IE41663B1 - Alkyl and haloalkyl androst-4-ene and androsta-1,4-diene17-carboxylates - Google Patents

Abstract

Steroids with antiinflammatory activity and the formula I in which R' is methyl, ethyl, n-propyl or isopropyl; R'' is methyl, chloromethyl, fluoromethyl, bromomethyl, iodomethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl or 2-iodoethyl; X is hydrogen or fluorine; and @ is a single or double bond are prepared by esterifying or transesterifying, respectively, with an agent supplying the radical R'' or the radical R', respectively, a corresponding 17 alpha -acyloxy-17ss-carboxylic acid or a functional derivative thereof or a 17 alpha -hydroxy-17ss-carboxylate. Resulting DELTA <1>-steroids of the formula I can subsequently be reduced to the corresponding saturated compounds or resulting 1,2-saturated compounds can be dehydrogenated to the corresponding DELTA <1> compounds. In addition, halogen substituents present in the group R'' can be replaced by other halogens; thus, for example, compounds of the formula I in which R'' is an alkyl group substituted by chlorine, bromine or iodine can be converted by this exchange reaction to the corresponding fluoroalkyl compounds. The compounds of the formula I are distinguished by very good antiinflammatory activity and can be converted into pharmaceuticals for topical or internal administration.

Description

The present invention relates to novel antiinflammatory steroids of the androstane series.

U.S, Patent No, 3,636,010 broadly discloses a class of androstane steroids having the general formula OH F (wherein R^ represents either a β-hydroxy group together with a hydrogen atom,or an oxo group, represents a hydrogen atom or a free or esterified hydroxy group and -— represents a single or double bond) together with carboxylic acid metal salts and esters thereof. These steroids are described in the Patent as having a pronounced anti-inflammatory action as well as a strong thymolytic action after systemic administration. The said Patent 1 4 suggests that Δ ’ -16a-methyl-6a,9a-difluoro-lip,17a15 dihydroxy-3-oxo-androstadiene-17p-carboxylic acid methyl ester is the preferred compound according to the invention on account of its good anti-inflammatory activity. It should be noted that this compound is a 17a-hydroxy compound - 2 41663 and that the remaining compounds specifically described in the Patent (including the Examples) likewise possess a free hydroxy group in the 17«-posltion. Indeed, the Patent does not specifically describe any androstane compounds of the above general formula having an esterified hydroxy group in the 17a-position.

We have now discovered that a narrow class of new androstane compounds, some of which fall within the scope of the above general formula, having certain ester groups (as hereinafter defined) in the I7cc-position, possess greatly superior anti-inflammatory activities, particularly on topical application, to those of the 17«hydroxy compounds disclosed in the above Patent. We have further discovered that the new class of androstane compounds referred to above possess, in general, a good ratio of topical anti-inflammatory activity to undesired glucocorticoid activity as measured for example in the thymus involution test on the mouse.

The new class of androstane compounds can be represented by the general formula 416 6 3 preferably a fluorine atom, wherein X represents a hydrogen or fluorine atom,/R represents a methyl, ethyl, n-propyl or iso-propyl group, R represents a methyl, chioromethyl, fluoromethyl, bromomethyl or 2-fluoroethyl group and —.Υ represents a single or double bond. In the above general formula I, R' preferably represents an ethyl group. R preferably represents a methyl, chioromethyl or fluoromethyl group.

Preferred compounds according to the present invention on account of their high topical anti-inflammatory activity are methyl 6a,9a-difluoro-110-hydroxy-16a methyl-3-oxo-17a-propionyloxyandrosta-l,4diene-170-carboxylate and fluoromethyl 6a, 9a-difluoro110-hydroxy-160-methyl-3-oxo-17a-propionyloxy-androst4-ene-170-carboxylate.

The new compounds described above may .be prepared in a number of ways, for example from appropriate 6a-fluoro compounds or by the introduction of a fluorine substituent into corresponding 6-unsubstituted compounds.

Thus, for example, the new compounds may be prepared by esterifying a corresponding 17a-acyloxy 170-carboxylic acid (or functional equivalent thereof) or - 4 41663 by acylating a corresponding /17a-hydroxy 17p-carboxylate to produce the desired compound. Thus, the parent 17a-acyloxy-173-carboxylic acid of compounds of formula I may be esterified, to provide 17p-carboxylate esters according to the invention.

For example, in order to prepare a methyl ester the 17βcarboxylic acid may be reacted with diazomethane, the J reaction being preferably effected in a solvent medium, eg ether, tetrahydrofuran or methanol, and at a low temperature, preferably at -5 to +30°C. Alternatively, the 173-carboxylic acid may be reacted with 0-methyl N,N '-dicyclohexyl-isourea, preferably in an aprotic solvent such as ethyl acetate, and advantageously at a temperature of 25-100°C. Alternatively, a salt of the parent 17βcarboxylic acid,for example an alkali metal e.g. lithium, sodium or potassium, salt or a quaternary ammonium, e g. triethy^^ammonium or tetrabutyl^ammonium, salt may be a reacted with/methylating agent, for example, a methyl halide e.g. the iodide, or a sulphonyloxy compound including dimethylsulphate, preferably in a polar solvent medium such as a ketone, e.g. acetone or methylethyl ketone or an amide solvent e.g. dimethylformamide or hexamethylphosphoramide conveniently at a temperature in the range 15 - 100°C.

