IL38589A - 11beta-hydroxy-17alpha-acyloxy-3-oxo-androst-4-ene-17beta-carboxylic acid esters - Google Patents

Description

This invention is concerned with steroid compounds having anti-inflamrnatory properties.

Since the discovery of cortisone, a wide variety of compounds of analogous structure have been prepared having anti-' inflammatory properties, such compounds being generally members of the pregnane series.

Anti- inflammatory steroids have found wide use in medicine and in latter years considerable attention has been directed to compounds having high anti-inflamrnatory action on topical administration.

Anti- inflamrnatory steroids of the pregnane series so far described, being generally analogous to cortisone^ tend to a greater or lesser extent to exert the physiological action of the natural hormone and thus possess, in addition to antiinflammatory action other actions similar to cortisone- like compounds,. The physiological effects of the pregnane-type anti-inflamrnatory steroids may be broadly classified as glucocorticoid and mineralocorticoid effects, anti-inflamrnatory action at least until recently having been regarded as a glucocorticoid action. Glucocorticoid effects also include general disturbance of the body metabolism and may be very undesirable. Mineralocorticoid effects involve disturbance of the salt and water balance within the body and compounds having marked mineralocorticoid action are thus likely to produce undesirable effects on admin stration.

Even in the topical application of anti- in lammatory steroids, there is a risk that the steroid may be absorbed into the system through the skin, with subsequent development of undesired side effects.

There is thus a general desire' to have available an anti-inflammatory steroid with high antiinflammatory action but with which the undesired effects, either mineralocorticoid or glucocorticoid in nature, are reduced.

German Patent Specification No. 1,964,356 describes a series of 6a-fluoro-androstane compounds having a free or esterified 17 -carboxylic acid group and a free or esterified 17a-hydroxy group, an especially preferred compound being given as methyl ' ^-16a-methyl-6a , 9a-difluoro- 11β , 17a-dihvdroxy- 3-oxo-androstadiene- 176-carboxylate. These compounds are said to be useful as anti-inflammatory agents.

We have now found that certain new steroids of the androstane series, possess particularly advantageous antiinflammatory action, particularly on topical application compared with the preferred compound of the above-described prior German Specification. Moreover our researches indicate that generally the ratio of anti- inflammatory action to undesired cortisone- like action in our new compounds is generally good.

The steroid compounds "vith which the invention is concerned are compounds of the general formula wherein a) X represents a hydrogen, chlorine or fluorine atom; represents a hydroxy group in the β-configuration or (when X represents a chlorine atom) may also represent a chlorine atom in the β-configuration; R represents a hydrogen atom, a methylene group or a methyl group (in either the aj>r R3 represents a hydrogen atom, an al yl group containing 1 to 3 carbon atoms or a phenyl group; R4 represents a Cj ^ alkyl group; a C1 >4 alk l group substituted by either at least one halogen or an alkoxycarbonyl group wherein the alkoxy moiety contains 1 to 4 carbon atoms; or a (^2-4) alk l group substituted by a C2_5 alkanoyloxy group; and -„ ~ represents a single or double bond; or (when X represents a fluorine atom, Rj represents a ^-hydroxy group, 2 represents a (^-methyl group, R3 represents an ethyl group and. represents a double bond) 4 may also represent a 2-hydroxy-ethyl group; provided t R4 Is not propyl , isopropyl or n-butyl unless one or more of X , 2 and j 1s other than hydrogen and/or ^n^ represents a double bond; or b) X represents a chlorine or fluorine atom R cepresents an oxo group; R2 represents a hydrogen atom, a methylene group or a methyl group (in either $he a-or ^configuration) ; R3 represents a methyl or ethyl group; 4 represents a alkyl group; a alkyl group substituted by either at least one halogen atom or an alkoxycarbonyl group wherein the alkoxy moiety contains 1 to 4 carbon atoms; or a (C2^) alkyl group substituted by a C2-5 alkanoyloxy group; and -— represents a single or double bond.

The new androstane compounds have antl -inflammatory action on topical and Internal administration, the antl -Inflammatory activity of the compounds on topical administration being generally high .

In general , the group 3 1n formula 1 1s preferably an alkyl group containing up to 3 carbon atoms. I .e. a 385β9/£ methyl , ethyl , n-propyl or 1so-propyl group. In compounds wherein Rg represents a hydrogen atom R^ preferably represents a methyl group.

The group R^ in formula I is preferably a methyl , ethyl or propyl group.

In regard to the possible substituents of the l ower alkyl group, the halogen atom is preferably a fluorine, chlorine or bromine atom, the C2_5 alkanoyloxy group 1s preferably an acetoxy group and th al koxycarbonyl group is advantageously a methoxycarbonyl group.

General ly compounds of formula I in which Rj represents a β-hydroxy group are preferred. Also 1n general terms , compounds of formula I in which R2 represents a methyl group 1n the β -configuration are preferred on account of their high topical anti-inflammatory activity.

A preferred class of compounds of formul a I having particularly good topical antl -Inflammatory activity with a favourable ratio of topical antl -inflammatory activity to gl ucocorticoid activity are those compounds wherein X represents a chlorine or fluorine atom (preferably a fluorine atom), R^ represents a β-hydroxy group, represents a methyl group (preferably in the β-configuration) , represents a methyl, ethyl or n-propyl group, represents a methyl group and represents a double bond. A further preferred class of compounds of formula I also having good topical anti- inflammatory activity with a favourable ratio of topical anti-inflammatory activity to glucocorticoid activity are those wherein X represents a fluorine or chlorine atom (preferably a fluorine atom) , represents a keto group, R^ represents a methyl group in the β-configuration, R^ represents a methyl or ethyl group, R^ represents a methyl group and represents a double bond.

Yet another preferred class of compounds of formula I having high topical anti-inflammatory activity are those wherein X represents a fluorine or chlorine atom (preferably a fluorine atom), R^ represents a β-hydroxy group, R2 represents a methylene group, R^ represents a methyl, ethyl n-propyl or iso-propyl group, R^ represents a methyl or ethyl group (preferably a methyl group) and Γ7ΓΓΓΓ7 preferably represents a double bond.

A preferred class of Δ compounds of formula I (i.e. compounds wherein represents a single bond) having especially good topical anti-inflammatory activity and ratio ' of topical anti- inflammatory activity to glucocorticoid activity are those wherein X represents a' fluorine or chlorine atom (preferably a fluorine atom), represents a β-hydroxy group, represents a methyl group (preferably in the β- configuration) , represents a methyl, ethyl or n-propyl group and represents a methyl or ethyl group (preferably a methyl group).

A still further class of compounds of formula I having good topical anti- inflammatory activity are those wherein X represents a hydrogen atom, R^represents a β-hydroxy group and preferably represents a hydrogen •atom or a methyl group (especially in the β-configuration) R preferably represents an alkyl group containing, parti cul arly contai ni ng 2 carbon atoms , 1 , 2 or 3 carbon aLoms/, Ry preferably represents a lower alkyl group (e.g. a methyl group) and preferably represents a double bond. Indeed, those compounds of this class wherein represents a methyl group in the β-configuration have been found to possess especially high topical anti-in lammatory activity.

' Yet another class of compounds of formula I having good topical anti- inflammatory activity and a good ratio of topical anti- inflammatory activity to glucocorticoid activity are those wherein X and represent chlorine atoms, R2 represents a methyl group preferably in the a-configuration , represents a methyl or ethyl group, represents a methyl or" ethyl group and ~=^ ^ r-preferably represents a double bond.

Individual preferred androstanes which have been found to have especially good topical anti- inflammatory activity with generally low levels of glucocorticoid activity include: methyl 17a-acetoxy- 9a-fluoro- 11β - hydroxy- 16β-methyl- 3-oxo-androsta~l , methyl 9a-fluoro- 11β -hydroxy- 16β -methy 1- 3-oxo- 17 a-propion loxy-androsta- 1 , -diene- 17β-carboxylate methyl 17a-butyryloxy-9a-fluoro- 11β -hydroxy- 16β -methyl- 3-oxoandrosta- 1 , 4-dlone-17β-carboxyla e methyl 17a-acetoxy-9a-fluoro- 11β-hydroxy- 16 a-methyl- 3-oxo-androsta-l , 4-diene- 17 ~carboxylate methyl 9a-fluoro- 11β -hydroxy- 16a-methyl- 3-oxo-l 7a-propionyl.oxy~ androsta- 1 , 4-diene- 17β- a bo yla e methyl 17a-butyryloxy-9a-fluoro-ΙΙβ-hydroxy-16a-methy1-3-oxo-androsta-1 , -diene-17p-carboxylate methyl 9a-fluoro-ΙΙβ-hydroxy- 16-methylene-3-oxo-17a-propionyloxy-androsta-1 ,4-diene-17β-ca boxylate methyl 9a-fluoro-ΙΙβ-hydroxy-16β-methy1-3-oxo-17a-propionyloxy-androst— 4-ene-l^-carboxylate methyl 17a-acetoxy-9a-f1^Γο-16β-ιηε ^1-3 , 11-uioxoandrosta- 1 , -diene-17β-carboxylate ethyl 9a-fluoro-ΙΙβ-hydroxy-ΐββ -methy1- 3-oxo-17a-propionyloxy androsta— 1 ,4-diene-17β-carboxylate methyl 17a-acetoxy-9a , llp-dichloro-16a-methyl-3-oxo-androsta-1 , -diene- 17β-carboxylate . methyl 9a-fluoro-l^-hydroxy-17a-isobutyryloxy-16-methylene-3-oxo-androsta- 1 ,4-diene- 17β-carbox ].ate ethyl 9a-flυoro-llβ-hydroxy- 17a- isobutyryloxy- 16-methylene-3-oxo-androsta-1 , -diene- 17β-carboxylate and methyl Ιΐβ-hydroxy- 16β-meth 1-3-oxo-17α-propionyloxyandrosta-1 , -diene- 17β-carboxylate.

