FR2485542A1 - COMPOUNDS FOR THE PREPARATION OF CARBOTHIOATES OF ANDROSTANES - Google Patents

Abstract

THE SUBJECT OF THE INVENTION IS INTERMEDIATE COMPOUNDS FOR THE PREPARATION OF ANDROSTANE CARBOTHIOATES, OF FORMULA (CF DRAWING IN BOPI)

Description

The present invention relates to anti-steroid

  inflammatory drugs of the androstane series.

  Anti-inflammatory steroids are, for the

  most of them, of the type of corticoid, that is,

  to say that they are derivatives of pregnane. British Patent Nos. 1 384 372, 1 438 940 and 1 514 476 of the Applicant disclose esters of certain androstane-17β-carboxylic acids which have an anti-inflammatory activity. European Patent Application No. 79300500.0 (Publication No. 0004741) discloses

  androstane-170-carbothiolic acid esters which

  also have anti-inflammatory activity. The Applicant has now discovered that certain compounds

  androstane containing a haloalkylcarbonyl group

  thioate in position 17P exhibited particularly advantageous anti-inflammatory properties, such as

  it will be described in more detail in the rest of the preface.

have memory.

  The new androstane compounds according to the present invention can be represented by the following general structure formula: COSR1 R3 a (t)

R5

  wherein R1 represents a fluoro-, chloro-

  or bromo-methyl or a 2'-fluorethyl group, R2 represents

  COR or R represents a C 1 -C 3 alkyl radical, or OR 2 and R 3 together form a 16a, 17a-isopropylidenedioxy group; R3 represents a hydrogen atom, a methyl radical (which may be in configuration a or in configuration P) or a methylene radical, R4 represents a hydrogen atom, a chlorine or fluorine atom, R5 represents a hydrogen atom, hydrogen or a fluorine atom and the symbol -. represents a

single or double bond.

  The novel compounds of the formula (I) possess good anti-inflammatory activity, particularly by topical application, as judged by the application of the McKenzie patch test in humans and as measured by the reduction

  induced edema with croton oil when applying

  plicates the compounds by the topical route on the skin of

mice and rats.

  Some of the compounds exhibit good topical anti-inflammatory activity during the ear test

  with croton oil, associated with hypothalamic activity

  minimal adrenal hypophyso-suppressive

  by the topical route in the same species of animals.

  These results indicate that such compounds are of great value for the local treatment of inflammations in humans and animals with a minimal possibility of causing undesirable systemic side effects. The compounds of formula (I) which are preferred because of their excellent anti-inflammatory activity include the substances belonging to the following categories, more specifically (a) those in which R represents a chloro- or fluoromethyl group, (b) those in which R 1 represents an acetyl or propionyl group, preferably propionyl, (c) those in which R 4 represents a fluorine atom, (d) those in which R 5 represents a fluorine atom, (e) 1,4-dienes and (f) 1,4-dienes wherein R represents a fluorine atom and R represents a hydrogen atom, a methylene or methyl group in the α or P configuration. The compounds of the formula (I) which exert a good anti-inflammatory activity associated with an effect

  minimal hypothalamic-pituitary-adrenal supressive

  applied topically, include

  1,4-dienes in which R represents a chlorinated group

  or fluoro-methyl, R and R5 are fluorine atoms and, more particularly, those in which R3

represents a c-methyl group.

  Compounds according to the present invention which are particularly preferred because of their perfect anti-inflammatory activity by the topical route and the favorable ratio of their anti-inflammatory activity.

  topically to their undesired systemic activity.

  include the following substances:

  S-chloromethyl-9-fluoro-11-hydroxy-16-

  Methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene 17-5

carbothioic;

  S-chloromethyl-9u-fluoro-11-hydroxy-16-

  methylene-3-oxo-17a-propionyloxyandrosta-l, 4-diene-170-

  carbothicate; S-fluoromethyl 6c, 9a-difluoro-1-hydroxy-16c,

  17a-isopropylidenedioxy-3-oxoandrosta-l, 4-diene! 17e-

carbothioic;

  S-fluoromethyl 6α, 9α-difluoro-1-hydroxy-16α-

  methyl-3-oxo-17a-propionyloxyandrosta-l, 4-diene-17e-

carbothiate;

  S-chloromethyl 6α, 9β-difluoro-16-hydroxy-16-one

  methyl-3-oxo-17c-propionyloxyandrosta-1,4-diene-17 -

carbothiate.

  The compound last mentioned is especially

  particularly advantageous because of its special relationship

  favorable and due to minimal skin atrophy

it causes.

  The compounds of the formula (I) can be prepared by

  implementation of a whole series of different processes.

  One of these processes is characterized by

  of an androstane compound corresponding to the

  formula (I), but containing either a 17P-acid group

  free carbothiolene (or a radical functionally equivalent to this group) or a free 17a-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 it proves desirable.

  For example, a salt of the cognate 17β-carbothioic acid may be reacted as an alkali metal salt, for example a lithium, sodium or potassium salt,

  or an alkylammonium salt, for example a triethyl

  ammonium or tetrabutyl ammonium chloride, on an alkyl

  suitable, preferably in a polar solvent, such as a ketone, for example acetone or an amide, such as

  dimethylformamide, dimethylacetamide or hexamethylene

  methylphosphoramide, conveniently at a temperature of 15 to 1000C. The alkylating agent may comprise a suitable dihalogen compound, ie a substance containing an additional halogen atom (preferably a bromine or ion atom) besides the halogen atom of the desired R1 group. . This process is particularly applicable to the preparation of compounds in which R represents a

  chloromethyl group, the alkylating agent being

chlorobromomethane.

  The 16-hydrogen, methyl or 17-methylhydroxy-17-carbothioates corresponding to the compounds of the formula (I) can also be subjected to esterification of the -30 17a-hydroxyl group. This can be done by using conventional techniques, for example by reacting the related 17a-hydroxyl compound on 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 appropriate anhydride, such as trifluoroacetic anhydride, preferably in the presence of an acid catalyst, by

  for example p-toluenesulphonic acid or sulfosalicylic acid.

  Mixed anhydride can also be generated in situ by the reaction of a symmetrical anhydride of the desired acid on

  another suitable acid, for example trifluoride

  acetic. 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 also possible to esterify the

  17a-hydroxyl group by the reaction of 17 "-

  hydroxylated acid on the appropriate anhydride or acid chloride, if desired, in the presence of non-hydroxylated solvent, for example chloroform, methylene chloride or benzene, and preferably in the presence of a catalyst of the strong acid type, for example perchloric acid, p-toluenesulphonic acid or a strong acidic cation exchange resin, for example

  Amberlite IR 120, the reaction being conveniently

  killed at a temperature that varies from 25 to 100 C.

  The compounds of the formula can also be prepared

  (I) by reacting a compound of androstane corresponding to

  substituent 170 of the formula -COS (CH2) nY (wherein Y represents a displaceable substituent and n is 1 or 2) on a compound

  used to replace the group Y with a halogen atom.

  Thus, the compounds of formula (I) can be subjected to a halo-exchange reaction to replace the group Y when the latter is a halogen atom by a different halogen atom. Therefore, we can

  prepare the bromomethyl-, fluoromethyl- and fluoroethyl-

  17 P-carbothioates from iodomethyl- or bromoethyl-

  Corresponding 17 P-carbothioates using a bromide type salt, such as lithium bromide, in the case

  bromomethyl-17β-carbothioates, or a suitable fluoride

  nable, for example silver monofluoride or silver difluoride, in the case of fluoromethyl- or fluoroethyl-173-carbothioates. The starting iodomethyl-17β-carbothioates can be prepared from

  corresponding chloromethyl 17P-carbothioates using

  for example, reading an alkali metal, alkaline earth metal or quaternary ammonium iodide, for example

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 reactions mentioned above can also be

  born on starting materials that possess diverse

  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 11p compounds can therefore be prepared.

  hydroxylated compounds of formula (I) by reduction of a corresponding 11-oxo compound, for example by using an alkali metal borohydride or an alkaline earth metal borohydride,

  for example, sodium or calcium borohydride,

  moderately in an aqueous alcoholic or alcoholic solvent,

such as methanol or ethanol.

  A 11-keto compound of this type can be prepared by oxidation of a corresponding 11-hydroxysteroid, for example using a chromic acid reagent,

such as Jones's reagent.

  It is also possible to obtain an 11-hydroxy compound

  of the formula (I) by the deprotection of a compound

  respondent with a protected hydroxyl group in

  11, for example a (C 1 -C 6) alkylsilyloxy group, such as trimethylsilyloxy group, or a radical

  perfluoro- or chloro-alkanoyloxy such as the trifluoro-

  acetoxy. The hydrolysis protecting group can be removed, the trialkylsilyl group being easily removed by moderate acid or basic hydrolysis.

  or, much more advantageously, using a fluorescent

  rure, for example hydrofluoric acid or ammonium fluoride. The perfluoro or chloralkanoyl protecting group can also be removed by mild hydrolysis with an acid or a base or by alcoholysis, but preferably under acidic conditions when R 4 is a chlorine atom. . Such a protected hydroxyl group can be introduced, for example by reacting a 110-hydroxysteroid on a suitable reagent, such as

  a trialkylsilyl halide or an anhydride

fluorine or chloralkanoic.

  Compounds of formula (I) can also be produced by the reaction of a corresponding compound having

  a double bond in positions 9, 11 (and no substitute

  killing in position 11) on reagents used to introduce

  to obtain the desired 9a-halo-11p-hydroxy group. This may involve the initial formation of a bromhydrin

  reaction on an N-bromamide or imide, such as N-

  bromosuccinimide, followed by the formation of 9p, 11-

  corresponding epoxide by treatment with a base and the reaction of the epoxide on hydrofluoric acid or

  hydrochloric acid, so as to introduce the group

  fluorhydrine or chlorohydrin required.

  The 9,11-olefin can also be reacted with an N-

  chloramide or -imide, so as to introduce directly

  the 9-chloro-11H-hydroxy group.

  Compounds A4 according to the present invention can be conveniently prepared by the partial reduction of

  corresponding compound A1, 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 under 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 a previous step. The above-mentioned compounds having a free -COSH group in position 17P can be prepared, for example by

  aminolysis with transposition of a 17P-thiocarbamoyloxy

  suitable carbonyl-androstane. 17P-thiocarbamoyloxy

  carbonyl-androstane is a mixed anhydride of the acid

  Corresponding 17 P-carboxylic acid and a thiocarba-

  and is conveniently prepared by the reaction of a salt

  16a, 17a-acetonide or 17a-ester of 170-car-

  boxylic acid, on a thiocarbamoyl halide. The group

  thiocarbamoyl is N, N-disubstituted and can therefore

  According to the formula: -COOCSNRARB o RA and RB which may be identical or different, represent alkyl radicals, for example alkyl radicals in C1-C4, or RA and RB together with the nitrogen atom to which they are attached, a 5-8 membered ring

  which may optionally contain an additional heteroatom

  selected from oxygen, nitrogen and sulfur and /

  or which may possibly be substituted by 1 or 2 radi-

  C 1 -C 6 alkyl groups, for example methyl groups.

  Preferably, R 1 and R 3 are C 1 -C 4 alkyl substituents, with N, N-dimethylthiocarbamoyl being preferred. The thiocarbamoyl halide is preferably chloride. The reaction can be accelerated by the addition of an iodide type salt, for example

sodium iodide.

  The initial fandrostane-17P-carboxylate salt may be, for example, an alkali metal salt, for example sodium or potassium, alkaline earth metal, for example calcium, or a tertiary amine, for example

for example triethylamine.

  Aminolysis with transposition can be achieved, for example, by heating the mixed anhydride to

  a high temperature, for example in the presence of ammonia

  niac, a primary amine or, more preferably, a secondary amine, such as diethylamine or pyrrolidine. In the starting 17 P-carboxylic acids, positions 16 and 17 "will be conveniently substituted with the desired groups -R 3 and -OR 2 for the final product.

of the formula (I).

  16-Methylenic 17α-hydroxy-androstanes which contain the desired acid-carbothioic acid group can be prepared as described above,

  from 16f-methyl-16x, 17a-epoxy 17P-thio-

  corresponding carboxylic acid, by carrying out a transposi-

  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 173carboxylic acids by treatment with an onium salt of a 2-halo-azaaromatic compound, followed by

  treatment of the product thus obtained with hydrogen sulfide

  or a salt thereof, so as to obtain the free 17 P-carbothiolac acid which can then be alkylated in the manner described above, preferably in situ, of

  to obtain the desired 17P-carbothioate group.

  The compounds of the 16a, 17-isopropylidenedioxy type of the formula (I) can similarly be prepared by treating the corresponding 17-carboxylic acid with an onium salt of a 2-halo-azaaromatic compound, which treatment is followed by that of the product thus obtained. by acid

  sulphohydric acid, so as to recover the acid 17P-carbothie-

  free of charge that can then be esterified in the

described above.