For the preparation of those compounds of formula I wherein R represents a chloromethyl, fluoromethyl, bromomethyl or 2-fluoroethyl group, the esterification of the 17β-carboxyl group can be carried out in an analogous manner to that described above for the preparation of the methyl ester. Thus, for example, such esters may be prepared by reacting a salt of the parent 17p-carboxylic acid with a compound R Y where Y is an appropriate displaceable substituent e.g. a halogen atom, preferably iodine. This method is particularly applicable to the preparation of those compounds of formula I wherein R represents a chloromethyl group, the said halo compound in this case being iodochloromethane. The salt of the parent 17p-carboxylic acid employed in this process may be one specifically mentioned above in relation to the preparation of the methyl 17β-carboxylate compounds of the invention.

Alternatively, the parent 17a-hydroxy-17p-carboxylates corresponding to compounds of formula I may be subjected 2θ t0 acylation of the 17α-hydroxyl group; such 17 ahydroxy-17p-carboxylates may be prepared by esterifying the corresponding 17a-hydroxy-17$-9arboxylic acids by the methods described above. -6-41663 The acylation of the 17oc-hydroxy group in the preparation of the new androstance compounds may, if desired, be effected by conventional techniques, e.g. by reacting the parent 17a-hydroxy compound with a mixed anhydride of the required carboxylic acid, which may, for example, be generated in situ by reacting the carboxylic acid with an appropriate anhydride such as trifluoroacetic anhydride, preferably in the presence of an acid catalyst, e.g. p-toluene-sulphonic acid or sulphosalicylic acid. Alterna10 tively, the mixed anhydride may be generated in situ by reaction of a symmetrical anhydride of the required 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, the reaction being conveniently effected at a temperature of 20-100°C.

Alternatively, the 17a-hydroxy group may be acylated by reaction of the parent 17a-hydroxy compound with the - 7 41663 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 (Registered Trade Hark) exchange resin, e.g. Amberlite/IR 120, the reaction being conveniently effected at a temperature of 25 to 100°C.

For the preparation of the 17 a- acyl oxy- 17βcarboxylic acids which may be employed in the preparation of the compounds according to the invention, it is often preferred to treat the parent 17a-hydroxy 17p-carboxylic acid with the appropriate carboxylic acid anhydride, if desired in the presence of a base such as potassium carbonate. Any mixed anhydride formed may be solvolysed under acidic (e.g. aqueous acetic acid) or basic (e.g. aqueous pyridine or diethylamine/acetone) conditions. Alternatively, the parent 17a-hydroxy 17n-carboxylic acid may be treated with the appropriate carboxylic acid chloride, preferably in a solvent such as an halogenated hydrocarbon e.g. methylene chloride, and advantageously in the presence of a base such as triethylamine, preferably at a low temperature e.g. O'’C.

Those compounds.of formula I wherein R** represents a chloromethyl, fluoromethyl, bromomethyl or 2-fluoroethyl group may also be prepared by reacting a compound of formula - 8 41663 » F (wherein X, R' and— are as defined above, n is 1 or 2 and Y represents a displaceable substituent) with a compound serving to replace the group Y by a fluorine, chlorine or bromine atom when n is 1 or by a fluorine atom when n is 2.

Y may thus, for example, be a chlorine,, bromine or iodine atom.

In accordance with the last-mentioned process fluoromethyl or 2-fluoroethyl 17f-carboxylate compounds of formula I may be prepared from the corresponding chloro-, bromo or iodo-methyl or -ethyl compounds by reaction with an appropriate fluoride, e.g. silver monofluoride or silver difluoride, conveniently in a solvent, for example acetonitrile.

The new 2-£luoroethyl 17^-carboxylate compounds of formula 1 can also be prepared from a corresponding sulphonyloxyethyl, e.g. mesyloxyethyl, compound of formula II by reaction with an appropriate alkali metal, alkaline earth metal or quaternary ammonium fluoride conveniently in a solvent medium, e.g. acetone, dimethyl formamide, hexamethylphosphoramide or ethanol. The sulphonyloxy ethyl compound may be prepared from a corresponding 2-hydroxyethyl compound produced, for example, by reaction of a 17?-carboxylic acid salt with an appropriate halohydrin.

The compounds of general formula II as well as the parent 17p-carboxylic acids referred to above may be prepared for example in accordance with the general procedures described in Belgian Patents Nos. 778285 and 802481.

The Δ compounds according to the invention can conveniently be prepared by partial reduction of the cor1 4 responding Δ ’ compound, for example, by hydrogenation using a palladium catalyst, conveniently in a solvent e.g. ethyl acetate or by homogeneous hydrogenation using for example tris(triphenylphosphine)rhodium chloride, conveniently in a solvent such as benzene, or by exchange hydrogenation using for example cyclohexene in the presence of a palladium catalyst in a solvent 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.

