CA1205464A - Androstane carbothioates - Google Patents
Androstane carbothioatesInfo
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- CA1205464A CA1205464A CA000476250A CA476250A CA1205464A CA 1205464 A CA1205464 A CA 1205464A CA 000476250 A CA000476250 A CA 000476250A CA 476250 A CA476250 A CA 476250A CA 1205464 A CA1205464 A CA 1205464A
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Abstract
Abstract Compounds of the formula:
( 1 )
( 1 )
Description
'lZ~
"Androstane Carbothioates"
The present invention relakes to anti-inflammatory steroids of the adrostane series. More particularly the present invention relates to processes for the preparation of certain new androstane compounds and to such compounds when prepared by the said processes.
Anti-inflammatory steroids are most typically of the corticoid type, i.e. are pregnane derivatives.
Our United Kingdom Patents Nos. 1384372, 1438940 and 1514476 describe esters of certain androstane 17~-carboxylic acids having anti-inflammatory activity.
European Patent Application No. 79300500.0 (Publication No. 0004741) describes esters of androstane 17~-carbothioic acids also possessing anti-inflammatory activity. We have now discovered that certain androstane compounds containing a haloalkyl carbothioate grouping in the 17~-position have particularly advantageous anti inflammatory properties as discussed in greater detail below.
The new androstane compounds may be represented by the formula COSR
~ J , (Ia) wherein Rl represents a fluoro-7 chloro- or bromo-methyl group or a 2'-fluoroethyl group; R2 represents a group COR6 where R6 is a Cl 3 alkyl group or ... ~
~ 3 OR and R together form a 16~,17~-isopropylidenedioxy group; R represents a hydrogen atomt a methyl group Iwhich may be in either the ~- or B- configuraton) or a methylene group; R4 represents a hydrogen, chlorine or fluorine atom; R5 represents a hydrogen or fluorine atom and symbol ....-~ represents a singLe or double bond.
The new compounds of formula (Ia~ have good an~i-inflammatory activity, particularly on topical application, 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 ratsO
Certain of the compounds show good topical anti-inflammatory ac~ivity in the croton oil ear test coupled with minimal hypothalamus-pituitary-adrenal-suppressive activity after topical application ! in the same animal species. These results indicate that such compounds may be of value in the loca1 treatment of inflammation in man and animals with minimal liability to cause undesired systemic side effects.
The present invention relates to processes for preparing two such compounds of formula Ia as hereinbefore defined viz S-fluoromethyl 6~,9~-di~luoro~ -hydroxy~16~-methyl-3-oxo~17~-propionyloxy-androsta-1,4-diene-17~-carbothioate and the corresponding S-chloromethyl analogue and to such compounds when prepared by the said processes. The present application i divided out of Canadian Patent Application No~
370,853 which latter application describes and claims processes for preparing the remaining compounds of formula Ia and such remaining compounds when prepared by said processes.
Thus according to the present invention there is provided a process for the preparation of compounds of the formula:-~ ~5~
cosp~l (I~
o F
wherein Rl represents a fluoromethyl or chloromethyl group; in which process (a1 a compound corresponding to formula I but containing either a free l7R-carbothioic acid group (or functionally equivalent group) or a free 17~-hydroxy group, any other reactive groups present optionally being in protected form, is subjec~ed to esterification;
(b) a compound corresponding to formula I but containing a 17~-substituent of formula -COSCH2Y
(wherein Y represents a displaceable substituent) is reacted with a compound serving to replace the group Y by a fluorine or chlorine atom, whereby a compound of formula I is formed;
(c) a compound corresponding to formula I but carrying an ll-oxo group is subjected to reduction to orm the re~uired llR-hydroxy androstane; ~~
(d) a compound corresponding to formula I but carrying a protected llR-hydroxy group i~ ~ubjected to deprotection;
(e) a compound corresponding to formula I but having a 9,ll~double bond (and no substituent in the ll-position) is reacted with one or more reagents serving to introduce the required 9-halo-llR-hydroxy grouping.
The compounds of the present invention have good anti-inflammatory activity coupled with minimal ~\
hypothalamus-pituita_y-adrenal-suppressive activity when applied topically.
In particular they possess a favourable ratio of topical anti-inflammatory activity to undesired systemic activity.
S-chloromethyl 6~,9~-difluoro-llB-hydroxy-16~-methyl-3-oxo-17-propionyloxyandrosta-1,4-diene-17~-carbothioate is especially preferred in view of its particularly favourable ratio of topical anti-inflammatory activity to undesired systemic activity and in addition minimal skin atrophy.
As stated above the compounds of formula (I) may be prepared by a variety of different processesO
One such process comprises esterifying an androstane compound corresponding to formula (I) but con~aining either a free 17~-carbothioic acid I group (or functionally equivalent group) or a free 17~-hydroxy group, any other reactive groups present op~ionally being in protected form.
For example, a salt of the parent 17B-carbothioic acid such as an alkali metal~ e.g. lithium, sodium or potassium, salt or an alkylammonium, e.g. triethyl-ammonium or tetrabutylammonium, salt may be reacted ~5 with an appropriate alkylating agent, preferably in a polar solvent such as a ketone, e.g. acetone or an amide such as dimethylformamide, dimethylac~tamide or hexamethyl-phosphoramide, conveniently at a temperature of 15 to 100C. The alkylating agent may comprise an appropriate dihalo compound i.e.
one containing a ~urther halogen atom (preferably a bromine or iodine atom) in addltion to the halogen atom of the desired Rl group. This process is particularly applicable to the preparation of compounds in which Rl i~ a choromethyl group, the alkylating agent advantageously being bromochloromethane.
Alternatively, the parent 16~-methyl-17~-.~
hydroxy-17~-carbothioates corresponding to compounds of formula I may be subjected to esterification of the 17~-hydroxyl group. This may be effected by conventional techniques, e.g. by rea~ting the parent 17~ hydroxy compound with a mixed anhydride of propionic acid, which may, for example, be generated in situ by reacting the propionic acid with an appropriate anhydride such as trifluoroacetic anhydride, preferably in ~he presence of an acid catalyst, e.g. p-toluene-sulphonic acid or sulphosalicylic acid. Alternatively, the mixed anhydride may be generated 1n situ by reaction of a symmetrical anhydride of propionic acid with an appropriate further acid, e.g. 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, i the reaction being conveniently effected at a temperature of 20-100C.
Alternativelyr the 17~-hydroxy group may be esterified by reaction of the parent 17~-hydroxy compound with the appropriate acid anhydride or acid chloride, if desired, in the presence of non-hydroxylic solvents, e.g~ chloroform, methylene chloride or benzene, and preferably in the presence of a strong acid catalyst, e.g. perchloric acid, p-toluene sulphonic acid or a strongly acidic cation exchange resin~ e.g. Amberlite *IR 120, the reaction being conveniently effected at a ~emperature of 25 to 100C.
The compounds of formula (I) may also be prepared by reacting a corresponding androstane compound containing a 17~-substituent of formula -COSCH2Y (wherein Y represents a displaceable substituent) with a compound serving to replace the group Y
by a fluorine or chlorine atom.
