Process for the preparation of novel androstanecarbothioates

(42) Date of commencement of the patent: 15. 5. 1992 (45) Date of issue: 28.12.1992 (62) Elimination from application No: 674/81 (30) Priority:

(73)

Patentee:

15th 2,180 GB 8005174 claims. 23. 4.1980 GB 8013339 claims.

GLAXO GROUP LIMITED W1Y 8DH LONDON (GB).

(54) PROCESS FOR PREPARING NEW ANDROSTANTS BOTHIOATES (57) The invention relates to a process for the preparation of novel androstane carbothioates I in which a compound II is reacted with a compound which serves to replace the group Y by a halogen atom.

CD

AT 395 428

<img file="AT395428B_D0001.tif" />

DDR 6078646

The invention relates to a process for the preparation of new androstancarbothioates of the general formula

<img file="AT395428B_D0002.tif" />

wherein R¹ a fluoro, chloro or bromomethyl group or a 2'-fluoroethyl group, R² is a group COR6 in which R6 is a C3_3 alkyl group, orOR²and R³together represent 6a, 17a-isopropylidenedioxy group, further R³ represents a hydrogen atom, a methyl group (which may be in α- or β-configuration) or a methylene group, R ^ represents a hydrogen, chlorine or fluorine atom, R $ represents a hydrogen or fluorine atom, and the symbol represents a single or Double bond means, characterized in that a

Compound of the formula

<img file="AT395428B_D0003.tif" />

wherein R, R^J, R, R^J and the sign are as defined above, n is 1 or 2, and Y represents a removable substituent such as a halogen atom, with a compound serving to replace the group Y with a halogen atom.

The novel compounds prepared according to the invention are anti-inflammatory steroids of the androstane series, anti-inflammatory steroids are most typical of the corticoid type, that is, they are free-ngeran derivatives.

British Patents 1,384,372, 1438,940 and 1514,476 describe esters of certain androstane-17β-carboxylic acids having anti-inflammatory activity. EP-Al-0004741 describes esters of androstane-17β-carbothioic acids which also have anti-inflammatory activity. It has now been found that certain androstane compounds which have a haloalkyl-caibothioate group in the 17β-position have particularly advantageous anti-inflammatory properties, as will be discussed in more detail below.

The novel compounds of formula (I) have good anti-inflammatory activity, especially when applied topically, as assessed by the McKenzie patch test in humans and measured by the reduction of croton oil-induced edema when the compounds are applied topically to the skin of Be applied to mice and rats.

Certain of the compounds show good topical anti-inflammatory activity in the croton oil ear test, coupled with minimal hypothalamic-pituitary adrenal supressive action after topical application in the same animal species. The results indicate that such compounds may be valuable in the local treatment of inflammation in humans and animals, with minimal possibility of causing undesirable systemic side effects.

Compounds of formula (I) which are preferred because of their good anti-inflammatory activity,

-2AT395428B include the following categories, namely (a) those in which chloro or thiomethyl is (b) those in which R² Acetyl or propionyl, preferably propionyl, (c) those in which R⁴ Fluorine is, (d) those in which R $ is fluorine, (e) the 1,4-dienes and (f) those 1,4-dienes wherein R⁴ Fluorine is and R³ Is hydrogen, α- or ß-methyl or methylene.

Compounds of formula (I) coupled with good anti-inflammatory activity coupled with minimal hypothalamic-pituitary-adrenaline-suppressive potency in topical application include 1,4-dienes wherein R 1 is chloro or fluoromethyl, R⁴ and R 1 are fluorine, and in particular those in which R³ is α-methyl.

Particularly preferred compounds because of their good topical anti-inflammatory activity and the favorable ratio of topical anti-inflammatory activity to undesirable systemic activity include:

S-chloromethyl-9ct-fluoro-11β-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-1,4-dicin-17β-carbo thioate;

S-chloromethyl-9a-fluoro-LLSs-hydroxy-16-methylene-3-oxo-17a-propionyloxy-l, 4-diene-17.beta.-carbothioate;

S-fluoromethyl-6a, 9a-difluoro-LLβ-hydroxy-16a, 17a-isopropylidenedioxy-3-oxoandrosta-1,4-diene-17β-carbonylthioate;

S-fluoromethyl-6a, 9a-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbo thioate;

S-Chloromethyl-6cc, 9a-difluoro-LLβ-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17β-carbonyl thioate.

The latter compound is particularly preferred because of its particularly favorable ratio and additionally minimal skin atrophy.

The compounds of formula I can be prepared by several different methods.

The compounds of formula I are prepared by reaction of a corresponding androstane compound containing a 17β-substituent of the formula -COS (CH 2)_nY includes (wherein Y represents a replaceable substituent and η is 1 or 2) with a compound serving to substitute the group Y with a halogen atom .

Thus, the compounds of formula I can be subjected to a halogen exchange reaction which serves to replace the group Y, if this is halogen, by a different halogen substituent. Thus, the bromomethyl, fluoromethyl and fluoroethyl-17β-carbothioate compounds can be prepared from the corresponding iodomethyl or bromoethyl-17β-carbothioate compounds using a bromide salt such as lithium bromide, in the case of the bromomethyl-17β-carbothioate compounds or a suitable fluoride, e.g. B. Silver monofluoride or silver difluoride in the case of fluoromethyl or fluoroethyl-17β-carbothioate compounds. The starting iodomethyl-17β-carbothioate compounds can be prepared from the corresponding chloromethyl-17β-carbothioate compounds using, for example, an alkali metal, alkaline earth metal or quaternary ammonium iodide, e.g. B. Sodium iodide.

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

The starting materials used in the process described herein for the preparation of the compounds of formula I are novel, they include compounds of general formula II

<img file="AT395428B_D0004.tif" />

wherein R^a a thiocarbamoyloxycarbonyl group -COOCSNR^AR^Bin which R^A and R® are as defined above, or a group of the formula -COSR ^, where R^{1 A} is a hydrogen atom or a group as described above for R¹ is defined, or is a convertible into this group, and R® represents an esterified hydroxyl group or R ^ and R^c together form an isopropylidenedioxy group; or if R^a a group is COSR ^, R * 'is optionally a hydroxyl group;

-3AT395428B

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

R^b a hydroxy or protected hydroxy group (either in the α or β configuration) or an oxo group;

R^e represents a hydrogen, bromine, chlorine or fluorine atom; or R ^ and R^e together form a carbon-carbon bond or an epoxy group in the β-configuration;

R^f represents a hydrogen or a fluorine atom; and the symbol πτππ-. represents a single or double bond;

and salts of such compounds having a free carbothioic acid group; with the exception of compounds of the formula I as defined above.

When R 1 represents a protected hydroxyl group, it may be, for example, a trialkylsilyloxy group or a perfluoro or perchloroalkanoyloxy group as defined above.

17a-Hydroxy-17β-carbothioic acids of the formula II and the salts thereof can be converted to the 17α-hydroxy-17β-carbothioates of the formula II, wherein R^a the group COSR¹ represents, as defined in the formula I, or in the 17ß-carbothioic acid 17a-ester of formula II.

For example, a salt of the starting 17β-carbothioic acid such as an alkali metal, e.g. B. Lithium, sodium or potassium salt or an alkylammonium, e.g. B. Triethylammonium or tetrabutylammonium be reacted with a suitable alkylating agent, preferably in a polar solvent such as a ketone, for. B. Acetone, or an amide such as dimethylformamide, dimethylacetamide or hexamethylphosphoramide, suitably at a temperature of 15 to 100 ° C. The alkylating agent may comprise a suitable dihalogen compound, e.g. B. one which contains another halogen atom (preferably a bromine or iodine atom) in addition to the halogen atom of the desired R¹ Group contains. This process is particularly applicable to the preparation of compounds wherein R is a chloromethyl group, which alkylating agent is advantageously bromochloromethane

The esterification of the 17a-hydroxy group can be carried out by conventional techniques, for. B. by reacting the starting 17α-hydroxy compound with a mixed anhydride of the required carboxylic acid, which may be prepared, for example, in situ by reaction of the carboxylic acid with a suitable anhydride, such as trifluoroacetic anhydride, preferably in the presence of an acidic catalyst, e.g. Bp-toluenesulfonic acid or sulfosalicylic acid. Alternatively, the mixed anhydride can be generated in situ by reaction of a symmetrical anhydride of the required acid with a suitable further acid, e.g. B. Trifluoroacetic acid.

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

Alternatively, the 17a-hydroxy group can be esterified by reacting the 17a-hydroxy starting compound with the appropriate acid anhydride or acid chloride, optionally in the presence of non-hydroxylic solvents, e.g. B. Chloroform, methylene chloride or benzene, and preferably in the presence of a strongly acidic catalyst, for. B. Perchloric acid, p-toluenesulfonic acid or a strongly acidic cation exchange resin, for. B. Amberlite IR120, wherein the reaction is conveniently carried out at a temperature of 25 to 100 ° C.

The esterification of the 17a-hydroxy group is preferably effected with the corresponding carboxylic acid chloride in a solvent such as a halogenated hydrocarbon, e.g. Example, methylene chloride, and advantageously in the presence of a base such as triethylamine, preferably at a low temperature, for. Eg 0 ° C.

The 17a-hydroxy-17ß-carbothioic acid of the formula Π and the salts thereof are particularly useful intermediates for the preparation of Androstan- 17ß-carbothioate of formula I; those in which R^c represents a hydrogen atom, an α- or β-methyl group or a methylene group, R^e represents a hydrogen, chlorine or fluorine atom, represents a hydroxy group in the β-configuration or an oxo group, are preferred. More preferred compounds and salts thereof include those compounds wherein R^c a methyl group in the α- oda β configuration or a methylene group; R^e represents a fluorine atom, represents a hydroxy group in the β-configuration or an oxo group and the symbol τππττ. in the 1,2-position means a carbon-carbon double bond.

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

9a-fluoro-LLSs, 17a-dihydroxy-16ss-methyl-3-oxo-androsta-l, 4-diene-17-carbothioic acid;

9a-fluoro-LLSs, 17a-dihydroxy-16a-methyl-3-oxo-androsta-l, 4-diene-17-carbothioic acid;

9a-fluoro-LLSs, 17a-dihydroxy-16-methylene-3-oxo-androsta-l, 4-diene-17-carbothioic acid;

6a, 9a-Difluoro-IIβ, 17a-dihydroxy-16a-methyl-3-oxo-androsta-l, 4-diene-17β-carbothioic acid and the corresponding 11-ketones and salts thereof.

-4AT395428B

An advantage of the above intermediates is that they allow direct haloalkylation to form haloalkyl-17β-carbothioates when the corresponding thiols R 1 -SH are not available. The salts of these 17a-hydroxy-17ß-carbothioic acids, for example, alkali metal, z. B. Lithium, sodium or potassium salts; Alkaline earth metal, e.g. B. Calcium or magnesium salts; tertiary amine salts, e.g. B. Pyridinium or triethylammonium salts; or quaternary ammonium salts, e.g. B. Tetrabutylammonium salts, be.

For example, the 17a-hydroxy-17β-carbothioic acids can be prepared by reaction of a reactive derivative of a corresponding 17α-hydroxy-17β-carboxylic acid with hydrogen sulfide or a sulfide or hydrosulfide salt or Hydrogen sulfide salt thereof. In general, the cation of the sulfide or hydrosulfide salt may be, for example, an alkali metal salt, such as sodium or potassium hydrogen sulfide. The reactive derivatives mentioned above correspond to compounds of formula Π wherein R ^ is a hydroxyl group and the group -COR² is in the 17β position, where R² a group of the formula

<img file="AT395428B_D0005.tif" />

wherein X, Y and Z, which may be the same or different, each represents CH or N, one or two of X, Y and ZN, the heterocyclic ring optionally substituted on at least one carbon atom is represented by a lower alkyl group (e.g. B. with 1 to 4 carbon atoms, such as a methyl group) and / or wherein the heterocyclic ring contains two adjacent carbon atoms, which ring optionally bears a benzene ring fused to these two adjacent carbon atoms

The previously mentioned reactive derivatives of the formula II are preferably prepared by reacting corresponding 17a-hydroxy-17ß-carboxylic acids of the formula II with a symmetrical or asymmetric compound of the formula

R²WR² (ΠΙ) where W is the group CO, CS, SO or SO₂ represents and the groups R², which may be the same or different, have the above meanings.

The compounds of formula ΠΙ are suitably symmetrical. In general, compounds of the formula ΠΙ are used in which W has the meaning of CO, CS or SO. For example, particularly useful compounds include N, N'-carbonyldi (l, 2,4-triazole), Ν, Ν'-carbonyldibenzotriazole, Ν, Ν'-carbonyldibenzimidazole, N, N'-carbonyldi (3,5-dimethylpyrazole ), Ν, Ν'-thionyldiimidazole and especially NN'-carbonyldiimidazole and N, N'-thiocarbonyldiimidazole.

Preparation of a 17a-hydroxy-17β-carbothioic acid of formula II as defined above is conveniently effected by reaction of a 17a-hydroxy-17β-carboxylic acid with a compound of formula III, followed by reaction of the intermediate with 17β-COR⁷Group with hydrogen sulfide or a salt thereof, preferably in situ, without isolating the intermediate.

