FR2477156A1 - ANDROSTANE CARBOTHIOATES, THEIR PREPARATION PROCESS, COMPOUNDS FOR THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION - Google Patents

Abstract

Compounds of the formula 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

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

Anti-inflammatory steroids are, for the most part, of the corticosteroid type, that is to say that they are derivatives of the pregnant woman. British Patents Nos. 1,384,372, 1,438,940 and 1,514,476 by the Applicant describe esters of certain androstane-17P-carboxylic acids which exert anti-inflammatory activity. European patent application N 79 300 500.0 (publication number Q004741) describes esters of androstane-17ss-carbothiols which also have anti-inflammatory activity. The Applicant has now discovered that certain androstane compounds containing a haloalkylcarbothioate group in position 17p exhibited particularly advantageous anti-inflammatory properties, as will be described in more detail later in this specification.

dans laquelle R1 représente un groupe fluoro-, chloroou bromo-méthyle ou un groupe 2'-fluoréthyle, R2 repré- * sente un groupe COR6 où R6 représente un radical alkyle en C1 -C3, ou bien oR2 et R3 forment ensemble un groupe 16&alpha;, 17&alpha;-isopropylidènedioxy; R3 représente un atome d'hydrogène, un radical méthyle (qui peut se trouver en configuration &alpha;; ou en configuration ss) ou un radical méthylène, R4 représente un atome d'hydrogène, un atome de chlore ou de fluor, R5 représente un atome d'hydrogène ou un atome de fluor et le symbole # représente une liaison simple ou double.The new isandrostane compounds according to the present invention can be represented by the following general structural formula

in which R1 represents a fluoro-, chloro or bromo-methyl group or a 2'-fluorethyl group, R2 represents a COR6 group where R6 represents a C1 -C3 alkyl radical, or alternatively oR2 and R3 together form a 16 & alpha group ;, 17 &alpha;-isopropylidenedioxy; R3 represents a hydrogen atom, a methyl radical (which can be in the &alpha;; configuration or in the ss configuration) or a methylene radical, R4 represents a hydrogen atom, a chlorine or fluorine atom, R5 represents a hydrogen atom or fluorine atom and the symbol # represents a single or double bond.

The new compounds of formula (I) possess good anti-inflammatory activity, in particular by topical application, as could be judged during the performance of the McKenzie plaster test.
in humans and as measured by the reduction in croton oil-induced edema when the compounds are applied topically to the skin of mice and rats.

Some of the compounds show good topical anti-inflammatory activity in the croton oil ear test, associated with minimal hypothalamic-pituitary-adrenal-suppressive activity after topical application in the same species of animals.

These results indicate that such compounds are of great value for the local treatment of inflammation in humans and animals with minimal possibility of causing unwanted systemic side effects.

Preferred compounds of formula (I) due to their excellent anti-inflammatory activity include substances belonging to the following categories, more specifically (a) those in which
R1 represents a chloro- or fluoromethyl group, (b) those in which R1 represents an acetyl or propionyl group, preferably propionyl, (c) those in which R4 represents a fluorine atom, (d) those in which R5 represents an atom of fluorine, (e) 1,4-dienes and (f) 1,4-dienes in which R4 represents a fluorine atom and R3 represents a hydrogen atom, a methylene or methyl group in the a or ss configuration.

Compounds of formula (I) which exert good anti-inflammatory activity associated with minimal hypothalamic-pituitary-adrenal-suppressive effect when applied topically include 1,4-dienes in which R1 represents a chloro or fluoro-methyl group, R4 and R5 represent fluorine atoms and, more particularly, those in which R3 represents an α-methyl group.

Compounds according to the present invention which are very particularly preferred on account of their perfect topical anti-inflammatory activity and the favorable ratio of their topical anti-inflammatory activity to their undesirable systemic activity, include the following substances:
S-chloromthyl 9 -f luoro-llss-hydroxy-16a-methyl-3-oxo-17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-
carbothioate;
S-chloromethyl 9 &alpha; -fluoro-11ss-hydroxy-16- methyline-3-oxo-17a-propionyloxyandrosta-1,4-ditne-17ss-
carbothioate;
S-fluoromethyl 6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha;, 1? A-isopropylidenedioxy-3-oxoandrosta-1,4-diene-17ss-
carbothioate;
S-fluoromethyl 6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha; - methylo3-oxo-17ff-propionyloxyandrosta-1,4-diene-17ss-
carbothiate;
S-chloromethyl 6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha; - methyl-3-oxo-17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-
carbothiate.

The compound mentioned last is very particularly advantageous on account of its particularly favorable ratio and on account of the minimal skin atrophy which it causes.

The compounds of formula (I) can be prepared by carrying out a variety of different methods.

One of these processes is characterized by the esterification of an androstane compound corresponding to formula (I), but containing either a free 17ss-carbothiolic acid group (or a radical functionally equivalent to this group) or a free 17α-hydroxyl group (R3 being a hydrogen atom or a methyl or methylene radical), all the other reactive groups present in the molecule being suitably protected if this proves to be desirable.

For example, a salt of the related 17ss-carbothiolic acid can be reacted such as an alkali metal salt, for example a lithium, sodium or potassium salt, or an alkylammonium salt, for example a triethylammonium salt. or tetrabutylammonium, on a suitable alkylating agent, preferably in a polar solvent, such as a ketone, for example acetone or an amide, such as dimethylformamide, dimethylacetamide or hexamethylphophoramide, conveniently at a temperature from 15 to 1000C. The alkylating agent may comprise a suitable dihalogen compound, i.e. a substance containing an additional halogen atom (preferably a bromine or iodine atom3 in addition to the halogen atom of the group R1. This process applies most particularly to the preparation of compounds in which R 1 represents a chloromethyl group, the alkylating agent advantageously being chlorobromomethane.

It is also possible to subject the 16-hydrogen, methyl- or methylene-I a-hydroxy-I 7-carbothioates corresponding to the compounds of formula (I) to an esterification of the group
17α-hydroxyl. This can be accomplished by practice of conventional techniques, for example by reacting the related 17-hydroxy compound with a mixed anhydride of the desired carboxylic acid which can, for example, be generated in situ by reaction of the acid. carboxylic acid on the suitable andhydride, such as trifluoroacetic anhydride, preferably in the presence of an acid catalyst, for example p-toluenesulphonic or sulphosalicylic acid.

The mixed anhydride can also be generated in situ by reacting a symmetrical anhydride of the desired acid with another suitable acid, for example 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 to 100 C. It is possible to further esterify the 17 α; - hydroxyl group by reacting the related hydroxylated compound 17a with the appropriate acid anhydride or chloride, if desired, in the presence of a non-hydroxylated solvent, for example chloroform, methylene chloride or benzene, and preferably in the presence of a strong acid type catalyst, for example perchloric acid, p-toluenesulfonic acid or a strongly acidic cation exchange resin, for example Amberlite IR 120, the reaction being conveniently carried out at a temperature that fluctuates from 25 to 100 C.

Compounds of formula (I) can also be prepared by reacting a corresponding androstane compound containing a 17ss substituent of formula -COS- (CH2) nY (wherein Y represents a displaceable substituent and n is equal to I or 2) on a compound serving to replace the Y group with a halogen atom.

Thus, the compounds of formula (I) can be subjected to a halo-exchange reaction serving to replace the group Y when the latter is a halogen atom by a different halogen atom. Therefore, bromomethyl-, fluoromethyl- and fluoroethyl17ss-carbothioates can be prepared from the corresponding iodomethyl- or bromoethyl17ss-carbothioates using a bromide-type salt, such as lithium bromide, in the case of bromomethyl-17ss-carbothioates, or a suitable fluoride, for example silver monofluoride or silver difluoride, in the case of fluoromethyl or fluoroethyl-17ss-carbothioates. The starting iodomethyl-17ss-carbothioates can be prepared from the corresponding chloromethyl 17ss-carbothioates using, for example, an alkali metal, alkaline earth metal or quaternary ammonium iodide, for example sodium iodide.

The reaction is advantageously carried out in a solvent medium consisting, for example, of one of the following substances: acetone, acetonitrile, methyl ethyl ketone, dimethylformamide, dimethylacetamide or ethanol.

The aforementioned reactions can also be carried out on starting materials which have various substituents or groups which are subsequently converted into the substituents or groups which are present in the compounds according to the invention defined above.

The 11-hydroxy compounds of formula (I) can therefore be prepared by reduction of a corresponding 11-oxo type compound, for example using an alkali metal or alkaline earth metal borohydride, for example. sodium or calcium borohydride, conveniently in an alcoholic or aqueous alcoholic solvent, such as methanol or ethanol.

An 11-keto compound of this type can be prepared by the oxidation of a corresponding 11 α-hydroxysteroid, for example using a chromic acid reagent, such as Jones's reagent.

An 11ss-hydroxylated compound of formula (I) can also be obtained by deprotecting a corresponding compound having a hydroxyl group protected at the 11ss-position, for example a (C1-C6) alkyl -silyloxy group, such as the trimethyl group. -silyloxy, or a perfiuoro- or chloro-alkanoyloxy radical such as the trifluoroacetoxy group. The protective group can be removed by hydrolysis, the triakylsilyl group being easily removed by acidic or basic hydrolysis. moderate or, much more preferably, using a fluoride, for example hydrofluoric acid or ammonium fluoride. The perfluor- or chlor-alkanoyl protecting group can also be removed and by moderate hydrolysis using an acid or a base or by alcoholysis, but preferably under acidic conditions when
R4 is a chlorine atom. Such a protected hydroxyl group can be introduced, for example by reacting an I1-hydroxysteroid with a suitable reagent, such as a trialkylsilyl halide or a perfluor- or chloralkanoic anhydride.

Compounds of formula (I) can also be produced by reacting a corresponding compound having a double bond in positions 9, 11 (and no substituent in position 11) on reagents serving to introduce the 9a-halo group. 11-hydroxy desired. This may involve the initial formation of a bromhydrin by reaction with an N-brom -amide or -imide, such as Nbromosuccinimide, followed by the formation of the corresponding 9ss, 11ss-epoxide by treatment with a base and the reaction of the. epoxy on hydrofluoric acid or hydrochloric acid, so as to introduce the respective fluorohydrin or chlorohydrin group required.

The 9,11-olefin can also be reacted with an Nchloramide or -imide, so as to directly introduce the 9a-chloro-IIf3-hydroxy group.

The compounds a4 according to the present invention can be conveniently prepared by the partial reduction of the corresponding compound A, 4, for example, by hydrogenation, using a palladium catalyst, conveniently in a solvent, for example 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, for example ethanol, preferably at reflux. This reduction can be carried out on a haloalkyl ester which is sufficiently stable during such a reaction or the reduction can be carried out in an earlier step.

The above-mentioned compounds containing a free -COSH group in the 17ss position can be prepared, for example by aminolysis with transposition of a suitable 17ss-thiocarbamoyloxycarbonyl-androstane. 17ss-thiocarbamoyloxycarbonyl-androstane is a mixed anhydride of the corresponding 17ss-carboxylic acid and a thiocarbamic acid and is conveniently prepared by the reaction of a salt of 16, 17a-acetonide or 17a-ester of acid. 17ss-carboxylic, on a thiocarbamoyl halide.The thiocarbamoyl group is N, N-disubstituted and can therefore correspond to the formula: -COOCSNRARB where RA and RB which may be the same or different, represent alkyl radicals, by example of alkyl radicals in
C1-C4, or else RA and RB 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 1 or 2 C -C alkyl radicals, for example methyl groups.

Preferably, R and RB represent C 1 -C 4 alkyl substituents, the N, N-dimethylthiocarbamoyl group being preferred. The thi.ocarbamoyl halide is preferably the chloride. The reaction can be accelerated by the addition of an iodide salt, for example sodium iodide.

The initial androstane-17ss-carboxylate salt can be, for example, an alkali metal salt, for example sodium or potassium, alkaline earth metal, for example calcium, or a tertiary amine, for example. example triethylamine.

Aminolysis with transposition can be carried out, for example, by heating the mixed anhydride to an elevated temperature, for example in the presence of ammonia, a primary amine or, more preferably, a secondary amine, such as than diethylamine or pyrrolidine. In the starting 17ss-carboxylic acids, the 16 and 17a positions will conveniently be substituted with the -R3 and -OR2 groups desired for the final product of formula (I).

I7α-hydroxy-androstanes of the 16-methylenic series which contain the desired 17P-carbothioic acid moiety, as described above, can be prepared from 16ss-methyl-16 &alpha;, 17 &alpha; -epoxy acid. Corresponding 17ss-thiocarboxylic, by effecting a transposition by the use of a strong acid, for example a strong carboxylic acid, such as trichloroacetic acid.

These 16a, 17a-epoxides can be prepared from the corresponding 170-carboxylic acids by treatment with an onium salt of a 2-halo-aza-aromatic compound, followed by treatment of the product thus obtained with hydrogen sulfide or a salt thereof, so as to obtain the free 17ss-carbothioic acid which can then be alkylated as described above, preferably in situ, so as to obtain the desired 17ss-carbothioate group.

The compounds of the 16 &alpha;, 17 &alpha; -isopropylidenedioxy type of formula (I) can be prepared similarly by treating the corresponding 17ss-carboxylic acid with an onium salt of a 2-halo-aza-aromatic compound, this treatment being followed by that of the product thus obtained by hydrogen sulfide, so as to collect the free 17ss-carbothioic acid which can then be esterified as described above.

Onium salts of 2-halo-aza-aromatic compounds are able to effect carboxylic activation. Such reagents comprise salts of 2-halo-N-alkyl- or 2-halo-N-phenyl-pyridinium or pyrimidinium bearing 1 to 2 additional substituents chosen from phenyl and lower alkyl radicals (for example C1-C4), such as methyl. Atoms of the 2-halogen type can be fluorine, chlorine, bromine or iodine. The salts are preferably sulfonates, for example tosylates, halides, for example iodides, fluoroborates or perfluoroalkylsulfonates, a convenient salt being 2-fluoro-N-methylpyrîdinium tosylate or 2- trifluoromethanesulfonate. chloro-N-methylbenzothiazolium.

The 16 &alpha; 17 &alpha; -epoxy-16ss-methyl-17ss-carboxylic acids used as starting materials in the above process can be prepared in a conventional manner, for example as described in the British patent.
No. 1,517,278.

dans laquelle Ra représente un groupe thbcarbamoyloxy- carbonyle -COOCSNRAR où RA et RB sont tels que définis plus haut, ou un groupe de la formule -COSR1A dans la lA quelle R représente un atome d'hydrogène ou est un groupe tel que défini plus haut à propos de R1, ou est un groupe convertible en un tel groupe et Rb représente un groupe hydroxyle estérifié, ou bien Rb et Rc représentent ensemble un groupe isopropylidène dioxy, ou bien lorsque Ra représente un groupe COSR1A, b est éventuellement un groupe hydroxyle,
Rc représente un atome d'hydrogène, un groupe méthyle (qui peut être en configuration a ou ss) ou un groupe méthylène,
Rd représente un groupe hydroxyle ou hydroxyle protégé (en configuration a ou en configuration ss) ou un groupe oxo,
R e représente un atome d'hydrogène, un atome de brome, un atome de chlore ou un atome de fluor, ou bien Rd et R e représentent ensemble une liaison carbone à carbone ou un groupe époxy en configuration ss ou un groupe oxo,
R e représente un atome d'hydrogène, de brome, de chlore ou de fluor, ou bien Rd et R e représentent ensemble une liaison carbone à carbone ou un groupe époxy en configu- ration ss,
Rf représente un atome d'hydrogène ou de fluor et le symbole # représente une liaison simple ou double, ainsi que les sels des composés qui possèdent un groupe carbothioïque libre, à l'exclusion des composés de la formule (I) telle que précédemment définie.The starting materials used for carrying out the process described in the present specification for the preparation of the compounds of formula (I) are new and it is therefore obvious that the scope of the invention also extends to them. ; these compounds include substances which correspond to the following general structural formula (II)

in which Ra represents a thbcarbamoyloxycarbonyl group -COOCSNRAR where RA and RB are as defined above, or a group of the formula -COSR1A in which R represents a hydrogen atom or is a group as defined above in relation to R1, or is a group convertible into such a group and Rb represents an esterified hydroxyl group, or alternatively Rb and Rc together represent an isopropylidene dioxy group, or when Ra represents a COSR1A group, b is optionally a hydroxyl group,
Rc represents a hydrogen atom, a methyl group (which may be in the a or ss configuration) or a methylene group,
Rd represents a hydroxyl or protected hydroxyl group (in a configuration or in ss configuration) or an oxo group,
R e represents a hydrogen atom, a bromine atom, a chlorine atom or a fluorine atom, or else Rd and R e together represent a carbon-to-carbon bond or an epoxy group in ss configuration or an oxo group,
R e represents a hydrogen, bromine, chlorine or fluorine atom, or else Rd and R e together represent a carbon to carbon bond or an epoxy group in configuration ss,
Rf represents a hydrogen or fluorine atom and the symbol # represents a single or double bond, as well as the salts of compounds which have a free carbothioic group, excluding the compounds of formula (I) as defined above .