  Onium salts of 2-halo-aza-aromatic compounds are capable of effecting carboxylic activation. Such reagents include 2-halo-N-alkyl- or 2-halo-N-phenyl-pyridinium or pyrimidinium salts bearing 1 to 2 additional substituents selected from phenyl and lower alkyl (for example C 1 -C 4) radicals, such as methyl. The 2-halogen type atoms may be fluorine, chlorine, bromine or iodine. The salts are preferably sulfonates, for example tosylates, halides, for example iodides, fluoroborones or perfluoroalkylsulfonates, a convenient salt being

  2-fluoro-N-methylpyridinium tosylate or tri-

  2-chloro-N-methylbenzothiazine fluoromethanesulfonate

  zolium. 16 ", 17α-epoxy-160-methyl-170-carboxylic acids,

  used as starting materials in the above process.

  above. can be prepared in a conventional manner, for example, as described in the British patent

No. 1,517,278.

  The starting materials used for carrying out the process described herein for the preparation of the compounds of the formula (I) are novel and it is therefore obvious that the scope of

  the invention also extends therein; these compounds include

  substances which correspond to the structural formula

  following General Title (II): a R Rf

  wherein Ra represents a thbcarbamoyloxy group

  carbonyl -COOCSNRARB o RA and RB are as defined

  above, or a group of the formula -COSR A in the-

  which R1A represents a hydrogen atom or is a group as defined above with respect to R1, or is a group convertible into such a group and Rb represents

  an esterified hydroxyl group, or else Rb and Rc represent

  together they are an isopropylidene dioxy group, or when Ra represents a COSR1A group, Rb is optionally a hydroxyl group, Rc represents a hydrogen atom, a methyl group (which may be in the α or β configuration) or a methylene group; , Rd represents a protected hydroxyl or hydroxyl group (in configuration a or P configuration) or an oxo group, Re represents a hydrogen atom, a bromine atom, a chlorine atom or a fluorine atom, or Rd and Re together represent a carbon-carbon bond or an epoxy group in the f-configuration or an oxo group, Re represents a hydrogen, bromine, chlorine or fluorine atom, or Rd and Re together represent a

  carbon-to-carbon bond or an epoxy group in

  R 1 represents a hydrogen or fluorine atom and the symbol represents a single or double bond, as well as the salts of the compounds which have a free carbothiolic group, with the exception of the compounds of

  formula (I) as previously defined.

  When Rd represents a protected hydroxyl group,

  this can be, for example, a trialkyl group

  silyloxy or a perfluoro or perchloroalkanoyloxy group

as previously defined.

  The 17d-hydroxy 17P-carbohydrate acids can be converted

  thioic compounds of the formula (II) and their salts

  hydroxy-170-carbothioate of the formula (II), wherein Ra represents the COSR1 group as defined in connection with

  formula (I), or 17a-esters of 173-carbothiol

  of the formula (II) by carrying out the processes described above in connection with the preparation of the compounds

  of the formula (I). Esterification of the group 17a

  The hydroxyl 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 0 C.

  The 17α-hydroxy-17β-carbothiolic acids of the

  The formula (II) and their salts are therefore particularly

  interesting as intermediaries for the pre-

  androstane-17β-carbothioates of the formula (I), those in which Rc represents a hydrogen atom, a

  a- or P-methyl group or a methylene group, Re represents

  a hydrogen, chlorine or fluorine atom, Rd re-

  has a hydroxyl group in the P configuration or an oxo group being particularly suitable. The most preferred compounds and their salts include the substances in which Rc represents a methyl group

  in the α or β configuration or a methylene group, R 1 represents

  At a fluorine atom, Rd represents a hydroxyl group in the y-configuration or an oxo group and the 1,2-symbol in the 1,2-positions represents a carbon-to-carbon double bond. Particularly preferred compounds of formula (II) include, for example, the following substances:

  9α-fluoro-11,17a-dihydroxy-16β-methyl-3-oxoacetate

  androsta-1,4-diene-17P-carbothioic acid; 9ax-fluorinated acid

  11P, 17c-dihydroxy-16ac-methyl-3-oxoandrosta-1,4-diene-17p-

  carbothioic; 9α-fluoro-11α, 17α-dihydroxy-16-

  methylene-3-oxoandrosta-1,4-dien-17f-carbothioic;

  6a, 9-difluoro-11-py17x-dihydroxy-16a-methyl-3- acid

  oxoandrosta-1,4-diene-17p-carbothioic and the 11 ketones

corresponding salts and their salts.

  An advantage of the aforementioned intermediates is that they allow direct haloalkylation to obtain haloalkylcarbothioates when

  the corresponding R1SH thiols are not available.

  The salts of these 17c-hydroxy 17f-carbothiolic acids may be, for example, the alkali metal salts, for example lithium, sodium or potassium, alkaline earth metals, for example calcium or magnesium, tertiary amines, for example pyridinium or triethylammonium, or quaternary ammonium, by

example of tetrabutylammonium.

  The 17 "-hydroxy 17 P-carbohydrate acids can be prepared

  thioiques, for example, by the reaction of a reactive derivative of a 17a-hydroxy-17P-carboxylic acid on the sulfnydric acid or a sulfide or hydrosulfide thereof. In general, the cation of sulphide or hydro

  sulphide may be, for example, an alkali metal cation.

  flax, such as sodium or potassium. The derivatives

  the above-mentioned reactants are compounds of the formula (II) wherein Rb is hydroxyl and -COR7 is present at the 17P position, where R7 is a group of the formula YX -NZ wherein X, Y and Z. which may be the same or different, each represents a nitrogen atom or a

  group CH, or one or two of the symbols X, Y and Z represent

  each nitrogen, the heterocyclic ring being optionally substituted on at least one carbon atom by a lower alkyl group (for example with 1 to 4 carbon atoms, such as a methyl group), and (or) when the ring heterocyclic ring contains two adjacent carbon atoms, said ring optionally carries a

  benzene ring condensed on these ad-

  Underlying. The above-mentioned reactive derivatives of formula (II) are preferably prepared by reacting the corresponding 17α-hydroxy carboxylic acids of formula (II) with a symmetrical or asymmetric compound of the formula

- W - R7 (III)

  wherein W is CO, CS, SO or SO2

  and R7 groups that may be the same or different

  rents, possess the abovementioned meanings.

  The compounds of formula (III) are advantageously

  symmetrically. In general, compounds of the formula (III) in which W represents a group are used.

  CO, CS or SO. Thus, for example, as compounds

  particularly interesting are: NN'-

  carbonyldi (1,2,4-triazole); N, N'-carbonyldibenzotriazole;

  N, N '-carbonyldibenzimidazole; N, N' -carbonyldi (3,5-

  dimethylpyrazole); N, N'-thionyldiimidazole and special-

  N, N'-carbonyldiimidazole and N, N'-thiocarbonyldi

imidazole.

  The preparation of a 17α-hydroxy-17-carboxylic acid

  The thioic acid of formula (II) as defined herein is conveniently accomplished by the reaction of a 17α-hydroxycarboxylic acid with a compound of formula (III), which reaction is followed by

  reaction of the intermediate product comprising the

  17P-COR7, on hydrogen sulfide or a salt thereof, preferably in situ, without isolation of

the intermediary in question.

  The 17α-acyloxy 17β-carbothiol acid can be obtained.

  Ique of the formula (II) in a similar way, directly

* from 17 "-acyloxy 17 P-carboxylic acid

  corresponding, by reaction on a compound of the

  mule (III). The 17a-acyloxy acids can be prepared

  17 P-carboxylic acids by esterification of 17α-acids

  corresponding acyloxy-170-carboxylic acid by

  processes described in the British patent -

No. 1,384,372.

  The reaction is conveniently carried out with the compound of formula (III) in the presence of an inert anhydrous solvent, for example a substituted amide solvent,

  such as N, N-dimethylformamide or N, N-dimethyl-

  acetamide, advantageously in the absence of water, preferably at ambient temperature or at a temperature below room temperature, for example at a temperature which varies from -30 to + 30WC. We realize

  conveniently the reaction under conditions

  Neutral, advantageously in an inert atmosphere, for example under a nitrogen atmosphere. The same solvents

  and conditions also apply to the sub-

  sequentially with H2S or a salt of the latter. The compound

  heterocyclic, for example imidazole or 1,2,4-

  triazole, formed as a by-product can be easily

  removed, for example, by extraction with water.

  The above reactions can also be carried out on compounds which have various substituents or

  groups which are then converted in the same way as

  previously described in compounds of formula (I).

  The starting 17 P-carboxylic androstane acids used for carrying out the aforesaid processes can be prepared in a conventional manner, for example by oxidation of a suitable 21-hydroxy-20-keto-pregnane, for example with the aid of periodic acid, in a solvent medium and preferably at room temperature. Sodium bismuthate can also be used to effect the desired oxidative removal of the carbon atom by

  position 21 of a 17a-acyloxy-pregnane compound.

  As will be fully understood, the starting pregnane compound may contain any of the above-mentioned oxidation-sensitive substituents and a

  such group must then be adequately protected.

  The following examples illustrate this

  vention. Melting points were determined on a

  Kofler block in degrees Celsius and are not fixed.

  Rotational powers were determined at the temperature

  ambient temperature on solutions in dioxane.

  Thin layer chromatography (t.l.c.), preparative layer chromatography (p.l.c.) and high-level liquid chromatography were carried out.

  performance (h.p.l.c.) on silica.

  The solutions were dried over magnesium sulfate,

unless otherwise specified.

Preparation I

  9a-Fluoro-11-hydroxy-163-methyl-3-oxo-17x-propionyl acid

  oxyandrosta-1,4-diene-173-carbothioic acid (I) The solvation of an acid solution

  9c-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxy-

  androsta-1,4-diene-17β-carboxylic acid (5.00 g) with ethyl acetate (0.5 mole) and triethylamine (5.3 ml) in dichloromethane (75 ml) and stirred under nitrogen and treated with dimethylthiocarbamoyl chloride (5.071 g). After 24 hours, we have

  added an additional amount of reagent (5.320 g).

  After 47 hours, the mixture was diluted with ethyl acetate

  and was washed with N hydrochloric acid, a solution of

  at 5% sodium bicarbonate and water, it was

  dried and evaporated to give a yellow oil

  kernel (9.043 g). This oil was dissolved in diethylamine (50 ml) and then stirred and refluxed under nitrogen 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, and the acid products were reextracted with a 5% solution of sodium carbonate. The aqueous phase was acidified with 6N hydrochloric acid (50 ml) and extracted with acetate.

  ethyl. The extracts were washed with chlorinated

  N water and water, dried and evaporated to give a buff solid (3,440 g). This product was recrystallized from acetone to give pale buff (1.980 g) crystals.

  of the 17 P-carbothioic acid indicated in the title,

  sedating a melting point of 172-173C.

  The analytical sample was obtained after 2 recrystallizations from acetone as crystals.

  whites, EF. 177-179, LUD +1100 (c 1.05).

Preparation II

  S-Chloromethyl 9c-fluoro-160-methyl-3,11-dioxo-17a-pro-

  pionyl-oxyandrosta-1,4-diene-170-carbothioate I Jones 8N reagent (1.5 ml) was added dropwise over 10 minutes to a stirred solution of the compound of Example I (described later in this

  memory) (998 mg) in acetone (2 ml) and dimethyl

  formamide (2ml). After 30 minutes, we slowly diluted

  the reaction mixture with water (100 ml), with stirring

  tation and refrigerated the suspension thus obtained

  1 hour. The precipitate was collected by filtration, washed with water and dried to give a

  solid cream (879 mg). The p.l.c. 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) mp 204-

2050, Z / 7D +940 (c 1.04).

Preparation III

  N, N-dimethylthiocarbamoyloxycarbonyl-9c-fluoro-11

  hydroxy-16α-methyl-17m-propionyloxyandrosta-1,4-diene-3-

  one (III) A 9-fluoro-11-hy acid solution was treated

  hydroxy-16a-methyl-3-oxo-17 "-propionyl-1,4-oxyandrosta

  diene-17β-carboxylic acid (0.434 g) in dichloromethane (8 ml), successively with triethylamine (0.14 ml), dimethylthiocarbamoyl chloride (0.248 g) and sodium iodide (0.149 g) and The mixture is stirred under a nitrogen atmosphere at 20 ° C. for 6 hours. Ethyl acetate (30 ml) was added and the

  total volume of half under vacuum. A quantity was added

  additional amount of ethyl acetate (50 ml) and the solution was washed with water, 2N hydrochloric acid, water, 3% sodium bicarbonate solution, water and a saturated solution of sodium chloride, and then dried. The solution was concentrated under vacuum

  when the product crystallized (0.329 g). We have recreated

  the product in acetone (twice) to give the title anhydride as white needles with a melting point of

191-193, Z7D +820 (c 0.57).

Preliminary IV

  9α-Fluoro-110-hydroxy-16α-methyl-3-oxo-17α-propionyl acid

  Oxyandrosta-1,4-diene-17α-carbothioic acid (IV) A suspension of the product obtained in (III) (2.477 g) in diethylamine (25 ml) was stirred under reflux, under reflux.

  nitrogen atmosphere. After 3.5 hours, the material was

  The reaction mixture was cooled in 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 and then overlaid with acetate.

  -ethyl and acidified with hydrochloric acid

  at a pH of 1. The aqueous phase was extracted with additional ethyl acetate and the combined extracts were washed with water, saturated sodium chloride solution, dried and the solvent was removed in vacuo. The residues were crystallized twice in acetone to give the acid

  carbothiolac indicated in the title in the form of

  white guilleas (1,309 g) m.p. 141-143 *, Z "7D +30

(c 0.51).

