BG60700B2 - Androstane thiocarboxylates - Google Patents

Abstract

The compounds have good anti-inflammatory activity and can be used in medicine. They are of the general formula, the meanings of the substituents are given in the description.

Description

(54) ANDROSTANE THIOCARBOXYLATES

The invention relates to anti-inflammatory steroids in the androstane series.

Most typically, anti-inflammatory steroids are of the corticoid type, ie. they are chase derivatives. U.S. Patent Nos. 1384372, 1438940 and 1514476 disclose esters of some androstane 17 β-thiocarboxylic acids having anti-inflammatory activity. European Patent Application No. 79300500.0 (Publication No. 0004741) discloses androstan 17 β-thiocarboxylic acid esters, which also have an anti-inflammatory effect. It has now been found that some androstane compounds having the 17-position halogenalkyl thiocarboxyl group have particularly favorable anti-inflammatory properties, as described below.

New androstan compounds can be represented by the formula:

in which R ¹ denotes a fluoro-, chloro- or bromo-methyl group or a 2'-fluoroethyl group,

R ² represents a group COR ⁶ wherein R ⁶ is a C _{| 3} alkyl or OR ² and R ³ together form a 16 a, 17 a-isopropylidene dioxy group,

R ³ denotes hydrogen, a methyl group (which may be in the α- or β -configuration) or a methylene group,

R ⁴ represents hydrogen, chlorine or fluorine,

R ⁵ denotes hydrogen or fluorine and the symbol rg represents a single or double bond.

The new compounds of Formula I have good anti-inflammatory activity, especially with external (topical) administration, as judged by the McKenzie test in humans, and as measured by the reduction of croton oil-induced edema when the compounds are administered externally to mouse skin or rats.

Some of the compounds exhibit good anti-inflammatory activity externally administered in the croton oil test that is associated with minimal hypothalamic-pituitary-adrenaline-suppressing activity after external administration in the same animal species. These results indicate that the compounds may be valuable agents in the local treatment of inflammation in humans and animals with minimal potential to cause undesirable systemic side effects.

The compounds of formula I, which are preferred because of their good anti-inflammatory activity, are the following groups:

(a) those in which R ¹ represents chloro- or -fluoromethyl;

(b) those wherein R ² is acetyl or propionyl, preferably propionyl;

(c) those in which R ⁴ is fluorine;

(d) those where R ⁵ is fluorine;

(e) 1,4-dienes;

(f) those 1,4-dienes in which R ⁴ is fluorine and R ³ represents hydrogen, α- or β methyl or methylene.

Compounds of formula I having good anti-inflammatory activity and minimal hypothalamic-pituitary-adrenaline suppressive activity when administered externally include 1,4-dienes wherein R ¹ is chloro or fluoromethyl, R ⁴ and R ⁵ are fluorine and especially those in which R ³ represents a -methyl group.

Particularly preferred compounds of the invention with regard to their good external anti-inflammatory action and favorable ratio of external anti-inflammatory action to undesirable systemic activity are:

9? -Fluoro-N β-hydroxy- S-chloromethyl ester! 6? -Methyl-3-oxo-17? -Propionyloxyandrosta-1,4-diene-17? -Thiocarboxylic acid;

9? -Fluoro-N? -Hydroxy-16-methylene-3-oxo-17? -Propionyloxyandrosta-1,4-diene-17 β-thiocarboxylic acid S-chloromethyl ester;

6a, 9a-difluoro-N β-hydroxy-16a, 17a-isopropylidenedioxy-3-oxoandrosta-1,4-diene-17 β-thiocarboxylic acid S-fluoromethyl ester;

6a, 9a-difluoro-N β-ΧΗ3ρο ^ π-16 α-methyl-3-oxo-1,7α-propionyloxyandrosta-1,4-diene-17 β-thiocarboxylic acid S-fluoromethyl ester;

6a, 9a-difluoro-N? -Hydroxy-16? -Methyl-3-oxo-17 apropionyloxyandrosta-1,4-diene-17? -Thiocarboxylic acid S-chloromethyl ester.

The latter compound is a particularly favorable ratio of external anti-inflammatory action to undesirable systemic activity and in addition causes minimal skin atrophy.

The compounds of formula I can be prepared by various methods.

One method is to esterify an androstane compound according to Formula I but containing either a free 17 β-thiocarboxylic acid group (or a functionally equivalent group) or a free 17 α-hydroxyl group (R ³ means hydrogen or methyl or methylene group) , any other reactive group present in the molecule may be protected if desired.

For example, a 17-thiocarboxylic acid starting salt such as an alkali metal, for example a lithium, sodium or potassium salt or an alkyl ammonium, for example triethylammonium or tetrabutylammonium salt, can be reacted with a suitable alkylating agent, preferably in a polar solvent such as ketone, ketone, or ketone, such as dimethylformamide, dimethylacetamide or hexamethylphosphoramide, typically at a temperature of 15 to 100 ° C. The alkylating agent may be a suitable respiratory compound, i. E. compound containing another halogen atom (preferably bromine or iodine) in addition to the halogen atom for the desired R 'group. This method is particularly well suited to the preparation of a compound wherein R ¹ is a chloromethyl group, the alkylating agent being preferably bromochloromethane.

Alternatively, the starting 16-hydrogen, methyl or metal-17 α-χπΑρο ^ Η-17β-ηκ ^ 3ρ6oxylates corresponding to the compounds of formula I may be esterified on the 17 α-hydroxyl group. This can be accomplished in the usual way, for example by reacting the starting 17? -Hydroxy compound with the mixed carboxylic acid anhydride, which can for example be obtained by reacting the carboxylic acid with a suitable anhydride such as trifluoroacetic anhydride, preferably in the presence of an acid catalyst, for example p-toluenesulfonic acid or sulfosalicylic acid. Alternatively, the mixed anhydride can be prepared locally by reacting symmetric anhydride from the corresponding acid with a suitable additional acid, for example trifluoroacetic acid.

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

Alternatively, the 17 α-hydroxyl group may be esterified by reacting the starting 17 α-hydroxy compound with a suitable acid anhydride or acid chloride, if desired, in the presence of solvent-free hydroxyl group, for example chloroform, methylene chloride or benzene, and preferably strong an acid catalyst, for example perchloric acid, p-toluenesulfonic acid or a strong cation exchange resin, for example Amberlite IR 120 (the name "amberlite" is a trademark), the reaction being carried out at a temperature of o 25 to 100 ° C.

Compounds of formula I may also be prepared by reacting the corresponding androstane compound containing a 17 β-substituent of formula -COS (CH ₂ ) _n Y (in which Y is a substituent and η is 1 or 2) with a compound which replaces its group with a halogen atom.

Thus, the compounds of formula I may be subjected to a halogen exchange reaction, providing for the substitution of its group when it is halogen with another different halogen substituent. Thus, bromometal, fluoromethyl and fluoroethyl 17 β-thiocarboxyl compounds can be prepared from the corresponding iodomethyl or bromometall 17 β-thiocarboxyl compounds using bromides such as lithium bromide, in the case of bromometall 17 α-thiocarboxylate compounds, for example silver monofluoride or silver difluoride in the case of fluoromethyl or fluoroethyl 17 β-thiocarboxylate compounds. The starting iodomethyl 17 β-thiocarboxylate can be obtained from the corresponding chloromethyl 17 β-thiocarboxylate using, for example, alkaline, alkaline earth or quaternary ammonium iodide, for example sodium iodide.

The reaction is efficiently carried out in a solvent medium such as acetone, acetonitrile, methyl ethyl ketone, dimethylformamide, dimethylacetamide or ethanol.

The above reactions can also be carried out using starting compounds having different substituents or groups and which are subsequently converted into substituents or groups present in the compounds of the invention as described above.

Thus, the 11 β-hydroxy compounds of formula I can be prepared by reducing the corresponding N-oxo compound, for example using alkaline or alkaline earth borohydride, for example sodium or calcium borohydride, usually in an alcoholic or aqueous-alcoholic solvent such as methanol or ethanol. The n-keto compound can be prepared by oxidizing the corresponding II? -Hydroxysteroid, for example, using a chromic acid based reagent such as Johnny's reagent.

The II β-hydroxy compound of formula I can also be prepared by removing the protecting group of the corresponding compound having a protected hydroxyl group in the II β-position, for example three C _1-6 alkylsilyloxy group, such as trimethylsilyloxy group, or perfluoro or chloro- an alkanoyloxy group such as a trifluoroacetoxy group. Removal of the protecting group can be accomplished by hydrolysis. The trialkylsilyl group is easily removed by acidic or alkaline hydrolysis under mild conditions, or especially readily using fluoride, for example hydrogen fluoride or ammonium fluoride. The perfluoro- or chloro-alkanoyl protecting group may also be removed under mild acid or alkaline hydrolysis or alcoholic conditions, but preferably under acidic conditions when R ⁴ represents a chlorine atom. Protection of a hydroxyl group may be introduced, for example, by reacting II β-hydroxysteroid with a suitable reagent such as trialkylsilyl halide or perfluoro or chloroalkane anhydride.

Compounds of formula I may also be prepared by reacting the corresponding compound having a 9-N-double bond (and no substituent in the 5-position) with a reagent for the introduction of the corresponding 9 α-halogen-β-hydroxy grouping. This may include the initial formation of bromohydrin by reaction with N-bromoamide or imide, such as N-bromosuccinimide, followed by the formation of the corresponding 9 β, II β epoxide by reacting with the base and reacting the epoxide with hydrogen fluoride or hydrogen chloride to introduce the corresponding the desired fluorohydrin or chlorohydrin group. Alternatively, the 9,11-olefin compound may be reacted with N-chloroamide or -imide to introduce the desired 9 α-chloro-N β-hydroxy group directly.

The Δ ⁴ - compounds of the invention can conveniently be obtained by partial reduction of the corresponding Δ ^1,4 - compound, for example by hydrogenation, using a palladium catalyst, usually in a solvent medium, such as ethyl acetate or by homogeneous hydrogenation, if used e.g. tris (triphenylphosphine) rhodium chloride, usually in a solvent such as benzene, or by exchange hydrogenation, using for example cyclohexane in the presence of a palladium catalyst in a solvent, for example ethanol, preferably at boiling point. This reduction may also be carried out on the haloalkyl ester when it is sufficiently stable, or may be carried out at an earlier stage.

The aforementioned compounds containing the free -COSH group at the 17 β-position can be prepared, for example, by aminolysis by rearrangement of a suitable 17 β-thiocarbamoyloxycarbonyl androstane. 17 β-Thiocarbamoyloxycarbonyl androstane is a mixed anhydride of the corresponding 17 β-carboxylic acid and thiocarbamic acid and is conveniently prepared by reacting a 17 β-carboxylic acid salt of 17 α-ester or 16 α 17 α-acetonide with thiocarbamoyl halide. The thiocarbamoyl group is Ν, Ν-disubstituted and therefore may have the formula -COOCSNR ^A R ^B , where R ^A and R®, which may be the same or different, represent alkyl groups, for example C1-4 alkyl groups or R ^A and R® together with the nitrogen atom to which they are attached form a 5-8 membered ring which may optionally contain an additional heteroatom selected from oxygen, nitrogen and sulfur and / or which may be optionally substituted by one or two C, 3 -alkyl, for example methyl groups. Preferably, R ^A and R ® together with the nitrogen atom to which they are attached form a 58 membered ring which may optionally contain an additional heteroatom selected from oxygen, nitrogen and sulfur and / or which may be optionally substituted by one or two

With ₁₃ alkyl, for example methyl groups. Preferably R ^A and R ® represent C _1-4 alkyl substituents, most preferably being a N, N-dimethylthiocarbamoyl group. Thiocarbamoyl halides are the preferred chloride. The reaction may be accelerated by the addition of an iodine salt, for example sodium iodide.

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

Aminolysis by rearrangement can be accomplished, for example, by heating the mixed anhydride at elevated temperature, for example in the presence of ammonia, a primary amine, or most preferably a secondary amine, such as diethylamine or pyrrolidine. In the starting 17 β-carboxylic acids, the 16- and 17 α-positions are well substituted by the -R ³ and -OR ² groups required for the final product of formula I.

α-Hydroxyandrostane compounds in the 16-methylene series containing the desired 17 β-thiocarboxylic acid group as described above can be obtained from the corresponding 16 β-methyl-16 a, 17 α-epoxy 17 β-thiocarboxylic acid by regrouping using a strong acid, for example a strong carboxylic acid such as trifluoroacetic acid. These 16a, 17a-epoxides can be obtained from the corresponding 17 β carboxylic acids by exposure to the one salt of the 2-halogen-aza-aromatic compound, followed by action on the resulting product with hydrogen sulfide, or a salt thereof, to obtain the free 17 β -thiocarboxylic acid, which can be alkylated as described above, preferably "init" and to obtain the desired 17 β-carbothioate group.

a, 17? -isopropylidenedioxy compounds of formula I can be similarly prepared by treating the corresponding 17 β-carboxylic acid with that salt of a 2-halogen-aza-aromatic compound and adding hydrogen sulfide to the product obtained free 17 β-thiocarboxylic acid, which can then be esterified as described above.

The salts of 2-halogen-aza-aromatic compounds are capable of activating the carboxyl group. Such reagents are 2-halo-N-alkyl- or 2-halogen-N-phenyl-pyridine or pyrimidine salts having 1 to 2 other substituents such as phenyl and lower (e.g. (C ₍₄ ) alkyl groups such as methyl. 2- halogen atoms may be fluorine, chlorine, bromine or iodine atoms The salts are preferably sulfonates, for example tosylates; halides, for example iodides, fluoroborates or perfluoroalkylsulfonates, the convenient salt being 2-fluoro-N-methylpyridinium chloro tosylate tosylate tosylate methylbenzothiazole trifluoromethanesulfonate.