The 17a-acyloxy-17ß-carbothioic acid of the formula II can be obtained in the same way directly from the corresponding 17a-acyloxy-17ß-carboxylic acid by reaction with a compound of formula HI. The 17a acyloxy-17β-carboxylic acids can be prepared by esterifying the corresponding 17a-hydroxy-17β-carboxylic acids according to the methods described in British Patent 1,384,372.

The reaction with the compound of formula III is conveniently carried out in the presence of an inert anhydrous solvent, e.g. B. a substituted amide solvent, such as Ν, Ν-dimethylformamide or Ν, Νdimethylacetamide, conveniently in the absence of water, advantageously at or below room temperature, e.g. B. at a temperature of -30 ° C to +30 ° C. The reaction is conveniently effected under about neutral conditions, advantageously in an inert atmosphere, e.g. B. under nitrogen. The same solvents and conditions can also be applied to the following reaction with H₂S or a salt thereof. The heterocyclic compound, z. For example, imidazole or 1,2,4-triazole formed as a by-product can be easily removed, for example, by extracting with water.

The 11 ß-hydroxy compounds of formula Π can be prepared by reduction of a corresponding 11 -Oxoverbindung, z. Using an alkali metal or alkaline earth metal borohydride, eg sodium or calcium borohydride, suitably in an alcoholic or aqueous-alcoholic solvent such as methanol or ethanol.

Such a 1 l keto compound can be prepared by oxidation of a corresponding 11a hydroxysteroid, for example using a chromic acid reagent such as Jones reagent.

-5AT395428B

A 1-L-hydroxy compound of the formula Π can also be obtained by deprotecting a corresponding compound having a protected hydroxyl group in the IIβ-position, for example a tri-C 1-7 -alkylsilyloxy group, such as the trimethylsilyloxy group or a perfluoro or -chloroalkanoyloxy group, such as the trifluoroacetoxy group. The removal of the protecting group may be effected by hydrolysis, the trialkylsilyl group being conveniently removed by mild acid or base hydrolysis, or more conveniently using fluoride, e.g. B. Hydrogen fluoride or an ammonium fluoride. The perfluoro or chloroalkanoyl protecting group can also be removed by mild acid or base hydrolysis or alcoholysis, but preferably under acidic conditions. When R 1 is a chlorine atom. Such a protected hydroxyl group can be introduced, for example, by reaction of an IIβ-hydroxy steroid with a suitable reagent such as a trialkylsilyl halide or perfluoro - or chloroalkanoic anhydride.

The compounds of formula Π may also be prepared by reacting a corresponding compound having a 9.1-l double bond (not having any substituent at the 1-L position) with reagents which serve to form the required 9a halogeno-1-hydroxy group introduce. This can involve the initial formation of a bromohydrin by reaction with an N-bromamide or imide such as N-bromosuccinimide, followed by formation of the corresponding 9β, IIβ epoxide by treatment with a base and reaction of the epoxide with hydrofluoric acid or hydrogen chloride for introduction the required Flurahydrin or Chlorohydrin. Alternatively, the 9.1 L olefin compound can be reacted with an N-chloroamide or imide to directly introduce the required 9a-chloro-L-β-hydroxy group.

The Δ-compounds of the formula II can be conveniently prepared by partial reduction of the corresponding Δ¹^ Compound, for example by hydrogenation using a palladium catalyst, suitably in a solvent, for. B. Ethyl acetate or by homogeneous hydrogenation using, for example, tris (triphenylphosphine) rhodium chloride, conveniently in a solvent such as benzene, or by exchange hydrogenation using, for example, cyclohexene in the presence of a palladium catalyst in a solvent, eg Ethanol, preferably under reflux. This reduction can be carried out in a haloalkyl ester, if it is sufficiently stable in such a reaction, or can be effected in an earlier stage.

The compounds of formula II which contain a free -COSH group in the 17β position can be prepared, for example, by aminolysis with rearrangement of a suitable 17β-thiocarbamoyloxycarbonylandrostane. The 17β-thiocarbamoyloxycarbonylandrostane is a mixed anhydride of the corresponding 17β-carboxylic acid and a thiocarbamic acid and is conveniently prepared by reacting a 17β-carboxylic acid 17α-ester or 16a, 17a-acetonide with a thiocarbamoyl halide. The thiocarbamoyl group is Ν, Ν-disubstituted and may thus have the formula -COOCSNR^AR^B in which R^A and R^Bwhich may be the same or different, alkyl groups, e.g. B. Cj ^ 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 optionally be substituted by one or two Cj. ^ - alkyl z. As methyl groups. Preferably, R^A and R^BC 1-4 alkyl substituents, with the N, N-dimethylthiocarbamoyl group being preferred. The thiocarbamoyl halide is preferably the chloride. The reaction can be accelerated by the addition of a iodide salt, e.g. For example, sodium iodide.

The original androstane-17ß-carboxylate salt may for example be an alkali metal, e.g. For example, sodium or potassium, alkaline earth metal, z. As calcium salt or a salt of a tertiary amine, for. B. triethylamine, be.

The aminolysis with rearrangement can be carried out, for example, by heating the mixed anhydride to an elevated temperature, for. In the presence of ammonia, a primary amine, or more preferably a secondary amine such as dimethylamine or pyrrolidine. In the starting 17ß-carboxylic acids, the 16- and 17a-position are suitably substituted by the -R ^ - and -OR²Groups desired for the final product of formula I.

17a-hydroxyandrostane compounds in the 16-methylene series bearing the desired 17β-carbothioic acid group as described above can be prepared from the corresponding 16β-methyl-16a, 17a-epoxy17β-thiocarboxylic acid by effecting rearrangement using a strong acid, e.g. , B. a strong carboxylic acid such as trifluoroacetic acid. These 16a, 17a epoxides can be prepared from the corresponding 17β-carboxylic acids by treatment with an onium salt of a 2-halo-aza-aromatic compound followed by treating the resulting product with hydrogen sulfide or a salt thereof to form the free 17β-carbothioic acid which can be alkylated as described above, preferably in situ, to form the desired 17β-carbothioate group.

16a, 17a-Isopropylidenedioxy compounds of the formula Π can be prepared in the same manner by treating a corresponding 17β-carboxylic acid with an onium salt of a 2-halo-aza-aromatic compound followed by treating the resulting product with hydrogen sulfide to form the free one

-6AT395428B

17β-carbothioic acid, which can then be esterified as described above.

Onium salts of the 2-halo-aza-aromatic compounds are capable of effecting carboxyl activation. Such reagents include 2-halo-N-alkyl or 2-halo-N-phenylpyridium or -pyrimidinium salts carrying 1 to 2 further substituents selected from phenyl and lower (ζB.Cj.sub.j).

alkyl groups, such as methyl. The 2-halogen atoms may be fluorine, chlorine, bromine or iodine atoms. The salts are preferably sulfonates, ζ. For example tosylates; Halides, ζ. Iodides; Fluorocarbonates or perfluoroalkylsulfonates, where a suitable salt is 2-hydior-N-methylpyridinium tosylate or 2-chloro-N-methylbenzothiazolium trifluoromethanesulfonate

The 16a, 17a-epoxy-16β-methyl-17β-carboxylic acid compounds, which may be used as starting materials in the above process, can be prepared in a conventional manner. As described in GB Patent Publication No. 1517,278.

The above reactions may also be carried out on compounds having various substituents or moieties, which are subsequently converted into compounds of formula I as described above.

The androstane-17β-carboxylic acid starting materials used in the above process can be prepared in a conventional manner, ζ. B. by oxidation of a corresponding 21-hydroxy-20-ketopregnane, for example with piperic acid, in a solvent medium and preferably at room temperature. Alternatively, sodium bismuthate can be used to effect the desired oxidative removal of the 21-carbon of a 17a-acyloxypregnane compound. It will be appreciated that should the parent pregnane bond contain any substituents which are sensitive to the oxidation desired above, such moieties should be suitably protected.

The following examples serve to illustrate the invention. Melting points were determined in ° C on a Kofler block and are uncorrected. Optical rotations were determined at room temperature on solutions in dioxane.

DieDünnschichtchromatografie (T, lc), diepräparativeSchichtchromatografie (plc) unddiehochleistungsfahige

Liquid chromatography (hplc) was performed over silica.

Solutions were dried over magnesium sulfate unless otherwise stated.

Production I

9a-fluoro-LLSs-hvdroxv-16B-Methyl-3-oxo-17a-propionvloxvandrosta-1,4-diene-17.beta.-carbothioic acid (D

A solution of 5.00 g of 9a-fluoro-11β-hydroxy-16β-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17β-carboxylic acid solvated with ethyl acetate (1/2 mol) and 5.3 ml of triethylamine in 75 mL of methylene chloride was stirred under nitrogen and treated with 5.071 g of dimethylthiocarbamoyl chloride. After 24 h, another 5.320 g of reagent was added. After 47 h, the mixture was diluted with ethyl acetate and treated with n-hydrochloric acid, 5%.

Sodium bicarbonate solution and water, dried and evaporated to give 9.043 g of a viscous yellow oil. This was dissolved in 50 ml of ethylamine, then stirred and stirred at reflux under nitrogen for 5.75 h. The resulting brown solution was added to a mixture of 50 ml of concentrated hydrochloric acid, 250 ml of water and 50 ml of ethyl acetate. The products were further extracted with ethyl acetate, then the acidic products were back-extracted in 5% sodium carbonate solution. The aqueous phase was acidified with 50 ml of 6N hydrochloric acid and extracted with ethyl acetate. The extracts were washed with n-hydrochloric acid and water, dried and evaporated to give 3,440 g of a buff solid. This was recrystallized from acetone to give 1.980 g of pale-tan crystals Title 17β-Carbothioic acid of Mp. 172-173 °.

The analytical sample was obtained after two recrystallizations from acetone as white crystals of

Mp 177-179 °, [tt]_D + 110 ⁰ (c 1.05).

Production Π

S-Chlormethvl-9a-fluoro-16ss-Methyl-3.11-dioxo-17a propionvloxvandrosta-1.4-dien-17.beta.-carbothioate (ID

1.5 ml of 8n Jones reagent was added dropwise over 10 minutes to a stirred solution of 998 mg

Example of Example 1 (described below) in 2 ml of acetone and 2 ml of dimethylformamide added. After 30 minutes, the reaction mixture was slowly diluted with 100 mL of water with stirring and the resulting suspension was cooled for 1 h. The precipitate was collected by filtration, washed with water and dried to give 877 mg of a cream solid. plc in chloroform-acetone (10: 1) gave 755 g of a white foam, which was crystallized twice from acetone to give 523 mg of white needles of the title II ketone, m.p. 204-205 ° [a]_D+ 94 ° (c 1.04).

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Production ΠΙ

17β-N, N-dimethylthiocarbamovloxvcarbonyl-9a-fluoro-llβ-hvdroxv-16a-methvl-17a-propionyloxvandrosta1,4-dien-3-one (IIP

A solution of 0.434 g9a-fluoro-11β-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-l, 4-diene-17β-carboxylic acid in 8 ml of methylene chloride was added successively with 0.14 ml of triethylamine, 0.248 g of dimethylthiocarbamoyl chloride and 0.149 g of sodium iodide and the mixture was stirred at 20 ° C under nitrogen for 6 h. 30 ml of ethyl acetate were added and the total volume was reduced by half in vacuo. Another 50 ml of ethyl acetate was added, and the solution was washed with water, 2N-hydrochloric acid, water, 3% sodium hydrogencarbonate, water and saturated sodium chloride solution, and then dried. The solution was concentrated in vacuo as the product crystallized (0.329 g). This was recrystallized from acetone (twice) to give the title anhydride as white needles of mp. 191-193 °

M_D + 82 ° (c 0.57).

Production IV

9FL-fluoro-LLSs-hvdroxv-16a-Methyl-3-oxo-17a-propionvloxvandrosta-1,4-diene-17.beta.-carbothioic acid (IV)

A stirred suspension of 2.467 g of ΠΙ in 25 ml of diethylamine was heated to reflux under nitrogen. After 2.5 hours, the reaction was poured into 300 ml of iced 3N hydrochloric acid and the mixture was extracted with ethyl acetate. The combined extracts were washed with water and extracted with 5% sodium carbonate solution. The combined aqueous extracts were washed with ethyl acetate, then covered with ethyl acetate and acidified to pH 1 with hydrochloric acid. The aqueous phase was extracted with more ethyl acetate and the combined extracts were washed with water, saturated sodium chloride, dried and the solvent removed in vacuo. The residue was crystallized twice from acetone to give 1.309 g of the title carbothioic acid as white needles from the Fp. 141-143 °.

[A]_D+ 30 ° (c 0.51).

Preparation V Lβ-Hvdroxv-3-oxo-17-propionvloxvandrosta-1,4-diene-17β-carboxylic acid (V)

A solution of 13.5 g, 17a-dihydroxy-3-oxoandrosta-l, 4-diene-17β-carboxylic acid and 18 ml of triethylamine in 500 ml of methylene chloride was cooled to 4 ° C and then in portions over 15 min with 14.2 ml Propionyl chloride was treated. The mixture was further stirred at 4 ° C. for a total time of 1 h and the mixture was washed successively with 3% sodium bicarbonate, Water, 2 hydrochloric acid, Washed with water and saturated brine, then dried and evaporated under reduced pressure. The residue was dissolved in 300 ml of acetone and 14.3 ml of diethylamine was added with stirring. After 1 h at 20 ° C, the solvent was removed under reduced pressure and the residue was dissolved in 150 ml of water. After acidification; with hydrochloric acid the product was extracted with ethyl acetate. The combined extracts were washed with water and saturated brine, dried and concentrated to a small volume. The solid product was collected by filtration, washed with ethyl acetate and dried in vacuo at 50 ° to afford 13.309 g of the title 17a-propionate carboxylic acid in the form of crystals [α] ρ + 2 ° (c 1.10). A 389 mg portion was recrystallized twice from methanol to give an analytical sample of 256 mg, m.p. 244-245 ° C (decomp.).