Preparation V

  11-Hydroxy-3-oxo-17α-dihydroxy-3-oxoandrosta- 1,4-acid

diene-17β-carboxylic acid (V)

  A solution of 119,17a-dihydroxy acid was cooled

  3-oxoandrosta-1,4-diene-17β-carboxylic acid (13.5 g) and triethylamine (18 ml) in dichloromethane (500 ml) up to 4 ° C. and treated, in portions, with chloroform. 'space

  15 minutes, with propionyl chloride (14.2 ml).

  Stirring was continued at 4 ° C. for a total time 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 (14.3 ml) was added under stirring.

  tion. After 1 hour at 200 ° C, the solvent was removed under reduced pressure and the residue was dissolved in water (150 ml). After acidification to pH 1 with 2N hydrochloric acid, the product was extracted with ethyl acetate. The combined extracts were washed with

  water and saturated brine, dried and

  concentrated to a small volume. The solid product was collected by filtration, washed with acetate

  of ethyl and dried under vacuum at 50 ° so as to obtain

  hold the 17a-propionate carboxylic acid indicated in the title as crystals (13.309 g), Z_7D +20

  (c 1,10). A fraction of the product (389 g) was recreated

  twice taller in methanol to generate an analytical sample (256 mg) m.p. 244-245 '

(decomp), Zú7D + 30 (c 0.83).

Preparation VI

  6c, 9a-difluoro-1-hydroxy-1 6c-methyl-3-oxo-17

  propionyloxyandrosta-1,4-diene-170-carboxylic acid (VI) A solution of 6a, 9a-difluoro-110 acid was stirred,

  17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17p-

  carboxylic acid (2.113 g) and triethylamine (2.5 ml) in dichloromethane (60 ml) and treated with

  about 0 ° C with propionyl chloride (1.85 ml).

  After 1 hour, the mixture was diluted with a

  additional solvent (50 ml) and washed successfully.

  with 3% sodium bicarbonate solution, water, 2N hydrochloric acid, water, saturated brine, then dried and evaporated to give a buff solid . This solid was dissolved in acetone (50 ml) and diethylamine (2.5 ml) was added thereto. -After 1 hour at 22 C, we have

  The solvent was removed in vacuo and the gum was dissolved.

  in water (30 ml). Acidification to pH 1 with 2N hydrochloric acid precipitated a solid which was collected, washed with water and dried to obtain the carboxylic acid.

  17a-propionate shown in the title (2,230 g), m.p.

2250, to 7D + 40 (c 0.70).

Preparation VII

  171-N, N-Dimethylthiocarbamoyloxycarbonyl-9a-fluoro-1i

  hydroxy-16?, 17? isoproiy] Ldènedioxyandrosta-1,4-diene-3-

one (VII)

  A solution of 9α-fluoro acid was treated.

  hydroxy-16a, 17a-isopropylidenedioxy-3-oxoandrosta-1,4

  diene-17β-carboxylic acid (1,000 g) in dichloromethane (15 ml) and triethylamine (0.33 ml) under a nitrogen atmosphere, with N, N-dimethylthiocarbamoyl chloride

  (588 mg) and the mixture was stirred at room temperature.

  ature. After 68 hours, the reaction mixture was diluted

  with ethyl acetate (50 ml) and washed with N hydrochloric acid (2.10 ml), 5% sodium bicarbonate solution and water, dried and evaporated to a pale yellow crystalline solid (1.123 g). The p.l.c. from a fraction of the product (200 mg) in a mixture of chloroform and acetone (9: 1) gave a whitish solid (161 mg) which was crystallized from ethyl acetate in the form of of white needles of the title mixed anhydride (131 mg), mp 279-281, / z7D + 1740 (c 0.61 dimethyl sulfoxide). Preparation VIII

  17e-N, N-Dimethylthiocarbamoylcarbonyl-6 ", 99-difluoro-1-

  hydroxy-16at 17α-isopropyl] denedioxyandrosta-1,4-diene-3-

  one (VIII) A solution of 6a, 9a-difluoro-11p-acid was treated

  hydroxy-1 6a, 17-i-propylidenedioxy-3-oxoandrosta-1,4-

  diene-17β-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 22, for 80 minutes. Ethyl acetate was added

  (500 ml) and the resulting solution was washed successively

  with 2N hydrochloric acid, water,

  sodium bicarbonate solution, water and a solution

  Saturated sodium chloride solution and dried to finally concentrate. Crystallization occurred during cooling and the solid was washed and dried in vacuo to give the title anhydride (3.562 g) as yellow prisms.

  pale, mp. 283-287 (dec), Z-7D + 156 (c 0.84, dimethyl-

sulfoxide). -

Preparation IX

  6x, 9a-difluoro-11-hydroxyl-16a, 17a-isopropylidene acid

  dioxy-3-oxoandrosta-1,4-diene-17-carbothiolide (IX)

  A suspension of the product of the prepa-

  ration VIII (3.455 g) in diethylamine (200 ml) under reflux, under a nitrogen atmosphere, for 6 hours. The

  initial suspension dissolved rapidly, but a

  Pension pale brown 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 water. 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 6N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with water and saturated sodium chloride solution, then dried and the solvent was removed in vacuo to give a pale gray solid (2.31 g) . Part of the product (0.408 g) was crystallized from ethyl acetate to give the title carbothioic acid (0.149 g), mp 191-199, ZE7D + 124 (c 1.04). dimethylsulfoxide). Preparation X

  6a-Fluoro-11,17a-dihydroxy-3-oxoandrosta-1,4-diene-acid

  (X) A solution of 6c-fluoroprednisolone (4.98 g) in tetrahydrofuran (50 ml) was stirred with a solution of periodic acid (10.0 g) in water (24 ml).

  at 22. After 50 minutes, the tetrahydro-

  furan 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 recover the acid indicated in FIG.

  - titre (171 mg) in the form of white needles

  having a melting point of 241-248, LZ7D + 54 (c 0.825).

Preparation XI

  6c-fluoro-110f-hydroxyl-3-oxo-17a-propionyloxvandrostatic acid

  1,4-diene-17β-carboxylic acid (XI) A solution of the product of the preparation

  X (4.491 g) and diethylamine (4.46 ml) in dichloromethane

  dry methane (160 mL) at -5 and treated dropwise with propionyl chloride (2.80 mL, 2.96 g) in dry dichloromethane (ca. 5 mL), in vacuo 5 minutes at a temperature below 0. After additional minutes to less than 0, the reaction mixture was diluted with dichloromethane (160 ml), washed with sodium bicarbonate solution, water and dried and evaporated to room temperature. obtaining a white solid (5.701 g). This product was stirred with diethylamine (4.60 mL, 3.24 g) in acetone

  (30 ml), so as to obtain a clear yellow solution.

  After 30 minutes, the solution was concentrated, water (150 ml) was added thereto and the resulting solution 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

  extracted the product 3 times with ethyl acetate.

  The extracts were combined, washed with water (50 ml), dried and evaporated to give a white foam (5.819 g). A fraction of the foam (304 mg) was crystallized from ethyl acetate to give the title compound: 17α-propionate (144 mg) as small plates having

  melting of 224-227, / L7D + 30 (c 0.861).

  Preparations XII - XXIII After repeating the same general procedure as that described in Preparation 1, but using 170-carboxylic acid corresponding to the desired 17-carbothioate as starting material (the details of the process are summarized in FIG. following table I), the following acids could be prepared:

  XII.-17c- & ketoxy-9a-fluoro-11p-hydroxy-16f-methyl-3-oxo-

  androsta-1,4-diene-17β-carbothiolec, m.p. 178.5-179O, / Z7D +980 (c 1.02);

  XIII. 7-Butyryloxy-9u-fluoro-1-hydroxy-16e-methyl-3-

  oxoandrosta-1,4-diene-17e-carbothio; Mp 175-176, [+] D + 1070 (c 0.96);

  XIV. 9-fluoro-110-hydroxy-17c-isobutyryloxy-16e-methyl-

  3-oxoandrosta-1,4-diene-17-carbothioic acid amide; Mp 177-179 [C] D + 119 (c 0.95);

  XV. 1-p -hydroxy-3-oxo-17α-propionyloxyandrosta-1,4-

  diene-175-carbothioic acid, mp.134-138, [e] D + 67o (c 0.66);

  XVL - 1-hydroxy-16e-methyl-3-oxo-17a-propionyloxy-

  androsta-1,4-diane-17 $ -carbothioiqUe; Mp 159-1630, [1] D + 113 (c 0.78);

  XYIL - 9x-chloro-1H-hydroxy-16β-methyl-3-oxo-17α-propionyl

  oxyandrosta-1,4-diene-17-carbothioic acid; Mp 167-171, [+] 128 (c 0799);

  XV77. 9-Rho-11-hydroxy-16α-methyl-3-oxo-17α-propionyl

  oxyandrosta-1,4-diene-17-carbothioic acid; M.F.141-143, [t] D +30 (c 0.51);

  XDL-6ac, 9c-difluoro-11e-hydroxy-16α-methyl-3-oxo-17α-pro-

  pionyloxyandrosta-1,4-diene-17 $ -carbothioique;: P..F. 136-139, [a] D-30o (c 0.56);

  XX. 9-Fluoro-11S-hydroxy-16-methylene-3-oxo-17a-pro-

  pionyloxyandrosta-1,4-diene-17-carbothioic m.p.

236-239o, [C] 71 (c 099);

  XXL - 11-hydroxy-3-oxo-17a-propionyloxyandrosta-4-ene-17e

  carbothio.que-; Mp 176-177, [C] D +101 (c 0.96)

  XXI. 9x-fluoro-11-hydroxy-16L, 17c-isopropylidenedioxy-3-

  oxoandrosta-1,4-diene-175-carbothioic acid; Mp 274-304 (dec), [a] D + 121 (c 0.51, dimethyl sulfoxide);

  XXIII. 6-fluoro-1-hydroxy-3-oxo-17a-propionyloxyandrosta-

  1,4-diene-17-carbothioic acid; P.F.189-193, [C] D +720

(c 0.74). -

TABLE I

  Formation of mixed anhydrides 17P-acid Preparation time carboxyCl-CSNMe2 NEt3 Reaction solvent (CH2C12) (days) to

quantity the temperature

  (g) (g) (mi) (ml) ambient background XII 5,000 2,940 1,66 75 5la

XIII 15,354 8,809 4., 8,250 6

XIV 4,182 2,399 173 80 4

  XV 7,148 4,40 2,6 150 6lb XVI 6,) 137 3,77 2,05 140 6lc

XVII 5,973 3,350 1,34 100 7

XVIII 4.207 2.39 1.35 80 0.677, ld i

XIX 2,130 1.80 0., 66 50 6

xOC 5,000 2,507 1,41 75 3

XXI 1,000 2,442 1,22 15 2,7

XXII 1,000 0.1588 0.33 15 2.88

XXIII 6,000 3.55 2.I0 120 1.2510

  TABLE I (continued) Treatment of Mixed Intermediate Anhydrides for Diethylamine

  Preparation NHEt Product Duration Crystalline Solvent

(ml) 2 reaction (g) tallization

(h) in the

-flux XII 50 5.5 2.104 EA2a

XIII 250 4 5,244 EA3

XIV 60 4.5 1.00 EA

,., ..-,, -,

XV 60 4 3.29 EA

XVI 50 3.5 1X382 EA

T _ ,, - ,. ,, ',

XVII 60 5.7 0.527 EA

XVIII 25 4.75 1.309 A

XIX 12 6 0.418 EA

-., 'XX 50 3.75 1.296 EA2b

XXI 15 4 0 3976 A5

XXII a) 8 (a) 3 9

b) 16 (b) 2.5 __.

XXIII 60 4,5 2,88 EA-P

  Notes: EA = ethyl acetate A = acetone P = petroleum

Bp 60-80o.

  1. Fractions of (a) 500 mg were taken, (b) 670 mg, -

  (c) 424 mg, (d) 171 mg of dimethylthioid anhydride

  intermediate carbamic for characterization purposes.

  2. The characterization was performed on a sample recrystallized twice more in acetate

  ethyl. Recoveries (a) 84%, (b) 69 5.

  3. The product was solvated with ethyl acetate (about 0.2 mole). 4. Dimethylthiocarbamic anhydride was crystallized

  intermediate (1.435 g) in ethyl acetate.

  Part of the product (95 mg) was removed for

characterization.

  5. The characterization was performed on a sample recrystallized twice more in 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. Intermediate dimethylthiocarbamic anhydride (1.13 g) was crystallized from ethyl acetate. A fraction of the product (200 mg) was chromatographed

  (p.l.c., chloroform-acetone, 9: 1) and recreated

  tallied this fraction in ethyl acetate

(recovery 65 56).

  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

  9c-Chloro-11-hydroxy-160-methyl-3-oxo-17H-propionic acid

  oxyandrosta-1,4-diene-170-carbothioic

  9,11i-eoxy-160-methyl-3-oxo-17 "-propionyloxy-acid

  drosta-1,4-diene-17-carbothioic acid (XXIV)

  A mixture of 17 P-N, N-dimethylthiocar-

* Bamoyloxycarbonyl-9S-chloro-1-hydroxy-16β-methyl-17α

  propionyloxyandrosta-1,4-dien-3-one (5.586 g) in diethylamine (60 ml) under reflux under nitrogen for 5 hours and 40 minutes. The reaction mixture was poured into water (450 ml), acidified to pH 10 with concentrated hydrochloric acid.

  and extracted with ethyl acetate (3 x 60 mL).