The 1 * 6 a, 17 a-epoxy-16 β-methyl-1-7 β-carboxylic acids used as starting materials in the above method can be prepared in the usual way, for example, as described in English patent No. 1 517 278 .

The starting materials used in the methods described herein for preparing the compounds of formula I include compounds of general formula II

(in which R * means a thiocarbamoyloxycarbonyl group -COOCSNR ^A R® where R ^A and R® have the meanings given above or a group of the formula -COSR ^IA where R ^IA stands for hydrogen or is a group having the meanings given by above for R ¹ or is a group that can be transformed into and

R ^b represents an esterified hydroxyl group or

R ® and R ^c together represent an isopropylidene dioxy group; or when R ^a represents the group -COSR ' ^A , R ^b is optionally a hydroxyl group;

R ^c represents hydrogen, a methyl group (which may be in the α- or β-configuration) or is a methylene group;

R ^d represents a hydroxyl or protected hydroxyl group (in the α- or β-configuration) or oxo group;

R 'represents hydrogen, bromine, chlorine or fluorine; or

R ^d and R 'together denote a carbon-carbon bond or epoxy group in the β-configuration;

R ^f stands for hydrogen or fluorine atom and symbol

T77- means single or double bond) and salts of those compounds having a free thiocarboxylic acid group; except for the compounds of formula I as described above.

When R ^d is a protected hydroxyl group, it may be a trialkylsilyloxy group or a perfluoro or perchloroalkanoyloxy group as described above.

The compounds of formula II as described herein, and methods for their preparation, are provided in our related unresolved application (British Application No. 8325400), and are therefore not included in the present description.

a- Hydroxy 17 β-thiocarboxylic acids of formula II and their salts can be converted to 17 α-hydroxy 17 β-thiocarboxylates of formula II, in which R 'denotes the group -COSR ¹ as defined in formula I or in 17 α-esters of 17 β-thiocarboxylic acid of formula II by the methods described above for the preparation of compounds of formula I. The esterification of the 17 α-hydroxyl group is preferably carried out with the corresponding carboxylic acid chloride in a solvent such as halogenated hydrocarbons, for example dichloromethane and preferably in the presence based on triethylamine, preferably at low temperature, for example 0 ° C.

α-hydroxy 17 β-thiocarboxylic acids of formula II and their salts are particularly suitable as intermediates in the preparation of androstane 17 β-thiocarboxylates of formula I, those in which R ^c represents a hydrogen atom, a - or β-methyl group or a methylene group, R ^e represents a hydrogen, chlorine or fluorine atom, R ^d represents a hydroxyl group in the β-configuration or is an oxo group preferably. More preferred compounds and salts thereof are those compounds in which R ^c denotes a methyl group in the α- or β-configuration or methylene group, R ′ denotes a fluorine atom, R ^d stands for a hydroxyl group in the β-configuration or oxo group and the symbol mt in 1 , 2 position means carbon carbon double bond.

Particularly preferred compounds of formula II are, for example, the following:

α-fluoro-N β, 17 α-dihydroxy-16 β-methyl-3-oxo-androsta-1,4-diene-17 β-thiocarboxylic acid;

α-fluoro-N-β, 17 α-dihydroxy-16-methyl-3-oxoandrost-1,4-diene-17 β-thiocarboxylic acid;

α-fluoro-N β, 17 α-dihydroxy-16-methylene-3-oxo-androsta-1,4-diene-17 β-thiocarboxylic acid;

a, 9 a difluoro-N β, 17 α-dihydroxy-16 α-methyl-3-oxoandrost-1,4-diene-17 β-thiocarboxylic acid and the corresponding 11 ketones and their salts.

The advantage of the above intermediates is that they can be directly halogenated to give haloalkyl 17 β-thiocarboxylates when the corresponding R'SH thiols are not available. The salts of these 17? -Hydroxy 17 β-thiocarboxylic acids may for example be alkali metals, for example lithium, sodium or potassium salts, alkaline earth metals, for example calcium or magnesium salts, tertiary amine salts, for example pyridine or triethylammonium salts ammonium salts, such as tetrabutylammonium salts.

α-hydroxy 17 β-thiocarboxylic acids can be obtained, for example, by reacting a reactive derivative of the corresponding 17 α-hydroxy-17 β-carboxylic acid with a hydrogen sulfide or sulfide or hydrosulfide salt. In general, the cation of the sulfide or hydrosulfide salt may be, for example, an alkaline salt such as sodium or potassium hydrogen sulfide. The above reactive derivatives correspond to compounds of formula II, in which R ^b represents a hydroxyl group and the -COR ⁷ group is present in the 17 β-position and R ⁷ represents a group of formula

in which Χ, Υ and Ζ, which may be the same or different, each denote CH or Ν, with one or two of X, Y, and Ζ denote M. the heterocycle may be optionally substituted on at least one carbon atom with a lower alkyl group (e.g. containing from 1 to 4 carbon atoms, e.g. methyl) and / or where the heterocyclic ring contains two adjacent carbon atoms and this ring optionally has a benzene ring fused to the adjacent carbon atoms.

The above reactive derivatives of formula II are preferably prepared by reacting the corresponding 17 α-hydroxy-17 β-carboxylic acids of formula II with a symmetric or asymmetric compound of formula:

R ⁷ - W - R ⁷ III in which W represents the group CO, CS, CO or SO ₂ and the groups R ⁷ , which may be the same or different, have the above meanings.

The compounds of formula III are conveniently symmetrical. Compounds of formula III are generally used in which W is CO, CS or SO. For example, particularly useful compounds are N, N-carbonyldi (1,2,4triazole), N, N'-carbonyldibenzotriazole, N, N'carbonyldibenzimidazole, N, N'carbonyldi (3,5dimethylpyrazole), N, N'-thionyldiimidazoimidazo, especially, N, N'-carbonyldiimidazole and N, N'thiocarbonyldiimidazole.

The preparation of 17 α-hydroxy 17 β-thiocarboxylic acid of formula II, as defined above, is accomplished by reacting 17 α-hydroxy 17 β-carboxylic acid with a compound of formula III, followed by reaction of the intermediate having 17 β-COR ⁷ grouping with hydrogen sulfide or a salt thereof, preferably "in situ", without isolating the intermediate.

α-acyloxy 17 β-thiocarboxylic acid of formula II can similarly be obtained directly from the corresponding 17 acacyloxy 17 β-carboxylic acid by reaction with a compound of formula III. 17 α-acyloxy 17 β-carboxylic acid can be obtained by esterification of the corresponding 17 α-hydroxy 17 β-carboxylic acid according to the methods described in GB 1 384 372.

The reaction with a compound of formula III is carried out in the presence of an inert anhydrous solvent, for example a substituted amide solvent such as Ν, Ν-dimethylformamide or Ν, мети dimethylacetamide, preferably in the absence of water, and preferably at or at ambient temperature, e.g. temperature from -30 ° C to + 30 ° C. The reaction is conducted under approximately neutral conditions, preferably in an inert atmosphere, i. under nitrogen. The same solvents and conditions are also used in the next step with hydrogen sulfide or a salt thereof. The heterocyclic compound, for example imidazole or 1,2,4-triazole formed as a by-product, can for example be easily removed by extraction with water.

The above reactions can also be carried out with compounds having various substituents or groupings, which are then converted, as described above, to compounds of formula I.

The starting androstane 17 β-carboxylic acids used in the above methods can conveniently be prepared, for example, by oxidizing 21-hydroxy-20-ketopregnan with periodic acid, in a solvent medium and preferably at room temperature. Alternatively, sodium bismuth may be used to effect the desired oxidative removal of the 21st carbon atom in the 17 α-acyloxy pregnane compound. Naturally, if the source of the distillate contains a substitute sensitive to the oxidation described above, then such a group should be suitably protected.

The following examples illustrate the invention.

Melting points were determined in ° C on the Koffler block and are not adjusted. Optical spins were determined at room temperature in dioxane solution.

TLC (thin layer chromatography), p.l.c. (preparative chromatography) and HPLC (high performance liquid chromatography) were performed on silica.

The solutions were dried over magnesium sulphate unless otherwise stated.

Getting I.

α-Fluoro-N β-hydroxy-16 β-methyl3-oxo-17 α-propionyloxy-androsta-1,4-diene 17 β-thiocarboxylic acid (I)

Solution of 9? -Fluoro-N? -Hydroxy-16? -Methyl-3-oxo-17? -Propionyloxyandrost-

1,4-Diene-17 β-carboxylic acid (5.00 g) dissolved in ethyl acetate (1/2 mol) and triethylamine (5.3 ml) in dichloromethane (75 ml) was stirred under nitrogen and dimethylthiocarbamoyl chloride () was added thereto. 5,071 g). After 24 hours, more reagent (5.320 g) was added. After 47 hours, the mixture was diluted with ethyl acetate and washed with N-hydrochloric acid, 5% sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to give a viscous yellow oil (9.043 g) . It was dissolved in diethylamine (50 ml) and stirred 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 extracted with ethyl acetate, then the acidic products were again extracted into 5% sodium carbonate solution. The aqueous phase was acidified with 6 N-hydrochloric acid (50 ml) and extracted with ethyl acetate. The extracts were washed with N-hydrochloric acid and water, dried and evaporated to an off-white solid (3.440 g). It was recrystallized from acetone to give off-white crystals (1.980 g) of the title 17 β-thiocarboxylic acid, m.p. 172-173 ° C.

The analytical sample is obtained after two recrystallizations from acetone and is white crystals of m.p. 177-179 °, [α] _D + 110 ° (c 1.05).

Receipt II.

S-chloromethyl 9a-fluoro-16 β-methyl3,11-dioxo-17-propionyl-oxyandrost-1,4diene-17-thiocarboxylate (II).

John's N-reagent (1.5 ml) was added dropwise over 10 minutes with stirring to a solution of the compound of Example I (described below) (998 mg) in acetone (2 ml) and dimethylformamide (2 ml). After 30 minutes, the reaction mixture was slowly diluted with water (100 ml) with stirring and the resulting suspension was kept in the cold for 1 hour. The resulting precipitate was collected by filtration, washed with water and dried to give a cream solid (877 mg). After preparative chromatography in chloroform-acetone (10: 1), a white foam (755 mg) was obtained which was recrystallized twice with acetone to yield white needles from the titled P-ketone (523 mg), m.p. 204-205 °, [α] _D + 94 ° (c 1.04).

Receipt III.

β-N, N-dimethylthiocarbamoyloxycarbonyl-9? -fluoro-N? -hydroxy-16? -methyl-17? -propionyloxyandrosta-1,4-dien-3-one (III).

To a solution of 9? -Fluoro-N? -Hydroxy-16? -Methyl-3-oxo-17? -Propionyloxyandrost-1,4-diene-17? -Carboxylic acid (0.434 g) in dichloromethane (8 ml) was added sequentially triethylamine (0.14 ml), dimethyl thiocarbamoyl chloride (0.248 g) and sodium iodide (0.149 g) and the mixture was stirred under nitrogen at 20 ° C for 6 hours. Ethyl acetate (30 ml) was added and the total volume was reduced in half under vacuum. Ethyl acetate (50 ml) was added again and the solution was washed with water, 2 N hydrochloric acid, water, 3% bicarbonate solution, water and saturated sodium chloride solution. The solution was concentrated in vacuo and the product crystallized (0.329 g). Recrystallized from acetone (2 x) to give the title anhydride as white needles, m.p. 191 DEG-193 DEG, [[alpha]] _D + 82 DEG (p.0.57).

Receipt IV.

α-fluoro-N β-hydroxy-16 α-methyl 3 -oxot! 7? -Propionyloxyandrosta-1,4-diene17 β-thiocarboxylic acid (IV).

A suspension of (III) (2.467 g) in diethylamine (25 ml) was stirred under nitrogen at reflux. After 3.5 hours, the reaction mixture was poured onto glacial 3 N hydrochloric acid (300 ml) and the mixture 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, coated with ethyl acetate and acidified with hydrochloric acid to pH I. The aqueous phase was further extracted with ethyl acetate and the combined extracts washed with water and saturated sodium chloride solution. They are dried and the solvent removed in vacuo. The residue was recrystallized twice from acetone to give the title thiocarboxylic acid as white needles (1.309 g), m.p. 141-1430, [α] _D + 30 ° (c 0.51).

Getting V.

II β-hydroxy-3-oxo-17? -Propionyloxyandrosta-1,4-diene-17 β-carboxylic acid (V).

A solution of II β, 17 α-dihydroxy-3-oxoandrost-1,4-diene-17 β-carboxylic acid (13.5 g) and triethylamine (18 ml) in dichloromethane (500 ml) was cooled to 4 ° C Propionyl chloride (14.2 ml) was added dropwise over 15 minutes. Stirring at 4 ° C was continued for a total of one hour and the mixture was washed sequentially with 3% sodium bicarbonate, water, 2 N hydrochloric acid, water and saturated sodium chloride solution. It is dried and evaporated in vacuo. The residue was dissolved in acetone (300 ml) and diethylamine (14.3 ml) was added with stirring. After 1 h at 20 ° C, the solvent was removed in vacuo and the residue was dissolved in water (150 ml). After acidification to pH 1 with 2 N hydrochloric acid, the product was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried and concentrated to a small volume. The solid was separated by filtration, washed with ethyl acetate and dried in vacuo at 50 ° to give 17 propionate carboxylic acid from the title in the form of crystals (13.309 g), [a] _D + 2 ° (by 1.10) .

A 389 mg portion was recrystallized twice from methanol to give an analytical sample (256 mg); 244-245 ° (decomposition), [cc] _D + 3 ° (c 0.83).

