IE66261B1 - Preparation of intermediates for 16,17-acetalsubstituted androstane-17beta-carboxylic acid esters - Google Patents

Description

The present invention relates to a process for the preparation of intermediates for producing pharmacologically active compounds that are described and claimed in Irish Patent Application No. 879/86, from which this application is divided.

It is known that certain glucocorticosteroids (GCS) can be used for local therapy of inflammatory, allergic or immunologic diseases in respiratory airways (e.g. asthma, rhinitis), in skin (eczema, psoriasis) or in bowel (ulcerative colitis, Morbus Crohn). With such local glucocorticoid therapy, clinical advantages over general therapy (with e.g. glucocorticoid tablets) are obtained, especially regarding 15 reduction of the unwanted glucocorticoid effects outside the diseased area. To reach such clinical advantages, in e.g. severe respiratory airway disease, GCS must have a suitable pharmacological profile. They should have high intrinsic glucocorticoid activity at the application site but also a 2Q rapid inactivation by e.g. hydrolysis In the target organ or after uptake Into the general circulation.

Since binding of GCS to the glucocorticoid receptor is a pre-requisite for their anti-inflammatory and allergic effects to occur, the ability of steroids to bind to their receptor(s) can be used as an adequate method for determining the biological activity of GCS. A direct correlation between the affinity of GCSs to the receptor and their antiinflammatory effects has been shown using ear edema test in the rat. (Correlation between chemical structure, receptor binding, and 30. biological activity of some novel, highly active, 16a,17aacetalsubstituted glucocorticoids. E. Dahlberg, A. Thalen, R. Brattsand, J-A Gustafsson, u. Johansson, K. Roempke, and T. Saartok, Mol. Pharmacol. 25 (1984), 70.] Irish Patent Application No. 879/86, which is the parent of the present divisional specification, relates to certain 3" oxoandrosta-1,4"diene-170-carboxylic acid esters possessing high binding affinity to the glucocorticosteroid receptor. In particular, the compounds of Irish Patent Application No 879/86, which can be used for the treatment and control of inflammatory conditions, are of the formula: Hl CH ?p'3 C - 0 CH wherein the 1,2-position is saturated or is a double bond; X! is hydrogen, fluorine, chlorine or bromine; X2 is hydrogen, fluorine, chlorine or bromine; Rj is hydrogen or a straight or branched hydrocarbon chain having 1-4 carbon atoms; R2 is hydrogen or a straight or branched hydrocarbon chain having 1-10 carbon atoms; and R3 is selected from O O Y is 0 or S; R. is hydrogen, straight or branched hydrocarbon chain having 1-10 carbon atoms or phenyl; r5 is hydrogen or methyl; and fq is hydrogen, straight or branched, saturated or unsaturated hydrocarbon chain having 1-10 carbon atoms, alkyl substituted by at least one halogen, a heterocyclic ring system containing 3-10 atoms in the ring system, °(CH2)mCH(CH2)„ (m=0,l,2; n=2,3,4,5,6), phenyl or benzyl which are unsubstituted or substituted by one or more alkyl, nitro, carboxy, alkoxy, halogen, cyano, carbalkoxy or trifluoromethyl group(s), provided that R, and R2 are not simultaneously hydrogen.

The present invention provides a process for the preparation of a compound of the formula D: or a stereoisomer thereof, in which formula: the l,2-position is saturated or is a double bond; X, is hydrogen, fluorine, chlorine or bromine; X2 is hydrogen, fluorine, chlorine or bromine; R2 is a straight or branched hydrocarbon chain having 1-10 carbon atoms; and R7 is hydrogen or an acyl group with 1-10 carbon atoms arranged in a straight or branched chain, which process comprises reaction of a compound of the formula F: CHj CHj with a compound of the formula ,K / wherein X2f R2, R7 and --- have the meanings given above, in the presence of an acid catalyst.

Irish Patent Application No. 879/86 discloses that the 5 individual stereoisomeric components present in a mixture 0 a steroid having the above formula (I) can be elucidated in the following way: The individual stereoisomeric components present, in a mixture of steroid 178-carboxylic acid esters having the formulas Ο O II il StCOCR^RgOClU (IV) or O O StCOCR^Rjoi-yRg (V) where St is the steroid moiety, can be elucidated in the following way and o R„o n ι 4,l( StCOCOCR, A, VI O R,0 StCOCOCR, A.

VII O R.O ij p.|| StCOCOCYR vm SM StCO0OCYR( IX In diasteroisomers like II, III, VI, vii, VIII and IX, the 15 configuration differs only at one out of several asymmetric carbon atoms. Such diastereoisomers are denoted epimers.

Alkyl in the definitions above is a straight or branched hydrocarbon chain with 1-5 carbon atoms, preferably 1-4 C.

