. 11. S-Chloromethyl-9α-fluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate. 12. S-Chloromethyl-9α-fluoro-11β-hydroxy-16-methylene-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate. 13. S-Fluoromethyl-6α, 9α-difluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrost-1,4-diene-17β-carbothioate. 14. S-fluoromethyl-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate. 15. S-Chloromethyl-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-α-17α-propionyloxyandrost-1,4-diene-17β-carbothioate. Pharmaceutical compositions for use in anti-inflammatory therapy, characterized in that they comprise at least one compound of androstane of formula I as defined in claim 1 together with one or more pharmaceutical carriers or excipients. Pharmaceutical compositions according to claim 16, characterized in that they are in a form suitable for topical administration. Pharmaceutical compositions according to claim 17, characterized in that they are suitable for administration by aerosol. Pharmaceutical compositions according to claim 18, characterized in that they are in a measured aerosol dose, the aerosol is adapted to deliver a dose containing 20 µg to 100 µg of a compound of formula I as defined in claim 1. Pharmaceutical compositions according to claim 19, characterized in that each dose contains from 50 µg to 100 µg of the compound of formula I according to claim 1. Pharmaceutical compositions according to any one of claims 16 to 20, characterized in that the androstane compound of formula I according to claim 1 is selected from: S-chloromethyl-9α-fluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-170-carbothioate, S-chloromethyl-9α-fluoro-11β-hydroxy- 16-methylene-3-oxo-17α-propionyloxyandrost-1,4-diene-17β * carbothioate S-fluoromethyl-6α, 9α-difluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrost-1,4- diene-17β-β-α (β-fluoromethyl-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate, S-Chloromethyl-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-173-carbothioate. Pharmaceutical compositions according to claim 21, characterized in that the androstane compound of formula I according to claim 1 is selected from: S-fluoromethyl-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α- propionyloxyandrost-l, 4-diene-170-carbothioate S-chloromethyl-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrost-1,4-diene-17β-carbothioate. Pharmaceutical compositions according to claim 17, characterized in that the compound of androstane of formula I according to claim 1 is S-chloromethyl-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrost-1, 4-diene-17βΛ8Γΐχ> ίίοέί Pharmaceutical compositions according to claims 17 to 20, characterized in that the androstane compound of formula I according to claim 1 is S-fluoromethyl-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrost -l, 4-diene - ^ - carbothioate.