FI70904C - FREQUENCY REFERENCE FOR THERAPEUTIC USE OF THERAPEUTIC ACID 11ETA, 17ALFA-DIHYDROXI-3-OXO- -ANDROST-4-EN-17BETA-THIOCARBOX XYATER - Google Patents

Abstract

Compounds of the formula <IMAGE> in which R<1> is a fluoro-, chloro- or bromomethyl group or a 2'-fluoroethyl group, R<2> is a group COR<6> in which R<6> is a C1-3-alkyl group, or OR<2> and R<3> together form a 16 alpha ,17 alpha -isopropylidenedioxy group; R<3> is a hydrogen atom, a methyl group (which can be present in either the alpha or the ss configuration) or a methylene group; R<4> is a hydrogen, chlorine or fluorine atom; R<5> is a hydrogen or fluorine atom, and the symbol ..... is a single or double bond. The compounds have good anti-inflammatory activity, in particular on topical application. The compounds of the formula I are prepared by esterification, halogenation, reduction, elimination of protective groups and reaction at a 9,11 double bond to form a 9 alpha -halo-11ss-hydroxy group.

Description

1 70904

The invention relates to a process for the preparation of novel 11β, 17β-dihydroxy-3-oxo-androst-4-ene-17'-thiocarboxylates. for the preparation of androst-4-ene-17A-thiocarboxylates having anti-inflammatory activity.

Anti-inflammatory steroids are generally of the corticoid type, i. they are pregnane derivatives. GB-pa-10 patents 1,384,372, 1,438,940 and 1,514,476 describe anti-inflammatory esters of certain androstane-17β-carboxylic acids. EP application 79300500.0 (application publication 0004741) describes esters of androstane-17/3-carboxylic acids which also have an anti-inflammatory effect. It has now been found that certain Androstane compounds having a haloalkyl carbothioate moiety at the 17/3 position have particularly advantageous anti-inflammatory properties.

The formula of the new 11,3,17cn-dihydroxy-3-oxo-androst-4-ene-20β / thiocarboxylates is COSR1.1)

25 i CT

1 R4 30 R5 wherein R1 is a fluoro, chloro or bromomethyl group or a 2,6'2'-fluoroethyl group, R is a group COR wherein R is a C1-3 alkyl group, and R is a hydrogen atom, x- or a methyl group 2 3 35 or a methylene group, or OR and R together form a 4 16 xf 17/4-isopropylidenedioxy group, and R is a hydrogen, chlorine-2 70904 or fluorine atom, R is a hydrogen or fluorine atom and the symbol - <τ-ii is simple or a double bond.

The novel compounds of formula (I) have good anti-inflammatory activity, especially when applied topically when the human McKenzie patch test and the reduction of croton oil-induced edema are applied topically to the skin of mouse and rat.

Certain compounds, when used topically, have good anti-inflammatory activity in the croton oil substitute test, while the inhibitory effect on the hypothalamus, pituitary and adrenal glands is minimal when topically applied to the same animal species. These results indicate that these compounds may have utility in the topical treatment of inflammation in humans and animals, with a minimal tendency to cause undesirable systemic side effects.

Due to their good anti-inflammatory activity, the preferred compounds of formula (I) include the following groups: a) compounds in which R 1 is chloro or 2 fluoromethyl, b) compounds in which R is acetyl or propionyl, preferably propionyl, c) compounds , of which R is fluorine, d) compounds in which R is fluorine, e) 4 1,4-dienes, and f) 1,4-dienes in which R is fluorine and R is hydrogen,% - or / - methyl or methylene.

Compounds of formula (I) which, when applied topically, have good anti-inflammatory activity and minimal inhibitory effect on the hypothalamus, pituitary and adrenal glands include 1,4-dienes in which 1 4 5 30 R is chloro or fluoromethyl and R and R are fluorine 3 and especially those 14,-dienes where R is χ-methyl.

Particularly preferred compounds of formula I are: 35 S-chloromethyl-9 ° C-fluoro-11H-hydroxy-16 ° <-methyl-3-oxy-17β-propionyloxandrosta-1,4-diene-17β-carbo thioate, 3 70904 S-chloromethyl-9 * x, -fluoro-11-hydroxy-16-methylene-3-oxy-17'1C-propionyloxandandrost-1,4-diene-17'-carbothioate, Sf fluoromethyl 6α, N, N-difluoro-11β-hydroxy-16β, 17β-isopropylidenedioxy-3-oxoandrost-1,4-diene-17β'-carbothioate, S-fluoromethyl-6 (X, 9 N-difluoro-11β-hydroxy-16β-methyl-3-oxy-17,6-propionyloxandrosta-1,4-diene-17β-carbothioate, 10S-chloromethyl-6α6,9,9β-difluoro-11 N-hydroxy-1M-methyl-3-oxy-17β-propionyloxyandrosta-14,-diene-17β-carbothioate.

The latter compound is particularly preferred due to its minimal skin atrophy.

Compounds of formula (I) may be prepared by a) a compound of formula (I) having a 17β-thio-carboxyl group or a functionally equivalent 3 group, or a free 17X-hydroxy group, in which case R 20 is hydrogen or methyl or methylene, wherein, if desired, all other reactive groups are in protected form, 1 2 is esterified with an esterifying agent corresponding to R or R, or b) a compound of formula (I) having a 1 H-substituent of formula - COStCH 2, wherein Y is a displaceable substituent and n is 1 or 2, is reacted with a compound capable of replacing the group Y with a fluorine, chlorine or bromine atom when n is 1 and a fluorine atom when n is 2, or C) a compound of formula (I) having an 11-oxo group is reduced to an 11/6-hydroxyandrostane of formula (I), or d) a compound of formula (I) having a protected 11β-hydroxy group; deprotection, or e) a compound of formula (I) having 9.1 1-epoxy group, is reacted with hydrogen fluoride or hydrogen chloride 4 70904 to give a compound of formula I wherein 4 R is fluorine or chlorine, or f) a compound of formula (I) wherein ...; is a double bond, is partially reduced to give a compound of formula (I) wherein .τ ... is a single bond.

According to process variant a), e.g. a salt of the starting N-carbothioic acid, e.g. an alkali metal, e.g. lithium, sodium or potassium salt 10 or an alkylammonium, e.g. triethylammonium or tetrabutylammonium salt, can be reacted with a suitable alkylating agent, preferably in a polarizing agent. , such as a ketone, e.g. acetone, or an amide, such as dimethylformamide, dimethylacetamide or hexamethylphosphoramide, suitably at a temperature of 15-100 ° C.

The alkylating agent may be a dihalogen compound, i. it has an additional halogen atom (preferably a bromine or iodine atom) in addition to the halogen base of the desired R 1 group. In particular, this process is suitable for the preparation of compounds in which R 2 is a chloromethyl group and the alkylating agent is preferably bromochloromethane.

Alternatively, the starting 16-hydrogen methyl or methylene-N, N-hydroxy-N, N-carbothioate can be esterified at the 17X-hydroxyl group. This can be accomplished by conventional methods, e.g., by reacting a 17 ° (-hydroxy compound) with a mixed carboxylic acid mixed anhydride, which can be prepared, e.g., in situ by reacting the carboxylic acid with a suitable anhydride such as trifluoroacetic anhydride, preferably an acid catalyst such as p-toluene Alternatively, the mixed anhydride can be prepared in situ by reacting a symmetrical anhydride of the required acid with another suitable acid, such as trifluoroacetic acid.

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

Alternatively, the 1? 10 or a strongly acidic cation exchange resin such as

In the presence of Amberlite IR 120. The reaction is suitably carried out at a temperature of 25 to 100 ° C.

According to process variant b), e.g. a halogen exchange reaction is carried out in which the group Y, if it is halogen, is replaced by another halogen substituent.

Thus, bromomethyl, fluoromethyl and fluoroethyl 17A carbothioate compounds can be prepared from the corresponding iodomethyl or bromoethyl N, N-carbothioate compounds using a bromine salt such as lithium bromide to give bromomethyl n-fluoride or fluoride fluoride or a suitable fluoride such as fluoride. to obtain fluoroethyl 17A-carbothioate compounds. The iodomethyl 17β-carbothioate compounds used as starting materials can be prepared from the corresponding chloromethyl 17β-carbothioate compounds using, for example, an alkali metal, alkaline earth metal or quaternary ammonium iodide such as sodium iodide.

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

The reactions described above can also be carried out using starting materials containing various substituents or moieties which are converted in the reaction into substituents or moieties contained in the compounds of formula I.

According to process variant c), the 11β-hydroxy compounds of formula (I) can be prepared by reduction of the corresponding 11-oxo compound, e.g. with an alkali metal or alkaline earth metal borohydride, such as sodium or calcium borohydride, suitably in alcohol or water-alcoholic solvents. in methanol or ethanol.

The 11-keto compound can be prepared by oxidizing the corresponding 10C-hydroxy steroid with, for example, a chromic acid reagent such as Jones' reagent.

According to process variant d), the compound having a protected hydroxyl-10 group at the II-position, e.g. tri-C, is deprotected. -alkylsilyloxy group such as

1, "D

a trimethylsilyloxy group or a perfluoro or chloroalkanoyloxy group such as a trifluoroacetoxy group. The deprotection can be carried out by hydrolysis, whereby the trialkylsilyl group can be easily removed by mild acid or base hydrolysis, or the removal can be carried out particularly suitably with a fluoride such as hydrogen fluoride or 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 4 R is a chlorine atom. Such a protected hydroxyl group may be attached, e.g., by reacting the 11β-hydroxysteroid with a suitable reagent such as a trialkylsilyl halide or perfluoro or chloroalkane anhydride. The starting material used in process variant e) can be prepared by reacting a corresponding compound of formula I having a 9,11-xixis bond (and no substituent at the 11-position) with reagents capable of attaching the required β-halo-11-hydroxy group. In this case, it may be necessary to first prepare the bromohydrin by reacting it with an N-bromamide or imide, such as N-bromosuccinimide, to form the corresponding 9 (, (iy)) epoxide by treatment with a base, after which the epoxide is reacted with hydrogen fluoride or hydrogen chloride. to attach the required 35 fluorohydrin or chlorohydrin moieties, respectively.

7 70904

According to process variant f), the A compounds can be prepared by partial reduction of the corresponding A 'compounds, e.g. by hydrogenation over a palladium catalyst in a suitable solvent, such as ethyl acetate, or by homogeneous hydrogenation, e.g. e.g. with cyclohexane in the presence of a palladium catalyst in a solvent such as ethanol, preferably under heating with vertical cooling. This reduction can be carried out with a haloalkyl ester if this is sufficiently stable in such a reaction.