The invention further includes the compound 2'-hydroxy-eth 1-9a-fluoro-lip-hydroxy-16 -methyl-3-oxo-17a-propionyloxy-androsta-1 ,4-diene-17β-carboxy].ate which is useful as an. intermediate for the preparation of the corresponding halogen substituted alkyl derivatives and moreover has topical antiinflammatory activity.

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 compound may be formulated into a preparation suitable for topical administration with the aid of a topical vehicle therefor. Examples 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 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.

Lotions may be formulated with an aqueous or oily base and will in general also include one or more of the follov?ing thickening agents, colouring agents and perfumes.

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. dichloro-difluoromethane 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% b 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, olive oil etc.

Preferred forms of preparation 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 ma be prepared for example with conventional commercial suppository bases, provide a dosage unit form for rectal administration. Sterile tablet 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 sj^stemic adreno-cortical therapy is indicated.

In general terms preparations for internal administration may contain from 0.01 to 5.0% of active ingredient dependent upon the type of preparation involved. The daily dose may vary from 0.05 to 10.0 mg. dependent on the conditio 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, chloro- cresol or benzalkonium chlorides. The compositions according to the invention ma}' also contain other active ingredients such as antimicrobial agents, particularly antibiotics, such as neomycin.

The compounds of formula I (as defined above )may be generally prepared by esterifj^ing a corresponding 17a-monoester 17p-carboxylic acid (or functional equivalent thereof) or 17a-hydroxy 17p-carboxylate to produce the desired compound of formula I.

As is well known to those skilled in the ar it may frequently be convenient to elaborate the desired substituents in the 17a- and 17β- ositions at an intermediate stage of the preparation of the desired final compound, one or more other substituents (or unsaturation) being introduced at a later stage. For example, it is possible for the preparation of 11-oxo compounds first to prepare an 1 lp -hydroxy compound having the desired 17a-acyloxy group and the desired 17 -carboxylate ester group and then oxidise the ].1β-hydroxy group. Other 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 17 -carboxylate ester groups, completion of the elaboration of Rings A, B and C then being The elaboration of the characteristic 17 - substituents of our new androstane compounds may be conveniently effected from pregnane compounds (having the following partial formula at the 17--position: CH 0H by an oxidation in known manner to form a corresponding androstane 17p-carboxylic acid which acid may then be esteri fied. The 17cc-hydroxy group may be esterified or otherwise functionally converted prior to oxidation, and thereafter regenerated or converted, if desired, to a different 17a-acyloxy group.

The oxidative removal of the 21-carbon atom of the pregnane starting material may be effected for example with periodic acid, in a solvent medium and preferably at room temperature. Alternatively, sodium bismuthate may be employed to effect the desired oxidative removal of the 21-carbon atom of a 17cc-acyloxy pregnane compound.

As will be appreciated should the starting pregnane compound contain any substituent sensitive to the above-described oxidation such group should be suitably protected .

The parent 17p-carboxylic acids of compounds of formula I may be esterified in knovm manner to provide 17p-carboxyl- ate esters according to the invention. For example, in order to prepare a lower alkyl ester the 17p-carboxylic acid may be reacted with an appropriate diazoalkane, e.g. diazomsth- ane; the reaction being preferably effected in a solvent medium, e.g. ether, tetrahydrofuran or methanol, and at a low temperature, preferably at - 5 to +30 ° C . Alternatively, the 17p-carboxylic acid may be reacted with an appropriate 1 1 0-alkyl~N,N -dicyclohexyl-isourea e.g. O-t-butyl-Ν,Ν -di- cyclohexyl 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 17p-carboxylic acid for example, an alkali metal e.g. lithium, sodium or potassium, salt or a quaternary ammonium, e.g. triethyl ammonium or tetrabutyl ammonium, salt may be reacted with an appropriate alkylating agent, for example, an ally 1 halide e.g. the iodide or a dialkyl sulphate e.g. diimethylsulphate , prefer¬ ably in a polar solvent medium such as acetone, methylethyl ketone or dimethyl, formamide, conveniently at a temperature in the range 25 - 100 ° C . The reaction with an alkyl halide may conveniently be employed to prepare the ethyl and propyl l7p-carboxylate esters and higher allyl esters according to the present invention.

Alternatively, the parent 17a--hydroxy- 17p-carboxylic carboxylate esters. For example, the l7 -carboxylic acid may be reacted with a diazoalkane or an O-alkyl-dicyclo-hexyl-isourea, or a salt of the l7 -carboxylic acid may be reacted with an alkylating agent as described above for the preparation of the 17β-carboxylate esters of the invention. The 17a-hydroxy-l7p-carboxylate esters may then be further esterified in known manner to produce the compounds of the invention.

The esterification of the 17a-hydroxy group in the above-described preparation of the new androstane compounds may be effected in known manner, e.g. by reacting the parent 17a-hydroxy compound with an appropriate carboxyl acid, advantageously in the presence of trifluoroacetic anhydride and preferably in the presence of an acid catalyst, e.g. p- toluene- sulphonic acid or sulphosalicyl.ic 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 -100°C Alternatively, the 17a-hydroxy group may be esterified by reaction of the parent 17a-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 temperature of 25 to 100°C.

For the preparation of the 17a-esters of the 17β-carboxylic 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 compound with the appropriate carboxylic acid anhydride to give the 17cc-ester of the mixed anhydride of the androstane 17β-carboxylic acid and the carboxylic acid of the starting anhydride, th s reaction being conveniently effected at an elevated temperature, the resulting anhydride then being solvolysed under acidic conditions (e.g. using aqueous acetic acid) or under basic conditions (e.g. using aqueous pyridine or a secondary amine such as diethylamine in acetone) .

Alternatively, the parent 17a-hydroxy compound may be treated with the appropriate carboxj^lic 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. 0°C.

Compounds wherein the ll-position contains a keto group may be prepared for example by oxidation of a corresponding Ιΐβ-hydroxy compound, e.g. by means of chromium trioxide, conveniently in an inert solvent such as acetone, preferably in the presence of sulphuric acid. t Alternatively, chromium trioxide in the presence of pyridine may be employed.

The above-described oxidation of an Ιΐβ-hydroxy group into an 11-keto group may be effected at any convenient stage in the synthesis of the androstane compounds, e.g. prior to or after the oxidative removal of the 21-carbon atom of the above-mentioned pregnane starting material or the esterification of the 17a-hydroxy group.

Those compounds of formula I (wherein represents a Cl-4 i er a gen. atom or lkyl. group s ed for example by reacting a salt of the parent l7p-carboxylic acid with an appropriate halo compound serving to introduce - the desired group in the compound of formula I.

This reaction is advantageously effected using as the salt of the parent 17 -carboxylic acid an alkali metal e.g. lithium, sodium or potassium, salt or a quaternary ammonium salt such as the triethylammonium or tetrabutylammonium salt, conveniently in a polar solvent such as acetone, methylethyl ketone or dimethyl formamide.

Thus, iu the case when R^ in formula I represents an alkyl group substituted by a lower alkoxy-carbonyl group, the resulting compound may, if desired, be converted into a compound wherein represents an alkyl group with a different alkoxycarbonyl substituent by ester exchange e.g. by treatment with methanol in the presence of an acid catalyst such as perchloric acid to convert an ethoxy-carbonyl compound into the corresponding methoxy-carbonyl compound.

In addition, the above-identified reaction of the salt of a 17(3-carboxylie acid with a halo compound may be used to prepare compounds of the type of formula I wherein represents a lew^r alkyl group ceH-t->Hi«g--at--Leae-fc--two--&arixw¾-a-t-oifls substituted by a hydroxy group (in other than the a-position) which compounds may be converted into the corresponding halogen-substituted compounds via the corresponding sulph-onyloxyalkyl e.g. mesyloxyalkyl derivatives, such conversion being carried out in conventional manner.

Thus, the sulphonyloxyalkyl compound may be advantageously reacted with an alkali metal, alkaline earth metal or quaternary ammonium halide, preferably lithium chloride, conveniently in a solvent medium comprising, for example, acetone, dimethyl formamide or ethanol.