When Rd represents a protected hydroxyl group, the latter can be, for example, a trialkylsilyloxy group or a perfluoro- or perchloro-alkanoyloxy group as defined above.

The 17α-hydroxy-17ss-carbothioates of the formula (II) and their salts can be converted to the 17α-hydroxy-17ss-carbothioates of the formula (II), wherein
Ra represents the COSR1 group as defined with regard to formula (I), or in 17 α-esters of 170-carbothioic acids of formula (II) by carrying out the processes described above with regard to the preparation The esterification of the 17a-hydroxyl group is preferably carried out with the appropriate carboxylic acid chloride, in a solvent such as a halogenated hydrocarbon, for example dichloromethane and, advantageously in the presence of a base, such as triethylamine, preferably at a low temperature, for example OOC.

The 17α-hydroxy-17ss-carbothioates of formula (II) and their salts are therefore particularly useful as intermediates for the preparation of androstane-17ss-carbothioates of formula (I), those in which R c represents a hydrogen atom, an a- or methyl group or a methylene group, R e represents a hydrogen, chlorine or fluorine atom, Rd represents a hydroxyl group in ss configuration or an oxo group being very particularly suitableS. The most advantageous compounds and their salts include those substances in which R c represents a methyl group in the a or ss configuration or a methylene group, R1 represents a fluorine atom, Rd represents a hydroxyl group in the ss configuration or an oxo group and the symbol .... in positions 1,2 represents a carbon to carbon double bond.

As very particularly preferred compounds of formula (II) there may be mentioned, for example, the following substances
9 &alpha; -fluoro-11ss, 17 &alpha; -dihydroxy-16ss-methyl-3-oxo-androsta-1,4-diene-17ss-carbothioic acid; 9 &alpha; -fluoro-11ss, 17 -dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17ss-carbothioic acid; 9 &alpha; -fluoro-11ss, 17 &alpha; -dihydroxy-16-methylene-3-oxoandrosta-1,4-diene-17ss-carbothioSque acid; 6 &alpha; 9 &alpha; -difluoro-11ss, 17 &alpha; -dihydroxy-16 &alpha; -methyl-3-oxoandrosta-1,4-diene-17ss-carbothioic acid and the corresponding 11 ketones and their salts.

An advantage of the aforementioned intermediates resides in the fact that they allow direct haloalkylation so as to obtain haloalkyl 17 (3-carbothioates when the corresponding R SH thiols are not available.

The salts of these 17α-hydroxy 17ss-carbothioic acids can be, for example, the salts of alkali metals, for example of lithium, of sodium or of potassium, of alkaline earth metals, for example of calcium or of magnesium, of tertiary amines, for example of pyridinium or of triethylammonium, or of quaternary ammonium, for example of tetrabutylammonium.

dans laquelle X, Y et Z, qui peuvent être identiques ou différents, représentent chacun un atome d'azote ou un groupe CH, ou un ou deux des symboles X, Y et Z représentent chacun un azote, le noyau hétérocyclique étant éventuellement substitué sur au moins un atome de carbone par un groupe alkyle inférieur (par exemple avec 1 à 4 atomes de carbonate, tel qu'un groupe méthyle), et(ou), lorsque le noyau hétérocyclique contient deux atomes de carbone adjacents, ledit noyau porte éventuellement un noyau benzénique condensé sur ces atomes de carbone adjacents. The 17-hydroxy-17ss-carboxylic acids can be prepared, for example, by the reaction of a reactive derivative of a 17α-hydroxy-17 (3-carboxylic acid with hydrogen sulfide or a sulfide or hydrosulfide thereof. In general, the cation of the sulphide or of the hydrosulphide may other, for example, an alkali metal cation, such as sodium or potassium. The reactive derivatives mentioned above correspond to compounds of formula (II) in in which Rb represents a hydroxyl group and the radical -COR7 is present in position 17ss, where R7 represents a group of the formula

in which X, Y and Z, which may be the same or different, each represent a nitrogen atom or a CH group, or one or two of the symbols X, Y and Z each represent a nitrogen, the heterocyclic ring being optionally substituted on at least one carbon atom with a lower alkyl group (for example with 1 to 4 carbonate atoms, such as a methyl group), and (or), when the heterocyclic ring contains two adjacent carbon atoms, said ring optionally carries a benzene ring condensed on these adjacent carbon atoms.

The aforementioned reactive derivatives of formula (II) are preferably prepared by reacting the corresponding 17α-hydroxy 17ss-carboxylic acids of formula (II) with a symmetrical or asymmetric compound of formula
- W - R7 (III) in which W represents the group CO, CS> SO or SO2 and the groups R7 which may be identical or different, have the aforementioned meanings.

The compounds of formula (III) are advantageously symmetrical. In general, compounds of formula (III) are used in which W represents a group CO, CS or SO. Thus, for example, as particularly interesting compounds, there may be mentioned: carbonyldi (1,2,4-triazole); N, N'-carbonyldibenzotriazole;
N, N'-carbonyldibenzimidazole; N, N'-carbonyldi (3,5dimethylpyrazole); N, N'-thionyldiimidazole and especially N, N'-carbonyldiimidazole and N, N '-thiocarbonyldiimidazole.

The preparation of a 17α-hydroxy-17ss-carboxylic acid of formula (II), as defined herein, is conveniently carried out by reacting a 17-hydroxy-17ss-carboxylic acid with a compound of formula (III), this reaction being followed by reaction of the intermediate product comprising the 17ss-COR7 group, on hydrogen sulphide or a salt thereof, preferably in situ, without isolation of the intermediate in question .

17α-Acyloxy 17ss-carbothioic acid of formula (II) can be obtained in a similar manner, directly from the corresponding 17 &alpha; -acyloxy 17ss-carboxylic acid, by reaction with a compound of formula (III). The 17 &alpha; -acyloxy 17ss-carboxylic acids can be prepared by esterification of the corresponding 17aacyloxy 17ss-carboxylic acids by carrying out the processes described in the British patent.
No. 1,384,372.

The reaction with the compound of formula (III) is conveniently carried out in the presence of an inert anhydrous solvent, for example a solvent of the substituted amide type, such as N, N-dimethylformamide or N, N-dimethylacetamide, advantageously in the absence of water, preferably at room temperature or at a temperature below room temperature, for example at a temperature which fluctuates from -30 to + 30 C. The reaction is conveniently carried out under approximately conditions. neutral, advantageously in an inert atmosphere, for example under a nitrogen atmosphere. The same solvents and conditions also apply to the subsequent reaction with H2S or a salt thereof. The heterocyclic compound, for example imidazole or 1> 2,4-triazole, formed as a by-product can be easily removed, for example, by water extraction.

The above reactions can also be carried out on compounds which have various substituents or groups which are then converted in the manner previously described into compounds of formula (I).

The starting androstane 17ss-carboxylic acids used for carrying out the aforementioned processes can be prepared in a conventional manner, for example, by oxidation of a suitable 21-hydroxy-20-keto-pregnane, for example, using periodic acid in a solvent medium and preferably at room temperature. Sodium bismuthate can also be used for oxidative removal! desired carbon atom in position 21 of a compound of the type I7a-acyloxy-pregnane.

As will be fully understood, the starting pregnane-type compound may contain any of the above-mentioned oxidation-sensitive substituents and such a group must then be suitably protected.

The following examples illustrate the present invention. Melting points were determined on a Kofler block in degrees Celsius and are not corrected.

Rotations were determined at room temperature on solutions in dioxane.

Thin layer chromatography (tlc), preparative layer chromatography was performed
(plc) and high performance liquid chromatography (hplc) on silica.

Solutions were dried over magnesium sulfate, unless otherwise specified.

Preparation I
9 &alpha; -fluoro-11ss-hydroxy-16ss-methyl-3-oxo-17 &alpha; -propionyl-oxyandrosta-1,4-diene-17ss-carbothioic acid (I)
A solution of 9-fluoro-11ss-hydroxy-16p-methyl-3-oxo-17O-propionyloxy-androsta-1,4-diene-17ss-carboxylic acid (5.00 g) was caused to be solvated with ethyl acetate (0.5 mole) and triethylamine (5.3 ml) in dichloromethane (75 ml) and stirred under nitrogen atmosphere and treated with dimethylthiocarbamoyl chloride (5.071 g). After 24 hours, an additional amount of reagent (5.320 g) was added.

After 47 hours, the mixture was diluted with ethyl acetate and washed with N hydrochloric acid, 5% sodium bicarbonate solution and water, dried and dried. evaporated to obtain a viscous yellow oil (9.043 g). This oil was dissolved in diethylamine (50 ml) and then stirred and heated to reflux under a nitrogen atmosphere for 5.75 hours. The brown solution thus obtained was added to a mixture of concentrated hydrochloric acid (50 ml), water (250 ml) and ethyl acetate (50 ml). The products were further extracted with ethyl acetate, then the acidic products were re-extracted with 5% sodium carbonate solution. The aqueous phase was acidified with 6N hydrochloric acid (50 ml) and it was extracted with ethyl acetate. The extracts were washed with N hydrochloric acid and water, dried and evaporated to obtain a buff colored solid (3.440 g). This product was recrystallized from acetone to obtain pale buff colored crystals (1.980 g) of the title 17ss-carbothioic acid having a melting point of 172-1730C.

The analytical sample was obtained after 2 recrystallizations from acetone, as banos crystals, m.p. 177-179, #D +110 (c 1.05).

Preparation II S-Chloromethyl 9 &alpha; -fluoro-16ss-methyl-3,11-dioxo-17 &alpha; -propionyl-oxyandrosta-1,4-diene-17ss-carbothioate (II)
8N Jones reagent (1.5 ml) was added dropwise over 10 minutes to a stirred solution of the compound of Example 1 (described later in this specification) (998 mg) in acetone (2ml) and dimethylformamide (2ml). After 30 minutes, the reaction mixture was slowly diluted with water (100 ml), with stirring, and the suspension thus obtained was refrigerated for 1 hour. The precipitate was collected by piltration, washed with water and dried to obtain a cream-colored solid (879 mg). The plc in a mixture of chloroform and acetone (10 : 1) gave a white foam (755 mg) which was crystallized twice in acetone to obtain white needles of the 11-ketone indicated in the title (523 mg) PF 204 2050, #D +94 (c 1.04).

Preparation III 17ss N, N-dimethylthiocarbamoyloxycarbonyl-9 &alpha; -fluoro-11ss hydroxy-16 &alpha; -methyl-17 &alpha; -propionyloxyandrosta-1,4-diene-3-one (III)
A solution of 9 &alpha; -fluoro-11ss-hy hydroxy-16 &alpha; -methyl-3-oxo-17 &alpha; -propionyl-oxyandrosta-1,4-diene-17ss-carboxylic acid (0.434 g) in dichloromethane ( 8ml), successively with triethylamine (0.14 ml), dimethylthiocarbamoyl chloride (0.248 g) and sodium iodide (0.149 g) and the mixture was stirred under a nitrogen atmosphere at 200C for 6 hours. Ethyl acetate (30 mL) was added and the total volume reduced to half in vacuo. More ethyl acetate (50ml) was added and the solution washed with water, 2N hydrochloric acid, water, 3% sodium bicarbonate solution. water and saturated sodium chloride solution.

then we dried it. The solution was concentrated in vacuo when the product crystallized (0.329 g). The product was recrystallized from acetone (2 times) to obtain the title anhydride in the form of white needles having a melting point of 191-193, #D +82 (c 0.57 ).

Preparation IV
9 &alpha; -fluoro-11ss-hydroxy-16 &alpha; -methyl-3-oxo-17 &alpha; -propionyl-oxyandrosta-1,4-diene-17ss-carbothioic acid (IV)
A suspension of the product obtained in (III) (2.467 g) was stirred in diethylamine (25 ml), at reflux, under a nitrogen atmosphere. After 3.5 hours, the reaction mixture was poured into ice-cold 3N hydrochloric acid (300 ml) 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 acetate. ethyl and acidified with US hydrochloric acid to pH 1. The aqueous phase was extracted with additional ethyl acetate and the combined extracts washed with water. water, saturated sodium chloride solution, dried and the solvent removed in vacuo. The residues were crystallized twice from acetone to give the title carbothiolic acid as white needles (1.309 g) PF 141-143, #D +30 (c 0.51 ).

Preparation V
11fl-hydroxy-3-oxo-17a-dihydroxy-3-oxoandrosta-7,4-diene-17ss-carboxylic acid (V)
A solution of 11fi, 17 -dihydroxy-3-oxoandrosta-1,4-diene-17ss-carboxylic acid (13.5 g) and triethylamine (18 ml) in dichloromethane (500 ml) was cooled to 40C and treated in fractions over 15 minutes with propionyl chloride (14.2 ml).

Stirring was continued at 40C for a total of one hour and the mixture was washed successively with a 3% solution of sodium bicarbonate, water, 2N hydrochloric acid, water. and saturated brine, then dried and evaporated under reduced pressure. The residue was dissolved in acetone (300 ml) and diethylamine (143 ml) was added with stirring. After 1 hour at 200C, the solvent was removed under reduced pressure and the residue was dissolved in water (150 ml), After acidification to a pH of 1 with 2N hydrochloric acid, it was extracted The product with ethyl acetate. The combined extracts were washed with water and saturated brine, dried and then concentrated to small volume. The solid product was collected by filtration, washed with ethyl acetate and dried in vacuo at 500, to afford the title 17α-propionate carboxylic acid as crystals (13.309 g), #D +20 (c 1.10). A fraction of the product (389 g) was recrystallized twice from methanol to generate an analytical sample (256 mg) m.p. 244-245 (decomp), #D +30 (c 0.83).

Preparation VI
6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha; -methyl-3-oxo-17 &alpha; - propionyloxyandrosta-1,4-diene-17ss-carboxylic acid (VI)
A solution of 6 &alpha;, 9 &alpha; -difluoro-11ss, 17a-dihydroxy-16a-methyl-3-oxoandrostå-1,4-diene-17p-carboxylic acid (2.113 g) and triethylamine (2, 5 ml) in dichloromethane (60 ml) and treated at about 0 C with propionyl chloride (1.85 ml).

After 1 hour, the mixture was diluted with an additional amount of solvent (50 ml) and washed successively with a 3 5 'solution of sodium bicarbonate, water, 2N hydrochloric acid, water, saturated brine, then dried and evaporated to obtain a buff colored solid. This solid was dissolved in acetone (50ml) and thereto was added dietylamine (2.5ml). -After 1 hour at 220C, the solvent was removed in vacuo and the residual gum dissolved in water (30ml). Acidification to pH 1 with 2N hydrochloric acid caused precipitation of a solid which was collected, washed with water and dried, so as to obtain the 17a-propionate carboxylic acid indicated in the title (2.230 g), PF 220 2250, #D +40 ( c 0.70).