  The combined extracts were washed with water and extracted with an aqueous solution of sodium carbonate (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 give

colorless broth (2.834 g).

  Two crystallizations of the mixture in acetate

  of ethyl gave 9a-chloro-110-hydroxy-16β-

  methyl-3-oxo-17o-propionyloxyandrosta-1,4-diene-17p-

  carbothioic (0.527 g) as white prisms having a melting point of 167 to 171, LZ7D, +128

  (c 0.99). Mother liquors from crystallisation

  contained an additional amount of the above-mentioned 9α-chloro-11β-hydroxycarbothioic acid, at the same time

  9p, 11p-epoxy-16p-methyl-3-oxo-17-

  propionyloxyandrosta-1,4-diene-17P-carbothioic acid.

Preparation XXV

  S-Iodomethyl 9 "-fluoro-11-hydroxy-160-methyl-3-oxo-17c

  propionyloxyandrosta-1,4-diene-17β-carbothioate (XX) A solution of the compound of Example 1, described hereinafter, (500 mg) and sodium iodide (XX) was stirred and refluxed ( 1.874 g) in acetone (15 ml) for 6.5 hours. Ethyl acetate (75 ml) was then added and the solution was washed successively with water, 10% sodium thiosulfate solution, 5% sodium bicarbonate solution and water. water, dried and evaporated to give a whitish foam (525 mg). The p.l.c. in a mixture of chloroform and acetone (6: 1) gave a whitish foam (478 mg) which was crystallized twice in acetone without heating above room temperature, so that to obtain colorless crystals of the ester

  S-iodomethylic indicated in the title. (241 mg) m.p.

196-197, Z7D -32 (c 1.01).

  Preparations XXVI - XXXVII By repeating the same general procedure as that described in Preparation XXV, but using,

  as a starting material, S-chloromethyl-17 -

  carbothioate corresponding to the desired product (the details of the process are summarized in the following Table II), the following compounds were obtained:

  XXVI. S-Iodomethyl 17? -Acetoxy-9? -Fluoro-11-hydroxy-16?

  methyl-3-oxoandrosta-1,4-diene-17-carbothioate, m.p.

204-205o, Z7D -29 (c 0.98)

  XXVII. S-Iodomethyl-11-hydroxy-3-oxo-17-propionyloxy

  androsta-1,4-dine-17β-carbothioate, [C] D + 260 (c 0.47).

  XXVIII. S-Iodoamethylethyl-16-hydroxy-methyl-3-oxo-1,7 "-

  propionyloxyandrosta-1,4-diene-17 $ -carbothioate, [a] D +5

(c 0 74).

  XXIX. S-Iodomethyl 9a-chloro-11s-hydroxy-16-r-methyl-3-

  oo-17a-propionyloxyandrosta-1,4-diene-17 -carbothioate $,

[] D +70 (c 0.36).

  YXX. S-Iodomethyl 9a-fluoro-1-hydroxy-16c-methyl-3-

  oxo-17α-propionyloxyandrosta-1,4-diene-17-carbothioate,

[] D + 85 (c 0.55).

  XXXI. S-Iodomethyl 6a, 9c-difluoro-11-hydroxy-16α-methyl

  3-oxo-17α-propionyloxyandrosta-1,4-diene-17-carbothioate.

  XXXII. S-Iodomethyl 9a-fluoro-11-hydroxy-16-methylene-3-

  oxo-17α-propionyloxyandrosta-1,4-diene-17-carbothioate,

P..F. 191-199, [C] D -31 (c 0.99).

  XXXIII. S-Iodomethyl 9α-fluoro-1-hydroxy-3-oxo-17α

  propionyloxyandrosta-1,4-diene-17e-carbothioate, p.

-178, [C] D + 40 (c 0.50).

  XXXIV. S-Iodomethyl 6α-fluoro-11-hydroxy-3-oxo-17α

  propionyloxyandrosta-1,4-diene-17β-carbothioate, Pr.

-197, [a] D + 18 (c 0.64).

3O

  XXXV. S-Iodomethyl 17c-acetoxy-6a, 9c-difluoro-11-yl

  hydroxy-c16L-methyl-3-oxoandrosta-1,4-diene-17-carbothioic acid,

M.p. 241-243, [CL] +780 (c 0.78).

  XXXVI. S-Iodomethyl 17c-butyryloxy-6a, 9a-difluoro-11S-

  hydroxy-16c-methyl-3-oxoandrosta-1,4-diene-17 -carbothioate $,

M.p. 210-212, [C] D + 89 (c 0.90).

D

  XXXVII. S-Iodomethyl 9a-fluoro-11-hydroxy-16a, 17a-iso

  propyid-nedioxy-3-oxoandrosta-1,4-diane-17-carbothioate,

  Mp 261-270 (dec), [C] D + 97 0 (c 0.48, dimethylsulfoxide).

TABLE II

  Exchange of halogens on 5-haloalkyl 17α-acyloxyandro-

stane-170-carbothioates

__________ I

  NaI (mg) starting steroid H-iogenide. Amount [{mfr OLVNT DURATION DPLC SOLVENT PRODUCT (ac / tone) pREACTDN (CRIS Silica) (mg)

(ml) (h) at CHC1 - TALLISA-

ebb TION

e2..T :: - -.-

  ___________1 '- DJ 1t T JUJj_ _ _ _ _ _ 1900C 549] C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 C1 6.5 4,5 5 19: 1 9: 1 EA A M SA-P EA EA A

  j _ __ _ __ _ _ J _ _ _ __ _ 1- __ _ __ __ __ __ - __ _ _ __.

  = ethyl acetate = acetone = methanol o = petroleum P.E.60-80 T

Prepared-

No. XXVI XXVII

XXXVIII

xxi XXI XXII

XXXIII

XXXIII

XXXIV XXV XXVI XXVII EA TO M P

I |

  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

-5 crude (2.058 g).

  3. The product was used directly for the preparation

  corresponding fluoromethyl 170-carbothioate.

  4. Lithium chloride was used instead of iodide

of lithium.

5. Solvated with 0.5 H2O.

6. Solvated with 0.1 EA.

7. Solvated with 0.2 EA + 0.5 H20.

  8. Obtained from a fraction (300 mg) of the product

crude crystalline (1.611 g).

Preparation XXXVIII

  S-Iodomethyl 6α, 9α-difluoro-1-hydroxy-16α-isopropanol

  Isenedioxy-3-oxoandrosta-1-4-diene-17-carbothioate (xXVIII)

  A solution of the compound described in the ex-

  Example 4 (hereinafter described, 0.795 g) in acetone (50 ml) was refluxed with sodium iodide (2.969 g) for 5.5 hours. We added

  ethyl acetate (75 ml) and the solution was washed successively

  with water, a solution of sodium methabisulphite, then dried and the solvent removed

  under vacuum to obtain a whitish solid (0.93 g).

  A portion of this product (0.205 g) was crystallized twice from ethyl acetate to give the title title S-iodomethylthioester (0.105 g) as white prisms having

  melting point 260-262o (dec) / c7D + 810 (c 0.6;

sulfoxide). Preparation XXXIX S-2-Bromo-ethyl 9c-fluoro-11β-hydroxy-160-methyl-3-oxo

  17α-propionyllxyandrosta-1-diene-175-carbothioate (XXXIX) The product of Preparation I (0.5 g) was treated

  as described for the S-chloromethyl ester

  (Example 1, Method A, which is given later in this report), but using 1,2-dibromethane,

  in order to obtain colorless crystals of the ester S-

  2'-bromethylic acid in the title (0.409 g)

  having a melting point of 174-145, 7 +120 (c 1.04).

PreDaration XL

  16 2 1 7-Etpoxy-9a-fluoro-11-hydroxy-163-methyl-3- acid

  oxoandrosta-1,4-diene-17r-carbothiola (XL)

  A mixture of 16c, 17c-epoxy-9a-fluorinated acid was stirred.

  11p-hydroxy-16p-methyl-3-oxoandrosta-1,4-diene-17p-car-

  boxyl (377 mg) and 2-fluoro-1-methyl tosylate

  pyridinium (340 mg) in dry dichloromethane (7 ml), ice-cooled and treated for one minute with triethylamine (0.42 ml). After 1 hour, hydrogen sulfide was passed through

  mixing for 30 minutes, so as to obtain a

  yellow version. The t.l.c. (chloroform-acetone-acetic acid

  tick, 30: 8: 1) revealed that a less polar product

  Cipal had formed. After allowing to warm to room temperature over one hour, the mixture was treated with 2N hydrochloric acid (30 ml) and the product was extracted with sodium acetate. ethyl (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 and extracted with sodium acetate. 'ethyl. The combined acid extracts were washed with water, dried and concentrated under reduced pressure to give, after filtration, whitish crystals (274 mg) probably

  part 16a, 177-epoxy-9a-fluoro-11p-hydroxy-160-acid

  unstable methyl-3-oxoandrosta-1,4-diene-17β-carbothioic (no starting oxyacid present) as judged

  by t.l.c. (chloroform-acetone-acetic acid 30: 8: 1, RF 0.7).

XLI preparation

  S-Chloromethyl 16 ", 17-epoxy-9e-fluoro-11p-hydroxy-16f-

  Methyl-3-oxoandrosta-1,4-diene-17-carbothioate (XLI) Method A

  A 16c, 17a-epoxy acid suspension was treated

  9α-fluoro-11-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene

  173-carboxylic acid (753 mg) and 2-fluorinated tosylate

  1-methylpyridinium (680 mg) in dichloromethane (7 ml) dropwise at 0 C with triethylamine (1.39 ml)

  and then stirred at 0 C for 1 hour. We have

  then passes hydrogen sulfide through the

  mixture for 15 minutes and the mixture was then stirred

  thus obtained at 0 ° C for an additional hour.

  Bromochloromethane (0.26 ml) was then added and

  the mixture was stirred and allowed to warm up

  than at 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% bicarbonate solution.

  of sodium, dried and evaporated to the point of

  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 from acetone to give

  white needles of the S-chloromethyl ester epoxide

  indicated in the title (447 mg), m.p. 246-251, L_7D

+131 (c 0.67).

Method B

  A 16a, 17a-epoxy-9a acid suspension was treated.

  fluoro-11-hydroxy-16-methylene-3-oxoandrosta-1,4-diene

  17 P-carboxylic acid (376 mg) and trifluoromethanesulfonate

  2-chloro-N-methylbenzothiazolium (400 mg) in

  chloromethane, drop by drop and at 0 C, by

  ethyl amine (0.7 ml). The resulting solution was stirred at 0 ° C for 1.25 hours and then

  to pass hydrogen sulfide through the mixture

  10 minutes. After an additional 1 hour at 0 ° C, bromochloromethane (0.13 ml) was added and the mixture was stirred at room temperature. Two additional fractions of bromochloromethane were then added

  (0.13 ml) after an additional 1.5 and 1.8 hours. 15 half

  After the final addition, the mixture was diluted

  Acetate with ethyl acetate (200 ml) and washed successively with 2N hydrochloric acid, 5% sodium bicarbonate solution and water, dried and evaporated to a red crystalline solid. This solid was subjected to a p.l. c. in a mixture of chloroform and acetone (19: 1) (3 trials). The more polar band gave a pale pink solid consisting of the indicated S-chloromethyl ester

  in the title (134 mg), identical to a sample above

  the product's own according to the t.l.c.

XLII preparation

  S-Chloromethyl-9a-fluoro-11,17a-dihydroxy-16-methylene-3-

  oxoandrosta-1,4-diene-17-carbothioate (XLII) A solution of the product of preparation XLI (400 mg) in trifluoroacetic acid (16 ml) was stirred at room temperature. After 5.5 hours, the reaction mixture was evaporated to near dryness and

  dissolved in ethyl acetate (100 ml).

  The solution was washed with a 5% bicarbonate solution

  sodium bonate and water, dried and evaporated to a yellow-green foam (466 mg). The foam was subjected to a p.l.c. in a mixture of chloroform and acetone (9: 1) (3 trials). A fraction (80 mg) of the main band (315 mg) was crystallized twice in acetone to give white crystals of 16-methylene-17α-alcohol as indicated in the title (48 mg), PF 242-243, / 7D +36

(c 0.50).

XLIII preparation

  9α-Fluoro-17α-hydroxy-16β-methyl-3,11-dioxoandrostatic acid

  1,4-diene-170-carboxylic acid (XLIII) A stirred suspension of 9α-fluoro-17,21-dihydroxy-16β-methyl-1,4-trans-1,4-diene-3,11,20-trione (4,842) was cooled g) in tetrahydrofuran (50 ml) in ice and treated, dropwise over a period of 5 minutes, with a periodic acid solution (4.255 g) in water (15 ml); ml). The reaction was stirred at 22 for 2.25 hours after which time most of the suspension had dissolved.