Compounds of formula I (wherein -....-. represents a double bond) may be prepared by dehydrogenating a corresp5fidTng'compound of formula I wherein —— represents a single bond, generally under neutral or mildly acidic conditions e.g. using dichlorodicyanoquinone or civloranil. Suitable solvents for this reaction include hydrocarbon solvents, e.g; benzene esters e.g. ethyl acetate, and ether solvents, e.g. dioxan. - 10 41663 .

The new compounds can also be prepared, as indicated above, from the corresponding 6-unsubstitiited compounds, e.g. by preparation of a corresponding 3-enol ester or ether followed by reaction with an electrophilic fluorinating agent such as perchloryl fluoride and subsequent hydrolysis to yield the corresponding δβ-fluoro compound.' Where no 1,2-double bond is present, treatment with a strong acid such as hydrogen chloride or more preferably hydrogen bromide effects epimerisation to form the desired δα-fluoro compound. io The epimerisation is preferably effected in a non-aqueous solvent medium,dioxan being particularly preferred; other solvents which may be used include tetrahydrofuran, ester solvents such as ethyl acetate, ketone solvents and amide solvents such as dimethylacetamide of dimethylformamide.

The·epimerisation is also advantageously effected in the presence of a carboxylic acid such as acetic acid, especially when hydrogen bromide employed. In the case of Δ ’ -compounds, It is.necessary to hydrogenate the 1,2-double bond, e.g. by catalytic hydrogenation, effect the epimerisation and re-introduce the 1,2-double bond by dehydrogenation» e.g. as described above. . . · As is well known to those skilled in the art it may frequently be convenient to elaborate the desired substituents in the 17a- and 17β- positions at an intermediate stage of the preparation of the aesired final compound, one or more other substituents (or unsaturation) being introduced at a later stage. Instances where the desired substituents may be introduced before final elaboration of the remainder of the desired androstane molecule include for example preparing Δ^^ or Ring A saturated compounds having the desired 17a-acyloxy and 17p-carboxylate ester groups, completion of the elaboration of Rings A, B and C then being effected in conventional manner. - 11 41663 There are also provided pharmaceutical compositions for use in anti-inflammatory therapy, comprising at least one androstane compound of formula I (as defined above), together with one or more pharmaceutical carriers or excipients. Such compositions may be in forms adapted for topical or internal administration.

The active androstane cornpoundsmay be formulated into preparations suitable for topical administration with the aid of a topical vehicle therefor. Example of various types of preparation for topical administration include ointments, lotions, creams, powders, drops, (e.g. eye or ear drops), sprays, (e.g. for the nose or throat), suppositories, retention enemas, chewable or suckable tablets or pellets (e.g. for the treatment of aphthous ulcers) and aerosols.

Ointments and creams may,for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents and/or glycols. Such a base may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a glycolic solvent such as propylene glycol or 1,3-butane-diol. Thickening agents which may be used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, woolfat, hydrogenated lanolin and beeswax and/or glyceryl monostearate and/or non-ionic emulsifying agents.

The solubility of the steroid in the ointment or cream may be enhanced by incorporation of an aromatic alcohol such as benzyl alcohol, phenylethyl alcohol or phenoxyethyl alcohol.

Lotions may be formulated with an aqueous or oily base and will in general also include one or more of the following namely, emulsifying agents, dispersing agents, suspending agents, thickening agents, colouring agents, perfumes and solvents.

IQ Powders may be formed with the aid of any suitable powder base e.g. talc, lactose or starch. Drops may be formulated with an aqueous base also comprising one or more dispersing agents, suspending agents or solubilising agents etc.

Spray compositions may for example be formulated as aerosols with the use of a suitable propellant, e.g. dichlorodifluoromethane or trichlorofluoromethane.

The proportion of active androstane compound in the topical compositions according to the invention depends on the precise type of formulations to be prepared but will generally be within the range of from 0.0001 to 5.0% by weight. Generally however for most types of preparations ·· -.. advantageously the proportion used will be within the range of from 0.001 to 0.5% and preferably 0.01 to 0.25%.

Topical preparations may be administered by one or more applications per day to the affected area; over skin areas occlusive dressings may often be used with advantage.

For internal administration the new compounds according to the invention may, for example, be formulated for oral, parenteral or rectal administration. For oral administration syrups, elixirs, powders and granules may be used which may be formulated in conventional manner. Dosage unit forms are however preferred as described below.

For parenteral administration the compounds may be presented in sterile aqueous or oily vehicles, suitable oily vehicles including arachis oil and olive oil.

Preferred forms of preparations for internal administration are dosage unit forms i.e. presentations in unitary form in which, each unit contains a desired dose of the active steroid. Such dosage unit forms contain from 0.05 to 2.0 mg, preferably from 0. 25 to 1.0 mg, of the active steroid. For oral administration suitable dosage unit forms include tablets, coated tablets and capsules. For parenteral administration dosage unit forms include sealed ampoules or vials each containing a desired dose of the steroid. Suppositories, which may be prepared for example with conventional commercial suppository bases, provide a dosage unit form for rectal administration. Sterile tablets Or pellet implants may also be used, e.g. where slow systemic absorption is desired.