Preparation VII 17ss-N, N-Dimethylthiocarbamoyloxycarbonyl-9 &alpha; -fluoro-11ss hydroxy-16 &alpha;, 17 &alpha; -isopropylidenedioxyandrosta-1,4-diene-3-one (VII)
A solution of 9a-fluoro-I1-hydroxy-16 &alpha;, 17 &alpha; -isopropylidenedioxy-3-oxoandrosta-1,4-diene-17ss-carboxylic acid (1000g) in dichloromethane (15ml) and treated was treated. triethylamine (0.33 ml) under nitrogen atmosphere, with N, N-dimethylthiocarbamoyl chloride (588 mg) and the mixture was stirred at room temperature. After 68 hours, the reaction mixture was diluted with ethyl acetate (50ml) and washed with N hydrochloric acid (2.10ml), 5% sodium bicarbonate solution. and water, dried and evaporated to a pale yellow crystalline solid (1.123 g). Plc of a fraction of the product (200 mg) in a mixture of chloroform and acetone (9: 1) gave an off-white solid (161 mg) which was crystallized from ethyl acetate under the white needle form of the title mixed anhydride (131 mg), PF 279-281, 7D + 1740 (c 0.61 dimethyl sulfoxide).

Preparation VIII 17ss-N, N-Dimethylthiocarbamoylcarbonyl-6 &alpha;, 9 &alpha; -difluoro-11ss hydroxy-16 &alpha;, 17 &alpha; -isopropylidénedioxyandrosta-1,4-diene-3-one (viii)
A solution of 6a, 9a-difluoro-1I (3-hydroxy-16 &alpha;, 17 &alpha; -isopropylidenedioxy-3-oxoandrosta-1,4-diene-17ss-carboxylic acid (4.354 g) in dichloromethane (150 ml) containing triethylamine (1.4 ml) with N, N-dimethylthiocarbamoyl chloride (2.519 g) and the reaction mixture was stirred under nitrogen at 220 for 80 minutes. ethyl acetate (500 ml) and the solution thus obtained was washed successively with 2N hydrochloric acid, water, sodium bicarbonate solution, water and saturated sodium chloride solution. and dried to finally concentrate Crystallization proceeded during cooling and the solid was washed and dried in vacuo to obtain the title anhydride (3.562 g) under the form of pale yellow prisms; PF 283-287 (dec), z 7D + 1560 (c 0.84, dimethyl sulfoxide).

Preparation IX
6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha;, 17 &alpha; -isopropylidene-dioxy-3-oxoandrosta-1,4-diene-17ss-carbothioic acid (IX)
A suspension of the product of Preparation VIII (3.455 g) in diethylamine (200 ml) was heated under reflux under a nitrogen atmosphere for 6 hours. The initial suspension dissolved quickly, but a pale brown suspension formed after 30 minutes and remained unchanged. The cooled reaction mixture was poured into water (1.0 L), acidified with concentrated hydrochloric acid (210 ml) to pH 1 and extracted with ethyl acetate. The combined extracts were washed with water and extracted with 5% sodium carbonate solution and water and the aqueous extracts combined. The combined extracts were acidified with acid. 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 removed in vacuo, to obtain a pale gray solid (2.31 g). . Part of the product (0.408 g) was crystallized from ethyl acetate to obtain the title carbothioic acid (0.149 g), PF 191-199, #D +1240 (c 1.04 , dimethylsulfoxide).

Preparation X
6 &alpha; -fluoro-11ss, 17 &alpha; -dihydroxy-3-oxoandrosta-1,4-diene-17sscarboxylic acid (X)
A solution of 6α-fluoroprednisolone (4.987g) in tetrahydrofuran (50ml) was stirred with a solution of periodic acid (10.0g) in water (24ml) at 220. After 50 minutes, it was stirred. the tetrahydrofuran evaporated and the aqueous suspension was filtered. The solid product was washed with water (300 ml) and dried to collect a white solid (15.80 g). A fraction of the product (271 g) was crystallized from methanol to collect the title acid (171 mg) in the form of white needles having a melting point of 241-248, La7 + 540 ( c 0.825).

Preparation XI
6a-Fluoro-I 1 (3-hydroxv-3-oxo-1 7a-propionvloxvandrosta- 1,4-diene-17ss-carboxylic acid (XI)
A solution of the product of the preparation was stirred
X (4.491g) etdetriethylamine (4.46ml) in dry dichloromethane (160ml) at -5 and treated dropwise with propionyl chloride (2.80ml, 2.96g) in dry dichloromethane (about 5 ml), over 5 minutes, at a temperature below 0. After a further 20 minutes at less than 00, the reaction mixture was diluted with dichloromethane (160 ml), washed with sodium bicarbonate solution, water and dried and evaporated to obtaining a white solid (5.701 g). This product was stirred with diethylamine (4.60 ml, 3.24 g) in acetone (30 ml), to obtain a light yellow solution.

After 30 minutes, the solution was concentrated, water (150 ml) was added thereto, and the solution thus obtained was washed with ethyl acetate (2 x 30 ml). The aqueous phase was acidified to pH 2 using 2N hydrochloric acid (50 mL) with stirring and the product was extracted 3 times with ethyl acetate.

The extracts were combined, washed with water (50 ml), dried and evaporated to obtain a white foam (5.819 g). A fraction of the foam (304 mg) was crystallized from ethyl acetate to obtain the title 17α-propionate (144 mg), in the form of small plaques having a melting point of 224. -227, #D +3 (c 0.861).

Preparations XII - XXIII
After repeating the same general procedure as that described in Preparation 1 ', but using, as starting material, the 17ss-carboxylic acid corresponding to the desired 17ss-carbothioate (the details of the process being summarized in Table I below), the following acids could be prepared: XII.-17 &alpha; -acetoxy-9 &alpha; -fluoro-11ss-hydroxy-16ss-methyl-3-oxo- androsta-1,4-diene-17ss-carbothioic , Mp 178.5-179, -1-7D +980 (c 1.02);
XIII. - 17 &alpha; -butyryloxy-9 &alpha; -fluoro-11ss-hydroxy-16ss-methyl-3-oxoandrosta-1,4-diene-17ss-carbothioic acid; PF 175-176, such +1070 (c 0.96);
XIV. - 9 &alpha; -fluoro-11ss-hydroxy-17 &alpha; -isobutyryloxy-16ss-methyl-3-oxoandrosta-1,4-diene-17ss-carbothioic acid; PE 177-179, washed +1190 - (c 0.90);
XV. - 11ss-hydroxy-3-oxo-17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carbothioic acid, PF 134-138, [&alpha;] D +67 (c 0.66);
XVI. - 11ss-hydroxy-16ss-methyl-3-oxo-17 &alpha; -propionyloxy- androsta-1,4-diene-17ss-carbothioic acid; PF 159-163,
[&alpha;] D +113 (c 0.78);
XVII. - 9 &alpha; -chloro-11ss-hydroxy-16ss-methyl-3-oxo-17 &alpha; -propionyl-oxyandrosta-1,4-diene-17ss-carbothioic acid; PF 167-171,
[&alpha;] D +128 (c 0.99); XVIII. - 9 &alpha; -fluoro-11ss-hydroxy-16 &alpha; -methyl-3-oxo-17 &alpha; -propionyl-oxyandrosta-1,4-diene-17ss-carbothioic acid; PF141-143, [&alpha;] D +30 (c 0.51);
XIX. - 6 &alpha; 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha; -methyl-3-oxo-17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carbothioic acid; PF

136-139, [&alpha;] D -30 (c 0.56);
XX. - 9 &alpha; -flyoro-11ss-hydroxy-16-methylene-3-oxo-17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carbothioic acid; PF

236-239, [&alpha;] D -71 (c 0.99);
XXI. - 11ss-hydroxy-3-oxo-17 &alpha; -propionyloxyandrosta-4-ene-17ss-carbothioic acid; PF 176-177, [&alpha;] D +101 (c 0.96);
XXII. - 9 &alpha; -flouro-11ss-hydroxy-16 &alpha;, 17 &alpha; -isopropylidenedioxy-3-oxoandrosta-1,4-diene-17ss-carbothioic acid; PF 274-304 (dec.), [&Alpha;] D +121 (c 0.51; dimethyl sulfoxide);
XXIII. - 6 &alpha; -fluoro-11ss-hydroxy-3-oxo-17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carbothioic acid; PF 189-193, [&alpha;] D +72
(c 0.74).

TABLE I
Formation of mixed anhydrides

<tb><SEP> Acid <SEP> 17ss- <SEP> Duration <SEP> of
<tb> Preparation <SEP> carboxy- <SEP> Cl-CSNMe2 <SEP> NEt3 <SEP> Solvent <SEP> reaction
<tb><SEP> lique <SEP> (CH2Cl2) <SEP> (days) <SEP> to
<tb><SEP> quantity <SEP> the <SEP> tempered
<tb><SEP> (g) <SEP> (g) <SEP> (ml) <SEP> (ml) <SEP> erase
<tb><SEP> ambient
<tb><SEP> XII <SEP> 5,000 <SEP> 2,940 <SEP> 1.66 <SEP> 75 <SEP> 5la
<tb><SEP> XIII <SEP> 15.354 <SEP> 8.809 <SEP> 4.8 <SEP> 250 <SEP> 6
<tb><SEP> XIV <SEP> 4,182 <SEP> 2,399 <SEP> 1,3 <SEP> 80 <SEP> 4
<tb><SEP> XV <SEP> 7.148 <SEP> 4.40 <SEP> 2.6 <SEP> 150 <SEP> 6lb
<tb><SEP> XVI <SEP> 6.137 <SEP> 3.77 <SEP> 2.05 <SEP> 140 <SEP> 6lc
<tb><SEP> XVII <SEP> 5.973 <SEP> 3.350 <SEP> 1.34 <SEP> 100 <SEP> 7
<tb><SEP> XVIII <SEP> 4.207 <SEP> 2.39 <SEP> 1.35 <SEP> 80 <SEP> 0.677, ld
<tb><SEP> XIX <SEP> 2.130 <SEP> 1.80 <SEP> 0.66 <SEP> 50 <SEP> 64
<tb><SEP> XX <SEP> 5,000 <SEP> 2.507 <SEP> 1.41 <SEP> 75 <SEP> 3
<tb><SEP> XXI <SEP> 1,000 <SEP> 2,442 <SEP> 1,22 <SEP> 15 <SEP> 2,7
<tb><SEP> XXII <SEP> 1.000 <SEP> 0.588 <SEP> 0.33 <SEP> 15 <SEP> 2.88
<tb><SEP> XXIII <SEP> 6,000 <SEP> 3.55 <SEP> 2.0 <SEP> 120 <SEP> 1.2510
<tb>
TABLE I (continued)
Treatment of intermediate mixed anhydrides for
diethylamine

<tb> Preparation <SEP> NHEt @ <SEP><SEP> Duration <SEP> of <SEP> Product <SEP> Solvent <SEP> of <SEP> cris
<tb><SEP> (ml) <SEP> reaction <SEP> (g) <SEP> tallisatton <SEP> J <SEP>
<tb><SEP> (h) <SEP> to <SEP> re- <SEP>
<tb><SEP> stream
<tb><SEP> XII <SEP> 50 <SEP> 5.5 <SEP> 2.104 <SEP> EA2a <SEP>
<tb><SEP> XIII <SEP> 250 <SEP> 4 <SEP> 5,244
<tb><SEP> XIV <SEP> 60 <SEP> 4.5 <SEP> 1.00 <SEP> EA
<tb><SEP> XV <SEP> 60 <SEP> 4 <SEP> 3.29
<tb><SEP> XVI <SEP> 50 <SEP> | <SEP> 3.5 <SEP> 1.382
<tb><SEP> XVII <SEP> 60 <SEP> 5.7 <SEP> 0.527 <SEP><SEP> EA <SEP>
<tb><SEP> XVIII <SEP> 25 <SEP> 4.75 <SEP> 1.309 <SEP> A
<tb><SEP> XIX <SEP> 12 <SEP> 6 <SEP> 0.418 <SEP> EA
<tb><SEP> XX <SEP> 50 <SEP> 3.75 <SEP> 1.296 <SEP> EA2b
<tb><SEP> XXI <SEP> 15 <SEP> 4 <SEP> 0.3976 <SEP> A5
<tb><SEP> XXII <SEP> (a) <SEP> 8 <SEP> (a) 3
<tb><SEP> 0.4649 <SEP> A
<tb><SEP> (b) 16 <SEP> (b) 2.5
<tb><SEP> XXIII <SEP> 60 <SEP> 4,5 <SEP> 2,88 <SEP> EA-P
<tb>
Notes: EA = ethyl acetate A = acetone P = petroleum
PE 60-80.

1. Fractions of (a) 500 mg, (b) 670 mg,
(c) 424 mg, (d) 171 mg of dimethylthio anhydride
intermediate carbamic for characterization.

2. The characterization was carried out on a sample
recrystallized two more times from acetate
ethyl. (A) 84 5 ', (b) 69% recoveries.

3. The product was subjected to solvation with
ethyl acetate (about 0.2 moles).

4. Dimethylthiocarbamic anhydride was crystallized
intermediate (1.435 g) in ethyl acetate.

Part of the product (95 mg) was taken for
characterization.

5. The characterization was carried out on a sample
recrystallized two more times from acetone
(recovery: 73%).

6. The product was crystallized from ethyl acetate.

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

8. Dimethylthiocarbamic anhydride was crystallized
intermediate (1.123 g) in ethyl acetate.

A fraction of the product (200 mg) was chromatographed.
(plc, chloroform acetone, 9: 1) and recruits
tallized this fraction in ethyl acetate
(recovery 65).

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

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

Preparation XXIV
9 &alpha; -chloro-11ss-hydroxy-16ss-methyl-3-oxo-17 &alpha; -propionyl-oxyandrosta-1,4-diene-17ss-carbothioic acid
9ss, 11ss-epoxy-16ss-methyl-3-oxo-17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carbothioic acid (XXIV)
A mixture of 17ss-N, N-dimethylthiocar bamoyloxycarbonyl-9 &alpha; -chloro-11ss-hydroxy-16ss-methyl-17 &alpha; - propionyloxyandrosta-1,4-diene-3-one (5.586g) in diethylamine was heated. (60 ml) at reflux, under a nitrogen atmosphere, for 5 hours and 40 minutes. The reaction mixture was poured into water (450 ml), acidified to pH 10 with concentrated hydrochloric acid and extracted with ethyl acetate ( 3 x 60 ml).

The combined extracts were washed with water, then extracted with aqueous sodium carbonate solution (4 x 50 mL). The aqueous extracts were acidified with hydrochloric acid to pH 1 and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water and saturated sodium chloride solution and dried and the solvent removed in vacuo to obtain a colorless broth (2.834 g).

Two crystallizations of the mixture from ethyl acetate gave 9 &alpha; -chloro-11ss-hydroxy-16ss-methyl-3-oxo-17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carbothioSque acid (0.527 g) in the form of white prisms having a melting point of 167 to 171, #D, +128 (c 0.99). The mother liquors from crystallizations contained an additional amount of the acid
Aforementioned 9 &alpha; -chloro-11ss-hydroxycarbothioic acid, together with 9ss, 11ss-epoxy-16ss-methyl-3-oxo-17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carbothioic acid.

Preparation XXV
S-Iodomethyl 9 &alpha; -fluoro-11ss-hydroxy-16ss-methyl-3-oxo-17 &alpha; - propionyloxyandrosta-1,4-diene-17ss-carbothioate (XXV)
A solution of the compound of Example 1, described hereinafter, (500 mg) and sodium iodide (1.874 g) in acetone (15 ml), was stirred and refluxed for 6.5 hours. Ethyl acetate (75 ml) was then added and the solution washed successively with water, 10% sodium thiosulfate solution, 5% sodium bicarbonate solution and sodium bicarbonate. It was dried and evaporated to give an off-white foam (525 mg). Plc in a mixture of chloroform and acetone (6: 1) gave an off-white foam (478 mg) which was crystallized twice from acetone without heating above room temperature, so as to obtain colorless crystals of the ester
S-iodomethyl indicated in the title. (241 mg) PF

196-197, #D -32 (c 1.01).