Thus the compounds of formula (I) may be *Trade Mark 54~4 subjected to a halogen exchange reaction serving to replace the group Y where this is halogen by a different halogen substituent. Thus the fluoromethyl 17~-carbothioate compound of the invention may be prepared from the corresponding iodomethyl 17~-carbothioate compound using an appropriate fluoride e.g. silver monofluoride or silver difluoride.
The starting iodomethyl 17B-carbothioate compound may be prepared from the corresponding chloromethyl 17~ carbothioate compound using for example, an alkali metal, alkaline earth metal or quaternary ammonium iodide e.g. sodium iodide.
The reaction is advantageously effected in a solvent medium comprising for example acetone, acetonitrile, methyl ethyl ketone~ dimethylformamide, dimethylacetamide or ethanol.
The foregoing reactions may also be carried out on starting materials having a variety of substituents or groupings which are subsequently converted into those substituents or groupings which are present in the compounds of the invention as defined above.
The llB~hydroxy compounds of formula ~I) may thus be prepared by reduction of a corresponding ll-oxo compound, e.g. using an alkali metal or alkaline earth metal borohydride, e.g. sodium or calcium borohydride, conveniently in an alcoholic or aqueous alcoholic solvent such as methanol or ethanol.
Such an ll-keto compound may be prepared by oxidation of a corresponding ll~-hydroxysteroid, for example using a chromic acid reagent such as Jones' reagent.
An 116-hydroxy compound of formula (I) may also be obtained by deprotection of a corresponding compound having a protected hydroxyl group at the llB-position, for example a tri Cl 6 alkylsilyloxy group such as the trimethylsilyloxy group or a .~
;~ 5469L
perfluoro- or chloro-alkanoyloxy group such as the trifluoroacetoxy group~ Removal of the protecting groups may be effected by hydrolysis, the trialkylsilyl group being readily removed 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 basic hydrolysis or alcoholysis. Such a protected hydroxyl group may be introduced, for example, by reacting an llB-hydroxy steroid with an appropriate reagent such as a trialkylsilyl halide or a perfluoro-or chloro-alkanoic anhydride.
Compounds of formula (I~ may also be produced by reaction of a corresponding compound having a 9,11-double bond ~and no substituent in the 11-position) with reagents serving to introduce the required 9~-halo~ hydroxy group. This may involve initial formation of a bromohydrin by reaction with an N-bromo-amide or -imide such as N-bromosuccinimide, followed by formation of the corresponding gB,llB-epoxide by treatment with a base and reaction of the epoxide with hydrogen fluoride to introduce the required fluorohydrin grouping.
The above mentioned compounds containing a free -COSH group in the 17~-position may be prepared for example by aminolysis with rearrangement of --.
a suitable 17~ thiocarbamoyloxycarbonyl androstane.
The 17~-thiocarbamoyloxycarbonyl androstane is a mixed anhydride of the corresponding 17B-carboxylic acid and a thiocarbamic acid and is conveniently prepared by reaction of a salt of the 176-carboxylic acid 17-ester or 16~, 17~-acetonide with a thiocarbamoyl halide.
The thiocarbamoyloxycarbonyl group is N,N-disubstituted, and may thus have the formula -COOCSNR R , where RA and R , which may be the same or different, are alkyl groups, e.g. Cl_4 alkyl groups or RA and RB
together with the nitrogen atom to which they are a~tached form a 5-8 membered ring which may optionally con~ain an additional hetero atom selected from oxygen, nitrogen and sulphur and/or which may optionally be substituted by one or two C1 3 alkyl e.g. methyl groups.
Preferably RA and RB are Cl 4 alkyl substituents, the N,N-dimethylthiocarbamoyl group being preferred. The thiocarbamoyl 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~-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 elevated temperature e.g. in the presence of ammonia, a primary amine or more preferably a s~condary amine such as diethylamine or pyrrolidine. In the starting 17B-carboxylic acids, the 16~- and 17~-positions will conveniently be substituted by a 16~-methyl group and a 17~-propionyloxy group respectively, viz the groupings desired for the final product of formula (I~.
The starting materials employed in the process described h~rein for the preparation of the compounds of the present invention are new and include compounds of the general formula tII) --Ra RC~ ~ R-CH3 ~ (II) O ~
F
'~
6~
wherein Ra represents a thiocarbamoyloxycarbonyl group -COOCSNRARB where RA and R~ are as defined above, or a group of the formula -COSRlA, where RlA represents a hydrogen atom or a chloromethyl or fluoromethyl group or is a group convertible thereto and ~b represents a propionyloxy group;
or where Ra represents a group COSRlA, Rb is optionally a hydroxy group;
R represents a hydroxy or protected hydroxy group (in either the ~- or B-configuration) or an oxo group;
Rd represents a fluorine atom, or Rc and Rd together represent a carbon-carbon bond or an epoxy group in the ~-configuration; and salts of those compounds which have a free carbothioic acid group; with the exclusion of compounds of formula (Ia) as hereinbefore definedO
! Where Rc represents a pro~ected hydroxy group, this may, for example be a trialkylsilyloxy group or a perfluoro- or perchloro-alkanoyloxy group as defined previously.
The 17~-hydroxy 17~-carbothioic acids of formula (II) and salts thereof may be converted into the 17~-hydroxy 17B-carbothioates of formula (II) where Ra represents the group COSRl as defined in formula (I) or into the 17B-carbothioic acid 17~-propionic acid ester of formula (II) by the --processes described above for preparing the compounds of formula (I). The esterification of the 17~-hydroxy group is preferably effected with propionic acid chloride in a solvent such as a halogenated hydrocarbon e.g. dichloromethane, and advantageously in the presence of a base such as triethylamine, preferably at a low temperature e.g. 0C.
The 17~-hydroxy 17B-carbothioic acids of formula (II) and salts thereof are thus particularly useful intermediates for preparing the androstane !,`~`, ~
17B-carbothioates of the present invention; those in which Rc represents a h~droxy group in the ~-configuration or an oxo group being preferred.
6~,9~-difluoro-11~,17~-dihydroxy-16~ methyl-3-oxoandrosta-1,4-diene-17~-carbothioic acid and the corresponding ll-ketone and salts thereof are especially preferred compounds of formula (II).
One advantage of the above intermediates is that they permit direct haloalkylation to give haloalkyl 17~-carbothioates when the corresponding thiols RlSH
are not available. The salts of these 17~-hydroxy 17~-carbothioic acids may, for example be alkali metal, e.g. lit~ium, sodium or potassium salts; tertiary amine salts, e.g. pyridinium or triethylammonium salts; or quaternary ammonium salts, eOg. tetrabutylammonium salts.
The 17~-hydroxy 17~-carbothioic acids may, i for example, be prepared by reaction of a reactive derivative of a corresponding 17~-hydroxy-17~-carboxylic acid with hydrogen sulphide or a sulphide or hydrosulphide salt thereof. In general, the ca~ion of the sulphide or hydrosulphide salt may be for example an alkali metal salt such as sodium or potassium hydrogen sulphide.
The above-mentioned reactive derivatives corresponding to compounds of formula (II) where Rb is a hydroxyl group and the group -CoR7 is present at the 17B position wherein R7 represents a group of the formula ~~
Y - - X
N ''~
z in which X, Y and Z, which may be the same or different, each represent CH or N, one or two of X, Y and Z
being N, the heterocyclic ring optionally being substituted - 3 r~o5 9~69L
~ 11 --on at least one carbon atom by a lower alkyl group (eOg. with 1 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 carbon atoms.