[A]_D+ 3 ° (c 0.83).

Production VI

a) 6a.9a-Difluoro-LLSs-hvdroxv-16a-Methyl-3-oxo-17a-propionvloxvandrosta-1,4-diene-17.beta.-carboxylic acid (VI)

A solution of 2.113 g of 6a, 9a-difluoro-IIβ, 17a-dihydroxy-16a-methyl-3-oxoandrosta-l, 4-diene-17β-carboxylic acid and 2.5 ml of triethylamine in 60 ml of methylene chloride was stirred and stored at about 0 ° C treated with 1.85 ml of propionyl chloride. After 1 h, the mixture was diluted with 50 mL of additional solvent and washed successively with 3% sodium bicarbonate, water, 2N hydrochloric acid, water, saturated brine, then dried and evaporated to a buff solid. This was dissolved in 50 ml of acetone and 2.5 ml of dimethylamine was added. After 1 h at 22 ° C, the solvent was removed in vacuo and the remaining gummy product was dissolved in 30 ml of water. Acidification to pH 1 with 2N hydrochloric acid precipitated a solid which was collected, washed with water and dried to give 2.230 g of the title carboxylic acid 17a-propionate, m.p. 220-225 °.

[A]_D+ 4 ° (c OJO)

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Hgrstclluns YII

17β-N, N-dimethylthiocarbamovloxvcarbonyl-9a-fluoro-llβ-hvdroxv-16a, 17a-isopropylenedioxvandrosta1,4-dien-3-one (VIR

A solution of 1,000 g of 9a-fluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxoandrosta-l, 4-diene-17β-carboxylic acid in 15 ml of methylene chloride and 0.33 ml of triethylamine was treated under nitrogen with 588 mg of N, N-dimethylthiocarbamoyl chloride and the mixture was stirred at room temperature. After 68 hours, the mixture was diluted with 50 ml of ethyl acetate and washed with 2.10 ml of n-hydrochloric acid, 5% sodium bicarbonate solution and water, dried and evaporated to give 1.123 g of a pale yellow crystalline solid. plc a level of 200 mg in chloroform-acetone (9: 1) gave an almost white solid of 161 mg, which crystallized from ethyl acetate as 131 mg of white needles of the title mixed anhydride, m.p. 279-281 ° [α] jj + 174 ° (c 0.61, dimethylsulfoxide).

Production VIII

17β-N, N-dimethylthiocarbamovloxvcarbonyl-6a, 9a-difluoro-llβ-hvdroxv-16a, 17a-isopropylidenedioxvandrosta-1,4-dien-3-one fVIIR

A solution of 4.354 g of 6a, 9a-difluoro-LLβ-hydroxy-16a, 17a-isopropylidenedioxy-3-oxoandrosta-1,4-dienitol-β-carboxylic acid in 150 ml of methylene chloride containing 1.4 ml of triethylamine was mixed with 2.519 g of N, N Dimethylthiocarbamoylchlorid and the reaction was stirred under nitrogen for 80 min at 22 °. 500 1 ml of ethyl acetate was added, and the resulting solution was washed with 2N hydrochloric acid, water, sodium hydrogen carbonate solution, water and saturated sodium chloride solution successively and dried, and the solution was concentrated. Upon cooling, crystallization occurred and the solid was filtered and dried in vacuo to give 3.562 g of the title anhydride as pale yellow prisms, m.p. 283-287 ° (Tiers.) [A]_D + 156 ° (c 0.84, dimethylsulfoxide).

Conclusion IX

6a, 9a-Difluoro-1β-hvdroxv-16a, 7α-isopropylenedioxv-3-oxo-androsta-1,4-diene-17β-carbothioic acid (IX)

A suspension of 3.455 g of VIII in 200 ml of diethylamine was heated at reflux under nitrogen for 6 h. The original suspension dissolved rapidly but a brown suspension formed after 30 minutes and remained unchanged. The cooled reaction mixture was poured into 1.01 water, acidified to pH 1 with 210 ml concentrated hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water and extracted with 5% sodium carbonate solution and water, and the aqueous extracts were combined. The combined extracts were acidified with 6N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with water and saturated sodium chloride solution, then dried, and the solvent was removed in vacuo to give 2.31 g of a pale gray solid.

A portion of the product of 0.408 g was crystallized from ethyl acetate to give 0.149 g of the title carbothioic acid, m.p. 191-199 ° [&lt;x] p + 124 ° (c 1.04, dimethylsulfoxide).

Production X

a) 6α-Fluoro-1,1,4-diazo-3-oxoandrosta-1,4-diene-17β-carboxylic acid (X)

A solution of 4.987 g of 6a-fluoroprednisolone in 50 ml of tetrahydrofuran was stirred with a solution of 10.0 g of periodic acid in 24 ml of water at 22 °. After 50 minutes, the tetrahydrofuran was evaporated and the aqueous suspension was filtered. The solid product was washed with 300 ml of water and dried to give 4.80 g of a white solid. A 271 mg portion was crystallized from methanol to give 171 mg of the title acid of white needles, mp 241-248 °.

[&lt;X]_D+ 54 ° (c 0.825)

Production 11

6a-Fluoro-1-l-hydroxy-3-oxo-17a-propionvloxvandrosta-1,4-diene-17β-carboxylic acid (XD

A solution of 4.491 g of X and 4.46 ml of triethylamine in 160 ml of dry methylene chloride at -5 ° was stirred and treated dropwise with 2.80 ml (2.96 g) of propionyl chloride in about 5 ml of dry methylene chloride for 5 min at below 0 ° , After a further 20 minutes at 0 °, the reaction mixture was diluted with 160 ml of methylene chloride, washed with sodium bicarbonate solution and water, dried and evaporated to give 5.701 g of a white solid. This was combined with 4.60 ml (3.24 g) of diethylamine in 30 ml of acetone Formation of a clear yellow solution stirred After 30 minutes, the solution was concentrated, 150 ml of water was added and the resulting solution was washed twice with 30 ml of ethyl acetate. The aqueous phase was used

Acidified to pH 2 with stirring from 50 ml of 2 N hydrochloric acid and the product was extracted three times with ethyl acetate. The extracts were combined, washed with 50 ml of water, dried and evaporated to give 5.891 g of a white foam. A portion of 304 mg of the foam was crystallized from ethyl acetate to give 144 mg of the title 17a propionate as small platelets, mp 224-227 °.

[A]_D+ 3 ° (c = 0.861).

Preparations ΧΠ-ΧΧΙΙΙ

However, following the general procedure described in Preparation I but using as the starting material 17ß-carboxylic acid corresponding to the desired 17β-carbothioate, the following compounds were prepared (process details are given in Table I below):

XII. 17a-acetoxy-9a-fluoro-16ss-hydroxy-LLSs-methyl-3-oxo-androsta-l, 4-diene-17-carbothioic acid,

Mp 178.5-179 °, [a]_D+ 98 ° (c 1.02).

ΧΠΙ. 17a-Butyryloxy-9a-fluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid of

Mp 175-176 °, [a]_D+ 107 ° (c 0.96).

XIV 9a-fluoro-11β-hydroxy-17a-isobutyryloxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid,

Mp 177-179 °, [a]_D+ 119 ° (c0,90).

XV. 11β-Hydroxy-3-oxo-17a-propionyloxyandrosta-1,4-diene-17β-carbothioic acid, m.p. 134-138 °, [a]_D+ 67 ° (c 0.66).

XVI. 11β-Hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioic acid of

Mp 159-163 °, [a]_D+ U3 ° (Co, 78).

XVn.9a-chloro-LLSs-hydroxy-16ss-methyl-3-oxo-17a-propionyloxy-l, 4-dien-17-carbothiosäurevom

Fp. 167-171, [a]_D+ 128 ° (c 0.99).

XVHI.9a-fluoro-LLSs-hydroxy-16a-methyl-3-oxo-17a-propionyloxy-l, 4-dien-17-carbothiosäurevom

Mp 141-143 °, [a]_D+ 3O ° (Co, 51).

XIX. 6a, 9a-Difluoro-1-l-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17β-carbothioic acid, m.p. 136-139 °, [a]_D -30 ° (c 0.56).

XX. 9a-fluoro-11β-hydroxy-16-methylene-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioic acid,

Mp 236-239 °, [a]_D-71 ° (c 0.99).

XXI. 11β-Hydroxy-3-oxo-17α-propionyloxyandrosta-4-ene-17β-carbothioic acid, m.p. 176-177 °, [a]_D+ 101 ° (c 0.96).

ΧΧΠ. 9a-Fluoro-1-l-hydroxy-16a, 17a-isopropylidene-dioxy-3-oxoandrosta-1,4-diene-17β-carbothioic acid of

Mp. 274-304 ° (dec.), [A]_D + 121 ° (c 0.51, dimethyl sulfoxide).

XXIII. 6a-fluoro-LLβ-hydroxy-3-oxo-17a-propionyloxyandrosta-1,4-diene-17β-carbothioic acid of the

Mp. 189-193 °, [&lt;X]_D + 72 ° (c 0.74).

-10AT395428B

Table I

Formation of mixed anhydrides

<td>manufacturing</td><td>17-carboxylic acid- commitment (G)</td><td>Cl-CSNMe2 (G)</td><td>NEt₃(Ml)</td><td>solvent medium (CH₂C1₂) (Ml)</td><td>reaction Time (Days) at room temperature</td>

<td>XII</td><td>5000</td><td>2940</td><td>1.66</td><td>75</td><td>5¹*</td>

<td>XIII</td><td>15354</td><td>8809</td><td>4.8</td><td>250</td><td>6</td>

<td>XIV</td><td>4182</td><td>2399</td><td>1.3</td><td>80</td><td>4</td>

<td>XV</td><td>7148</td><td>4:40</td><td>2.6</td><td>150</td><td>6^lb</td>

<td>XVI</td><td>6137</td><td>3.77</td><td>2:05</td><td>140</td><td>6^{, c}</td>

<td>XVII</td><td>5973</td><td>3350</td><td>1:34</td><td>100</td><td>7</td>

<td>XVIII</td><td>4207</td><td>2:39</td><td>1:35</td><td>80</td><td>067 ^¹³</td>

<td>XIX</td><td>2130</td><td>1.80</td><td>0.66</td><td>50</td><td>6⁴</td>

<td>XX</td><td>5000</td><td>2507</td><td>1:41</td><td>75</td><td>3</td>

<td>XXI</td><td>1000</td><td>2442</td><td>1.22</td><td>15</td><td>2.7</td>

<td>XXII</td><td>1000</td><td>0588</td><td>12:33</td><td>15</td><td>2.8 "</td>

<td>XXIII</td><td>6000</td><td>3:55</td><td>2.0</td><td>120</td><td>125 '</td>

Table I (cont.)

Treatment of mixed anhydride intermediates with diethylamine

<td>manufacturing</td><td>NHEto (Ml)</td><td>reaction time (H) under reflux</td><td>product (G)</td><td>crystallization solvent</td>

<td>XII</td><td>50</td><td>5.5</td><td>2104</td><td>EA²*</td>

<td>XIII</td><td>250</td><td>4</td><td>5244</td><td>EA³</td>

<td>XIV</td><td>60</td><td>4.5</td><td>1:00</td><td>EA</td>

<td>XV</td><td>60</td><td>4</td><td>3.29</td><td>EA</td>

<td>XVI</td><td>50</td><td>3.5</td><td>1382</td><td>EA</td>

<td>XVII</td><td>60</td><td>5.7</td><td>0527</td><td>EA</td>

<td>XVIII</td><td>25</td><td>4.75</td><td>1309</td><td>A</td>

<td>XIX</td><td>12</td><td>6</td><td>0418</td><td>EA</td>

<td>XX</td><td>50</td><td>3.75</td><td>1296</td><td>EA^{2 B}</td>

<td>XXI</td><td>15</td><td>4</td><td>0397 '</td><td>A⁵</td>

<td>XXII</td><td>(a) 8 (b) 16</td><td>(a) 3 (b) 2.5</td><td>Ö464⁵</td><td>A</td>

<td>XXIII</td><td>60</td><td>4.5</td><td>2.88</td><td>EA-P</td>

Remarks:

EA = ethyl acetate. A = acetone. P = petroleum ether Kp 60-80 °

-11AT395428B

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

Second The characterization was carried out on a sample which was recrystallized twice from ethyl acetate. Yield (a) 84%, (b) 69%.

Third The product was solvated with ethyl acetate (about 0.2 mol).

4th The intermediate dimethylthiocarbamic anhydride (1.435 g) crystallized from ethyl acetate. A 95 mg portion is used for characterization

5th The characterization was carried out on a sample, recrystallized twice from acetone (yield 73%).

6th The product crystallized from ethyl acetate.