Preparations XXVI - XXXVII
By repeating the same general procedure as that described in Preparation XXV, but using, as the starting material, the S-chloromethyl-17ss-carbothioate corresponding to the desired product (the details of the process are summarized in Table II which follows), the following compounds were obtained
XXVI. S-Iodomethyl 17 &alpha; -acetoxy-9 &alpha; -fluoro-11ss-hydroxy-16ss-methyl-3-oxoandrosta-1,4-diene-17ss-carbothioate, PF

204-205, #D -29 (c 0.98)
XXVII. S-Iodomethyl 11ss-hydroxy-3-oxo-17 &alpha; -propionyloxy- androsta-1,4-diene-17ss-carbothioate, [&alpha;] D +26 (c 0.47).

XXVIII. S-Iodomethyl 11ss-hydroxy-16ss-methyl-3-oxo-17 &alpha; - propionyloxyandrosta-1,4-diene-17ss-carbothioate, [&alpha;] D +5 (c 0ç74).

XXIX. S-Iodomethyl 9 &alpha; -chloro-11ss-hydroxy-16ss-methyl-3-oxo-17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carbothioate, [&alpha;] D +70. (C 0.36).

XXX. S-Iodomethyl 9 &alpha; -fluoro-11ss-hydroxy-16 &alpha; -methyl-3-oXo-17a-propionyloxyandrosta-1,4-diane-17ss-carbothioate, [&alpha;] D +850 (c 0.55).

XXXI. S-Iodomethyl 6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha; -methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ss-carbothioate.

XXXII. S-Iodomethyl 9 &alpha; -fluoro-11ss-hydroxy-16-methylene-3- oxo-17 -propionyloxyandrosta-1,4-diene-17ss-carbothioate,
PF 191-199, [&alpha;] D - 31 (c 0.99).

XXXIII. S-Iodomethyl 9 &alpha; -fluoro-11ss-hydroxy-3-oxo-17 &alpha; - propionyloxyandrosta-1,4-diene-17ss-carbothioate, P.F.

175-178, [&alpha;] D +4 (c 0.50).

XXXIV. S-Iodomethyl 6 &alpha; -flouro-11ss-hydroxy-3-oxo-17 &alpha; - propionyloxyandrosta-1,4-diene-17ss-carbothioate, P.F.

195-197, [&alpha;] D +18 (c 0.64).

XXXV. S-Iodomethyl 17 &alpha; -acetoxy-6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17ss-carbothioate,
PF 241-243, [&alpha;] D +78 (c 0.78).

XXXVI. S-Iodomethyl 17 &alpha; -butyryloxy-6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha; -methyl-3-oxoandrosta-1,4-diene-17ss-carbothioate,
PF 210-212, [&alpha;] D +89 (c 0.90).

XXXVII. S-Iodomethyl Sa-fluoro-11S-hydroxy-16e, 17a-isopropylidenedioxy-3-oxoandrosta-1,4-diene-17ss-carbothioate,
PF 261-270 (dec.), [&Alpha;] D +97 (c 0.48; dimethyl sulphoxide).

TABLE II
Halogen exchanges on S-haloalkyl 17a-acyloxyandro-
stane-17ss-carbothioates

<tb> Prepara- <SEP> NaI <SEP> Steroid <SEP> of <SEP> SOLV <SEP> ANT <SEP> DURATION <SEP> OF <SEP> PLC <SEP> SOLVENT <SEP> PRODUCT
<tb> tion <SEP> No. <SEP> (mg) <SEP> start <SEP> (acetone) <SEP> REACTION <SEP> (Silica) <SEP> DE <SEP> CRIS- <SEP> (mg)
<tb><SEP> Halide <SEP> (ml) <SEP> (h) <SEP> to <SEP> CHCl3- <SEP> TALLISA
<tb><SEP> Quantity <SEP> reflux <SEP> Me2CO <SEP> TION
<tb><SEP> (mg)
<tb> XXVI <SEP> 663 <SEP> Cl <SEP> 1715 <SEP> 20 <SEP> 3,5 <SEP> - <SEP> EA <SEP> 216 @ <SEP>
<tb> XXVII <SEP> 3800 <SEP> Cl <SEP> 925 <SEP> 10 <SEP> 4 <SEP> - <SEP> - <SEP> 1084
<tb> XXXVIII <SEP> 3260 <SEP> Cl <SEP> 840 <SEP> 10 <SEP> 3 <SEP> - <SEP> - <SEP> 969
<tb> XXIX <SEP> 1995 <SEP> Cl <SEP> 536 <SEP> 20 <SEP> 6.5 <SEP> - <SEP> - <SEP> 591
<tb> XXX <SEP> 2160 <SEP> Cl <SEP> 580 <SEP> 10 <SEP> 3 <SEP> - <SEP> - <SEP> 685
<tb> XXXI <SEP> 1200 <SEP> Cl <SEP> 303 <SEP> 30 <SEP> 5 <SEP> - <SEP> - <SEP> 3173
<tb> XXXII <SEP> 736 <SEP> Cl <SEP> 1953 <SEP> 23 <SEP> 6 <SEP> 19: 1 <SEP> A <SEP> 2962
<tb> XXXIII <SEP> 5500 <SEP> Cl <SEP> 1300 <SEP> 35 <SEP> 4 <SEP> - <SEP> M <SEP> 1250 '
<tb> XXXIV <SEP> 840 <SEP> Cl <SEP> 2000 <SEP> 54 <SEP> 425 <SEP> i <SEP> EA-P <SEP> 1800
<tb><SEP> 19000 <SEP> Cl <SEP> 4750 <SEP> 200 <SEP> 5 <SEP> - <SEP> EA <SEP> 46206
<tb><SEP> 6500 <SEP> Cl <SEP> 1620 <SEP> 70 <SEP> 5.5 <SEP> - <SEP> EA <SEP> 16105
<tb><SEP> XXVII <SEP> 549 <SEP> Cl <SEP> 1419 <SEP> 20 <SEP> 24 <SEP> 9 :: 1 <SEP> A <SEP> 2248
<tb>
EA = ethyl acetate
A = acetone
M = methanol
P = petroleum PE60-80
Notes 1. Obtained from a fraction (300 mg) of the product
crude (2.024 g).

2. Obtained from a fraction (400 mg) of the product
crude (2.058 g).

3. The product was used directly for the preparation.
ration of the corresponding fluoromethyl 17ss-carbothioate.

4. Lithium chloride was used instead of iodide
lithium.

5. Solvated with 0.5 H2O.

6. Solvated with 0.1 EA.

7. Solvated with 0.2 RA + 0.5 H2O.

8. Obtained from a fraction (300 mg) of the product
Crude crystalline (1.611 g).

Preparation XXXVIII
S-Iodomethyl 6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha;, 17 &alpha; -isopropyl- idenedioxy-3-oxoandrosta-1,4-diene-17ss-carbothioate (XXXVIII)
A solution of the compound described in Example 4 (described later in this specification, 0.795 g) in acetone (50 ml) was heated at reflux with sodium iodide (2.969 g) for 5.5 hours. Ethyl acetate (75 ml) was added and the solution washed successively with water, sodium methabisulfite solution, then dried and the solvent removed in vacuo from so as to obtain a whitish solid (0.93 g).

A part of this product (0.205 g) was crystallized twice from ethyl acetate, so as to obtain the S-iodomethylthioester indicated in the title (0.105 g) in the form of white prisms having a point of. fusion of 260-262 (dec) #D +81 (c 0.6; dimethylsulfoxide).

Preparation XXXIX
S-2'-Brom-ethyl 9 &alpha; -fluoro-11ss-hydroxy-16ss-methyl-3-oxo-17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carbothioate (XXXIX)
The product of Preparation I (0.5 g) was processed as described for S-chloromethyl ester (Example 1, Method A, which appears later in this specification), but using 1 , 2-dibromethane, so as to obtain colorless crystals of the S2′-bromethyl ester indicated in the title (0.409 g) having a melting point of 174-1450, / a7D +1200 (c 1.04).

XL preparation
16 &alpha;, 17 &alpha; -epoxy-9 &alpha; -fluoro-11ss-hydroxy-16ss-methyl-3-oxoandrosta-1,4-diene-17ss-carbothioic acid (XL)
A mixture of 16a, 17a-epoxy-9-fluoro-11p-hydroxy-16ss-methyl-3-oxoandrosta-1,4-diene-17ss-carboxylic acid (377 mg) and tosylate was stirred. -fluoro-1-methyl pyridinium (340 mg) in dry dichloromethane (7 ml), cooled with ice and treated for one minute with triethylamine (0.42 ml). After 1 hour, hydrogen sulfide was passed through the mixture for 30 minutes, so as to obtain a yellow solution. Tlc (chloroform-acetone-acetic acid, 30: 8: 1) revealed. that a less polar major product had formed.After allowing it to warm to room temperature over one hour, the mixture was treated with 2N hydrochloric acid (30 mL) and the product was extracted with ethyl acetate (3 x 20 mL). The acidic product was extracted from the organic phase with 5% sodium carbonate solution, the aqueous extracts were combined and acidified with 6N hydrochloric acid, then extracted with acetate. The combined acid extracts were washed with water, dried and concentrated under reduced pressure to obtain, after filtration, whitish crystals (274 mg), probably largely the same. unstable 16 &alpha;, 17 &alpha; -epoxy-9 &alpha; -fluoro-11ss-hydroxy-16ss-methyl-3-oxoandrosta-1,4-diene-17ss-carbothioic acid (no starting oxyacid present) as could be seen judge by tlc (chloroform-acetone-acetic acid 30: 8: 1; RF # 0.7).

XLI preparation
S-Chloromethyl 16,17wl-epoxy-9d-fluoro-ii-hydroxy-16B methyl-3-oxoandrosta-1,4-diene-17 -carbothioate (XLI)
Method A
A suspension of 16,17a-epoxy-9a-fluoro-11ss-hydroxy-16ss-methyl-3-oxoandrosta-1,4-diene 17ss-carboxylic acid (753 mg) and 2-fluoro1- tosylate was treated. methylpyridinium (680 mg) in dichloromethane (7ml) dropwise and at OOC, with triethylamine (1.39ml) and then stirred at 0 C for 1 hour. Hydrogen sulfide was then passed through the mixture for 15 minutes and the resulting solution was then stirred at 0 C for a further 1 hour.

Bromochloromethane (0.26ml) was then added and the mixture stirred and allowed to warm to room temperature. After another 1.5 hours, the reaction mixture was diluted with ethyl acetate (250 ml) and washed successively with 2N hydrochloric acid, 5% sodium bicarbonate solution, it was dried and evaporated to obtain a pale yellow solid (818 mg). This solid was subjected to a p.l.c. in a mixture of chloroform and acetone (9: 1) (2 tests) The main band (515 mg) was crystallized in acetone, so as to obtain white needles of the S ester epoxide -chloromethyl- ic indicated in the title (447 mg), PF 246-251, t 7D +131 (c 0.67).

Method B
A suspension of 16 &alpha;, 17 &alpha; -epoxy-9 &alpha; - fluorO-11ss-hydroxy-16-methylene-3-oxoandrosta-1,4-diene-17ss-carboxylic acid (376 mg) and trifluoromethane sulfonate was treated of 2-chloro-N-methylbenzothiazolium (400 mg) in dichloromethane, dropwise and at OOC, with de- triethyl-amine (0.7 ml). The resulting solution was stirred at 0 C for 1.25 hours, and then hydrogen sulfide was passed through the mixture for 10 minutes. After an additional 1 hour at OOC, bromochloromethane (0.13 ml) was added and the mixture was stirred at room temperature, then two more fractions of bromochloromethane (0.13 ml) were added after 1.5 and 1. , 8 hours overtime. 15 minutes after the final addition, the reaction mixture was diluted with ethyl acetate (200 mL) and washed successively with 2N hydrochloric acid, 5 'sodium bicarbonate solution. sodium and water, dried and evaporated to a red crystalline solid. We subjected this solid to a
plc in a mixture of chloroform and acetone (19: 1) (3 trials). The more polar band gave a pale pink solid consisting of the title S-chloromethyl ester (134 mg), identical to a thentical sample of product according to tlc

Preparation XLII
S-Chloromethyl 9 &alpha; -fluoro-11ss, 17 &alpha; -dihydroxy-16-methylene-3- oxoandrosta-1,4-diene-17ss-carbothioate (XLII)
A solution of the product of the preparation was stirred
XLI (400 mg) in trifluoroacetic acid (16 ml), at room temperature. After 5.5 hours, the reaction mixture was evaporated almost to dryness and the residue dissolved in ethyl acetate (100 ml).

The solution was washed with 5% sodium bicarbonate solution and water, dried and evaporated to a yellowish-green foam (466 mg). The foam was subjected to p.l.c. in a mixture of chloroform and acetone (9: 1) (3 tests). A fraction (80 mg) of the main band (315 mg) was crystallized twice in acetone, so as to obtain white crystals of the 16-methylene-17 -alcohol indicated in the title (48 mg), PF 242-243, #D +360 (c 0.50).

Preparation XLIII
9a-Fluoro-170c-hydroxy-16ss-methyl-3,11-dioxoandrosta 1,4-diene-17ss-carboxylic acid (XLIII)
A stirred suspension of 9α-fluoro-17,21-dihydroxy-16ss-methylandrosta-1,4-diene-3,11,20-trione (4.842 g) in tetrahydrofuran (50 mL) in ice and was cooled. It was treated, dropwise and over 5 minutes, with a solution of periodic acid (4.255 g) in water (15 ml). The reaction was stirred at 220 for 2.25 hours, by which time most of the suspension had dissolved.

The solvent was removed in vacuo, with the periodic addition of water so as to maintain the original volume. The precipitate thus obtained was filtered off, washed with water and dried in air and in vacuo, so as to collect the carboxylic acid indicated in the title in the form of prisms. cream (4.55 g) PF 270-272 (dec.), #D +1360 (c 1.04, dimethyl sulfoxide).

XLIV preparation
9 &alpha; -fluoro-11ss, 17 &alpha; -dihydroxy-16ss-methyl-3-oxoandrosta- 1,4-diene-17ss-carbothioic acid (XLIV)
A stirred solution of 9α-fluoro 11ss, 17a-dihydroxy-16ss-methyl-3-oxoandrostaw diene-17ss-carboxylic acid in dry N, N-dimethylformamide (15 ml) was cooled to -5 under an atmosphere of. nitrogen and treated with N,
N'-carbonyldiimidazole (0.435 g) and the reaction mixture was stirred at -5 for 18 hours. Hydrogen sulfide gas was bubbled through the reaction mixture for 5 minutes and the solution stirred for a further 4 hours, gradually allowing it to warm to 220. The reaction mixture was poured into water. ethyl acetate and the solution thus obtained was washed with 2N hydrochloric acid and water, then extracted with 2N sodium carbonate solution (3 x 50 ml). The combined extracts were washed with ethyl acetate (60 ml), then covered with an additional layer of ethyl acetate (100 ml) and acidified with acid. hydrochloric acid to pH 1.0 The aqueous layer was extracted with additional ethyl acetate -and the extracts were washed with water and saturated sodium chloride solution, followed by they were dried and the solvent removed in vacuo, so as to obtain a white solid which was crystallized twice from ethyl acetate, so as to obtain the carbothiolic acid indicated in the title (0.315 g) PF 1982010 (dec.), #D + 1890 (c 0.71).

XLV preparation
9 &alpha; -fluoro-17 &alpha; -hydroxy-16ss-methyl-3,11-dioxoandrosta- 1,4-diene-17ss-carbothioic acid (XLV)
A stirred solution of the product of Preparation XLIII (5.587 g) in dry N, N-dimethylformamide (150 ml) at 200 and under a nitrogen atmosphere was treated with
N, N'-carbonyldiimidazole (4.847 g) and the reaction mixture was stirred at 200 for 4 hours. Hydrogen sulfide gas was bubbled through the reaction mixture for 10 minutes and the solution stirred for an additional 1 hour. The solution was poured onto ice (300 ml) and 2N hydrochloric acid (100 ml), so as to obtain a buff precipitate. This precipitate was filtered off, dried in air. overnight (6.268 g) and crystallized from ethyl acetate to collect the title carbathiolic acid (3.761 g) as white prisms, having a melting point from 215-218, #D +143 (c 0.88, dimethylformamide).