The above-mentioned reactive derivatives corresponding to formula (Il) are preferably prepared by reacting corresponding 17~-hydroxy 17~-carboxylic acids of formula (II) wi~h a symmetric or asymmetric compound of the formula:
R - W - R7 (III) wherein W represents the group CO, CS, SO or S02 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 (III) in which W represents CO, CS or SO will be used.
Thus, for example, especially useful compounds include N,N'-carbonyldi(1,2,4-triazole), N,N'-carbonyl-dibenzotriazole, N,N'-carbonyldibenzimida201e, N,N'-carbonyldi(3,5-dimethylpyrazole)~ N,N'-thionyldi-imidazole and especially N,N'-carbonyldiimidazole and N,N'-thiocarbonyldiimidazole.
The preparation of a 17~-hydroxy 17B-carbothioic acid having the formula (II) as he~ein defined in conveniently effected by reaction of a 17~-hydroxy 17B-carboxylic acid with a compound of formula (III) followed by reaction of the intermediate product having the 17B-COR7 grouping with hydrogen sulphide or a salt thereof preferably ln situ without isolation of the intermediate.
The 17~ propionyloxy 17B-carbothioic acid of formula (II) may be obtained in a similar manner directly from the corresponding 17~-propionyloxy `\ !
6~
17R-carboxylic acid by reaction with a compound of formula (III). The 17~-propionyloxy 17~-carboxylic acids may be prepared by esterification of the corresponding 17-hydroxy 17B-carboxylic acids by the methods described in BP 1,384,372.
The reaction with the compound of formula (III~ is conveniently effected in the presence of an inert anhydrous solvent e.g. a substituted amide solvent such as N,N-dimethylformamide or N,N-dimethylace~amide, desirably in the absence of water, advantageously at or below ambient temperature e.g. at a temperature of from -30C to +30C.
The reaction is conveniently effected under approximately neutral conditions, advantageously in an inert atmosphere, e.g. under nitrogen. The same solvents and conditions are also applicable to the subsequent reaction with H2S or a salt ~hereof. The heterocyclic I compound e.g. imidazole or 1,2,~-triazole formed as a by-product may, for example, be readily removed by extraction with water.
The foregoing reactions may also be carried out on compounds having a variety of substituents or groupings which are subsequently converted as described previously to compounds of formula (I).
The androstane 17B-carboxylic acid starting materials employed in the above processes may be prepared in conventional manner, e~g. by oxidation~--of an appropriate 21-hydroxy-20-keto pregnane for example with periodic acid, in a solvent medium 3G and preferably at room temperature. Alternatively, sodium bismuthate may be employed to Pffect the desired oxidative removal of the 21-carbon atom of a 17-acyloxy pregnane compound. As will be appreciated should the starting pregnane compound contain any substituent sensitive ~o the above desired oxidation~ such a group should be suitably protected.
; , .
~ z~ 6~
The following examples illustrate the inv~ntion.
Melting points were determined in C on a Kofler block and are uncorrected. Optical rotations were determined at room temperature on solutions in dioxan.
T~loc~ (Thin layer chromatography), p,l.c~
(Preparative layer chromatography) and h.p.l.c.
(High performance liquid chromatography) were carried out over silica.
Solutions were dried over magnesium sulphate unless stated otherwise.
~L2~6~
Preparation I
6~,9~-Difluoro~ hydroxy-16~-meth~1-3-oxo-17~-propionyloxy androsta-1,4-diene-17~-carbothioic acid (I) a) 6~,9~-Difluoro-ll~-hydroxy-16~-methyl-3 oxo-17~-E~ropionyloxyandrosta-1,4-diene-17B-carboxylic acid A solution of 6~,9~-difluoro-11~,17~-dihydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylic acid (2.113 g) and triethylamine (2.5 ml) in dichloro-methane (60 ml) was stirred at treated at ca 0Cwith propionyl chloride (1.85 ml). After 1 H the mixture was diluted with more solvent (50 ml) and washed successively with 3% sodium hydrogen carbonate, water, 2N-hydrochloric acid, water, saturated brine, lS 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 22C the solvent i was removed in vacuo and the residual 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 give the title carboxylic acid 17~ ~roPionate (2.230 g), m.p. 220-225, [~]D ~4 (c 0.70).
b) A solution of 6~,9~-difluoro-11~ hydroxy-16~-methyl-3-oxo-17~-propionyloxyandrosta-1,4-diene-17B-carboxylic acid (2.130 g) solvated with ethyl -~acetate (1/2 mole) and triethylamine (0.66 ml) in dichloromethane (50 ml) was stirred under nitrogen and treated with dimethylthiocarbamoyl chloride (1.80 g). After 6 days at room temperature, the intermediate dimethylthiocarbamic anhydride (1.435 g) is crystallised from ethyl acetate. A portion (95 mg) being removed for characterisation. The remaining anhydride was dissolved in diethylamine (12 ml) then stirred and heated at reflux under nitrogen for 6 h. The resulting brown solution '~
~2~)S46~
was added to a mixture of concentrated hydrochloric acid (50 ml~ ~ater (250 ml) and ethyl acetate (50 ml).
The products were further extracted with ethyl acetate, then the acid products were back-extracted into 5% sodium carbonate solution. The aqueous ; phase was acidified with 6N-hydrochloric acid (50 ml) and extracted with ethyl acetate. The extracts were washed with N-hydrochloric acid and water, dried and evaporated to a buff solid. This was recrystallized from ethyl acetate to give pale buff crystals (0.418 g) of the title 17B-carbothioic acid.
The analytical sample was obtained after two recrystallizations from ethyl acetate as white crystals, m.p. 136-139, [~]D ~30 (c 0.56).
Preparation II
S-Iodomet~yl 6~,9~-difluoro-11~ hydroxy-16~-methyl-3-oxo-17~-propionyloxyandrosta-1,4-diene-17B-carbothioate (II~
A~solution of the compound of Example 1 (hereinafter disclosed) (303 mg) and sodium iodide (1~200 9) in acetone (30 ml) was stirred and heated under reflux for 5 h~ Ethyl acetate (75 ml) was then added and the solution was washed successively with wa~er, 10% sodium thiosulphate solution, 5%
sodium hydrogen carbonate solution and water, dried and evaporated to give an off white foam (525 mg).
P~loc~ in chloroform-acetone ~6:1) gave an off- -~white foam which was crystallized twice from acetone without being heated above room temperature to give colourless crystals of the title S-iodomethyl ester (317 mg). The product was used directly for the preparation of the corresponding fluoromethyl 17B-carbothioate as described in Example 2.
Preparation III
S-Chloromethyl 6~,9~-difluoro 16-methyl-3-oxo-~, 17~-pro~ionyloxy-11~-trifluoroacetoxyandrosta-1,4-diene-17~-carbothioate (III) -- ~2~15~4 A solution of the compound of Example 1 (hereinafter disclosed) ~1~0 mg) in dry tetrahydrofuran (2 m~ and pyridine (O.lml) was treated wi~h trifluoroacetic anhydride (0.05 ml) and the mixture was kept at room temperature for 0.5 h. The reaction mixture was poured into water and the product was extracted with ethyl acetate (3x). The organic extracts were washed with water, dried and evaporated to give the homogen~ous title trifluoroacetate (116 mg) according to H nmr spec~roscopy (singlet at 8.59l, l9-protons, in deuterio-chloroform) and t.l.c. on silica (acetone-petrol, b.p.