Compounds which contain a free -COSH group at the 17β position can be prepared, e.g., by aminolysis and coupling of the appropriate 17β-thiocarbamoyloxycarbonylandrostane. The latter compound can be conveniently prepared by reacting a 17β-carboxylic acid salt, a 17β-ester or a 16β, 17β-acetonide with a thiocarbamoyl halide such as chloride. thiocarbamoyl

AB AB

the formula is -COOCSNR R, wherein R and R are the same or different alkyl groups, e.g. C 1-4 alkyl groups, and a Ν, Ν-dimethylthiocarbamoyl group is preferred. The reaction can be accelerated by the addition of an iodide salt, e.g. sodium iodide.

The starting salt of androstane-17 () - carboxylate-25 used as starting material may be, for example, an alkali metal, e.g. sodium or potassium salt, an alkaline earth metal, e.g. calcium salt or a salt of a tertiary amine, such as triethylamine.

Aminolysis and related rearrangement can be performed, e.g., by heating the mixed anhydride to an elevated temperature, e.g., in the presence of ammonia, a primary amine, and especially a secondary amine such as diethylamine or pyrrolidine. In the 17β-carboxylic acids used as starting materials, the 16 and 17 ° C positions can be substituted with the desired groups -R 3a -OR.

The 17β-hydroxyandrostane compounds of the 16-methylene series containing the desired 17β-carboxylic acid moiety as described above can be prepared from the corresponding 16β-methyl-11-16,7,17-arepoxy-17β-thiocarboxylic acid by rearrangement. with a strong acid, e.g. a strong carboxylic acid such as trifluoroacetic acid-5a. These 16β, 17oG epoxides can be prepared from the corresponding 17β-carboxylic acids by treating the onium salt of the 2-haloazao-aromatic compound and then treating the resulting product with hydrogen sulfide or a salt thereof to give the free 17β-carbothioic acid, which can be alkylated as described above. preferably in situ as the desired $ 17 carbothioate group.

Similarly, 16-6,17.-isopropylidenedioxy compounds of formula (I) can be prepared by treating the corresponding 17β-carboxylic acid with the onium salt of a 2-haloaza-15 aromatic compound, followed by treatment of the resulting product with hydrogen sulfide to give the free 17β-carbothioic acid, which can then be esterified. as described.

The onium-20 salts of 2-haloaza aromatic compounds are capable of activating the carboxyl. Such reagents include 2-halo-N-alkyl or 2-halo-N-phenylpyridinium or pyrimidinium salts and a suitable salt is 2-fluoro-N-methylpyridinium tosylate or 2-chloro-n-methylbenzostiazolium trifluoromethanesulfonate. The 16β, 17β-epoxy-16β-methyl-17β-carboxylic acid compounds used as starting materials in the process described above can be prepared in a conventional manner, e.g., as described in GB Patent 1,517,278.

17β-Hydroxy-17β-carbothioic acids and their salts can be converted to the corresponding 17β-hydroxy-17β-carbothioates or 17β-carbothioic acid 17, X, -esters by the methods described above. (I) in connection with the preparation of the compounds.

17β-Hydroxy-17β-carboxylic acids can be prepared, e.g., by reacting the corresponding reactive derivative of 17β-hydroxy-17β-carboxylic acid with hydrogen sulfide 9 70904 or a sulfide or hydrogen sulfide salt thereof. The cation of the sulfide or hydrogen sulfide salt may generally be, for example, an alkali metal salt such as sodium or potassium hydrogen sulfide.

The reactive derivatives are preferably prepared by reacting the corresponding 17α-hydroxy-17β-carboxylic acid with N, N'-carbonyldi- (1,2,4) -triazole), N, N'-carbonyldibenzothiazoles, N, N ' with carbonyldibenzimidazole, N, N * -carbonyldi (3,5-dimethylpyrazole), 10 N, N'-thionyldiimidazole and in particular N, N'-carbonyldiimidazole or N, N'-thiocarbonyldiimidazole .

The reaction is conveniently carried out in an inert, anhydrous solvent such as a substituted amide solvent, e.g.

In the presence of Ν, Ν-dimethylformamide or Ν, Ν-dimethylacetamide, preferably excluding water. The reaction is preferably carried out at or below ambient temperature, e.g. -30 to 30 ° C. The reaction is conveniently carried out under approximately neutral conditions and preferably under an inert atmosphere, e.g. a nitrogen atmosphere. The same solvents and conditions also apply in the subsequent reaction with I ^ Srn or a salt thereof. The by-product heterocyclic compound, e.g. imidazole or 1,2,4-triazole, can be easily removed by extraction with water.

The above reactions may also be carried out with compounds having various substituents or moieties which are then converted to compounds of formula (I) as described above.

The androstane-17β-carboxylic acid used as starting material in the processes described above can be prepared in a conventional manner, e.g. by oxidizing the appropriate 21-hydroxy-20-ketopregnane, e.g. with periodic acid in a solvent medium and preferably at room temperature. Alternatively, sodium bismuthate may be used if it is desired to oxidatively remove the 21-carbon atom 17 from the TU-acyloxypregnane compound. It should be noted that if the pregnane compound used as a starting material contains a substituent sensitive to the intended oxidation described above, this must be suitably protected.

The antirinflammatory effect of the androstane carbothioates of formula (I) is shown in Table A. The local anti-inflammatory potency was determined by a croton-oil ear test using male mice weighing 23-28 g. Various amounts of test compound were dissolved in croton oil: pyridine: ether (2:20:78). Groups of ten mice were treated with a solution of croton oil containing the test compound, and 0.02 ml of the test compound was administered to each ear of each mouse. solution. A group receiving croton oil solution without test compound was used as a control. After six hours, the mice were sacrificed and their ears removed and weighed. The average weight of the ears in each dose group was calculated and the relative potency of the 20 test compounds was calculated from the values obtained. In Table A, known, closely related compounds are used as reference compounds.

11 70904

Table A

Example Compound of Formula (I) Relative potency 5 Ncu determined by mouse *-__ croton oil test 1 S-chloromethyl-9 o (-fluoro-5.13 11β-hydroxy-16β-methyl-3-oxo-17 c * -propionyloxyandrost-1,4-diene-1H-carbono-10thioate 5S-chloromethyl-6α, 9β-di- 7.00fluoro-11β-hydroxy-16? Methyl 3-oxo-17β-propionyloxyandrosta-1,4-diene-17-carbothioate 7S-chloromethyl-9,3,3-fluoro-5,25 II-3-hydroxy-16-methylene -3-Oxo-17β-propionyloxyandrosta-1,4-diene-17 (3-carbothioate 8S-chloromethyl-17β-acetoxy-7,38 20 9 o <-fluoro-11β-hydroxy -16β-methyl-3-oxoandrost-1,4-diene-17β-carbothate 19Sf-fluoromethyl-6d, 9C-di-14,13-fluoro-11β-hydroxy-16β-methyl - 17β-propionyloxy-3-oxoandrost-1,4-diene-17β-carbothate 20 Sf fluoromethyl-6 <9,9-di-5,63 fluoro-11 (3-hydroxy-16 α, 17-isopropylidenedioxy-3-oxoandrost-1,4-diene-1H-carbothioate 30 23 Sf fluoromethyl-11β-hydroxy-6.25 16 ^ -methyl 3-oxo-17α-propionyloxandrosta-1,4-diene-17β-carbothioate 24 S-fluoromethyl-9α-chloro-11/3 to 12.50 hydroxy-16 (S -methyl 3-oxo-, ς 1 71 * -propionyloxyandrosta-1,4-diene-17 (h-carbothioate 29 S-fluoromethyl-17 <* - butyryl-6,88 oxy-6,9 rK, difluoro- 11β-hydroxy-16β-methyl-3-oxoandrostta-1,4-diene-17β-carbothioate 40 12 70904

F1 Patent Publication 66393

Table 1 S-methyl-β, 90β-difluoro-11β-1

Compound A hydroxy-16,6-methyl-3-oxo-17 <X -5-propionyloxandrosta-1,4-diene-17/6-carbothioate GB Patent Specification 1438940 10 1 Chloromethyl g · * -fluoro-11 / 3- Hydroxy-16,6-methyl-3-oxo-1-PC-propionyloxandrosta-1,4-diene-17β-carboxylate 3,16 Fluoromethyl-9β-fluoro-11β-carboxylate .38 “roxy-16β-methyl-3-oxo-17β-propionyloxandrosta-1,4-diene-17β-carboxylate 1-6 GB Application Publication 2014579 2.5 2.8 The following examples illustrate the invention . Melting points were determined in degrees Celsius on a Kofler melting point apparatus and are uncorrected. Optical rotation was determined at room temperature in dioxane solutions. TLC (thin layer chromatography), PLC (preparative thin layer chromatography) and HPLC (high performance liquid chromatography) were performed on silica.

Unless otherwise stated, the solutions were dried over magnesium sulfate.

Preparation of starting materials 30 Example I

9% rf fluoro-11β-hydroxy-16,3-methyl-3-oxo-17X-propionyloxyandrost-1,4-diene-17β-carbothioic acid (I)

A solution of 5.00 g of 9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17 ° C-propionyloxandrosta-1,4-diene-35β-carboxylic acid solvated with half a mole of ethyl acetate, and 5.3 ml of triethylamine in 75 ml of dichloromethane, stirred under nitrogen and treated with 5.071 g of dimethylthiocarbamoyl chloride. After day 13, 70904, an additional 5.320 g of reagent was added. After 47 hours, the mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid, 5% sodium bicarbonate solution and water, dried, evaporated to give 9.043 g of a viscous yellow oil. This was dissolved in 50 ml of diethylamine, stirred and heated under reflux under nitrogen for 5.75 hours. The resulting brown solution was added to a mixture of 50 ml of concentrated hydrochloric acid, 250 ml of water and 50 ml of ethyl acetate. The products were further extracted with ethyl acetate and then the acidic products were co-extracted with 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 1N hydrochloric acid and water, dried, evaporated to give 3.440 g of a brown-yellow solid. This was recrystallized from acetone to give 1.980 g of the title compound 17-carbothioic acid as pale brown yellow crystals, m.p. 172-173 °.

After two recrystallizations from acetone, an analytical sample was obtained as white crystals, m.p.

177-179 ° / Qj7D = + 110 ° (c = 1.05).

Example II

S-chloromethyl-9α-fluoro-16β-methyl-3,11-dioxo-17β-propionyloxandrosta-1,4-diene-17β-carbothioate (II) 25 1.5 ml of 8 ml were added dropwise over 10 minutes. of

Jones reagent to a stirred solution of 998 mg of the compound of Example 1 (described below) in 2 mL of acetone and 2 mL of dimethylformamide. After 30 minutes, the reaction mixture was slowly diluted with 100 ml of water with stirring and the resulting suspension was cooled for one hour. The precipitate was isolated by filtration, washed with water, dried to give 877 mg of a cream solid. PLC gave 755 mg of a white foam from chloroformacetone (10: 1) which was crystallized twice from acetone to give 523 mg of the title compound 11-ketone as white needles, m.p. 204-205 °, = + 94 ° (c = 1.04).