The compounds according to the invention may in general be given by internal administration in cases where systemic adreno-cortical therapy is indicated.

In general terms preparations for internal administration may contain from 0.01 to 5.0% of active ingredient depending upon the type of preparation involved. The daily dose may vary from 0.5 to 10.0 mg. dependent on the condition being treated and the duration of treatment desired.

The compositions according to the invention may also include one or more preservatives or bacteriostatic agents e.g. methyl hydroxy benzoate , propyl hydroxy benzoate, chlorocresol or benzalkonium chlorides. The compositions according to the invention may also contain other active ingredients such as antimicrobial agents, particularly antibiotics such as neomycin.

The following Examples illustrate the present invention. In the Examples (and also the Preparations), the ultra viclet spectra are in ethanol. Melting points were determined on a Kofler block, and are uncorrected. Preparative thin layer chromatography (P.L.C.) was carried out on silica; following P.L.C., products were isolated by elution with ethyl acetate. Example l Methyl 6α, 9q - difluoro - llg-hydroxy-lStt-methyl-d-oxo-iygpropionyloxyandrosta -1,4-diene-17p-carboxylate.

A suspension of methyl 6α,9a - difluoro- 11β, 17αdihydroxy-16a-methyl-3-oxoandrosta-l,4-diene-17p-carboxylate (394 ing.) in propionic acid (3.9 ml.) was treated, at room temperature, with trifluoroacetic anhydride (0.78 ml.) and toluene p-sulphonic acid (0.08 ml. of a dry chloroform solution concentration 0.12g. per ml.). The resulting solution was stirred at 75-80¾for 30 mins., then added slowly to a stirred solution of 3% aqueous sodium bicarbonate (ca.250ml). The product was extracted into ethyl acetate, The extract was washed with saturated aqueous sodium bicarbonate solution, and water, dried over magnesium sulphate, and evaporated in vacuo to give an off-white solid (466 mg.) which was purified by preparative thin layer chromatography (on silica, develop16 ing the plates three-times in chloroform). A portion (156mg.) of the total purified material (356 mg.) was reerystallised twice from methanol to give the title compound (119 mg.) as white hexagonal plates, m.p. 267-269 J D — max Example 2 Chloromethyl 6a,9a-difluoro-ll|3-hydroxy-16fi-methyl-3-oxo17g-propionyloxyandrost-4-ene-17g-carboxylate (a) A solution of 6g,9a-difluoro-llp,17,21-trihydroxy10 16f3-methylpregn-4-ene-3,20-dione (0.848g.) in tetrahydrofuran (10ml) was treated with a solution of periodic acid (0.682g., Η^ΙΟθ) in water (3ml.). After stirring for two hours, water (10ml.) was added and the solution concentrated in vacuo. Water (40ml.) was added and the product (an oil) was extracted into ethyl acetate. The combined extracts were washed with water, dried and evaporated to give 6a,9a-difluoro-ΙΙβ,17a-dihydroxy-16β-methyl-3-oxoandrost4-ene-17β-carboxylic acid as a foam [0,866g, (ethyl acetate solvate, ca 1 mole)], (b) A stirred suspension of 6a,9a-difluoro-llp,17adihydroxy-16β-methyl-3-oxoandros t-4-ena-17 β-carboxylic acid [0.828g., (ca. 1 mole, ethyl acetate solvate)] in dry, redistilled dichloromethane (22ml.) was cooled to 0uC. and treated with redistilled triethylamine (0.96ml), then with propionyl chloride (0,63ml.), added dropwise. After stirring at ca. 0°G for 80 minutes, dichloromethane (15ml,) was added, and the solution washed with 3% aqueous sodium bicarbonate, N hydrochloric acid and water, dried (Mg SO^) and evaporated to give the intermediate mixed anhydride as a foam (1.02g). The foam was dissolved in acetone (33ml) and treated with diethylamine (0.75ml), After being stirred for 85 mins, solvent was evaporated, and the residue was dissolved in water (50ml.). The mixture was washed with ethyl acetate. The aqueous phase was acidified with 2N-hydrochloric acid, and the product extracted into ethyl acetate.

The combined extracts were washed with Water, dried and evaporated to give 6a,9a-difluoro-llp-hydroxy-16p-methyl3-oxo-17a-propionyloxyandrost-4-ene-170-carboxylic acid as a solvated (ethyl acetate) foam (0.803g.), λ 234nm (ε 14,990) max (c) A suspension of 6a,9a-difluoro-ll0-hydroxy-160methyl-3-oxo-17a-propionyloxyandrost-4-ene-170-carboxylic acid 41683 (0.754g.) in methanol (4ml,) was treated with 2M sodium hydroxide in methanol (0.9ml) to give a solution of pH 10. Ether (100ml) was added and the mixture was then refrigerated for two hours. The precipitate was collected by filtration, washed well with ether, then dried In vacuo to give the sodium salt (O,379g.) of the above 17p-earboxylic acid. The filtrates were evaporated, triturated with ether (50ml.) and the solid collected by filtration, Washed with ether, and dried in vacuo, giving more of the sodium salt (O.336.g).

