United States Patent [19J
`Phillipps ·et al.
`
`[54] ANDROSTANE CARBOTHIOATES
`
`[75]
`
`Inventors: Gordon H. Phillipps, Wembley; Brian
`M. Bain, Chalfont St. Peter; Ian P.
`Steeples, Ruislip Manor; Christopher
`Williamson, Cobham, all of England
`
`[73] Assignee: Glaxo Group Limited, London,
`England
`
`(21] Appl. No.: 234,113
`Feb. 13, 1981
`
`(22] Filed:
`Foreign Application Priority Data
`[30]
`Feb. 15, 1980 [GB] United Kingdom ................. 8005174
`
`Int. Cl) ......................... C07J 7/00; A6IK 31/56
`(51]
`[52] U.S. CI . .................................. 424/241; 260/397.1
`[58] Field of Search ...................... /Steroids MS File;
`260/397.1; 424/241
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`3,636,010 1/1972 Basel et al. .... ................... 260/397.1
`3,828,080 8/1974 Phillipps et al .................. 260/397.1
`4,093,721 6/1978 Phillipps et al. ................. 260/397.1
`4,188,385 2/1980 Edwards .. ........................ 260/397.l
`
`Primary Examiner-Elbert L. Roberts
`Attorney, Agent, or Firm-Bacon & Thomas
`
`ABSTRACT
`(57]
`Compounds of the formula
`
`(11]
`
`[45]
`
`4,335,121
`Jun. 15, 1982
`
`COSR1
`
`(I)
`
`wherein R I represents a fluoro-, chloro- or bromo(cid:173)
`methyl group or a 2'-fluoroethyl group, R2 represents a
`group CQR6where R6 is a Ct-3 alkyl group or OR2 and
`R 3 together form a 16a, 17 a-isopropylidenedioxy group;
`R3 represents a hydrogen atom, a methyl group (which
`may be in either the a- or .B-configuration) or a methy(cid:173)
`lene group; R4 represents a hydrogen, chlorine or fluo(cid:173)
`rine atom; R5 represents a hydrogen or fluorine atom
`represents a single or double
`· • • • • •
`and symbol
`bond have good anti-inflammatory activity, particularly
`on topical applications.
`The compounds of formula I are prepared by esterifica(cid:173)
`tion, halogenation, reduction, deprotection and reaction
`at a 9,11-double bond to form a 9a-halo-11,B-hydroxy
`grouping.
`the com(cid:173)
`Pharmilceu.tical compositions containing
`pounds of formula I and methods for the use of the
`compounds are described and claimed.
`
`25 Claims, No Drawings
`
`

`

`1
`
`4,335,121
`
`ANDROSTANE CARBOTHIOATES
`
`The present invention relates to anti-inflammatory
`steroids of the androstane series.
`Anti-inflammatory steroids are most typically of the
`corticoid type, i.e. are pregnane derivatives. Our United
`Kingdom Pat. Nos. 1,384,372, 1,438,940 and 1,514,476
`describe esters of certain androstane 17a-carboxylic
`acids having anti-inflammatory activity. European Pa- 10
`tent Application No. 79300500.0 (Publication No.
`0004741) describes esters of androstane 17/:1-carbothioic
`acids also possessing anti-inflammatory activity. We
`have now discovered that certain androstane com(cid:173)
`pounds containing a haloalkyl carbothioate grouping in 15
`the 17.{3-position have particularly advantageous anti-in(cid:173)
`flammatory properties as discussed iri greater detail
`below.
`The new androstane compounds may be represented
`by the formula
`
`20
`
`COSR 1
`
`(I)
`
`25
`
`2
`ro- or fluoro-methyl, R4 and R 5 are fluorine and in par(cid:173)
`tiL:ular those in which R·' is a-methyl.
`Especially preferred compounds according to the
`invention in view of their good topical anti-inflamma(cid:173)
`tory activity and favourable ratio of topical anti-inflam(cid:173)
`matory activity to undesired systemic activity include:
`
`S-chloromethyl 9a-fluoro-l l/:l-hydroxy-16a-methyl-3-
`oxo-l 7a-propionyloxyandrosta-1,4-diene-l 7 /3-carbo(cid:173)
`thioate;
`S-chloromethyl 9a-fluoro-l l/3-hydroxy-l 6-methylene-
`3-oxo-17a-propionyloxyandrosta-1,4-diene-l 7 /3-car(cid:173)
`bothioate;
`S-fluoromcthyl 6a,9a-difluoro- l l/3-hydroxy-16a,l 7a(cid:173)
`isopropylidenedioxy-3-oxoandrosta-l,4-diene-17.B(cid:173)
`carbothioate;
`S-fluoromethyl 6a,9a-difluoro-l l/3-hyd roxy-l 6a-meth(cid:173)
`yl-3-oxo-J 7a-propionyloxyandrosta- J ,4-diene-17 /3-
`carbothioate;
`S-chloromethyl
`6a,9.a-difluoro-l l/3-hydroxy-16a-
`methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-
`17,8-carbothioate. The last compound is especially
`preferred in view of its particularly favourable ratio
`and in addition minimal skin atrophy.