70904

Example III

17β-N, N-dimethylthiocarbamoyloxycarbonyl-9α-fluoro-11H-hydroxy-160β-methyl-17α-propionyloxandandrost-1,4-dien-3-one (III) 5 A solution of 0.434 g of 90 E-fluoro-11β-hydroxy-16β-methyl-3-oxo-17β-propionyloxandrosta-1,4-diene-17β-carboxylic acid in 8 ml of dichloromethane was treated successively with 0.14 ml of triethylamine, 0.248 g of dimethylthiocarbamoyl chloride and 0.149 g of sodium iodine-10 dia and the mixture was stirred under nitrogen at 20 ° for six hours. 30 ml of ethyl acetate were added and the total volume was halved in vacuo. An additional 50 mL of ethyl acetate was added, the solution was washed with water, 2N hydrochloric acid, water, 3% sodium bicarbonate solution, water and saturated sodium chloride solution, and then dried. The solution was concentrated in vacuo to give 0.329 g of product. This was crystallized twice from acetone to give the title anhydride as white needles, m.p. 191-193 °, Δ7d = + 82 ° (c = 0.57).

20 Example IV

90L- [1-fluoro-11/5-hydroxy] -160C-methyl-3-oxo-17dt-propionyloxyandrosta-1,4-diene-17/3-carbothioic acid (IV)

A stirred suspension of 2.467 g of compound III in 25 ml of diethylamine was heated under reflux under nitrogen. After three and a half hours, the reaction mixture was poured into 300 ml of ice-cooled 3N hydrochloric acid and the mixture was extracted with ethyl acetate. The combined extracts were washed with water and extracted with 5% sodium carbonate solution. The combined aqueous extracts were washed with ethyl acetate, then covered with ethyl acetate and acidified with hydrochloric acid to pH 1. The aqueous phase was further extracted with ethyl acetate, the combined extracts washed with water and brine, dried and the solvent removed in vacuo. Residue 35 was crystallized twice from acetone to give 1.309 g of the title carbothioic acid as white needles, m.p. 141-143c δ = §30 ° (c = 0.51).

15 70904

Example V

lly3-hydroxy-3-oxy-170C-propionyloxyandrost-1,4-diene-17/5-carboxylic acid (V)

A solution of 13.5 g of 11β, 17β-dihydroxy-3-oxo-5 androsta-1,4-diene-17β-carboxylic acid and 18 ml of triethylamine in 500 ml of dichloromethane was cooled to 4 °: and treated portionwise over 15 minutes with 14.2 ml of propionyl chloride. Stirring was continued at 4 ° for a total of one hour, the mixture was washed successively with 3% sodium bicarbonate solution, water, 2N hydrochloric acid, water and saturated brine, dried and evaporated in vacuo. The residue was dissolved in 300 ml of acetone and 14.3 ml of diethylamine was added with stirring. After 1 hour at 20 °, the solvent was removed in vacuo and the residue was dissolved in 150 ml of water. After acidification to pH 1 with 2N hydrochloric acid, the product was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried and concentrated to a small volume. The solid product was isolated by filtration, washed with ethyl acetate, dried in vacuo at 50 ° to give 13.309 g of the title compound 17-propionate carboxylic acid as crystals, 3 (7 - + 2 ° (c = 1.10)).

389 mg of this compound were crystallized twice from methanol to give 256 mg of an analytical sample, m.p. 244-245 ° (ha-25 flow), 37O = + 3 ° (c = 0.83).

Example VI

6α, 9α-Difluoro-11H-hydroxy-160C-methyl-3-oxy-170C-propionyloxyandrosta-1,4-diene-17/5-carboxylic acid (VI)

A solution of 2.113 g of 60 (90t-difluoro-11 / 5,17Cfc · 30 dihydroxy-160t-methyl-3-oxandandrost-1,4-diene-17/5-carboxylic acid and 2.5 ml of triethylamine 60 After 1 h, the mixture was diluted with an additional 50 mL of solvent, washed sequentially with 3% sodium bicarbonate solution, water, 2N hydrochloric acid, 1 mL, and stirred at about 0 ° C with 1.85 mL of propionyl chloride. , water and brine, dried and evaporated to a yellow-brown solid, which was dissolved in 50 ml of acetone and 2.5 ml of diethylamine were added, after 1 hour at 22 ° the solvent was removed in vacuo and the remaining resin was dissolved in 30 ml: Acidification to pH 15 with 2N hydrochloric acid precipitated a solid which was isolated, washed with water, dried to give 2.230 g of the title compound 1706-propionate, mp 220-225 °, 2 s / D = + 4 ° (c = 0.70).

Example VII

17β-N, N-Dimethylthiocarbamoyloxycarbonyl-6α, 9α-difluorolys-hydroxy-16α, 17β-isopropylidenedioxyandrostta-1,4-dien-3-one (VII)

A solution of 4.354 g of 6α, 9α-difluoro-11β-hydroxy-160β, 170β-isopropylidenedioxy-3-oxoandrost-1,4-di-15-ene-17β-carboxylic acid in 150 ml of dichloromethane with was 1.4 ml of triethylamine, treated with 2.519 g of N, N-dimethylthiocarbamoyl chloride and the reaction mixture was stirred under nitrogen for 80 minutes at 22 °. 500 ml of ethyl acetate were added, and the resulting solution was washed successively with 2N hydrochloric acid, water, sodium hydrogencarbonate solution, water and saturated sodium chloride solution, dried, and the solution was concentrated. On cooling, a solid crystallized which was isolated by filtration and dried in vacuo to give 3.562 g of the title anhydride as pale yellow prisms, m.p. 283-287 ° (decomposes), = + 156 ° (c = 0.84 dimethyl sulfoxide).

Example VIII

6 ° C, 9α-Difluoro-11β-hydroxy-160 ° C, 170α-isopropylidene-dioxo-3-oxandandrost-1,4-diene-17β-carbothioic acid (VIII)

A suspension of 3.455 g of compound VII

In 200 ml of diethylamine, was heated under reflux for six hours under a nitrogen blanket. The suspension initially formed rapidly dissolved, but after 30 minutes a light brown suspension formed which remained unchanged. The cooled reaction mixture was poured into 1.0 liter of water, acidified with 210 ml of concentrated hydrochloric acid to pH 1 and extracted with ethyl acetate. The combined extracts were washed with water, extracted with 5% sodium carbonate solution and water, and the aqueous extracts were combined. The combined extracts were oxidized with 6N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried, the solvent removed in vacuo to give 2.31 g of a light gray solid.

0.408 g of the product was crystallized from ethyl acetate to give 0.149 g of the title carbothioic acid, m.p. 191-10,199 °, λmax = + 124 ° (c = 1.04, dimethyl sulfoxide).

Example IX

606-fluoro-11β, 17 ° C-dihydroxy-3-oxoandrost-1,4-diene-1H-carboxylic acid (IX)

A solution of 4.987 g of 60t-fluoroprednisolone in 50 ml of tetrahydrofuran and a solution of 10.0 g of periodic acid in 24 ml of water were stirred 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, dried to give 4.80 g of a white solid. From this, 271 mg of methanol was crystallized to give 171 mg of the title acid as white needles, m.p. 241-248 °, Z & 7D = + 54 ° <c = 0.825).

Example X

6et-fluoro-11β-hydroxy-3-oxy-17β-propionyloxy-25 androsta-1,4-diene-17β-carboxylic acid (X)

A solution of 4.491 g of compound IX and 4.46 ml of triethylamine in 160 ml of dry dichloromethane at -5 ° was treated dropwise over 5 minutes at a temperature below 0 ° with 2.80 ml (2.96 g) of propionyl chloride in about 5 ml of dry water. dichloromethane. After a further 20 minutes below 0 °, the reaction mixture was diluted with 160 ml of dichloromethane, washed with sodium hydrogen carbonate solution and water, dried, evaporated to give 5.701 g of a white solid. This was mixed with 4.60 mL (3.24 g) of di-35 ethylamine in 30 mL of acetone to give a clear yellow solution. After 30 minutes, the solution was concentrated, 150 mL of water was added, and the resulting solution was washed with 18 x 70 mL of 2 x 30 mL of ethyl acetate. The aqueous phase was acidified with 50 ml of 2N hydrochloric acid to pH 2 with stirring and the product was extracted three times with ethyl acetate. The extracts were combined, washed with 50 ml of water, dried, evaporated to give 5.819 g of a white foam. From this, 304 mg of ethyl acetate was crystallized to give 144 mg of the title compound 1701-propionate in small plates, m.p. 224-227 °, δ $ 7D = + 3 ° (c = 0.861).

Examples XI-XXI

Following the general procedure described in Preparation I, but starting from the 17β-carboxylic acid corresponding to the desired 17β-carbothioate (method details in Table I below), the following compounds were prepared: XI. 17C-acetoxy-90C-fluoro-11β-hydroxy-16β-methyl-3-oxoandrost-1,4-diene-17β-carbothioic acid, m.p. 178.5-179 °, λ max = + 98 ° (c = 1.02).

XII. 17β-butyryloxy-90 C-fluoro-11β-hydroxy-16β-methyl-3-oxoandrost-1,4-diene-17β-carbothioic acid, m.p.

175-176 °, δ qlJo = + 107 ° (c = 0.96).

XIII. 9 ° C-fluoro-11H-hydroxy-17β-isobutyryloxy-16β-methyl-3-oxoandrost-1,4-diene-17β-carboxylic acid, m.p. 177-179 °, m / z = + 119 ° (c = 0.90).

XIV. 11β-hydroxy-3-oxo-17β-propionyloxandrosta-1,4-diene-17β-carbothioic acid, m.p. 134-138 °, / 0C / D = + 67 ° (c = 0.66).

XV. 12H-hydroxy-16H-methyl-3-oxo-17β-propionyloxandrosta-1,4-diene-17β-carbothioic acid, m.p. 159-163 °, m / o = + 113 ° (c = 0.78).

30 XVI. 9-α-chloro-1H] -hydroxy-16β-methyl-3-oxy-170β-propionyloxyandrosta-1,4-diene-17β-carbothioic acid, m.p.

167-171 °, <& 7d = + 128 ° (c = 0.99).

XVII. 90 C-fluoro-11β-hydroxy-16β-methyl-3-oxy-17β-propionyloxandrosta-1,4-diene-17β-carbothioic acid, m.p.

35 141-143 °, = + 30 ° (c * 0.51).