  The solvent was removed in vacuo, with the addition of

  periodically to maintain the original volume. The precipitate thus obtained was filtered off, washed with water and dried in air and under vacuum to recover the title carboxylic acid as prisms. cream colored (4.55 g) mp 270-272 (dec), a7D + 136 (c 1.04, dimethyl sulfoxide). XLIV preparation

  9α-Fluoro-11α, 17α-dihydroxy-163-methyl-3-oxoandrostatic acid

1,4-diene-17f-carbothiolcue (XLIV)

  A stirred solution of 9c-fluoro acid was cooled

  11,17a-dihydroxy-16P-methyl-3-oxoandrosta-1,4-diene-175-

  carboxylic acid in dry N, N-dimethylformamide (15 ml) at -5 under a nitrogen atmosphere and treated with N, N'-carbonyldiimidazole (0.435 g) and the reaction mixture stirred. at -5 for 18 hours. We were bubbled

  hydrogen sulfide gas through the mixture

  action for 5 minutes and the solution was shaken

  for another 4 hours, leaving it

  The reaction mixture was poured into ethyl acetate and the resulting solution was washed with 2N hydrochloric acid and water and extracted with water. a solution of

  2N sodium carbonate (3 x 50 ml). We washed the ex-

  ethyl acetate (60 ml) and then overlayed with an additional layer of ethyl acetate

  (100 ml) and acidified with hydrochloric acid.

  dries to a pH of 1.0. The aqueous layer was extracted with an additional amount of ethyl acetate and the extracts washed with water and saturated sodium chloride solution, dried and the solvent removed in vacuo. to give a white solid which was crystallized twice from ethyl acetate to give the title carbothiolic acid (0.315 g).

201 (dec.), Zo7D + 189 (c 0.71).

XLV Prévaration

  9α-Fluoro-17α-hydroxy-16β-methyl-3,1-dioxoandrostatic acid

1,4-diene-170-carbothioic (XLV)

  A stirred solution of the product of the pre-

  XLIII (5.587 g) in dry N, N-dimethylformamide (150 ml) was added under nitrogen to N, N'-carbonyldiimidazole (4.847 g) and the reaction mixture was stirred at room temperature for 20 minutes. hours. Hydrogen sulfide gas was bubbled through the reaction mixture for 10 minutes and the solution was stirred for a further 1 hour. We paid

  solution on ice (300 ml) and hydrochloric acid

  2N drique (100 ml), to obtain a buff precipitate. This precipitate was separated by filtration, it was

  air dried overnight (6.268 g) and crushed

  in ethyl acetate to give the title carbathioic acid (3.761 g) as white prisms, having a

  215-218 melting, LZ7D +143 (c 0.88, dimethylformamide).

PREPARATION XLVI

  9a-fluoro-17α-hydroxy-160-methyl-3,11-dioxoandrostatic acid

  1,4-diene-170-carbothioic acid (XLVI) A stirred solution of the product of Preparation XLIII (1.059 g) in dry N, N-dimethylformamide (50 ml) was treated at 20 under a nitrogen atmosphere. with N, N'thiocarbonyldiimidazole (1.368 g) and the reaction mixture was stirred at 20 for 4 hours. Hydrogen sulfide gas was bubbled into the reaction mixture for 5 minutes and the solution was stirred for a further 1 hour. The reaction mixture was partitioned between ethyl acetate (100 ml) and 2N hydrochloric acid (100 ml) and the organic phase was washed with 2N hydrochloric acid (100 ml) and dried. water (2 x 100 ml) and extracted with 2N sodium carbonate solution (2 x 75 ml). The combined extracts were washed with ethyl acetate (50 ml) and then

  covered with ethyl acetate (100 ml) and

  dified with hydrochloric acid to a pH of 1.

  The aqueous layer was extracted with an additional amount of

  The combined ethyl acetate (50 ml) was washed with water, saturated sodium chloride solution, dried and the solvent removed in vacuo. The residues have been crystallized in

  ethyl acetate, so as to collect the carboxylic acid

  thioic indicated in the title (0.559), m.p. 212-219,

  7D + 145 (c 0.81, dimethylformamide).

XLVII preparation

  S-Chloromethyl 9o-fluoro-1117c-dihydroxy-16-methyl-3-

  oxoandrosta-1,4-diene-17-carbothioate (XLVII)

  A stirred solution of the product of the pre-

  XLIV (0.169 g) and sodium bicarbonate (0.040 g) in N, N-dimethylformamide (6 ml) were added with bromochloromethane (0.1 ml) and stirring was continued at 22 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 a saturated solution of sodium chloride, then dried and the solvent removed in vacuo. The residue was crystallized twice in ethyl acetate to give the title S-chloromethylthiolic ester (0, 193 g) as white plates.

  solvated with ethyl acetate (1 mole), m.p.

o, 7D + 147.50 (c 0.64).

XLVIII preparation

  9a-fluoro-160-methyl-3,1-dioxo-17a-propionyloxy acid

  androsta-1,4-diene-170-carbothiazole (XLVIII) A stirred solution of the product of the preparation XLV (0.485 g) and triethylamine (0.55 ml) in dichloromethane in a mixture of ice and salt was cooled. it was 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 (75 ml) and 2N sodium carbonate solution (75 ml) and the organic layer was washed successively with an additional 2N sodium carbonate solution, followed by water, 2N hydrochloric acid, water and saturated sodium chloride solution, and then dried and the solvent removed in vacuo to give 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 22 for 1.25 hours. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (30 ml) and 2N hydrochloric acid (30 ml). The ethyl acetate layer was washed with water and extracted with 2N sodium carbonate solution (2 x 30 ml). The combined extracts were washed

  - with ethyl acetate (30 ml) and covered with acetylene

  ethyl acetate (60 ml) and acidified to pH 1.0 with hydrochloric acid. The ethyl acetate layer was washed with water and saturated sodium chloride solution and dried and the solvent was removed in vacuo to give a white solid which it was crystallized twice in ethyl acetate, so as to obtain the indicated ester

  in the title (0.290 g), m.p. 173-170 o, L7D +148 (c 1.03).

XLIX preparation

  S-Chloromethyl 9x-fluoro-17α-hydroxy-16β-methyl-3,11-

  1,4-dioxoandrosta-1,4-diene-carbothioate (XLIX) A solution of the product of the preparation XLV (5.006 g) and sodium bicarbonate (1.612 g) in N, N-dimethylacetamide (50 ml) was treated. ) with bromochloromethane (1.24 ml) and the reaction mixture was stirred at 22 for 3.3 hours. The solution was diluted with ethyl acetate (70 ml) and washed sequentially with 2N hydrochloric acid, water, sodium metabisulphite solution, water and a mixture of water. saturated solution of sodium chloride, then dried and the solvent was removed in vacuo to obtain a

  solid cream (3.638 g). We got the sample

  Analytical map after p.l.c. of preparation (silica gel, development with a mixture of chloroform and acetone 9: 1) and the product was crystallized from ethyl acetate as colorless prisms of the title ester ( 0.262 g), mp 223-228,

--D +251 (c 1,2).

Preparation L

  9c-fluoro-11-hydroxy-160-methyl-3-oxo-17-non-organic acid

  N-L-oxyldrosta-1,4-diene-170-carbothioic acid () A stirred solution of the product of Example XLIV (0.511 g) in dichloromethane (20 ml) containing triethylamine (0.6 ml) was cooled to room temperature. 2 and treated with propionyl chloride (0.45 ml) and

  the reaction mixture was stirred at 2 for 2.5 hours.

  The reaction mixture was partitioned between ethyl acetate and sodium bicarbonate and the organic phase was washed with water, 2N hydrochloric acid, water and saturated sodium chloride solution. sodium, dried and the solvent removed

  vacuum to obtain a colorless solid (0.634 g).

  This product was dissolved in acetone (30 ml) diethylamine (1.5 ml) was added and the clear solution was stirred at 22 for 55 minutes. The reaction mixture was diluted with ethyl acetate (50ml) and washed with 2N hydrochloric acid and water and extracted with water. a 5% solution of sodium carbonate. The combined extracts were acidified with 2N hydrochloric acid to pH

  of 1 and then extracted with ethyl acetate.

  The combined extracts were washed with water and a solution of

  saturated with sodium chloride and dried and the solvent was removed in vacuo to give a colorless broth (0.522 g) which was crystallized from ethyl acetate to give the ester indicated in the title as colorless prisms (0.307 g); 174-179, / 7D + 107 (c 1.0), PREPARATION LI

  9a-Fluoro-11,17a-dihydroxy-16-methylene-3-oxoacid

  androsta-1,4-diene-17-carbothiol (LI)

  A solution of 11β-fluoro-11β-acid, 17α-

  dihydroxy-16-methylene-3-oxoandrosta-1,4-diene-170-

  carboxylic acid (0.218 g) in dry N, N-dimethylformamide

  (10 ml) at 22, under a nitrogen atmosphere, with N, N'-

  carbonyldiimidazole (0.254 g) and the reaction mixture was stirred at 22 for 4 hours. Hydrogen sulfide gas was bubbled into the reaction mixture for 5 minutes and the pale green mixture was stirred for 1 hour at 22 °. 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 was removed in vacuo to give a yellow broth (0.222 g) which was crystallized twice from ethyl acetate to give the carbothiolic acid indicated in the title ( 0.078 g), in the form of colorless prisms, decomposing at about 250

without fusion, L / 7D + 117 (c 0.32).

LII preparation

  9a-Fluoro-11-yl, 17-dihydroxy-3-oxoandrosta-1,4-diene acid

  The suspension of 9m-fluoroprednisolone (10 g) in dry tetrahydrofuran (55 ml) was stirred and treated with a periodic acid solution (9.0 g) in water. water (90 ml) and the mixture was stirred at 22 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 and washed at

  water and dried in order to obtain the compound

  titled in the title as a solid (9.42 g).

  A product fraction recrystallized from methanol had a melting point of 289-293 ZE7D +660

* (c 0.73, methanol).

Preparation LIII

  9c-fluoro-112,17c-dihydroxy-3-oxoandrosta-1,4-diene acid

17P-carbothioic (LIII)

  A solution of 9α-fluoro-11,17,17-acid was stirred.

  dihydroxy-3-oxoandrosta-1,4-diene-17β-carboxylic acid (4.5 g) in dry dimethylformamide (100 ml) under a nitrogen atmosphere, with N, N'-carbonyldiimidazole (4.04 g) at 22 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 (about 100 g) and the precipitate thus obtained was collected, washed with water and

  it was dried to collect a white solid (4.56g).

  A product fraction (120 mg) was recrystallized from ethanol to give the thioacid indicated in

  title in the form of colorless crystals (70 mg), m.p.

222-225, 17D + 116o (c = 0.57).

LIV Preparation

  6a, 9-Difluoro-110,17a-dihydroxy-161-methyl-3- acid

  oxoandrosta-1,4-diene-17β-carbothiol (LIV) A solution of 6α, 9α-difluoro-110 acid was stirred,

  17a-dihydroxy-16c-methyl-3-oxoandrosta-1,4-diene-170-

  Carboxylic acid (12.0 g) in dry dimethylformamide (250 ml) and treated with N, N'-carbonyldiimidazole (9.94 g) under a nitrogen atmosphere at room temperature. After 4 hours, the hydrogen sulfide was passed through the solution for 0.5 hours and the mixture was kept for another 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 in vacuo to give the title thioacid as a white solid (11.47 g). ,

M.p. 230-232o, L "7D +94 (c 0.91).

LV preparation

  17x-acetoxy-6α, 9α-difluoro-11-hydroxy-16α-methyl

  3-Oxoandrosta-1,4-diene-17β-carboxylic acid (LV) A solution of the product of the preparation was stirred

  LIV (1.625 g) and triethylamine (2.0 ml) in

  chloromethane (75 ml) at about 0 ° C was treated dropwise with acetyl chloride (1.275 ml),

  then stirred at this temperature for 1.25 hours.

  The mixture was washed with 2N sodium carbonate (50 ml) water, 2N hydrochloric acid (50 ml), water (3 x 50 ml), brine (50 ml), then it was dried and

  evaporated to a white solid (1.91 g).

  This product was dissolved in acetone (40 ml) and stirred with diethylamine (4 ml) at 27 ° C. for minutes. The mixture was concentrated to a volume

  about 25 ml and poured into chlo-

  2N water (100 ml) containing ice (about 100 g).

  After stirring the mixture, the precipitate thus obtained was collected, washed with water and dried to give a solid (1.685 g). A product fraction (400 mg) was recrystallized from ethyl acetate to give the 17? -Acetate shown in the title.

(280 mg), mp 175-177.

LVI preparation

  17α-Butyryloxy-6α, 9α-difluoro-11-hydroxy-16x-acid

  Methyl-3-oxoandrosta-1,4-diene-170-carbothioic acid (LVI) By repeating the same procedure as described in Preparation LV, the product-of the preparation LIV (2.0 g) was converted with butyryl chloride (1.5 ml) instead of acetyl chloride, to the title compound of 17x-butyrate (2.08 g), a fraction of the product was recrystallized from ethyl acetate and

  then had a melting point of 155-157.

LVII preparation

  9α-fluoro 11-hydroxy-3-oxo-17α-propionyloxVandrostatic acid

  1,4-diene 17-carbothiol (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 triethylamine (10.35 ml), to the title 17apropionate (4.17 g). A fraction of the product (350 mg) was recrystallized from ethyl acetate, so

  to obtain colorless crystals (165 mg), m.p.

138o, Lo7D +72 '(c 0.92).