`
`wherein R I represents a fluoro-, chlorn- or bromo(cid:173)
`methyl group or a 2'-fluoroethyl group; R2 represents a
`group COR 11 where R6 is a C1.J alkyl group or OR2and 35
`R 3 together form a 16a, 17a-isopropylidenedioxy group;
`R3 represents a hydrogen atom, a methyl group (which
`may be in either the a- or .B- configuration) or a methy(cid:173)
`lene group; R4 represents a hydrogen, chlorine or fluo(cid:173)
`rine atom; R5 represents a hydrogen ot fluorine atom
`and symbol ........... represents a single or double bond.
`The new compounds of formula (I) have good anti(cid:173)
`inflammatory activity, particularly on topical applica(cid:173)
`tion, as judged by the McKenzie patch test in man and
`as measured by the reduction of croton oil induced
`oedema when the compounds are applied topically to
`the skin of mice and rats.
`Certain of the compounds show good topical anti-in(cid:173)
`flammatory activity in the croton oil ear test coupled
`with minimal hypothalamus-pituitary-adrenal-suppres(cid:173)
`sive activity after topical application in the same animal
`species. These results indicate that such compounds
`may be of value in the local treatment of inflammation
`in man and animals with minimal liability to cause unde(cid:173)
`sired systemic side effects.
`Compounds of formula (I) which are preferred for
`their good anti-inflammatory activity include the fol(cid:173)
`lowing categories namely (a) those in which R I is chlo(cid:173)
`ro- or fluoromethyl (b) those in which R2 is acetyl or
`propionyl, preferably propionyl, (c) those in which R4 is
`fluorine (d) those in which R5 is fluorine (e) the l,4-
`dicnes, and (f) those 1,4-dienes in which R4 is fluorine
`and R·1 is hydrogen, a- and /3-methyl or methylene.
`Compounds of formula (I) which have good anti-in(cid:173)
`flammatory activity coupled with minimal hypo(cid:173)
`thalamuspituitary-adrenal-suppressive activity when
`applied topically include 1,4-dienes in which R I is chlo-
`
`The compounds of formula (I) may be prepared by a
`variety of different processes.
`One such process comprises esterifying an androstane
`compound corresponding to formula (I) but containing
`30 either a free 17 /3-carbot)1ioic acid group (or functionally
`equivalent group) o.r a free 17a-hydroxy group (R3
`being a hydrogen atom or a methyl or methylene
`group), any other reactive groups present in the mole-
`cule being suitably protected as desired.
`For example, a salt of the parent 17 /3-carbothioic acid
`such as an alkali metal, e.g. lithium, sodium or potas(cid:173)
`sium, salt or an alkylammonium, e.g. triethylammonium
`or tetrabutylammonium, salt may be reacted with an
`appropriate alkylating agent, preferably in a polar sol-
`40 vent such as a ketone, e.g. acetone or an amide such as
`· dimethylformamide, dime.thylacetamide or hexamethyl(cid:173)
`phosphoramide, conven"iently at a temperature of 15° to
`l00° C. The alkylating a=gent may comprise an appropri(cid:173)
`ate dihalo compound i.e. one containing a further halo-
`45 gen atom (preferably a ·bromine or iodine atom) in addi(cid:173)
`tion to the halogen atom of the desired R I group. This
`process is particularly -applicable to the preparation of
`compounds in which R I is a choromethyl group, the
`alkylating agent advantageously being bromochlorome-
`50 thane.
`Alternatively, the parent 16-hydrogen, methyl or
`methylene-17a-hydroxy-l 7 /3-carbothioates
`corre(cid:173)
`sponding to compounds of formula I may be subjected
`to esterification of the 17a-hydroxyl group. This may
`55 be effected by conventional techniques, e.g. by reacting
`the parent 17a-hydro;,(y compound with a mixed anhy(cid:173)
`dride of the required carboxylic acid, which may, for
`example, be generated in situ by reacting the carboxylic
`acid with an appropriate anhydride such as trifluoroace-
`60 tic anhydride, preferably in the presence of an acid
`catalyst, e.g. p-toluenesulphonic acid or sulphosalicylic
`acid. Alternatively, the mixed anhydried may be gener(cid:173)
`ated in situ by reaction of a symmetrical anhydride of
`the required acid with an appropriate further acid, e.g.