Receipt VI.

a, 9? -difluoro-N? -hydroxy-16 amethyl-3-oxo-17? -propionyloxyandrosta-

1,4-Diene-17 β-carboxylic acid (VI)

A solution of 6 a, 9 a-difluoro-N β, 17 adihydroxy-16 α-methyl-3-oxoandrost-1,4-diene-17 β-carboxylic acid (2.113 g) and triethylamine (2.5 ml) in dichloromethane (60 ml) was stirred and propionyl chloride (1.85 ml) was added at about 0 ° C. After 1 hour, the mixture was diluted with more solvent (50 ml) and washed sequentially with 3% sodium bicarbonate, water, 2Ν hydrochloric acid, water and brine. Dry and evaporate to a creamy solid. It 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 residual resin was dissolved in water (30 ml). After acidification to pH 1 with 2 N hydrochloric acid, the precipitate was removed, washed, washed with water and dried to give the title carboxylic acid 17? -Propionate (2.230 g), m.p. 220-225 °, [α] _D + 4 ° (c 0.70).

β-Ν, Ν-dimethylthiocarbamoyloxycarbonyl-9 α-fluoro-β β-hydroxy-16 α-isopropylidenedioxyandrost-1,4-dien-3-one (VII)

To a solution of 9? -Fluoro-11? -Hydroxy-16 ?, 17? -Isopropyridinedioxy-3-oxoandrost-1,4-diene-17? -Carboxylic acid (1.000 g) in dichloromethane (15 ml) and triethylamine (0.33 ml) of N, N-dimethylthiocarbamoyl chloride (588 mg) was added under nitrogen and the mixture was stirred at room temperature. After 68 hours, the reaction mixture was diluted with ethyl acetate (50 ml) and washed with N-hydrochloric acid (2.10 ml), 5% sodium bicarbonate solution and water, dried and evaporated to give an off-white color. crystals (1,123 g). Preparative chromatography on a 200 mg portion in chloroform-acetone (9: 1) two cream solids (161 mg), which was recrystallized from ethyl acetate and obtained as white needles from the title compound mixed anhydride (131 mg), m.p. . 279-281®, [α] _D + 174 ° (c 0.61, dimethyl sulfoxide).

Receipt VIII.

β-Ν, Ν-dimethylthiocarbamoyloxycarbonyl-6a, 9a-difluoro-β β-hydroxy-16a, 17a -isopropylidenedioxyandrost 1,4-diene-3-one (VIII).

To a solution of 6 a, 9 a-difluoro-N β-hydroxy-16 a, 17-isopropylidenedioxy-3-oxoandrost-1,4-diene-17 β-carboxylic acid (4.354 g) in dichloromethane (150 ml) containing triethylamine ( 1.4 ml) was added Ν, Ν, dimethylthiocarbamoyl chloride (2.519 g) and the reaction mixture was stirred under nitrogen at 22 ° for 80 minutes. Ethyl acetate (500 ml) was added and the resulting solution was washed successively with 2 N-hydrochloric acid, water, brine and brine, dried and concentrated. Upon cooling, crystals were obtained and, after filtration and vacuum drying, the title anhydride (3.562 g) was obtained as light yellow prisms, m.p. 283-287 ° (decomposition), [a] _D + 156 °, (0.84, dimethyl sulfoxide).

Receipt IV.

a, 9 α-difluoro-β β-hydroxy-16 α, 17 α-isopropylidenedioxy-3-oxoandrost -

1,4-Diene-17 β-thiocarboxylic acid (IX).

A suspension of VIII (3.455 g) in diethylamine (200 ml) was heated at reflux under nitrogen for 6 hours. The initial suspension dissolves rapidly, but after 30 minutes a light brown suspension is formed which remains unchanged. The cooled reaction mixture was poured onto water (1.0 L), acidified with concentrated hydrochloric acid (210 ml) to pH 1 and extracted with ethyl acetate. The combined extracts were washed with water and extracted with 5% sodium carbonate solution and water. The aqueous extracts were collected. The extract was acidified with 6 N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with water and saturated sodium chloride solution, dried and the solvent removed in vacuo to give a pale gray solid (12.31 g). Part of the product was recrystallized (0.408 g) from ethyl acetate to give the title thiocarboxylic acid (0.149 g), mp 191-199 ° C, [α] _D + 124 ° (C 1.04, dimethyl sulfoxide).

Receive X.

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

A solution of 6? -Fluoroprednisolone (4.987 g) in tetrahydrofuran (50 ml) was stirred with a solution of periodic acid (10.0 g) in water (24 ml) at 22 ° C. After 50 minutes the tetrahydrofuran was evaporated and the aqueous suspension filtered. The solid was washed with water (300 ml) and dried to give a white solid (4.80 g). A portion of 271 mg was recrystallized from methanol to give the title acid (171 mg) as white needles, mp 241 - 248 ° C [a] + 54 ° (by 0.825).

Receipt XI.

α-fluoro-β β-hydroxy-3-oxo! 7? -Propionyloxyindrosta-1,4-diene-17 β-carboxylic acid (XI)

To a solution of X (4.491 g) and triethylamine (4.46 ml) in dry dichloromethane (160 ml) at 5® and stirring, propionyl chloride (2.80 ml, 2.96 g) in dry dichloromethane (about 6 ml) was added dropwise over 5 minutes at temperature below 0 ° C. The reaction mixture was kept at below 0 ° C for a further 20 minutes and diluted with dichloromethane (160 ml), washed with sodium bicarbonate solution, water, dried and evaporated to a white solid (5.701 g). It 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 using 2Ν hydrochloric acid (50 ml) while stirring and the product extracted with ethyl acetate three times. The extracts were combined, washed with water (50 ml), dried and evaporated to give a white foam (5.819 g). Part of it (304 mg) was recrystallized from ethyl acetate to give 17 propionate (144 mg) from the title as small plates, m.p. 224-227 °, [α] _D + 3 ° (c 0.861).

Receipt XII - XXIII.

Working as described in Preparation I, but using 17 β-carboxylic acids corresponding to the desired 17 β-thiocarboxylate as starting materials (details of the processes are given in Table 1 below), the following compounds are obtained:

XII 17a-acetoxy-9a-fluoro-11 β-hydroxy-16 β-methyl-3-oxo-androsta-1,4-diene-17 β-thiocarboxylic acid, m.p. 178.5-179 ° [a] _D + 98 ° (p.1.02).

XIII 17? -Butyryloxy-9? -Fluoro-N? 175176 ", [a] _D + 107" (c 0.96).

XIV 9 α-Fluoro-N β-hydroxy-17 α-isobutyryloxy-16 β-methyl-3-oxoandrost-1,4diene-17 β-thiocarboxylic acid, m.p. 177179 °, [α] _D + 119 ((c 0.90).

XV II β-hydroxy-3-oxo-! 7? -Propionyloxyandrosta-1,4-diene-17 β-thiocarboxylic acid, m.p. 134-138 °, [α] _D + 67 ° (c 0.66).

XVI II β-Hydroxy-6 β-methyl-3-oxo17? -Propionyloxyandrosta-1,4-diene-17 βthiocarboxylic acid, m.p. 159-163 ", [a] _D +113" (c 0.78);

XVII 9 α-chloro-N β-hydroxy-6 β-methyl-3-oxo-1 7 α-propionyloxyandrosta-1,4diene-17 β-thiocarboxylic acid, m.p. 167171 ", [α] _D + 128 ° (c 0.99);

XVIII 9 α-Fluoro-β β-χΗΑρο ^ π-16 α-methyl-3-oxo-17 α-propionyloxyandrosta -

1,4-diene-17 β-thiocarboxylic acid, m.p. 141-143 ° [a] _D + 30 (c 0.51);

XIX 6a, 9a-difluoro-N β-hydroxy16? -Methyl-3-oxo-17? -Propionyloxyandrosta-1,4-diene-17 β-thiocarboxylic acid, m.p. 136-139 ", [α] _D -30 ° (c 0.56);

XX. 9? -Fluoro-N? -Hydroxy-16-methylene-3-oxo-17? -Propionyloxyandrosta-1,4diene-17? -Thiocarboxylic acid, m.p. 236239 ", [a] _D -71" (c 0.99);

XXI. II β-hydroxy-3-oxo-17 α-propionyloxyandrosta-4-ene-17 β-thiocarboxylic acid, m.p. 176-177 «, [a] _D + 101®

XXII 9? -Fluoro-N? -Hydroxy-16 ?, 17? -Isopropylidenedioxy-3-oxoandrost-1,4diene-17? -Thiocarboxylic acid, m.p. 274304 (dec.), [Α] _D + 121 ° (c 0.51, dimethyl sulfoxide);

XXIII 6 α-Fluoro-N β-hydroxy-3-oxo-17 α-propionyloxyandrosta-1,4-diene-17 β-thiocarboxylic acid m.p. 189-193 (R), [] _D + 72 ° (c 0.74);

Table 1

Formation of mixed anhydrides

Receiving 17 β-carboxylic acid embedded (d) Cl-CSNMe ₂ (g) NEt ₃ (ml) solvent (CH ₂ Cl ₂ ) (ml) response time (days) at room temperature XII 5,000 2.940 1.66 75 5 ^1a XIII 15.354 8,809 4.8 250 6 XIV 4.182 2.399 1.3 80 4 XV 7.148 4.40 2.6 150 6 ^{, b} XVI 6.137 3.77 2.05 140 6 ^1s XVII 5.963 3.350 1.34 100 7 XVIII 4.207 2.39 1.35- 80 0.67 ^71d 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 1 (continued)

Interaction between mixed anhydride intermediates with diethylamine

Receive- bath NHEt ₂ (ml) Boiling time, in hours product (d) crystallization solvent XXII 50 5.5 2.104 EA ² » 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 ⁶ A ⁵ XXII (a) 8 (a) 3 0.464 ' A (B) 16 (B) 2.5 XXIII 60 4.5 2.88 EA - P

Note:

EA = ethyl acetate;

A = acetone;

P = petroleum ether, b.p. 60-80 ° C

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

Characterization was performed on the sample, which was further recrystallized twice from ethyl acetate.

Yield (a) 84%; (B) 69%.

3. The product is dissolved in ethyl acetate (about 0.2 mol).

4. The intermediate dimethylthiocarbamic anhydride (1.435 g) was recrystallized from ethyl acetate. A 95 mg sample is taken as characterized.

5. Characterization was performed on a sample twice more recrystallized from acetone (yield: 73%).

6. The product is crystallized from ethyl acetate.

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

8. The intermediate dimethylthiocarbamic anhydride (1.123 g) was crystallized from ethyl acetate. A 200 mg sample was chromatographed (preparative chromatography, chloroform-acetone 9: 1) and recrystallized from ethyl acetate (65% yield).

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

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

Preparation XXIV α-Chloro-N-p-hydroxy-16 β-methyl-3-oxo-17 α-propionyloxyandrost-1,4-diene-17 β-thiocarboxylic acid and 9 α, II β-επο ^ Η-16 β-methyl- With -oxo-17? -Propionyloxyandrost-

1,4-Dione-17 β-Thiocarboxylic acid (XXIV)

A solution of 17 β-Ν, Ν-dimethylthiocarbamoyloxycarbonyl-9 α-chloro-N β-ΧΗΛρο ^ Η-16β-methyl-17 α-propionyloxyandrost-1,4-dien-3-one (5.5586 g) in diethylamine (60 ml ) was refluxed under nitrogen for 5 hours and 40 minutes. The reaction mixture was poured into water (450 ml), acidified to pH 10 with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 60 ml). The combined extracts were washed with water, then extracted with aqueous sodium carbonate (4 x 50 ml). The aqueous extracts were acidified with 6 N hydrochloric acid to pH 1 and extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with water and brine, dried and the solvent removed in vacuo to give a colorless foamy product (2.834 g).

Two crystallizations of the ethyl acetate mixture gave 9? -Chloro-N? -Hydroxy-16? -Methyl-3-oxo-7? -Propionyloxyandrosta-1,4-diene-17? -Thiocarboxylic acid (0.527 g ) as white prisms with m.p. 167 to 171 °, [α] _D + 128 ° (c 0.99). The mother liquors contained an additional amount of the above 9? -Chloro-? Β-hydroxy-thiocarboxylic acid together with 9?

1,4-Diene-17 β-thiocarboxylic acid.

Receiving XXV

8-iodomethyl-9? -Fluoro-11? -Hydroxy16? -Methyl-3-oxo-17? -Propionyloxyandrost-1,4-diene-17? -Thiocarboxylate.

A solution of the compound of Example I (described below) (500 mg) and sodium iodide (1.874 g) in acetone (15 ml) was stirred and refluxed for 6.5 hours. Ethyl acetate (75 ml) was then added and the solution was washed sequentially with water, 10% sodium thiosulphate solution, 5% sodium bicarbonate solution and water, dried and evaporated to give an off white porous product (525 mg). Preparative chromatography and chloroform-acetone (6: 1) gave an off-white foamy product (478 mg) which was recrystallized twice from acetone without heating above room temperature to give colorless crystals of the title S-iodomethyl ester (241 mg) ) with m.p. 196-197 °, [α] _D -32 °) with 1.01).

Receipts XXVI - XXXVII.