40-60C, 1:3) An analytical sample from e~her-pentane had m.p. 158-162, [~]D +56 (c 0.23).
Preparation IV
6a,9a-Difluoro-11~,17a-dihydroxy-16a-methyl-3-oxoandrosta-15 1,4-diene-17~-carbothioic acid (IV) A solution of 6,9a-difluoro~ ,17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17~-carboxylic acid (12.0 g) in dry dimethylformamide (250 ml) was stirred and treated with N,~'-carbonyldiimidazole (9.94 g) under nitrogen a~
20 room t~mperature. After 4 h, hydrogen sulphide was passed through the solution for O.S h and the mixture was kept for a further 0.5 h. The reaction mixture was poured into 2N-hydrochloric acid (500 ml) containing ice (ca 250 g). The resulting precipitate was collected, washed with water and 25 dried ln vacuo to give the title thioacid as a white solid (11.47 g), m.pO 230 - 232, [a]D +94 (c 0.91).
Preparation V
,.", _ 6a,9-Difluoro-ll~-hydroxy-16a-methyl-3-oxo-17a-propionyloxy-androsta l,4-diene-17~-carbothioic acid (V) A solution of IY (5.0 g~ and triethylamine (6.15 ml) in dichloromethane (140 ml) was cooled with ice--salt and treated dropwise with propionyl chloride (4.74 ml). The reaction mixture was stirred further at ca 0C for 0.75 h
"Androstane Carbothioates"
The present invention relakes to anti-inflammatory steroids of the adrostane series. More particularly the present invention relates to processes for the preparation of certain new androstane compounds and to such compounds when prepared by the said processes.
Anti-inflammatory steroids are most typically of the corticoid type, i.e. are pregnane derivatives.
Our United Kingdom Patents Nos. 1384372, 1438940 and 1514476 describe esters of certain androstane 17~-carboxylic acids having anti-inflammatory activity.
European Patent Application No. 79300500.0 (Publication No. 0004741) describes esters of androstane 17~-carbothioic acids also possessing anti-inflammatory activity. We have now discovered that certain androstane compounds containing a haloalkyl carbothioate grouping in the 17~-position have particularly advantageous anti inflammatory properties as discussed in greater detail below.
The new androstane compounds may be represented by the formula COSR
~ J , (Ia) wherein Rl represents a fluoro-7 chloro- or bromo-methyl group or a 2'-fluoroethyl group; R2 represents a group COR6 where R6 is a Cl 3 alkyl group or ... ~
~ 3 OR and R together form a 16~,17~-isopropylidenedioxy group; R represents a hydrogen atomt a methyl group Iwhich may be in either the ~- or B- configuraton) or a methylene group; R4 represents a hydrogen, chlorine or fluorine atom; R5 represents a hydrogen or fluorine atom and symbol ....-~ represents a singLe or double bond.
The new compounds of formula (Ia~ have good an~i-inflammatory activity, particularly on topical application, 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 ratsO
Certain of the compounds show good topical anti-inflammatory ac~ivity in the croton oil ear test coupled with minimal hypothalamus-pituitary-adrenal-suppressive activity after topical application ! in the same animal species. These results indicate that such compounds may be of value in the loca1 treatment of inflammation in man and animals with minimal liability to cause undesired systemic side effects.
The present invention relates to processes for preparing two such compounds of formula Ia as hereinbefore defined viz S-fluoromethyl 6~,9~-di~luoro~ -hydroxy~16~-methyl-3-oxo~17~-propionyloxy-androsta-1,4-diene-17~-carbothioate and the corresponding S-chloromethyl analogue and to such compounds when prepared by the said processes. The present application i divided out of Canadian Patent Application No~
370,853 which latter application describes and claims processes for preparing the remaining compounds of formula Ia and such remaining compounds when prepared by said processes.
Thus according to the present invention there is provided a process for the preparation of compounds of the formula:-~ ~5~
cosp~l (I~
o F
wherein Rl represents a fluoromethyl or chloromethyl group; in which process (a1 a compound corresponding to formula I but containing either a free l7R-carbothioic acid group (or functionally equivalent group) or a free 17~-hydroxy group, any other reactive groups present optionally being in protected form, is subjec~ed to esterification;
(b) a compound corresponding to formula I but containing a 17~-substituent of formula -COSCH2Y
(wherein Y represents a displaceable substituent) is reacted with a compound serving to replace the group Y by a fluorine or chlorine atom, whereby a compound of formula I is formed;
(c) a compound corresponding to formula I but carrying an ll-oxo group is subjected to reduction to orm the re~uired llR-hydroxy androstane; ~~
(d) a compound corresponding to formula I but carrying a protected llR-hydroxy group i~ ~ubjected to deprotection;
(e) a compound corresponding to formula I but having a 9,ll~double bond (and no substituent in the ll-position) is reacted with one or more reagents serving to introduce the required 9-halo-llR-hydroxy grouping.
The compounds of the present invention have good anti-inflammatory activity coupled with minimal ~\
hypothalamus-pituita_y-adrenal-suppressive activity when applied topically.
In particular they possess a favourable ratio of topical anti-inflammatory activity to undesired systemic activity.
S-chloromethyl 6~,9~-difluoro-llB-hydroxy-16~-methyl-3-oxo-17-propionyloxyandrosta-1,4-diene-17~-carbothioate is especially preferred in view of its particularly favourable ratio of topical anti-inflammatory activity to undesired systemic activity and in addition minimal skin atrophy.
As stated above the compounds of formula (I) may be prepared by a variety of different processesO
One such process comprises esterifying an androstane compound corresponding to formula (I) but con~aining either a free 17~-carbothioic acid I group (or functionally equivalent group) or a free 17~-hydroxy group, any other reactive groups present op~ionally being in protected form.
For example, a salt of the parent 17B-carbothioic acid such as an alkali metal~ e.g. lithium, sodium or potassium, salt or an alkylammonium, e.g. triethyl-ammonium or tetrabutylammonium, salt may be reacted ~5 with an appropriate alkylating agent, preferably in a polar solvent such as a ketone, e.g. acetone or an amide such as dimethylformamide, dimethylac~tamide or hexamethyl-phosphoramide, conveniently at a temperature of 15 to 100C. The alkylating agent may comprise an appropriate dihalo compound i.e.
one containing a ~urther halogen atom (preferably a bromine or iodine atom) in addltion to the halogen atom of the desired Rl group. This process is particularly applicable to the preparation of compounds in which Rl i~ a choromethyl group, the alkylating agent advantageously being bromochloromethane.
Alternatively, the parent 16~-methyl-17~-.~
hydroxy-17~-carbothioates corresponding to compounds of formula I may be subjected to esterification of the 17~-hydroxyl group. This may be effected by conventional techniques, e.g. by rea~ting the parent 17~ hydroxy compound with a mixed anhydride of propionic acid, which may, for example, be generated in situ by reacting the propionic acid with an appropriate anhydride such as trifluoroacetic anhydride, preferably in ~he presence of an acid catalyst, e.g. p-toluene-sulphonic acid or sulphosalicylic acid. Alternatively, the mixed anhydride may be generated 1n situ by reaction of a symmetrical anhydride of propionic acid with an appropriate further acid, e.g. 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, i the reaction being conveniently effected at a temperature of 20-100C.