The sodium salt (0.714g.) was slowly added to a stirred solution of chloroiodomethane (0.53ml., freshly redistilled b.p. 108°C) in hexamethylphosphoramide (1.8ml.). More hexamethylphosphoramide (1,8ml.) was added, after about half of the sodium salt had been added, due to a sudden gelatinous precipitation. Stirring and steroid addition were continued. After 3 hours', the mixture was diluted with ethyl acetate (100ml) and washed with water 5% aqueous sodium bicarbonate and water, dried and evaporated to a foam (O,713g.). P.L.C. (chloroform-acetone 40:1) gave two products; the major, more polar component was a foam of which (472mg.),/a portion was crystallised twice from acetone to afford the title chloromethyl ester as solvated (acetone) colourless crystals (98mg.), m.p. 183-184°C, (+ 48.4° (c 0.135, dioxan), λ^χ 233nm (ε 16, 570).

Example 3 Fluoromethyl 6g,9o:-difluoro-'llp-hydroxy-16g-methyl-3-oxol7g-propionyloxyandrost-4-ene-17β-carboxylate A solution of chloromethyl 6a,9a-difluoro-llghydroxy-16p-methyl-3-oxO-17a-propionyloxy-androst-4-ene17g-carboxylate (O,368g,) in dry acetonitrile (5.5ml.) was stirred with silver fluoride (0.648g.) in the dark. After seven days, the mixtured was filtered through kieselguhr, which was then washed with ethyl acetate (200ml.). The combined filtrates were washed with water, dried and evaporated to a foam (354mg.). P.L.C. (chloroform) and crystallisation twice from acetone/ether gave the solvated (ether) title compound (177mg.)', m.p. 183-184°C, [α]θ + 57.6° (c 0.11, dioxan), λ 233.5nm (e 15,670).

Example.4 Methyl 6g,9g-difluoro-llg-hvdroxy-168-methyl-3-oxo-17g20 prfflionyloxyandrost-4-ene-17p-carboxylate (a) A solution of 6g,9a-difluoro-llg,17,2l-trihydroxy-16pmethylpregna-l,4-diene-3,20-dione (3..970g.) in tetrahydrofuran (40ml.) was treated with a solution of periodic acid (3.307g., ^ΙίΟθ) in water (10ml,). After being stirred for 1¾ hours, the solution was dilutedwith 5% aqueous sodium bicarbonate solution (100ml.) then concentrated in vacuo to ca. 100ml, The solution was washed with ethyl acetate, then acidified with 2N hydrochloric acid, and stirred for 45 minutes. The product was collected by filtration, washed well with water and dried in vacuo to give 6β,9a-difluoro-ΙΙβ,17a-dihydroxy-16p-methyl-310 oxoandrosta-l,4-diene-17p-carboxylic acid (3.509g.). (b) A stirred solution of 6p,9a-difluoro-llp,17adihydroxy-16p-methyl-3-oxoandrosta-l,4-diene-17p-earboxylic acid (3.443g.) in dry, redistilled dichloromethane (90ml.) and redistilled triethylamine (3.03ml.) was cooled to 0°C and treated with propionyl chloride (1.93ml.). After . stirring at ca. 0°C. for 40 minutes, dichloromethane (60ml.) was added, and the solution washed with 3% aqueous sodium bicarbonate, N-hydrochloric acid and water, dried and evaporated to give the intermediate mixed anhydride as a foam (4.913g, ). The foam, was dissolved in acetone (75ml.) and treated with diethylamine (3.1ml.). After being stirred for 50 minutes, the suspension was concentrated in vacuo and dissolved in water (100ml.), The solution was acidified to pH3 with 2N hydrochloric acid and the product was extracted into ethyl acetate. The combined extracts were Washed with water, dried and evaporated to a foam (4.637g.).