Working as described in Preparation XXV, but using S-chloromethyl 17 β-thiocarboxylates corresponding to the desired product as starting materials (the details of the processes are outlined in Table II below), the following compounds are obtained:

XXVI S-iodomethyl 17 α-acetoxy-9 afluoro-β β-χΗΑρο ^ Η-16 β-methyl-3-oxoandrost-1,4-diene-17 β-carbothioate, m.p. 204-205 °, [α] _D -29 ° (c 0.98);

XXVII S-iodomethyl II β-hydroxy-3-oxo-17 α-propionyloxyandrost-1,4-diene-17 β-thiocarboxylate, [α] _D + 26 ° (c 0.47);

XXVIII S-iodomethyl II β-hydroxy-16 βmethyl-3-oxo-1,7α-propionyloxyandrosta-1,4diene-17 β-thiocarboxylate, [α] _D + 5 ° (c 0.74);

XXIX S-iodomethyl 9? -Chloro-N? -Hydroxy-16? -Methyl-3-oxo-! 7 α-propionioxy androsta-1,4-diene-17 β-thiocarboxylate, [α] _D + 7 ° (c 0.36);

XXX S-Iodomethyl 9? -Fluoro-? Β-hydroxy-16? -Methyl-3-oxo-17? -Propionyloxyandrost-1,4-diene-17 β-thiocarboxylate, [a] _D + 85 ° (c 0.55) ;

XXXI S-Iodomethyl 6 a, 9 a-difluoro-N β-hydroxy-16 α-methyl-3-oxo-17 α-propionyloxyandrost-1,4-diene-17 β-thiocarboxylate

XXXII S-Iodomethyl 9? -Fluoro-N? -Hydroxy-16-methylene-3-oxo-17? -Propionyloxyandrost-1,4-diene-17? -Thiocarboxylate, m.p. 191-199 °, δ] _D -31 ° (c 0.99);

XXXIII S-iodomethyl 9 α-fluoro-β β-hydroxy-3-oxo-17 α-propionyloxyandrosta

1,4-diene-17 β-thiocarboxylate, mp.175-178 ^O , [α] _D + 4 (c 0.50);

XXXIV S-Iodomethyl 6 α-fluoro-β β hydroxy-3-oxo-17 α-propionyloxyandrosta -

1,4-diene-17 β-thiocarboxylate, m.p. 195-1970, [a] _D + 18 '(c 0.64);

XXXV S-Iodomethyl 17 α-acetoxy-βα, α-difluoro-β β-hydroxy-16α-methyl-3-oxoandrost-1,4-diene-17 β-thiocarboxylate; 241-243 °, [α] _D + 78 ° (c 0.78);

XXXVI - S iodomethyl 17 α-butyryloxy10 6 α, 9 α-difluoro-β β-hydroxy-16 α-methyl-3oxorosta-1,4-diene 17 β-thiocarboxylate, mp 210-212 ", [a] _D +89 "(c 0.90);

XXXVII S-iodomethyl 9 α-fluoro-β β-hydroxy-16 α-, 17 α-isopropylidenedioxy-315 oxoandrost-1,4-diene-17 β-thiocarboxylate, m.p. 261-270 ° (decomposition), [a] _D +97 (c 0.48, dimethyl sulfoxide).

Table 2

Halogen exchange at S-halogenoalkyl 17- (o6) -acyloxyandrostane-II β-thiocarboxylates

Receive- bath Nal (mg) source steroid acetone solvent (ml) reaction time (hour) at reflux PLC SNCMS ₂ CO (SiO ₂ ) recrystallization solvent product (mg) halide nested (mg) XXVI 6632 C1 1715 20 3.5 EA 216 ¹ XXVII 3800 C1 925 10 4 - 1084 XXVIII 3260 C1 840 10 3 - 969 XXIX 1995 C1 536 20 6.5 - 591 XXX 2160 C1 580 10 3 - 685 XXXI 1200 C1 303 30 5 - 317 ³ XXXII 7361 C1 1953 23 6 19: 1 A 296 ² XXXIII 5500 C1 1300 35 4 M 1250 ⁶ XXXIV 8400 C1 2000 54 4.5 EA-R 1800 XXXV 19000 C1 4750 200 5 EA 4620 ⁵ XXXVI 6500 C1 1620 70 5.5 EA 1610 « XXXVII 5491 C1 1419 20 24 9: 1 A 224 '

E A = ethyl cetate

A = acetone

M = methanol

P = petroleum ether, mp 60-80 ° C

Notes:

1. Obtained from a sample (300 mg) of the crude product (2.024 g).

2. Obtained from a sample (400 mg) of the crude product (3.058 g).

3. The product is rightly used to prepare the corresponding fluoromethyl 17 βthiocarboxylate.

4. Dissolved with 0.5 H ₂ O.

5. Dissolved with 0.1 E A.

6. Dissolved with 0.2 EA + 0.5 H ₂ O.

7. Obtained from a sample (300 mg) of the crude crystalline product (1.611 g).

Receiving XXXVIII.

S-iodomethyl 6 a, 9 a-difluoro-N β-hydroxy-16 a, 17 a-isopropylidenedioxy-3-oxoandrost-1,4-diene-17 β-thiocarboxylate.

(XXXVIII)

A solution of the compound of Example 4 (described below) (0.795 g) was heated at reflux with sodium iodide (2.969 g) for 5.5 hours. Ethyl acetate (75 ml) was added and the solution was washed successively with water, brine and then dried and the solvent removed in vacuo to give an off-white solid (0.893 g). Part of it (0.205 g ) was recrystallized twice from ethyl acetate to give the titleiodomethylthioester (0.105 g) as white prisms, m.p. 260-262 ° (decomposition), [α] _D + 81 ° (with 0.6, dimethyl sulfoxide).

Receiving XXXIX.

S-2-Bromethyl 9 α-fluoro-N β-hydroxy-16 β-methyl-3-oxo-17 α-propionyloxyandrosta-1,4-diene-17 β-thiocarboxylate (XXXIX) (0.05 g) was reacted as described for the S-chloromethyl ester (Example 1, method A, described below), but using 1,2-dibromoethane to obtain colorless crystals of the title 8-2'-bromoethyl ester (0.409 g), m .t. 174-175 ", [a] _D +120" (p. 1.04).

Getting XL.

α, 17 α-epoxy-9 α-fluoro-β β-hydroxy-16 β-methyl-3-oxoandrosta-1,4-diene-17 β-thiocarboxylic acid (XL)

Mixture of 16 a, 17 a-epoxy-9 a-fluoro-N β-hydroxy-16 β-methyl-3-oxoandrost-! , 4-diene-17 β-carboxylic acid (377 mg) and 2-fluoro-1-methylpyridine tosylate (340 mg) in dry dichloromethane (7 ml) were stirred, cooled in ice and triethylamine was added over one minute. (0.42 ml). After one hour, hydrogen sulfide was bubbled through the mixture for 30 minutes to give a yellow solution. Thin layer chromatography (chloroform-acetone-acetic acid, 30: 8: 1) indicated that much of the less polar product was formed. The reaction mixture was allowed to warm to room temperature for 1 hour and then 2 N-hydrochloric acid (30 ml) was added and the product was extracted with ethyl acetate (3 x 20 ml). The acidic product was extracted from the organic phase with 5% sodium carbonate, the aqueous extracts were combined and acidified with 6 N-hydrochloric acid and then extracted with ethyl acetate. The combined acidic extracts were washed with water, dried and concentrated in vacuo to give off after filtration. cava crystals (274 mg), probably in most of the unstable 16 a, 17 a-epoxy-9 afluorbg-II β-hydroxy-16 β-methyl-3-oxo-androsta-1,4-diene-17 β -thiocarboxylic acid (none of the starting oxyacid) as judged by thin layer liquid chromatography (chloroform-acetone-acetic acid 30: 8: 1, Ry about 0.7).

Getting XLI.

S-Chloromethyl 16a, 17a-epoxy-9a-fluoro-N β-hydroxy-16 β-methyl-3-oxoandrost-

1,4-diene-1Ί β-thiocarboxylate (XLI)

Method A

To a suspension of 16 a, 17 a-epoxy-9 afluoro-N β-hydroxy-16 β-methyl-3-oxoandrost-1,4-diene-17 β-carboxylic acid (753 mg) and 2-fluoro-1- methylpyridine tosylate (680 mg) in dichloromethane (7 ml) was added dropwise at 0 < 1 > C triethylamine (1.39 ml) and then stirred at 0 < 0 > C for 1 hour. Hydrogen sulfide was passed through the mixture for 15 minutes and the resulting solution was stirred at 0 ° C for another 1 hour. Bromochloroethane (0.26 ml) was then added and the mixture was heated to room temperature with stirring. After a further 1.5 hours, the reaction mixture was diluted with ethyl acetate (250 ml) and washed sequentially with 2 N hydrochloric acid, 5% sodium bicarbonate solution and water, dried and evaporated to a pale yellow solid (818 mg). . It was subjected to preparative chromatography with chloroform-acetone (9: 1) (twice). The main product (515 mg) was recrystallized from acetone to give white needles of the title S-chloromethyl ester epoxide (447 mg), m.p. 246-251 (R), [a] ^D + 131 (c 0.67).

Method B

To a suspension of 16 a, 17 a-epoxy-9 α-fluoro-N β-hydroxy-16 β-methyl-3-oxoandrost-1,4-diene-17 β-carboxylic acid (376 mg) and 2-chloro- N-methylbenzothiazole trifluoromethane sulfonate (400 mg) dichloromethane was added dropwise at 0 ° C triethylamine (0.7 ml). The resulting solution was stirred at 0 ° C for 1.25 hours and then hydrogen sulfide was passed through the mixture for 10 minutes. After another hour at 0 ° C, bromochloromethane (0.13 ml) was added and stirred at room temperature. Two new portions of bromochloromethane (0.13 ml) were then added after 1.5 and after 1.8 hours. Fifteen minutes after the last addition, the reaction mixture was diluted with ethyl acetate (200 mL) and washed sequentially with 21 N hydrochloric acid, 5% sodium carbonate solution and water, dried and evaporated to give a red solid with crystal structure. It was subjected to preparative chromatography in chloroform-acetone (19: 1) (three times). The more polar product gave a pale pink solid of the title S-chloromethyl ester (134 mg) identical to the authentic sample by thin layer chromatography.

Receipt XLIII.

S-chloromethyl 9 α-fluoro-β, 17 α-dihydroxy-16 β-methylene-3-oxoandrosta! , 4-diene-17 β-thiocarboxylate (XLII)

A solution of XII (400 mg) in trifluoroacetic acid (16 ml) was stirred at room temperature. After 5.5 hours, the reaction mixture was evaporated to almost dryness and the residue was dissolved in ethyl acetate (100 ml). The solution was washed with 5% sodium bicarbonate solution and water, dried and evaporated to give a yellowish green foam product (466 mg). It was subjected to preparative chromatography in chloroform-acetone (9: 1) (three times). A sample (80 mg) of the title product (315 mg) was recrystallized twice with acetone to give white crystals of the title 16-methyl 17-alcohol (48 mg), m.p. 242 243 °, [α] _D + 36 ° (c 0.50).

Receipt XLIII.

? -fluoro-17? -hydroxy-16 β-methyl3,11-dioxoandrost-1,4-diene-17 β-carboxylic acid (XLIII)

A suspension of 9? -Fluoro-17,21-dihydroxy-16 β-methylpregna-1,4-diene-3,11 -20-trion (4.842 g) in THF (50 ml) was stirred and cooled on and to ice a solution of periodic acid (4.255 g) in water (15 ml) was added dropwise over 5 minutes. The reaction mixture was stirred at 22 [deg.] For 2.25 hours, during which time most of the suspension was dissolved. The solvent was removed in vacuo by adding water periodically to maintain the original volume. The resulting precipitate was filtered off, washed with water and dried in air and in vacuo to give the title carboxylic acid as cream prisms (4.55 g), mp.270-272® (decomposed), [a] _D (c 1.04, dimethyl sulfoxide).

Receiving XLIV.

α-Fluoro-β, 17 α-dihydroxy-16 β-methyl-3-oxoandrost-1,4-diene-17 β-thiocarboxylic acid (XLIV)

To a solution of 9 α-fluoro-N β, 17 adihydroxy-16 β-methyl-3-oxoandrost-1,4-diene-17 β-carboxylic acid (0.502 g) in dry N, N-dimethylformamide (15 ml), N, N-Carbonyldiimidazole (0.435 g) was added under cooling and stirring at -5 ° C under nitrogen atmosphere and the reaction mixture was stirred at -5 ° for 18 hours. Hydrogen sulphide gas was bubbled through the mixture for 20 minutes and the solution stirred for another 4 hours, gradually allowing it to warm to 22 °. The reaction mixture was poured into ethyl acetate and the resulting solution was washed with 2 N-hydrochloric acid and water, then extracted with 2 N sodium carbonate solution (3 x 50 ml). The combined extracts were washed with ethyl acetate (60 ml) and new ethyl acetate (100 ml) was added. It is acidified with hydrochloric acid to pH 1.0. The aqueous layer was extracted with new ethyl acetate and the extracts were washed with water and brine, then dried and the solvent removed in vacuo to give a white solid which was recrystallized twice from ethyl acetate to give the acid. from the title (0.315 g), m.p. 198-201 ° (decomposition) p [axis] _D + 189 ° (c 0.71).

Getting XLV.

α-fluoro-17 α-hydroxy-16 β-methyl-

3,11-dioxoandrost-1,4-diene-17 β-thiocarboxylic acid (XLV).

To a solution of XLIII (5.587 g) in dry N, N-dimethylformamide (150 ml) at 20 DEG C. under nitrogen under stirring was added N, N -carbonyldiimidazole (4.847 g) and the reaction mixture was stirred at 20 DEG C. 4 hours. 10 minutes of hydrogen sulfide gas were bubbled through the reaction mixture and the solution was stirred for another hour. The solution was poured onto ice (300 ml) and 2 N-hydrochloric acid (100 ml) to give a creamy precipitate. It was filtered off, air-dried overnight (6.268 g) and recrystallized from ethyl acetate to give the title acid (3.761 g) as white prisms, m.p. 215218, [α] _D + 143 ° (c 0.88, dimethylformamide).