XVIII. 60t, 9ot-difluoro-11H-hydroxy-16-methyl-3-oxy-17α-propionyloxyandrosta-1,4-diene-17β-carbothioic acid, m.p. 136-139 °, λ = -30 ° (c = 0.56).

19 70904 XIX. 9α-fluoro-11β-hydroxy-16-methylene-3-oxy-17α-propionyloxyandrosta-1,4-diene-17β-carbothioic acid, m.p. 236-239 °, = -71 ° (c = 0.99).

XX. 11β-hydroxy-3-oxy-17α-propionyloxyandrosta-5,4-ene-17β-carbothioic acid, m.p. 176-177 °, λ max = + 101 ° (c = 0.96).

XXI. 6α-fluoro-11β-hydroxy-3-oxy-170β-propionyloxyandrosta-1,4-diene-β / 3-carbothioic acid, m.p. 189-193 °, 2 © & 7D = + 72 ° (c = 0.74).

10

Table I

Preparation of mixed anhydrides

Pre- 17/3-carboxy-Cl-CSNMe2 NEt3 Solvent Reaction time mark silicic acid (g) (ml) (CH2Cl2) (day) room ^ 5 feed (g) (ml) at XI 5.00 2.940 1.66 75 5la XII 15,354 8,809 4,8 250 6 XIII 4,182 2,399 1,3 80 4 XIV 7,148 4,40 2,6 150 6lb 20 XV 6,137 3,77 2,05 140 6lc XVI 5,973 3,350 1,34 100 7 XVII 4,207 2,39 1.35 80 0.677, ld XVIII 2,130 1.80 0.66 50 64 XIX 5,000 2,507 1.41 75 3 25 XX 1,000 2,442 1.22 15 2.7 XXI 6,000 3.55 2.0 120 1.2510 20 70904

Table I (continued)

Treatment of mixed anhydride intermediates with diethylamine

Pre- NHEt2 Reaction time (h) Product Crystallization solvent 5 mark (mi) at reflux temperature (g) XI 50 5.5 2,104 EA2a XII 250 4 5,244 EA3

XIII 60 4.5 1.00 EA

10 XIV 60 4 3.29 EA

XV 50 3.5 1.382 EA

XVI 60 5.7 0.527 EA

XVII 25 4.75 1.309 A

XVIII 12 6 0.418 EA

15 XIX 50 3.75 1.296 EA2b XX 15 4 0.3976 A5

XXI 60 4.5 2.88 EA-P

References: 20 EA = ethyl acetate, A = acetone, P = petroleum ether, b.p. 60-80 °.

1. For identification, parts (a) 500 mg, (b) 670 mg, (c) 424 mg and (d) 171 mg were taken from the intermediate dimethylthiourea anhydride.

2. Identification was performed on a sample recrystallized twice from ethyl acetate, yields (a) 84% and (b) 69%.

3. The product was solvated with about 0.2 moles of ethyl acetate.

4. As an intermediate, 1.435 g of dimethylthiocarbamic anhydride were obtained, which crystallized from ethyl acetate. Of this, 95 mg was taken for identification.

5. Identification was performed on a sample recrystallized twice from acetone, yield 73%.

35 6. The product crystallized from ethyl acetate.

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

10. The reaction also involved 2.13 g of sodium iodide.

70904

Example XXII

9β-chloro-11β-hydroxy-16β-methyl-3-oxy-17β-propionyloxyandrosta-1,4-diene-17β-carbothioic acid and 9β, 11β-epoxy-16β-methyl-3 -oxy-17α-propionyloxandrosta-1,4-diene-17β-carbothioic acid (XXII)

A solution of 5.586 g of 17 / N, N-dimethylthiocarbamoyloxycarbonyl-9-chloro-11β-hydroxy-16β-methyl-17β-propionyloxandrosta-1,4-dien-3-one in 60 ml of diethylamine was heated vertically cooling nitrogen-10 sa five hours 40 minutes. The reaction mixture was poured into 450 ml of water, acidified to pH 10 with concentrated hydrochloric acid and extracted with 4 x 50 ml of aqueous sodium carbonate solution. The aqueous extracts were acidified to pH 1 with 6N hydrochloric acid and extracted with 3 x 50 mL of ethyl acetate.

The combined extracts were washed with water and brine, dried, the solvent removed in vacuo to give 2.834 g of a colorless foam.

Crystallization of the mixture twice from ethyl acetate gave 0.527 g of 90β-chloro-1β-hydroxy-16β-methyl-3-oxy-20β-propionyloxyandrosta-1,4-diene-17β-carbothioic acid as white prisms, m.p. 167-171 °, λ = + 128 ° (c = 0.99). The mother liquors obtained from the crystallizations also contained the above-mentioned 90β-chloro-11β-hydroxycarbothioic acid and, in addition, 9/3,1β-epoxy-1- [3-methyl-3-oxy-17β-propionyloxyandros-25 ta-1,4 -diene-17 ^ -karbotiohappoa.

Example XXIII

S-iodomethyl-9H-fluoro-1H-hydroxy-16β-methyl-3-oxy-17β-propionyloxandrosta-1,4-diene-1H-carbothioate (XXIII) 30 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 were stirred and heated under reflux for 6.5 hours. 75 ml of ethyl acetate were then added, the solution was washed successively with water, 10% sodium thiosulphate solution, 5% sodium hydrogen carbonate solution and water, dried, evaporated to give 525 mg of an off-white foam. PLC in chloroform-22 7 0 9 0 4 acetone (6: 1) gave 478 mg of an off-white foam which was crystallized twice from acetone without heating above room temperature to give 241 mg of the title compound S-iodomethyl ester as colorless crystals, m.p. 196-197 °, 5 foc / O = -32 ° (c = 1.01).

Examples XXIV-XXXV

Following the general procedure described in Preparation XXIII, but starting from S-chloromethyl-17/3-carbothioate corresponding to the desired product (method details in Table II below), the following compounds were prepared: XXIV. S-iodomethyl-17β-acetoxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxandrosta-1,4-diene-17/5-carbothioate, m.p. 204-205 °, λ max = -29 ° (c = 0.98).

15 XXV. S-iodomethyl-11β-hydroxy-3-oxy-17β-propionyloxyandrosta-1,4-diene-17β-carbothioate, [α] 25 D = + 26 ° (c = 0.47).

XXVI. S-iodomethyl-1H-hydroxy-16β-methyl-3-oxy-17 ° C-propionyloxandrosta-1,4-diene-1'-N-carbothioate, 20-7o = + 5 ° (c = 0.74 ).

XXVII. S-iodomethyl-9α-chloro-11β-hydroxy-16β-methyl-3-oxy-17β-propionyloxandrosta-1,4-diene-17β-carbothioate, [α] D = + 7 ° (c = 0 , 36).

XXVIII. S-iodomethyl-906-fluoro-11β-hydroxy-10-methyl-3-oxy-17β-propionyloxyandrost-1,4-diene-17β-carbothioate, = + 85 ° (c = 0, 55).

XXIX. S-iodomethyl-6β, 90t-difluoro-1H * -hydroxy-16β-methyl-3-oxy-17β-propionyloxandrosta-1,4-diene-17β-carbothioate.

30 XXX. S-iodomethyl-90β-fluoro-11β-hydroxy-16-methylene-3-oxy-17β-propionyloxandrosta-1,4-diene-17β-carbothioate, m.p. 191-199 °, -31 ° (c = 0.99).

XXXI. S-iodomethyl-90C-fluoro-11β-hydroxy-3-oxy-170C-propionyloxandrosta-1,4-diene-17H-carbothioate, 35 M.p. 175-178 °, species Q = + 4 ° (c = 0.50).

XXXII. S-iodomethyl-6C6-fluoro-11β-hydroxy-3-oxy-17β-propionyloxandrosta-1,4-diene-17β-carbothioate, m.p. 195-197 °, = + 18 ° (c = 0.64).

23 70904 XXXIII. S-iodomethyl-170β-acetoxy-6α, 9α-difluoro-1 H -hydroxy-16α-methyl-3-oxandrosta-1,4-diene-17β-carbothioate, m.p. 241-243 °, λmax + 78 ° (c = 0.78).

XXXIV. S-iodomethyl-17α-butyryloxy-6α, 90C-difluoro-1H-hydroxy-160t-methyl-3-oxandrosta-1,4-diene-17β-carbothioate, m.p. 210-212 ° C, = + 89 ° (c = 0.90).

XXXV. S-iodomethyl-90β-fluoro-11β-hydroxy-ethyl, 170β-isopropylidenedioxy-3-oxandandrost-1,4-diene-17β-carbothioate, m.p. 261-270 ° (decomp.), = + 97 ° (c = 0.48, 10 dimethyl sulfoxide).

Table II

Halogen exchanges with S-haloalkyl-1706-acyloxyandrostane-N-carbothioates

Pre- Start Starting- Solvent Reaction- PLC Crystallization- Product -L5 mark (mg) roid / halo- (setting time (h) (silica solvent (mg) genide feed) (ml) (return bond) te ( mg) thermal CFICL · -

lassa) Me2CD

XXIV 6632 Cl 1715 20 3,5 - EA 2161 XXV 3800 Cl 925 10 4 - - 1084 20 XXVI 3260 Cl 840 10 3 - - 969 XXVII 1995 Cl 536 20 6,5 - - 591 XXVIII 2160 Cl 580 10 3 - - 685 XXIX 1200 Cl 303 30 5 - - 3173 XXX 7361 Cl 1953 23 6 19: 1 A 2962 25 XXXI 5500 Cl 1300 35 4 - M 12507 XXXII 8400 Cl 2000 54 4,5 - EA-P 1800 XXXIII 19000 Cl 4750 200 5 - EA 42606 XXXIV 6500 Cl 1620 70 5.5 - EA 16105 XXXV 5491 Cl 1419 20 24 9: 1 A 2248 30 EA = ethyl acetate, A = acetone, M = methanol, P = petroleum ether, b.p. 60-80 °.

References: 1. Obtained from 300 mg as part of 2.024 g of impure 35 product.

2. Obtained from 400 mg as a fraction of 2.058 g of crude product.

70904 3. The product was used as such to prepare the corresponding fluoromethyl 17β-carbothioate.

4. Lithium chloride was used instead of sodium iodide.

5 5. Solvated with 0.5 moles of 1 ^ 0.

6. Solvated with 0.1 mole of EA.

7. Solvated with 0.2 moles of EA and 0.5 moles of H 2 O.

8. 300 mg were obtained as a fraction of 1.611 g of 10 crude crystalline products.