Preparation LVIII

  Acide_6c, 9a-difluoro-110-hydroxy-16c-methyl-3-oxo-17c-

  propionyloxvandrosta-1,4-diene-170-carbothioic acid (LVIII)

  A solution of the product of the prepa-

  LIV (5.0 g) and triethylamine (6.15 ml) in dichloromethane (140 ml) with a mixture of ice and salt and treated dropwise with propionyl chloride (4 g). 74 ml). The reaction mixture was further stirred at about 0.degree. C. for 0.75 hours, then washed successively with 2N sodium carbonate.

  water, 2N hydrochloric acid, water and a

  blackberry. After drying, the solvent was removed to give a white solid (6.35 g). This solid was redissolved in acetone (120 ml) and diethylamine (12.5 ml); after stirring at room temperature for 1 hour, the volume was reduced to about

  ml. The solution was found to be in hydrochloric acid

  2N silver (200 ml) containing ice (about 300 g) and the precipitate thus obtained was collected, washed with water and dried in vacuo to give a white solid (5 g). 17 g) having a melting point of 152-155. Recrystallization of a fraction of the product

  (400 mg) in ethyl acetate, gave the thio-

  7a-propionate acid indicated in the analytical title-

  pure and in the form of colorless crystals (290 mg),

  161-164, La7D -27 (c 0.95) whose infra-red spectrum

  red in the solid state (in Nujol) revealed a crystalline form different from that of the sample obtained

in the preparation XIX.

LIX PREPARATION

  S-Chloromethyl 9α-fluoro-1,6β-methyl-3,11-dioxo-17α

  Propionyloxyandrosta-1,4-diene-17-carbothiate (LIX) A solution of the product of the XLIX preparation (409 mg) in propionic acid (5 ml), trifluoroacetic anhydride (2 ml) was stirred. ) and toluene p-sulfonic acid (0.1 ml of a dry chloroform solution,

  80 mg / ml) at 22 for 2.75 days. We have isolated the

  non-acidic extract by extraction with ethyl acetate after pouring into a saturated solution of sodium bicarbonate. 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 (eg 60-800C), in order to obtain the propionate indicated in the title, in the form of

  colorless crystals having a melting point of 205-

2060, Z7D +950 (c 1.15).

Preparation LX

  S-Chloromethyl 9 "-fluoro-110,17a-dihydroxy-16r-methyl-3-

  oxoandrosta-1,4-diene-17β-carbothioate (LX) A suspension of the product of the preparation was stirred

  XLIX (102 mg) in ethanol (2.5 ml) with boron

  sodium hydride (10 mg) at 22 for 1 hour. The reaction mixture was treated with acetone (5 ml) and then concentrated to near dryness; the residue was dissolved in ethyl acetate (20 ml), washed

  with hydrochloric acid N, with water and with brine.

  After drying, the organic solvent was removed by

  to obtain the title 11P-alcohol in the form of a colorless foam (103 mg), the component of which

  was equipolar with an authentic sample

  tick during the layer chromatographic comparison

  thin (silica, chloroform-acetone, 9: 1).

LXI preparation

  9α-fluoro-11-hydroxy-160-methyl-3-oxo-17α-propionyl acid

  Oxyandrosta-1,4-diene-175-carbothiazole (LXI)

  Methoxy A solution of 9α-fluoro-11β-hydroxy-acid was stirred.

  16P-methyl-3-oxo-17o-propionyloxyandrosta-1,4-diene-17p-

  carboxylic acid (603 mg, solvate with ethyl acetate 0.75 mole) and N, N'-carbonyldi (1,2,4-triazole) (0.997 mg) in dry dimethylformamide (45 ml), nitrogen atmosphere, at about 22, for 18.5 hours. A solution (15 ml) prepared from sodium hydride (305 mg) in dimethylformamide was added by saturation.

  with hydrogen sulphide, and the agitation continued.

  at room temperature for 3 days. The reaction mixture was poured into 2N hydrochloric acid (200 ml) and the product was extracted with ethyl acetate (3x). The organic extracts were combined, washed with water and reextracted with 5% sodium carbonate solution; the alkaline extracts were acidified with hydrochloric acid and extracted with ethyl acetate (3x). After washing with water and brine, the organic extracts were dried and concentrated to a small volume; the title thioacid separated as cream-colored crystals (101 mg), the only major constituent of which

  identified by comparison with an authentic sample

  tick with nuclear magnetic resonance (rmn) 1H

  and by t.l.c. (silica, chloroform-acetone 4: 1).

Method B

  A solution of 9α-fluoro-11β-hydroxy-acid was stirred.

  16p-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17t-

  carboxylic acid (701 mg, solvate with ethyl acetate 0.75 mole) and N, N'-carbonyldiimidazole (473 mg) in dry dimethylformamide (26 mg) under a nitrogen atmosphere and at about 22 ° C. for 19.5 hours and then treated with a solution (10 ml) of sodium hydride (60% dispersion in oil, 233 mg) in dimethylformamide (10 ml) saturated with sodium sulphide. hydrogen. The resulting mixture 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, then dried and evaporated to room temperature. obtaining a foam (186 mg). The indicated thioacid

  in the title proved to be the major component of the

  according to a comparison with an authentic sample according to rmn H and t.l.c. (silica, chloroform-acetone

  (4: 1), and chloroform-acetone-acetic acid (30: 8: 1).

  Method C According to 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) to 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; the t.l.c. (silica, chloroform-acetone 4: 1 and chloroform-acetone-acetic acid 30: 8: 1) revealed that the title thioacid was present as a major component, as compared to a

authentic sample.

PREPARATION LXII

  S-Chloromethyl 6 ", 9c-difluoro-16c-methyl-3-oxo-17α-pro-

  pionyloxy-llp-trifluoroacétoxyandrosta-1,4-diene-17l-

  Carbothioate (LXII) A solution of the compound of Example 5 (described later in this specification) (100 mg) in dry tetrahydrofuran (2 ml) and pyridine (0.1 ml) was treated.

2485'542

  with trifluoroacetic anhydride (0.05 ml) and the mixture was kept at room temperature for 0.5 hours. The reaction mixture was poured into water and the product was extracted with ethyl acetate (3x). The organic extracts were washed with water,

  they were dried and evaporated so as to obtain

  fluoracetate indicated in the homogeneous title (116 mg)

  according to 1 H nmr spectroscopy (singlet at 8.59, 19-

  protons, in deuterochloroform) and t.l.c. sure

  silica (acetone-petroleum, bp 40-600c, 1: 3). An exchange

  the product obtained from a mixture of ether and pentane had a melting point of

158-162, LZa7D + 56 (c 0.23).

Example 1

  S-Chloromethyl 9α-fluoro-115-hydroxy-160-methyl-3-oxo

  Example A A solution of the product of the preparation

  (2.115 g) in dimethylacetamide (7 ml) with

  sodium carbonate (592 mg) and bromochloromethane

  (2.46 ml) and the mixture was stirred at room temperature.

  ature. After two hours, the mixture was diluted

  Acetate with ethyl acetate (5 ml) and washed with 5% sodium bicarbonate solution and water, dried and evaporated to give get

  an orange foam (1.560 g). The p.l.c. in chlorine

  Form-acetone (19: 1) gave a whitish foam (803 mg) which was crystallized twice from methanol to obtain whitish needles of the ester.

  S-chloromethyl titrated (668 mg), m.p.

212-214 ° C, Za7D +440 (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 minutes, acetone (1 ml) was added and the solution was concentrated to about one quarter of its original volume. Ethyl acetate (30 ml) was then added and the solution was washed with acid.

  hydrochloric acid and water, dried and evaluated

  porated to obtain a white foam (239 mg). The p.l.c. in a mixture of chloroform and acetone (19: 1) gave a white foam (188 mg) which was crystallized twice from methanol, to obtain white needles of the S-chloromethyl ester indicated

  in the title (158 mg) m.p. 210-212, Lc7D +44 (c 1.07).

Example 2

  S-Chloromethyl 9α-fluoro-11-hydroxy-16α-methyl-3-oxo-17α

  propionyloxyandrosta-1,4-diene-17-carbothioate A solution of IV (0.927 g) in dimethylacetamide (4 ml) was treated with sodium bicarbonate (0.256 g) and bromochloromethane (0.20 ml) and agitated

  the mixture at 22 for 2 hours. We divided the

  The reaction mixture was partitioned between ethyl acetate (100 ml) and 2N hydrochloric acid (20 ml) and the aqueous layer was further extracted with ethyl acetate. The combined extracts were washed successively with 2N hydrochloric acid, water, 3% sodium bicarbonate, water and saturated brine. After drying, the solvent was removed and the crude product (757 mg) was crystallized twice from acetone to give the chloromethylthiolic ester indicated in the drawing.

  title (0.367 g), m.p. 247-250, F7D +50.50 (c 0.63).

Example 3

  S-Chloromethyl-11-hydroxy-3-oxo-17ac-propionyloxyandrosta-

  1,4-diene-170-carbothioate A solution of crude XV (2,366 g) in dimethylacetamide (10 ml) was treated with sodium bicarbonate

248554Z

  (756 mg) and bromochloromethane (0.59 ml) at 220 for 16 hours. It was then partitioned between ethyl acetate and 2N hydrochloric acid and

  extracted the aqueous layer with an additional

  of ethyl acetate. The combined organic layers were washed successively with 2N hydrochloric acid, water, sodium bicarbonate, water, saturated brine and then dried and the solvent removed in a manner to remove the water. get a yellow foam. The neutral product was purified by h.p.l.c. of preparation on silica (15) in 7% acetone in chloroform and the main product was crystallized from acetone to give the indicated chloromethyl thiolic ester

  in the title (0.522 g), mp 117-120, / 7D + 56 (C 1.3).

Example 4

  Sulfichloromethyl 6a, 9-difluoro-11-hydroxy-16c, 17a-iso

  propylidenedioxy-3-oxoandrosta-1,4-diene-17β-carbothioate A stirred solution of IX (1.360 g) in N, N-dimethylacetamide (10 ml) was treated with sodium bicarbonate (0.377 g) and bromochloromethane (0.3 ml) and stirring was continued for 1.5 hours. Ethyl acetate (100 ml) was added and the solution thus obtained was washed successively with 2N hydrochloric acid, water, sodium metabisulphite solution, water, a solution of sodium bicarbonate, water and a saturated solution of sodium chloride, and then

  dried and concentrated solution, crystallization

  in this way. The crystallized product (0.765 g) was purified by pol.c. on silica gel, proceeding

  developing with a mixture of chloroform and

  tone (9: 1). The main band was eluted with

  ethyl acetate and crystallized from acetate

  of ethyl to obtain the S-chloromethyl thioester

  liquefied (0.475 g) in the form of white prisms, m.p.

  271-278o, 57D +1160, (c 0.96, dimethylsulfoxide).

Example 5

  S-Chloromethyl 6α, 9α-difluoro-11-hydroxy-16α-methyl-3-one

  oxo-17α-propionyloxyandrosta-1,4-diene-170-carbothioate A solution of XIX (0.546 g) in dimethylacetamide (3 ml) was treated with sodium bicarbonate

  (202 mg) and bromochloromethane (0.16 ml) at 22

  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 afforded the title chloromethyl thioester (0.404 g), m.p. 272-275, / - 7D.

+49 (c 0.35).

Example 6-15

  By repeating the same general procedure as described in Example 1 (Method A), but using as a starting material, 17 P-carbothioic acid corresponding to the desired 17 P-carbothioate (details of the process being collected in following Table III) the following compounds were prepared:

  6. S-Chlorometethyl 11e-hydroxy-166-methyl-3-oxo-17a

  propionyloxyandrosta-1,4-diene-17-carbothioate, m.p.

192-193, [C] - + 65: (c 1.05).

  7. S-Chloromethyl 9α-fluoro-11-hydroxy-16-methylene

  3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothiolate,

M.p. 212-221, [a] D -56 (c 0.99).

  8. S-Chloromethyl 17α-acetoxy-9-fluoro-11S-hydroxy

  16-methyl-3-oxoanldrosta-1,4-diene-17-carbothiOate,

  M.p. 220-223, [a] D + 3915O <c 1.06).

  9. S-Chloromethyl 17α-butyryloxy-9α-fluoro-11-

  hydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carbothiol

  oate, mp 172-175, [c0 D +46 (c 1.10).

  10. S-Chloromethyl 9α-fluoro-11-hydroxy-17α

  isobutyryloxy-168-m2thyl-3-xooandrosta-1,4-dirne-17 -

  carbothioate, m.p. 234-239, [c] D +43, Cc 1.00).

  11. S-Chloromethyl 9Sa-fluoro-11e-hydroxy-3-oxo-17cL-

  propionyloxyandrosta-1,4-diene-17e-carbothioate, m.p.

196-199, [L] D + 380 (c 0.97).

  12. S-Chloromethyl-6α-fluoro-11-hydroxy-3-oxo-17α

  propionyloxyandrosta-1,4-diene-17-carbothioate, m.p.

188-191, [L] D +480 (c 0.91).

  13. S-Chloromethyl 17α-acetoxy-6,9a-difluoro-11-

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

Mp 280-283, [] D +450 (c 0.80).

  14. S-Chloromethyl 17ac-butryloxy-6a, 9c-difluoro-11-

  hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17-carbothioic acid,

M.p. 235-238, [a] D +490 (c 0.65).