Alternatively, the above-mentioned hydroxy-alkyl derivatives may be acylated e.g. with an appropriate carbox-ylic acid chloride or anhydride to produce compounds of Compounds of formula I wherein represents a lower alkyl group substituted by a halogen atom at the carbon atom attached to the oxygen atom of the 17p-carboxylate may be prepared for example by reacting the parent 17 -carboxylic acid with an appropriate aldehyde in the presence of a hydrohalic acid. The reaction may advantageously be effected in the presence of a catalyst for example, zinc chloride. 4 The Δ compounds according to the invention can conveniently be prepared by partial reduction of the cor- 1 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 t is (triphenyl phosphine) 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, prefe bly under reflux.

It is to be noted that androstane compounds correspond¬ ing to our new class of 17a-acyloxy compounds of the andro¬ stane series of formula I but characterised by a free hydroxy group at position 17 in the a configuration are new compounds apart from those compounds wherein X and are both hydrogen, is a methyl group, —— is a single bond and is a β -hydroxy or oxo group. Such new compounds are useful intermediates for the preparation of our new I7a- Other novel androstane compounds of use as intermediates in the preparation of the compounds of general formula I include the parent 17p-carboxylic acids of such compounds and their anhydrides, e.g. their mixed anhydrides with lower alkanoic acids, especially lower alkanoic acids such as acetic and propionic acids. Such 17 -carboxylic acids and their anhydrides also constitute further features of the present invention.

For a better understanding of the invention, the following Examples are given by. way of illustration only.

In the following Examples Nos . 1 - 38, the preparation of the compounds is described by reference to the following general methods of preparation A to F given below, details of the compound prepared in each case and its physical constants being given in the subsequent Tables.

Method A Preparation of androstane-17p-carboxylic acids.

A solution of the 20-keto-21-hydroxy pregnane steroid (1 part) in methanol (50 parts w/v) was treated with a solution of periodic acid (1.5 parts w/w) in water (10 parts w/v) at room* temperature until the reaction was judged complete (thin-layer chromatography). Most of the methanol was evaporated and after addition of water the solid steroid 17p-carboxylic acid was removed by filtration and purified by crystallization.

Method B Methylation of androstane 17p-carboxylic acids.

The androstane 17p-carboxylic acid (1 part) was dissolved in methanol (62-75 parts w/v) and treated at 0°C with an ethereal solution of diazomethane until a yellow colour persisted and the reaction was shown to be complete by thin- layer chromatography. After destruction of the excess diazomethane with a few drops of acetic acid the reaction mixture was evaporated to dryness in vacuo and the residue purified by crystallization.

Method C Ethylation and propylation of androstane-17p-carboxylic acids .

The androstane-l7 -carboxylic acid (1 part) in acetone (100 parts w/v) was treated with triethylamine (1.2 -5.0 equivalents based on the steroid) and then ethyl or propyl iodide (5 equivalents based upon the steroid). The mixture was refluxed until thin- layer chromatography indicated that the reaction was complete. Most of the solvent was removed in vacuo and the residue diluted with water to afford the product which was removed by filtration and purified by crystallization.

Preparation of C.-17 esters by acylation of 17ct-hydroxy-androstane-17 -carboxylates .

Method D The 17a-hydroxy-17p-carboxylate (1 part) was mixed with the appropriate aliphatic carbox lic acid (10 parts w/v), trifluoracetic anhydride (1-2.4 part w/v) and toluene-p_-sulphonic acid (0.005 - 0.03 parts w/w added as an anhydrous solution in chloroform) and the mixture heated in an oil bath at 80°C until the reaction was judged, by thin- layer chromatography, to be complete. The cooled reaction mixture was poured into excess dilute sodium bicarbonate solution and stirred until all the excess anhydride had been decomposed. The precipitated product was removed by filtration and purified by crystallization.

Method E The 17a-hydroxy-17p-carboxylate (1 part) in the appropriate aliphatic carboxylic acid (about 20 parts w/v) was treated with trifluoracetic anhydride (5 parts w/v) and toluene-p_-sulphonic acid (about 6 mg. as an anhydrous solution in chloroform) and the mixture kept at room temperature until the reaction was judged complete (t.l.c.) The mixture was poured into dilute sodium bicarbonate solution and the precipitated product was removed by filtration, dried and recrystallized.

Method F Oxidation of Ιΐβ-hydroxy steroids to ll-ketones.

The Ιΐβ-hydroxy steroid (1 part) was dissolved in acetone (25-150 parts w/v), cooled in an ice-bath and a solution of chromium trioxide (prepared by adding concentrated sulphuric acid (53.3 ml.) to chromium trioxide (66.7 g.) in water and making the volume up to 250 ml. by addition of water) (1.6 - 2.08 equivalents) was added. When the reaction was judged complete (t.l.c.) the mixture was diluted with ether or ether and ethyl acetate and washed thoroughly with water.

Evaporation of the solvent, afforded the crude 11-ketone which was purified by crystallization.

TABLE I (Continued) (1) The reaction mi dilution with s was filtered th alumina in chlo (2) A further quant was added to th (3) The crude produ purified by pre (4) No toluene-p-su which was heate (5) The crude produ chromatography (6) No toluene-p-su -25a- Exam le 3/9/ 38 Methyl 9a-fluoro-ΙΙβ , 17 -dihydrox3^-16 -methyl-3-oxo-androsta-l , 4-diene-17p-carboxylate .

Methyl iodide (12 ml.) was added to a solution of 9oc-fluoro-ΙΙβ , 17a-dihydroxy-16 -methyl-3-oxo-androsta-l , 4-diene-17p-carboxylic acid (10.045 g.) in acetone (500 ml.) containing triethylamine (4.6 ml.) and the mixture refluxed, more methyl iodide (6 ml.) being added after 4 hours. After 5.25 hours most of the solvent was evaporated in vacuo and the residue diluted with sodium bicarbonate solution. The precipitated solid was removed by filtration and, after dryings was filtered through a short plug of grade (III) neutral alumina in ethyl acetate containing a little methanol. Evaporation of the eluate gave methyl 9a- fluoro-ΙΙβ , 17a-dihydroxy-16β-methyl-3-oxo-androsta-1 , 4-diene-17 -carboxylate with infrared and n.m.r. spectra resembling that of the methyl ester prepared with diazomethane . .3 Example 17α-Acetoxy-9g-fluoro-ΙΙβ -hydroxy-16β-methy1-3-oxoandrosta~ 1 ,4-diene-17 -carboxylic acetic anhydride. 9a-Fluoro-lip , 17oc-dihydroxy-l6β-methy1-3-oxoandrosta- 1 ,4-diene-17p-carboxylic acid (1 g.) was suspended in acetic anhydride (15 ml.) and heated on a steam-bath for 45 minutes and then at 115" for 1 hour by which time all the steroid had dissolved. The mixture was cooled and the precipitated material removed by filtration and recrystallized from acetone-hexane to afford 17 -acetoxy- 9a-fluoro-ΙΙβ -hydroxy- 16β -methy1-3-oxoandrosta- 1,4-diene-17β-carboxylic acetic anhydride, m.p. 218-220°, [cc] + 2. ° (c 0.8, dioxan), λ r 238 m (ε 15,900) D — max .

(Found: C, 64.65; H, 6.5. c25H3iF07 squires C, 64.9; H, 6.75%). * 40 Example iL 17g-Acetoxy-9g-fluoro- 11β -hydroxy- 16β -me hy1-3-oxoandrosta-l , -diene-17 -carboxylic acid . (1) 17a-Acetoxy-9a-fluoro-li -hydroxir-16p-methy.l-3-oxo- ' androsta-1 , -diene-17 -carboxylic acetic anhydride (530 mg.) was dissolved in acetic acid (100 ml.) and water (50 ml.) added and the mixture kept at room temperature until reaction was complete (45 minutes).

Evaporation in vacuo afforded the product which, after crystallization from acetone-petroleum ether gave 17a-acetoxy-9a-f luoro- 11β -hydroxy- 16β-methy1-3-o oandrosta-1 , 4-diene-17 -carboxylic acid, m.p. 212-214°, [ct] +-22.2e (c 0.8, dioxan), λ " 239 nm (ε 14,700) (Found: max.

C, 64.1; H, 7.1. C23H29F06 recluires c> 6^-3; H, 7.05%). (2) 17a-Acetoxy-9a-fluoro- llβ~hydrox -16β -methyl-3-oxo-androsta-1 , 4-diene-17β-carboxylic acetic anhydride (57 mg. was dissolved in 50% aqueous pyridine ( 8 ml.) and kept at room temperature for 45 minutes. Evaporation of the solvent gave a solid whose infrared and n.m.r. spectra were similar to those of the material prepared in (l) above . 9a-Fluoro-ll|3 -hydroxy- 16S -methy1-3-oxo- 17a-propiony1oxy-androsta-l 4-dienc-l 7 -carbo lie ropionic anh dride,. 9a-Fluoro-lip , l7a~dihydroxy-16p-methyl-3-oxoandrosta- 1 , 4-diene-17p-carboxylic acid (1 g.) was suspended in propionic anhydride (15 ml.) and heated in an oil bath at 115° for 15 minutes during which time the steroid dissolved. The reaction mixture was diluted with petroleum ether (1G0 ml.) to afford a white crystalline solid which was removed by filtration and dried.