`65 trifluoroacetic acid.
`The reaction is advantageously effected in an organic
`solvent medium such as benzene, methylene chloride or
`an excess of the carboxylic acid employed, the reaction
`
`

`

`temperature of
`
`3
`being conveniently effected at a
`20°-100° C.
`Alternatively, the 17a-hydroxy group may be esteri(cid:173)
`fied by reaction of the parent I ?a-hydroxy compound
`with the appropriate acid anhydried or acid chloride, if
`desired, in the presence ofnon-hydroxylic solvents, e.g.
`chloroform, methylene chloride or benzene, and prefer(cid:173)
`ably in the presence of a strong acid catalyst, e.g. per(cid:173)
`chloric acid, p-toluene sulphonic acid or a strongly
`acidic cation exchange resin, e.g. Amberlite IR 120, the
`reaction being conveniently effected at a temperature of
`25° to 100° c.
`The compounds of formula (I) may also be prepared
`by reacting a corresponding androstane compound con(cid:173)
`taining a 17 /3-substituent of formula -COS(CH2)n Y 15
`(wherein Y represents a displaceable substituent and n is
`I or 2) with a compound serving to replace the group Y
`by a halogen atom.
`Thus the compounds of formula (I) may be subjected
`to a halogen exchange reaction serving to replace the 20
`group Y where this is halogen by a different halogen
`substituent. Thus the bromomethyl, fluoromethyl and
`fluoroethyl 17 /3-carbothioate compounds may be pre(cid:173)
`pared from the corresponding iodomethyl or bromo(cid:173)
`ethyl 17 /3-carbothioate compounds using a bromide salt 25
`such as lithium bromide in the case of the bromomethyl
`17 /3-carbothioate compounds or an appropriate fluoride
`e.g. silver monofluoride or silver difluoride in the case
`of the fluoromethyl or fluoroethyl 17 /3-carbothioate
`compounds. The starting iodomethyl 17 /3-carbothioate 30
`compounds may be prepared from the corresponding
`chloromethyl 17 /3-carbothioate compounds using for
`example, an alkali metal, alkaline earth metal or quater(cid:173)
`nary ammonium iodide e.g. sodium iodide.
`The reaction is advantageously effected in a solvent 35
`medium comprising for example acetone, acetonitrile
`methyl eythyl ketone, dimethylformamide, dimethylac-
`. etamide or ethanol.
`The foregoing reactions may also be carried out on
`starting materials having a variety of substituents or 40
`groupings which are subsequently converted into those
`substituents or groupings which are present in the com(cid:173)
`pounds of the invention as defined above.
`The 11/3-hydroxy compounds of formula (I) may thus
`be prepared by reduction of a corresponding 11-oxo 45
`compound, e.g. using an alkali metal or alkaline earth
`metal borohydride, e.g. sodium or calcium borohy(cid:173)
`dride, conveniently in an alcoholic or aqueous alcoholic
`solvent such as methanol or ethanol.
`Such an 11-keto compound may be prepared by oxi- 50
`dation of a corresponding 1 la-hydroxysteroid, for ex(cid:173)
`ample using a chromic acid reagent such as Jones' rea(cid:173)
`gent.
`An 11/3-hydroxy compound of formula (I) may also
`be obtained by deprotection of a corresponding com- 55
`pound having a protected hydroxyl group at the 11/3-
`position, for example a tri C1-6 alkylsilyloxy group such
`as the trimethylsilyloxy group or a perfluoro- or chloro(cid:173)
`alkanoyloxy group such as the trifluoroacetoxy group.
`Removal of the protecting group may be effected by 60
`hydrolysis, the trialkylsilyl group, being readily re(cid:173)
`moved by mild acid or basic hydrolysis or particularly
`conveniently using fluoride e.g. hydrogen fluoride or an
`ammonium fluoride. The perfluoro- or chloro-alkanoyl
`protecting group may also be removed by mild acid or 65
`basic hydrolysis or alcoholysis, but preferably under
`acidic conditions when R4 is a chlorine atom. Such a
`protected hydroxyl group may be introduced, for exam-
`
`4,335,121
`4
`ple, by reacting an 11/3-hydroxy steroid with an appro(cid:173)
`priate reagent such as a trialkylsilyl halide or a per(cid:173)
`fluoro- or chloro-alkanoic anhydride.