XLVI preparation
9a-Fluoro-17a-hydroxv-1 6methyl-34 II -dioxoandrosta- 1,4-diene-17ss-carbothioic acid (XLVI)
A stirred solution of the product of Preparation XLIII (1.059 g) in dry N, N-dimethylformamide (50 ml), at 200 and under nitrogen atmosphere, was treated with
N, N'-thiocarbonyldiimidazole (1.368 g) and the reaction mixture was stirred at 200 for 4 hours. Hydrogen sulfide gas was bubbled through the reaction mixture for 5 minutes and the solution stirred for an additional 1 hour. The reaction mixture was partitioned between ethyl acetate (100 ml) and ethyl acetate (100 ml) and ethyl acetate (100 ml). 2N hydrochloric acid (100ml) and the organic phase was washed with 2N hydrochloric acid (100ml) and water (2 x 100ml) and extracted with 2N sodium carbonate solution (2 x 75 ml). The combined extracts were washed with ethyl acetate (50 ml), then covered with ethyl acetate (100 ml) and acidified with hydrochloric acid to a temperature. pH of 1.

The aqueous layer was extracted with additional ethyl acetate (50 ml) and the combined extracts were washed with water, saturated sodium chloride solution, dried and dried. the solvent was removed therefrom in vacuo. The residues were crystallized from ethyl acetate, so as to collect the carbo thiolic acid indicated in the title (0.559), PF 212-219 #D +145 (c 0.81, dimethylformamide)
XLVII Preparation
S-Chloromethyl 9 &alpha; -fluoro-11ss, 17 &alpha;; - dihydroxy-16ss-methyl-3-oxoandrosta-1,4-diene-17ss-carbothioate (XLVII)
A stirred solution of the product of Preparation XLIV (0.169 g) and sodium bicarbonate (0.040 g) in N, N-dimethylformamide (6 ml) was treated with bromochioromethane (0.1 ml) and the procedure continued. stirring at 220 for 1 hour. The reaction mixture was diluted with ethyl acetate (100 ml) and the solution was successively washed with 2N hydrochloric acid, water, 2N sodium carbonate solution, water. and saturated sodium chloride solution, then dried and the solvent removed therefrom in vacuo. The residue was crystallized twice from ethyl acetate to obtain the title S-chloromethylthiolic ester (0.193 g) as white plaques solvated with ethyl acetate. (1 mole), mp 1261300, #D +147.50 (c 0.64).

L- / D
9 &alpha; -fluoro-16ss-methyl-3,11-dioxo-17 &alpha; -propionyloxy- androsta-1,4-diene-17ss-carbothioic acid (XLVIII)
A stirred solution of the product of Preparation XLV (0.485 g) and triethylamine (0.57 ml) in dichloromethane in a mixture of ice and salt was cooled, treated with propionyl chloride (0, 43ml) and the reaction mixture was stirred at 0 for 1.5 hours. The mixture was partitioned between ethyl acetate (75ml) and 2N sodium carbonate solution (75ml) and washed. the organic layer successively with additional 2N sodium carbonate solution, water, 2N hydrochloric acid, water and saturated sodium chloride solution, then dried and removed the solvent under vacuum so as to obtain a yellow crystalline solid (0.562 g). This product was dissolved in acetone (10 ml), diethylamine (1.0 ml) was added and the reaction mixture was stirred at 220 for 1.25 hours. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (30ml) and 2N hydrochloric acid (30ml). The ethyl acetate layer was washed with water and extracted with 2N sodium carbonate solution (2 x 30 mL). The combined extracts were washed with ethyl acetate (30ml) and covered with ethyl acetate (60ml) and acidified to pH 1.0 with acid. The ethyl acetate layer was washed with water and saturated sodium chloride solution, then dried and the solvent removed in vacuo, to obtain a solid. white which was crystallized twice from ethyl acetate, so as to obtain the ester indicated in the title (0.290 g), mp 173-170, #D +1480 (c 1.03) .

XLIX preparation
S-Chloromethyl 9 &alpha; -fluoro-17 &alpha; -hydroxy-16ss-methyl-3,11-dioxoandrosta-1,4-diene-17ss-carbothioate (XLIX)
A solution of the product of the preparation was processed
XLV (5.006g) and sodium bicarbonate (1.612g) in N, N-dimethylacetamide (50ml) with bromochloromethane (1.24ml) and the reaction mixture was stirred at 220 for 3.3 hours. The solution was diluted with ethyl acetate (70 ml) and washed successively with 2N hydrochloric acid, water, sodium methabisulfite solution, water and a solution. saturated sodium chloride solution, then dried and the solvent removed in vacuo to obtain a cream-colored solid (3.638 g). The analytical sample was obtained after plc of preparation ( silica gel, developed with a mixture of chloroform and acetone 9: 1) and the product crystallized from ethyl acetate as colorless prisms of the title ester (0.262 g) , PF 223-228, #D +251 (c 1,2).

Preparation L
9 &alpha; -fluoro-11ss-hydroxy-16ss-methyl-3-oxo-17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carbothioic acid (L)
A stirred solution of the product of Example XLIV (0.511 g) in dichloromethane (20 m) containing triethylamine (0.6 ml) was cooled to 20 and treated with propionyl chloride (0, 45 ml) and the reaction mixture was stirred at 20 for 2.5 hours.

The reaction mixture was distributed between ethyl acetate and sodium bicarbonate and the organic phase was washed with water, 2N hydrochloric acid, water and a saturated solution of. Sodium chloride, dried and the solvent removed in vacuo to give a colorless solid (0.634 g).

This product was dissolved in acetone (30 ml), diethylamine (1.5 ml) added and the clear solution stirred at 22% for 55 minutes. The reaction mixture was diluted with ethyl acetate (soma) and washed with 2N hydrochloric acid and water, then extracted with a 5% sodium carbonate solution. The combined extracts were acidified with 2N hydrochloric acid to pH 1 and then extracted with ethyl acetate.

The combined extracts were washed with water and saturated sodium chloride solution and dried and the solvent removed in vacuo, to obtain a colorless broth (0.522 g) which was crystallized. in ethyl acetate, so as to obtain the ester indicated in the title in the form of colorless prisms (0.307 g); M.p. 174-179, #D + 107 (c 1.0).

LI preparation
9a-Fluoro-1 1 ss .1 7a-dihydroxv-1 6-methylene-3-o xo- androsta-1,4-diene-17ss-carbothioic acid (LI)
A solution of 9a-fluoro-11ss, 17a-dihydroxy-16-methylene-3-oxoandrosta-1,4-diene-17ss-carboxylic acid (0.218 g) in dry N, N-dimethylformamide (10 ml) was treated. ), at 220, under a nitrogen atmosphere, with N, N'carbonyldiimidazole (0.254 g) and the reaction mixture was stirred at 220 for 4 hours. Hydrogen sulfide gas was bubbled through the reaction mixture for 5 minutes and the then pale green mixture was stirred for 1 hour at 220 The mixture was diluted with ethyl acetate (150 mL). and the solution was washed with 2N hydrochloric acid, water and saturated sodium chloride solution, dried and the solvent removed in vacuo to obtain a yellow broth (0.222 g) which was crystallized twice from ethyl acetate, so as to obtain the title carbothiolic acid (0.078 g), in the form of colorless prisms, decomposing to about 2500 without fusion, #D +117 (c 0.32).

LII preparation
9 &alpha; -fluoro-11ss, 17 &alpha; -dihydroxy-3-oxoandrosta-1,4-diene-17ss-carboxylic acid (LII)
The 9 α -fluoroprednisolone suspension (10 g) was stirred in dry tetrahydrofuran (55 ml) and treated with a solution of periodic acid (9.0 g) in water (90 ml). ) and the mixture was stirred at 220 for 2 hours. It was then poured into a mixture of ice and water (about 400 ml) and, after stirring for 15 minutes, the solid product was collected, washed with water and left on. dried to obtain the title compound as a solid (9.42 g).

A fraction of product recrystallized from methanol had a melting point of 289-293 Z 7D +660 (c 0.73; methanol).

Preparation LIII
9 &alpha; -fluoro-11ss, 17 &alpha; -dihydroxy-3-oxoandrosta-1,4-diene-17ss-carbothioic acid (LIII)
A solution of 9 &alpha; -fluoro-11ss, 17 &alpha; - dihydroxy-3-oxoandrosta-1,4-diene-17ss-carboxylic acid (4.5g) in dry dimethylformamide (100ml) was stirred under an atmosphere of. nitrogen, with N; N'-carbonyldiimidazole (4.04 g) at 220 for 4 hours. Hydrogen sulfide was then passed through the solution for 30 minutes and stored for an additional 15 minutes. The mixture was poured into a mixture of 2N hydrochloric acid (250 mL) and ice (approx. 100 g) and the precipitate thus obtained was collected, washed with water and dried to collect a white solid (4.56 g).

A fraction of product (120 mg) was recrystallized from ethanol, so as to obtain the thioacid indicated in the title in the form of colorless crystals (70 mg), m.p.

222-225, #D + 116 (c 0.57).

LIV preparation
Acid 6 &alpha;, 9 &alpha; -dilfuoro-11ss, 17 &alpha; -dihydroxy-16 &alpha; -methyl-3-oxcandrosta-1. 4-diene-17ss-carbothio igue (LIV)
A solution of e 6 &alpha;, 9 &alpha; -difluoro-11ss, 17a-dihydroxy-16 -methyl-3-oxoandrosta-1,4-diene-17ss-carboxylic acid (12.0 g) in dry dimethylformamide was stirred. (250ml) and treated with N, N'-carbonyldiimidazole (9.94g) under nitrogen atmosphere at room temperature. After 4 hours, the hydrogen sulfide was passed through the solution for 0.5 hour and the mixture was stored for an additional 0.5 hour. The reaction mixture was poured into 2N hydrochloric acid (500 ml) containing ice (about 250 g). The precipitate thus obtained was collected, washed with water and dried. under vacuum, so as to obtain the thioacid indicated in the title in the form of a white solid (11.47 g),
PF 230-232, a7D +940 (c 0.91).

LV preparation
17 &alpha; -acetoxy-6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha; -methyl-3-oxoandrosta-1,4-diene-17ss-carboxylic acid (LV)
A solution of the product of the preparation was stirred
LIV (1.625g) and triethylamine (2.0ml) in dichloromethane (75ml) at about OOC, treated, dropwise, with acetyl chloride (1.275ml), then treated. stirred at this temperature for 1.25 hours.

The mixture was washed with 2N sodium carbonate (50ml) water, 2N hydrochloric acid (50ml), water (3 x 50ml), brine (50ml), then it was dried and evaporated to obtain a white solid (1.91 g).

This product was dissolved in acetone (40ml) and stirred with diethylamine (4ml) at 270C for 45 minutes. The mixture was concentrated to a volume of about 25ml and poured into 2N hydrochloric acid (100ml) containing ice (about 100g).

After stirring the mixture, the precipitate thus obtained was collected, washed with water and dried to obtain a solid (1.685 g). A fraction of product (400 mg) was recrystallized from ethyl acetate to give the title 17-acetate (280 mg), m.p. 175-177.

LVI preparation
17 &alpha; -butyryloxy-6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha; - methyl-3-oxoandrosta-1,4-diene-17ss-carbothioic acid (LVI)
By repeating the same procedure as described in Preparation LV, the product of Preparation LIV (2.0 g) was converted with butyryl chloride (1.5 ml) instead of acetyl chloride, to the product. Title 17α-butyrate (2.08 g), a portion of the product was recrystallized from ethyl acetate and then had a melting point of 155-157.

LVII preparation
9a-Fluoro Il 11ss-hydroxy-3-oxo-17 &alpha; -propionyloxyandrosta- 1,4-diene-17ss carbothioic acid (LVI)
By repeating a procedure substantially similar to that described in Preparation LV, the product of Preparation LIII (3.8 g) was converted using propionyl chloride (3.9 mL) instead of acetyl chloride and , after aminolysis of the intermediate with trietylamine (10.35 ml), to the title 17αSpropionate (4.17 g). A fraction of the product (350 mg) was recrystallized from ethyl acetate, so as to obtain colorless crystals (165 mg), mp 135 1380, #D +720 (c 0.92).

Preparation LVIII
6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha; -methyl-3-oxo-17 &alpha; - propionyloxyandrosta-1,4-diene-17ss-carbothioic acid (LVIII)
A solution of the product of Preparation LIV (5.0 g) and triethylamine (6.15 ml) in dichloromethane (140 ml) was cooled with a mixture of ice and salt and treated, dropwise. drop, with propionyl chloride (4.74 ml). The reaction mixture was further stirred at about 0 C for 0.75 hour, then washed successively with 2N sodium carbonate, water, 2N hydrochloric acid, water and brine. . After drying, the solvent was removed so as to obtain. a white solid (6.35 g). This solid was dissolved in acetone (120 ml) and diethylamine (12.5 ml); after stirring at room temperature for 1 hour, the volume was reduced to about 75 ml. The solution was poured into 2N hydrochloric acid (200 ml) containing ice (about 300 g) and the precipitate thus obtained was collected, washed with water and dried under. empty so as to obtain a white solid (5.17 g) having a melting point of 152-155.

Recrystallization of a fraction of the product (400 mg) from ethyl acetate gave the title thioacid 7α-propionate> analytically pure and in the form of colorless crystals (290 mg), PF 161-164, Za7D 270 (c 0.95) whose infrared spectrum in the solid state (in Nujol) revealed a crystalline form different from that of the sample obtained in Preparation XIX.

LIX preparation
S-Chloromethyl 9 &alpha; -fluoro-16ss-methyl-3,11-dioxo-17 &alpha; - propionyloxyandrosta-1,4-diene-17ss-carbothiate (LIX)
A solution of the product of the preparation was stirred
XLIX (409 mg) in propionic acid (5 ml), trifluoroacetic anhydride (2 ml) and toluene p-sulfonic acid (0.1 ml of a dry chloroform solution, 80 mg / ml ), at 220, for 2.75 days. The non-acidic product was isolated by extraction with ethyl acetate after pouring it into saturated sodium bicarbonate solution. The crude material was chromatographed on silica in a mixture of chloroform and acetone ( 14: 1) and crystallized from a mixture of ethyl acetate and petroleum (pe 60-80 C), so as to obtain the propionate indicated in the title, in the form of colorless crystals having a mp 205 2060, La7 +95 (c 1.15).

Preparation LX S-Chloromethyl 9 &alpha; -fluoro-11ss, 17 &alpha; -dihydroxy-16ss-methyl-3-oxoandrosta-1,4-diene-17ss-carbothioate (LX)
A suspension of the product of the preparation was stirred
XLIX (102 mg) in ethanol (2.5 ml) with sodium borohydride (10 mg) at 220, for 1 hour. The reaction mixture was treated with acetone (5 ml), then concentrated to almost dryness; the residue was dissolved in ethyl acetate (20 ml), washed with N hydrochloric acid, water and brine.

After drying, the organic solvent was removed to obtain the title 11ss-alcohol, in the form of a colorless foam (103 mg), the main component of which was equipolar with an authentic sample at the time of drying. silica, chloroform-acetone thin-layer chromatographic comparison, 9: 1).