Recrystallization from acetone-hexane gave 9a-fluoro- li -hydroxy-16 -methyl-3-oxo-].7a-propionyloxy-androsta-l , 4-diene-17p-carboxylic propionic anhydride, m.p. 180- 182°, [c~L+ 50.5° (c 0.7, dioxan) , λ 238 nm ' 1 - D — ' max. (ε 15,700) (Found: C, 66.4; H, 7.1. C^H^FO., requires C, 66.1; H, 7.2%). 42 Example i 9a-Fluorο-11β-hydroxy-16β-methy1-3-oxo- 17 -propionyloxy- androsta-l , 4-diene-17p-carboxylic acid . (1) 9a-Fluoro~llp-hydroxy-16 -meth l-3-oxo-1 c- propiqnyloxyandrosta-1 , 4-diene-17p-carboxylic propionic anhydride (342 mg.) was dissolved in acetic acid (25 ml.) and water (15 ml.) added a d the mixture kept at room temperature until the reaction was judged complete (t.l.c.) Evaporation in vacuo of most of the solvent and dilution with water afforded the. product which was recrystallized from acetone-hexane to give 9a-fluoro-ll -hydroxy-16 - meth l-3-oxo-l7 - ro ion lox androsta-l -diene-l7 - carboxylic acid, m.p. 188-190° λ 239 nm (ε 15,600) ITlclX » (Found: C, 65.1; H, 7.5. C24H31F06.Me'2CO requires C, 65.8; H, 7.6%). (2) 9a-Fluoro-li -hydroxy-l6 -methyl -3-oxo-17a-propionyloxyandrosta- 1 , 4-diene-17p-carboxylic propionic anhydride (6.93 g.) in acetone (150 ml.) was treated with diethylamine (5 ml.) and the mixture kept at room temperature for about 0.5 hours. The solvent was evaporated in vacuo and the residue was dissolved in water, acidified and extracted with ethyl acetate.

The washed organic layer was evaporated in vacuo to give a solid which was triturated with ether to give 9a-fluoro-11β -hydroxy- 16β-methyl-3-oxo-l7a-propionyloxy-androsta-1 , 4-diene-17p-carb oxylic acid .

ExampleA 43 Methyl 9a-fluoro- 16-methylene-3 , ll-dioxo-17a-propionyloxy-androsta- 1 ,4-diene- 17 -carboxylate.

Methyl 9cc-fluoro-llp-hydroxy-16-methylene-3-oxo- 17a-propionyloxyandrosta-l ,4-diene-17 -carboxylate (204 mg. ) in acetone (4 ml. ) was treated at room temperature with a solution of chromium trioxide [0.23 ml; prepared by adding concentrated sulphuric acid (53.3 ml.) to chromium trioxide (66.7g.) in water and making the volume up to 250 ml with water]. After 30 minutes the reaction mixture sodium bicarbonate solution and water. The dried ethereal solution was evaporated in vacuo and the residue was recrystallised from methanol to afford the title compound, mp. 194-195°, [α]β -37.8° (c 1.06, dioxan) , λ 234.5 nm (ε 15,800), (Found: C, 67.3; H, 6.7. ma .

C25H29F06 rec¾uires C> 67·55; H, 6.58%).

Example jffi/ 44 Methyl 17a-benzoyloxy-9a-fluoro- Ιΐβ-hydroxy- 16 -methyl-3-oxo-androsta-l ,4-diene-17 -carboxylate.

A suspension of methyl 9a-fluoro-ΙΙβ , 17a-dihydroxy-16p-methylandrosta-I,4-diene-17p-carboxylate (439 mg. ) in methylene chloride (15 ml. ) was treated with benzoic acid (573 mg.), trifluoroacetic anhydride (O.6 ml.) and toluene-p-sulphonic acid (12 mg. ) and the mixture was stirred at 80°. After 48 hours the mixture was cooled and diluted with methylene chloride and the solution was washed with sodium bicarbonate and water. Evaporation of the dried organic solution afforded a residue which was purified by preparative thin layer chromatography and crystallisation from methanol to give the title benzoate m.p. 166-168°, [α]β + 3.3° (c 1.09, dioxan). λ lax. 232 nm (ε 27,800). (Found: C, 70.0; H, 6.6.

C nH F0, requires C, 70.14; H, 6.7%). 29 33 b Exam le W 45 Methyl 9a-f1Moxo- 11β-hydroxy- 16β-methyl-3~oxo- 17cx-propionyloxy-androst-4-ene- 17 -carboxylate.

A solution of methyl 9cc-fluoro- Ιΐβ-hydroxy- 16β-methyl-3-oxo-17oc-propionyloxyandrosta- 1 , -diene-17β-carboxy- late (454 mg. ) in ethanol (45 ml) was treated with 5% palladium-charcoal (453 mg. ) and cyclohexene. (0.9 ml) and the mixture was refluxed for 15 minutes. Filtration of the cooled mixture and evaporation of the solvent in vacuo afforded a froth which, after purification by preparative thin layer chromatography and crystallisation from acetone-petroleum ether gave the title compound m.p. 204-208° λ 237.5 nm (ε 15,400) (Found: C, 66.8; ΓΓ-cLX.· H, 7.8. C25H35F06 requires C, 66.65; H, 7.8%).

Exam le 7 46 Methyl 9 -fluoro- 16β-methyl-3 , ll-dioxo- 17a-propionyloxy-androst- -eΏe-l·7β-carboxyl·ate♦ A solution of methyl 9a-fluoro- Ιΐβ-hydroxy- 16β~π^1τ/1-3-oxo-17a-propionyloxyandrost- -ene-17β-carbo late ( 100 mg) in acetone (7 ml) was treated, at 0°, with a solution of chromium trioxide [0.09 ml; prepared by adding concentrated - 35 _ sulphuric acid (53.3 ml.) to chromium trioxide (66.7g. ) in water and making the volume up to 250 ml with water]. After 1.25 hours the mixture was diluted with ether and ethyl acetate and washed thoroughly with water. Evaporation of the organic solvent then afforded a white solid which was crystallised from acetone-petroleum ether to give the title compound, m.p. 218-220° after previous softening, λ 234 nm (ε 16,000) (Found: C, 66.55; H, 7.4. C25H33F06 requires c> 66.95; H, 7.4%).

Example 4/ft 47 Methyl 17 ct-acetoxy- 11β-hydroxy-3-oxoandrosta -1 ,4-diene-17 -carboxylate.

Periodic acid (I4.163g.) in water (80 ml) was added to a solution of prednisolone (8.286g) in methanol (800 ml) and .the resulting mixture was kept at room temperature. After 1 hour most of the methanol was evaporated in vacuo, the residue was diluted with water, and the crystalline 11β , 17a-dihydroxy-3-oxoandrosta-l ,4-diene-17p-carboxylic acid removed by filtration. The analytical sample which was crystallized from wet acetone and petroleum ether had m.p. 264-266° (Found: C, 69.2; H, 7.4. ^20^2 ^5 recl1-1^res C, 69.3; H, 7.5%).

The above carboxylic acid (3.6g) in methanol (200 ml) was treated at 0° with an ethereal solution of diazomethane until the mixture was yellow. Evaporation of most of the organic solvent in vacuo and dilution of the residue with water afforded crystalline methyl 11β , 17a-dihydroxy-3- oxoandrosta-l,4-diene-17 -carboxylate m.p. 203-206°.

A sample crystallised from acetone-hexane had m.p. 202-205° [ The above methyl ester (464 mg) in acetic acid (5 ml) was treated with trifluoroacetic anhydride (l ml) and the mixture stirred at room temperature. After 1 hour toluene-p-sulphonic acid (7 mg) was added and the mixture kept at room temperature for a further 2.5 hours.

Dilution of the solution with sodium bicarbonate solution afforded a precipitate which was removed by filtration and purified by preparative thin- layer chromatography and crystallization to yield the title compound m. p.284-286° , [a]_ + 8.9° (c 0.7 dioxan), λ 243 nm (ε 15,000).

D — ' max.

(Found: C, 68.6; H, 7.6. C23H30°6 recluires c> 68-65; H, 7.5%).

Exam le /V 48 Methyl 9, -fluoro- 11β , 17 -dihydroxy- i 6β-methy1- 3-oxoandrosta- I , -dίene-l·7β-carbo l·a ε .

A solution of sodium 9a-f luoro-ΙΙβ , 17a-dihydroxy-16 -methyl-3-oxoaudrosta-i , 4-diene-l7fj-carboxylate [prepared - - - άΙΙ^άΓθχγ-Ιβ ^β^γΙ-Β-οχοβηάιτοε α-1 ,4-diene-17p-carboxylic acid (103 mg-) in methanol (20 ml) with aqueous-methanolie N-sodium hydroxide solution to pH 8.3] was treated with methyl iodide (0.085 ml) and the mixture was refluxed.