`Compounds of formula (I) may also be produced by
`5 reaction of a corresponding compound having a 9, 11-
`double bond (and no substituent in the 1 ]-position) with
`reagents serving to introduce the required 9a-halo-l 1/3-
`hydroxy grouping. This may involve initial formation
`of a bromohydrin by reaction with an N-bromo-amide
`10 or -imide such as N-bromosuccinimide, followed by
`formation of the corresponding 9/3,11/3-epoxide by
`treatment with a base and reaction of the epoxide with
`hydrogen fluoride or hydrogen chloride to introduce
`the required fluorohydrin or chlorohydrin grouping
`respectively. Alternatively, the 9, 11-olefin compound
`may be reacted with an N-chloro-amide or -imide to
`introduce the required 9a-chloro-l l/3-hydroxy group(cid:173)
`ing directly.
`The A4-compounds according to the invention can
`conveniently be prepared by partial reduction of the
`corresponding A 1.4-compound, for example, by hydro(cid:173)
`genating using a palladium catalyst, conveniently in a
`solvent e.g. ethyl acetate or by homogeneous hydroge(cid:173)
`nation using for example tris(triphenylphosphine)r(cid:173)
`hodium chloride, conveniently in a solvent such as
`benzene, or by exchange hydrogenation using for exam-
`ple cyclohexene in the presence of a palladium catalyst
`in a solvent e.g. ethanol, preferably under reflux. This
`reduction may be carried out on a haloalkyl ester where
`this is sufficiently stable in such a reaction or may be
`effected at an earlier stage.
`The above mentioned compounds containing a free
`-COSH group in the 17 /3-position may be prepared for
`example by aminolysis with rearrangement of a suitable
`17 /3-thiocarbamoyloxycarbonyl androstane. The 17 /3·
`thiocarbamoyloxycarbonyl androstane is a mixed anhy-
`dride of the corresponding 17 /3-carboxylic acid and a
`thiocarbamic acid and is conveniently prepared by reac(cid:173)
`tion of a salt of the 17 /3-carboxylic acid I ?a-ester or
`I 6a, 17 a-acetonide with a thiocarbamoyl halide. The
`thiocarbamoyl group is N,N-disubstituted, and may
`thus have the formula-COOCSNRARB, where RA and
`RB, which may_ be the same or different, are alkyl
`groups, e.g. Ci-4 alkyl groups or RA and RB together
`with the nitrogen atom to which they are attached form
`a 5-8 membered ring which may optionally contain an
`additional hetero atom selected from oxygen, nitrogen
`and s_ulphur and/or which may optionally be substituted
`by one or two CJ - 3 alkyl e.g. methyl groups. Preferably
`RA and RB are CJ-4 alkyl substituents, . the N,N-dime(cid:173)
`thylthiocarbamoyl group being preferred. The thiocar-
`bamoyl halide is preferably the chloride. The reaction
`may be accelerated by the addition of an iodide salt e.g.
`sodium iodide.
`The initial androstane 17 /3-carboxylate salt may be
`for example, an alkali metal, e.g. sodium or potassium,
`alkaline earth metal, e.g. calcium, salt or a salt of a
`tertiary amine, e.g. triethylamine.
`Aminolysis with rearrangement may be carried out
`for example by heating the mixed anhydride to an ele(cid:173)
`vated temperature e.g. in the presence of ammonia, a
`primary amine or more preferably a secondary amine
`such as diethylamine or pyrrolidine. In the starting
`17/1-carboxylic acids, the 16- and 17a-positions will
`conveniently be substituted by the -R3 and -OR2
`groupings desired for the final product of formula (I).
`I 6-
`the
`in
`I ?a-Hydroxy androstane compounds
`methylene series which contain the desired 17 /3-carbo-
`
`

`

`4,335,121
`
`10
`
`5
`6
`Rf represents a hydrogen or a fluorine atom; and the
`thioic acid grouping, as described above, may be pre(cid:173)
`symbol ==:. represents a single or double bond and salts
`pared from the corresponding 16,B-methyl-16a,17a(cid:173)
`epoxy 17,B-thiocarboxylic acid, by effecting a rear(cid:173)
`of these compounds which have a free carbothioic acid
`rangement using a strong acid e.g. a strong carboxylic
`group; with the exclusion of compounds of formula (I)
`acid such as trifluoroacetic acid. These 16a,17a-epox(cid:173)
`5 as hereinbefore defined.
`ides may be prepared from the corresponding 17,B-car(cid:173)
`Where Rd represents a protected hydroxyl group, this
`boxylic acids by treatment with an onium salt of a 2-
`may, for example be a trialkylsilyloxy group or a per(cid:173)
`halo-azaaromatic compound, followed by treatment of
`fluoro- or perchloro-alkanoyloxy group as defined pre(cid:173)
`the resulting product with hydrogen sulphide or a salt
`viously.
`thereof to give the free 17,B-carbothioic acid which may
`The 17a-hydroxy 17,B-carbothioic acids of formula
`be alkylated as described above, preferably in situ to
`(II) and salts thereof may be converted into the l 7a(cid:173)
`give the desired 17,B-carbothioate group.