Example XXXVI

S-iodomethyl-βΛ, 9ot-difluoro-1H-hydroxy-16A, 11 (Xr isopropylidenedioxy-3-oxanedrosta-1,4-diene-17/3 -carbothioate (XXXVI) 15 Solution containing 0.795 g of the compound of Example 4 described below in 50 ml of acetone and 2.969 g of sodium iodide were heated under reflux for 5.5 hours, 75 ml of ethyl acetate were added, the solution was washed successively with water and sodium metabisulphite solution, dried, the solvent removed in vacuo to give 0.893 g. A 0.205 g portion of this was crystallized twice from ethyl acetate to give 0.105 g of the title compound S-iodomethylthioester as white prisms, mp 260-262 ° (decomposes), / 0 = + 81 ° (c = 0.6, dimethyl sulfoxide) .

25 Example XXXVII

S-2'-bromoethyl-90t-fluoro-11β-hydroxy-16β-methyl-3-oxy-170β-propionyloxyandrosa-1,4-diene-17β-carbonothioate (XXXVII) 0.5 g of compound I was treated as described for S-chloro-30-rimethyl ester (method A of Example 1 described below) but using 1,2-dibromoethane to give 0.409 g of the title compound S-2'-bromoethyl ester, m.p. 174-175 °, foci = + 120 ° (c = 1.04).

70904

Example XXXVIII

S “chloromethyl-16β, 17β-epoxy-90C-fluoro-11β-hydroxy-11β-methyl-3-oxandandrost-1,4-diene-17β-carbothioate (XXXVIII)

5 Method A

A suspension of 753 mg of 16β, 17 ° C-epoxy-9β-fluoro-11β-hydroxy-16β-methyl-3-oxandrosta-1,4-diene-1,3-carboxylic acid and 680 mg of 2 -fluoro-1-methylpyridinium tosylate in 7 ml of dichloromethane, treated dropwise at 0 ° with 1.39 ml of triethylamine and stirred for one hour at 0 °. Hydrogen sulfide was then passed through the mixture for 15 minutes and the resulting solution was stirred for an additional hour at 0 °. 0.26 ml of bromochloromethane was then added and the mixture was stirred and allowed to warm to room temperature. After a further 1.5 hours, the reaction mixture was diluted with 250 ml of ethyl acetate, washed successively with 2N hydrochloric acid, 5% sodium hydrogen carbonate solution and water, dried, evaporated to give 818 mg of a pale yellow solid. This was performed by PLC in chloroform-acetone (9: 1) (two runs). The main zone (515 mg) was crystallized from acetone to give 447 mg of the title compound S-chloromethyl ester epoxide as white needles, m.p. 246-251 °, / p (JO = + 131 ° (c = 0.67)).

Method B

A suspension of 376 mg of 160 ° C, 17β-epoxy-9α-fluoro-11β-hydroxy-16-methylene-3-oxanedrosta-1,4-diene-1H-carboxylic acid and 400 mg of 2-chloro- N-methylbenzothiazolium trifluoromethanesulfonate in dichloromethane was treated at 0 ° with 0.7 ml of triethylamine. The resulting solution was stirred at 0 ° for 1.25 hours and then hydrogen sulfide was passed through the mixture for 10 minutes. After stirring for an hour at 0 °, 0.13 ml of bromochloromethane was added and the mixture was stirred at room temperature. Two 0.13 ml portions of bromochloromethane were then added after 1.5 hours and 1.8 hours. 15 minutes after the last addition, the reaction mixture was diluted with 200 ml of ethyl acetate, 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 PLC in chloroform-acetone (19: 1) (three runs). From the more polar zone, 5,134 mg of the title compound S-chloromethyl ester was obtained as a pale rose-red solid which was identical to the authentic sample by TLC.

Example XXXIX

S-chloromethyl-9β-fluoro-1H-3,17β-dihydroxy-16-methyl-10-ethylene-3-oxandrosta-1,4-diene-1H-carbothioate (XXXIX)

A solution of 400 mg of XLI in 16 ml of trifluoroacetic acid was stirred at room temperature. After 5.5 hours, the reaction mixture was evaporated to near dryness and the residue was dissolved in 100 ml of ethyl acetate. The solution was washed with 5% sodium bicarbonate solution and water, dried and evaporated to 466 mg of a yellow-green foam. The foam was subjected to PLC in chloroform-acetone (9: 1) (three runs). From the main zone weighing 3.5 mg, a portion of 80 mg was crystallized twice from acetone to give 48 mg of the title compound 16-methylene-17-alcohol as white crystals, m.p. 242-243 °, = + 36 ° (c = 0.50).

Example XL

906-Fluoro-17CC-hydroxy-1H-methyl-3,11-dioxandrosta-1,4-diene-1H-carboxylic acid (XL) A stirred suspension of 4.842 g of 90C-fluoro-17 21-dihydroxy-16,3-methylandrosta-1,4-dimethylene-3,11,20-trione in 50 ml of tetrahydrofuran, cooled on ice and treated dropwise over 5 minutes with a solution of 4.255 g of periodic acid in 15 ml of water. The reaction mixture was stirred for 2.25 hours at 22 °, during which time the suspension almost completely dissolved. The solvent was removed in vacuo and water was added occasionally to maintain the original volume. The precipitate formed was isolated by filtration, washed with water, dried in air and vacuum to give 4.55 g of the title carboxylic acid as cream-colored prisms, m.p. 270-272 ° (decomposes), [.alpha.] D @ 20 = + 136 DEG (c = 1.04, dimethyl sulfoxide).

70904 27

Example XLI

9Cfc-fluoro-1β, 3,170β-dihydroxy-1- (β-methyl-3-oxyandrosta-1,4-diene-17β-carbothioic acid (XLI)

A stirred solution of 0.502 g of 9Q-fluoro-V3-517Ct-dihydroxy-16H-methyl-3-oxanandrosta-1,4-diene-17β-carboxylic acid in 15 ml of dry N, N- dimethylformamide, cooled to -5 ° under nitrogen and treated with 0.435 g of N, N'-carbonyldiimidazole and the reaction mixture was stirred at -5 ° for 18 hours. Hydrogen sulfide gas was bubbled through the reaction mixture for 20 minutes and the solution was stirred for an additional hour, gradually allowing to warm to 22 °. The reaction mixture was poured into ethyl acetate, the resulting solution was washed with 2N hydrochloric acid and water, and extracted with 3 x 50 ml of 2N sodium carbonate solution. The combined extracts were washed with 60 mL of ethyl acetate, covered with 100 mL of ethyl acetate and acidified to pH 1.0 with hydrochloric acid. The aqueous layer was extracted with ethyl acetate, the extracts washed with water and brine, dried, the solvent removed in vacuo to give a white solid which was crystallized twice from ethyl acetate to give 0.315 g of the title carboxylic acid, m.p. 198-201 ° (decomposes), = + 189 ° (c = 0.71).

Example XLII

9α-fluoro-1 H -C-hydroxy-1 H -methyl-3,11-dioxandros-25α-1,4-diene-17,3-carbothioic acid (XLII)

A stirred solution of 5.587 g of compound XL in 150 ml of dry N, N-dimethylformamide at 20 ° and under nitrogen was treated with 4.847 g of N, N-1-carbonyldiimidazole and the reaction mixture was stirred for 4 hours at 20 °. .

Hydrogen sulfide gas was bubbled through the reaction mixture for 10 minutes and the solution was stirred for another hour. The solution was poured into 300 ml of ice and 100 ml of 2N hydrochloric acid to give a yellow-brown precipitate. This was isolated by filtration, air dried overnight to give 6.268 g, which was crystallized from ethyl acetate to give 3.761 g of the title carbothioic acid as white prisms, m.p. 215-218 °, = + 143 ° (c = 0.88, dimethylformamide).

70904 28

Example XLIII

S-chloromethyl-9 ° C-fluoro-11,3,170fc-dihydroxy-16,3-methyl-3-oxandandrost-1,4-diene-1H-carbothioate (XLIII)

A stirred solution of 0.169 g of compound 5 XLI and 0.040 g of sodium hydrogen carbonate in 6 ml of N, N-dimethylformamide was treated with 0.1 ml of bromochloromethane and stirring was continued for one hour at 22 °. The reaction mixture was diluted with 100 ml of ethyl acetate. The solution was washed successively with 2N hydrochloric acid, water, 2N sodium carbonate solution, water and saturated sodium chloride solution, dried and the solvent was evaporated in vacuo. The residue was crystallized twice from ethyl acetate to give 0.193 g of the title compound S-chloromethylthioester as white plates and solvated with one mole of ethyl acetate, m.p. 126-130 °, / 0ζ / ο = + 147.5 ° (c = 0.64).

Example XLIV

9 O-fluoro-16,3-methyl-3,11-dioxo-17β-propionyloxyandrosta-1,4-diene-1H-carbothioic acid (XLIV)

A stirred solution of 0.485 g of XLV 20 and 0.57 ml of triethylamine in dichloromethane was cooled in ice-salt mixture, treated with 0.43 ml of propionyl chloride and the reaction mixture was stirred for 1.5 hours at 0 °. The mixture was partitioned between 75 ml of ethyl acetate and 75 ml of 2N sodium carbonate solution, the organic layer was washed with a new amount of 2N sodium carbonate solution, water, 2N hydrochloric acid, water and saturated sodium chloride solution 0.5 g, dried, the solvent removed, the solvent removed yellow, crystalline solid. This was dissolved in 10 ml of acetone, 30 μl of diethylamine was added and the reaction mixture was stirred for 1.25 hours at 22 °. The solvents were removed in vacuo and the residue was partitioned between 30 ml of ethyl acetate and 30 ml of 2N hydrochloric acid. The ethyl acetate layer was washed with water and extracted with 2 x 30 mL of 2N sodium carbonate solution. The combined extracts were washed with 30 ml of ethyl acetate, covered with 60 ml of ethyl acetate and oxidized to pH 1.0 with hydrochloric acid. The ethyl acetate layer was washed with water and brine, dried, the solvent 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.

5 173-180 ° C, / mp = + 148 ° (c = 1.03).

Example XLV

S-chloromethyl-90β-fluoro-17α-hydroxy-16β-methyl-3,11-dioxandrosta-1,4-diene-1,3-carbothioate (XLV)

A solution of 5.006 g of XL1I and 1.612 g of sodium bicarbonate in 50 ml of N, N-dimethylacetamide was treated with 1.24 ml of bromochloromethane and the reaction mixture was stirred for 3.3 hours at 22 °. The solution was diluted with 70 ml of ethyl acetate, washed successively with 2N hydrochloric acid, water, sodium metabisulfite solution, water and saturated sodium chloride solution, dried, the solvent removed in vacuo to give 3.638 g of a cream solid. An analytical sample was obtained by preparative TLC (silica gel, developed with a 9: 1 mixture of chloroform and acetone), crystallized from ethyl acetate to give 0.262 g of the title ester as colorless prisms, m.p. 223-228 °, δ Ec7q = + 251 ° (c = 1.2).