7th 1.46 g of sodium iodide were also present in the reaction.

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

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

10th 2.13 g of sodium iodide were also present in the reaction.

Making xxry

9a-chloro-LLSs-hvdroxv-16ss-Methyl-3-oxo-17a-propionyloxy-1,4-dien-17-carbothiosäureund

9ß.llß-Epoxv-16ss-Methyl-3-oxo-17a-propionvloxvandrosta-1,4-diene-17.beta.-carbothioic acid (XXIV)

One of 5. 586 g of 17b-N, N-dimethylthiocarbamoyloxycarbonyl-9a-chloro-11β-hydroxy-16β-methyl-17apropionyloxyandrosta-1,4-dien-3-one in 16 ml of diethylamine was refluxed under nitrogen for 5 hrs , The reaction was poured into 450 ml of water, acidified to pH 10 with concentrated hydrochloric acid and extracted with 60 ml of ethyl acetate three times. The combined extracts were washed with water and then extracted with four times 50 ml of aqueous sodium carbonate solution. The aqueous extracts were acidified to pH 1 with 6N hydrochloric acid and extracted with three times 50 ml of ethyl acetate. The combined extracts were washed with water and saturated sodium chloride solution and dried and the solvent removed in vacuo to give 2.834 g of a colorless foam.

Two crystallizations of the ethyl acetate mixture gave 0.527 g of 9a-chloro-11β-hydroxy-16β-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17β-carotenoic acid in the form of white prisms, mp. 167-171 ° [a ]_D+ 128 ° (c 0.99).

The mother liquors of the crystallizations contained an additional amount of the above 9a-chloro-11β-hydroxycarbothioic acid together with 9β, 11β-epoxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-dicarboxylic acid.

Production XXV

S-iodomethyl-9a-fluoro-llβ-hvdroxv-16β-methvl-3-oxo-17a-propionvloxvandrosta-1,4-diene-17B-carbothioate ffXV)

A solution of 500 mg of the compound of Example 1 (described below) and 1.874 g of sodium iodide in 15 ml of acetone was stirred at reflux for 6.5 hours and heated. 75 ml of ethyl acetate were then added and the solution was washed successively with water, 10% sodium thiosulfate solution, 5% sodium bicarbonate solution and water, dried and evaporated to give 525 mg of an almost white foam. plc in chloroform-acetone (6: 1) gave 478 mg of an almost white foam which was crystallized twice from acetone without warming above room temperature to give 241 mg of colorless crystals of the title S-iodomethyl ester of mp. 196-197 °, [a]_D -32 ° (c 1.01).

Preparations XXVI - XXXVII

However, following the same general procedure as described in Preparation XXV but using the S-chloromethyl-17β-carbothioate corresponding to the desired product as the starting material (the process details are given in Table II below), the following compounds were prepared:

XXVI.S-iodomethyl-17a-acetoxy-9a-fluoro-16ss-hydroxy-LLSs-methyl-3-oxo-androsta-l, 4-diene-17.beta.-carbothioate,

Mp 204-205 ° [a] _D -29 ° (c 0.98).

XXVII. S-iodomethyl-L-β-hydroxy-3-oxo-17a-propionyloxy-androsta-1,4-diene-17β-carbothioate, [α] p + 26 ° (c0,47).

-12AT395428B

XXVni. S-iodomethyl-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate, [ot]_D +5 ⁰ (c 0.74).

XXIX. S-iodomethyl-9a-chloro-11β-hydroxy-16β-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17β-carbothioate, [a]_D + 7 ° (c 0.36).

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

XXXI. S-iodomethyl-6a, 9a-difluoro-LLSs-hydroxy-16a-methyl-3-oxo-17a-piopionyloxyandrosta-l, 4-dien-17ßcarbothioat.

ΧΧΧΠ. S-iodomethyl-9a-fluoro-11β-hydroxy-16-methylene-3-oxo-17a-propionyloxyandrosta-1,4-diene-17β-carbothioate, m.p. 191-199 °, [a]_D -31 ° (c 0.99).

ΧΧΧΠΙ. S-iodomethyl-9a-fluoro-1-hydroxy-3-oxo-17a-propionyloxyandrosta-1,4-diene-17β-carbothioate, m.p. 175-178 °, [a]_D 44 ° (c 0.50).

XXXIV. S-iodomethyl-6α-fluoro-11β-hydroxy-3-oxo-17a-propionyloxyandrosta-1,4-diene-17β-carbothioate, m.p. 195-197 °, [a]_D 418 ° (c 0.64).

XXXV. S-iodomethyl-17a-acetoxy-6a, 9a-difluoro-11β-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, m.p. 241-243 °, [a]_D 478 ° (0.78).

XXXVI. S-iodomethyl-17a-butyryloxy-6a, 9a-difluoro-LLβ-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, m.p. 210-212 °, [a]_D 489 ° (c 0.90).

XXXVII. S-iodomethyl-9-fluoro-11β-hydroxy-16a, 17a-isopropylidenedioxy-3-oxoandrosta-1,4-diene-17β-carbothioate, m.p. 261-270 ° (dec.) [A]_D 497 ° (c 0.48, dimethyl sulfoxide).

tables

Halogen exchange on S-haloalkvl-17a-acvloxvandrostane-17ß-carbothioaten

<td>Production no.</td><td>Nal (Mg)</td><td colspan="2">output steroid Halogen- commitment (Mg)</td><td>solvent medium (Ml)</td><td>Reaction time (h) and reflux</td><td>PLC (silicon ziumdi- oxide) CHC1₃- me₂CO</td><td>crystallization LISA TION solvent medium</td><td>Per- domestic product (Mg)</td>

<td>XXVI</td><td>6632</td><td>CI</td><td>1715</td><td>20</td><td>3.5</td><td></td><td>EA</td><td>216 '</td>

<td>XXVII</td><td>3800</td><td>CI</td><td>925</td><td>10</td><td>4</td><td>-</td><td>-</td><td>1084</td>

<td>XXXVIII</td><td>3260</td><td>CI</td><td>840</td><td>10</td><td>3</td><td>-</td><td>-</td><td>969</td>

<td>XXIX</td><td>1995</td><td>CI</td><td>536</td><td>20</td><td>6.5</td><td>-</td><td>-</td><td>591</td>

<td>XXX</td><td>2160</td><td>CI</td><td>580</td><td>10</td><td>3</td><td>-</td><td>-</td><td>685</td>

<td>XXXI</td><td>1200</td><td>CI</td><td>303</td><td>30</td><td>5</td><td>-</td><td>-</td><td>317³</td>

<td>XXXII</td><td>7361</td><td>CI</td><td>1953</td><td>23</td><td>6</td><td>19: 1</td><td>A</td><td>296²</td>

<td>XXXIII</td><td>5500</td><td>CI</td><td>1300</td><td>35</td><td>4</td><td>-</td><td>M</td><td>1250 '</td>

<td>XXXIV</td><td>8400</td><td>CI</td><td>2000</td><td>54</td><td>4.5</td><td>-</td><td>FA-P</td><td>1800</td>

<td>XXXV</td><td>19000</td><td>CI</td><td>4750</td><td>200</td><td>5</td><td></td><td>EA</td><td>4620⁶</td>

<td>XXXVI</td><td>6500</td><td>CI</td><td>1620</td><td>70</td><td>5.5</td><td>-</td><td>EA</td><td>1610 '</td>

<td>XXXVII</td><td>5491</td><td>CI</td><td>1419</td><td>20</td><td>24</td><td>9: 1</td><td>A</td><td>224^8th</td>

EA ss ethyl acetate; A = acetone; M = methanol; P = petroleum ether bp. 60-80 °

Remarks:

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

Second Obtained from a portion of 400 mg of the crude product (2.058 g)

-13AT395428B

Third The product was used directly to prepare the corresponding fluoromethyl-17β-carbothioate.

4th Lithium chloride was used instead of sodium iodide.

5th Solvated with 0.5 H₂O.

6th Solvated with 0.1 EA.

7th Solvated with 0.2 EA + 0.5 H₂O

8th. Obtained from a portion of 300 mg of the crude crystalline product (1.611 g).

Production X

S-iodomethyl-6a.9a-difluoro-llβ-hvdroxv-16a.l7a-isopropylidene-dioxv-3-oxoandrosta-1,4-diene-17β-carbothioate ixxxyim

A solution of 0.795 g of the Example 4 compound described below in 50 ml of acetone was heated at reflux with 2.969 g of sodium iodide for 5.5 hours. 75 ml of ethyl acetate were added and the solution was washed in turn with water, sodium metabisulfite solution, then dried and the solvent was defatted in vacuo to give 0.833 g of an almost white solid. A portion of 0.205 g of it was crystallized twice from ethyl acetate to give 0.105 g of the title S-iodomethylthioester in the form of white prisms of mp. 260-262 ⁰ (Dec.) [A] p + 81 ° (c 0.6, dimethyl sulfoxide).

Production XXXIX

S-2'-Bromoethyl-9-yl-fluoro-llβ-hvdfoxv-16β-methyl-3-oxo-17a-propionvloxvandrosta-1,4-diene-17β-carbothioate (XXXIX)

0.5 g of I was treated as for the S-chloromethyl ester (Example 1, method A as described below), but using 1,2-dibromoethane to give 0.409 g of colorless crystals of the title S-2'bromoethylesta of mp 174-145 ° [a]_D + 120 ° (c 1.04)

Production XL

16a, 17a-epoxy-9a-fluoro-llβ-hvdroxv-16β-methvl-3-oxoandrosta-1,4-diene-17β-carbothioic acid (XL)

A mixture of 377 mg of 16a, 17a-epoxy-9a-fluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid and 340 mg of 2-fluoro-1-methylpyridinium tosylate in 7 ml of dry methylene chloride stirred, cooled in ice and treated with 0.42 ml of triethylamine for 1 min. After 1 h of hydrogen sulphide roof, the mixture was passed for 30 min to form a yellow solution. tlc (Chloroform-acetone-acetic acid, 30: 8: 1) showed that a less polar major product had formed. After warming to room temperature for 1 h, the mixture is treated with 30 ml of 2N hydrochloric acid and the product is extracted with ethyl acetate (three times 20 ml). The saae product is extracted from the organic phase with 5% sodium carbonate, which combines aqueous extracts calf, acidified with 6N hydrochloric acid and then extracted with ethyl acetate. The combined saaen extracts were washed with water, dried under reduced pressure, concentrated to give after filtration of 274 mg of nearly white crystals, presumably largely the unstable 16a, 17a-epoxy-9a-fluoro-11β-hydroxy-16β-methyl-3-oxo -androsta-l, 4-dien-17ß-carbonthiosäae (no starting Oxysae was present) as by the tlc (chloroform-acetone-acetic acid, 30: 8: 1, Rf about 0.7).

Manufacturing XLI

S-Chloromethvl-16a.l7a-epoxv-9a-fluoro-LLSs-hvdroxv-16ss-Methyl-3-oxo-androsta-1,4-dien-17.beta.-carbothioate

CXLD

Method A

A suspension of 753mgl6a, 17a-epoxy-9a-fluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid and 680 mg of 2-fluoro-1-methylpyridinium tosylate in 7 ml of methylene chloride was added dropwise at 0 ° C Treated 1.39 ml of triethylamine and then stirred at 0 ° C for 1 h. Hydrogen sulfide then wade the mixture passed for 15 min and finally wade the resulting solution for a further hour at 0 ° C stirred. 0.26 ml of bromochloromethane then added and the mixture was stirred wade and allowed to warm to room tempera. After a further 1.5 hours, the reaction mixture was diluted with 250 ml of ethyl acetate and washed successively with 2N hydrochloric acid, 5% sodium bicarbonate solution and water, dried and evaporated to 818 mg of a pale yellow solid. The solid calf of a plc in chloroform-acetone (9: 1) (two passes). The major band (515 mg) was crystallized from acetone to give ναι 447 mg of white needles of the title S-chloromethyl ester epoxide of mp. 246-251 ° [a]_D+ 131 ° (c 0.67).

-14AT395428B

A suspension of 376 mg of 16a, 17a-epoxy-9a-fluoro-11β-hydroxy-16-methylene-3-oxoandrosta l, 4-dien17β-carboxylic acid and 400 mg of 2-chloro-N-methylbenzothiazolium trifluoromethane-sulfonate in methylene chloride was added dropwise 0 ° C treated with 0.7 ml of triethylamine. The resulting solution was stirred for 1.25 h at 0 ° C and then hydrogen sulfide was passed through the mixture for 10 min. After another hour at 0 ° C, 0.13 ml of bromochloromethane was added and the mixture was stirred at room temperature. Two additional portions of bromochloromethane (0.13 ml) were then added after an additional 1.5 hours and 1.8 hours.

After the last addition, the reaction mixture was diluted with 200 ml of ethyl acetate and washed successively with 2N hydrochloric acid, 5% sodium bicarbonate solution and water, dried and evaporated to a red crystalline solid. The solid was subjected to a plc in chloroform-acetone (19: 1) (three passes). The polar bands were pale pink solid of 15mg of the title S-chloromethyl ester, identical to an authentic sample in tlc

Production XLII

S-Chlortnethvl-9a-fluoro-l 1β.17α, dihydro-16-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate (XLII)

A solution of 400 mg XLI in 16 ml trifluoroacetic acid was stirred at Raulm temperature. After 5.5 h, the reaction mixture was evaporated to near dryness and the residue was washed with 5% sodium bicarbonate solution and water, dried and evaporated to 466 mg of a yellowish-green foam. The foam became a plc in chloroform-acetone (9: 1) (three passes). A 80 mg portion of the major band (315 mg) was crystallized twice from acetone to give 48 mg of white crystals of the title 16-methylene-17a-alcohol of mp. 242-243 ° [a]_D + 36 ° (c 0.50).