`hydroxy 17/3-carbothioates of formula (II) where Ra
`16a, 17 a-lsopropylidenedioxy compounds of formula
`represents the group COSR I as defined in formula (I) or
`(I) may similarly be prepared by treating a correspond(cid:173)
`into the 17,B-carbothioic acid 17a-esters of formula (II)
`ing 17,B-carboxy lie acid with an onium salt of a 2-halo(cid:173)
`IS by the processes described above for preparing the
`azaaromatic compound followed by treatment of the
`compounds of formula (I). The esterification of the
`resulting product with hydrogen sulphide to give the
`17a-hydroxy group is preferably effected with the ap(cid:173)
`free 17,B-carbothioic acid which may then be esterified
`propriate carboxylic acid chloride in a solvent such as a
`as described above.
`halogenated hydrocarbon e.g. dichloromethane, and
`20 advantageously in the presence of a base such as trieth(cid:173)
`Onium salts of 2-halo-aza-aromatic compounds are
`capable of effecting carboxyl activation. Such reagents
`ylamine, preferably at a low temperature e.g. 0° C.
`include 2-halo-N-alkyl- or 2-halo-N-phenyl-pyridinium
`The l 7a-hydroxy 17,B-carbothioic acids of formula
`or pyrimidinium salts carrying 1 to 2 further substitu(cid:173)
`(II) and salts thereof are thus particularly useful inter(cid:173)
`ents selected from phenyl and lower (e.g. C1.4) alkyl
`mediates for preparing the androstane 17,B-carbothio(cid:173)
`groups, such as methyl. The 2-halogen atoms can be 25
`ates of formula (I); those in which Re represents a hy(cid:173)
`fluorine, chlorine, bromine or iodine atoms. The salts
`drogen atom, an a- or ,B-methyl group or a methylene
`are preferably sulphonates, e.g. tosylates; halides e.g.
`group, Re represents a hydrogen, chlorine or fluorine
`iodides; fluoroborates or perfluoroalkylsulphonates, a
`atom, Rd represents a hydroxy group in the /3-configu-
`convenient salt being 2-fluoro-N-methylpyridinium
`30 ration or an oxo group being preferred. More preferred
`tosylate or 2-chloro-N-methylbenzothiazolium
`tri(cid:173)
`compounds and salts thereof include those compounds
`fluoromethanesulphonate.
`in which Re represents a methyl group in the a- or
`The 16a, 17 a-epoxy-16,B-methyl-17,B-carboxylic acid
`,B-configuration or a methylene group; Re represents a
`compounds used as starting materials in the above pro(cid:173)
`fluorine atom, Rd represents a hydroxy group in the
`cess may be prepared in conventional manner, e.g. as
`described in British Patent Specification No. 1,517,278. 35 ,B-configuration or an oxo group and the symbol =-= in
`the 1,2 position represents a carbon-carbon double
`The starting materials employed in the process de(cid:173)
`bond.
`scribed herein for the preparation of compounds of
`Especially preferred compounds of formula II thus
`formula (I) are new and constitute a further feature of
`irn;:lude, for example, the following:
`the invention; they include compounds of the general
`9a-fluoro-l 1,B, 17a-dihydroxy-16,B-methyl-3-oxoan-
`formula (II)
`drosta-1,4-diene-l 7,B-carbothioic
`acid;
`9a-fluoro-
`11,8, 17 a-dihydroxy-16a-methyl-3-oxoandrosta- l ,4-
`diene-17,B-carbothioic acid; 9a-fluoro-l l,8, 17 a-dihy(cid:173)
`droxy-16-methylene-3-oxoandrosta- l ,4-diene-17,B-car-
`45. bothioic acid; 6a,9a-difluoro-11,B,17a-dihydroxy-16a(cid:173)
`methyl-3-oxoandrosta-1,4-diene-17,B-carbothioic
`acid
`and the corresponding 11-ketones and salts thereof.
`One advantage of the above intermediates is that they
`permit direct haloalkylation to give haloalkyl 17,B-car-
`50 bothioates when the corresponding thiols R 1SH are not
`available. The salts of these I ?a-hydroxy 17,B-carbothi(cid:173)
`oic acids may, for example be alkali metal, e.g. lithium,
`sodium or potassium salts; alkaline earth metal, e.g.
`calcium or magnesium salts; tertiary amine salts, e.g.
`55 pyridinium or triethylammonium salts; or quaternary
`ammonium salts, e.g. tetrabutylammonium salts.