Alkoxy in the definition above is a group -O-alkyl wherein the alkyl moiety has the given definition.

( Halogen in the definition above is preferably a chlorine, bromine or fluorine atom.

Cartoalkoxy in the definition above is a group -COO-alkyl wherein the alkyl' moiety has the above given, definition.

Heterocyclic ring system is a ring system containing as hetero atoms N, O or SPreferred systems are pyrolyl, pyridyl, pyrimidyl, pyrazinyl, furyl, pyranyl, benzofuranyl, indolyl and thienyl.

Preferred compounds described and claimed in xrisn Paten*. Application No. 879/86 are: 1'Ethoxycarbonyloxyethyl δα,9a~di£luoro-1ίβ-hydroxy-16α,17α[ (l-methylethylidene)bis(oxy) ]-androsta-X, 4-diene-3-one-17Scarboxylate, the epimeric mixture A + B and epimer B. 1'-isopropoxycarbonyloxyethyl 9g-fluoro-11Q-hydroxy-16 1’propoxycarbonyloxyethyl 6a, 9a-difluoro-1IS-hydroxy-lSa,17a[(Is -methylethylidene)bis(oxy) ]androsta-l, 4-diene-3-one-17Bcarboxylate, epimer 3. 1s -isopropoxycarbonyloxyethyl 6a, 9a-difluoro-1lfl-hydroxy16a,17a- [ (l-methylethylidene)fois(axy) Jandrosta-1,4-diene-3one-17S-carboxylate, epimeric mixture A + B and epimer B. 1' -Acetoxyethyl ( 2OR) -9a-fluoro-llfi-hydroxy-16a, 17apropylmethylenedioxyandrosta-l, 4-diene~3~one-17S-carboxylate, epimer 3. 1’ -Ethoxycarbonyloxyethyl (22R) -9a-fluoro-11Q-hydroxy-16a, 17a propylmethylenedioxyandrosta-l,4"diene-3-one-17fl-carboxylate, epimer B. 1’-isopropoxycarbonyloxyethyl (20R)-9a-fluoro-llB-hydroxy16a, 17a-pr opy lmethy lenedioxyandrosta-X, 4-diene-3-ene- 17Scarboxylate, epimer B. 18 -Ethoxycarbonyloxyethyl (2OR) -6a, 9a-difluoro-1IB-hydroxy16a, 17a-propylmethylenedioxyandrosta-l, 4-diene-3-one-178carboxylate, epimeric mixture A + B and epimer B.

The compounds of formula I of Irish Patent Application No. 879/86 are prepared by the oxidation of a compound of the formulas X, XI and XII to the corresponding 17 β-carboxylie acid: — o 0-^12 CH„-OR, I 2 7 ( ( * H. 'fL wherein the solid and broken lines between C-l and C-2 represent a single or double bond, X^, X?, R1 and R? have the meaning given above for formula I, and is hydrogen or an acyl group with 1-10 carbon atoms arranged in a straight or branched chain.

The 176~carboxylic acids then are esterified to give compounds 10 characterized by the formula I-IX, whereinzrztX.,, X2* Ri ' and Rj have the meaning given above for formula I.

The process of this invention to convert a compound of formulas X, XI or XII to the corresponding 17-carboxylic acids is carried out in a suitable oxygenated hydrocarbon solvent such as a lower alkanol. Methanol and ethanol are preferred, particularly the former. The reaction medium is made slightly alkaline by the addition of a suitable weak inorganic base such as an alkali metal carbonate, for example sodium, lithium or potassium carbonate. The latter is perferred. The conversion of a compound of formula X, XI or XII to a 17Bcarboicylic acid of formula I, II or III (Rj-H) takes place at ambient temperatures, i.e. 20-25°C.

The presence of oxygen is necessary for the reaction. Oxygen can be supplied by bubbling a stream of air or oxygen into the reaction mixture.

The oxidative degradation of the 176 side-chain of compounds of formula X, XI and XII to the corresponding 176 carboxylic acids can also be carried out with periodic acid, sodium hypobromate or with sodium toismuthate- The reaction is performed, in a mixture of water and a suitable oxygenated hydrocarbon solvent such as a lower ether- Dioxane and tetrahydrofuran© are preferred, particularly the former.