After 16 hours the solvent was evaporated in vacuo, the residue triturated with water and the insoluble material removed by filtration.

The n.m. r. spectrum of this material in (CD^^SO showed methyl signals at τ 6.36, 8.47, 8.84, and 8.92 due to the title compound.

Example jty 49 -hydroxy -16 β - 2' -Hydroxyethyl 9a- f luoro-ll --methyl-3-oxo-17a- propionyloxyandrosta--! ,4-diene- 17p--carboxylate A solution of 9a-fluoro-llp-hydroxy~16p-methyl- 3-oxo-17a-propionyloxy androsta-1 ,4-diene-17 - carboxylic acid (200 mg. ) in acetone (20 ml.) was treated with redistilled triethylamine (0.38 ml.) and 2-iodoethanol (0.36 ml.) and the mixture was refluxed for 20 hours when the reaction was judged to be complete (t.l.c). Most of the solvent was removed in vacuo and water (45 ml.) was added to give the product which was recrystallised. first from methanol then from acetone to give the title compound, ■ m. p. 171-173° , [a]^ + 39.7° (c 0.99, dioxan), λ 237.5 ran (€ 15,650).. (Found: C, max. 64.95; H, 7.2.. C^H^FO., requires C, 65.3; H, 7.4%).

Example 50 2t-meth.anesulphonyloxyethyl 9«-fluoro- 11 -hydroxy 163- methyl-3-oxo-l7a-propionyloxyandrosta-l,4-diene-l7g~carb" oxylate A solution of 2 ' -hydroxyethyl 9a-fluoro-llp-hydroxy- 16p-methyl-3-oxo-17a-propionyloxyandrosta-l,4-diene-17p-carboxylate (240 mg.) in dry pyridine (/ml.) was treated dropwise at -1° to -10° with redistilled methanesulphonyl chloride (0.2 ml.). After 40 minutes acid (8 ml. ) and triturated to give a solid which was purified by preparative thin- layer chromatography and recrystallisat ion from methanol to give the title compound m.p. 129-131°, λ 238 nm (t 15,850) (Found: C, 58.5: H, max. . . 6.7, Co--H --F0nS requires C, 58.3; H, 6.7%).

Exam le 5fl 51 · 7 2 ' -Chloroethyl 9a- fluoro-lip-hydroxy- 16p-methyl-3-oxo- 17a-propionyloxyandrosta-l >4-diene-17 -carboxylate A mixture of 25 -methanesulphonyloxyeth l 9a- fluoro-ΙΙβ-·hydroxy l6p-methyl~3-oxo-17a-propionyloxyandr~ osta-l,4-diene-17 -carboxylate (223 mg.) and dry lithium chloride (170 mg.) on acetone (9 ml.) was refluxed for 22 hours. After removal of solvent in vacuo the residue was triturated with water to give a solid which was purified by preparative thin- layer chromatography and crystallisation from ether to afford the title chloroethyl ester, m.p. 194-196°, [α]β + 43.4° (c 0.99, dioxan) , λ 237 nm (i. 15,800). (Found: C, 62.9: H, 6.9; max. .

CI, 7.0. C26H34C1F06 requires C, 62.8; H, 6.9; CI, 7.1%).

Exam le ββ 52 21 -Broinoethyl 9a--fl·uo o-l·l·β-hydroxy-l·6β-me hyl·-3-oxo- 17a- Treatment of 2 ' -methanesulphonyloxyethyl 9a-fluoro- 11β-hydroxy l6p~meth3^1-3~oxo-l7a-propioiiyloxyandrosta- 4-diene-17j~carbox'Tlate 222 m . with dr lithium (348 mg. ) in acetone (9 ml. ) for 2 hours followed by work-up as described in Example52, with purification from ether afforded the title bromoethyl ester, m.p. 182-184.5°, softening above 122°, [a] + 38.8° (c 1.02, dioxan), λ 237.5 nm (£ 16,000). (Found: C, 57.9: max.

H, 6.3; Br, 14.6. C^H^BrFO,- requires C, 57.7; H, 6.3; Br,' 14.8%).

Example ?ff 53 9a-Chloro- 11(3 , 17a-dihydroxy-16 -methyl-3-oxoandrosta- I ,4-diene-17 -carboxy1 ic acid Treatment of 9a--chloro-llp , 17a-21-trihydroxy-16 - methylpregna-1 ,4-diene-3, 20-dione by the procedure described in Method A afforded, after recryscallisation from acetone-ethanol-petrol the title carboxylic acid, m .p. 247-249°, [a]n + 93.0° (c 0.7, dioxan), λ 238.5 nm (£ 14,300). (Found: C, 63.3; H, 7.1.

C21H27C104 re¾uires C> 63·85> H> 6-9%).

Exam le / 54 9 -Chloro- 11β-hydroxy- 16β-methyl-3-oxo-17a-pro iony1oxy- androsta-l ,4-diene- 17j3- arboxylic acid A mixture of 9a-chloro-llp , 17a-dihydroxy-16 - with propionyl chloride (1.32 ml.). After 35 minutes - - at 0° the solution was diluted with methylene chloride, washed successively with 3% sodium bicarbonate solution, -hydrochloric acid and water; after being dried (magnesium sulphate) solvent was removed in vacuo to give a colourless crystalline solid. This solid was dissolved in acetone (40 ml. ) and treated with redistilled diethylamine (1.3 ml.); concentration in vacuo gave the crystalline diethylamine salt which was collected, dried, dissolved in water and the solution was acidifed with 2N-hydrochloric acid.

The product was extracted with ethyl acetate and solvent was removed to give crystalline 9a-chloro- ll -hydroxy-16 -methyl-3-oxo-17a-propionyloxyandrosta- l,4-diene-17p-carboxylic acid (1.49 g. ) m.p. 187-188° (decomp. ), [ a] + 52.0° (c 0.95, dioxan), λ Example 55 Methyl 9a-chloro-ΙΙβ-hydroxy-16 -me hy1-3-oxo-17a-propionyl- oxyandrosta-l ,4-diene- 17ft-carboxylate A solution of 9a-chloro-l^-hydroxy-16p-methyl- 3-oxo-17a-propionyloxyandrosta-l ,4-diene-17p-carboxylie acid (501 rag. ) in acetone (20 ml.) was cooled in ice and treated with an ethereal solution of diazomethane - accordin to Method B. After bein sub ected to to chromatography on silica the product was recrystallised from methanol to give the title methyl ester, m.p. 214-217° (decomp.), ^ ^D + 60.3° (c 0.97, dioxan), λ 237 nm (i 15,700). — ' ' max.

(Found: C, 64.5; H, 7.2; CI, 7.5. C^H^ClOj, requires C, 64.6; H, 7.15; CI, 7.6%).

Example 57 56 li , 17a-Dihydroxy-16p-methyl-3-oxoandrosta-I ,4-diene- 17 -carboxylic acid A solution of 11β , 17α, 21-trihydroxy-16p-methylpregna- I ,4-diene-3 , 20~dione (640 mg. ) in dioxan (28 ml.) was stirred and treated with a solution of periodic acid (1.76 g. ) in water (14 ml.). After 40 minutes the solution was diluted with water (14 ml. ) and concentrated in vacuo. The crystalline product (579 mg. ) was recrys¬ tallised from acetone to give the title acid, m.p. 226-229° (decomp.), [cc] -+ 78.0° (c 0.50, dimethylsul- phoxide), λ 242 nm ( 14,850), (Found: C, 70.1; H, 1 ' max. 8.0. C lH o0-. requires C, 70.0; H, 7.8%).

Zl Zo _> Example 7$ 57 II.p-Hydroxy-16p-methyl"3-oxo-17a-propionyloxyatidrosta- 1 ,4-diene- 17p-carboxylic acid Treatment of lip ,17a-dihydroxy-16p-methyl-3-oxo- androsta-1 ,4~diene-17P"carboxylic acid (310 mg. ) with propionyl chloride (0.269 ml.) followed by solvolysis of the resulting product with diethylamine by the method described in Example 55 afforded crystalline li -hydroxy-16 -methyl-3-oxo-17o:-propionyloxyandrosta- 1 ,4-diene-17p-carboxylic acid, m.p. 202-205° (decomp. ), [a] + 24..4° (c 0.97, dioxan), λ 242.5 nm (1 14,820).

Example f> 58 Methyl 11β-hydroxy- 16β-methy1-3-oxo-17a-propionyloxy- androsta- 1 ,4~diene-17p-carbox late A suspension of lip-hydroxy-16p-methyl-3-oxo-17a- propioriyloxyandrosta-1 ,4-diene-17 -carboxylic acid (250 mg. ) in acetone (10 ml.) was cooled to 0° and treated with an ethereal solution of diazomethane according to Method B. After being subjected to preparative thin- layer chromatography on silica the product was crystallised from methanol to give the title methyl ester, m.p. 223-226°, [cc]D + 45.4° (c 0.98, dioxan), λ 242 nm (i 14,820). (Found: — max.