Production XLIII

9a-fluoro-17a-hydroxyprop-16β-methyl-3,11-dioxoandrosta-1,4-diene-17β-carboxylic acid (XLIII)

A stirred suspension of 4.842 g of 9a-fluoro-17,21, dihydroxy-16β-methylandrosta-1,4-diene-3,11,20-trione in 50 ml of tetrahydrofuran was cooled in ice and added dropwise over 5 min with a solution of 4.255 g of periodic acid in 15 ml of water. The reaction was stirred at 22 ° for 2.25 h, with most of the suspension having dissolved. The solvent was removed in vacuo with periodic addition of water to maintain the original volume. The resulting precipitate was filtered off, washed with water and dried in air and in vacuo to give 4.55 g of the title carboxylic acid as cream-colored prisms of mp. 270-272 ° (dec.) [Α] ρ + 136 ° (c 1.04, dimethyl sulfoxide).

Production XLIV

9a-fluoro-llβ.l7a-dihydro-16β-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid (XLIV)

A stirred solution of 0.502 g of 9a-fluoro-11β-17a-dihydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid in 15 ml of dry Ν, Ν-dimethylformamide was cooled at -5 ° under nitrogen and washed with 0.435 g of NN'-carbonyldiimidazole was treated and the reaction was stirred at -5 ° for 18 hours. Hydrogen sulfide gas was bubbled into the reaction for 20 minutes and the solution was stirred for a further 4 hours and allowed to gradually warm to 22 °. The reaction was poured into ethyl acetate, and the resulting solution was washed with 2N hydrochloric acid and water, followed by extraction with 2N sodium carbonate solution (3 times 50 ml). The combined extracts were washed with ethyl acetate (60 ml) and then covered with a further 100 ml of ethyl acetate and acidified to pH 1.0 with hydrochloric acid. The aqueous layer was extracted with more ethyl acetate and the extracts were washed with water and saturated sodium chloride solution, then dried and the solvent was removed in vacuo to give a white solid which was crystallized twice from ethyl acetate to give 0.315 g of the title carbothioic acid from the Fp. 198-201 ° (Zers.) [A]_D+189 ° (c 0.71).

Manufacturing XLV

9a-fluoro-17a-hydroxv-16β-methyl-3,11-dioxoandrosta-1,4-diene-17β-carbothioic acid (XLV)

A stirred solution of 5.877 g XLIII in 150 ml dry Ν, Ν-dimethylformamide was treated at 20 ° under nitrogen with 4.847 g Ν, Ν'-carbonyldiimidazole and the reaction was stirred at 20 ° for 4 h. Hydrogen sulphide gas was added to the reaction for 10 min and the solution was stirred for an additional hour. The solution was poured into 300 ml of ice and 100 ml of 2N hydrochloric acid to give a

-15AT395428B buffalo-colored precipitate. This was filtered off, dried overnight (6.268 g) and crystallized from ethyl acetate to give 3.761 g of the title cartoothioic acid in the form of white prisms, m.p. 215-218 ° [α] p + 143 ° (c 0.88, dimethylformamide )

Manufacturing XLVI

9g-fluoro-17a-hydroxv-16β-methyl-3,11-dioxoandrosta-1,4-diene-17β-carbothioic acid (XL VI)

A stirred solution of 1.059 g of XLIII in 50 ml of dry NJQ-dimethylformamide was treated at 20 ° under nitrogen with 1.368 g of N, N'-thiocarbonyldiimidazole, and the reaction was stirred at 20 ° for 4 hours. Hydrogen sulfide gas was bubbled into the reaction for 5 minutes, and the solution was stirred for an additional 1 hour. The reaction was partitioned between 100 mL of ethyl acetate and 100 mL of 2N hydrochloric acid, and the organic phase was washed with 100 mL of 2N hydrochloric acid and twice 100 mL of water extracted twice with 75 ml of 2N sodium carbonate solution. The combined extracts were washed with 50 ml of ethyl acetate, then covered with 100 ml of ethyl acetate and acidified to pH 1 with hydrochloric acid. The aqueous layer was extracted with another 50 mL of ethyl acetate and the extracts were washed with water, saturated sodium chloride solution, dried and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to give 0.559 g of the title carbothioic acid of mp. 212-219 ° [a]_D + 145 ° (c 0.81, dimethylformamide).

Production XLVII

S-Chloromethyl-9a-fluoro-llβ.l7a-dihydro-16β-methyl-3-oxo-androsta-1,4-diene-17β-carbothioate (XLVII)

A stirred solution of 0.160 g of XLIV and 0.040 g of sodium bicarbonate in 6 ml of N, N-dimethylformamide was treated with 0.1 ml of bromochloromethane and stirred for a further hour at 22 °. The reaction mixture was diluted with 100 ml of ethyl acetate and the solution was washed successively with 2N hydrochloric acid, water, 2N sodium carbonate solution, water and saturated sodium chloride solution, then dried and the solvent was removed in vacuo. The residue was crystallized twice from ethyl acetate to give 0.193 g of the title S-chloromethyl thiol ester as white plates, solvated with ethyl acetate (1 mol), m.p. 126-130 ° [a]_D+ 147.5 ° (c 0.64).

Production XLVIII

9a-fluoro-16β-methyl-3.1 l-dioxo-17a-pro-dione vloxvandrosta-l4-diene-17β-carbothioic acid (XLVM)

A stirred solution of 0.485 g of XLV and 0.57 ml of triethylamine in methylene chloride was cooled in ice-salt, treated with 0.43 ml of propionyl chloride, and the reaction was stirred at 0 ° for 1.5 hours. The mixture was partitioned between 75 ml of ethyl acetate and 75 ml of 2N sodium carbonate solution, and the organic layer was washed successively with further 2N sodium carbonate solution, water, 2N hydrochloric acid, water and saturated sodium chloride solution, then dried and the solvent was removed in vacuo to give 0.562 g of a yellow crystalline solid. This was dissolved in 10 ml of acetone, 1.0 ml of diethylamine was added and the reaction was stirred for 1.25 h at 22 °. The solvents were removed in vacuo and the residue was partitioned between 30 ml of ethyl acetate and 30 ml of hydrochloric acid. The ethyl acetate layer was washed with water and extracted with twice 30 ml of 2 N sodium carbonate solution. The combined extracts were washed with ethyl acetate (30 ml) and covered with ethyl acetate (60 ml) and acidified to pH 1 with hydrochloric acid. The ethyl acetate layer was washed with water and saturated sodium chloride solution, then dried, and the solvent was removed in vacuo to give a white solid which was crystallized twice from ethyl acetate to give 0.290 g of the title ester, m.p. 173-180 ° [a]_D+ 148 ° (c 1.03).

Manufacturing XL1X

S-Chlormethvl-9a-fluoro-17a-hvdroxv-16ss-Methyl-3.11 dioxoandrosta-1,4-diene-17.beta.-carbothioate (XLIX)

A solution of 5.006 g of XLV and 1.612 g of sodium bicarbonate in 50 ml of Ν, Ν-dimethylacetamide was treated with 1.24 ml of bromochloromethane and the reaction was stirred at 22 ° for 3.3 hours. The solution was diluted with 70 ml of ethyl acetate and washed successively with 2N hydrochloric acid, water, sodium tebisulfide solution, water and saturated sodium chloride solution, then dried and the solvent was removed in vacuo to give 3.638 g of a cream solid. The analytical sample was obtained after preparative tlc (Silica gel, developed with chloroform: acetone = 9.1) and crystallized from ethyl acetate in the form of 0.262 g of colorless prisms of the title ester, mp. 223-228 ° [a]_D+ 251 ° (c 1,2).

-16AT395428B

Production L

9a-fluoro-LLSs-hvdroxv-16ss-Methyl-3-oxo-17a-propionvloxvandrosta-1,4-diene-17.beta.-carbothioic acid (L)

A stirred solution of 0.511 g XL1V in 20 ml methylene chloride containing 0.6 ml triethylamine was cooled to 2 ° and treated with 0.45 ml propionyl chloride and the reaction was stirred at 2 ° for 2.5 h. The reaction was partitioned between ethyl acetate and sodium bicarbonate, and the organic phase was washed with water, hydrochloric acid, water-saturated sodium chloride solution, dried, and the solvent removed in vacuo to give 0.634 g of a colorless solid. This was dissolved in 30 ml of acetone, 1.5 ml of diethylamine was added and the clear solution was stirred at 22 ° for 55 min. The reaction was diluted with 50 ml of ethyl acetate and was washed with 2N hydrochloric acid and water and then extracted with 5% sodium carbonate solution. The combined extracts were acidified to pH 1 with 2N hydrochloric acid and treated with ethyl acetate extracted The combined extracts were washed with water and saturated sodium chloride solution and dried and the solvent was removed to give 0.522 g of a colorless foam, which was crystallized from ethyl acetate to give the title ester in the form of 0.307 g of colorless prisms of mp. 174-179 °.

[A]_D+ 107 ° (c 1,0)

Production LI

9a-fluoro-1-lB.17a-dihydro-16-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid (LI)

A solution of 0.218 g9a-fluoro-llβ, 17a-dihydroxy-16-methylene-3-oxoandrosta-l, 4-diene-17β-carboxylic acid in 10 ml of dry N, Ν-dimethylformamide was added at 22 ° under nitrogen with 0.254 g of N, N '-CarbonyldiimidazoI treated and the reaction was stirred for 4 h at 22 °. Hydrogen sulfide gas was bubbled into the reaction for 5 minutes, and the mixture, which was now pale green, was stirred for 1 hour at 22 °. The mixture was diluted with 150 ml of ethyl acetate and the solution was washed with 2N hydrochloric acid, water and saturated sodium chloride solution, dried and the solvent was removed in vacuo to give 0.222 g of a yellow foam which was crystallized twice from ethyl acetate to give 0.078 the title carbothioic acid in the form of white prisms, which decomposed at about 250 ° without melting;

[A]_D+ 117 ° (Co, 32).

Production LII

9tt-fluoro-1-l, 7l-dihydroxy-3-oxoandrosta-1,4-diene-17β-carboxylic acid (LTD

A suspension of 10 g of 9a-fluoroprednisolone in 55 ml of dry tetrahydrofuran was stirred and treated with a solution of 9.0 g of periodic acid in 90 ml of water, and the mixture was stirred at 22 ° C for 2 hours. It was then poured into about 400 ml of iced water, and after stirring for 15 minutes, the solid product was recovered, washed with water and dried to give 9.42 g of the title compound as a solid. A portion thereof, recrystallized from ethanol, had a mp. from 289-293 ° to [α] β + 66 ° (c 0.73, methanol).

Production LIII

9a-fluoro-1 B.17a-dihydro-3-oxoandrosta-1,4-diene-17β-carbothioic acid (LUD

A solution of 4.5 g of 9a-fluoro-11β, 17a-dihydroxy-3-oxoandrosta-l, 4-diene-17β-carboxylic acid in 100 ml of dry dimethylformamide was added under nitrogen with 4.04 g of Ν, Ν'-carbonyldiimidazole 4 Stirred at 22 ° C h. Hydrogen sulfide was then bubbled through the solution for 30 minutes and then left for a further 15 minutes. The mixture was poured into a mixture of 250 ml of 2N hydrochloric acid and about 100 g of ice, and the resulting precipitate was collected, washed with water and dried to give 4.56 g of a white solid. A 120 mg portion was recrystallized from ethanol to give the title thiosäure in the form of 70 mg colorless crystals of mp. 222-225 °;

[A]_D+ 116 ° (Co, 57).

Production LIV

6a.9a-Difluoro-llß.l7a-dihvdroxv-L6A-Methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic acid (LIV)

A solution of 12.0 g of 6α, 9a-difluoro-IIβ, 17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid in 250 ml of dry dimethylformamide was stirred and treated with 9.94 g of Ν, Ν'-Carbonyldiimidazole treated under nitrogen at room temperature After 4 h, hydrogen sulfide was passed through the solution for 0.5 h and the mixture was left for a further 0.5 h. The reaction mixture was poured into 500 ml of 2N hydrochloric acid containing about 250 g of ice. The resulting precipitate was collected, washed with water and dried in vacuo to give the title thioacid as 11.47 g of a white solid m.p. 230-232 ° [a]_D + 94 ° (c 0.91).

-17AT395428B

H? RSt9llungLV

17a-Acetoxv-6a.9a-difluoro-LLSs-hvdroxv-16a-Methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic acid (LV)

A solution of 1.625 g of LIV and 2.0 ml of triethylamine in 75 ml of methylene chloride was stirred at about 0 ° C and treated dropwise with 1.275 ml of acetyl chloride and stirred at this temperature for 1.25 h. The mixture was washed with 50 ml of 2 N sodium carbonate, water, 50 ml of 2 N hydrochloric acid, three times 50 ml of water, 50 ml of brine, then dried and evaporated to give 1.91 g of a white solid. This was dissolved in 40 ml of acetone and washed with 4 ml of ethylamine for 45 min at 27 ° C stirred. The mixture was concentrated to about 25 ml and poured into 100 ml of 2N hydrochloric acid containing about 100 g of ice. After stirring, the resulting precipitate was collected, washed with water and dried to give 1.685 g of a solid. A portion of 400 mg was recrystallized from ethyl acetate to give 280 mg of the title 17a acetate, mp. 175-177 °.