Getting XLVI.

α-fluoro-17 α-hydroxy-16 β-methyl-

3,11-Dioxoandrost-1,4-diene-17 β-thiocarboxylic acid (XLVI)

To a solution of XL1II (1.059 g) in dry мети, dimethylformamide (50 ml) at 20 ° and under stirring was added Ν, ′ -thiocarbonyldiimidazole (1.368 g) and the reaction mixture was stirred at 20 ° for 4 hours. Hydrogen sulphide gas was bubbled through the mixture for 5 minutes and the solution was stirred for another hour. The reaction mixture was partitioned between ethyl acetate (100 ml) and 2 N hydrochloric acid (100 ml) and the organic layer was washed with 2 N hydrochloric acid (100 ml) and water (2 x 100 ml) and extracted with 2 N sodium hydroxide solution. sodium carbonate (2 x 75 ml). The combined extracts were washed with ethyl acetate (50 ml), then new ethyl acetate (100 ml) was added and acidified to pH I with hydrochloric acid. The aqueous layer was extracted with a new amount of ethyl acetate (50 ml) and the combined extracts washed with water and brine, dried and the solvent evaporated in vacuo. The residue was recrystallized from ethyl acetate to give the title acid (0.559); 212-219 °, [α] _D + 145 ° (c 0.81, dimethylformamide).

Getting XLVII.

S-hydromethyl 9 α-fluoro-β β, 4-ΛΗβΗ-17 β-thiocarboxylate (XLVII)

To a solution of XLIV (0.169 g) and sodium bicarbonate (0.040 g) in N, N-dimethylformamide (6 ml) was added bromochloromethane (0.1 ml) under stirring and stirring at 22 ° was continued for one hour. The reaction mixture was diluted with ethyl acetate (100 ml) and the solution was washed sequentially with 2N hydrochloric acid, water, 2N sodium carbonate solution, water and brine. Dry and remove the solvent in vacuo. The residue was recrystallized twice from ethyl acetate to give the title S-methylthioester (0.193 g) as white plates, solvated with ethyl acetate (I mole), m.p. 126-130 °, [a] _D + 147.5 ° (c 0.64).

Getting XLV1II.

? -fluoro-16 β-methyl-C ,! 1-dioxo-17? -Propionyloxyandrosta-1,4-diene-17? -Thiocarboxylic acid (XLVIII)

Propionyl chloride (0.43 ml) was added to a solution of XLV (0.485 g) and triethylamine (0.57 ml) in dichloromethane with stirring and cooling in ice and salt, and the reaction mixture was stirred at 0 ° for 1.5 hours. The mixture was partitioned between ethyl acetate (75 ml) and 2 N sodium carbonate solution (75 ml) and the organic layer was washed sequentially with a new 2N sodium carbonate solution, water, 2N hydrochloric acid, water and saturated sodium hydroxide solution. chloride. It was then dried and the solvent removed in vacuo to give a yellow crystalline mass (0.562 g). It was dissolved in acetone (10 ml), diethylamine (1.0 ml) was added and the reaction mixture was stirred at 22 ° for 1.25 hours. The solvents were removed in vacuo and the eu residue was partitioned between ethyl acetate (30 ml) and 2N-hydrochloric acid (30 ml). The ethyl acetate layer was washed with water and extracted with 2N sodium carbonate solution (2 x 30 ml). The combined extracts were washed with ethyl acetate (30 ml), ethyl acetate (60 ml) was added to cover the solution and acidified to pH 1.0 with hydrochloric acid. The ethyl acetate layer was washed with water and saturated sodium chloride solution, then dried and the solvent removed in vacuo to give a white solid which was recrystallized twice from ethyl acetate to give the title ester (0.290 g ) with m.p. 173-180 °, [a] _D + 148 (C 1.03).

Getting XLIX.

S-hydromethyl 9 α-fluoro-17 α-hydroxy-16 β-methyl-3,11-dioxoandrosta-1,4-diene 17 β-thiocarboxylate (XLIX)

A solution of XLV (5.006 g) and sodium bicarbonate (1.612 g) in N, N-dimethylacetamide (50 ml) was reacted with bromochloromethane (1.24 ml) and the reaction mixture was stirred at 22 ° for 3.3 hours. The solution was diluted with ethyl acetate (70 ml) and washed sequentially with 2N-hydrochloric acid, water, sodium metabisulphite solution, water and saturated sodium chloride solution. Dry and remove the solvent in vacuo to give a cream solid (3.638 g). Analytical sample obtained after preparative thin layer chromatography (silica gel, manifested with chloroform: acetone = 9: 1) and recrystallization from ethyl acetate, represent colorless prisms of the title ester (0.262 g), m.p. 223-228 °, [α] _D + 251 ° (c 1.2).

Getting L.

α-Fluoro-N β-hydroxy-16 β-methyl3-oxo-17 β-propionyloxyandrosta-1,4-diene 17 β-thiocarboxylic acid (L)

A solution of XLIV (0.511 g) in dichloromethane (20 ml) containing triethylamine (0.6 ml) was cooled to 2 ° and propionyl chloride (0.45 ml) was added. The reaction mixture was stirred at 2 DEG C. for 2.5 hours. The mixture was partitioned between ethyl acetate and sodium bicarbonate and the organic phase was washed with water, 2N hydrochloric acid, again with water and saturated sodium chloride solution. Dry and remove the solvent in vacuo to give a colorless solid (0.634 g). It was dissolved in acetone (30 ml) at 22 ° for 55 minutes. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with 2 N hydrochloric acid and water and then extracted with 5% sodium carbonate solution. The combined extracts were acidified with 2 N hydrochloric acid to pH 1 and extracted with ethyl acetate. The combined extracts were washed with water and with saturated sodium chloride solution, dried and the solvent removed to give a colorless foam (0.522 g) which was recrystallized from ethyl acetate to give the title ester as colorless prisms ( 0.307 g) m.p. 174-179 DEG [a] _D + 107 DEG (c 1.0).

Getting LI.

α-Fluoro-β, 17 α-dihydroxy-16methylene-3-oxoandrost-1,4-diene-17 β-thiocarboxylic acid (LI)

To a solution of 9 α-fluoro-N β, 17 adihydroxy-16-methylene-3-oxoandrost-1,4-diene-17 β-carboxylic acid (0.218 g) in dry N, N-dimethylformamide (10 ml) at 22 And N, N-carbonyl diimidazole (0.254 g) was added to a nitrogen atmosphere and the reaction mixture was stirred at 22 ° for 4 hours. Hydrogen sulfide gas was bubbled through the reaction mixture for 5 minutes and the mixture, at this time light green, was stirred for one hour at 22 °. It was diluted with ethyl acetate (150 ml) and the solution was washed with 2 N hydrochloric acid, water and saturated sodium chloride solution. Dry and remove the solvent in vacuo to give a yellowish foam (0.222 g) which was recrystallized twice from ethyl acetate to give the title acid (0.078 g) as white prisms which decomposed at about 250 ° without melting, [α] _D + 117 ° (c0.32).

Getting LII.

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

To a suspension of 9? -Fluoroprednisolone (South) in dry tetrahydrofuran (55 ml) was added with stirring a solution of periodic acid (9.0 g) in water (90 ml) and the mixture was stirred at 22 ° C for 2 hours. Pour into a mixture of water and ice (about 400 ml) and after stirring for 15 minutes, remove the solid, wash with water and dry to give the title acid as a solid (9.42 g). A sample of it, recrystallized from ethanol, m.p. 289-293 ° [α] _D + 66 ° (c 0.73, methanol).

Getting LIII.

α-Fluoro-β, 17 α-dihydroxy-3-oxondrosta-1,5-diene-17 β-thiocarboxylic acid (LIII)

A solution of 9 α-fluoro-N β, 17 α-dihydroxy-3-oxo-androsta-1,4-diene-17 β-carboxylic acid (4.5 g) in dry dimethylformamide (100 ml) was stirred under nitrogen with Ν , N '-carbonyldiimidazole (4.04 g) at 22 ° 4 hours. Hydrogen sulfide was then bubbled through the solution for 30 minutes and allowed to stand for another 15 minutes. The mixture was poured into a mixture of 2 N hydrochloric acid (250 ml) and ice (about 100 g) and the resulting precipitate was separated, washed with water and dried to give a white solid (4.56 g). 120 mg) was recrystallized from ethanol to give the title thioacid as colorless crystals (70 mg), mp 222-225 ^O , [α] _D + 116 ° (0.57).

Getting LIV.

α, 9 β-difluoro-β, 17 α-dihydroxy-16 α-methyl-3-oxoandrost-1,4-diene-17 β-thiocarboxylic acid (LIV)

A solution of 6 a, 9 β-difluoro-N β, 17 α-dihydroxy-16 α-methyl-3-oxoandrost-1,4diene-17 β-carboxylic acid (12.0 g) in dry dimethylformamide (250 ml) was stirred and N, N'-Carbonyldiimidazole (9.94 g) was added thereto under nitrogen at room temperature. After 4 hours, sulfur carbon was bubbled through the solution for 0.5 hours and the mixture was kept for another 0.5 hours. The reaction mixture was poured into 2 N hydrochloric acid (500 ml) containing ice (about 250 g). The resulting precipitate was separated, washed with water and dried in vacuo to give the title acid as a white solid (11.47 g), m.p. 230-232 °, [α] ₀ + 94 ° (c.0.91).

Getting LV.

α-acetoxy-α, 9α-difluoro-β β-hydroxy-16 α-methyl-3-oxo-androsta-1,4-diene-17 β-thiocarboxylic acid (LV)

A solution of LIV (1.625 g) and triethylamine (2.0 ml) dichloromethane (75 ml) was stirred at about 0 ° C and acetyl chloride (1.275 ml) was added thereto and stirred at this temperature for 1.25 hours. The mixture was washed with 2 N sodium carbonate (50 ml), water, 2 N-hydrochloric acid (50 ml), again with water (3 x 50 ml) and saturated sodium chloride solution (50 ml). It was dried and evaporated to give a white solid (1.91 g). It was dissolved in acetone (40 ml) and stirred with diethylamine (4 ml) at 27 ° C for 45 minutes. The mixture was concentrated to about 25 ml and poured into 2 N hydrochloric acid (100 ml) containing ice (about 100 g). After stirring, the resulting precipitate was collected, washed with water and dried to give a solid product (1.689 g). A sample of it (400 mg) was recrystallized from ethyl acetate to give 17 α-acetates from the title (280 mg), m.p. 175-177 ° C.

Getting LVI.

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

Working as described in the preparation of LV, LIV (2.0 g) was converted with butyryl chloride (1.5 ml) instead of acetyl chloride to compound 17 α-butyrate from the title (2.08 g). A sample thereof recrystallized from ethyl acetate, m.p. 155—157 °.

Getting LVII.

α-Fluoro-N β-hydroxy-3-oxo-17 α-propionyloxyandrosta-1,4-diene-17 β-thiocarboxylic acid (LVII).

Working similarly to the LX preparation described, LI1I (3.8 g) was converted using propionyl chloride (3.9 ml) instead of acetyl chloride and after aminolysis of the intermediate with diethylamine (10.35 ml) in the 17 α-propion of the title (4.17 g). Part of it (350 mg) recrystallized from ethyl acetate gave colorless crystals (165 mg), m.p. 135-138 °, [α] _D + 72 ° (1c 0.92).

Getting LV1II.

a, 9? -difluoro-N? -hydroxy-16 amethyl-3-oxo-17? -propionyloxyandrosta-1,4diene-17 β-thiocarboxylic acid (LVIII)

Propionyl chloride (4.74 ml) was added dropwise as a solution of LVI (5.0 g) and triethylamine (6.15 ml) in dichloromethane (140 ml), cooled in ice and salt. The reaction mixture was stirred at about 0 ° for 0.75 hours and then washed sequentially with 2N sodium carbonate solution, water, 2N hydrochloric acid, again with water and brine. After drying, the solvent was removed to give a white solid (6.35 g). It was dissolved in acetone (120 ml) and diethylamine (12.5 ml). It was stirred for one hour at room temperature and the volume was reduced to about 75 ml. The solution was poured into 2 N hydrochloric acid (200 ml) containing ice (about 300 g) and the resulting precipitate was separated, washed with water and dried in vacuo to a white mass (5.1 (7 g), mp 152). Part of it (400 mg) was recrystallized from ethyl acetate to give analytically pure title thioacid as colorless crystals (290 mg), mp 161-164 °, [a] _D -27 ° ( 0.95) The infrared spectrum (1c mujol) of these crystals in the solid state shows a different crystalline form from the sample obtained in the preparation of XIX.

Getting L1X.

S-chloromethyl 9a-fluoro-16 β-methyl-

3,11-dioxo-17 α-propionyloxyandrost-1,4diene-17 β-thiocarboxylate (LIX)

A solution of XLIX (409 mg) in propionic acid (5 ml), trifluoroacetic anhydride (2 ml) and toluene p-sulfonic acid (0.1 ml in dry chloroform solution) 80 mg / ml) was stirred at 22 ° 2.75 days. The acidic product was isolated by extraction with ethyl acetate after being poured into saturated sodium bicarbonate solution. The crude product was chromatographed on silica in chloroform-acetone (14: 1) and recrystallized from ethyl acetate-petroleum ether (bp 60 80 ° C) to give the title 17 α-propionate as colorless crystals with mp 205206 °, [α] _D + 95 ° (c 1.15).

Getting LX.