Crystallisation from ethyl acetate gave 6(3,9a-difluoro-liphydroxy-16p-methyl-3-oxo-17a-propionyloxyandrosta-l, 4‘-dieile17p-carboxylic acid (2.553g). A portion (92mg.) was further crystallised from ethyl acetate to give an analytical sample as solvated (ethyl acetate) colourless crystals (89mg), m.p. 171-174l'C, |a]p - 25.4° (c 1.08, dimethylsulphoxide), λ 240nm (ε 16,360). max Further quantities of the 17a-propionyloxy-17pcarboxylic acid were obtained from the evaporated mother liquors, from above, by repeated extractions with 5% aqueous sodium bicarbonate and washing with ethyl acetate, acidification and extraction with ethyl acetate. This was performed twice to give the 6p-fluoro-17a-propiOnyloxy-17pcarboxylic acid (0.800g., and 0.262g.). (c) A solution of 6p,9a-difluoro-lip-hydroxy-16p-methyl20 3-oxo-17 α-propionyloxy-androsta-1,4-diene-17 β-carboxylic acid (2.966g.) in methanol (8ml.) and benzene (200ml.) was treated with tris(triphenylphosphine)rhodium chloride (1.694g.), and stirred with hydrogen gas at room temperature and ’ atmospheric pressure for 93 hours (uptake 262ml) · The solution was concentrated in vacuo to ca. 100ml., diluted with benzene (50ml., as a wash) and extracted with 2N sodium carbonate solution. The combined extracts were washed with benzene (200ml.) then acidified to pH2 with 6N hydrochloric acid, and the products were extracted into ethyl acetate. Combined extracts were washed with water, dried and evaporated to a foam (2.923g,), containing 6p,9a-difluoro10 lip-hydroxy-16p-raethyl-3-oxo-17a-propionyloxy-androst-4-ene17p-carboxylic acid. (d) The above prepared material (2.906g.) was dissolved in, methanol, cooled to 0°C and treated with an excess of ethereal diazomethane. A few drops of acetic acid were added, and the solution was evaporated to .a foam (2.985g.). This was redissolved in ethyl acetate (100ml.) and washed with 5% aqueous sodium bicarbonate and water, dried and evaporated (2.757g.). P.L.C. (chloroformacetone, 20:1) gave three components; the least polar foam ' (1.420g.) was methyl 6p,9a-difluoro-llp-hydroxy-16p-methyl3-oxo-17a-propionyloxyandrost-4-ene-17p-carboxylate. (e) A solution of methyl 6p,9a-difluoro-llp-hydroxy16p-methyl-3-oxo-17a-propionyloxyandrost-4-ene-17p-carboxylate (1.420g.) in dioxan (18ml.) was treated with 50% w/v hydrogen bromide in acetic acid (0.22ml.). After 48 hours, the mixture was added to water (300ml.) and the product extracted into ethyl acetate. The combined extracts were washed with 5% aqueous sodium bicarbonate and water, dried and evaporated to a foam (1.410g.). P.L.C. (chloroformacetone, 14:1) gave two components; the more polar was the title Ga-fluoro ester (0.365g.), the less polar was unchanged 6 β-fluoro ester (0.974g.).

The latter material was redissolved in dioxan (12ml.) and treated with 50% w/v hydrogen bromide in acetic acid (0.15ml.). After 66 hours a similar isolation of product, followed by P.L.C. (chloroform-acetone, 16:1) gave two components; the more polar was the title 6a-fluoro ester (O.557g.).

The two batches (0.365g. and 0.557g) were combined and crystallised twice from methanol to give the analytical sample (0.423g.), m.p. 195-197°C, [a]D + 44° (c 0.17, dioxan), λ 233.5nm (ε 15,730). ’ max · ’ Example 5 Methyl 6g,9tt-dlfluoro-llg-hydroxy-lSg-methyl-S-oxo-lla:propionyloxyandros ta-1,4-diene-17 0-carboxylate A solution of methyl 6a,9a-difluoro-llp-hydroxy5 16|3-methyl-3-oxo-17a-propionyloxyandrost-4-ene-l7p-carboxylate (O,657g.) and 2,3-dichloro-5,6-dicyanobenzoquinone (O'.546g.) in benzene (50ml) was heated under reflux for 7 days. The solvent was evaporated, and the mixture was purified by P.L.C. (chloroform/acetone, 20:1), The major steroid product was a foam (0.413g.). Crystallisation (3x) from methanol gave the title compound (O.273g.) m.p. 236-238°C. i αίθ + 31.6° (c 0.1 dioxan), 237,5nm (ε 16,200).

Preparation 1 21-Acetoxy-3-benzoyloxy-9a-fluoro-11β,17a-dihydroxy-160-methyl pregna-1,3,5-trien-20-one.

Redistilled benzoyl chloride (340 ml.) was added to a solution of betamethasone acetate (134 g.) in pyridine (550 ml.), cooled in an ice-bath, and the mixture was then heated at 50°, in a thermostatically controlled bath, for 2 hr. The cooled suspension was poured into an excess of saturated aqueous sodium hydrogen carbonate and the product was extracted into ethyl acetate. The extract was washed with , 2N-hydrochloric acid, aqueous sodium hydrogen carbonate, and water, and dried (MgSO^). The extract was concentrated in vacuo and the crystals of the enol benzoate which separated (57.9 g.) m.p. 124-126°, [α]β-138ο (c, 1.0 in CHCl^) were collected and washed with ether.

Recrystallisation of a sample of the enol benzoate from benzene - ether gave an analytical sample of the title compound m.p. 124°, [ak- 144° (CHC1-), λ 230nm, (e 20,200) and u J max 309ran (ε 6,880).

Preparation 2 6p-riuorobetamethagone 21-acetate (21-Αοβίοχν-6β,9α-άί11οοΓθllg,17g-dihydroxy-16p-methylpregna-l,4-diene-3,20-dione).

Perchloryl fluoride (ca 25 g., = ca. 14 ml. at -70°) was passed slowly, in a nitrogen stream, into a solution of 21-acetoxy-3-benzoyloxy-9a-fluoro-ΙΙβ.17a-dihydroxy-16p15 methylpregna-1,3,5 - trien-20-one (117 g. ) in pyridine (400 ml., previously distilled from selenium dioxide) kept at 5 The reaction flask was fitted with a cold finger condenser at -70° and the excess of perchloryl fluoride was kept refluxing from the stirred suspension for 1 hr. The excess of reagent was removed with a vigorous stream of nitrogen and the mixture was poured into ice-water and carefully neutralised with hydrochloric acid. The precipitate was collected by filtration and dried at room temperature in air.