LXI preparation
9a-Luoro-11ss-hydroxy-160-methyl-3-oxo-1 acid? -proEionyl-
oxyandrosta-1,4-diene-17ss-carbothioic acid (LXI)
Method A A solution of 9a-fluoro-1p-hydroxy-16ss-methyl-3-oxo-17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carboxylic acid (603 mg, solvated with acetate) was stirred. ethyl 0.75 mol) and N, N'-carbonyldi (1,2,4-triazole) (0.997 mg) in dry dimethylformamide (45 mL), under nitrogen atmosphere, at about 220, for 18 ,5 hours. A solution (15 ml), prepared from sodium hydride (305 mg) in dimethylformamide was added by saturation with hydrogen sulfide, and stirring was continued at room temperature for 3 days. The reaction mixture was poured into 1 t 2N hydrochloric acid (200 ml) and the product was extracted with ethyl acetate (3x). The organic extracts were combined, washed with water and re-extracted with 5% sodium carbonate solution; the alkaline extracts were acidified with hydrochloric acid and extracted with ethyl acetate (3x). After washing with water and brine, the organic extracts were dried and left to dry. concentrated to low volume; the title thioacid separated as cream-colored crystals (101 mg), the only major constituent of which was identified by comparison with an authentic sample using 1H nuclear magnetic resonance (nmr) and by tlc (silica, chloroform-acetone 4: 1).

Method B
A solution of 9a-fluoro-11 (3-hydroxy-16ss-methyl-3-oxo-17 -propionyloxyandrosta-1,4-diene-170-carboxylic acid (701 mg, solvate with acetate d) was stirred. ethyl 0.75 mol) and N, N'-carbonyldiimidazole (473 mg) in dry dimethylformamide (26 mg), under nitrogen atmosphere and at about 220C, for 19.5 hours, then treated with a solution (10 ml) of sodium hydride (60 c / o dispersion in oil, 233 mg) in dimethylformamide (10 ml) saturated with hydrogen sulphide. The mixture thus obtained was then stirred at room temperature for 5.5 hours. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with 2N hydrochloric acid, water and brine, followed by dried and evaporated to a foam (186 mg). Title thioacid was found to be the major component of the product when compared to an authentic sample according to HMR and tlc (silica, chloroform-acetone (4: 1), and chloroform-acetone-acetic acid (30: 8: 1).

Method C
Following a reaction substantially identical to that described in Method A, the carboxylic acid was treated with 1,1'-carbonyldibenzotriazole (1.587 g) instead of
N, N'-carbonyldi (1,2,4-triazole) at room temperature for 6 hours. After the addition of the solution obtained from hydrogen sulfide and sodium hydride in dimethylformamide, the reaction was continued for 41.5 hours. The crude product was obtained in the form of a foam; tlc (silica, chloroform-acetone 4: 1 and chloroform-acetone-acetic acid 30: 8: 1) revealed that the thioacid indicated in the title was present as a major constituent, compared to an authentic sample.

Preparation LXII
S-Chloromethyl 6a, 9a-difluoro-I 6a-methyl-3-oxo-I 7a-propionaloxy-11ss-trifluoroacetoxyandrosta-1,4-diene-17ss-carbothioate (LXII)
A solution of the compound of Example 5 was worked up
(described later in this specification) (100 mg) in dry tetrahydrofuran (2 ml) and pyridine (0.1 ml) with trifluoroacetic anhydride (0.05 ml) and the mixture was stored at room temperature for 0.5 hour. The reaction mixture was poured into water and the product was extracted with ethyl acetate (3x). The organic extracts were washed with water, dried and evaporated so as to obtain the trifluoroacetate indicated in the homogeneous titer (116 mg) according to the spectroscopy of 1H rmn (singlet at 8.59, 19protons, in deuterechloroform) and tlc on silica (acetone-petroleum, PE 40-6O0C, 1: 3) . An analytical sample of the product obtained from a mixture of ether and pentane had a melting point of 158-162, #D + 560 (c 0.23).

Example 1
S-Chloromethyl 9 &alpha; -fluoro-11ss-hydroxy-16ss-methyl-3-oxo17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carbothioate
Method A
A solution of the product of the preparation was processed
I (2.115 g) in dimethylacetamide (7 ml) with sodium bicarbonate (592 mg) and bromochloromethane (2.46 ml) and the mixture was stirred at room temperature. After two hours, the reaction mixture was diluted with ethyl acetate (5 ml) and washed with 5% sodium bicarbonate solution and water, dried and dried. it was evaporated to give an orange foam (1.560 g) .Plc in chlorform-acetone (19: 1) gave an off-white foam (803 mg) which was crystallized twice from methanol of way to get whitish needles of the ester
Title S-Chloromethyl (668 mg), PF

212-214 C, #D + 44 (c 1.06).

Method B
The title compound was prepared in a similar manner using chloroiodomethane instead of chlorobromomethane.

Method C
Sodium borohydride (19 mg) was added to a solution of Product II (230 mg) in ethanol (3.5 ml) and the solution was stirred at room temperature. After 20 minutes, acetone (1 ml) was added and the solution was concentrated to about a quarter of its original volume. Then ethyl acetate (30 ml) was added, the solution was washed with N hydrochloric acid and water, dried and evaporated to obtain a foam. white (239 mg) Plc in a mixture of chloroform and acetone (19: 1) gave a white foam (188 mg) which was crystallized twice from methanol to obtain needles white of the title S-chloromethyl ester (158 mg) PF 210-212, #D +440 (c 1.07).

Example 2
S-Chloromethyl 9 &alpha; -fluoro-11ss-hydroxy-16 &alpha; -methyl-3-oxo-17 &alpha; - propionyloxyandrosta-1,4-diene-17ss-carbothioate
A solution of IV (0.927g) in dimethylacetamide (4ml) was treated with sodium bicarbonate (0.256g) and bromochloromethane (0.20ml) and the mixture was stirred at 220 for 2 hours. The reaction mixture was partitioned between ethyl acetate (100ml) and 2N hydrochloric acid (20ml) 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 crystallized. the crude product (757 mg) twice in acetone, so as to obtain the chloromethyl-thiolic ester indicated in the title (0.367 g), PF 247-250, #D +50.50 (c 0, 63), Example 3
S-Chloromethyl 11ss-hydroxy-3-oxo-17 &alpha; -propionyloxyandrosta- 1,4-diene-17ss-carbothioate
A solution of crude XV (2.366 g) in dimethylacetamide (10 ml) was treated with sodium bicarbonate (756 mg) and bromochloromethane (0.59 ml) at 220, for 16 hours. It was then partitioned between ethyl acetate and 2N hydrochloric acid and the aqueous layer was extracted with a further quantity of ethyl acetate. The combined organic phases were washed successively with l. 2N hydrochloric acid, water, sodium bicarbonate, water, saturated brine and then dried and solvent removed to obtain a yellow foam. The neutral product was purified by preparative hplc over silica (15R) in 7% acetone in chloroform and the main product was crystallized from acetone to obtain the chloromethyl / thiol ester. indicated in the title (0.522 g), PF 117-120, Ja7D +560 (c 1.3).

The / 4
S-Chloromethyl 6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha;, 17 &alpha; -isopropylidenedioxy-3-oxoandrosta-1,4-diene-17ss-carbothioate
A stirred solution of IX (1.360g) in N, N-dimethylacetamide (10ml) was treated with sodium bicarbonate (0.377g) and bromochioromethane (0.3ml) and stirring continued for 1 , 5 hours. Ethyl acetate (100 ml) was added and the solution thus obtained was washed successively with 2N hydrochloric acid, liteau, sodium meta-bisulfite solution, water, sodium bicarbonate solution, water and saturated sodium chloride solution, then the solution was dried and concentrated, crystallization taking place in this manner. The crystallized product (0.765 g) was purified by plc on silica gel, developing with a mixture of chloroform and acetone (9: 1). The main band was eluted with ethyl acetate and crystallized from ethyl acetate to give S-chloromethyl thioester (0.475 g) as white prisms, PF

271-278, #D +116, (c 0.96, dimethyl sulfoxide).

Example 5
S-Chloromethyl 6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha; -methyl-3-oxo-17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carbothioate
A solution of XIX (0.546 g) in dimethylacetamide (3 ml) was treated with sodium bicarbonate (202 mg) and bromochioromethane (0.16 ml) at 220 for 3 hours. The mixture was treated with 2N hydrochloric acid (50 ml) 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 removed. Two recrystallizations from ethyl acetate gave the title chloromethyl thioester (0.404 g), mp 272-275, 7D +490 (c 0.35).

Example 6-15
By repeating the same general procedure as that described in Example 1 (Method A), but using as starting material 17ss-carbothioic acid corresponding to the desired 17ss-carbothioate (the details of the method being gathered in the table III which follows) the following compounds were prepared 6. S-Chloromethyl 11ss-hydroxy-16ss-methyl-3-oxo-17 &alpha; - propionyloxyandrosta-1,4-diene-17ss-carbothioate, PF

192-193, [&alpha;] + 65 (c 1.05).

7. S-Chloromethyl 9 &alpha; -fluoro-11ss-hydroxy-16-methylene-
3-oXo-17a-propionyloxyandrosta-1,4-diene-17ss-c bothioate,
PF 212-221, [α] D -56 (c 0.99).

8. S-Chloromethyl 17 &alpha; -acetoxy-9 &alpha; -fluoro-11ss-hydroxy-16ss-methyl-3-oxoandrosta-1,4-diene-17ss-carbothioate,
PF 220-223, [&alpha;] D + 39.5 (c 1.06).

9. S-Chloromethyl 17 &alpha; -butyryloxy-9 &alpha; -fluoro-11ss-
hydroxy-16ss-methyl-3-oxoandrosta-1,4-diene-17ss-carbothi
oate, PF 172-17S0, lalD +460 (c 1ss10).

10. S-Chloromethyl 9 &alpha; -fluoro-11ss-hydroxy-17 &alpha; -
isobutyryloxy-16ss-methyl-3-oxoandrosta-1,4-diene-17ss carbothioate, PF 234-239, [&alpha;] D +43 (c 1.00).

11. S-Chloromethyl 9 &alpha; -fluoro-11ss-hydroxy-3-oxo-17 &alpha; - propionyloxyandrosta-1,4-diene-17ss-carbothioate, P.F.

196-1990, EaJ +380 (c 0.97).

12. S-Chloromethyl 6 &alpha; -fluoro-11ss-hydroxy-3-oxo-17 &alpha; - propionyloxyandrosta-1,4-diene-17ss-carbothioate, P.F.

188-191, [&alpha;] D + 48 (c 0.91).

13. S-Chloromethyl 17 &alpha; -acetoxy-6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha; -methyl-3-oxoandrosta-1,4-diene-17ss-carbothioate,
PF 280-283, [&alpha;] D +45 (c 0.80).

14. S-Chloromethyl 17 &alpha; -butryloxy-6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha; -methyl-3-oxoandrosta-1,4-diene-17ss-carbothioate,
PF 235-238, [&alpha;] D +49 (c 0.65).

15. S-Chloromethyl 9 &alpha; -fluoro-11ss-hydroxy-16 &alpha;, 17 &alpha; - isopropylidenedioxy-3-oxoandrosta-1,4-diene-17ss-carbothioate
PF 276-280 (dec), [a] D +1270 (c 0.51; dimethyl sulfoxide)

<SEP> Ex <SEP> REAGENT <SEP> NaHCO3 <SEP> STEROID <SEP> SOL- <SEP> DURATION <SEP> OF <SEP> PLC <SEP> SOLVENT <SEP> PRODUCT
<tb><SEP> QUANTI- <SEP> VANT <SEP> REACTION <SEP> (Silica) <SEP> DE <SEP> CRIS- <SEP> (mg)
<tb> No. <SEP> (ml) <SEP> (mg)
<tb><SEP> TE <SEP> A <SEP> LA <SEP> TEM- <SEP> CHCl3- <SEP> TALLISA (DMA)
<tb><SEP> (mg) <SEP> PERATURE <SEP> TION
<tb> Me2CO
<tb><SEP> (ml) <SEP> AMBIENT
<tb><SEP> 6 <SEP> BrCH2Cl <SEP> 300 <SEP> 981 <SEP> 5 <SEP> 3 <SEP> - <SEP> EA <SEP> 826
<tb><SEP> (0.25)
<tb><SEP> 7 <SEP> BrCH2Cl <SEP> 749 <SEP> 2000 <SEP> il <SEP> 1.5 <SEP> 19: 1 <SEP> 201
<tb><SEP> (0.58) <SEP>
<tb><SEP> 8 <SEP> BrCH2Cl <SEP> 565 <SEP> 1955 <SEP> 7 <SEP> 2,0 <SEP> - <SEP> EA <SEP> 307+
<tb><SEP> (0.44)
<tb><SEP> 9 <SEP> BrCH2Cl <SEP> 421 <SEP> 1501 <SEP> 10 <SEP> 1.8 <SEP> 14 :: 1 <SEP> EA <SEP> 871
<tb><SEP> (0.32)
<tb><SEP> 10 <SEP> BrCH2Cl <SEP> 121 <SEP> 385 <SEP> 3 <SEP> 2.75 <SEP> - <SEP> EA <SEP> 255
<tb><SEP> (0.084)
<tb><SEP> 11 <SEP> BrCH2Cl <SEP> 1100 <SEP> 2750 <SEP> 20 <SEP> 1,25 <SEP> - <SEP> M <SEP> 1600
<tb><SEP> (0.90)
<tb><SEP> 12 <SEP> BrCH2Cl <SEP> 1080 <SEP> 2740 <SEP> 20 <SEP> 2 <SEP> - <SEP> EA-P <SEP> 2460
<tb><SEP> (0.86)
<tb><SEP> 13 <SEP> BrCH2Cl <SEP> 2500 <SEP> 6600 <SEP> 40 <SEP> 1.75 <SEP> - <SEP> A <SEP> 5410
<tb><SEP> (2.00) <SEP>
<tb><SEP> 14 <SEP> BrCH2l <SEP> 1600 <SEP> 4600 <SEP> 46 <SEP> 2 <SEP> - <SEP> A <SEP> 2140
<tb><SEP> 1 <SEP>
<tb><SEP> 15 <SEP> BrCH2Cl <SEP> 615 <SEP> 1600 <SEP> 12 <SEP> 1.5 <SEP> 4: 1 <SEP> A <SEP> 244 **
<tb><SEP> (0.48)
<tb>
Notes: EA = ethyl acetate
A = acetone
M = methanol
p = petroleum PE 60-800 * Obtained from a fraction (400 mg) of the product
crude (2.35 g).

** Obtained from a fraction (300 mg) of the product
crude (1.72 g).

Example 16
S-Chloromethyl 9 &alpha; -chloro-11ss-hydroxy-16ss-methyl-3-oxo- 17 &alpha; -propionyloxyandrosta-1,4-diene-17b-carbothioate and S-Chloromethyl 9ss, 11ss-epoxy-16ss-methyl-3- oxo-17 &alpha; -pro- pionylandrosta-1,4-diene-17ss-carbothioate
A solution of mixture XIV (1.032 g) in dimethylacetamide (5 ml) was treated with sodium bicarbonate (0.203 g), this treatment being followed by treatment with chlorobromomethane (0.2 ml) and the mixture was stirred. reaction at 220 for 1.5 hours, after which time it was partitioned between ethyl acetate (50 ml) and 2N hydrochloric acid (35 ml). The aqueous phase was extracted with an additional amount of ethyl acetate (2 x 30 mL) and the combined extracts were washed with 2N hydrochloric acid, water, saturated sodium bicarbonate solution, water, solution saturated with sodium chloride and dried and the solvent removed therefrom in vacuo to obtain a cream-colored foam (0.856 g) containing a mixture of the S-chloromethyl esters.

These products were separated by p.l.c. on silica, developing with a mixture of chloroform and acetone (19: 1). The more polar component (0.306 g) was crystallized twice from ethyl acetate, so as to obtain S-chloromethyl 9a-chlorow -hydroxy-16ss-methyl-3-oxo-17 -propionyloxy- androsta-1,4-diene-17P-carbothioate (0.232 g) as white plates PF 222-229 La7 +700 (c 1.23).

The less polar component (0.210 g) was crystallized from a mixture of acetone and petroleum, so as to obtain S-chloromethyl 9ss, 11ss-epoxy-16ss-methyl-3-oxo-17 -propionyloxyandrosta-1, 4-diene-17ss-carbothioate (0.065 g), mp 169-173, #D +490 (c 0.60).