C, 69.4; H, 7.9. C25H3 0& requires C, 69.7: H, 8.0%).

Example 0059 t-Butyl 9a-fluoro-lip-hydroxy- 166-methy1-3-oxo-17a- propionyloxyandrosta-l ,4-diene-1 -carboxylate A suspension of 9a-fluoro-ll -hydroxy-16 -methyl- 3-oxo-17a-propionyloxyandrosta- 1 , 4-diene-17p-carbox lie acid (400 mg. ) in ethyl acetate (5 ml. ) was treated with 0-t-butyl-N,N'-dicyclohexylisourea (1.14 g. ) and the mixture was refluxed for 10^/4 hours. 2N-Hydrochloric acid was added and the mixture was stirred thoroughly; solid material was removed and washed thoroughly with ethyl acetate and water. The combined ethyl acetate solutions were washed with saturated sodium bicarbonate solution, and water, dried over magnesium sulphate and solvent was removed in vacuo. The resulting product (398 mg. ) was purified by chromatography on silica and crystallised first from acetone-petrol then from methanol to give the title t-butyl ester, m.p. 200-207°, [a]n + 35.2° (c 0.95, dioxan), λ JJ """" ΓΠ3.Χ· 238-238.5 nm (£ 14,600), (Found: C, 68.8; H, 8.1.

C oH nF0,. requires C, 68.55; H, 8.0%).

Example (A 60 11β , 17ft-Dihydroxy-3-oxo-androst-4-ene-17p-carboxylic acid Reaction of 11β , 17α, 21-trihydroxypregn-4-ene-3,20-dione (5.0 g. ) with periodic acid according to Method A gave a crude product which was partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous phase was separated and acidified with dilute sulphuric acid and the resulting precipitate was collected, washed with water and dried in vacuo ; recrystallisation from methanol gave the title acid, m.p. 235-239° (decomp.), [a] + 123..50 (c 0.57, dioxan), λ 241.5 nm, (½ 15,650). (Found: max.

C, 68.4: H, 7.8. C nHoo0-. requires C, 68.9: H, 8.1%).

Example ffl 61 17g-Butyryloxy-li -hydroxy-3-oxoandrost-4-ene- 17p-carboxylic acid 11β , 17a-Dihydroxy-3-oxoandrost-4-ene-17p- carboxylic acid (1.5 g. ) was treated with n- butyr'yl chloride (3.0 ml.) and the product was solvolysed with diethylamine by the method described in Example 55 to give, after recrystallisation from methanol , 17a-butyryloxy- llp-hydroxy-3-oxoandrost- 4~ene-17p-carboxylic acid, m.p. 222-223° (decomp.) [a]_ + 45.1° (c 0.98, dioxan), λ 240 nm D ¾ — ' ' max. (116,300). (Found: C, 68.3; H, 8.2. C^H 0& requires C, 68.9; H, 8.2%).

Example ββ 62 Methyl 17o:-butyryloxy- li -hydroxy-3-oxoandrost~4-ene- 17β-carboxy1ate Treatment of 17a-butyryloxy-li -hydroxy-3-oxo- androst-4-ene-17 -carboxylic acid (400 mg. ) in methanol (40 ml. ) with ethereal diazomethane according to method B gave, after recrystallisation from methanol, the title methyl ester, m,p. 162-165°, [a] + 49.4° (c 0.71, dioxan), λ 240 ran ( 16,550). (Found: C, 69.05: max. ' ' H, 8.3. C25H35°6 squires C, 69.4; H, 8.4%).

Example £4 63 li -Hydroxy-3-oxo-17a-propionyloxyandrost-4-ene-17 -carbox lic acid Treatment of 11β , 17a-dihydroxy-3-oxoandrost-4-ene-17 -carboxylic acid (3.0 g. ) with propionyl chloride (2.7 ml.) and solvolysis of the product with diethylamine (3.25 ml.) b}' the method described in Example 55 afforded, after reci stallisation from acetone-petrol , 11β-hydroxy-3-oxo-17a-propionyloxy- androst·-4-ene-17β-carbox)^lic acid, m.p. 225-226° (decomp.), [a] + 46.2° (c 0.98, dioxan), λ 240.5 nm (£ 15,500). (Found: C, 67.1; H, 7.8.

C23H32°6' ¾° re¾uir^s C' 66·8; Η' 7·8%)-Example 6/5 64 Methyl 11 -hy'droxy-3-oxo- 17a-propionyloxyandrost-4- ene- 17β-carboxyla_te Treatment of l^-hydroxy-3-oxo-17a-pi-opionyloxy- androst-4-ene-17β-carboxylic acid (2.5 g. ) in methanol, (400 ml. ) with ethereal diazomethane according to Method B gave a crude product; chromatography of a portionon silica afforded, after recrystallisation rom methanol , the title methyl ester, m.p. 176-178° [ex! + 51.1° (c 0.59, dioxan), λ , 240 ran (115,800).

™~ (Found: C, 68.9; H, 8.3. C /H /0, requires C, 68.9; 24 34 H, 8.2%) .

Example Jffl 65 17 -Acetoxy- lip-hydroxy-3-oxoandrost-4-ene-"J-7p- carboxylic acid Reaction of 11β , 17 Example Example 67 2' -Acetoxyethyl 9g-fluoro-li -hydroxy-l6 ^methyl-3-oxo- 17g-propionyloxyandros ta-l , 4-diene- 17 -carboxyla te A solution of 2 ' -hydroxye hyl 9oc-fluoro-ΙΙβ- hydroxy-16p-methyl-3-oxo-17a-propionyloxyandrosta- 1 ,4-diene-17p-carboxylate (300 mg. ) in dry pyridine (6 ml.) was treated with acetic anhydride (0.6 ml.). 3 After being kept at room temperature for 2 /4 hours the mixture was poured into well-stirred N-sulphuric acid to give a colourless solid (311 mg.) which was purified by preparative thin-layer chromatography on silica. Two recrystallisations from acetone afforded colourless crystals of the title a et i>xyethyl ester, m.p. 156-158°, [α]β + 31.9° (c 0.98, dioxan), ?max 237 nm (ε 15,800). (Found: C, 64.6; H, 7.3.

C oH .F0o requires C. 64.6; H, 7.2%). 2o J / o 49 Example 6f§ Methyl Ιΐβ-hydroxy- 16p-methyl-3-oxo- I7g-propionyloxy- androst-4-ene- 17p-carboxylate.

% Pd/C (50 mg) in ethyl acetate (30 ml), water 0. ( .02 ml) and pyridine (2C μΐ) was pre-reduced. Methyl 11β-hydroxy- 16β-methy1-3-oxo- 17 The following examples (a) - (d) illustrate the preparation of ointments.

Example (a) Active ingredient 0.1% w/w Liquid paraffin B.P. 10.0% w/w White soft paraffin to produce · 100 parts by weight Ball-mill the steroid with a little of the liquid paraffin until the particle size is reduced to 95% by number below 5μ. Dilute the paste and rinse out the mill with the remaining liquid paraffin, mix and add the suspension to the melted white soft paraffin at 50° C.

Stir until cold to give a homogeneous ointment.

Example (b) Active ingredient 0.25% w/w Aluminium stearate 3.2% w/w Liquid paraffin B.P. to 100 parts Disperse the aluminium stearate in the liquid paraffin by vortex stirring and heat the suspension with continued stirring, at a temperature rise rate of 2°C per minute until 90° C is reached. Maintain the temperature at 90-95° C for 30 minutes until solution is complete and a gel is formed. Cool quickly, preferably b the use of cooling coils or concentric cooling rings to produce a transparent solid gel. Mill the active ingredient to produce microfine particles of 'which not less than 90% by number are below 5μ . Triturate with a small portion of the gel and incorporate the remaining gel to give a homogeneous mix.

I Example (c) ' Active ingredient '0.1% w/w Woolfat 12.0% w/w Cetostearyl alcohol B.P.C. 20.0 w/w Liquid paraffin B.P. 25.0% w/w White soft paraffin to 100 parts w/w Ball-mill the steroid with a little of the liquid paraffin as in Example (a) and add the resulting paste, diluted with the remaining liquid paraffin, to a mixture of cetostearyl alcohol, woolfat and white soft parafin, melted together by gentle warming. Stir until cold to give a homogeneous mix.

Example (d) Active ingredient 0.05% w/w Hydrogenated lanolin e.g. 20.0 w/w Lanocerina sold by Croda Ltd. of London, W.C.2. England.