Manufacturing LVI

17a-Butvrvloxv-6a.9a-difluoro-LLSs-hvdroxv-16a-Methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic acid (LVD

Using the same procedure as described in Preparation LV, 2.0 g of LIV with 1.5 ml of butyryl chloride in place of the acetyl chloride was converted to 2.08 g of the title 17a-butyrate. A portion which was recrystallized from ethyl acetate had a mp of 155-157 °.

Production LVII

9a-fluoro-1β-hydroxy-3-oxo-17a-propionyloxvandrosta-1,4-diene-17β-carbothioic acid (LVII)

Using the same procedure as described in Preparation LV, 3.8 g of LIII were used using 3.9 ml of propionyl chloride in place of acetyl chloride and after aminolysis of the intermediate with 10.35 ml of diethylamine in 4.17 g of the title 17a. Propionate converted to 350 mg, recrystallized from ethyl acetate, yielded 165 mg of colorless needles, mp 135-138 ° [a]_D + 72 ° (c 0.92).

Production LVIII

6a.9a-difluoro-LLβ-hydroxy-16a-methy1-3-oxo-17a-propionvloxv-androsta-1,4-diene-17β-carbothioic acid (LVIII)

A solution of 5.0 gLIV and 6.15 ml of triethylamine in 140 ml of methylene chloride was cooled with ice salt and treated dropwise with 4.74 ml of propionyl chloride. The reaction mixture was stirred at 0.degree. C. for an additional 0.75 h and then washed successively with 2N sodium carbonate, water, 2N hydrochloric acid, water and brine. After drying, the solvent was removed to give 6.35 g of a white solid. This was redissolved in 120 ml of acetone and 12.5 ml of diethylamine, and after stirring at room temperature for 1 hour, the volume was reduced to about 75 ml. The solution was poured into 200 ml of 2N hydrochloric acid containing about 300 g of ice, and the resulting precipitate was collected, washed with water and dried in vacuo to give 5.17 g of a white solid, m.p. 152-155 °. Recrystallization of a 400 mg portion from ethyl acetate gave 290 mg of the analytically pure title thioacid 17a-propionate as colorless crystals of mp. 161-164 ° [a]_D-27 ° (c = 0.95), whose solid-state infrared spectrum (in nujol) showed a different crystalline form from that obtained in preparation XIX.

Production LIX

S-Chloromethyl-9a-fluoro-16β-methyl-3,11-dioxo-17a-propionvloxv-androsta-1,4-diene-17β-carbothioate (LIX)

A solution of 409 mg XLIX in 5 ml propionic acid, 2 ml trifluoroacetic anhydride and toluene-p-sulfonic acid (0.1 ml dry chloroform solution, 80 mg / ml) was stirred at 22 ° C for 2.75 days. The non-acidic product was isolated by extraction with ethyl acetate after being poured into saturated sodium bicarbonate. The crude material was chromatographed on silica in chloroform-acetone (14: 1) and extracted from ethyl acetate-petroleum ether (b.p. 60-80 ° C) crystallized to give the title 17a-propionate as colorless crystals of mp. 205-206 ° [a]_D+ 95 ° (c 1.15).

Manufacturing LX

S-Chloromethyl-9a-fluoro-1-L7a-dihydro-16β-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate (LX)

A suspension of 102 mg XLIX in 2.5 ml ethanol was stirred with 10 mg sodium borohydride at 22 ° C for 1 h. The reaction mixture was treated with 5 ml acetone and then almost to dryness

The residue was dissolved in 25 ml of ethyl acetate, washed with n-hydrochloric acid, water and brine. After drying, the organic solvent was removed to afford the title IIβ alcohol in the form of 103 mg of a colorless foam, the sole major component of which was equi-polar with an authentic sample by TLC (silica, chloroform-acetone, 9: 1).

Manufacturing LXI

Method A

9a-fluoro-LLSs-hvdroxv-16ss-Methyl-3-oxo-17a-proDionvloxv-androsta-1,4-diene-17.beta.-carbothioic acid (LXI)

A solution of 603 mg (0.75 moles of ethyl acetate solvate) of 9a-fluoro-11β-hydroxy-16β-methyl-3-oxo-17apropionyloxyandrosta-1,4-diene-17β-carboxylic acid and 0.997 mg of Ν, Ν'-carbonyldi (1,2,4-triazole) in 45 ml of dry dimethylformamide was stirred under nitrogen for 18.5 hours at about 22 ° C. 15 To a solution prepared from 305 mg of sodium hydride in dimethylformamide by saturation with hydrogen sulfide was added and stirred at room temperature for 3 days. The reaction mixture was poured into 200 ml of 2N hydrochloric acid, and the product was extracted three times with ethyl acetate. 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 three times with ethyl acetate. After washing with water and brine, the organic extracts were dried and concentrated to a small volume. The title thioacid separated in the form of 101 mg of cream-colored crystals, the only major component of which was by comparison with an authentic sample in .sup.1 H NMR and by T.l.c. (Silica, chloroform-acetone, 4: 1).

Method B

A solution of 701 mg (0.75 moles of ethyl acetate solvate) of 9a-fluoro-11β-hydroxy-16β-methyl-3-oxo-17apropionyloxyandrosta-1,4-diene-17β-carboxylic acid and 473 mg of Ν, Ν'-carbonyldiimidazole in 26 mg of dry dimethylformamide was stirred under nitrogen for 19.5 h at about 22 ° C and then with 10 ml of a solution of sodium hydride (60% dispersion in oil, 233 mg) in 10 ml of dimethylformamide, saturated with hydrogen sulfide, treated. The resulting mixture was then stirred at room temperature for 5.5 h. The reaction mixture was diluted with 100 mL of ethyl acetate and washed with 2N hydrochloric acid, water and brine, then dried and evaporated to 186 mg of a foam. The title thioacid was found to be the major component in the Product by ^ H NMR and by tc (Silica, chloroform-acetone, 4: 1, and chloroform-acetone-acetic acid, 30: 8: 1) compared with an authentic sample.

Method C

In an almost identical reaction to that described in Method A, the carboxylic acid was treated with 1.587 g of Ι, Γ-carbonyldibenzotriazole instead of Ν, Ν'-carbonyldi (1,2,4-triazole) at room temperature for 6 h after the addition of Solution obtained from hydrogen sulfide and sodium hydride in dimethylformamide, the reaction was continued for 41.5 h. The crude product was obtained as a foam; (Silica, chloroform-acetone, 4: 1 and chloroform-acetone-acetic acid, 30: 8: 1) showed that the title thioacid was present as a major component, using a comparison with an authentic sample.

Production LXII

S-Chloromethyl-6a, 9a-difluoro-16a-methvl-3-oxo-17a-propionyl-oxy-11β-trifluoroacetoxandane-1,4-diene-17β-carbothioate (LXII)

A solution of 100 mg of the compound of Example 5 (listed below) in 2 ml of dry tetrahydrofuran and 0.1 ml of pyridine was treated with 0.05 ml of trifluoroacetic anhydride and the mixture was kept at room temperature for 0.5 h. The reaction mixture was poured into water and the product was extracted three times with ethyl acetate. The organic extracts were washed with water, dried and evaporated to give 116 mg of the homogeneous title trifluoroacetate according to ^ H NMR spectroscopy (singlet at 8.59, 19 protons in deuterochloroform) and t.c. on silica (acetone-petroleum ether, b.p. 40-60 ° C, 1: 3). An analytical sample of ether-pentane showed mp. 158-162 ° [a]_D +56 ° (c 0.23).

example 1

S-Chloromethyl-9a-fluoro-1β-hydroxy-16β-methyl-3-oxo-1α-7α-propionvloxvandrosta-1,4-diene-17β-carbothioate

Method A

A solution of 2.115 g of I in 7 ml of dimethylacetamide was treated with 592 mg of sodium bicarbonate and 0.46 ml of bromochloromethane, and the mixture was stirred at room temperature. After 2 h, the reaction mixture was diluted with 500 mL of ethyl acetate and washed with 5% sodium bicarbonate solution and water, dried and evaporated to give 1.560 g of orange-colored foam. plc in chloroform-acetone (19: 1) gave 803 mg of an almost white foam, which was crystallized twice from methanol to give 668 mg of solid white needles of the title S-chloromethyl ester, m.p. 212-214 ° C [a]_D 444 ° (c 1.06).

Method P

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

Method C mg of sodium borohydride was added to a solution of 230 mg of II in 3.5 ml of ethanol and the solution was run at room temperature. After 20 min, 1 ml of acetone was added and the solution was concentrated to approximately one quarter volume. 30 ml of ethyl acetate were then added and the solution was washed with hydrochloric acid and water, dried and evaporated to give 239 mg of a white foam. plc in chloroform-acetone (19: 1) gave 188 mg of a white foam as it was crystallized twice from methanol to give 158 mg of white needles of the title S-chloromethyl ester of mp. 210-212 ° [a]_D+ 44 ° (c 1.07).

EsiscisLZ

S-Chloromethyl-9a-fluoro-llβ-hvdroxv-16a-methvl-3-oxo-17a-propionvloxvandrosta-1,4-diene-17β-carbo thioate

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

Example 3

S-Chlormethvl-LLSs-hvdroxv-3-oxo-17a-propionvloxvandrosta-1,4-dien-17.beta.-carbothioate

A solution of 2.366 g of crude XV in 10 ml of dimethylacetamide was treated with 756 mg of sodium bicarbonate and 0.59 ml of bromochloromethane for 16 h at 22 ° C. It was partitioned between ethyl acetate and 2N hydrochloric acid, and the aqueous layer was further extracted with ethyl acetate. The combined organic phases were washed successively with 2N hydrochloric acid, water, sodium bicarbonate, water and saturated brine, and then dried and the solvent was removed to give a yellow foam. The neutral product was purified by hplc on silica (15 gbzw. mm) in 7% acetone in chloroform and the major product crystallized from acetone to give 0.511 g of the title chloromethyl thiolester of mp. 117-120 ° [a]_D+ 56 ° (c 1,3).

Example 4

S-Chlormethvl-6g.9a-difluoro-LLSs-hvdroxv-16a.l7a-isopropvliden-dioxv-3-oxo-androsta-1,4-dien-17ßcartothioat

A stirred solution of 1, 360g of IX in 10 mL of N, N-dimethylacetamide was treated with O, 377g sodium bicarbonate and 0.3 mL of bromochloromethane and stirred for an additional 1.5 h. 100 mL of ethyl acetate was added and the resulting solution was hydrated with hydrochloric acid, Water, sodium metabisulfite, Water, sodium bicarbonate, Washed with water and saturated sodium chloride solution, then dried and the solution was concentrated, followed by crystallization. The crystallized product (0.765 g) was replaced by plc purified on silica gel, developed with chloroform: acetone (9: 1). The major band was eluted with ethyl acetate and crystallized from ethyl acetate to give 0.475 g of the title chloromethylthioester in the form of white prisms of mp. 271-278 ° [a] p + 116 ° (c 0.96, dimethylsulfoxide).

-20AT395428B

Example 5

S-Chlormethvl-6a.9a-difluoro-LLSs-hvdroxv-16a-Methyl-3-oxo-17a-propionvloxvandrosta-1.4-dien-17ßcarbothioat

A solution of 0.546 g of XIX in 3 ml of dimethylacetamide was treated with 202 mg of sodium bicarbonate and 0.16 ml of bromochloromethane at 22 ° for 3 h. The mixture was treated with 50 ml of 2N hydrochloric acid and the product was extracted with ethyl acetate. The extracts were combined and washed successively with 2N hydrochloric acid, water, saturated brine, dried and the solvent was removed. Crystallization from ethyl acetate gave 0.404 g of the title chloromethylthiolester of mp. 272-275 ° [a]_D + 49 ° (c 0.35).

Examples 6 to 15

Following the general procedure of Example 1 (Method A) but using the 17β-carbothioate as the starting material (the process details are set forth in Table III below), the following compounds were prepared:

6th S-chloro-methyl-1β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate,

Mp 192-193 °, [a]_D+ 65 ° (c 1.05).

7th S-chloro-methyl-9a-fluoro-11β-hydroxy-16-methylene-3-oxo-17a-propionyloxyandrosta-1,4-diene-17β-carbothioate, mp. 212-221, [a]_D -56 ° (c 0.99).

8th. S-chloro-methyl-17a-acetoxy-9a-fluoro-16ss-hydroxy-LLSs-methyl-3-oxo-androsta-l, 4-diene-17.beta.-carbothioate,

Mp 220-223 °. [&lt;X]_D + 39.5 ° (c 1.06).

9th S-chloro-methyl-17a-butyryloxy-9a-fluoro-16ss-hydroxy-LLSs-methyl-3-oxo-androsta-l, 4-diene-17.beta.-carbothioate,

Mp 172-175 °, [a]_D + 46 ° (c 1.10).