Alternativelyr the 17~-hydroxy group may be esterified by reaction of the parent 17~-hydroxy compound with the appropriate acid anhydride or acid chloride, if desired, in the presence of non-hydroxylic solvents, e.g~ chloroform, methylene chloride or benzene, and preferably in the presence of a strong acid catalyst, e.g. perchloric acid, p-toluene sulphonic acid or a strongly acidic cation exchange resin~ e.g. Amberlite *IR 120, the reaction being conveniently effected at a ~emperature of 25 to 100C.
The compounds of formula (I) may also be prepared by reacting a corresponding androstane compound containing a 17~-substituent of formula -COSCH2Y (wherein Y represents a displaceable substituent) with a compound serving to replace the group Y
by a fluorine or chlorine atom.
Thus the compounds of formula (I) may be *Trade Mark 54~4 subjected to a halogen exchange reaction serving to replace the group Y where this is halogen by a different halogen substituent. Thus the fluoromethyl 17~-carbothioate compound of the invention may be prepared from the corresponding iodomethyl 17~-carbothioate compound using an appropriate fluoride e.g. silver monofluoride or silver difluoride.
The starting iodomethyl 17B-carbothioate compound may be prepared from the corresponding chloromethyl 17~ carbothioate compound using for example, an alkali metal, alkaline earth metal or quaternary ammonium iodide e.g. sodium iodide.
The reaction is advantageously effected in a solvent medium comprising for example acetone, acetonitrile, methyl ethyl ketone~ dimethylformamide, dimethylacetamide or ethanol.
The foregoing reactions may also be carried out on starting materials having a variety of substituents or groupings which are subsequently converted into those substituents or groupings which are present in the compounds of the invention as defined above.
The llB~hydroxy compounds of formula ~I) may thus be prepared by reduction of a corresponding ll-oxo compound, e.g. using an alkali metal or alkaline earth metal borohydride, e.g. sodium or calcium borohydride, conveniently in an alcoholic or aqueous alcoholic solvent such as methanol or ethanol.
Such an ll-keto compound may be prepared by oxidation of a corresponding ll~-hydroxysteroid, for example using a chromic acid reagent such as Jones' reagent.
An 116-hydroxy compound of formula (I) may also be obtained by deprotection of a corresponding compound having a protected hydroxyl group at the llB-position, for example a tri Cl 6 alkylsilyloxy group such as the trimethylsilyloxy group or a .~
;~ 5469L
perfluoro- or chloro-alkanoyloxy group such as the trifluoroacetoxy group~ Removal of the protecting groups may be effected by hydrolysis, the trialkylsilyl group being readily removed 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 basic hydrolysis or alcoholysis. Such a protected hydroxyl group may be introduced, for example, by reacting an llB-hydroxy steroid with an appropriate reagent such as a trialkylsilyl halide or a perfluoro-or chloro-alkanoic anhydride.
Compounds of formula (I~ may also be produced by reaction of a corresponding compound having a 9,11-double bond ~and no substituent in the 11-position) with reagents serving to introduce the required 9~-halo~ hydroxy group. This may involve initial formation of a bromohydrin by reaction with an N-bromo-amide or -imide such as N-bromosuccinimide, followed by formation of the corresponding gB,llB-epoxide by treatment with a base and reaction of the epoxide with hydrogen fluoride to introduce the required fluorohydrin grouping.
The above mentioned compounds containing a free -COSH group in the 17~-position may be prepared for example by aminolysis with rearrangement of --.
a suitable 17~ thiocarbamoyloxycarbonyl androstane.
The 17~-thiocarbamoyloxycarbonyl androstane is a mixed anhydride of the corresponding 17B-carboxylic acid and a thiocarbamic acid and is conveniently prepared by reaction of a salt of the 176-carboxylic acid 17-ester or 16~, 17~-acetonide with a thiocarbamoyl halide.
The thiocarbamoyloxycarbonyl group is N,N-disubstituted, and may thus have the formula -COOCSNR R , where RA and R , which may be the same or different, are alkyl groups, e.g. Cl_4 alkyl groups or RA and RB
together with the nitrogen atom to which they are a~tached form a 5-8 membered ring which may optionally con~ain an additional hetero atom selected from oxygen, nitrogen and sulphur and/or which may optionally be substituted by one or two C1 3 alkyl e.g. methyl groups.
Preferably RA and RB are Cl 4 alkyl substituents, the N,N-dimethylthiocarbamoyl group being preferred. The thiocarbamoyl 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~-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 elevated temperature e.g. in the presence of ammonia, a primary amine or more preferably a s~condary amine such as diethylamine or pyrrolidine. In the starting 17B-carboxylic acids, the 16~- and 17~-positions will conveniently be substituted by a 16~-methyl group and a 17~-propionyloxy group respectively, viz the groupings desired for the final product of formula (I~.
The starting materials employed in the process described h~rein for the preparation of the compounds of the present invention are new and include compounds of the general formula tII) --Ra RC~ ~ R-CH3 ~ (II) O ~
F
'~
6~
wherein Ra represents a thiocarbamoyloxycarbonyl group -COOCSNRARB where RA and R~ are as defined above, or a group of the formula -COSRlA, where RlA represents a hydrogen atom or a chloromethyl or fluoromethyl group or is a group convertible thereto and ~b represents a propionyloxy group;
or where Ra represents a group COSRlA, Rb is optionally a hydroxy group;
R represents a hydroxy or protected hydroxy group (in either the ~- or B-configuration) or an oxo group;
Rd represents a fluorine atom, or Rc and Rd together represent a carbon-carbon bond or an epoxy group in the ~-configuration; and salts of those compounds which have a free carbothioic acid group; with the exclusion of compounds of formula (Ia) as hereinbefore definedO
! Where Rc represents a pro~ected hydroxy group, this may, for example be a trialkylsilyloxy group or a perfluoro- or perchloro-alkanoyloxy group as defined previously.
The 17~-hydroxy 17~-carbothioic acids of formula (II) and salts thereof may be converted into the 17~-hydroxy 17B-carbothioates of formula (II) where Ra represents the group COSRl as defined in formula (I) or into the 17B-carbothioic acid 17~-propionic acid ester of formula (II) by the --processes described above for preparing the compounds of formula (I). The esterification of the 17~-hydroxy group is preferably effected with propionic acid chloride in a solvent such as a halogenated hydrocarbon e.g. dichloromethane, and advantageously in the presence of a base such as triethylamine, preferably at a low temperature e.g. 0C.
The 17~-hydroxy 17B-carbothioic acids of formula (II) and salts thereof are thus particularly useful intermediates for preparing the androstane !,`~`, ~
17B-carbothioates of the present invention; those in which Rc represents a h~droxy group in the ~-configuration or an oxo group being preferred.
6~,9~-difluoro-11~,17~-dihydroxy-16~ methyl-3-oxoandrosta-1,4-diene-17~-carbothioic acid and the corresponding ll-ketone and salts thereof are especially preferred compounds of formula (II).