S-chloromethyl 9? -Fluoro-β, 17? -Dihydroxy-16 β-methyl-3-oxoandrost - ?, 4-diene-17 β-thiocarboxylate (LX)

A suspension of XLIX (102 mg) in ethanol (2.5 ml) was stirred with sodium borohydride (10 mg) at 22 ° C for 1 hour. Acetone (5 ml) was added to the reaction mixture, then concentrated to near dryness. The residue was dissolved in ethyl acetate (25 ml), washed with N-hydrochloric acid, water and brine. After drying, the organic solvent was removed to afford the title II β-alcohol as a colorless foam (103 mg), the only major component of which was equipolar to the authentic sample when compared by thin layer chromatography (silica, chloroform-acetone, 9: 1).

Getting LXI.

α-fluoro-H β-χΗΑρο ^ π-16 β-methyl3-oxo-17 α-propionyloxyandrosta-, 14-diene17 β-thiocarboxylic acid. (LXI)

Method A

Solution of 9? -Fluoro-N β-hydroxy-6 β-methyl-3-oxo-17? -Propionyloxyandrosta 1,4-diene-17 β-carboxylic acid (603 mg, 0.75 mol ethyl acetate solution) and Ν, Ν ' -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 solution (15 ml) obtained from sodium hydride (305 mg) in dimethylformamide by saturation with hydrogen sulfide was added and stirring continued for 3 days at ambient temperature. The reaction mixture was poured into 2 N hydrochloric acid (200 ml) and the product extracted with ethyl acetate (3 x). The organic extracts were combined, washed with water and back extracted with 5% sodium carbonate solution. The alkaline extracts were acidified with hydrochloric acid and extracted with ethyl acetate (3 x). After washing with water and brine, the organic extract is dried and concentrated to a small volume. The title acid was separated as cream crystals (101 mg) and identified as the only major component when compared to the authentic sample by H (1 ^H NMR) and by thin layer chromatography (silica, chloroform-acetone 4: 1).

Method B

Solution of 9? -Fluoro-N β-hydroxy-6 β-methyl-3-oxo-17? -Propionioloxyandrosta 1,4-diene-17 β-carboxylic acid (701 mg, 0.75 mol ethyl acetate solvate) and Ν, Ν ' -carbonyldiimidazole (473 mg) in dry dimethylfor mamide (26 mg) was stirred under nitrogen at about 22 ° C for 19.5 hours. A solution (10 ml) of sodium hydride (60% dispersion in oil, 233 mg) in dimethylformamide (10 ml) and saturated with hydrogen sulfide was then added. The resulting mixture was stirred at ambient temperature for 5.5 hours. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with 2 N hydrochloric acid, water and brine, then dried and evaporated to give a foam (186 mg). The title thioacid was shown to be the major component in this product by ¹ H NMR and by thin layer chromatography (silica, chloroformacetone 4: 1 and chloroform-acetone-acetic acid 30: 8: 1) when compared to an authentic sample.

Method C

In a nearly identical reaction to that described in method A, the carboxylic acid was treated with 1,1'-carbonyldibenzotriazole (1.587 g) instead of N, N'-carbonylldi (1,2,4-triazole) at room temperature for 6 hours. o'clock. After the solution obtained from hydrogen sulfide and sodium hydride in dimethylformamide was added, the reaction continued for 41.5 hours. The crude product is obtained as a foam product. Thin layer chromatography (silica, chloroform-acetone, 4: 1, and chloroform-acetone-acetic acid 30: 8: 1) shows that the title thioacid is present as a major component by comparison with an authentic sample.

Getting LXII.

S-chloromethyl 6a, 9a-difluoro-16 amethyl-3-oxo-17a-propionyloxy-N β-trifluoroacetoxyandrosta-1,4-diene 17-thiocarboxylate (LXII).

To a solution of the compound of Example 5 (described below) (100 mg) in dry tetrahydrofuran (2 ml) and pyridine (0.1 ml) was added trifluoroacetic anhydride (0.05 ml) and the mixture was kept at room temperature for 0.5 hours. The reaction mixture was poured into water and the product was extracted with ethyl acetate (3 x). The organic extracts were washed with water, dried and evaporated to give the title trifluoroacetate (116 mg) according to H ¹ NMR spectroscopy (singlet at 8.59 τ, 19 protons, in deuteriochloroform) and according to thin layer chromatography on silica. (acetone-petroleum ether, bp 40-60 ° C, 1: 3). An analytical sample of ether-pentane has m.p. 158-162 °, [α] ₀ + 56 ° (c 0.23).

Example 1.

S-chloromethyl 9? -Fluoro-N? -Hydroxy-16? -Methyl-3-oxo-17? -Propionyloxyandrost-1,4-diene-17? -Thiocarboxylate

Method A

A solution of compound 1 (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 give an orange foam product (1.560 g). After preparative chromatography in chloroform-acetone (19: 1), an off-white foam product (803 mg) was obtained which, after twice crystallization from methanol, gave off-white needles from the title S-chloromethyl ester (668 mg), m.p. 212214 ° C, [α] + 44 ° (c 1.06).

Method B

The title compound can also be prepared in a similar manner using chloroiodomethane instead of bromochloromethane.

Method C

Sodium borohydride (19 mg) was added to a solution of compound II (230 mg) in ethanol (3.5 ml) and the solution was stirred at room temperature. After 20 minutes, acetone (1 ml) was added and the solution was concentrated to approximately 1/4 of its volume. Then ethyl acetate (30 ml) was added and the solution was washed with N-hydrochloric acid and water, dried and evaporated to give a white foam product (239 mg). Chloroform-acetone preparative chromatography (19: 1) gave a white foamy product (188 mg) which, after twice crystallization from methanol, gave white needles of the title S-chloromethyl ester (158 mg), m.p. 210-212 °, [α] _D + 44 ° (c 1.07).

Example 2.

S-chloromethyl 9? -Fluoro-N? -Hydroxy-16? -Methyl-3-oxo-17? -Propionyloxyandrost-1,4-diene-17? -Thiocarboxylate.

To a solution of IV (0.927 g) in dimethylacetamide (4 ml) was added sodium bicarbonate (0.256 g) and bromochloromethane (0.20 ml) and the mixture was stirred at 22 ° C. 2:00. The reaction mixture was partitioned between ethyl acetate (100 ml) and 2 N hydrochloric acid (20 ml) and the aqueous layer was then extracted with ethyl acetate. The combined extracts were washed sequentially with 2 N-hydrochloric acid, water, 3% sodium bicarbonate solution, again with water and brine. After drying, the solvent was removed and the crude product (757 mg) was recrystallized twice from acetone to give the title chloromethyl thiolester (0.367 g), m.p. 247-250 ° [a] _D + 50.5 ° (c 0.63).

Example 3.

S-chloromethyl-N β-χκΑρο ^ Η-3-ο ^ ο-17 propionyloxyandrost-1,4-diene-17 β-thiocarboxylate

To a solution of crude XV (2.266 g) in dimethylacetaviz (10 ml) was added sodium bicarbonate (7546 mg) in bromochloromethane (0.59 ml) at 22 ° C for 16 hours. The reaction mixture was partitioned between ethyl acetate and 2 N hydrochloric acid and the aqueous layer was then extracted with ethyl acetate. The combined organic layers were washed sequentially with 2 N hydrochloric acid, water, sodium bicarbonate, water and saturated sodium chloride solution. Dry and remove the solvent to give a yellow foam. The neutral product was purified by preparative chromatography (FETX) on silica (15 μm) in 7% acetone in chloroform and the main product was crystallized from acetone to give the title chloromethyl thiolester (0.511 g), m.p. 117-120 °, [a] _D + 56 ° (c 1.3).

Example 4.

S-chloromethyl 6a, 9a-difluoro-β-hydroxy-16a, 17a-isopropylidenedioxy-3-oxoandrost-1,4-diene-17a-thiocarboxylate.

To a solution of IX (1.360 g) in N, N-dimethylacetamide (10 ml) was added sodium bicarbonate (0.377 g) and bromochloromethane (0.3 ml) with stirring and stirring continued for 1.5 hours. Ethyl acetate (100 ml) was added and the resulting solution was washed sequentially with 2 N hydrochloric acid, water, sodium metabisulphate solution, again with water, sodium bicarbonate solution, again with water and saturated sodium chloride solution. It is dried and the solution is concentrated to crystallize. The crystalline product (0.765 g) was purified by preparative chromatography on silica gel using chloroform: acetone (9: 1). The main product was eluted with ethyl acetate and recrystallized from ethyl acetate to give the title S-chloromethylthioester (0.475 g) as white prisms, m.p. 271-278 °, [α] _D + 116 °, (with 0.96, dimethyl sulfoxide).

Example 5.

S-chloromethyl 6a, 9a-difluoro-ββhydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-thiocarboxylate

To a solution of XVX (0.546 g) in dimethylacetamide (3 ml) was added sodium bicarbonate (202 mg) and bloomochloromethane (0.16 ml) at 22 ° for 3 hours. 2 N hydrochloric acid (50 ml) was added to the mixture and the product was extracted with ethyl acetate. The extracts were combined and washed sequentially with 2 N hydrochloric acid, water and saturated sodium chloride solution. Dry and remove the solvent. Recrystallization from ethyl acetate twice gave the title chloromethylthiolester (0.404 g), m.p. 272-275 °, [axis] _D + 49 ° (c 0.35).

Examples 6 to 15.

Following the procedure described in Example 1 (method A), but using 17 β-thiocarbosilic acid corresponding to the desired 17 β-thiocarboxylate as starting materials (the details of the processes are given in Table III below), the following compounds:

6. S-Chloromethyl II β-hydroxy-16 β-methyl-3-oxo-17α-propionyloxyandrosta-1,4diene-17 β-thiocarboxylate, m.p. 192-193 °, [α] _D + 650 (c 1.05);

7. S-chloromethyl 9? -Fluoro-N? -Hydroxy-16-methylene-3-oxo-17? -Propionyloxy androsta-1,4-diene-17? -Thiocarboxylate, m.p. 212-221, [axis] _D -56 ° (c 0.99);

8. S-Chloromethyl 17a-acetoxy-9a-fluoro-N β-χΗΑρο ^ Η-16 β-methyl-3-oxoandrost, 14-diene-17 β-thiocarboxylate, m.p. 220-223 °, [α] _D + 35.5 ° (c 1.06);

9. S-chloromethyl 17 α-butyryloxy-9 afluoro-β β-hydroxy-16 β-methyl-3-oxoandrost-1,4-diene-17 β-thiocarboxylate, m.p. 172175 °, [α] _D + 46 ° (c 1.10);

10. S-Chloromethyl 9a-fluoro-N β-hydroxy-17 α-isobutyryloxy-16 β-methyl-3-oxoandrost-1,4-diene-17 β-thiocarboxylate, m.p.

234- 239 °, [a] _D + 43 «(c 1.00);

11. S-chloromethyl 9? -Fluoro-N? -Hydroxy-3-oxo-17? -Propionyloxyandrosta-1,4diene-17? -Thiocarboxylate, m.p. 196-199 °, [a] _D +38 '(c 0.97);

12. S-chloromethyl 6? -Fluoro-? Β-hydroxy-3-oxo-17? -Propionyloxyandrost-1,4diene-17 β-thiocarboxylate, mp 188-191 °, [a] _D + 48 "(c 0.91);

13. S-Chloromethyl 17a-acetoxy-6a, 9a-difluoro-β-hydroxy-16α-methyl-3-oxoandrost-1,4-diene-17 β-thiocarboxylate, m.p. 280 - 283 ", [a] _D +45" (c 0.80);

14. S-chloromethyl 17a-butyryloxy-6a, 9a, difluoro-N β-hydroxy-16α-methyl-3-oxoandrost-1,4-diene-17 β-thiocarboxylate, m.p.

235-238, [α] _D + 49 ° (c 0.65);

15. S-chloromethyl 9a-fluoro-N β-hydroxy-16a, 17a-isopropylidenedioxy-3-oxoandrost-1,4-diene-17 β-thiocarboxylate, m.p. 276-280 (decomposition), [α] _D + 127 ° (c 0.51, dimethyl sulfoxide).

Table 3

Example No. Reagent (ml) NaHCO ₃ (mg) Steroid Nested (mg) DMA solvent (ml) reaction time at room temperature PLC (silica) CHCl _{1 3} -Me ₂ CO for cry- crystallization solvent product (mg) 6 BrCH ₂ C1 (0.25) 300 981 5 3 - EA 826 7 BrCH ₂ C1 (0.58) 749 2000 II 1.5 19: 1 EA 201 8 BrCH ₂ C1 (0.44) 565 1955 7 2.0 - EA 307 ⁺ 9 BrCH ₂ Cl 421 1501 10 1.8 14: 1 EA 871

10 (0.32) BrCH ₂ C1 (0.084) 121 385 3 2.75 - EA 255 11 BrCH ₂ C1 (0.90) 1100 2750 20 1.25 M 1600 12 BrCH ₂ C1 (0.86) 1080 2740 20 2 - EA-R 2460 13 BrCH ₂ C1 (2.00) 2500 6600 40 1.75 - A 5410 14 BrCH ₂ C1 (1.40) 1600 4600 46 2 0 A 2140 15 BrCH ₂ C1 (0.48) 650 1600 12 1.5 4: 1 a 244 ”

Notes:

EA = ethyl acetate

A = acetone

.. 20

M = methanol = pertol ether, b.p. 60-80 + Obtained from a sample (400 mg) of the crude product (2.35 g).

++ Obtained from a sample (300 mg) of the crude product (1.72 g).

Example 16.