10th S-Chloro-methyl-9a-fluoro-11β-hydroxy-17a-isobutyryloxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, m.p. 234-239 °, [a]_D + 43 ° (c 1.00).

11th S-chloro-methyl-9a-fluoro-LLSs-hydroxy-3-oxo-17a-propionyloxy-l, 4-diene-17.beta.-carbothioate,

Mp 196-199 °, [a]_D + 38 ° (c 0.97).

12th S-chloro-methyl-6a-fluoro-LLSs-hydroxy-3-oxo-L7A-propionyloxy-l, 4-diene-17.beta.-carbothioate,

Mp 188-191 °, [a]_D + 48 ° (c 0.91)

13th S-chloro-methyl-17a-acetoxy-6a, 9a-difluoro-11β-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, mp 280-283, [a]_D + 45 ° (c 0.80).

14th S-chloro-methyl-17a-butyryloxy-6a, 9a-difluoro-LLβ-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, m.p. 235-238 °, [a] p + 49 ° (c 0.65).

15th S-chloro-methyl-9a-fluoro-1-hydroxy-16a, 17a-isopropylidene-dioxy-3-oxoandrosta-1,4-diene-17β-carbothioate, m.p. 275-280 ° (dec.) [A] jj +127 ° (c 0.51, dimethyl sulfoxide).

Table ΙΠ

<td>Ex. No.</td><td>reagent (Ml)</td><td>NaHCO₃(Mg)</td><td>Steroid- commitment (Mg)</td><td>solvent medium (DMA) (Ml)</td><td>Reaction time (h) at room temperature</td><td>PLC (silicon dioxide) chci₃- me₂CO</td><td>crystallization lisations- solvent medium</td><td>product (Mg)</td>

<td>6</td><td>BrCH₂Cl (0.25)</td><td>300</td><td>981</td><td>5</td><td>3</td><td>-</td><td>EA</td><td>826</td>

<td>7</td><td>BrCH₂Cl (12:58)</td><td>749</td><td>2000</td><td>11</td><td>1.5</td><td>19: 1</td><td>EA</td><td>201</td>

<td>8th</td><td>BrCH₂Cl (12:44)</td><td>565</td><td>1955</td><td>7</td><td>2.0</td><td>-</td><td>EA</td><td>307 *</td>

-21AT395428B

Table III (continued!

<td>Ex. No.</td><td>reagent (Ml)</td><td>NaHCO₃(Mg)</td><td>Steroid- commitment (Mg)</td><td>solvent medium (DMA) (Ml)</td><td>Reaction time (h) at room temperature</td><td>PLC (silicon dioxide) chci₃me₂CO</td><td>crystallization lisations- solvent medium</td><td>product (Mg)</td>

<td>9</td><td>BrCH₂Cl (12:32)</td><td>421</td><td>1501</td><td>10</td><td>1.8</td><td>14: 1</td><td>EA</td><td>871</td>

<td>10</td><td>BrCH₂Cl (0.084)</td><td>121</td><td>385</td><td>3</td><td>2.75</td><td>-</td><td>EA</td><td>255</td>

<td>11</td><td>BrCH₂Cl (0.90)</td><td>1100</td><td>2750</td><td>20</td><td>1.25</td><td>-</td><td>M</td><td>1600</td>

<td>12</td><td>Bich₂C1 (0.86)</td><td>1080</td><td>2740</td><td>20</td><td>2</td><td>-</td><td>EA-P</td><td>2460</td>

<td>13</td><td>Bich₂C1 (2.00)</td><td>2500</td><td>6600</td><td>40</td><td>1.75</td><td>-</td><td>A</td><td>5410</td>

<td>14</td><td>BrCH₂Cl (1.40)</td><td>1600</td><td>4600</td><td>46</td><td>2</td><td>-</td><td>A</td><td>2140</td>

<td>15</td><td>BrCH₂Cl (12:48)</td><td>615</td><td>1600</td><td>12</td><td>1.5</td><td>4: 1</td><td>A</td><td>244 **</td>

Remarks:

EA = ethyl acetate; A = acetone; M = methanol; P = petroleum ether bp 60-80 ° * Obtained from a 400 mg portion of the crude product (2.35 g) ** Obtained from a 300 mg portion of the crude product (1.72 g)

Example 16

S-Chloimethyl-9a-chloro-llβ-hydroxy-d-16β-methyl-3-oxo-17a-propionyloxvandrosta-1,4-diene-17β-carbothioate and S-chloromethyl-9β.l 1β-epoxyc-16β-methvl-3 oxo-17a-propionyl-oxvandrosta-1,4-diene-17β-carbothioate

A solution of 1.032 g of mixture XXIV in 5 ml of dimethyl 1-acetamide was treated with 0.203 g of sodium bicarbonate followed by 0.2 ml of bromochloromethane, and the reaction was stirred at 22 ° C for 1.5 hours, after which it was partitioned between 50 ml of ethyl acetate and 35 ml of 2N hydrochloric acid was split. The aqueous phase was extracted with another two times 30 ml of ethyl acetate, and the combined extracts were washed with 2N hydrochloric acid, water, saturated sodium bicarbonate solution, water, saturated sodium chloride solution and dried, and the solvent was removed in vacuo to give 0.856 g of a cream foam a mixture of the title S-chloromethyl ester

These were separated by plc on silica developed with chloroform: acetone (19: 1). The more polar component (0.306 g) was crystallized twice from ethyl acetate to give 0.232 g of S-chloromethyl-9-chloro-11β-hydroxy-16β-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17β-carbothioate in the form of white plates of mp 222-229 ° [a]_D + 70 ° (c 1.23).

-22AT395428B

The less polar component (0.210 g) was crystallized from acetone-petroleum ether to give 0.065 g of S-chloromethyl-9β, IIβ-epoxy-16β-methyl-3-oxo-17 &lt;x-propionyloxyandrosta-l, 4-diene-17β- carbothioate of Mp. 169-173 ° [a]_D +49 ° (c 0,60).

Beispigl.l7

SrHuoimethvl-9a-Fluct-LLSs-hvdroxv-16ss-Methyl-3-oxo-17a-propionvloxvandrosta-1,4-dien-17.beta.-carbothioate

660 mg XXV was stirred with a suspension of 1.421 g of silver fluoride in 8.5 ml of acetonitrile in the dark at room temperature. After 72 h, the reaction mixture was diluted with 200 mL of ethyl acetate and filtered through a plug of diatomaceous earth. The filtrate was washed with water, dried and evaporated to give 517 mg of a white foam. plc chloroform-cyclohexane (19: 1) and chloroform gave 270 mg of an almost white foam, which was crystallized from methanol followed by methanol-diethyl ether to give 176 mg of the title S-fluoromethyl ester of mp. 241-242 ° C ta]_D+ 97.5 ° (c 0.98).

Example 18

S-Fluormethvl-9a-fluoro-LLSs-hvdroxv-16a-Methyl-3-oxo-17a-propionvloxvandrosta-1,4-dien-17.beta.-carbothioate

A solution of 0.640 g of XXX in 8 ml of acetonitrile was treated with 1.51 lg of dry silver fluoride and stirred in the dark for 46.5 h at 22 ° C. The mixture was diluted with 200 ml of ethyl acetate and filtered through diatomaceous earth. The solution was washed with 2N hydrochloric acid, water and saturated sodium chloride solution, and the solvent was removed in vacuo to give 0.504 g of a pale yellow foam. This was cromatographed (plc) on silica gel developed with 5% acetone in chloroform. The major band was eluted with ethyl acetate and crystallized twice from acetone to give 0.244 g of the title fluoromethylthioester of mp. 242-243 ° (Zers.) [A]_D +37 ° (c 0.75).

Example 19

S-Fluormethvl-6a.9a-difluoro-LLSs-hvdroxv-16a-Methyl-17a-propionvloxv-3-oxo-androsta-1,4-dien-17ßcarbothioat

A solution of 310 mg XXXI in 10 mL acetonitrile was stirred with 947 mg silver fluoride for 3 days at room temperature in the dark. 100 mL ethyl acetate was added and the mixture was filtered through diatomaceous earth. The filtrate was washed successively with 2N hydrochloric acid, water, saturated brine, washed and then dried. The solvent was removed and the residue was added to a plc in chloroform and then chloroform-acetone (19: 1). The product was eluted with ethyl acetate and crystallized by concentrating the solution to give O, 075mg of the title fluoromethyl thiolester of mp. 272-273 ° (Zers.) [A]_D + 30 ° (c 0.35).

Example 20

S-FluOTmethvl-9a-fluoro-LLSs-hvdroxv-16a.l7a-isopropvlidendioxv-3-oxo-androsta-1,4-dien-17.beta.-carbothioate

A suspension of 1.290 g of XXXVII in 20 mL of acetonitrile was stirred with 2.842 g of silver fluoride at room temperature in the dark. After 11 days (leaving no starting iodide, tlc, chloroform, six passes), the reaction mixture was diluted with 400 mL of ethyl acetate and passed through diatomaceous earth filtered. The filtrate was evaporated to 726 mg of a pale yellow crystalline solid and the diatomaceous earth extracted continuously with ethyl acetate in a Soxhlet apparatus to give 197 mg of a yellow solid. The solid form of the filtrate was suspended in chloroform-methanol (10: 1), and the insoluble fraction (203 mg) was collected. This was combined with the solid from the Soxhlet extraction in 300 ml of ethyl acetate and filtered through a column of silica (Merck Kieselgel 60) (50 g). The eluates containing the product (tlc) were combined, washed with water, dried with simultaneous charcoal treatment and concentrated to a small volume. The resulting white solid (276 mg) was collected and recrystallized from ethyl acetate to give 231 mg of colorless crystals of the title S-fluoromethyl ester of Mp. 320-322 ° C (dec.), [A] jj + 132 ° (c 0.22, dimethyl sulfoxide).

-23AT395428B

Example 21

S-Fluormethvl-6a.9a-difluoro-LLSs-hvdroxv-16a.l7a-isopropylidenedioxy-3-oxoandrosta-1,4-diene-17ßcarbothioat

A solution of 0.804 g of XXXVIII in 60 ml of acetonitrile was treated with 1.821 g of silver fluoride and the reaction was stirred in the dark for 18 h. The reaction was diluted with ethyl acetate and filtered through kieselguhr. The filtrate was washed with water and saturated sodium chloride solution, then dried and the solvent was removed in vacuo to give 0.636 g of a pale cream solid. This one was by plc on silica gel, developed twice with chloroform: acetone (14: 1) purified. The major band was eluted with ethyl acetate and crystallized five times from ethyl acetate to give 0.118 g of the title S-fluoromethylthioester in the form of white prisms, m.p. 305-311 ° C [a] jj + 125 ° (c 0.73, dimethylsulfoxide), example? 2? to 30

Following the general procedure of Example 17, but using the S-iodomethyl-17β-carbothioate corresponding to the desired product as starting material (procedure details are given in Table IV below), the following compounds were prepared:

22nd S-Fhior-methyl-17a-acetoxy-9a-fluoro-16ss-hydroxy-LLSs-methyl-3-oxo-androsta-l, 4-diene-17.beta.-carbothioate,

Mp 248-249 °, [a]_D+ 101 ° (c 1.08).

23rd S-Fluoro-methyl-1 L, 3-hydroxy-3-oxo-17a-propionyloxyandrosta-1,4-diene-17β-carbothioate, m.p. 112-117 °, [a]_D + 67 ° (c 0.76).

24.5-fluoromethyl-LLβ-hydroxy-16β-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17β-carbothoiate,

Mp 224-225 °, [&lt;x]_D + 103 ° (c 0.38).

25th S-fluoromethyl-9a-chloro-11β-hydroxy-16β-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17β-carbothioate, m.p. 182-193, [a]_D + 116 ° (c 0.75).

26.5-Fluoromethyl-9a-fluoro-11β-hydroxy-16-methylene-3-oxo-17a-propionyloxyandrosta-1,4-diene-17β-carbothioate, m.p. 205-215, [q]_D -58 ° (c 1.00).

27th S-fluoro-methyl-9a-fluoro-LLSs-hydroxy-3-oxo-17a-propionyloxy-l, 4-diene-17.beta.-carbothioate,

Mp 207-211 °, [a]_D +70 ⁰ (c 0.88).

28th S-fluoro-methyl-6-fluoro-LLSs-hydroxy-3-oxo-17a-propionyloxy-l, 4-diene-17.beta.-carbothioate,

Mp 224-225 °, [q]_D +70 '(c 0.79).

29th S -fluoro-methyl-17a-acetoxy-6a, 9a-difluoro-LLβ-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, m.p. 308-310 °, [q] p + 29 ° (c 0.80).

30th S -fluoro-methyl-17a-butyryloxy-6a, 9a-difluoro-LLβ-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, m.p. 249-252 °, [alp + 32 ° (c 1.05).