One advantage of the above intermediates is that they permit direct haloalkylation to give haloalkyl 17~-carbothioates when the corresponding thiols RlSH
are not available. The salts of these 17~-hydroxy 17~-carbothioic acids may, for example be alkali metal, e.g. lit~ium, sodium or potassium salts; tertiary amine salts, e.g. pyridinium or triethylammonium salts; or quaternary ammonium salts, eOg. tetrabutylammonium salts.
The 17~-hydroxy 17~-carbothioic acids may, i for example, be prepared by reaction of a reactive derivative of a corresponding 17~-hydroxy-17~-carboxylic acid with hydrogen sulphide or a sulphide or hydrosulphide salt thereof. In general, the ca~ion of the sulphide or hydrosulphide salt may be for example an alkali metal salt such as sodium or potassium hydrogen sulphide.
The above-mentioned reactive derivatives corresponding to compounds of formula (II) where Rb is a hydroxyl group and the group -CoR7 is present at the 17B position wherein R7 represents a group of the formula ~~
Y - - X
N ''~
z in which X, Y and Z, which may be the same or different, each represent CH or N, one or two of X, Y and Z
being N, the heterocyclic ring optionally being substituted - 3 r~o5 9~69L
~ 11 --on at least one carbon atom by a lower alkyl group (eOg. with 1 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 carbon atoms.
The above-mentioned reactive derivatives corresponding to formula (Il) are preferably prepared by reacting corresponding 17~-hydroxy 17~-carboxylic acids of formula (II) wi~h a symmetric or asymmetric compound of the formula:
R - W - R7 (III) wherein W represents the group CO, CS, SO or S02 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 (III) in which W represents CO, CS or SO will be used.
Thus, for example, especially useful compounds include N,N'-carbonyldi(1,2,4-triazole), N,N'-carbonyl-dibenzotriazole, N,N'-carbonyldibenzimida201e, N,N'-carbonyldi(3,5-dimethylpyrazole)~ N,N'-thionyldi-imidazole and especially N,N'-carbonyldiimidazole and N,N'-thiocarbonyldiimidazole.
The preparation of a 17~-hydroxy 17B-carbothioic acid having the formula (II) as he~ein defined in conveniently effected by reaction of a 17~-hydroxy 17B-carboxylic acid with a compound of formula (III) followed by reaction of the intermediate product having the 17B-COR7 grouping with hydrogen sulphide or a salt thereof preferably ln situ without isolation of the intermediate.
The 17~ propionyloxy 17B-carbothioic acid of formula (II) may be obtained in a similar manner directly from the corresponding 17~-propionyloxy `\ !
6~
17R-carboxylic acid by reaction with a compound of formula (III). The 17~-propionyloxy 17~-carboxylic acids may be prepared by esterification of the corresponding 17-hydroxy 17B-carboxylic acids by the methods described in BP 1,384,372.
The reaction with the compound of formula (III~ is conveniently effected in the presence of an inert anhydrous solvent e.g. a substituted amide solvent such as N,N-dimethylformamide or N,N-dimethylace~amide, desirably in the absence of water, advantageously at or below ambient temperature e.g. at a temperature of from -30C to +30C.
The reaction is conveniently effected under approximately neutral conditions, advantageously in an inert atmosphere, e.g. under nitrogen. The same solvents and conditions are also applicable to the subsequent reaction with H2S or a salt ~hereof. The heterocyclic I compound e.g. imidazole or 1,2,~-triazole formed as a by-product may, for example, be readily removed by extraction with water.
The foregoing reactions may also be carried out on compounds having a variety of substituents or groupings which are subsequently converted as described previously to compounds of formula (I).
The androstane 17B-carboxylic acid starting materials employed in the above processes may be prepared in conventional manner, e~g. by oxidation~--of an appropriate 21-hydroxy-20-keto pregnane for example with periodic acid, in a solvent medium 3G and preferably at room temperature. Alternatively, sodium bismuthate may be employed to Pffect the desired oxidative removal of the 21-carbon atom of a 17-acyloxy pregnane compound. As will be appreciated should the starting pregnane compound contain any substituent sensitive ~o the above desired oxidation~ such a group should be suitably protected.
; , .
~ z~ 6~
The following examples illustrate the inv~ntion.
Melting points were determined in C on a Kofler block and are uncorrected. Optical rotations were determined at room temperature on solutions in dioxan.
T~loc~ (Thin layer chromatography), p,l.c~
(Preparative layer chromatography) and h.p.l.c.
(High performance liquid chromatography) were carried out over silica.
Solutions were dried over magnesium sulphate unless stated otherwise.
~L2~6~
Preparation I
6~,9~-Difluoro~ hydroxy-16~-meth~1-3-oxo-17~-propionyloxy androsta-1,4-diene-17~-carbothioic acid (I) a) 6~,9~-Difluoro-ll~-hydroxy-16~-methyl-3 oxo-17~-E~ropionyloxyandrosta-1,4-diene-17B-carboxylic acid A solution of 6~,9~-difluoro-11~,17~-dihydroxy-16~-methyl-3-oxoandrosta-1,4-diene-17~-carboxylic acid (2.113 g) and triethylamine (2.5 ml) in dichloro-methane (60 ml) was stirred at treated at ca 0Cwith propionyl chloride (1.85 ml). After 1 H the mixture was diluted with more solvent (50 ml) and washed successively with 3% sodium hydrogen carbonate, water, 2N-hydrochloric acid, water, saturated brine, lS 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 22C the solvent i was removed in vacuo and the residual 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 give the title carboxylic acid 17~ ~roPionate (2.230 g), m.p. 220-225, [~]D ~4 (c 0.70).
b) A solution of 6~,9~-difluoro-11~ hydroxy-16~-methyl-3-oxo-17~-propionyloxyandrosta-1,4-diene-17B-carboxylic acid (2.130 g) solvated with ethyl -~acetate (1/2 mole) and triethylamine (0.66 ml) in dichloromethane (50 ml) was stirred under nitrogen and treated with dimethylthiocarbamoyl chloride (1.80 g). After 6 days at room temperature, the intermediate dimethylthiocarbamic anhydride (1.435 g) is crystallised from ethyl acetate. A portion (95 mg) being removed for characterisation. The remaining anhydride was dissolved in diethylamine (12 ml) then stirred and heated at reflux under nitrogen for 6 h. The resulting brown solution '~
~2~)S46~
was added to a mixture of concentrated hydrochloric acid (50 ml~ ~ater (250 ml) and ethyl acetate (50 ml).
The products were further extracted with ethyl acetate, then the acid products were back-extracted into 5% sodium carbonate solution. The aqueous ; phase was acidified with 6N-hydrochloric acid (50 ml) and extracted with ethyl acetate. The extracts were washed with N-hydrochloric acid and water, dried and evaporated to a buff solid. This was recrystallized from ethyl acetate to give pale buff crystals (0.418 g) of the title 17B-carbothioic acid.
The analytical sample was obtained after two recrystallizations from ethyl acetate as white crystals, m.p. 136-139, [~]D ~30 (c 0.56).