Example XLVI

9 A-Fluoro-11β-hydroxy-16β-methyl-3-oxy-17β-propionyloxyandrosta-1,4-diene-β-carbothioic acid (XLVI)

A stirred solution of 0.511 g of XLI

In 20 ml of dichloromethane with 0.6 ml of triethylamine was cooled to 2 °, treated with 0.45 ml of propionyl chloride and the reaction mixture was stirred for 2.5 hours at 2 °. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen carbonate solution, the organic phase was washed with water, 2N hydrochloric acid, water and saturated sodium chloride solution, dried, 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 for 55 minutes at 22 °. The reaction mixture was diluted with 50 ml of ethyl acetate, washed with 2N hydrochloric acid and water and extracted with 5% sodium carbonate solution. The combined extracts were acidified to pH 1 with 2N hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried, the solvent removed to give 0.522 g of a colorless foam which was crystallized from ethyl acetate to give 0.397 g of the title ester as colorless prisms, m.p. 174-179 °, f (K 7 O = + 107 ° (c = 1.0)).

Example XLVII

109 ct-fluoro-11 / 5,17β-dihydroxy-16-methylene-3-oxyandrosta-1,4-diene-17/5-carbothioic acid (XLVII)

A solution of 0.218 g of 9CC-fluoro-11β, 17 ° C-dihydroxy-16-methylene-3-oxandandrost-1,4-diene-1,3'-carboxylic acid in 10 ml of dry N , N-di-15-methylformamide, was treated with 0.254 g of N, N1-carbonyl-diimidazole and the reaction mixture was stirred for four hours at 22 °. Hydrogen sulfide gas was bubbled into the reaction mixture for five minutes and now the light green mixture was stirred for one hour at 22 °. The mixture was diluted with 150 ml of ethyl acetate-20, the solution was washed with 2N hydrochloric acid, water and saturated sodium chloride solution, dried, the solvent removed in vacuo to give 0.222 g of a yellow foam which was crystallized twice from ethyl acetate to give 0.078 g of at about 250 ° without melting, = + 117 ° (c = 0.32).

Example XLVIII

9ot-fluoro-11,17,17-dihydroxy-3-oxandrosta-1,4-diene-17/3 carboxylic acid (XLVIII)

A suspension of 10 g of 90t-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 for two hours at 22 °. It was then poured into about 400 ml of ice-water and after stirring for 15 minutes, the solid product was isolated, washed with water, dried to give 9.42 g of the title acid as a solid. The m.p. portion recrystallized from ethanol m.p. 289-293 °, ε (xjp = + 66 ° (c = 0.73, methanol)).

31 70904

Example XLIX

6ct, 9ct-difluoro-11β, 17β-dihydroxy-16β-methyl-3-oxyanocrosta-1,4-diene-1,3-carbothioic acid (XLIX)

A solution of 12.0 g of 6Ct, 90t-dirluoro-1] [3,170C-5 dihydroxy-160E-methyl-3-oxandrosta-1,4-diene-17β-carboxylic acid in 250 ml of dry dimethylformamide, stirred under nitrogen and at room temperature and treated with 9.94 g of N, N'-carbonyldiimidazole. After four hours, hydrogen sulphide was passed through the solution during the 10-hour half and the mixture was stirred for another half hour. The reaction mixture was poured into 500 ml of 2N hydrochloric acid with about 250 g of ice. The precipitate formed was isolated, washed with water, dried in vacuo to give 11.47 g of the title thioic acid as a white solid, m.p. 230-232 °, 15 DEG = + 94 DEG (c = 0.91).

Example L

17β-acetoxy-6β, 9α-difluoro-1 H -hydroxy-16β-methyl-3-oxanandrosta-1,4-diene-11β-carbothioic acid (L)

A solution of 1.625 g of XLIX and 2.0 ml of triethylamine in 75 ml of dichloromethane was stirred at about 0 °, treated dropwise with 1.275 ml of acetyl chloride and then stirred at this temperature for 1.25 hours. The mixture was washed with 50 ml of 2N sodium carbonate solution, water, 50 ml of 2N hydrochloric acid, 3 x 50 ml of hydrogen and 50 ml of brine, dried, evaporated to give 1.91 g of a white solid. . This was dissolved in 40 ml of acetone and stirred with 4 ml of diethylamine for 45 minutes at 27 °. The mixture was concentrated to ca.

To 25 ml and poured into 100 ml of 2N hydrochloric acid containing about 100 g of ice. After stirring, the precipitate formed was isolated, washed with water, dried to give 1.685 g of a solid. From this, a 400 mg portion was recrystallized from ethyl acetate to give 280 mg of the title compound 170f-acetate, m.p. 175-177 °.

70904 32

Example LI

17C-t-butyryloxy-6β, 9ef-difluoro-1H-hydroxy-16α-methyl-3-oxanedrosta-1,4-diene-1H-carbothioic acid (LI) Using a method similar to that described in Preparation L, , 2.0 g of XLIX was converted with 2.8 ml of butyryl chloride from acetyl chloride to 2.8 g of the title compound 170C-butyrate. Part of this was recrystallized from ethyl acetate and m.p. was 155-157 °.

Example LII

10a, 9a-Difluoro-1β-hydroxy-160t-methyl-3-oxy-17α-propionyloxyandrosta-1,4-diene-17β-carbothioic acid (LII)

A solution of 5.0 g of XLIX and 6.15 ml of triethylamine in 140 ml of dichloromethane was cooled in an ice-salt mixture and treated dropwise with 4.74 ml of propionyl chloride. The reaction mixture was stirred for a further 0.75 hours at about 0 ° and then washed successively with 2N sodium carbonate solution, 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 was added. After stirring for one hour at room temperature, the volume was reduced to about 75 ml. The solution was poured into 200 ml of 2N hydrochloric acid containing n.

300 g of ice, the precipitate formed was isolated, washed with water, dried in vacuo to give 5.17 g of a white solid, m.p. 152-155 °. Recrystallization from a 400 mg portion of ethyl acetate gave 290 mg of analytically pure title compound 17C-propionate as colorless crystals, m.p. 161-164 °, 2® <7d = -27 ° (c = 0.95), the crystalline form of which according to the solid state IR spectrum (in nujol) was different from that of the sample obtained in Example XIX.

Example LIU

S-chloromethyl-90t-fluoro-16β-methyl-3,11-dioxo-17α-propionyloxy.androsta-1,4-diene-17β-carbothioate 35 (LIU)

A solution of 409 mg of XLV in 5 ml of propionic acid, 2 ml of trifluoroacetic anhydride and 0.1 ml of a solution of 33 70904 p-toluenesulfonic acid in dry chloroform (80 mg / ml) was stirred for 2.75 days at 22 °. The non-acidic product was isolated by extraction with ethyl acetate-saturated sodium hydrogen carbonate solution after pouring. The crude material 5 was chromatographed on silica in chloroform-acetone (14: 1) and crystallized from a mixture of ethyl acetate and petroleum ether (b.p. 60-80 °) to give the title compound 17α-propionate as colorless crystals, m.p. 205-206 °, species λ = + 95 ° (c = 1.15).

10 Example LIV

S-chloromethyl-9β-fluoro-11β-5,17β-dihydroxy-16β-methyl-3-oxandrosta-1,4-diene-1H-carbothioate (LIV)

A suspension of 102 mg of XLV in 2.5 ml of ethanol was stirred with 10 mg of sodium borohydride for 15 hours at 22 °. The reaction mixture was treated with 5 mL of acetone and concentrated to near dryness. The residue was dissolved in 25 ml of ethyl acetate and washed with 1N hydrochloric acid, water and brine. After drying, the organic solvent was removed to give 103 mg of the title compound -20-alcohol as a colorless foam, the only major component of which was monopolar by TLC comparison with an authentic sample (silica, chloroform-acetone, 9: 1).

Example LV

S-chloromethyl-60t, 90C-difluoro-16β-methyl-3-oxy-17β-propionyloxy-13,3-trifluoroacetoxyandrosta-1,4-diene-17/3-carbothioate (LV)

A solution of 100 mg of the compound of Example 5 (described below) in 2 ml of dry tetrahydrofuran and 0.1 ml of pyridine was treated with 0.05 ml of trifluoroacetane-hydride and the mixture was allowed to stand at room temperature for half an hour. 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, evaporated to give 116 mg of homogeneous title trifluoroacetate by HNMR spectroscopy 35 (singlet 8.59 X, 19-protons, in deuteriochloroform) and by TLC on silica (acetone and petroleum ether, b.p. 40-60). °, 1: 3 mixture). An analytical sample of ether pentane 70904 m.p. 158-162 °, λ max = + 56 ° (c = 0.23).

Manufacture of finished products

Example 1 S-Chloromethyl-9β-fluoro-11β-hydroxy-16β-methyl-5,3-oxy-17β-propionyloxandrosta-1,4-diene-17β-carbothioate

Method A

A solution of 2.115 g of compound I in 7 ml of dimethylacetamide was treated with 2 x 2 mg of sodium hydrogen carbonate and 0.46 ml of bromochloromethane and the mixture was stirred at room temperature. After 2 hours, the reaction mixture was diluted with 500 mL of ethyl acetate and washed with 5% sodium bicarbonate solution and water, dried, evaporated to give 1.560 g of an orange-15 blue foam. PLC in chloroform-acetone (19: 1) gave 803 mg of an off-white foam which was crystallized from two methanol to give 668 mg of the title compound S-chloromethyl ester as off-white needles, m.p. 212-214 °, / CC 7 O = + 44 ° (c = 1.06).

20 Method B

The title compound was prepared in a similar manner using chloroiodomethane instead of bromochloromethane.

Method C

19 mg of sodium borohydride was added to a solution of 230 mg of compound II in 3.5 ml of ethanol, and the solution was stirred at room temperature. After 20 minutes, 1 mL of acetone was added and the solution was concentrated to about a quarter of its original volume. 30 ml of ethyl acetate were then added, the solution was washed with 1N hydrochloric acid and water, dried, evaporated to give 239 mg of a white foam. PLC in chloroform-acetone (19: 1) gave 188 mg of a white foam which was crystallized twice from methanol to give 158 mg of the title compound S-chloromethyl ester as white needles, m.p. 210-212 °, = + 44 ° 35 (c = 1.07).