Liquid paraffin B.P. 15.0% w/w White soft paraffin to 100 parts w/w Ball-mill the steroid with liquid paraffin as in Example (a), and add the resulting paste, diluted with the remaining liquid paraffin to the mixture of hydrogen-ated lanolin and white soft paraffin, melted together by gently warming. Stir until cold to give a homogeneous mix, The following examples (e) and (f) illustrate the preparation of water-miscible creams : -Example (e) Active ingredient 0.1% w/w Beeswax (White) 15.0% w/w Cetostearyl alcohol B.P.C. 7.0% w/w Cetomacrogel 1000 B.P.C. 3.0% w/w Liquid paraffin B.P. 5.0% w/w Chlorocresol 0.1% w/w Distilled water to produce 100 parts by weight Ball-mill the steroid with a little liquid paraffin as described in Example (a). Heat the available water to 100°C, add the chlorocresol, stir to dissolve and cool to 65° C. Melt together the beeswax, cetostearyl alcohol" and cetomacrogel 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^ and stir rapidly while the emulsion cools over the gelling point (40-45°C).

Continue to stir at slow speed until the cream sets.

Examp1e (f) Active ingredient 0.1% w/w Cetostearyl alcohol B.P.C. 7.2% w/w Cetomacrogel 1000 B.P.C. 1.8% w/w Liquid paraffin B,P. 6.0% w/w White soft paraffin 15.0% w/w Chlorocresol 0.1% w/w Distilled water to produce * 100 parts by weight Prepare as described in Example (e), replacing the beesv/ax with white soft paraffin in the oily phase.

The following examples (g) and (h) illustrate the preparation of lotions: Example (g) Active ingredient . 0.25% w/v Lanbritol wax*. 0.93% w/v Diethylene glycol monostearate 0.65% w/v Cetostearyl alcohol B.P.C. 0.65% w/v Liquid paraffin B.P. 1.95% w/v Glycerin 5.0% w/v Isopropyl alcohol ^ 6.5% v/v Methyl p_-hydroxy benzoate 0.15% w/v Distilled water to produce 100 volumes *Lanbritol wax is a non-ionic wax for stabilising emulsions consisting of a mixture of fatty alcohols with polyethylene glycol ethers of fatty alcohols sold by Ronsheim Moore of London W.C.I England.

Ball-mill the steroid with half the glycerin, as in Example (a), and use the isopropyl alcohol for dilution and rinsing purposes.

Melt together the lanbritol wax, diethylene glycol monostearate , cetostearyl alcohol and liquid paraffin and maintain at 60° C. Heat the available water and remaining glycerin to 95°C. Add the methyl parahydroxy benzoate and stir until dissolved. Cool to 65°C. Add the oily mix at 60 °C to the aqueous phase at 65° C and allow to cool while stirring rapidly until the emulsion gels at 40 - 45° C, thereafter stir slowly. Add the well mixed steroid suspension slowly to the lotion base and stir to obtain a homogeneous mix.

Example (h) Active ingredient 0.05% w/v Tween 80 (Polyoxyethylene sorbitan rnono-oleate) 0.01% w/v Carbopol 934 (Carboxy vinyl polymers) 0.3% w/v Diethanolamine 0.5% w/v (approx.) Distilled water to produce . 100 volumes.

Ball-mill the steroid with a little water and the Tween 80 as in Example (a). Disperse the Carbopol 934 in the available water by vortex stirring. Add the diethanolamine slowly with stirring until the clear thickened mix has a pH of 7.0. Incorporate the steroid slurry into the lotion base and mix well.

Example (i) Aerosol Sp a}^ Lotion * Active ^ingredient (microfine) 2.5 mgm.

Fractionated coconut oil to 1.20 g.

Dichlorodifluoromethane 16.32 g.

Trichlorofluoromethane 24.48 g.

Dry the steroid overnight at 60° C under vacuum and over phosphorus pentoxide. Ball-mill the dried powder for at least 4 hours with a little of the dried filtered oil. Rinse out the mill with more dried filtered oil and pass the suspension through a 325 mesh B.S. sieve. Assay the suspension and dilute with more dried filtered oil to the required concentration. Incorporate the suspension into the pressure container with the propellants in a conventional manner.

Example (j) Aphthous Ulcer Pellets Active ingredient (microfine) 0.25 mg.

Lactose 69.90 mg.

Acacia 3.00 mg.

Magnesium stearate 0.75 mg.

Pass the steroid, lactose and acacia, separately through a No. 60 B.S. mesh sieve. Blend the powders and granulate with 50% ethanol in water. Pass the mass through a No. 12 mesh sieve and dry the granules at 50° C, Pass the dried granules through a No. 20 mesh B.S. sieve and blend in the magnesium stearate, previously passed through a No. 100 mesh B.S. sieve. Compress in a conventional manner on 7/32 inch diameter punches, to give a pellet that will dissolve slowly in the mouth.

Example (k) Retention Enema Active ingredient (microfine) 0.0005% w/v Tween 80 0.05% w/v Ethanol ' ' 0.015% v/v Methyl p_~hydroxy benzoate 0.08% w/v Propyl p_-hydroxy benzoate 0.02% w/v Distilled water to 100 vols.

Heat the available water to 95°C, add the methyl and propyl p_-hydroxy benzoates and stir to dissolve.

Cool the vehicle to room temperature. Disperse the steroid in the ethanol and add to the Tween 80; warm the mixture to 50°C and stir until the steroid is in solution. Add the steroid solution to the vehicle, stirring vigorously to avoid precipitation, and make up to volume with water if required. Distribute the enema into plastic bags e.g. P.V.C. bags for self-administration or into other containers suitable for use.

Example (1) Eye Drops Active ingredient 0.025% w/v Tween 80 2.5% w/v Ethanol 0.75% w/v Benzalkonium chloride 0.02% w/v Phenyl ethanol 0.25% v/v Sodium chloride 0.60% w/v Water for injection to 100 volumes.

Dissolve the sodium chloride, benzalkonium chloride and phenyl ethanol in the water for injection. Suspend the steroid in the alcohol and add to the Tween 80.

Warm the mixture to 50°C and stir until dissolved. Add the steroid solution to the eye-drop vehicle with rapid stirring to obtain a clear solution. Sterilise the bulk by filtration through a sintered -glass filter and distribute into sterile small well filled, neutral glass eye-drop containers.

•Example (tn) Nasal Drops Active ingredient 0.005% w/v Tween 80 0.05% w/v Alcohol 95 0.15% v/v Methyl paraben (p_-hydroxy benzoate) 0.04% w/v Propyl "paraben (p_-hydroxy benzoate) 0.02% w/v Sodium chloride 0.70% w/v Distilled water to 100 volumes Dissolve the sodium chloride and the parabens in the distilled water heated to 95°C, and allow the solution to cool. Disperse the steroid in the alcohol and add to the Tween 80. Warm the mixture to 50° C and stir until solution of thesteroid is effected. Add the steroid solution to the vehicle with rapid stirring to obtain a clear solution. Filter the solution free from particulate matter through a sintered glass filter and distribute into small, well filled containers.

The following Examples (n) and (o) illustrate formulatioiis for internal administration according to the invention. In both Examples the active ingredient used may be any of the active steroid' hereinb disclosed.

Example (n) 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.

Total weight 200.0 mg.

A suspension of 300 mg. of the active ingredient in 2 ml. of water containing 0.1% of Tween 80 was milled for 16 hours in a 10 ml. nylon pot about three quarters filled with steatite balls, until 90% by number of the particles had a diameter of less than 10 microns. The maize starch and lactose were blended and passed through a 60 mesh B.S.- sieve and granulated with a 10% 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 were 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 5/32 inch flat"bevelled punch.

Example (o) Intra-Articular Injection a) Preparation of small particle active ingredient. 2.8 g. Tween 80 was dissolved in 130 ml. of dimethyl acetamide (DMA). 12 g. of the active ingredient was then dissolved in 130 ml. of this solution and the resulting solution was filtered successively through two dry sintered glass filters (No. 3 and No. 4).

The solution of active ingredient was then added, under aseptic conditions, in a fine stream to a stirred sterile aqueous solution of benzyl alcohol (10 g. in 1 litre water) over a period of ten minutes. The preparation was allowed to stand for at least three hours and the resulting crystals collected by filtration or centrifuging . The preparation was washed with aqueous benzyl alcohol (10 g. in 1 litre water) and the wet-cake transferred to a well-sealed container. 90% by number of the particles had a diameter less than 10 μ and none were above 50 μ in diameter. b) Production of Injectable Preparation Composition: % w/v Fine particle ingredient prepared as in a) 0.50 Hydroxyethyl cellulose 0.40 Benzyl alcohol 1.00 Sodium citrate 0.30 Sodium salt of EDTA* 0.01 • Sodium chloride 0.44 Citric acid q . s .

Water for injection to 100.0 pH value 4.80 to 5.50 *EDTA is ethylene diamine tetracetic acid. 1. Vehicle the hydroxyethyl cellulose was dissolved in 17.5 litres of Water for Injection using a high speed vortex stirrer. The benzyl alcohol was added with stirring. The sodium chloride, sodium citrate salt of EDTA were dissolved in 1 litre of water and added to the bulk vehicle with stirring. The pH value of the bulk vehicle was adjusted to 4.80 to 5.50 with a solution of citric acid. The volume was then adjusted to 19.3 litres and the vehicle clarified by filtration through nylon. The vehicle was finally sterilised by autoclaving. 2. Sterile wet-cake of small particle active ingredient prepared as in a) containing 100 g. of the active ingredient was added with stirring and under aseptic conditions to 19 litres of the vehicle, and' he volume made up to 20 litres .