S-Chloromethyl 9 α-chloro-β β-hydroxy16 β-methyl-3-okco-17 α-propionyloxyandrost-1,4-diene-17 α-thiocarboxylate and S-chloromethyl 9 β, II β-επο ^ Η-16 β-methyl-3-oxo-17 α-propionioxylandrosta-1,4-diene-17 β-thiocarboxylate

To a solution of XXVI mixture (1.032 g) in dimethylacetamide (5 ml) was added sodium biocarbonate (0.203 g) and then bromochloromethane (0.2 ml) and the reaction mixture was stirred at 22 ° C for 1.5 hours. It was then partitioned between ethyl acetate (50 mL) and 2Ν hydrochloric acid (35 mL). The aqueous phase was extracted with new ethyl acetate (2 x 20 ml) and the combined extracts washed with 2 N-hydrochloric acid, water, saturated sodium bicarbonate solution, again with water and saturated sodium chloride solution. Dry and remove the solvent in vacuo to give a creamy foam (0.856 g) containing a mixture of the title S-chloromethyl esters.

They were separated by preparative chromatography on silica, and triturated with chloroform: acetone (19: 1). The лярο-polar component was recrystallized two times from ethyl acetate (0.306 g sample) to give S-chloromethyl 9 α-chloro-N β-hydroxy-16 β-methyl-3-oxo-17 α-propionyloxyandrost-1,4 -diene-17 β-thiocarboxylate (0.232 g) as white plates, mp 222-229 ^O , [α] _D + 70 ° (c 1.23).

The less polar component (0.210 g) was recrystallized from acetone-petroleum ether to give S-chloromethyl 9 α, II β-επο ^ κ-16 β-methyl-3-oxo-17 α-propionylandrosta-1. 4-diene-17 β-thiocarboxylate (0.065 g) m.p. 169-173 °, [a] _D + 49 (c 0.60).

Example 17.

S-fluoromethyl, 9α-fluoro-βα-hydroxy-16 β-methyl-3-oxo-17 α-propionyloxyandrosta-1,4-diene-17 β-thiocarboxylate

XXV (660 g) was stirred in 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 diluted with ethyl acetate (200 ml) and filtered through kieselguhr. The filtrate was washed with water, dried and evaporated to give a white foam product (517 mg). After preparative chromatography in chloroform-cyclohexane (19: 1) and in chloroform, an off-white foam product (270 mg) was obtained, which was recrystallized from methanol and then from methanol-diethyl ether to give the title S-fluoromethyl ester ( 176 mg), m.p. 241-242 ° C, [α] _D + 97.5 (c0.09).

Example 18

S-fluoromethyl 9? -Fluoro-? Β-hydroxy-16? -Methyl-3-oxo-17? -Propionyloxyandrost-1,4-diene-17 β-thiocarboxylate

To a solution of XXX (0.640 g) in aceto nitrile (8 ml) was added 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 through kieselguhr. The solution was washed with 2 N hydrochloric acid, water and saturated sodium chloride solution. The solvent was removed in vacuo to give a pale yellow foam product (0.5043 g). It was chromatographed on silica gel and displayed with 5% acetone in chloroform. The title product was eluted with ethyl acetate and recrystallized twice from acetone to give the title fluoromethyl thioester (0.244 g), m.p. 242-243 ° (decomposition), [α] _D + 37 ° (c 0.75).

Example 19.

S-fluoromethyl 6 a, 9 a-difluoro-β β-hydroxy-16 α-methyl-17 α-propionioxy-3-oxoandrost-1,4-diene-17 β-thiocarboxylate

A solution of XXXI (310 mg) in acetonitrile (10 ml) was stirred with silver fluoride (947 mg) for three days at room temperature in the dark. Ethyl acetate was added and filtered through kieselguhr. The filtrate was washed successively with 2Ν hydrochloric acid, water and saturated sodium chloride solution, then dried. The solvent was removed and the residue was subjected to preparative chromatography in chloroform and then chloroform-acetone (19: 1). The product was eluted with ethyl acetate and crystallized after concentration of the solution to give the title fluoromethyl thiol ester (0.075 g), m.p. 272-273 ° (decomposition), [a] _D + 30 (p.35).

Example 20.

S-fluoromethyl 9a-fluoro-N β-hydroxy-16a, 17a-isopropylenedioxy-3-oxoandrost-1,4-diene-17 β-thiocarboxylate

A suspension of XXXVII (1.290 g) in acetonitrile (20 ml) was stirred with silver (I) fluoride (2.842 g) at room temperature in the dark. After 11 days (no residual iodide evidenced by thin layer chromatography / chloroform, six analyzes / reaction mixture was diluted with ethyl acetate (400 ml) and filtered through kieselguhr. The filtrate was evaporated to give light yellow crystals (726 mg) and extracted with kieselguhr continuously with ethyl acetate in a Soxkeleton apparatus to give a yellow solid (197 mg), the filtrate solid was suspended in chloroform-methanol (10: 1) and the insoluble fraction (203 mg) was combined. Soxcell solid extract in ethyl acetate tat and filtered through a column of silica (50 g) The eluates containing the product (in thin layer chromatography) were combined, washed with water, dried, simultaneously treated with charcoal and concentrated to a small volume. mass (276 mg was recrystallized from ethyl acetate) to give colorless crystals of the title S-fluoromethyl ester (213 mg), mp 320-322 ° C (decomposed), [a] _D + 132 ° (c 0.22, dimethyl sulfoxide).

Example 21.

6-fluoromethyl 6 a, 9 a-difluoro-P β-hydroxy-16 a, 17 a-isopropylidenedioxy-3-oxoandrost-1,4-diene-17 β-thiocarboxylate

To a solution of XXXVIII (0.804 g) in acetonitrile (60 ml) was added silver fluoride (1.821 g) and the reaction mixture was stirred in the dark for 18 hours. Dilute with ethyl acetate and filter through kieselguhr. The filtrate was washed with water and saturated sodium chloride solution and dried. The solvent was removed in vacuo to give a cream solid (0.636 g). It was purified by preparative chromatography on silica gel, showing twice with chloroform: acetone (4: 1). The title product was eluted with ethyl acetate and recrystallized five times from ethyl acetate to give the title S-fluoromethylthioester (118 g) as white prisms, m.p. 305-311 °, [α] _D + 125 ° (c 0.73, dimethyl sulfoxide).

Examples 22-30.

Working as described in Example 17, but using as starting materials s-iodomethyl 17 β-thiocarboxylates corresponding to the corresponding desired products (details of the processes are given in Table IV below), the following compounds are obtained:

22. s-fluoromethyl 17 α-acetoxy-9 afluoro-β β-ΧΗΛρο ^ π-16 β-methyl-3-oxoandrost-1,4-diene-17 β-thiocarboxylate, m.p. 248249 °, [α] _D + 101 ° (c 1.08);

23. S-Fluoromethyl II β-hydroxy-3-oxo17 α-propionyloxyandrost-1,4-diene-17 βthiocarboxylate, m.p. 112-117 °, [α] _D + 67 ° (c 0.76);

24. S-Fluoromethyl II β-χΗΑρο ^ π-16 βmethyl-3-oxo-17 α-propionyloxyandrost-1.4diene-17 β-thiocarboxylate; 223-225 °, [α] _D + 103 ° (c 0.38);

25. S-Fluoromethyl 9 α-chloro-11 β-hydroxy-16 α-methyl-3-oxo-17 α-propionyloxyandrosta-1,4-diene-17 β-thiocarboxylate, mp 1882193 °, [a] _D + 116 ° (c 0.75);

26. S fluoromethyl 9? -Fluoro-N? -Hydro-5 roxy-16? -Methylene-3-oxo-17? -Propionyloxyandrost-1,4-diene-17? -Thiocarboxylate, mp. 05215 °, [ axis] _D -58 ° (c 1.00);

27. S-Fluoromethyl 9a-fluoro-N β-hydroxy-3-oxo-17 α-propionioalkyandrosta-1,4-10 diene-17 β-thiocarboxylate, mp 207-211 °, [a] _D +70 »(C 0.88);

28. S-fluoromethyl 6? -Fluoro-N? -Hydroxy-3-oxo-17? -Propionyloxyandrosta-1,4diene-17? -Thiocarboxylate, m.p. 224-225 °, [α] + 70 ° (c 0.79);

29. S-Fluoromethyl 17α-acetoxy-6α, 9α-difluoro-β β-hydroxy-16α-methyl-3-oxoandrost-1,4-diene-17 β-thiocarboxylate, mp 308-310 »[A] + 29 ° (by 0.80);

30. S-Fluoromethyl 17α-butyryloxy-6α, 9α-difluoro-ββ-hydroxy-16α-methyl-3-oxoandrost-1,4-diene 17 β-thiocarboxylate, m.p. 249-252 °, [α] _D + 32 ° (c 1.05).

Table 4

S-fluoromethyl 17 α-acyloxyandrostane-17 β-thiocarboxylates by halogen exchange

Example No. AgF (mg) Source steoride solvent (MeCN) (ml) reaction time at room temperature PLC (silica) CHCl _{3 3} Me ₂ CO Recrystallization solvent Product (mg) halogen embedded (mg) 22 375 1 1702 22 20 24: 1 A 477 23 2071 1 1034 10 26 19: 1 EA 585 * 24 1945 1 850 6 26 19: 1 EA 166 25 1161 1 550 8 23.5 19: 1 M 106 26 3574 1 1658 26 24 19: 1 A 300 27 700 1 1000 50 3 - M 470 28 462 1 700 35 2 - EA-R 350 29 2600 1 4000 200 0.75 - EA 2280 30 780 1 1200 60 1 - EA 755

EA = ethyl acetate

A = acetone

M = methanol

P = petroleum ether, mp 60-80 ° ⁺ purity about 95%

Example 31

S-bromomethyl 9? -Fluoro-? Β-hydroxy-16 3-methyl-3-oxo-17? -Propionyloxyandrost-1,4-diene-17 β-thiocarboxylate

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

Example 32

S-bromomethyl 6 α, 9 α-difluoro-β β-hydroxy-16 α-methyl-3-oxo-17 α-propionyloxyandrost-1,4-diene-17 β-thiocarboxylate.

A solution of XXXI (850 mg) in acetone (25 ml) was stirred with lithium bromide (1.21 g) at about 22 ° C for 5 days. The product was isolated as described in Example 31 and recrystallized twice with ethyl acetate to give colorless crystals (690 mg). They were further treated under the same reaction conditions for a further 4 days to obtain the pure title s-bromomethyl ester (600 mg) as colorless ethyl acetate crystals, mp.255-257 °, [a] _D + 62 ° (c 0.82).

Example 33.

8-2'-fluoroethyl 9? -Fluoro-N? -Hydroxy-16? -Methyl-3-oxo-17? -Propionyloxyandrost-1,4-17? -Thiocarboxylate

A solution of XXXIX (910 mg) in acetonitrile (20 ml) was stirred with silver (I) fluoride (2.071 g) at room temperature in the dark. After 6 days, the reaction mixture was diluted with ethyl acetate (150 ml) and filtered through kieselguhr. The filtrate was diluted with more 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 the less polar product as a yellow foam (431 mg), which was recrystallized twice from methanol to give the 5-2'-fluoroethyl ester of the title (253 mg) with so. 133-1340C, [α] _D + 10.4.5 ₀ (c 0.98).

Example 34

S-chloromethyl 9? -Fluoro-N? -Hydroxy-16-methylene-3-oxo-17? -Propionyloxyandrost-1,4-diene-17? -Thiocarboxylate

To a suspension of XLII (227 mg) in propionic acid (2.2 ml) and trifluoroacetic anhydride (0.7 ml) was added a dry chloroform solution of toluene-p-sulfonic acid (0.044 ml, concentration about 80 mg / ml) and then stirred at room temperature for 6 hours and 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 ground to a brown gummy product (254 mg). The resin was subjected to preparative chromatography in chloroform-acetone (19: 1) (three times). The main product (152 mg) was recrystallized twice from ethanol to give white crystals (30 mg of the title s-chloromethyl 17 α-propionate, contaminated with s-chloromethyl 9 α-fluoro-17 α-hydroxy-16-methylene-3 -oxo-N β-propionyloxyandrost-1,4-diene-17 β-thiocarboxylate as evidenced by Ή NMR spectroscopy.

Example 35

S-Chloromethyl-II β-ΧΗΛρο ^ Η-16β-Μετίυι3-oxo-17 α-propionyloxyandrost-4-ene-17 β-thiocarboxylate

Catalytic reduction of the compound of Example 6 (0.517 g) in the presence of tris (triphenylphosphine) -chlororodium (I) (497 mg) in benzene (50 ml) for 22 hours gave after preparative chromatography on silica in chloroform (four times) eluting with ethyl acetate and twice recrystallizing from ethyl acetate Δ ⁴ -C-ketone from the title (0.130 g), m.p. 176-177 ° C, [α] _D + 78® (c 0.80).

Example 36

S-chloromethyl 9a-fluoro-N β-hydroxy-16 β-methyl-3-oxo-! 7? -Propionyloxyandrost-4-ene-17 β-thiocarboxylate.

Catalytic reduction of the compound of Example 1 (0.646 g) with trie (triphenylphosphine) chlororodium (I) (800 mg) in benzene (100 ml) for 21.5 hours gave after chromatography on silica in chloroform-acetone (9: 1) and two acetone recrystallizations from the title chloromethyl thioester (0.142 g) as white needles, m.p. 217225 °, [α] + 54 ° (c 0.73).

Example 37

S-Fluoromethyl II β-ΧΗΛροΠεπ-16 β-methyl-3-oxo-17 α-propionyloxyandrost-4-ene17 β-thiocarboxylate

Catalytic reduction of the compound of Example 24 (0.413 g) in the presence of tris (triphenylphosphine) chlororodium (I) (432 mg) in benzene (60 ml) at 22 ° C for 24 hours gave after repeated chromatography on silica in a mixture of chloroform-acetone and recrystallization from acetone D ⁴ -3-ketone from the title (0.106 g), m.p. 174177 ° C, [α] _D + 123 ° (c 0.55).