`The 17a-hydroxy 17,B-carbothioic acids may, for
`example, be prepared by reaction of a reactive deriva(cid:173)
`tive of a corresponding 17a-hydroxy-17,B-carboxylic
`60 acid with hydrogen sulphide or a sulphide or hydrosul(cid:173)
`phide salt thereof. In general, the cation of the sulphide
`or hydrosulphide salt may be for example an alkali
`metal salt such as sodium or potassium hydrogen sul(cid:173)
`phide. The above-mentioned reactive derivatives corre-
`65 spond to compounds of formula (II) where Rh is a hy(cid:173)
`droxyl group and the group -COR 7 is present at the
`17,B-position wherein R 7 represents a group of the for(cid:173)
`mula
`
`I r
`R,
`(wherein Ra represents a thiocarbamoyloxycarbonyl
`group -COOCSNRARB where RA and RB are as de(cid:173)
`fined above, or a group of the formula -COSRIA,
`where RIA represents a hydrogen atom or is a group as
`defined above for R 1 or is a group convertible thereto
`and Rh represents an esterified hydroxyl group or Rb
`and Re together represent in
`isopropylidenedioxy
`group; or where Ra represents a group COSRIA, R b is
`optionally a hydroxyl group;
`Re represents a hydrogen atom, a methyl group
`(which may be in either the a- or ,B-configuration) or a
`methylene group;
`Rd represents a hydroxy or protected hydroxy group
`(in either the a- or /3-configuration) or an oxo group;
`Re represents a hydrogen, bromine, chlorine or fluo(cid:173)
`rine atom; or Rd and Re together represent a carbon-car(cid:173)
`bon bond or an epoxy group in the ,B-configuration;
`
`40
`
`(II)
`
`

`

`7
`
`4,335; 121
`
`in which X, Y and Z, which may be the same or differ(cid:173)
`ent, each represent CH or N, one or two of X, Y and Z
`being N, the heterocyclic ring optionally being substi(cid:173)
`tuted on at least one carbon atom by a lower alkyl
`group (e.g. with I to 4 carbon atoms, such as a methyl
`group) and/or where the heterocyclic ring contains
`two adjacent carbon atoms, the said ring optionally
`carrying a benzene ring fused to the said adjacent car(cid:173)
`bon atoms.
`The reactive derivatives of formula (Ill) ar~ prefera(cid:173)
`bly prepared by reacting corresponding l7a-hydroxy
`17 .B-carboxylic acids of formula (11) with a symetric or
`asymmetric compound of the formula:
`
`(IV)
`
`8
`The androstane 17.B-carboxylic acid starting materi(cid:173)
`als employed in the above processes may be prepared in
`conventional manner, e.g. by oxidation of an appropri(cid:173)
`ate 2 l-hydroxy-20-keto pregnane for example with peri-
`5 odic acid, in a solvent medium and preferably at room
`temperature. Alternatively, sodium bismuthate may be
`employed to effect the desired oxidative removal of the
`21-carbon atom of a 17a-acyloxy pregnane compound.
`As will be appreciated should the starting pregnane
`10 compound contain any substituent ·sensitive to the
`above desired oxidation, such a · group shoulc! be suit(cid:173)
`ably protected.
`The following examples illustrate the invention.
`Melting points were determined in °C. on a Kofler
`15 block and are uncorrected. Optical rotations were de(cid:173)
`termined at room temperature on solutions in dioxan.
`T.l.c. (Thin layer chromatography), p.l.c. (Prepara(cid:173)
`tive layer chromatography) and h.p.tc. (High perfor(cid:173)
`mance liquid chromatography) were carried out over
`20 silica.
`Solutions were dried over magnesium sulphate unless
`stated otherwise.
`
`wherein W represents the group CO, CS, SO or SO2
`and the groups R7, which may be the same or different,
`have the above meanings.
`The compounds of formula (III) are conveniently
`symmetric. In general, compounds of formula (Ill) in
`which W represents CO, CS or SO will be used. Thus,
`for example, especially useful compounds include N,N'-
`N,N'-carbonyldibenzo- 30
`carbonyldi(l,2,4-triazole),
`triazole, N,N' -carbonyldibenzimidazole, N,N' -car(cid:173)
`N,N' -thionyl(cid:173)
`bonyldi(3,5-dimethylpyrazole),
`diiinidazole and especially N,N'-carbonyldiimidazole
`and N,N' -thiocarbonyldiimidazole.
`The preparation of a l7a-hydroxy 17.B-carbothioic 35
`acid having the formula (II) as herein defined is conve(cid:173)
`niently effected by reaction ofa !?a-hydroxy 17.B-car-
`. boxy lie acid with a compound of formula (Ill) followed
`by reaction of the intermediate product having the
`17J3-COR7 grouping with hydrogen sulphide or a salt 40
`thereof preferably in situ without isolation of the inter(cid:173)
`mediate.