The resulting suspension was passed through a sterile 100 mesh British Standard sieve and stored in a sealed container. Dosage units for injection were prepared by aseptically filling neutral glass ampoules or vials closed by a pure latex plug. 62 -

Claims (7)

1. where

a hyd

group

atom)

R? re

(in either the - or β-configuratinn) ; R^ represents a hydrogen

atom, an alkyl group containing 1 to 3 carbon atoms or a phenyl "~

group; and ^ represents a ^ alkyl group; a ^. ^ alkyl group

substituted by either at least one halogen or an alkoxycarbonyl

group wherein the alkoxy moiety contains 1 to 4 carbon atoms; or

a C2_ ^ a3-^y'l group substituted by a ^ alkanoyloxy group; or

(when X represents a fluorine atom, R^ represents a β-hydroxy

group, R^ represents a β-methyl group, represents an .. ethyl., :

group and represents a double bond) R^ may also represent ·,

a 2-hydroxy-ethyl group; provided that R, is not n-propyl

■ / isopropyl or n-butyl unless one or more of X, R and

R„ is other than hydrogen and/o: represents a double

bond;1 or b) X represents a chlorine or fluorine ;.atom; R^ re

385S9/2

.-figuration) ; represents a methyl or ethyl group;

represents a alkyl group; a C^ ^ alky1 group subs ituted

by either at least one halogen atom or an alkoxycarbonyl group

wherein the alkoxy moiety contains/ 1 to 4 carbon atoms; or a

(C? alkyl group substituted by a ^2-5 alkanoyloxy group;

and represents a single or double bond. .

2. .. Compounds as claimed in claim 1 wherein R^ represents

an alkyl group containing 1 to 3 carbon atoms^ a phenyl group

or (when R is a methylene or methyl .group) a hydrogen atom. ,

3. Compounds as claimed in claim 1 wherein R^ represents a

methyl, ethyl, n-propyl or iso-propyl group.

4. Compounds as claimed in claim 1 wherein R^ represents

a hydrogen atom and R^ represents a methyl group. ..

5. Compounds as claimed in any of. the preceding claims

wherein R^ represents a C^ alkyl group.

6. Compounds as, claimed in.claim 5 wherein R^. represents

a methyl group.

7. Compounds as claimed in claim 5 wherein R. represents

4

an ethyl or propyl .group.

8. Compounds as claimed in claim 1 wherein R. represents ·

4

a alkyl group substituted by a chlorine, fluorine or

bromine atom.

38589/2

ΐόο Compounds as claimed In claim 15 wherein X represents

a fluorire atom and R^ represents a methyl group and ____________ represents a double bond*

17, Compounds as claimed in claim 1 wherein ■ represents a single bond, X represents a fluorine or chlorine atom,

represents a 6-hydroxy group, Rg represents a methyl group,

represents a methyl, ethyl or n-propyl group and ^ represents a methyl or ethyl group.

18« Compounds as claimed in claim 17 wherein X represents a fluorine atom, 2 represents a methyl group in the β-configuration and R^ represents a methyl group0

19, Compounds as claimed in claim 1 wherein X represents a hydrogen atom, R represents a β-hydroxy group and R represents a hydrogen atom or a methyl group,

20, Compounds as claimed in claim 19 wherein Rg represents a methyl group in the β-con iguration,

21 , Compounds as claimed in claim 19 or claim 20 wherein R^

represents an alkyl group containing 1 , 2 or 3 carbon atoms.

22, Compounds as claimed in claim 21 wherein represents an alkyl group containing 2 carbon atoms.

23, Compounds as claimed in any of claims 19 to 22 wherein R^ represents a C^ ^ alkyl group.

2k, Compounds as claimed in claim 23 wherein R^ represents a methyl group.

25, Compounds as claimed in any of claims 19 to 2h wherein

: ---- represents a double bond.

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50 . Λ proce s as claimed in claim 44 wherein a salt of the 17a-monoester 17p-carboxylie acid is reacted with an alkyl halide or dialkyl sulphate to effect esterification.

5 . Λ process is claimed in claim 50 wherein the said salt is an alkali metal or quaternary amnio?ium salt.

52. A process as claimed in claim-50 ^ wherein the said salt is a lithium, sodium, potassium, triethylammonium or tetrabutylammon:i/um salt.

53'. A process as claimed in any of claims 50 to- 52 wherein the said salt is reacted with an alhyl iodide. 54/. A process as claimed in any of claims 50 to. 52 wherein the said salt is reacted with dimethyl sulphate. 55. A process as claimed in any of claims 50 to 54 wherein the reaction is effected in a polar solvent medium.

56.. A process as claimed in any of 'claim's 50 to 55 wherein the reaction is effected at a temperature of 25 to 100°C.

5.7. A process as claimed in claim 44 wherein "the 17a-hydroxy 17 -carboxylate is reacted with an appropriate carboxyli.e acid.

58. A process as claimed in claim 57' wherein the reactio is effected in the presence of trifluoroacetic anhydride.

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0

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9 . A process as claimed in claim 57 or claim .58.

wherein the reaction is effected in the presence

of an acid.

60 . A process as claimed in claim- 59 wherein the

acid is p- toluene- sulphonic acid or sulphosalicylic acid.

61 . A process as claimed in any of claims 57 to .,60 wherein the reaction is effected in an organic solvent medium.

62. A process as claimed in any cf claims 57 to 61.

wherein the reaction is effected' at a temperature of 20-100°C.

63. A process as claimed in claim 44 wherein the 17a-hydroxy 17p-carboxylate is reacted with the acid

anhydride or chloride of an appropriate carboxylic acid.

64. A process as claimed in claim 63' wherein the reaction is effected in a non-hydroxylic solvent. - -65, A process as claimed in claim .63 or claim- 64 wherein the reaction is effected in the presence of a strong acid or a strongly acidic cation exchange resin.

6¾ A process for the preparation of compounds of formula I (where in represents an oxo group) which comprises oxidising corresponding compound of formula I wherein represents a p -hydrox -group.

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67. A process as claimed In claim 66 wherein the oxidation Is effected by means of chromium trloxide.

68. A process for the preparation of compounds of formula I (wherein represents a single bond) which comprises partially reducing a corresponding compound of formula I

(wherein , ■ represents a double bond) to produce the desired compound.

69. A process as claimed 1n claim 68 wherein the partial

reduction Is effected by hydrogenatlon wi th a pal ladium catalyst.

70. A process as claimed In claim 68 wherein the partial

reduction Is effected by homogeneous hydrogenatlon using trl s-(trl phenyl phosphlne) rhodium chloride.

71 . A process as claimed In claim 68 wherein the partial reduction Is effected by exchange hydrogenatlon with cyclohexene in the presence of a pal ladium catalyst.

72. A process for the preparation of compounds of formula I (wherein represents a Cj _4 al kyl group substituted by either a halogen atom or a C2_5 alkoxycarbonyl group or a (C2-4) alkyl group substituted by a C2_5 alkanoyloxy group) which comprises reacting a salt of the parent 17 β -carboxyl lc add with an appropriate halo compound serving to Introduce the desired group R. in the compound of formula I .

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\ . -

73. A process as claimed 1n claim 72 wherein the salt of the

parent 17 β -carboxyl ic acid Is an al kal i metal sal t or a quaternary ammonium salt.

74. A process as claimed 1n claim 73 wherein the said sal t 1s

a l ithium, sodium, potassium, trlethyl ammoni um or tetrabutyl-ammonlum sal t.

75. A process for the preparation of compounds of formula I

wherei n ^represents a (C2_4) alkyl group substituted by a

C2_5 al kanoyloxy group which comprises acylatlng a corresponding

hydroxy-substituted compound to Introduce the desired acyl

group.

76. A process for the preparation of compounds of formula I

wherein R^ represents a Cj _4 alkyl group substituted by a

methoxy carbonyl group which comprises reacting a corresponding compound of formula I (wherein R^ represents a al kyl group substituted by an ethoxycarbonyl group) with methanol 1n the presence of an add catalyst.

77. A process for the preparation of compounds of formula I

wherein represents a al kyl group substituted by at least

one halogen atom (other than 1 n the a-pos1tion) which comprises

converting the corresponding hydroxy substituted compound of

formula I into the corresponding sul phony loxyal kyl 17 ^ -carboxylate ■ compound which is subsequently converted Into the corresponding

halo-compound.

78. A process for the preparation of compounds of formula I

wherei n R4 represents a Cj _4 alkyl group substituted by a hal ogen

atom at tite carbon atom attached to the

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-4

in any of claims l-43.

10^. Pharmaceutical compositions comprising at least one

compound of formula I, substantially as herein described..

105. Pharmaceutical compositions substantially as herein

described with reference to any of Examples*

77-