Part (90%) of the crude solid was suspended in ethyl acetate (500 ml.) and water (200 ml.) containing sodium metabisulphite (30 g, ) and then acetic acid (15 ml.) was added. The mixture was shaken until all the steroid dissolved and the organic layer was then separated, washed with aqueous sodium hydrogen carbonate and water, and dried (MgSO^). Removal of the solvent in vacuo left a residue, which was partly-dissolved by warm chloroform. After separation of the insoluble material (5,3 g.), the chloroform was evaporated to dryness and the resultant foam was crystallised from ethyl acetate to give ββ-fluorobetamethasone 21-acetate as a solvate (41.3 g.), m.p. 111-112°C, λ max. 239 292^ [ct]D+ 41° (CHCip. After drying at 150° in vacuo it had m.p. 130° and analysed approximately for a solvate with one molecule of ethyl acetate.

Preparation 3 6p,9oi-Dlf luoro-11β,17,21-trihydroxy-16p-methylpregna-1,4-diene3, 20-dione A solution of ββ-fluoro-betamethasone 21-acetate (6.184g,J in methanol (130ml.) and dioxan (130ml.) · was treated with a solution of potassium carbonate (l.651g.) in water (10ml.). The mixture was stirred for 80 mins, acidified to pH 5 with acetic acid, then concentrated in vacuo to ca. 100ml. Water (700ml.) was added, and the mixture stirred in ice for one hour. The solid was collected by filtration washed well with water and dried in vacuo to give the title compound (3.998g.) The following Examples illustrate pharmaceutical compositions according to the invention.

Example A: Water-miscible cream 0.1% w/w 15.0% w/w 7.0% w/w 3.0% w/w 5.0% w/w 0.1% w/w 100 parts by weight Active ingredient Beeswax (White) Cetostearyl alcohol Β.P. C.

Cetomacrogol 1000 Β.P.C.

Liquid paraffin Β.P.

Chlorocresol Distilled water to produce Ball-mill the steroid with a little liquid paraffin until the particle size is reduced to 95% by number below 5μ. Heat the available water to 100°C, add the chlorocresoi, stir to dissolve and cool to 65°C. Melt together the beeswax, cetostearyl alcohol and cetomacrogol and maintain at 65°C.

Add the steroid suspension using the remaining liquid paraffin for rinsing. Add the steroid oil phase at 60°C to the chlorocresol aqueous phase at 65°C and stir rapidly while the emulsion cools over the gelling point (40-45°C).

Continue to stir at slow speed until the cream sets.

Example B: Oral tablet Active ingredient 0.5 mg. Lactose 175.5 mg. Maize starch (dried) 20.0 mg. Gelatin 2.0 mg. Magnesium stearate 2.0 mg. Tween (Registered Trade Mark) 80 Trace Total weight 200.0 mg.

A suspension of 300 mg. of the active ingredient in >0 2 ml. of water containing 0.1% of Tween 80 is milled for hours in a 10 ml. nylon pot about three quarters filled with steatite balls, until 90% by number of the particles have a diameter of less than 5 microns with none greater than microns. The maize starch and lactose are blended and /ς passed through a 60 mesh B.S. sieve and granulated with a % solution of gelatin containing the suspension of the active ingredient and washings from the nylon pot, by passing through a 16 mesh B.S. sieve. The granules are dried at 40°C overnight, passed through a 20 mesh B.S. sieve and blended with magnesium stearate and tabletted using a tabletting machine having a 5/16 inch flat-bevelled punch.

Claims (5)