Table IV

S-fluoromethyl-17a-acvloxvandrostane-17β-carbothioate by halogen exchange

<td rowspan="2">Ex. No.</td><td rowspan="2">AgF (Mg)</td><td colspan="2">output steroid</td><td rowspan="2">solvent medium (MeCN) (Ml)</td><td rowspan="2">Reaction time (h) at room temperature</td><td rowspan="2">PLC (silicon dioxide) CHC1₃Me2CO</td><td rowspan="2">crystallization LISA TION solvent medium</td><td rowspan="2">Per- domestic product (Mg)</td>

<td>Halo- halide</td><td>On- sentence (Mg)</td>

<td>22</td><td>3745</td><td>I</td><td>1702</td><td>22</td><td>20</td><td>24: 1</td><td>A</td><td>47</td>

<td>23</td><td>2071</td><td>I</td><td>1034</td><td>10</td><td>26</td><td>19: 1</td><td>EA</td><td>585 *</td>

<td>24</td><td>1945</td><td>I</td><td>850</td><td>6</td><td>26</td><td>19: 1</td><td>EA</td><td>166</td>

<td>25</td><td>1161</td><td>I</td><td>550</td><td>8th</td><td>23.5</td><td>19: 1</td><td>M</td><td>106</td>

<td>26</td><td>3574</td><td>I</td><td>1658</td><td>26</td><td>24</td><td>19: 1</td><td>A</td><td>300</td>

-24AT395428B

Table IV (continued)

<td rowspan="2">Ex. No.</td><td rowspan="2">AgF (Mg)</td><td colspan="2">output steroid</td><td rowspan="2">solvent medium (MeCN) (Ml)</td><td rowspan="2">Reaction time (h) at room temperature</td><td rowspan="2">PLC (silicon dioxide) CHCUMe₂CO</td><td rowspan="2">crystallization LISA TION solvent medium</td><td rowspan="2">Per- domestic product (Mg)</td>

<td>Halo- halide</td><td>On- sentence (Mg)</td>

<td>27</td><td>700</td><td>I</td><td>1000</td><td>50</td><td>3</td><td></td><td>M</td><td>470</td>

<td>28</td><td>462</td><td>I</td><td>700</td><td>35</td><td>2</td><td>-</td><td>EA-P</td><td>350</td>

<td>29</td><td>2600</td><td>I</td><td>4000</td><td>200</td><td>0.75</td><td>-</td><td>EA</td><td>2280</td>

<td>30</td><td>780</td><td>I</td><td>1200</td><td>60</td><td>1</td><td></td><td>EA</td><td>755</td>

EA = ethyl acetate A = acetone M = methanol P = petroleum ether, bp. 60-80 ° * purity about 95%

Example 31

S-Bromomethyl-9a-fluoro-l 1β-hvdiOxv-16β-methvl-3-oxo-17a-propionvloxvandrosta-1,4-diene-17β-carbothioate

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

Example 32

S-Brommethvl-6a.9a-difluoro-LLSs-hvdroxv-16a-Methyl-3-oxo-17a-propionvloxvandrosta-1.4-dien-17ßcarbothioat

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

Example 33

S-2'-fluoroethyl-9a-fluoro-LLSs-hvdroxv-16ss-methyl-3-oxo-17a-propionvloxvandrosta-1,4-dien-17.beta.-carbothioate

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

-25AT395428B

Example 34

S-Chlormethvl-9a-fluoro-LLSs-hvdroxv-16-methvlen-3-oxo-17a-propionvloxvandrosta-1,4-dien-17.beta.-carbothioate

A suspension of 227 mg XLII in 12 ml propionic acid and 0.7 ml trifluoroacetic acid was treated with a dry chloroform solution of 0.044 ml (c about 80 mg / ml) of toluene-p-sulfonic acid and then at room temperature for 6 h and then at 3 ° C was stirred for 16.5 h. The reaction mixture was diluted with 75 mL of 5% sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried and evaporated to give 254 mg of a brown gum. The gummy product became a plc in chloroform-acetone (19: 1) (three passes). The major band (152 mg) was crystallized twice from ethanol to give 30 mg of white crystals of the title S-chloromethyl ester 17a-propionate contaminated with S-chloromethyl-9a-fluoro-17a-hydroxy-16-methylene-3-oxo-IIβ propionyloxyandros ta-1, 4-diene-17β-carbothioate, which was demonstrated by ^ HNMR spectroscopy.

Example 35

S-chloromethyl-LLSs-Hydroxy-16ss-methyl-3-oxo-17a-propionvloxv-androst-4-ene-17.beta.-carbothioate

Catalytic reduction of 0.517 g of the compound of Example 6 in the presence of 497 mg of tris (triphenylphosphine) chlororhodium (I) in 50 ml of benzene for 22 h gave, after chromatography (plc) on silica in chloroform (four passes), elution with ethyl acetate and crystallization twice Ethyl acetate, 0.130 g of Title A.⁴-3-ketone, mp. 176-177 ° [a]_D + 78 ° (c 0.80).

Example 36

S-chloromethyl-9a-fluoro-LLSs-hvdroxv-16ss-Methyl-3-oxo-17a-propionvloxvandrost-4-ene-17.beta.-carbothioate

Catalytic reduction of 0.646 g of the compound of Example 1 with 800 mg of tris (triphenylphosphine) chloroiodomethane (I) in 100 ml of benzene over 21.5 hours gave, after chromatography on silica in chloroform-acetone (9: 1) and two crystallizations Acetone 0.142 g of the title chloromethyl thiol ester in the form of white needles, mp 217-225 ° [a]_D + 54 ° (c 0.83).

Example 37

S-fluoromethyl-LLSs-hvdroxv-16ss-Methyl-3-oxo-17a-propionvl-oxvandrost-4-ene-17.beta.-carbothioate

Catalytic reduction of 0.413 g of the compound of Example 24 in the presence of 432 mg of tris (triphenylphosphine) chlororhodium (I) in 60 ml of benzene at 22 ° C for 24 h gave after repeated chromatography on silica in chloroform-acetone mixtures and crystallization from acetone 0.106 of Title-A⁴-3-ketone, mp. 174-177 ° C [a]_D+ 123 ° (c 0.55).

Example 38

S-Chloromethyl-9a-fluoro-l 1β-hydroxy-16β-methyl-3-oxo-17a-propionvloxvandrosta-1,4-diene-17β-carbothioate

About 0.9 mg of S-chloromethyl-9β, IIβ-epoxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate of Example 16 was treated with about 1 ml of hydrogen fluoride-urea complex and total Stirred at room temperature for 24 h The mixture was treated with sodium bicarbonate and the product was extracted twice with ethyl acetate. The extracts were washed twice with water, dried and evaporated. The resulting product showed in tlc on silica in three different solvent systems (acetone-petroleum ether, b.p. 40-60 ° C, 1: 2; Chloroform-acetone, 9: 1; Ethyl acetate-petroleum ether, b.p.40-60 ° C, 1: 2, two passes) to contain the title fluorohydrin as compared to an authentic sample.

Example 39

S-Chlormethvl-6a.9a-fluoro-LLSs-hvdroxv-16a-Methyl-3-oxo-17a-propionvloxvandrosta-1.4-dien-17ßcarbothioat

A solution of 29 mg LXII in 2 ml methanol was kept at room temperature for 3 hours. The mixture was evaporated to dryness to give 25 mg of the title III L-Al alcohol, identified by comparison of its HNMR spectrum (in deuterodimethyl sulfoxide) and its LI.c. properties (silica, acetone-petroleum ether, b.p. 60 ° C, 1: 3) with those of an authentic sample.

Also provided are pharmaceutical compositions for use in anti-inflammatory therapy, comprising at least one androstano compound of formula I (as defined above) together with one or more parenteral carriers or excipients. Such compositions may be in forms adapted for topical or internal administration.

-26AT395428B

The active androstane compounds may advantageously be formulated in a conventional manner into preparations suitable for topical administration with the aid of a topical vehicle therefor. By topical administration is meant here the administration by insufflation and inhalation. Examples of the various types of preparations for topical administration include ointments, lotions, creams, powders, drops (e.g. B. Augen5 or Ohrentropfen), sprays (z. B. for the nose, pharynx, pharynx, lungs or skin), suppositories, retention enemas, chewable or suckable tablets or pellets (e.g. B. for the treatment of aphthous ulcers), capsules or cartridges for use in an inhaler or insufflator, and aerosols (e.g. B. for the nose, throat or lungs).

Ointments and creams may for example be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents and / or solvents. Such bases may include, for example, water and / or oil, such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as a polyethylene glycol having an average molecular weight in the range of 200 to 600. Depending on the nature of the base (or Base) and include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycols having an average molecular weight in the range of 4,000 to 6,000, wool fat and beeswax, and / or glyceryl monostearate and / or nonionic

Emulsifier.

Spray compositions can be formulated, for example, as aqueous solutions or suspensions or as aerosols using a suitable propellant, e.g. B. Dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Capsules and cartridges for use in an inhaler or insufflator, e.g. B. gelatin, may be formulated to contain a powder mix of a compound according to the invention and a suitable powder base such as lactose or cities. Each capsule or cartridge may generally contain between 20 pg to 10 mg of the active androstane compound.

The proportion of the active andiostane compound in the topical compositions of the invention depends on the exact nature of the formulation to be prepared, but is generally within the range of

0.001 to 5.0 wt .-%. In general, however, proportions are beneficial for most types of preparations

Range of from 0.005 to 0.5%, and preferably from 0.01 to 0.25%. However, in the case of powders for inhalation or insufflation, the proportion is in the range of 0.1 to 2%.

The above formulations for topical application to the skin can be used for the treatment of inflammatory dermatoses of humans and animals, for example eczema, which normally respond to corticosteroid therapy as well as less responsive disorders such as human psoriasis.

The formulations for administration by inhalation or insufflation are intended for administration on a prophylactic basis to humans suffering from allergic and / or inflammatory diseases of the nose, throat or lungs, such as asthma and rhinitis, including hay fever.

Aerosol formulations are preferably arranged so that each metered dose or "aerosol" expulsion contains from 20 pg to 1000 pg, preferably from about 50 pg to 100 pg, of a compound of the invention. Administration may be repeated several times daily, for example, 2,3,4 or 8 times, each time for example

1,2 or 3 dosages are available. The total daily dose with an aerosol is in the range of 100 pg to 10 mg, preferably 200 pg to 1000 pg. The total daily dose and the measured dose administered by capsules and

Cartridges in an inhaler or insufflator is generally twice the dose of those with aerosol formulations.

Topical preparations may be administered by one or more jobs per day on the affected area; Over skin surfaces, occlusive dressings can often be used to advantage.

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

Preferred forms for preparation for internal administration are unit dosage forms, ie, tablets and capsules. Such unit dosage forms contain from 0.1 mg to 20 mg, preferably 2.5 to 10 mg of the active

Steroids.

The compounds of the invention can generally be administered by internal administration in the case of systemic adreno-cortical therapy.

In general, preparations for internal administration may contain 0.05 to 10% of the active ingredient depending on the type of preparation contemplated. The daily dose may range from 0.1 mg to 60 mg,

z. B. 5 to 30 mg, vary depending on the condition to be treated and the duration of the desired treatment.

-27AT395428B

Example (Μ

ointment

Active ingredient 0.1% w / w

liquid paraffin BP 10% w / w.

white, soft paraffin to form 100 parts by weight

The active ingredient is ball-milled with a little of the liquid paraffin until the particle size is reduced to 95% to a number below 5 μ or 5 μπι. The paste is diluted and rinsed from the mill with the remaining liquid paraffin, mixed, and the suspension is added to the molten white soft paraffin at 50 ° C. It is stirred until it cools to form a homogeneous ointment.

Example CB)

cream

<td>active ingredient</td><td>0.1</td>

<td>cetostearyl</td><td>10.0</td>

<td>Cetamacrogol 1000</td><td>2.5</td>

<td>white soft paraffin</td><td>10.0</td>

<td>liquid paraffin</td><td>10.0</td>

<td>chlorocresol</td><td>0.1</td>

<td>acidic sodium phosphate</td><td>0.5</td>

<td>purified water</td><td>100.0</td>

<td>Production method:</td><td></td>

<td colspan="2">The chlorocresol and the acid sodium phosphate are dissolved in water at about 70 to 75 ° C. The waxes are fused together at about 65 to 70 ° C and added with stirring to the aqueous phase, when this has cooled to 65 to 70 ° C. The steroid is micronized (particle size as defined in BPC 1973, page 911 for ultrafine powder) and dispersed in a proportion of the liquid paraffin. The steroid suspension and the remainder of the liquid paraffin are added to the base with stirring at 60 to 65 ° C. The preparation is stirred</td>

cooled to room temperature.

Example (C)

Aerosol simulation with measured dosages pr &lt;? Dogis% w / w

active ingredient 0.05 mg 0.059

Fluorotrichloromethane 25.5 mg 30.0

Dichlorodifluoromethane to 85.0 mg to 100.0

The active ingredient is micronized (particle size as defined in BPC 1973, page 911 for ultrafine powder) and dispersed in the fluorotrichloromethane. This suspension is filled into aluminum aerosol containers, the supernatant space is purged with gas-dense dichloridifluorine to exclude air, and an aerosol metering valve is mounted in position on the container. Liquid dichloride fluoromethane is pumped through the metering valve under pressure to the weight.

Example D

Inhalation capsule (100 mg / dose) per capsule% w / w

active ingredient 0,1mg 0,4

Lactose to 25.0 mg to 100.0

The active ingredient is micronized (particle size as defined in BPC 1973, page 911 for ultrafine powder) and mixed with lactose in the proportions indicated in the above formulation. The steroid lactose mixture is filled into hard gelatin capsules to be administered with an inhalation device.

-28AT395428B