Preparation II
S-Iodomet~yl 6~,9~-difluoro-11~ hydroxy-16~-methyl-3-oxo-17~-propionyloxyandrosta-1,4-diene-17B-carbothioate (II~
A~solution of the compound of Example 1 (hereinafter disclosed) (303 mg) and sodium iodide (1~200 9) in acetone (30 ml) was stirred and heated under reflux for 5 h~ Ethyl acetate (75 ml) was then added and the solution was washed successively with wa~er, 10% sodium thiosulphate solution, 5%
sodium hydrogen carbonate solution and water, dried and evaporated to give an off white foam (525 mg).
P~loc~ in chloroform-acetone ~6:1) gave an off- -~white foam which was crystallized twice from acetone without being heated above room temperature to give colourless crystals of the title S-iodomethyl ester (317 mg). The product was used directly for the preparation of the corresponding fluoromethyl 17B-carbothioate as described in Example 2.
Preparation III
S-Chloromethyl 6~,9~-difluoro 16-methyl-3-oxo-~, 17~-pro~ionyloxy-11~-trifluoroacetoxyandrosta-1,4-diene-17~-carbothioate (III) -- ~2~15~4 A solution of the compound of Example 1 (hereinafter disclosed) ~1~0 mg) in dry tetrahydrofuran (2 m~ and pyridine (O.lml) was treated wi~h trifluoroacetic anhydride (0.05 ml) and the mixture was kept at room temperature for 0.5 h. The reaction mixture was poured into water and the product was extracted with ethyl acetate (3x). The organic extracts were washed with water, dried and evaporated to give the homogen~ous title trifluoroacetate (116 mg) according to H nmr spec~roscopy (singlet at 8.59l, l9-protons, in deuterio-chloroform) and t.l.c. on silica (acetone-petrol, b.p.
40-60C, 1:3) An analytical sample from e~her-pentane had m.p. 158-162, [~]D +56 (c 0.23).
Preparation IV
6a,9a-Difluoro-11~,17a-dihydroxy-16a-methyl-3-oxoandrosta-15 1,4-diene-17~-carbothioic acid (IV) A solution of 6,9a-difluoro~ ,17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17~-carboxylic acid (12.0 g) in dry dimethylformamide (250 ml) was stirred and treated with N,~'-carbonyldiimidazole (9.94 g) under nitrogen a~
20 room t~mperature. After 4 h, hydrogen sulphide was passed through the solution for O.S h and the mixture was kept for a further 0.5 h. The reaction mixture was poured into 2N-hydrochloric acid (500 ml) containing ice (ca 250 g). The resulting precipitate was collected, washed with water and 25 dried ln vacuo to give the title thioacid as a white solid (11.47 g), m.pO 230 - 232, [a]D +94 (c 0.91).
Preparation V
,.", _ 6a,9-Difluoro-ll~-hydroxy-16a-methyl-3-oxo-17a-propionyloxy-androsta l,4-diene-17~-carbothioic acid (V) A solution of IY (5.0 g~ and triethylamine (6.15 ml) in dichloromethane (140 ml) was cooled with ice--salt and treated dropwise with propionyl chloride (4.74 ml). The reaction mixture was stirred further at ca 0C for 0.75 h
2~6~
then washed successively with 2N~sodium carbonate, water 2N-hydrochloric acid, water and brine. After being dried~
solvent was removed to give a white solld (6.35 g~. This was redissolved in acetone (120 ml~ and diethylamine (12O5 5 ml): a~ter being stirred at room temperature for 1 h the volume was reduced to _ 75 ml. The solution was poured into 2N-hydrochloric acid (200 ml) containing ice (ca 300g) and the resulting precipitate was collected, washed with water and dried in ~acuo to a white solid (5.17 g) m.p. 152-10 155. Recrystallisation of a portion (400 mg) from ethylacetate gave the analytically pure title thioacid 17a-proplonate ascolourless crystals (290 mg), m.p. 161 - 164, [~D -27 (c 0.95), whose solid-sta~e infrared spectrum (in Nujol~ showed a different crystalline form from the 15 sample obtained in Preparation II.
Example S-Chloromethyl ~a,9a-difluoro-11~-hydro.Yy-16a-methyl-
then washed successively with 2N~sodium carbonate, water 2N-hydrochloric acid, water and brine. After being dried~
solvent was removed to give a white solld (6.35 g~. This was redissolved in acetone (120 ml~ and diethylamine (12O5 5 ml): a~ter being stirred at room temperature for 1 h the volume was reduced to _ 75 ml. The solution was poured into 2N-hydrochloric acid (200 ml) containing ice (ca 300g) and the resulting precipitate was collected, washed with water and dried in ~acuo to a white solid (5.17 g) m.p. 152-10 155. Recrystallisation of a portion (400 mg) from ethylacetate gave the analytically pure title thioacid 17a-proplonate ascolourless crystals (290 mg), m.p. 161 - 164, [~D -27 (c 0.95), whose solid-sta~e infrared spectrum (in Nujol~ showed a different crystalline form from the 15 sample obtained in Preparation II.
Example S-Chloromethyl ~a,9a-difluoro-11~-hydro.Yy-16a-methyl-
3-oxo-17-proplonylo~vandrosta-l~4-diene-l7~-carb thioate A sol~ltion of I (0.546 g) in dimethylacetamide (3 ml) was treated with sodi~n hydrogen carbonate (202 mg) and bromochloromethane (0.16 ml) at 22 for 3 h. The mixture was treated with 2N hydrochloric acid (50 ml) and the product was extracted with ethyl acetate. The ~5 extracts were combined and washed successively with 2N
hydrochloric acid, water, saturated brine, dried and the solvent was removed. Two crystallisations from ethyl acetate gave the title chloromethyl thiolester (0.404 g)~ m.p. 272 - 275, [a]D +49 (_ 0.35).
2~
Exam~le 2 S-Fluoromethyl 6~,9~-Difluoro~ -hydroxy-16~-methyl-17~-propionyloxy-3-oxoandrosta-1,4-diene-17B-carbothioate A solution of II (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, then dried. The solvent wsa remove and the residue was subjected to p.l.c.
in chloroform then chloroform-acetone (19 1)~ The product was eluted with ethyl acetate and crystallised on concentration of the solution to give the title fluoromethyl thiolester (0.075 9) m p. 272-273 (dec), 15 [~]D ~30 (c 0.35).
Example 3 I S-chloromethyl 6~,9~-difluoro-11~-hydroxY-16~0-methyl 3-oxo-17~-propionyloxYandrosta-1,4-diene-17B-carbothioate A solution of III (29 mg) in methanol (2 ml) was kept at room temperature for 3 h. The mixture was evaporated to dryness to give the title ll~-alcohol (25 mg) identified by comparison of its lH nmr spectrum (in deuteriodimethylsulphoxide) and t.l.c. properties 25 (silica, acetone-petrol b.p. 40-60C, 1~3) with those of an authentic specimen.
s~
The active androstane compounds may advantageously be formulated in conventional manner into preparations suitable for topical administration with the aid of a topical vehicle therefor. By topical administration as used herein, we include administration by insufflation and inhalation.
The foregoing formulations for topical application to the skin may be used for the treatment of inflammatory dermatoses of humans and animals, for example ecæema, which are normally responsive to corticosteroid therapy, and also of less responsive conditions such as psoriasis in humans~
For internal administration the new compounds according to the invention may, for example, be formulated in conventional manner for oral, parenteral or rectal administration.
hydrochloric acid, water, saturated brine, dried and the solvent was removed. Two crystallisations from ethyl acetate gave the title chloromethyl thiolester (0.404 g)~ m.p. 272 - 275, [a]D +49 (_ 0.35).