  15. S-Chloromethyl 9a-fluoro-115-hydroxy-16ca, 17ca-

  isopropylidenedioxy-3-oxoandrosta-1,4-diane-17-carbothioate

  Mp 276-280 (dec), [+] +127 (c 0.51;

  sulfoxide) .D sulfoxide). Ex. ACTIVE NaHCO3 STEROIE SOL- JREEE PIC SOLVENT PRODUCT; No. (ml) QUANTITY R TETON (Silica) FROM CRIS- (r) 1

  l o (ml) (mg) TE W-CC13- TALLISA-

  (mg) () PERATURE TION _______ _- __ ml) AILBIAN e2C BrC2Cl

(0.25)

BrCH2C1

(0.58)

BreCl

(0744)

aC1

(0132)

BrQ! 2C1

(0.084)

D: C "2C1

(0.90)

BrCe2Cl

(0.86)

BrCE2C1

(2.00).

BdC C1

(1140)

r (0C482C)

(0.48)

  I he 12- 1.5 2.0 2.75 1.25 1.75 1.5 19: 1 14: 1 4: 1 M EA-P AAA 307 * 2460. 244 ** - - ii I liiij Notes: SA = ethyl acetate A = acetone M = methanol p = oil PE 60-80 * 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 9α-chloro-13-hydroxy-16β-methyl-3-oxo

  17a-oropionyloxvandrosta-1,4-diene-17b-carbothioate and

  S-Chloromethyl 9B, 11-epoxy-160, -methyl-3-oxo-17α-pro-

  pionyllandrosta-1,4-diene-17β-carbothioate A solution of mixture XIV (1.032 g) in dimethylacetamide (5 ml) was treated with sodium bicarbonate.

  sodium (0.203 g) this treatment being followed by a

  chlorobromomethane (0.2 ml) and the mixture was stirred

  The reaction mixture was stirred at 220 for 1.5 hours at 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, saturated sodium chloride solution and dried and the solvent was removed in vacuo to obtain a cream-colored foam. (0.856 g) containing a mixture

S-chloromethyl esters.

  These products were separated by p.l.c. on silica,

  developing with a mixture of chlorinated

  form and acetone (19: 1). The constitution has crystallized

  killing the more polar (0.306 g) twice in ethyl acetate, to give S-chloromethyl

  9c-chloro-ll-hydroxy-16p-methyl-3-oxo-17a-propionyloxy-

  androsta-1,4-diene-170-carbothioate (0.232 g) under the

  white plate form m.p. 222-2290 TD +700 (c 1.23).

  The least polar component (0.210 g) was crystallized from a mixture of acetone and petroleum,

  to obtain S-chloromethyl 9p, 11-epoxy-16p-

  methyl-3-oxo-17o-propionyloxyandrosta-1,4-diene-17p-

  carbothioate (0.065 g), m.p. 169-173, LZ7D +49 (c 0.60).

Example 17

  S-Fluoromethyl 9α-fluoro-11α-hydroxy-16-methyl-3-oxo

  17a-Drooionyloxyandrosta-1,4-diene-170-carbothioate XXV (660mg) was stirred with a suspension of silver fluoride (1.421g) in acetonitrile (8.5ml) in the dark at room temperature. ambient temperature. After 72 hours, the reaction mixture was diluted with ethyl acetate

  (200 ml) and filtered through a kieselguard pad.

  guhr. The filtrate was washed with water, dried and evaporated to give a white foam (517 mg). The p.l.c. in a mixture of chloroform and cyclohexane (19: 1) and chloroform gave a foam

  whitish (270 mg) which was crystallized from

  thanol, then in a mixture of methanol and methyl ether.

  to obtain the S-fluoromethyl ester

  titled in the title (176 mg), mp 241-242, ZD +97.5

(c 0.98).

Example 18

  S-Fluoromethyl-9a-fluoro-118-hydroxy-16a-methyl-3-oxo

  17α-propionyloxyandrosta-1,4-diene-17β-carbothioate A solution of XXX (0.640 g) in acetonitrile (8 ml) was treated with dry silver fluoride (1.511 g)

  and stirred in the dark at 22 for 46.5 hours.

  The mixture was diluted with ethyl acetate (200 ml) and filtered through diisocyanide. The solution was washed with 2N hydrochloric acid, water and saturated sodium chloride solution and the solvent was removed in vacuo to give a pale yellow-colored foam (0.504 g). This foam (p.l.c.) was chromatographed on silica gel by developing with 5% acetone in chloroform. The main band was eluted with ethyl acetate and the product was crystallized twice.

* taken up in acetone, so as to obtain the thio-

  esterfluoromethyl (0.244 g), mp 242-243 (dec), Z7D + 57 (c 0.75).

EXAMPLE 19

  S-Fluoromethyl 6α, 9α-difluoro-11-hydroxy-16α-methyl-17α-

  propionyl-3-oxoandrosta-1,4-diene-17-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 was 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 slurried. in

  chloroform, then in a mixture of chloroform and

  tone (19: 1). The product was eluted with acetate

  of ethyl and crystallized by concentration of the

  in order to obtain the chloromethylthioester indicated in the title ((0.075 g) mp 272-273 (dec),

L7D +300 (c 0.35).

EXAMPLE 20

  S-Fluoromethyl-9a-fluoro-11-hydroxy-16O 17a-isopro-dylidine

  Dimexyoxy-3-oxoandrosta-1,4-diene-17β-carbothioate A suspension of XXXVII (1.290 g) in acetonitrile (20 ml) was stirred with silver fluoride (I) (2.842 g), the ambient temperature, in the dark. After

  11 days (no more iodide left, t.l.c.

  (chloroform, 6 tests)), the reaction mixture was diluted

  with ethyl acetate (400 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 give a yellow solid (197 g). 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 silica gel 60) (50 g). The eluates containing the product (t.l.c.) 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 give

  colorless crystals of the S-fluoromethyl ester

  titled in the title (231 mg), m.p. 320-322 C (dec),

  o7D + 132 (c 0.22, dimethyl sulfoxide).

EXAMPLE 21

  S-Fluoromethyl 6α, 9α-difluoro-113-hydroxy-16 ", 17α-iso

  propylidenedioxy-3-oxoandrosta-1,4-diene-175-carbothioate A solution of XXXVIII (0.804 g) in acetonitrile (60 ml) was treated with silver fluoride (1.821 g) and stirred at room temperature. reaction mixture in the dark for 18 hours. The reaction mixture was diluted with

  ethyl acetate and filtered through diatomaceous earth

  guhr. The filtrate was washed with water and saturated sodium chloride solution, then dried and the solvent removed in vacuo to give a pale cream solid (0.636 g). This solid was purified

  by p.l.c. on silica gel, proceeding with the development

  twice with a mixture of chloroform and acetone (14: 1). The main band was eluted with ethyl acetate and crystallized five times

  in ethyl acetate, so as to obtain the thio-

  S-chloromethyl ester title (0.118 g) as white prisms, m.p. 305-311 C, 1a7D

+125 (c, Q73, dimethylsulfoxide).

  Examples 22-30 By repeating the same general procedure as that described in Example 17, but using, as a

  starting material, the S-iodomethyl 17p-carbothioate cor-

  corresponding to the desired product (the details of the process are summarized in Table IV which follows, the following compounds have been obtained:

  22. S-Fluoromethyl 17 "-acetoxy-9? -Fluoro-113-hydroxy-

  16S-methyl-3-oxoandrosta-1,4-diane-17-carbothioate,

  pp. 248 - 249, [C] D +101 (c 1.08).

  23. S-Fluoromethyl 11-hydroxy-3-oxo-17a-propionyloxy

  androsta-1,4-diane-17e-carbothioate, mp 112 = 117,

ctLD +670 (c 0.76).

  24. S-Fluoromethyl 11-hydroxy-16-methyl-3-oxo-17α

  propionyloxyandrosta-1,4-diene-17-carbothioate, m.p.

223-225 0, [] D +103 (c 0.38).

  25. S-Fluoromethyl 9a-chloro-11-hydroxy-16-methyl-methyl

  3-oxo-17α-propionyloxyandrosta-1,4-diane-17-carbothioate,

Mp 182-1930, [a] D + 116 (c 0.75).

  26. S-Fluoromethyl-9a-fluoro-11-hydroxy-16-methylene

  3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate,

M.p. 205-215, [a] D-58 (c 1.00).

  27. S-Fluoromethyl 9α-fluoro-11-hydroxy-3-oxo-17α

  propionyloxyandrosta-1,4-diene-17β-carbothioate, m.p.

207-211 O, [αD +700 (c 0.88).

  28. S-Fluoromethyl 6α-fluoro-11-hydroxy-3-oxo-17α

  propionyloxyandrosta-1,4-diene-17-carbothioate,] m.p.

224-225, [a] D +70 (c 0.79).

  29. S-Fluoromethyl 17α-acetoxy-6α, 9α-difluoro-11β-

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

-P.F. 308-310 [aID +29 (c 0.80).

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

  hydroxy-16a-methyl-3-oxoandrosta-1,4-diane-17e-

  carbothioate, m.p. 249-252, [a] +320 (c 1.05).

  S-Fluoromethyl 17α-acyloxyandrostane-173-carbothioates by halogen exchange EA A M p = ethyl acetate = acetone = methanol = petroleum P.E. 60-80 * Purity approx. 95%

Example 31

  S-Bromomethyl 9c-fluoro-1-hydroxy-16-methyl-3-oxo-17 "-

  Propionyloxyandrosta-1,4-diene-170-carbothioate A solution of XXV (66 μg) 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 a solution of NO (mg) I DEPARTURE (MeCN) REACTION (Silica) OF CRIS- (mg)

  HALO-. QUAN- (ml) (h) at CHC1 - TALLI-

  GENUR TITE TEMPERATURE Me2C SATION (mg) Ambient 2

22 3745 I 1702 22 20-- 24: 1 To 477

23 2071 I 1034 10 26 19: 1 EA 585 *

24 1945 I 850 6 26 19: 1 EA 166

1161 I 550 8 23; 5 19: 1 M 106

26 3574 I 1658 26 24 19: 1 A 300

27 700 I 1000 50 3 - M 470.

28 462 I 700 35 2 - EA-P 350

29 2600 I 4000 200 0; 75 - EA 2280

780 I 1200 60 1 - EA 755

  to 10% sodium thiosulfate and brine, dried and evaporated to give a whitish foam (624 mg). This product was crystallized twice from a mixture of acetone and petroleum ether (bp 40-60) to give colorless crystals of the title S-bromomethyl ester (499 mg).

  M.p. 186.5-187 ° C, zu7D +2 (c 0.99).

Example 32

  S-Bromomethyl 6 ", 9α-difluoro-11α, -hydroxy-16α-methyl-3-oxo

  17α-propionyloxyandrosta-14-diene-17β-carbothioate A solution of XXXI (850 mg) in acetone (25 ml) was stirred with lithium bromide (1.21 g) at about 22 ° C for 5 days. The product was isolated as described in Example 31 and recrystallized twice from ethyl acetate to give colorless crystals (690 mg). These crystals were worked up under the same reaction conditions for a further 4 days, to obtain the pure methyl bromomethyl ester (600 mg), in the form of colorless crystals, from acetate.

  ethyl, m.p. 255-257, 7D + 62 (c 0.82).

Example 33

  S-2'-Fluoro-ethyl 9a-fluoro-1H-hydroxyl-16P-methyl-3-oxo

  17α-prooionyloxyandrosta-1,4-diene-175-carbothioate A solution of XXXIX (910 mg) in acetonitrile (20 ml) was stirred with silver fluoride (I) (2.071 g) at room temperature. ambient, 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 stripped to dryness. a white foam (704 mg). The p.l.c. in a mixture of chloroform and acetone (9: 1) gave the less polar product as a yellow foam (431 g) which was crystallized twice from methanol, so that to obtain the title S-2'-fluorethyl ester in the title (253 mg), mp 133-134 ° C, LZ7D

+104.5 (c 0.98).

  EXAMPLE 34 S-Chloromethyl 9α-fluoro-11β-hydroxy-16-methylene-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioate A suspension of XXII (-227 mg) was treated in

  propionic acid (2.2 ml) and trifluorohydride

  acetic acid (0.7 ml), with a dry chloroform solution of toluene-sulphonic acid (0.044 ml, about 80 mg / ml) and then stirred at room temperature for 6 hours and then stirred at 3 ° C. for 16.5 hours. The reaction mixture was diluted with 5% sodium bicarbonate solution (75 ml) and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried and evaporated to a brown gum (254 mg). The gum was subjected to a p.l.c. in a mixture of chloroform and acetone (19: 1) (3 trials). The main band (152 mg) was crystallized twice from ethanol, from

  to obtain white crystals (30 mg) of S-chloro

  methyl 17o-propionate indicated in the titrecontaminated with

  S-chloromethyl-9α-fluoro-17α-hydroxy-16-methylene-3-

  oxo-llp-propionyloxyandrosta-1,4-diene-17p-carbothioic acid,

  as revealed by 1H nmr spectroscopy.

Example 35

  S-Chloromethyl 11-hydroxy-160-methyl-3-oxo-17a-propionyl

  Oxyandrosta-4-ene-17-carbothioate Catalytic reduction of the compound of Example 6

  (0.517 g)> in the presence of tris'triphenylphosphine)

  rhodium (I) (497 mg) in benzene (50 ml), for 22 hours, after chromatography (plc) on silica in chloroform (4ms), elution with ethyl acetate and crystallization twice in ethyl acetate, the A4-3-ketone indicated in

  title (0.130 g), mp 176-177, Lc7D + 78 (c 0.80).