`The 17a-acyloxy 17.B-carbothioic acid of formula JI
`may be obtained in a similar manner directly from the
`corresponding 17a-acyloxy 17,8-carboxylic acid by 45
`reaction with a compound of formula (III). The 17a(cid:173)
`acyloxy 17.B-carboxylic acids may be prepared by ester(cid:173)
`ification of the corresponding 17a-acyloxy 17,8-car(cid:173)
`boxylic acids by the methods described in BP No.
`1,384,372.
`The reaction with the compound of formula (III) is
`conveniently effected in the presence of an inert anhy(cid:173)
`drous solvent e.g. a substituted amide solvent such as
`N,N-dimethylformamide or N,N-dimethylacetamide,
`desirably in the absence of water, advantageously at or 55
`below ambient temperature e.g. at a temperature of
`from - 30° C. to + 30° C. The reaction is conveniently
`effected under approximately neutral conditions, ad(cid:173)
`vantageously in an inert atmosphere, e.g. under nitro(cid:173)
`gen. The same solvents and conditions are also applica- 60
`ble to the subsequent reaction with H2S or a salt
`thereof. The heterocyclic compound e.g. imidazole or
`1,2,4-triazole formed a:s a by-product may, for example,
`be readily removed by extraction with water.
`The foregoing reactions may also be carried out on 65
`compounds having a variety of substituents or group(cid:173)
`ings which are subsequently converted as described
`previously to compounds of formula (I).
`
`25
`
`PREPARATION I
`9a-Fluoro-11J3-hydroxy-16J3-methyl-3-oxo-17a-pro(cid:173)
`pionyloxyandrosta- I ,4-diene-17,8-carbothioic acid (I)
`A solution of 9a-fluoro-llJ3-hydroxy-16J3-methyl-3-
`oxo-17a-propionyloxyandrosta-1,4-diene-17,8-carboxy(cid:173)
`lie acid (5.00 g) solvated with ethyl acetate O mole) and
`triethylamine (5.3 ml) in dichloromethane (75 inl) was
`stirred under nitrogen and treated with dimethylthi(cid:173)
`ocarbamoyl chloride (5.071 g). After 24 h more reagent
`(5.320 g) was added. After 47 h the mixture was diluted
`with ethyl acetate and washed with N-hydrochloric
`acid, 5% sodium bicarbonate solution and water, dried
`and evaporated to give a viscous yellow oil (9.043 g).
`This was dissolved in diethylamine (50 ml) then stirred
`and heated at reflux under nitrogen for' 5. 75 h. The
`resulting brown solution was added to a mixture of
`concentrated hydrochloric acid (50 ml), water (250 ml)
`and ethyl acetate (50 ml). The products were further
`extracted with ethyl acetate, then the a\:id products
`were back-extracted into 5% sodium carbonate solu-
`tion. The acqueous phase was acidified with 61'!11-hydro(cid:173)
`chloric acid (50 ml) and extracted with ethyl acetate.
`The extracts were washed with N-hydrochloric acid
`and water, dried and evaporated to .a buff so!id (3.440
`g). This was recrystallised from acetone to· give pale
`50 buff crystals (1.980 g) of the title 17.B-carbothioic acid,
`·
`m.p. 172°-173°.
`The analytical sample was obtained after two recrys(cid:173)
`tallizations from acetone as white crystals, m.p.
`l77°~179°, [a]v+ll0° (c 1.05).
`PREPARATION II
`S-Chloromethyl
`9a-fluoro-16J3-methyl-3, l l-dioxo-17a-propionyloxyan(cid:173)
`drosta- l ,4-diene:1_7,8-carbothioate (II)
`8 N-Jones reagent (1.5 ml) was added dropwise over
`10 mins to a stirred solution of the compound of Exam(cid:173)
`ple I (hereinafter disclosed) (998 mg) in acetone (2 ml)
`and dimethylformamide (2 ml). After 30 mins the reac(cid:173)
`tion mixture was slowly diluted, with· water ( IOO ml)
`with stirring, and the resulting suspension was refriger(cid:173)
`ated for I h. The precipitate was collected by filtration,
`washed with water and dried to give a cream coloured
`solid (877 mg). P..l.c. in chloroform-acetone (10:1) gave
`
`

`

`9
`a white foam (755 mg) which was crystallised twice
`from acetone to give white needles of the title I I-ketone
`(523 mg) m.p. 204°-205°, [a]n+94° (c 1.04).