35 70904

Example 2 S-Chloromethyl-90L-fluoro-1H-hydroxy-16β-methyl-3-oxy-17β-propionyloxandrosta-1,4-diene-1H-carbothioate 5 A solution of 0.927 g of the compound IV In 4 ml of dimethylacetamide, 0.256 g of sodium hydrogen carbonate and 0.20 ml of bromochloromethane were treated and the mixture was stirred for two hours at 22 °. The reaction mixture was partitioned between 100 ml of ethyl acetate and 20 ml of 2N chloro-10 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 hydrogencarbonate solution, water and saturated brine. After drying, the solvent was removed to give 757 mg of crude product, which was crystallized twice from acetone to give 0.367 mg of the title chloromethylthiol ester, m.p. 247-250 °, / fit = + 50.5 ° (c = 0.63).

Example 3

The title compound was prepared in a similar manner using Preparation XIV, m.p. 117-120 °, 1 H = + 56 ° (c - 1.3).

Example 4 S-Chloromethyl 6 - [?, 90? -Difluoro-11β-hydroxy-16β, 17β-isopropylidenedioxy-3-oxanandrosta-1,4-diene-1 ', β-carbothioate 25 a solution of 1.360 g of compound VIII in 10 ml of Ν, Ν-dimethylacetamide was treated with 0.377 g of sodium hydrogen carbonate and 0.3 ml of bromochloromethane and stirring was continued for 1.5 hours. 100 ml of ethyl acetate were added, and the resulting solution was washed successively with 2N hydrochloric acid, water, sodium metabisulfite solution, water, sodium bicarbonate solution, water and saturated sodium chloride solution, dried, and the solution was concentrated and concentrated. 0.765 g of crystalline product was obtained, which was purified by PLC on silica gel, eluting with chloroform-acetone (9: 1). The main zone was eluted with ethyl acetate, crystallized from ethyl acetate to give 0.475 g of the title compound S-chloro-36 7C904 methylthioester as white prisms, m.p. 271-278 °, [α] D = + 116 ° (c = 0.96, dimethyl sulfoxide).

Example 5 S-Chloromethyl-60?, 9? -Difluoro-1 H -hydroxy-16α-methyl-5H-3-oxy-1706-propionyloxandrosta-1,4-diene-17β-carbothioate

A solution of 0.546 g of compound XVIII in 3 ml of dimethylacetamide was treated for three hours at 22 ° with 202 mg of sodium hydrogen carbonate and 0.16 ml of bromo-10 chloromethane. The mixture was treated with 50 ml of 2N hydrochloric acid and the product was extracted with ethyl acetate. The extracts were combined, washed successively with 2N hydrochloric acid, water and saturated brine, dried and the solvent removed. Crystallization twice from ethyl acetate gave 0.404 g of the title chloromethylthiol ester, m.p. 272-275 °, δ = + 49 ° (c = 0.35).

Examples 6-15

Following the general procedure of Example 1 (Method A), but starting from the desired 1β-carbothioic acid corresponding to the desired 17β-carbothioate (method details in Table III below), the following compounds were prepared: 6. S-chloromethyl-11β-hydroxy-16 / 3- methyl 3-oxy-170β-propionyloxandrosta-1,4-diene-17β-carbothioate, m.p. 192-193 °, = + 65 ° (c = 1.05).

7. S-chloromethyl-9 (Xf fluoro-11-N-hydroxy-16-methylene-3-oxy-170C-propionyloxandrosta-1,4-diene-1H-carbothioate, m.p. 212-221 °, -q ~ "56 ° (c = 0.99).

8. S-chloromethyl-17β-acetoxy-9Q6-fluoro-11β-hydroxy-1H-methyl-3-oxandandrost-1,4-diene-17β-carbothioate, 30 M.p. 220-223 °, mp = + 39.5 ° (c = 1.06).

9. S-chloromethyl-17β-butyryloxy-90β-fluoro-11β-hydroxy-16,5-methyl-3-oxandandrost-1,4-diene-1H-carbothioate, m.p. 172-175 °, q = + 46 ° (c = 1.10).

10. S-chloromethyl-906-fluoro-11β-hydroxy-170β-iso-35-butyryloxy-1H-methyl-3-oxandrosta-1,4-diene-17/5-carbothioate, m.p. 234-239 °, ε pQD = + 43 ° (c = 1.00).

37 70904 11. S-chloromethyl-9β-fluoro-11β-hydroxy-3-oxy-17Cl-propionyloxandrosta-1,4-diene-17β-carbothioate, m.p. 196-199 °, = + 38 ° (c = 0.97).

12. S-chloromethyl-60β-fluoro-11β-hydroxy-3-oxy-5,17β-propionyloxandrosta-1,4-diene-17β-carbothioate, m.p. 188-191 °, + 0 ° = + 48 ° (c = 0.91).

13. S-chloromethyl-170C-acetoxy-60C, 9β-difluoro-11β-hydroxy-16β-methyl-3-oxandrosta-1,4-diene-17β-carbothioate, m.p. 280-283 °, Jpf = + 45 ° (c = 0.80).

14. S-chloromethyl-170t-butyryloxy-60C, 9Ct-difluoro-1] [5-hydroxy-16β-methyl-3-oxandrosta-1,4-diene-17β-carbothioate, m.p. 235-238, δ 7D = + 49 ° (c = 0.65).

15. S-chloromethyl-9β-fluoro-1H-hydroxy-16β, 17β-isopropylidenedioxy-3-oxandandrost-1,4-diene-17β-carbo-15-thioate, m.p. 276-280 ° (decomposes), [α] 25 D = + 127 ° (c = 0.51, dimethyl sulfoxide).

70904 38

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XX

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Example 16 S-Chloromethyl-9β-chloro-11β-hydroxy-16/5-methyl-10β-oxy-17β-propionyloxandrosta-1,4-diene-17/5-carbonothioate and S-chloromethyl-9β / 5,11 / V * Epoxy-16,3-methyl-3-oxy-17β-propionyloxandrosta-1,4-diene-17β-carbothioate

A solution of 1.032 g of mixture XXII in 5 ml of di-15-methylacetamide was treated with 0.203 g of sodium bicarbonate and then 0.2 ml of bromochloromethane and the reaction mixture was stirred for 1.5 hours at 22 °. It was then partitioned between 50 ml of ethyl acetate and 35 ml of 2N hydrochloric acid. The aqueous phase was extracted with a further 20 x 30 ml of ethyl acetate, the combined extracts were washed with 2N hydrochloric acid, water, saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried, the solvent removed in vacuo to give 0.856 g of a cream color, which form 25 was formed from a mixture of the title S-chloromethyl esters. This was separated by PLC on silica to give a 19: 1 mixture of chloroform and acetone. 0.306 g of a more polar component was obtained, which was crystallized twice from ethyl acetate to give 0.232 g of S-chloromethyl-9 ° C-chloro-1 H -hydro-30-oxy-16 H -methyl-3-oxy-170C-propionyloxandrosta-1,4 -diene-17β-carbothioate as white plates, m.p. 222-229 ° / & D = + 70 ° (c = 1.23).

The more non-polar component weighing 0.210 g was crystallized from acetone-petroleum ether to give 0.065 g of 35 S-chloromethyl-9H, 11β-repoxy-1H-methyl-3-oxy-17β-propionyloxyandrosta-1,4-diene. 17 & carbothioate, m.p.

169-173 °, ^ 7d = + 49 ° (c = 0.60).

70904 40

Example 17 Sf fluoroethyl 90C-fluoro-11β-hydroxy-16β-methyl-3-oxy-17β-propionyloxandrosta-1,4-diene-17β-carbonothioate 5 Stirred at room temperature in the dark 660 mg of compound XXIII and a suspension of 1.421 g of silver fluoride in 8.5 ml of acetonitrile. After 72 hours, the reaction mixture was diluted with 200 mL of ethyl acetate and filtered through a pad of diatomaceous earth. The filtrate was washed with water, dried, evaporated to give 517 mg of a white foam. PLC in a 19: 1 mixture of chloroform and cyclohexane and chloroform gave 270 mg of an off-white foam which was crystallized from methanol and then methanol-diethyl ether to give 176 mg of the title compound 15 S-fluoromethyl ester, m.p. 241-242 °, fixation + 97.5 ° (c = 0.98).

Example 18 S-fluoromethyl-90t-fluoro-11H-hydroxy-1 H -methyl-S-oxy-N, N-propionyloxandrosta-1,4-diene-17β-carbo-20-thioate

A solution of 0.640 g of XXVIII in 8 ml of acetonitrile was treated with 1.511 g of dry silver fluoride and stirred for 46.5 hours in the dark at 22 °. The mixture was diluted with 200 mL of ethyl acetate and filtered through silica. The solution was washed with 2-hydrochloric acid, water and saturated sodium chloride solution, the solvent removed in vacuo to give 0.504 g of a pale yellow foam.

This was chromatographed on PLC on silica gel eluting with 5% acetone in chloroform. The main zone was eluted with ethyl acetate, crystallized twice from acetone to give 0.244 g of the title fluoromethylthioester, m.p. 242-243 ° (decomposes), fotJO = + 37 ° (c = 0.75).

70904 41

Example 19 Sf Fluoromethyl-6?, 90 C-difluoro-11β-hydroxy-16 ° C-methyl-170 C-propionyloxy-3-oxandandrost-1,4-diene-17/3-carbothioate 5 Solution containing 310 mg of compound XXIX in 10 ml of acetonitrile, and 947 mg of silver fluoride were stirred for three days at room temperature in the dark. 100 ml of ethyl acetate were added and the mixture was filtered through diatomaceous earth. The filtrate was washed successively with 2N hydrochloric acid, water and saturated brine, and dried. The solvent was removed and the residue was subjected to PLC first in chloroform and then in a 19: 1 mixture of chloroform and acetone. The product was eluted with ethyl acetate and crystallized by concentrating the solution. 0.075 g of the title fluoromethylthiol ester, 15 m.p. 272-273 ° (dec.), Species ^ = + 30 ° (c = 0.35).

Example 20 Sf fluoroethyl 6α, 90α-difluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-3-oxanedrosta-1,4-diene-17/3 -carbothioate 20 A solution of 0.804 g compound XXXVI in 60 ml of acetonitrile, treated with 1.821 g of silver fluoride and the reaction mixture was stirred for 18 hours in the dark. The reaction mixture was diluted with ethyl acetate and filtered through diatomaceous earth. The filtrate was washed with water and brine, dried, the solvent removed in vacuo to give 0.636 g of a light cream solid. This was purified by PLC on silica gel eluting twice with a 14: 1 mixture of chloroform and acetone. The main zone was eluted with ethyl acetate and crystallized five times from ethyl acetate. 0.118 g of the title S-fluoromethylthio ester was obtained as white prisms, m.p. 305-311 °, = + 125 ° (c = 0.73, dimethyl sulfoxide).