Example 38

S-chloromethyl 9a-fluoro-N β-hydroxy-16 β-methyl-3-oxo-! 7? -Propionioxyandrosta-1,4-diene-17 β-thiocarboxylate

S-chloromethyl 9 β, II β-επο !: Η-16 β-methyl-3-okco-177 α-propionyloxyandrost-1,4-diene-17 β-thiocarboxylate (about 0.9 mg) of Example 16 was treated with hydrogen fluoride-urea complex (about 1 ml) and stirred for a total of 24 hours for three hours at room temperature. The mixture was treated with sodium bicarbonate and the product extracted twice with ethyl acetate. The extracts were washed twice with water, dried and evaporated. The product obtained was subjected to thin layer chromatography on silica in three different solvent systems (acetone-petroleum ether, bp 40-60 ° C, 1: 2; chloroform acetone. 9: 1; ethyl acetate-petroleum ether m.p. 40-60 ° C 1: 2 (twice) and was shown to contain the title fluorohydrin when compared with an authentic sample.

Example 39.

S-chloromethyl 6a, 9a-fluoro-N β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17 β-thiocarboxylate.

A solution of LXII (29 mg) in methanol (2 ml) was kept at room temperature for 3 hours. The mixture was evaporated to dryness to give II β-alcohol from the title (25 mg), identified by comparison of its * H NMR spectrum (in deuteriodimethylsulfoxide) and its properties by thin layer chromatography (silica, acetone-petroleum ether). 40-60 ° C, 1: 3) with those of an authentic sample.

Pharmaceutical compositions have also been developed for use in the treatment of inflammatory processes containing at least one androstane compound of formula I (as defined above) together with one or more pharmaceutical carriers or excipients. These formulations may be adapted for external or internal use.

The active androstane compounds can be formulated in the usual way with preparations suitable for external use with suitable binders. External administration, as used herein, includes administration by inhalation (insufflation) and inhalation. Examples of different types of topical preparations are ointments, lotions, creams, powders, drops (for example, eye or ear drops), sprays (for example, nose, throat, lungs or skin), suppositories, delayed enema formulations. action, tablets or pellets for chewing or sucking (for example, for the treatment of aftershocks), capsules or cartridges for use in an inhaler or a doubler, and aerosols (for example, nose, throat or lungs).

Ointments and creams may, for example, be formulated on an aqueous or oily basis, with the addition of a suitable thickener and / or gelling agent and / or solvents. Such a base may, for example, be water and / or an oil such as liquid paraffin or a vegetable oil such as peanut or castor, or a solvent such as polyethylene glycol having an average molecular weight in the range of 200-600. The thickeners that may be used depend on the the base and include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycols with an average molecular weight in the range of 4000 - 6000, lanolin and beeswax and / or glyceryl monostearate, and / or non-ionic emulsifying agents.

The compositions in the form of a spray may, for example, be prepared as aqueous solutions or suspensions or as aerosols using a suitable propellant using a suitable propylene for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.

Capsules and cartridges for use in an inhaler or inhaler, e.g. gelatin, may be formulated to contain a mixture of powdered ingredients, for example, of the compound of the invention and a suitable base such as lactose or starch. Each capsule or cartridge may contain between 20 µg - 10 mg of the active androstan compound.

The amount of active androstane compound in the topical formulations according to the invention depends on the type of dosage form, but is generally in the range of 0.001 to 5.0 weight percent. However, for most compositions, it is appropriate that the amount is in the range of 0.005 to 0.5%, preferably 0.01 to 0.25%. For inhalation or inhalation powders, the amount will be from 0.1 to 2%.

External skin compositions can be used to treat inflammatory dermatoses in humans and animals, such as eczema, which are usually sensitive to corticosteroid treatment, but also in human psoriasis.

Formulations for administration by inhalation or inhalation are intended to be used prophylactically in people suffering from allergies and / or inflammatory processes of the nose, throat or lungs, such as asthma and rhinitis, including hay fever. The aerosol formulations are so calculated that each press or puff of the aerosol contains 20 µg - 1000 µg, preferably about 50 µg - 100 µg of a compound of the invention. Administration may be performed several times during the day, for example 2,3,4 or 8 times, with 1,2 or 3 doses each time. The total daily dose by aerosol is in the range of 100 µg - 10 mg, preferably 200 µg - 1000 µg. The total (full) daily dose and the fixed dose released from capsules or cartridges by inhaler or inhaler is generally twice as high as that of aerosols.

Exterior formulations may be applied to the affected area one or more times daily, with the use of occlusive dressing on the skin having some advantage.

For internal use, the novel compounds of the invention may, for example, be formulated in the usual oral (oral), parenteral or rectal administration routes. Syrups, elixirs, powders and granules may be used for oral administration. Preferred dosage forms are as described below.

Preferred forms of administration are those representing tablets and capsules. They may contain from 0.11 to 20 mg, preferably from 3.5 to 10 mg, of the active steoride.

The compounds of the invention may generally be administered internally when systemic adrenocortical treatment is prescribed.

Internal preparations may contain from 0.05 to 10% active substance depending on the type of formulation. The daily dose can range from 0.1 mg to 60 mg, for example 5-30 mg, depending on the patient's condition and the length of treatment.

Example (A).

Ointment active substance 0.1% w / w liquid paraffin BP 10% w / w white soft paraffin up to 100 parts by weight

In a ball mill, the active substance is ground with a little of the liquid paraffin, while at least 95% of the solid has sizes below 5 µm. The resulting paste was diluted and the mill was washed with the remaining amount of liquid paraffin, mixed and the suspension added to the molten white soft paraffin at 50 ° C. It was stirred until cool and a homogeneous ointment was obtained.

Example (B). Cream % w / w Active substance 0.1 Cetostearyl alcohol 10.0 Cetamacrogol 1,000 2.5 White soft paraffin 10.0 Liquid paraffin 10.0 Chlorocresol 0.1 Sodium acid phosphate 0.5 distilled water up to 100.0 Shipment method Chlorocresol and sodium phosphate dissolve

formed in water at about 70-75 ° C. The paraffins are mixed and melted at about 65-70 ° C and added with stirring to the aqueous phase when it is cooled to 65-70 ° C. The stearide is micronized (particle size as defined in BPC 1973, p.911 for the uranium powders) and dispersed in part of the liquid paraffin. The stearide suspension and the liquid paraffin residue are added to the base while stirring at 60-65 ° C. The mold is cooled with stirring to room temperature.

Example (B)

A fixed (metered) dose of aerosol form

for one dose % w / w active substance 0.05 mg 0.059 fluorotrichloromethane 25.5 mg 30.0 dichlorodifluoromethane up to 85.0 mg up to 100.0

The active substance was micronized (particle size according to BPC 1973, p.911 for ultrafine powder) and dispersed in fluorotrichloromethane. This slurry is filled into aluminum aerosol containers, purging the upper space to the closure with gaseous dichlorodifluoromethane to exclude air, and closing with the aerosol valve. Liquid dichlorodifluoromethane is pumped through the metering valve to the required weight.

Example (E).

Inhalation capsule (100 µg / dose).

per capsule% w / w active substance 0.1 mg 0.4 lactose to 25.0 mg to 100.0

The active substance was micronized (particle size according to BPC, p. 911 for ultrafine powders) and mixed with lactose in the ratio indicated above. The mixture is filled into hard gelatin capsules that are placed in an inhaler.

Claims (25)

Claims Compounds of formula wherein R ¹ represents a fluoro, chloro or bromo-methyl group or a 2'-fluoroethyl group R ² represents the COR ⁶ group, wherein R ⁶ is C ₁₃ alkyl or OR ² and R ³ together form a 16 a, 17 a-isopropylidene dioxy group; R ³ represents hydrogen, methyl (which may be either in the α or β configuration) or the methylene group; R ⁴ represents hydrogen, chlorine or fluorine; R ⁵ represents hydrogen or fluorine and the symbol ~ represents a single or double bond. Compounds according to claim 1 in which R 'represents a chloromethyl or fluoromethyl group. Compounds according to claims 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 the preceding claims, wherein R ⁴ is fluorine. Compounds according to any one of the preceding claims, wherein R ⁵ is fluorine. Compounds according to any one of the preceding claims, which are 1-4 dienes. Compounds according to claim 7, in which R ⁴ represents fluorine and R ³ represents hydrogen, and and or β-methyl or methylene. Compounds according to claim 2, which are 1-4-dienes and in which R ⁴ and R ⁵ are fluorine and R ³ is a - or β-methyl or methylene. Compounds according to claim 9, wherein R ³ represents an α-methyl group. 11. 9? -Fluoro-N-β-χπμρο ^--Ιό? -Methyl-3-oxo-17 propionyloxyandrosta-1,4-diene-17 β-thiocarboxylic acid S-chloromethyl ester. 12. 9? -Fluoro-11? -Hydroxy-16-methylene-3-oxo-17-propionyloxyandrosta-1,4-diene-17 β-thiocarboxylic acid S-chloromethyl ester. 13. S 6-fluoromethyl ester of 6 a, 9 adifluoro-N β-hydroxy-! 6a, 17a-Isopropylidenedioxy-3-oxoandrost-1,4-diene-17 β-thiocarboxylic acid. 14. 6 a, 9 adifluoro-N β-hydroxy-16? -Methyl-3-oxo-17? -Propionioxyandrosta-1,4-diene-17 β-thiocarboxylic acid S-fluoromethyl ester. 15. 6 a, 9 adifluoro-N β-hydroxy- S-chloromethyl ester! 6? -Methyl-3-oxo-17? -Propionyloxyandrosta-1,4-diene-17? -Thiocarboxylic acid. A process for the preparation of compounds according to claim 1, characterized in that (a) a compound of formula I having the meanings given in claim 1 but containing either a free 17 β-thiocarboxyl group (or functionally equivalent group) or a free 17 α-hydroxyl group (R ³ is a hydrogen atom or a methyl or methylene group), with all other reactive available groups possibly being protected, subjected to esterification; (b) a compound of formula I with the substituents mentioned in claim 1 but containing a 17 β-substituent of formula COS (CH,) Y (in which Y is a substituent and η is 1 or 2) is reacted with a compound serving to replace the group Y with a halogen atom to form a compound of formula I as claimed in claim 1; (c) a compound of formula I having the substituents mentioned in claim I but having one P-oxo group is reduced to give the corresponding II β-hydroxyandrostane; (d) a compound of formula I having the substituents mentioned in claim 1 but having a protected II β-hydroxyl group is released from its protecting group; (e) a compound of formula I having the substituents as claimed in claim I but having a 9, II-double bond (and no substituent at the ith position) reacts with one or more reagents serving to introduce the 9 halogen -N β-hydroxyl group. (f) a compound of formula I having the substituents referred to in claim 1 in which ~ represents a double bond is subjected to a partial reduction to obtain the corresponding compound wherein ~ means a single bond. Pharmaceutical compositions for use in the treatment of inflammation containing at least one androstane compound of formula I according to claim 1 together with one or more pharmaceutical carriers or binders. Compositions as claimed in claim 17 in a dosage form suitable for external use. 19. Compositions as claimed in claim 18 in a dosage form suitable for use as an aerosol. Compositions according to claim 19 in the form of metered aerosol dosage, the aerosol being adapted to deliver a dose containing from 20 μg to 100 μg of a compound of formula I according to claim I. 21. The composition of claim 20, wherein each dose contains from 50 µg to 100 µg of the compound of formula I according to claim 1. Compositions according to any one of claims 17 to 21, in which the androstane derivative of formula I according to claim 1 is selected from: 9? -Fluoro-N? -Hydroxy-16? -Methyl-3-oxo-17? -Propionyloxyandrosta-1,4-diene-l-β-thiocarboxylic acid S-chloromethyl ester, 9? -Fluoro-N? -Hydroxy-16-methylene-3-oxo-17? -Propionyloxyandrosta-1,4-diene-17 β-thiocarboxylic acid 5-chloromethyl ester, 6a, 9a-dif10 ester of 6a, 9a-dif10 fluoro-N β-hydroxy-16a, 17a-isopropylidenedioxy-3-androsta-1,4-diene-17 β-thiocarboxylic acid, 6α, 9α-difluoro-N β-hydroxy-16α-methyl-3-oxo-17 α15 propionyloxyandrosta-1,4-diene-17 β-thiocarboxylic acid S-fluoromethyl ester and 6a, 9a-Difluoro-N β-hydroxy-16? -Methyl-3-oxo-17 a-propionidioxyandrosta-1,4-diene-17 β-thiocarboxylic acid IS-chloromethyl ester. The compositions of claim 22, wherein the androstane compound of formula I, with the substituents defined in claim 1, is selected from: 6a, 9a-difluoro-N β-hydroxy-16α-methyl-3-oxo-17-propionyloxyandrosta-1,4-diene-17 β-thiocarboxylic acid S-fluoromethyl ester and 6α, 9α-difluoro-N β-hydroxy-16α-methyl-3-oxo-17 apropionyloxyandrosta-1,4-diene-17 β-thiocarboxylic acid S-chloromethyl ester. The pharmaceutical composition of claim 18, wherein the androstane compound of formula I, wherein the substituents are defined in claim 1, is the 6a, 9a-difluoro-11β-hydroxy-16-methyl-3-oxo S-chloromethyl ester. -17? -Propionyloxyandrosga-1,4diene-17? -Thiocarboxylic acid. A pharmaceutical composition according to any one of claims 18 to 21, in which the androstane compound of formula I in which the substituents are defined in claim 1 is the 6a, 9a-difluoro-N β-hydroxy-S-fluoromethyl ester. ? -methyl-3-oxo-17? -propionyloxyandrosta-1,4-diene-17 β-thiocarboxylic acid.