`
`4,335,121
`
`5
`
`PREPARATION III
`17/3 N,N
`Dimethylthiocarbamoyloxycarbonyl-9a-fluoro-1 1/3-
`hydroxy- l 6a-methyl- l 7 a-propionyloxyandrosta-1,4-
`diene-3-one (III)
`A solution of 9a-fluoro-l l/3-hydroxy-16a-methyl-3- 10
`oxo-17 a-propionyloxyandrosta- l ,4-diene-17 /3-carboxy-
`lic acid (0.434 g) in dichloromethane (8 ml) was treated
`successively with triethylamine (0.14 ml), dimethylthi(cid:173)
`ocarbamoyl chloride (0.248 g), and sodium iodide (0.149
`g) and the mixture was stirred under nitrogen at 20° C. 15
`for 6 h. Ethyl acetate (30 ml) was added and the total
`volume was reduced by half in vacuo. Further ethyl
`acetate (50 ml) was added and the solution was washed
`with water, 2 N-hydrochloric acid, water, 3% sodium
`hydrogen carbonate, water and saturated sodium chlo- 20
`ride solution then dried. The solution was concentrated
`in vacuo when the product crystallised (0.329 g). This
`was recrystallised from acetone (2 X ) to give the title
`anhydride as white needles, m.p. 191 ' -193°, [a]D+82°
`(c 0.57).
`
`25
`
`title I ?a-propionate carboxylic acid as crystals (13.309
`g), [a]v+2° (c 1.10,). A portion (389 mg) was recrystal(cid:173)
`lised twice from methanol to give an analytical sample
`(256 mg) m.p. 244° -245° (decomp), [a]D+ 3° (c 0.83).
`PREPARATION VI
`6a,9a-Difluoro-l l/3-hydroxy-16a-methyl-3-oxo-17a(cid:173)
`propionyloxyandrosta-1,4-diene-l 7 /3-carboxylic acid
`(VI)
`A solution of 6a,9a-difluoro-l l/3,17a-dihydroxy-
`16a-methyl-3-oxoandrosta-l,4-diene-l 7 /3-carboxylic
`acid (2.113 g) and triethylamine (2.5 ml) in dichloro(cid:173)
`methane (60 ml) was stirred and treated at ca 0° C. with
`propionyl chloride (1.85 ml). After 1 h the mixture was
`diluted with more solvent (50 ml) and washed succes(cid:173)
`sively with 3% sodium hydrogen carbonate, water, 2
`N-hydrochloric acid, water, saturated brine, then dried
`and evaporated to a buff solid. This was dissolved in
`acetone (50 ml) and diethylamine (2.5 ml) was added.
`After 1 h at 22° C. the solvent was removed in vacuo
`and the residual gum was dissolved in water (30 ml).
`Acidification to pH I with 2 N-hydrochloric acid pre(cid:173)
`cipitated a solid, which was collected, washed with
`water, and dried to give the title carboxylic acid l 7a(cid:173)
`propionate (2.230 g), m.p. 220°-225°, [a)D+4° (c 0.70).
`PREPARATION VII
`17 /3-N,N-Dimethylthiocarbamoyloxycarbonyl-9a-
`fluoro-11/3-hydroxy-l 6a, l 7a-isopropylidenedioxyan(cid:173)
`drosta- l ,4-diene-3-one (VII)
`A solution of 9a-fluoro-l lf3-hydroxy-l 6a, 17a-iso(cid:173)
`propylidenedioxy-3-oxoandrosta-1 ,4-diene-l 7 /3-car(cid:173)
`boxylic acid (1.000 g) in djchloromethane (15 ml) and
`triethylamine (0.33 ml) under nitrogen was treated with
`N,N-dimethylthiocarbamoyl chloride (588 mg) and the
`mixture was stirred at room temperature. After 68 g the
`reaction mixture was diluted with ethyl acetate (50 ml)
`and washed with N-hydrochloric acid (2.10 ml), 5%
`sodium hydrogen carbonate solution and water, dried
`and evaporated to a pale yellow crystalline solid (1.123
`g). P.l.c. of a portion (200 mg) in chloroformacetone
`(9:1) gave an off-white solid (161 mg) which crystallised
`45 from ethyl acetate as white needles of the title mixed
`anhydride (131 mg), m.p. 279°-281 °, [a]n+ 174° (c 0.61,
`dimethylsulphoxide).
`
`30
`
`PREPARATION IV
`9a-Fluoro- l 1/3-hydroxy-16a-methyl-3-oxo-l 7 a-pro(cid:173)
`pionyloxyandrosta- l,4-diene-17,6-carbothioic acid (IV)
`A stirred suspension of (III) (2.467 g) in diethylamine
`(25 ml) was heated at reflux under nitrogen. After 3.5 h.
`the reaction was poured into iced 3 N hydrochloric acid
`(300 ml) and the mixture was extracted with ethyl ace(cid:17