Example 17
S-Fluoromethyl 9 &alpha; -fluoro-11ss-hydroxy-16ss-methyl-3-oxo- 17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carbothioate
The XXV (660 mg) was stirred with a suspension of silver fluoride (1.421 g) in acetonitrile (8.5 ml) in the dark at room temperature. After 72 hours, the reaction mixture was diluted with ethyl acetate (200 mL) and filtered through a pad of kieselguhr. The filtrate was washed with water, dried and evaporated to give a white foam (517 mg). The plc in a mixture of chloroform and cyclohexane (19: 1) and chloroform gave an off-white foam (270 mg) which was crystallized in methanol, then in a mixture of methanol and methyl ether, so as to obtain the S-fluoromethyl ester indicated in the title (176 mg), PF 241-242, #D +97.50 (c 0.98).

Example 18
S-Fluoromethyl 9 &alpha; -fluoro-11ss-hydroxy-16 &alpha; -methyl-3-oxo- 17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carbothioate
A solution of XXX (0.640g) in acetonitrile (8ml) was treated with dry silver fluoride (1.511g) and stirred in the dark at 220 for 46.5 hours.

The mixture was diluted with ethyl acetate (200 mL) and filtered through kieselguhr. The solution was washed with 2N hydrochloric acid, water and saturated sodium chloride solution and the solvent removed in vacuo to give a pale yellow foam (0.504 g). This foam was chromatographed (plc) on silica gel, developing with 5% acetone in chloroform. The main band was eluted with ethyl acetate and the product was crystallized twice from acetone to obtain thio esteijfluoromethyl (0.244 g), mp 242-243 (dec.),
+37 (c 0.75).

L- / 19
S-Fluoromethyl 6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha; -methyl-17 &alpha; - propionyl-3-oxoandrosta-1,4-diene-17ss-carbothioate
A solution of XXXI (310 mg) in acetonitrile (10 ml) was stirred with silver fluoride (947 mg) for 3 days at room temperature in the dark.

Ethyl acetate (100 mL) was added and the mixture filtered through kieselguhr. The filtrate was washed successively with 2N hydrochloric acid, water, saturated brine and then dried. The solvent was removed and the residue was subjected to b.l.c. in chloroform, then in a mixture of chloroform and acetone (19: 1). The product was eluted with ethyl acetate and crystallized by concentrating the solution, to obtain the title chloromethyl thioester. ((0.075g) m.p. 272-273 (dec.), #D + 30 (c 0.35).

Example 20
S-Fluoromethyl 9 &alpha; -fluoro-11ss-hydroxy-16 &alpha;, 17 &alpha; -isopropylidenedioxy-3-oxoandrosta-1,4-diene-17ss-carbothioate
A suspension of XXXVII (1.290g) in acetonitrile (20ml) was stirred with silver (I) fluoride (2.842g) at room temperature in the dark. After 11 days (there was no starting iodide left, tlc

(chloroform, 6 runs)), the reaction mixture was diluted with ethyl acetate (C400 mL) and filtered through kieselguhr. The filtrate was evaporated to a pale yellow crystalline solid (726 mg) and the kieselguhr was continuously extracted with ethyl acetate in a Soxhlet apparatus to obtain a yellow solid (197 mg). The solid from the filtrate was suspended in a mixture of chloroform and methanol (10: 1) and the insoluble fraction (203 mg) was collected. This fraction was combined with the solid from the Soxhlet extraction in ethyl acetate (300 mL) and filtered through a silica column (Merck 60 silica gel) (50 g). The eluates containing the product (tlc) were combined, washed with water, dried by simultaneous treatment with charcoal and concentrated to a small volume. The white solid thus obtained (276 mg) was collected and recrystallized from ethyl acetate to obtain colorless crystals of the title S-fluoromethyl ester (231 mg), mp 320. -3220C (dec.), #D +1320 (c 0.22, dimethyl sulfoxide).

Example 21
S-Fluoromethyl 6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha;, 17 &alpha; -isopropylidenedioxy-3-oxoandrosta-1, 4-diene-I 7-carbothioate
A solution of XX2NIII (0.804g) in acetonitrile (60ml) was treated with silver fluoride (1.821g) and the reaction mixture was stirred in the dark for 18 hours. The reaction mixture 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 removed in vacuo to obtain a pale cream colored solid (0.636 g). This solid was purified by plc on silica gel, developing twice with a mixture of chloroform and acetone (14: 1). The main band was eluted with ethyl acetate and crystallized five times from ethyl acetate to obtain the title S-chloromethyl thioester (0.118 g) under ia form of white prisms, PF 305-3110C, L7D +1250 (c 473, dimethylsulfoxide).

Examples 22-30
By repeating the same general procedure as that described in Example 17, but using, as starting material, the S-iodomethyl 17ss-carbothioate corresponding to the desired product (the details of the process are collated in Table IV which Following, the following compounds were obtained 22. S-Fluoromethyl 17 &alpha; -acetoxy-9 &alpha; -fluoro-11ss-hydroxy-16ss-methyl-3-oxoandrosta-1,4-diene-17ss-carbothioate,
PF 248 - 249, [&alpha;] D + 101 (c 1.08).

23. S-Fluoromethyl 11ss-hydroxy-3-oxo-17 &alpha; -propionyloxy- androsta-1,4-diene - 17 ss-carbothioate, PF 112-117,
[&alpha;] D +670 (c 0.76).

24. S-Fluoromethyl 11ss-hydroxy-16ss-methyl-3-oxo-17 &alpha; - propionyloxyandrosta-1,4-diene-17ss-carbothioate, P.F.

223-225, [a] D + 1030 (c 0.38).

25. S-Fluoromethyl 9 &alpha; -chloro-11ss-hydroxy-16ss-methyl-3-oxo-17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carbothioate,
PF 182-193, [&alpha;] D + 116 (c 0.75).

26. S-Fluoromethyl 9 &alpha; -fluoro-11ss-hydroxy-16-methylene-3-oxo-17v-propionyloxyandrosta-1,4-diene-17ss-carbothioate,
PF 205-215, [&alpha;] D -58 (c 1.00).

27. S-Fluoromethyl 9 &alpha; -fluoro-11ss-hydroxy-3-oxo-17 &alpha; - propionyloxyandrosta-1,4-diene-17ss-carbothioate, P.F.

207-211, [&alpha;] D + 70 (c 0.88).

28. S-Fluoromethyl 6 &alpha; -fluoro-11ss-hydroxy-3-oxo-17 &alpha; - propionyloxyandrosta-1,4-diene-17ss-carbothioate, P.F.

224-225, [&alpha;] D + 70 (c 0.79).

29. S-Fluoromethyl L7a-acetoxy-Qa, 9a-difluoro-llB-hydroxy-16 &alpha; -methyl-3-oxoandrosta-1,4-diene-17ss-carbothioate
PF 308-310 [&alpha;] D + 29 (c 0.80).

30. S-Fluoromethyl 17 &alpha; -butyryloxy-6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha; -methyl-3-oxoandrosta-1,4-diene-17ss-carbothioate, PF 249-252, [&alpha;] D + 32 (c 1.05).
S-Fluoromethyl 17 &alpha; -acyloxyandrostane-17ss-carbothioates by halogen exchange

<tb> Ex. <SEP> Ag <SEP> F <SEP> STEROID <SEP> OF <SEP> SOLVENT <SEP> DURATION <SEP> OF <SEP> PLC <SEP> SOLVENT <SEP> PRODUCT
<tb> No. <SEP> (mg) <SEP> DEPART <SEP> (MeCN) <SEP> EXACTION <SEP> (Silica) <SEP> DE <SEP> CRIS- <SEP> (mg) <SEP>
<tb><SEP> HALO- <SEP> QUAN- <SEP> (ml) <SEP> (h) <SEP> to <SEP> the <SEP> CHCl3- <SEP> TALLI
<tb><SEP> GENURE <SEP> TITE <SEP> temperature <SEP> Me2CO3 <SEP> SATION
<tb><SEP> (mg) <SEP> ambient <SEP> 2
<tb> 22 <SEP> 3745 <SEP> I <SEP> 1702 <SEP> 22 <SEP> 20 <SEP> 24: 1 <SEP> A <SEP> 477
<tb> 23 <SEP> 2071 <SEP> I <SEP> 1034 <SEP> 10 <SEP> 26 <SEP> 19: 1 <SEP> EA <SEP> 585 *
<tb> 24 <SEP> 1945 <SEP> I <SEP> 850 <SEP> 6 <SEP> 26 <SEP> 19: 1 <SEP> EA <SEP> 166
<tb> 25 <SEP> 1161 <SEP> I <SEP> 550 <SEP> 8 <SEP> 23.5 <SEP> 19 :: 1 <SEP> M <SEP> 106
<tb> 26 <SEP> 3574 <SEP> I <SEP> 1658 <SEP> 26 <SEP> 24 <SEP> 19: 1 <SEP> A <SEP> 300
<tb> 27 <SEP> 700 <SEP> I <SEP> 1000 <SEP> 50 <SEP> 3 <SEP> - <SEP> M <SEP> 470
<tb> 28 <SEP> 462 <SEP> I <SEP> 700 <SEP> 35 <SEP> 2 <SEP> - <SEP> EA-P <SEP> 350
<tb> 29 <SEP> 2600 <SEP> I <SEP> 4000 <SEP> 200 <SEP> 0.75 <SEP> - <SEP> EA <SEP> 2280
<tb> 30 <SEP> 780 <SEP> I <SEP> 1200 <SEP> 60 <SEP> i <SEP> - <SEP> EA <SEP> 755
<tb>
EA = ethyl acetate
A = acetone
M = methanol
P = petroleum PE 60-80 * Purity approx. 95%
Example 31
S-Bromomethyl 9 &alpha; -fluoro-11ss-hydroxy-16ss-methyl-3-oxo-17 &alpha;; - propionyloxyandrosta-1,4-diene-17ss-carbothioate
A solution of XXV (66P mg) in acetone (20 ml) was stirred with lithium bromide (972 mg) at room temperature for 5 days. The reaction mixture was diluted with ethyl acetate (150 mL) and then washed successively with 10% sodium thiosulfate solution and brine, dried and followed. evaporated to collect an off-white foam (624 mg). This product was crystallized twice from a mixture of acetone and petroleum ether (PE 40-600), so as to obtain colorless crystals of the S-bromomethyl ester indicated in the title (499 mg).
PF 186.5-187 C, #D +20 (c 0.99).

Example 32
S-Bromomethyl 6 &alpha;, 9 &alpha; -difluoro-11ss-hydroxy-16 &alpha; -methyl-3-oxo- 17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carbothioate
A solution of XXXI (850 mg) in acetone (25 ml) was stirred with lithium bromide (1.21 g) at about 220C for 5 days. The product was isolated as described in Example 31 and recrystallized twice from ethyl acetate to give colorless crystals (690 mg). These crystals were reprocessed in same reaction conditions for a further 4 days, so as to obtain the pure title S-bromomethyl ester (600 mg), in the form of colorless crystals, from ethyl acetate, PF 255-257, 7D +620 (c 0.82).

Example 33
S-2'-fluor-ethyl 9 &alpha; -fluoro-11ss-hydroxy-16ss-methyl-3-oxo-17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carbothioate
A solution of XXXIX (910 mg) in acetonitrile (20 mL) was stirred with silver (I) fluoride (2.071 g) at room temperature in the dark. After 6 days, the reaction mixture was diluted with ethyl acetate (250 ml) and filtered through kieselguhr. The filtrate was diluted with additional ethyl acetate (150 mL) and washed with water, dried and evaporated to obtain. a white foam (704 mg). Plc in a mixture of chloroform and acetone5 (9: 1), gave the less polar product as a yellow foam (431 g) which was crystallized twice from methanol, of so as to obtain the S-2'-fluorethyl ester indicated in the title (253 mg), PF 133-1340C, #D +104.50 (c 0.98).

Example 34
S-Chloromethyl 9 &alpha; -fluoro-11ss-hydroxy-16-methylene-3-oxo-17a-propionyloxyandrosta-1,4-diene-17ss-carbothioate
A suspension of XXII (227 mg) in propionic acid (2.2 ml and trifluoroacetic anhydride (0.7 ml) was treated with a dry chloroform solution of toluene-p-sulfonic acid (0.044 ml, c. about 80 mg / ml) and then stirred at room temperature for 6 hours and then stirred at 30 ° C. for 16.5 hours The reaction mixture was diluted with a 5-fold solution. % sodium bicarbonate (75 ml) and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried and evaporated to a mixture. brown gum (254 mg). - The gum was subjected to plc in a mixture of chloroform and acetone (19: 1) (3 tests). The main band (152 mg) was crystallized twice from ethanol, so as to obtain white crystals (30 mg) of the S-chloromethyl I 7a-propionate indicated in the title, contaminated with S-chloromethyl 9 &alpha; -fluoro-17 &alpha; -hydroxy-16-methylene- 3- oxo-11ss-propionyloxyandrosta-1, 4-diene-17ss-carbothioate, as revealed by spectroscopy of rmn H.

Example 35
S-Chloromethyl 11ss-hydroxy-16ss-methyl-3-oxo-17 &alpha; -propionyl- exyandrosta-4-en-17ss-carbothioate
Catalytic reduction of the compound of Example 6 (0.517 g)> in the presence of tris (triphenylphosphine) -chlororhodium (I) (497 mg) in benzene (50 ml), for 22 hours, gave, after chromatography (plc) on silica in chloroform (4 runs), elution with ethyl acetate and crystallization twice from ethyl acetate, the # 4-3-detone given in the title ( 0.130 g), PF 176-1770, #D + 78 (c 0.80).

Example 36
S-Chloromethyl 9 &alpha; -fluoro-11ss-hydroxy-16ss-methyl-3-oxo- 17 &alpha; -propionyloxyandrost-4-ene-17ss-carbothioate
Catalytic reduction of the compound of Example 1 (0.646 g) with tris (triphenylphosphine) chlororhodium (I) (800 mg) in benzene (100 ml) for 21.5 hours gave, after chromatography on silica in a mixture of chloroform and acetone (9: 1) and two crystallizations from acetone, the title chloromethyl thioester (0.142 g) in the form of white needles, PF 217-225, La7 +54 ( c 0.83).

Example 37
S-Fluoromethyl 11ss-hydroxy-16ss-methyl-3-oxo-17 &alpha; -propionyl- oxyandrost-4-en-17ss-carbothioate
The catalytic reduction of the compound of Example 24 (0.413 g), carried out in the presence of tris (triphenylphosphine) chlororhodium (I) (432 mg) in benzene (60 ml) at 220C for 24 hours, gave, after multiple chromatographies on silica in mixtures of chloroform and acetone and crystallization in acetone, lad4-3-ketone (0.106 g) PF 174-177, #D +1230 (c 0.55) .

Example 38
S-Chloromethyl 9 &alpha; -fluoro-11ss-hydroxy-16ss-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-1? Ss-carbothioate
Schloromethyl 9ss, 11ss-epoxy-16ss-methyl-3-oXo-17 -propionyloxyandrosta-1,4-diene-17ss-carbothioate (# 0.9 mg) of Example 16 was treated with a urea complex and hydrochloric acid (about 1 ml) and stirred for a total of 24 hours at room temperature. 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. tlc, on silica in three different solvent systems (acetone-petroleum, PE 40-600C, 1: 2; chloroform-acetone
9: 1; Ethyl acetate-petroleum (PE 40-600C, 1: 2, two runs) revealed that the product thus obtained contained the fluorhydrin indicated in the title, compared to an authentic sample.

Example 39
S-Chloromethyl 6 &alpha;, 9 &alpha; -fluoro-11ss-hydroxy-16 &alpha; -methyl-3-oxo- 17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carbothioate
A solution of LXII (29 mg) in methanol (2 ml) was maintained at room temperature for three hours. The mixture was evaporated to dryness, so as to obtain the 11ss-alcohol indicated in the title (25 mg), identified by comparison of its spectrum of 1H rmn (in deuteriodimethylsulSoxide)) and its tlc properties ( silica, acetone-petroleum PE.40-600C, 1: 3) to those of an authentic sample.