2~
Exam~le 2 S-Fluoromethyl 6~,9~-Difluoro~ -hydroxy-16~-methyl-17~-propionyloxy-3-oxoandrosta-1,4-diene-17B-carbothioate A solution of II (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, then dried. The solvent wsa remove and the residue was subjected to p.l.c.
in chloroform then chloroform-acetone (19 1)~ The product was eluted with ethyl acetate and crystallised on concentration of the solution to give the title fluoromethyl thiolester (0.075 9) m p. 272-273 (dec), 15 [~]D ~30 (c 0.35).
Example 3 I S-chloromethyl 6~,9~-difluoro-11~-hydroxY-16~0-methyl 3-oxo-17~-propionyloxYandrosta-1,4-diene-17B-carbothioate A solution of III (29 mg) in methanol (2 ml) was kept at room temperature for 3 h. The mixture was evaporated to dryness to give the title ll~-alcohol (25 mg) identified by comparison of its lH nmr spectrum (in deuteriodimethylsulphoxide) and t.l.c. properties 25 (silica, acetone-petrol b.p. 40-60C, 1~3) with those of an authentic specimen.
s~
The active androstane compounds may advantageously be formulated in conventional manner into preparations suitable for topical administration with the aid of a topical vehicle therefor. By topical administration as used herein, we include administration by insufflation and inhalation.
The foregoing formulations for topical application to the skin may be used for the treatment of inflammatory dermatoses of humans and animals, for example ecæema, which are normally responsive to corticosteroid therapy, and also of less responsive conditions such as psoriasis in humans~
For internal administration the new compounds according to the invention may, for example, be formulated in conventional manner for oral, parenteral or rectal administration.
Claims (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of compounds of the formula:-(1 ) wherein R1 represents a fluoromethyl or chloromethyl group;
in which process (a) a compound corresponding to formula I but containing either a free 17?-carbothioic acid group (or functionally equivalent group) or a free 17.alpha.-hydroxy group, any other reactive groups present optionally being in protected form, is subjected to esterification;
(b) a compound corresponding to formula I but containing a 17?-substituent of formula -COSCH2Y (wherein Y
represents a displaceable substituent) is reacted with a compound serving to replace the qroup Y by a fluorine or chlorine atom, whereby a compound of formula I is formed:
(c) a compound corresponding to formula I but carrying an 11-oxo group is subjected to reduction to form the required 11?-hydroxy androstane;
(d) a compound corresponding to formula I but carrying a protected 11?-hydroxy group is subjected to deprotection;
(e) a compound corresponding to formula I but having a 9,11-double bond (and no substituent in the 11-position) is reacted with one or more reagents serving to introduce the required 9.alpha.-halo-11?-hydroxy grouping.
in which process (a) a compound corresponding to formula I but containing either a free 17?-carbothioic acid group (or functionally equivalent group) or a free 17.alpha.-hydroxy group, any other reactive groups present optionally being in protected form, is subjected to esterification;
(b) a compound corresponding to formula I but containing a 17?-substituent of formula -COSCH2Y (wherein Y
represents a displaceable substituent) is reacted with a compound serving to replace the qroup Y by a fluorine or chlorine atom, whereby a compound of formula I is formed:
(c) a compound corresponding to formula I but carrying an 11-oxo group is subjected to reduction to form the required 11?-hydroxy androstane;
(d) a compound corresponding to formula I but carrying a protected 11?-hydroxy group is subjected to deprotection;
(e) a compound corresponding to formula I but having a 9,11-double bond (and no substituent in the 11-position) is reacted with one or more reagents serving to introduce the required 9.alpha.-halo-11?-hydroxy grouping.
2. A process as claimed in claim 1(b) wherein S-iodomethyl 6.alpha.,9.alpha.-difluoro-11?-hydroxy-16.alpha.-methyl-3-oxo-17.alpha.-propionyl-oxyandrosta-1,4-diene-17.beta.-carbothioate is reacted with a compound serving to replace the iodine atom of the S-iodomethyl group by a fluorine atom whereby S-fluoromethyl 6.alpha.,9.alpha.-difluoro-11?-hydroxy-16.alpha.-methyl-3-oxo-17.alpha.-propionyl-oxyandrosta-1,4-diene-17.beta.-carbothioate is formed.
3. A process as claimed in claim 1(a) wherein 6.alpha.,9.alpha.-difluoro-11?-hydroxy-16.alpha.-methyl-3-oxo-17.alpha.-propionyloxyandrosta-1,4-diene-17.beta.-carbothioic acid is esterified to yield the corresponding S-chloromethyl 17.beta.-carbothioate.
4. A process as claimed in claim 1(d) wherein S-chloro-methyl 6.alpha.,9.alpha.-difluoro-16.alpha.-methyl-3-oxo-17.beta.-propionyloxy-11?-trifluoroacetoxyandrosta-1,4-diene-17?-carbothioate is subjected to deprotection to yield S-chloromethyl 6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alpha.-propionyloxyandrosta-1,4-diene-17?-carbothioate.
5. A compound of formula I as defined in claim 1 when prepared by a process of claim 1 or by an obvious chemical equivalent thereof.
6. S-Fluoromethyl 6.alpha.,9.alpha.-difluoro-11?-hydroxy-l6.alpha.-methyl-3-oxo-17?-propionyloxyandrosta-1,4-diene-17?-carbothioate when prepared by a process of claim 2 or by an obvious chemical equivalent thereof.
7. S-Chloromethyl 6.alpha.,9.alpha.-difluoro-11?-hydroxy-16.alpha.-methyl-3-oxo-17.alpha.-propionyloxyandrosta-l-4-diene-177?-carbothioate when prepared by a process of claim 3 or by an obvious chemical equivalent thereof.
8. S-Chloromethyl 6.alpha.,9.alpha.-difluoro-11?-hydroxy-16.alpha.-methyl-3-oxo-17.alpha.-propionyloxyandrosta-1l?-diene-17.beta.-carbothioate when prepared by a process of claim 4 or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000476250A CA1205464A (en) | 1980-02-15 | 1985-03-11 | Androstane carbothioates |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8005174 | 1980-02-15 | ||
| GB8005174 | 1980-02-15 | ||
| CA000370853A CA1201114A (en) | 1980-02-15 | 1981-02-13 | Androstane carbothioates |
| CA000476250A CA1205464A (en) | 1980-02-15 | 1985-03-11 | Androstane carbothioates |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000370853A Division CA1201114A (en) | 1980-02-15 | 1981-02-13 | Androstane carbothioates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1205464A true CA1205464A (en) | 1986-06-03 |
Family
ID=25669258
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000476250A Expired CA1205464A (en) | 1980-02-15 | 1985-03-11 | Androstane carbothioates |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1205464A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1911741A1 (en) * | 2005-07-26 | 2008-04-16 | Shanghai Aurisco International Trading Co., Ltd. | Method for the preparation of fluticasone propionate |
-
1985
- 1985-03-11 CA CA000476250A patent/CA1205464A/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1911741A1 (en) * | 2005-07-26 | 2008-04-16 | Shanghai Aurisco International Trading Co., Ltd. | Method for the preparation of fluticasone propionate |
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