Examples 21-29

Following the general procedure of Example 17, but starting from S-iodomethyl-N-carbothioate corresponding to the desired product (method details in Table IV below), the following compounds were prepared: 42 7 0 9 0 4 21. S-fluoromethyl-17β-acetoxy-90C- fluoro-11β-hydroxy-1H-methyl-3-oxandrosta-1,4-diene-17β-carbothioate, m.p. 248-249 °, / 2 (7D = + 101 ° (c = 1.08).

22. S-fluoromethyl-11β-hydroxy-3-oxy-17α-propio-5-yloxyandrosta-1,4-diene-17/5-carbothioate, m.p. 112-117 °, / VD = + 67 ° (° = ° '76) · 23. S-fluoromethyl-11β-hydroxy-16β-methyl-3-oxy-17β-propionyloxandrosta-1,4-diene -17β-carbothioate, m.p. 223-225 °, α D = + 116 ° (c = 0.38).

24. S-fluoromethyl-9β-chloro-11β-hydroxy-16β-methyl-3-oxy-17β-propionyloxandrosta-1,4-diene-1H-carbothioate, m.p. 182-193 °, / St7D = + 116 ° (c = 0.75).

25. S-fluoromethyl-9et-fluoro-11β-hydroxy-16-methylene-3-oxy-170β-propionyloxandrosta-1,4-diene-17β-carbothioate, m.p. 205-215 °, λ max -58 ° (c = 1.00).

26. S-fluoromethyl-9 <X-fluoro-11β-hydroxy-3-oxy-17β-propionyloxandandrost-1,4-diene-17β-carbothioate, m.p. 207-211 °, fic 10 = + 70 ° (c = 0.88).

27. S-fluoromethyl-6C6 * fluoro-11β-hydroxy-3-oxy-170C-propionyloxyandrosta-1,4-diene-1H-carbothioate, m.p. 224-225 °, ε <+ = 70 ° (c = 0.79).

28. S-fluoromethyl-170C-acetoxy-6et, 9C-difluoro-11β-hydroxy-16A-methyl-3-oxandandrost-1,4-diene-17β-carbothioate, m.p. 308-310 °, 2 & / D = + 29 ° (c = 0.80).

29. S-fluoromethyl-170C-butyryloxy-6β, 9et-difluoro-13/5-hydroxy-160t-methyl-3-oxandrosta-1,4-diene-1,3-carbothioate, m.p. 249-252 °, - + 32 ° (c = 1.05).

70904 43

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Example 30 S-Bromomethyl-9β-fluoro-11β-hydroxy-16/5-methyl-3-oxy-170β-propionyloxandrosta-1,4-diene-17/3 - carbothioate 5 A solution of 660 mg of compound XXIII in 20 ml of acetone was stirred with 972 mg of lithium bromide for five days at room temperature. The reaction mixture was diluted with 150 ml of ethyl acetate, washed successively with 10% sodium thiosulfate solution, water and brine, dried, evaporated to give 624 mg of an off-white foam. This was crystallized twice from acetone and petroleum ether, b.p. 40-60 °, to give 499 mg of the title compound S-bromomethyl ester, m.p. 186.5 - 187 °, / bcJO = + 2 ° (c = 0.99).

Example 31 S-2 1-Fluoroethyl-906-fluoro-11β-hydroxy-16β-methyl-3-oxy-17β-propionyloxandrosta-1,4-diene-17β-carboxylate botioaatti

A solution of 910 mg of XXXVII 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 further diluted with 150 ml of ethyl acetate, washed with water, dried, evaporated to give 704 mg of a white foam. PLC in a 9: 1 mixture of chloroform and acetone gave 431 mg of the more non-polar product as a yellow foam which was crystallized twice from methanol to give 254 mg of the title compound S-2'-fluoroethyl ester, m.p. 133-134 °, δς70 - + 104.5 ° 30 (c = 0.98).

Example 32 S-Chloromethyl-9H-fluoro-11β-hydroxy-16-methylene-3-oxy-17β-propionyloxandrosta-1,4-diene-17,3-carbothioate

35 A suspension of 227 mg of XXXIX

In 2.2 ml of propionic acid and 0.7 ml of trifluoroacetic anhydride, was treated with 0.044 ml of a dry solution of toluene-p-sulfonic acid (70 = 90 mg / ml) and stirred for six hours at room temperature and then for 16.5 hours. hours at 3 °. The reaction mixture was diluted with 75 ml of 5% sodium hydrogen carbonate solution and extracted with ethyl acetate.

The combined extracts were washed with water and brine, dried, evaporated to give 254 mg of a brown resin. This was performed by PLC in chloroform-acetone (19: 1) (three runs). The main zone (152 mg) was crystallized twice from ethanol to give 30 mg of the title compound S-chloro-10 rimethyl ester 17β-propionate as white crystals, which had an impurity according to 1 H-NMR spectroscopy of S-chloromethyl-9Ct-fluoro-170Chydroxy. -methylene-3-oxy-1 H -propionyloxyandrosta-1,4-diene-17/3-carbothioate.

Example 33 S-Chloromethyl-9α-fluoro-11β-hydroxy-16β-methyl-3-oxy-170β-propionyloxandrost-4-ene-17β-carbothioate

Catalytically reducing 0.646 g of the compound of Example 1 over 800 mg of tris (triphenylphosphine) chlorodium (I) in 100 ml of benzene over 21.5 hours, chromatographing on silica in chloroform-acetone (9: 1) and crystallizing twice from acetone, 0.142 g of the title chloromethylthiol ester was obtained as white needles, m.p. 217-225 °, = + 54 ° (c = 0.83).

Example 34 25 S-Fluoromethyl-11β-hydroxy-16,3-methyl-3-oxy-17β-propionyloxanddrost-4-ene-17β-carbothioate

Similarly catalytic reduction of the compound of Example 23 gave 0.106 g of the title compound Δ-3-ketone, m.p. 174-177 °, mp = + 123 ° (c = 0.55).

Example 35 S-Chloromethyl-9β-fluoro-11β-hydroxy-16β-methyl-3-oxy-17β-propionyloxandrosta-1,4-diene-17β-carbothioate Treated with about 0 .9 mg of the S-chloromethyl-35 9/3,11β-epoxy-16β-methyl-3-oxy-170β-propionyloxandrosta-1,4-diene-β-carbothioate of Example 16 in about 1 ml. hydrogen fluoride-urea complex and stirred for a total of 24 hours at room temperature. The mixture was treated with sodium hydrogen carbonate and the product was extracted twice with ethyl acetate. The extracts were washed twice with water, dried and evaporated.

TLC on silica using three different solvent systems (acetone-petroleum ether, b.p. 40-60 °, 1: 2; chloroform-acetone, b.p. 40: 60 °); ethyl acetate-petroleum ether, b.p. 40-60 ° , 1: 2, two runs) and compared to the authentic sample, the product formed was found to be the title cofluorohydrin.

Example 36 S-Chloromethyl-6α, 9α-difluoro-11,6-hydroxy-160 D-methyl-3-oxy-17β-propionyloxandrosta-1,4-diene-17β-carbothioate

A solution of 29 mg of LV in 2 ml of methanol was allowed to stand for three hours at room temperature. The mixture was evaporated to dryness to give 25 mg of the title compound 11 / alcohol, which was identified by comparing the 1 HNMR spectra (in deuteriodimethyl sulfoxide) and TLC properties of the authentic sample (silica, acetone-20 petroleum ether, b.p. 40-60 °). 1: 3).

The active androstane compounds are preferably formulated in the usual manner into preparations suitable for topical administration with a medium suitable for topical administration. In this connection, topical administration methods 25 also include inhalation and inhalation.

The topical formulations described above may be used in the treatment of human and animal skin diseases, such as rashes, which normally respond to corticosteroid therapy, as well as in the treatment of conditions that are less responsive to medication, e.g. psoriasis in humans.

When administered internally, the novel compounds of the invention may be formulated in the usual manner, e.g. orally, for parenteral or rectal administration.

Claims (10)

A process for the preparation of therapeutically useful 11S, 17 'C-dihydroxy-3-oxo-androst-4-ene-17β-thiocarboxylates of form in COSk H ° \ 3 10 mh where R is a fluoro, chloro or bromomethyl group or a 2'-266 fluoroethyl group, R is a group COR where R is a C 1-3 alkyl group, and R "is a hydrogen atom, a c R ^ is a hydrogen, chlorine or fluorine atom, R ^ is a hydrogen or fluorine atom, and the symbol is a R ^ is a hydrogen, chlorine or fluorine atom, and R är is a hydrogen or fluorine atom. single or double bond, characterized in that a) a compound of formula I which has a 17 / O-thiocarboxyl group or a functionally equivalent group, or a free 176 hydroxy group, in which case R is hydrogen, methyl or methylene, wherein, if desired, all of the other reactive groups are in protected form, esterified with an esterifying agent corresponding to the group R or R, or b) a compound of formula I having a 17, < 3-substituent of the formula -COS (CHO) Y, where Y is a substituent which can be replaced by n , where n is 1, and with a fluorine atom, where 2 is, or c) a compound of formula I with an 11-oxo group is reduced to 11β-hydroxyandrostane of formula I, or d) the protecting group is removed from a e) a compound of formula I having a 9,11 epoxy group is reacted with hydrofluorocarbon or hydrochloride to give a compound of formula I, where R4 is fluorine or chlorine, or f) a compound of formula I, which is a double bond, is partially reduced to give a compound of formula I, where τ is a single bond. Process according to claim 1, characterized in that a compound of formula I having a free 17/3 thiocarboxylic acid group or a functionally equivalent group is esterified by reacting it with a dihaloalkylating agent of formula R "Hal, where Hai is a halo genome, which can be replaced. 3. A process according to claim 1, characterized in that a compound of formula I having a free 17% hydroxy group is esterified by reacting it with an anhydride or an acid chloride. 4. A process according to claim 1, characterized in that, as a starting material, a compound of formula I is used which has a 17/3 substituent of formula - where Y is a halogen atom which can be replaced. 5. A process according to claim 1, characterized in that the reduction is carried out with an alkali metal or alkaline earth metal borohydride. 6. A process according to claim 1, characterized in that, as a starting material, a compound of formula I is used which has an 11/3 tri-C 1-6 alkylsilyloxy group or a 11/1 perfluoro or chloroalkanoyloxy group . 7. A process according to claim 1, characterized in that the removal of the protecting group is carried out by hydrolysis. 8. A process according to claim 1, characterized in that the partial reduction is carried out using tris (triphenylphosphine) chlorrodium as catalyst. 9. A process according to claim 1, characterized in that a compound of formula I, 17 is prepared wherein R is chloromethyl, R is propionyloxy, R is a methyl group, R and R are fluorine and the symbol is a double bond.