A subject of the present invention is also pharmaceutical compositions for use in anti-inflammatory therapy, characterized in that they comprise at least one androstane compound of formula (I) as defined above, as well as one or more pharmaceutical vehicles or excipients. Such compositions can be provided in forms suitable for topical or internal administration.

The active androstane compounds may advantageously be presented in a conventional manner in preparations which are suitable for topical administration, using a suitable topical vehicle. By the term "topical administration" as used herein, Applicants are intended to include administration by insufflation and inhalation.

Examples of various types of preparations which are suitable for topical administration include ointments, lotions, creams, powders, drops (e.g. for eyes or ears), sprays (e.g. for the nose, throat, lungs or skin), suppositories, medicated enemas, pills or tablets to chew or suck (e.g. for the treatment of aphthous ulcers) capsules or cartridges for use in an inhaler or insufflator and aerosols, for example for the nose, throat or lungs.

Ointments and creams can be composed, for example, with the aid of an aqueous or oily base, resorting to the addition of suitable solvents and / or gelling and / or thickening agents. Thus, such a base can, for example, comprise water and / or an oil, such as petroleum jelly or liquid paraffin, or a vegetable oil, such as peanut oil or peanut oil. castor oil, or a solvent, such as polyethylene glycol having an average molecular weight which fluctuates from 200 to 600. Thickening agents which can be used depending on the nature of the base, include soft paraffin, stearate d aluminum, cetostearyl alcohol, polyethylene glycols having an average molecular weight which fluctuates from 4,000 to 6,000, lanolin and beeswax and / or glyceryl monostearate and / or nonionic emulsifying agents.

The sprays can, for example, be in the form of suspensions or aqueous solutions, or in the form of aerosols, with the use of a suitable propellant, for example dichlorodifiuoromethane, dichloroluoromethane, dichlorotetrafluoroethane, anhydride. carbon dioxide or any other suitable gas.

Capsules and cartridges (eg gelatin, for use in an inhaler or insufflator, can be prepared so that they contain a powder mixture of a compound according to the invention and a suitable powder base, such as lactose. or starch.

Each capsule or each cartridge can generally contain from 20 µg to 10 mg of active androstane compound.

The proportion of the active androstane compound in the topical compositions according to the invention depends on the precise type of composition to be prepared, but generally fluctuates in the range 0.001 to 5.0 SJ by weight.

Generally, however, for most types of preparation, it is advantageous that the proportion of active compound used fluctuates from 0.005 to 0.5 e. and, preferably, from 0.01 to 0.25%. However, with powders which are suitable for inhalation or insufflation, the proportion of active ingredient which is used can vary from 0.1 to 2- / o.

The above compositions suitable for topical application to the skin can be used for the treatment of inflammatory dermatoses in humans and animals, for example eczema which are normally sensitive to corticosteroid therapy and also less sensitive diseases. to this therapy, such as psoriasis in humans.

Compositions which are intended for administration by inhalation or insufflation are intended for administration on a prophylactic basis to humans suffering from allergic and / or inflammatory conditions of the nose, throat or lungs, such as asthma. and rhinitis, including hay fever. The compositions for aerosols are preferably adapted so that each dose or puff delivered of aerosol contains from 20 g to 1000 g, preferably from about 50 g to 100 pg, of a compound according to the invention. The administration can be repeated several times a day, for example Z), 4 or 8 times, administering, for example, 1, 2 or 3 doses each time The overall daily dose with an aerosol fluctuates from 100 g to 10 mg , preferably 200 g to 1000 gg. The overall daily dose and the calibrated dose, delivered by the capsules and cartridges in an inhaler or insufflator, will generally be twice that given with aerosol compositions.

The topical preparations can be administered in one or more applications per day to the affected area; on skin areas, one can frequently benefit from the use of occlusive dressings.

For internal administration, the new compounds according to the invention can be presented, for example, in a conventional manner suitable for oral, parenteral or rectal administration. For oral administration, syrups, elixirs, powders and granules which can be prepared in a conventional manner can be used. However, it is preferred to use unit doses as described below.

Preferred forms of preparations suitable for internal administration are unit doses, i.e. tablets and capsules. Such unit doses contain 0.1 mg to 20 mg, preferably 2.5 to 10 mg, of the active steroid.

In general, the compounds according to the invention can be administered internally in cases where systemic cortico-adrenal therapy is indicated.

In general terms, preparations suitable for internal administration may contain from 0.05 to 10% of the active ingredient, depending on the type of preparation used. The daily dose may vary from 0.1 mg to 60 mg, for example 5 to 30 mg, depending on the condition to be treated and the desired duration of treatment.

Example (A)
Ointment: active ingredient 0.1% w / w
liquid paraffin BP 10% w / w
white soft paraffin
so as to produce 100 parts
in weight.

BP = British Pharmacopoeia
Pass the active ingredient through a ball mill with a little liquid paraffin until the particle size is reduced, so that 95 So of them in number have a size less than 5. Dilute the paste and rinse the mill with the residual liquid paraffin, mix and add the suspension to the white soft paraffin melted at 500C.

Stir until the mixture is cold, so as to obtain a homogeneous ointment.

Example CB)
Cream
Active ingredient 0.1
Cetostearyl alcohol 10.0
Cetomacrogol 1.000 2.5
White soft paraffin 10.0
Liquid paraffin 10.0
Chlorocresol 0.1
Sodium acid phosphate 0.5
Water purified up to 100.0.

SerEaration Method
The chlorocresol and sodium acid phosphate are dissolved in water at about 70-750C. The waxes are melted together at about 65-700C and added with stirring to the aqueous phase, then the latter is cooled to 65-700C. The steroid is subjected to micronization (particle size as defined in the 1973 British Pharmacopoeia Codex, page 911 for an ultra-fine powder) and dispersed in part of the liquid paraffin. The steroid suspension and the rest of the liquid paraffin are added to the base, with stirring at 60-650C. The preparation is cooled with stirring to room temperature.

Example (C) Aerosol composition at calibrated dose
per dose% w / w
Active ingredient 0.95 mg 0.059
Fluorotrichloromethane 25.5 mg 30.0
Dichlorodifluoromethane up to 85.0 mg up to 100.0
The active ingredient is subjected to micronization (particle size as defined in the British Pharmacopoeia Codex 1973, page 911, for an ultra-fine powder) and dispersed in fluorotrichloromethane. This suspension is placed in aluminum aerosol containers, the upper space is purged with dichlorodifluoromethane gas to expel the air, and an aerosol metering valve is placed on the container. The dichlorodifluoromethane is pumped out. liquid through the metering valve, under pressure, to the desired weight.

Example (D) Eour inhalation capsule (100 ssg / dose)
per capsule t0 p
Active ingredient 0.1 mg 0.4
Lactose up to 25.0 mg up to
100.0
The active ingredient is subjected to micronization (particle size as defined in the British Pharmacopoeia Codex 1973, page 911, for an ultra-fine powder) and mixed with lactose in the proportions indicated above. The mixture of steroid and lactose is introduced into hard gelatin capsules for administration through an inhalation device.

The results of a pharmacological study demonstrating the topical anti-inflammatory activity of the compounds will be given below.

The mouse ear croton oil test was used for this purpose.

Groups of 5 male mice weighing 23-28 g were used in this test.

Increasing doses of fluocinolone acetonide used as a standard and test compounds were dissolved in a mixture of croton oil: ethanol: ether of 2:20:78.

Such of the solution obtained is applied to the inner side of both ears of each mouse. A group of mice given the steroid-free croton oil solution served as a control.

6 hours after the applications, the mice are sacrificed and both ears are cut and weighed.

Increasing doses of the steroid reduce the inflammatory response to the solution of croton oil. Estimates of relative anti-inflammatory activity are made using log dose and ear weight as the response parameter.

Similar tests were also carried out in rats, on rats weighing 50 to 70 g with a mixture of croton oil: ethanol: ether of 5:20:75 and applying 50 μl of the solution to each ear.

A measurement of the adrenal hypothalamic-pituitary suppressor activity (H.P.A. suppression) was also carried out. For this purpose, groups of 10 male mice (23-28 g) or 6 male rats 150-160 g) were used which are shaved in the dorsal region. Increasing doses of fluocinolone acetonide used as a standard and test compounds were dissolved in acetone. 0.02 ml of each solution is applied to the shaved area of each animal once a day for 7 consecutive days. A group of animals serves as a control and receives acetone without steroid.

Two days after the final steroid dose, the animals are subjected to stress (exposure to ether for one minute). 15 to 20 minutes later, the animals are re-anesthetized (mice with ether and * rats with pentobarbitone intraperitoneally, for example 500 mg / kg) and blood is taken from these animals either from the heart, or the abdominal aorta.

For the determination of plasma corticosterone levels, the blood of two mice is pooled, while for the rats individual blood samples are used. The plasma corticosterone levels are determined by fluorimetry according to a variant of the method described by Zenker and Bernstein (J. Biol. Chem. 1958, 231, 695-701).

Increasing doses of the steroid produce a reduced stress response (i.e. lower plasma corticosterone levels). The estimate of relative activity is made using the logarithm of the Journalibre dose and plasma corticosterone levels as the response parameter.

The results are given in the table below.

TOPICAL ANTI-INFLAMMATORY ACTIVITY
IN MICE AND RATS IN THE OIL TEST
OF CROTON
Ex. N In mice In rats X
l 41 36
2+ 16 15 5+ 56
19+ 113 ** 85 *
21+ 45 71
26 41 20
28 56 97
29+ 35
30+ 55 55
34+ 42 12
Relative activity: fluocinolone acetonide = 100
Average of two results
Average of three results
These compounds have a superior therapeutic ratio.
laughing to 10 in both mice and
rats, while we get a thera report
canique with fluocinolone acetonide.

The therapeutic ratio is the ratio of ac
anti-inflammatory activity determined in
the croton oil test to suppress activity
sive HPA, these activities being determined
as previously indicated.

Claims (13)

1. Compounds which correspond to the following general structural formula

in which R1- represents a fluoro-, chloro- or bromo-methyl group or a 2'-fluorethyl group, R2 represents a COR6 group where R6 represents a C1 -C3 alkyl radical or else OR2 and R together form a group 16a, 17aisopropylidenedioxy, R3 represents a hydrogen atom, a methyl group (which can be in a configuration or in ss configuration) or a methylene group R represents a hydrogen atom, a chlorine atom or a fluorine atom, R5 represents a hydrogen atom or a fluorine atom, and the symbol. represents a single or double bond. 2. Compounds according to claim 1, characterized in that R1 represents a chloromethyl or fluoromethyl group. 3. Compounds according to claim 1 or claim 2, characterized in that R4 represents a fluorine atom. 4. Compounds according to any one of the preceding claims, characterized in that they are 1,4-dienes. 5. Compounds according to claim 2, characterized in that they are 1,4-dienes in which R4 and R5 represent fluorine atoms and R3 represents an or or methyl or methylene group. 6. Compounds according to claim 5, characterized in that R3 represents an &alpha; methyl. 7. Compounds according to claim 1, which are S-chloromethyl 9 &alpha; -fluoro-11 ss-hydroxy-16 &alpha; -methyl-3-oxo-17 &alpha; -propionyloxyandrosta-1,4-diene-17 ss-carbothioate, S-chloromethyl 9 4-fluoro-ll ss-hydroxy-16-methylene-3-oxo-17 &alpha; -propionyloxyandrosta-1,4-diene-17ss-carbothioate, S-fluoromethyl 6 &alpha;, 9 &alpha; -difluoro -11 ss-hydroxy-16 &alpha;, 17 &alpha; -isopropylidenedioxy-3-oxoandrosta-1,4-diene-17ss- carbothioate and S-fluoromethyl 6, 9 -difluoro-ll ss-hydroxy-16 &alpha; - methyl-3- oxo-17 &alpha;; - propionyloxyandrosta-1,4-diene-17 sscarbothioate. 8. A compound according to claim 1, which is: S-chloromethyl 6 &alpha;, 9 &alpha; -difluoro-11 ss-hydroxy-16 &alpha; - methyl-3-oxo-17 &alpha; -propionylandrosta-1,4, diene-17sscarbothioate . 9. Process for the preparation of a compound according to claim 1, characterized in that a) is subjected to esterification a compound corresponding to formula (I) as defined in claim 1, but containing3 either a 17ss-carbo acid group - free thiotque (or a functionally equivalent group) or a 17 &alpha;group; - free hydroxyl (R3 being a hydrogen atom or a methyl or methylene radical), all other reactive groups present being optionally in protected form b) reacting a compound corresponding to formula (I) as defined in claim 1, but containing a 175 substituent of the formula -COS (CH2) nY (in which Y represents a displaceable substituent and n is equal to 1 or 2), on a compound serving to replace the Y group with a halogen atom, so as to form a compound of formula (I) as defined in claim 1, (c) subjecting a compound corresponding to formula () as as defined in claim 1, but bearing a li-oxo group to a reduction, so as to generate the desired 11-hydroxy-androstane, (d) subjecting a compound corresponding to formula (I) as defined in claim 1, but bearing a deprotected 11P-hydroxy group, (e) reacting a compound corresponding to formula (I), as defined in claim 1, but having a double bond in positions 9,11 (and no substituent in position 11) on one or more reagents serving to introduce the desired 9a-halo-11ss-hydroxy group, (f) subjecting a compound corresponding to formula (I) as defined in claim 1, in which # represents a double bond , to partial reduction so as to generate a corresponding compound in which represents a single bond. 10. Compounds which correspond to the following general structural formula (II)

in which Ra represents a thiocarbamoyloxycarbonyl group -COOCSNRARB where RA and RB have the meanings indicated above, or a group of the formula -COSR1A, where R1A represents a hydrogen atom or is a group as defined above with regard to R1 or is a group convertible into such a group and Rb represents an esterified hydroxyl group, or Rb and Rc together represent an isopropylidenedioxy group, or when Ra represents a COSR A group, Rb optionally represents a hydroxyl group; Rc represents a hydrogen atom, a methyl group (which can be in the a configuration or in the ss configuration) or a methylene group, Rd represents a hydroxyl group or a protected hydroxyl group (in the α configuration or in the ss configuration) or an oxo group; Re represents a hydrogen atom, a bromine atom, a chlorine atom or a fluorine atom, or else Rd and Re together represent a carbon to carbon bond or an epoxy group in the ss configuration; Rf represents a hydrogen atom or a fluorine atom and the symbol # represents a single or double bond, as well as the salts of compounds which have a free carbothioic acid group, excluding the compounds of formula (I) such as than previously defined. 11. Compounds according to claim 10, characterized in that Ra represents a -COSH group, Rb represents a hydroxyl group, Rc represents a hydrogen atom, an a- or methyl group or a methylene group, Re represents a hydrogen atom, a chlorine atom or a fluorine atom and Rd represents a hydroxyl group in ss configuration or an oxo group. 12. A process for the preparation of compounds according to claim 10 bearing a free -COSH group in position 17, characterized in that (a) a compound according to claim 10 bearing a carbamoyloxycarbonyl group in position 17 is subjected to aminolysis with transposition, ( b) reacting a compound corresponding to formula (II) as defined in claim 10, carrying a 16a, 17a-epoxy group or a 16a, 17c-isopropylidenedioxy group, but having a 17ss-carboxyl group or a salt of the latter, with a 2-halo-aza-aromatic compound, this reaction being followed by treatment with hydrogen sulfide, (c) a compound corresponding to formula (II) according to claim 10 is reacted, in which Rb represents a hydroxyl group, but bearing in position 17 a group

wherein X, Y and Z, which may be the same or different, each represents a nitrogen atom or a CH group, on hydrogen sulphide or a sulphide or a hydrosulphide thereof. 13. Pharmaceutical compositions for use in anti-inflammatory therapy, characterized in that they contain at least one androstane compound of formula (I) according to any one of claims 1 to 8 as well as one or more vehicles or pharmaceutical excipients.