1 21, A process for the preparation of compounds of formula I (as defined in claim 1 wherein 7777-77 represents a single bond) which comprises epimerising a·corresponding όβ-fluoro compound. 22. A process as claimed in claim 21 wherein epimerisation is effected with a strong acid. 23. A process as claimed in claim 22 wherein epimersation is effected with hydrogen bromide. 24. A process as claimed in any of claims 21 to 23 wherein the epimerisation is effected in a non-aqueous solvent medium. - 33 41663 25. A process as claimed in any of claims 21 to 24 wherein the δβ-fluoro compound of formula I is prepared by converting a corresponding 6-hydrogen compound into a 3-enol ester or ether thereof which is then treated with 5 an electrophilic fluorinating agent to produce the corresponding δβ-fluoro compound which is then hydrolysed to remove the protective 3-enol ester or ether group. 26. A process for the preparation of compounds of formula 1 (wherein ~“ represents a double bond) which comprises 10 dehydrogenating a corresponding compound of formula I (wherein -- represents a single bond). I 27. A process as claimed in claim 26 wherein dehydrogenation is effected using dichloro-dicyanoquinone or chloranil. 15 28. A process for the preparation of compounds of formula I (as claimed in claim 1) substantially as herein described. 29. A process for the preparation of compounds of formula Ϊ (as claimed in claim 1) substantially as herein described 20 with reference to any of Examples 1 to 5. 30. Compounds of general formula I (as defined in claim 1) whenever prepared by a ρτ-ocess as claimed in any of claims 11 to 29. . 34 31. Ph-Tnnaceutical compositions comprising, as active ingredient^ at least one compound of formula I (as defined I in claim 1) together with at least one pharmaceutical carrier or excipient. 5 32. Compositions as claimed in claim 31 adapted for topical administration. 33. Compositions as claimed in claim 32 in the form of ointments, lotions, creams, powders, drops, sprays, suppositories, retention enemas, chewable or suckable ίθ pellets or aerosols. 34. Compositions as claimed in claim 32 or claim 33 containing 0,0001 to 5% by weight of active ingredient. 35. Compositions as claimed in claim 31 adapted for internal administration. 15 36. Compositions as claimed in claim 35 in the form of dosage units, 37. Compositions as claimed in claim 35 wherein each dosage unit contains 0.05 to 2.0 mg of active ingredient. 38. Compositions as claimed in claim 37 wherein each 20 dosage unit contains 0.25 to 1.0 mg of active ingredient. 39. Compositions as claimed in any of claims 35 to 38 in the form of tablets, coated tablets, capsules, ampoules suppositories or sterile tablets or pellet implants. 40. Pharmaceutical compositions comprising as active 25 ingredient, at least one compound of formula I (as 35 41663 defined ir claim 1) substantially as herein described. 41. Pharmaceutical composition comprising as active ί ingredient, at least one compound of formula I (as defined in claim l) substantially as herein described with / 1 (as defined in claim 1) which comprises esterifying a corresponding 17a-acyloxy 17p-carboxylic acid (or acylating functional equivalent thereof) or/a corresponding 17ahydroxy-17p-carboxylate to produce the desired compound 10 of formula I 12. A process as claimed in claim 11 wherein the said functional equivalent is an alkali metal or quaternary ammonium salt. 13. A process as claimed in claim 11 or claim 12 wherein 15 the salt of the 17β“carboxylic acid is esterified with a compound of formula R Y (wherein R is as defined in claim 1 and Y represents a displaceable substituent). 14. A pioccss as claimed in claim 13' wherein Y represents a halogen atom. 2q 15. A.process as claimed in claim 11 wherein the said corresponding 17a-acyloxy 17p-carboxylic acid is esterified with diazomethane to produce a compound of formula I wherein R represents a methyl group. - 31 41663 16. A process as claimed in claim Π wherein the said correspondingΊ7a-hydroxy-17p-carboxylate is acylated by reaction with an appropriate carboxylic acid or an acid nalide or anhydride thereof. 5 17. A process for the preparation of compounds of formula I (wherein R represents a chloromethyl, fluoro. methyl, bromomethyl or 2-fluoroethyl group) which comprises reacting a| cdmpound of formula 1 ' O-(CH 2 > n Y F , I (wherein X, R and -- are as defined in claim 1, n is 1 or 2 arid Y represents a displaceable substituent) with a compound serving to replace the group Y by a fluorine, chlorine or bromine atom when n is 1 or by a fluorine atom when n is 2. - 32 41663 18. A process as claimed in claim 17 wherein the group Y represents a chlorine, bromine or iodine atom. 19. A process' as claimed in claim 18 which comprises reacting a compound of formula II (wherein Y represents a chlorine, bromine or iodine atom) with a fluoride to produce a compound of foimula I wherein R represents a fluoromethyl or 2-xjiuyroethyl group; 20. A process for the preparation of compounds of formula I (wherein 7777__ represents a single bond) which comprises partially reducing a corresponding compound of formula I (wherein 77777 represents a double bond).

1. Compounds of the general formula 0-R · I F wherein X represents a hydrogen, or fluorine atom, R' represents a methyl, ethyl, n-propyi or iso-propyl group, 5 R represents a methyl, chloromethyl, fluoromethyl, bromomethyl or 2-fluoroethyl group and +-- represents a single or double bond.

2. Compounds as claimed in claim 1 wherein R* represents an ethyl group. 10

3. Compounds as claimed in claim 1 or claim 2 wherein R represents a methyl, chloromethyl or fluoromethyl group.

4. Compounds as claimed in any of the preceding claims wherein X represents a fluorine atom. 5. Compounds as claimed in any of the preceding claims wherein 15 the 16- methyl group is in the a- configuration. 6. Methyl 6a,9a-difluoro-lip-hydroxy-16a-methyl-3-oxo-17apropionyloxyandrosta-1,4-diene-17P-carboxylate. 7. Chloromethyl 6a,9a-difluoro-llp-hydroxy-16p-methyl-3-oxo17a-propionyloxyandrost-4-ene-17p-carboxylate. 20 8. Fluoromethyl 6a,9a-difluoro-lip-hydroxy-16p-methyl-3-oxo17a-propionyloxyandrost-4-ene-17p-carboxylate. - 30 41663 9. Methyl 6a,9a-difluoro-llp-hydroxy-16p-niethyl-3-oxo17a-propionyloxy-androsta-l,4-diene-17p-carboxylate 10. Methyl 6a,9a-difluoro-lip-hydroxy-16p-methyl-3-oxo17a-propioftyloxy-androst-4-ene-17β-carboxylate. 5 ]·). A process for the preparation of compounds of formula

5. Reference to either of Example A and B.