Example 36

  S-Chloromethyl 9α-fluoro-11-hydroxy-16β-methyl-3-oxo

  17a-nropionyloxyandrost-4-ene-1H-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 crystals

  acetone, the title chloromethylthioester (0.142 g) as needles

  white, m.p. 217-225, L_7D +54 (c 0.83).

EXAMPLE 37

  S-Fluoromethyl 10-hydroxy-160-methyl-3-oxo-17a-nropionyl

  oxyandrost-4-ene-170-carbothioate Catalytic reduction of the compound of Example 24

  (0.413 g), carried out in the presence of tris (triphenylphosphonate)

  phine) chlorcrhodium (I) (432 mg) in benzene (60 ml) at 22 ° C for 24 hours, after multiple chromatographies on silica in

  chloroform and acetone and crystallization in the

  Tone, LaA 4-3-ketone (0.106 g) m.p. 174-177 C, ZL7D +123

(c 0.55).

Example 38

  S-Chloromethyl 9α-fluoro-11-hydroxy-16β-methyl-3-oxo

  17a-propionyloxyandrosta-1,4-diene-173-carbothioic acid

  S-chloromethyl-9, 11β-epoxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17-carbothioate (-0.9 mg) was treated with

  Example 16 with a complex of urea and hydrochloric acid (about 1 ml) and the mixture was stirred

  everything for a total of 24 hours at the am-

  ature. 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 40-60oc, 1: 2, two tests) revealed that the product thus obtained contained the fluorhydrin indicated in the title, by comparison

with an authentic sample.

EXAMPLE 39

  S-Chloromethyl 6 "-, 9a-fluoro-11-hydroxy-1-6-methyl-3-oxo

  17α-propionyloxvandrosta-1,4-diene-17β-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 to give the title-indicated 11P-alcohol (25mg), identified by comparison of its 1H nmr spectrum (in deuteriodimethylsulfoxide) and its properties at t.l.c. (silica, acetone-petroleum BP 40-60 ° C, 1: 3) to

those of an authentic sample.

  The present invention also relates to

  pharmaceutical compositions for use in anti-cancer therapy

  characterized in that they comprise at least one androstane compound of the formula (I) as defined above, as well as one or more pharmaceutical carriers or excipients. Such compositions

  may be in forms suitable for the administration

  administered topically or internally.

  Active androstane compounds can advantageously

  to present oneself in a classical way in pre-

  which are suitable for topical administration, using a suitable topical vehicle. By the term "topical administration" as used herein, the Applicant intends 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 (for example for the eyes or ears), sprays (eg for the nose, throat, lungs or skin), suppositories, medical enemas, chewable or chewable pills or tablets (eg for the treatment of foot-and-mouth ulcers)

  capsules or cartridges for use in an inhalation

  tor or insufflator and aerosols, for example to

the nose, throat or lungs.

  We can compose ointments and creams, by

  For example, using an aqueous or oily base,

  common to the addition of suitable solvents and / or gelling agents and / or thickeners. Thus, such a base may, for example, comprise water and / or an oil, such as petroleum jelly or liquid paraffin, or a vegetable oil, such as peanut oil or coconut oil. castor, or a solvent, such as polyethylene glycol having an average molecular weight that ranges from 200 to 600. Thickening agents that can be used

  depending on the nature of the base, include the

  soft raffinate, aluminum stearate, keto alcohol

  stearyl, polyethylene glycols having a weight

  average molecular weight fluctuates from 4,000 to 6,000, the

  line and beeswax and / or glycerol monostearate

  ceryl and / or nonionic emulsifiers.

  The sprays may, 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 dichlorodifluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane,

  carbon dioxide or any other suitable gas.

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

  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 fluctuates.

  generally in the range of 0.001 to 5.0% by weight.

  Generally however, for most types of preparation, it is advantageous that the proportion of active compound used varies from 0.005 to 0.5% and preferably from 0.01 to 0.25%. However, with

  powders which are suitable for inhalation or insufflation

  the proportion of active ingredient used

can vary from 0.1 to 2 Sà.

  The aforementioned compositions suitable for topical application to the skin can be used for the treatment of inflammatory dermatoses of human beings and patients.

  animals, for example eczema, which are normally sen-

  to corticosteroid therapy and also to

  diseases less sensitive to this therapy, such as

psoriasis in humans.

  The compositions which are provided for the administration

  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 colds Hay. The aerosol compositions are preferably adapted so that each aerosol dose or puff dispensed contains from 20 μg to 1000 μg, preferably from about 50 μg to 100 gag, of a compound according to the invention. The administration may be repeated several times a day, for example 2,3, 4 or 8 times, administering, for example, 1,2 or 3 doses each time. The overall daily dose with an aerosol ranges from 100 gg to 10 mg, preferably from 200 gg to 1000 gg. The overall daily dose and the calibrated dose,

  the capsules and cartridges in an inha-

  or an insufflator, will usually be double

  those administered with aerosol compositions.

  Topical preparations may be administered in one or more applications per day over the affected area; on the cutaneous zones, one can frequently

  benefit from the use of occlusive dressings.

  For internal administration, the novel compounds according to the invention may be presented, for example, in a conventional manner which is suitable for

  oral, parenteral or recurrent administration.

  tale. For oral administration, it is possible to use syrups, elixirs, powders and granules which can be prepared conventionally. However, it is preferred to use unit doses such as

described below.

  Preferred forms of preparations suitable for use in

  internal administration are unit doses, i.e., tablets and capsules. Such unit doses contain from 0.1 mg to 20 mg, preferably from

2.5 to 10 mg of the active steroid.

  In general, the compliant compounds can be administered

  to the invention internally in cases where a tea-

  systemic adrenal corticosteroids is indicated.

  In general terms, preparations suitable for ad-

  administration may contain 0.05

  10% of the active ingredient, depending on the type of pre-

  paration that is used. The daily dose may vary from 0.1 mg to 60 mg, for example from 5 to 30 mg, depending

  the condition to be treated and the desired duration of treatment.

Example (A)

  Ointment: active ingredient 0.1 = C w / w liquid paraffin BP 10% w / w soft white paraffin, to produce 100 parts

in weight.

  B.P. = British Pharmacopoeia Pass the active ingredient in a ball mill with a little liquid paraffin until the particle size is reduced, so that

  5 of them have an inferior caliber

  at 5 y. Dilute the paste and rinse the grinder with residual liquid paraffin, mix and add the

  soft white paraffin suspension melted at 50 C.

  Shake until the mixture is cold, so that

get a homogeneous ointment.

  EXAMPLE (B) Cream% w / w 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

Purified water up to 100.0.

  PREPARATION METHOD Chlorocresol and sodium hydrogen phosphate are dissolved in water at about 70-750C. The waxes are melted together at about 65-70 ° C. and are added with stirring to the aqueous phase, and the latter is then cooled to 65 ° -70 ° C. The steroid is subjected to micronization (particle size as defined). in the 1973 British Pharmacopoeia codex, page 911 for an ultra-fine powder) and is dispersed in one part

  liquid paraffin. The suspension of the

  roEde and the rest of the liquid paraffin at the base, with stirring at 6065 C. The preparation is cooled under

  stirring at room temperature.

  EXAMPLE (C) Calose dose aerosol composition per dose Z p / p Active ingredient 0-05 mg 0.059 Fluorotrichloromethane 25.5 mg 30.0 Dichlorodifluoromethane up to 85.0 mg up to 0 The ingredient is submitted active to micronization (particle size as defined in the UK Pharmacopoeia 1973 codex, page 911, for a powder

  ultra-fine) and is dispersed in fluorotrichloro-

  methane. This suspension is introduced into aluminum aerosol containers, the upper space is purged with gaseous dichlorodifluoromethane in order to expel the air and a metering valve is placed to

  aerosol in place on the container. We pump the dichloro = -

  liquid difluoromethane through the metering valve, under

pressure, to the desired weight.

  Exemole (D) Cell for Inhalation (100 μg / dose) per capsule 2LL / Active Ingredient 0.1 mg 0.4 Lactose up to 25.0 mg up to 0 The active ingredient is micronized (size particles as defined in the 1973 British Pharmacopoeia codex, 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 the purpose of administering it via a device

inhalation.

  The results of a pharmacological study will be given below.

  ecological evidence of anti-inflammatory activity

topically compounds.

  The croton oil test was used for this purpose.

on the mouse's ear.

  In this test, groups of 5 mice were used

males weighing 23 to 28 g.

  Increasing doses of fluocinolone acetonide used as reference product and test compounds were dissolved in a mixture of croton oil: ethanol: ether

2:20:78.

  Lpl of the resulting solution is applied to the inner side of the two ears of each mouse. A group of mice receiving croton oil solution without steroids

serves as a witness.

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

  Increasing doses of steroid are reducing the

  inflammatory response to the croton oil solution. Estimates of relative anti-inflammatory activity are made using the logarithm of dose and weight

  of the ear as a response parameter.

  Similar rat experiments were also performed on rats weighing from 50 to 70 g with a croton oil: ethanol: ether mixture of 5:20:75 and applying

  501l of the solution at each ear.

  In addition, a measurement of the activity

  hypothalamic-pituitary adrenal suppression (suppres-

  H.P.A.). For this purpose, groups of 10 male mice (from 23 to 28 g) or 6 male rats (150 to 160 g) were shaved in the dorsal region. The increasing doses of fluocinolone acetonide used are

  reference product and compounds tested in

  tone. 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 witness and receives

acetone without steroid.

  Two days after the final dose of steroid, the

  animals are under stress (exposure to ether

  one minute), 15 to 20 minutes later, the animals are reanesthetized (mice with ether and rats with pentobarbitone intraperitoneally, eg 500 mg / kg) and blood is withdrawn from these cells. animals either

  heart, or the abdominal aorta.

  For the determination of plasma corticosterone levels, the blood of two mice is pooled, whereas

  for rats, individual blood samples are used

  duels. Plasma corticosterone levels are determined by

  fluorimetrically according to a variant of the method de-

  Written by Zenker and Bernstein (J. Biol Chem 1958, 231,

695-701).

  Increasing doses of steroid produce a reduction in stress response (i.e., lower plasma corticosterone levels). The estimate of

  the relative activity is carried out using logari-

  daily dose and corticosterone levels

  plasma as a response parameter.

* The results are given in the table below.

  TOPICAL ANTI-INFLAMIATORY ACTIVITY

  IN THE MOUSE AND THE RAT IN THE OIL TEST

FROM CROTON

Ex. N + 19 + 21+ In the mouse C

In the rat

  29 B = 88 * 34+ 29+ 113 'Relative activity: fluocinolone acetonide = 100 Average of two results Et. Average of three results

  + These compounds have a superior therapeutic ratio

  10 in both mice and

  rats, while we obtain a therapeutic report

  1 pellet with fluocinolone acetonide.

  The therapeutic relationship is the ratio of

  anti-inflammatory activity as determined in

  the croton oil test with suppressive activity

  H.P.A., these activities being determined

as previously indicated.

Claims (3)

  1. Com-osed that meet the UCI general structure formula) that follows; a: I -.Rb C * | | Re 0.. RR   in which Ra represents a thiocarbamoyloxy group   carbonyl -COdCShiS B o RA and RB have the meanings   cations previously indicated, or a group of the formula -COSR1A, where R1A represents a hydrogen atom or is a group as defined above with respect to R1 or is a b group convertible into such a group and R represents a hydroxyl group esterified, or Rb and Rc together represent an isopropylidenedioxy group, or when   Ra represents a COSR1A group, Rb represents possibly   a hydroxyl group; Rc represents a hydrogen atom, a methyl group   (which can be in configuration a or configu- ration Y) or a methylene group,   Rd represents a hydroxyl group or a hydroxyl group   protected droxyl (in configuration a or in configuration f) or an oxo group; Re represents a hydrogen atom, a bromine atom, a chlorine atom or a fluorine atom, or Rd and Re together represent a carbon-carbon bond or an epoxy group in 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 the compounds which have a free carbothioic acid group, excluding the compounds of the formula (I) Costi - OR2 - I.   Where R is a fluoro-, chloro- or bromomethyl group or a 2'-fluorethyl group, R is a group C0R o R6 is a C1-C4 alkyl group;   OR2 and R3 together form a group 16c, 17a   isopropylidenedioxy, R3 represents a hydrogen atom, a methyl group (which may be in configuration a or configuration 3) 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 Ra represents a group -COSH, Rb repre-   hydroxyl group, RC represents an atom of hy-   or a methylene group, Re represents a hydrogen atom, a chlorine atom or a fluorine atom and Rd represents a hydroxyl group in the form of a hydroxyl group. P configuration or an oxo group.   Process for the preparation of compounds according to claim 1 having a free -COSH group at position 17, characterized in that:   (a) a compound according to claim 1 is   carbamoyloxycarbonyl group at position 17 to aminolysis with transposition, (b) reacting a compound corresponding to formula (II) as defined in claim 1,   a 16 ", 17a-epoxy group or a 16a, 17a-isopropyl group   lidenedioxy, but having a 17p-carboxyl group or a salt thereof, on a 2-halo-aza-aromatic compound, this reaction being followed by a treatment with hydrogen sulfide, (c) reacting a compound corresponding to the formula   (II) according to claim 1, wherein R   has a hydroxyl group, but bearing in position 17 Y = _X   a group -CO-N "in which X, Y and Z, which can   may be identical or different, each represent   a nitrogen atom or a CH group on sulfuric acid.   water or a sulfide or hydrosulfide thereof.