The parent 17S-carboxylic acids of compounds of formula I, II and III (R3=H) may be esterified in known manner to provide 17Scarboxylate esters according to the invention. For example, the 176-carboxylic acid may be reacted with an appropriate alcohol and a carbodiimide„ e.g. dicyclohexylcarbodiimide, in a suitable solvent such as diethylether, tetrahydrofuran©, methylene chloride or pyridine advantageously at a temperature of 25-lQ0°C. Alternatively,, a salt of the 17S-carboxylic acid with an alkali metal,, e.g. lithium, sodium or potassium, a salt of a quaternary ammonium compound, such as a salt of triethyl-or tributylamine, or tetrahutylammonium, may be reacted with an appropriate alkylating agent, for example an acyloxyalkylhalide or haloalkyl alkylcarbonate preferably in a polar solvent medium such as acetone, methylethylketone or dimethyl formamide, dimethyl sulphoxide, methylenechloride or chloroform, conveniently at a temperature in the range 25-100°C. The reaction may also be performed in the presence of a crown ether.

The crude steroid ester derivatives formed are after isolation purified by chromatography on a suitable material, for instance cross-linked dextran gels of Sephadex (Trade Mark) LH-type with suitable solvents as eluants, e.g. halogenated hydrocarbons, ethers, esters such as ethyl acetate or acetonitrile.

The individual epimers, which are formed at the acetalisation to the 16a,17a-hydroxy groups or at the esterification of the 17B-carboxylic acids, possess practically indentical solubility characteristics. Accordingly, they have turned out to be impossible to separate and isolate from the epimeric mixture by conventional method for resolution of stereoisomers, e.g. fractionated crystallisation. In order to obtain the Individual epimers separately the stereoisomeric mixtures according to the formulas I, IV an V above are subjected to column chromatograhy, thus separating the epimers II, III, VI, VII, VIII and IX in view of different mobility on the stationary phase. The chromatography may be carried out for instance on cross-linked dextran gels of the type Sephadex LH, e.g. Sephadex LH-20 in combination with a suitable organic solvent as eluting agent. Sephadex LH-20, prepared by Pharmacia Fine Chemicals AB, Uppsala, Sweden, is a beadformed hydroxvpropylated dextran gel wherein the dextran chains are cross-linked to give a three-dimensional polysaccharide network. As eluting agent, halogenated hydrocarbons e.g. chloroform or a mixture of heptane-chloroform-ethanol in the proportions 0-50:50-100:10-1 has successfully been used, preferably a 20:20:1 mixture.

Compounds X, XI and XII are used as starting materials for compounds of formula I. They are prepared by transacetaiisation of the corresponding 15a, 17c-acetonides ch,or, j > z ι *2 wherein the solid and broken lines between and represent a single or double bond and X, , X9 and R7 have the meaning given above with an aldehyde of the formula wherein R? has the meaning given above.

The aldehyde is preferably acetaldehyde, propanal, butanal, isobutanal, pentanal, 3-methylbutanal, 2,2-dimethylpropanal, hexanal, heptanal, octanal, nonanal and dodecanal. The reaction is carried out by adding the steroid to a solution of the aldehyde together with a strong inorganic acid as catalyst, preferably perchloric or hydrochloric acid, in an ether, preferably dioxane or tetrahydrofurane, a halogenated hydrocarbon, preferably methylene chloride or chloroform, an aromatic hydrocarbon, preferably toluene, an alicyclic hydrocarbon, preferably cyclohexane or an aliphatic hydrocarbon, preferably heptane or isooctane, under the latter conditions eliminating th© chromatographic step for preparation of the epimers III and XII.

The compounds of formula I may be used for different modes of local administration dependent on the sice of inflammation, e.g. percutaneously, parenterally or for local administration in the respiratory tract by inhalation. An important aim of the formulation design is to reach optimal bioavailability of the active steroid ingredient. For percutaneous formulations this is advantageously achieved if the steroid is dissolved with a high thermodynamic activity in the vehicle. This is attained by using a suitable system of solvents comprising suitable glycols, such as propylene glycol or 1,3-butandiol either as such or in combination with water.

It is also possible to dissolve the steroid either completely or partially in a lipophilic phase with the aid of a surfactant as a solubilizer. The percutaneous compositions can be an ointment, an oil in water cream, a water in oil cream or a lotion. In the emulsion vehicles the system comprising the dissolved active component can make up the disperse phase as well as the contionuous one. The steroid can also exist in the above compositions as a micronized, solid substance.

Pressurized aerosols for steroids are intended for oral or nasal inhalation. The aerosol system is designed in such a way that each delivered dose contains 10-1000 ug, preferably 20-250 pg of the active steroid.

The most active steroids are administered in the lower part of the dose range. The micronized steroid consists of particles substantially smaller· than 5 ym. which are suspended in a propellent mixture with the assistance of a dispersant, such as sorbitan trioleate, oleic acid, lecithin or sodium salt of dioctylsulphosuccinic acid.

The invention will be further illustrated by the following non-limita2 -1 live examples. In the examples a flow-rate of 2.5 ml/cra · h is used at the preparative chromatographic runs. Molecular weights are in all examples determined with electron impact mass spectrometry and the melting points on a Leitz Wetzlar hot stage microscope. All HPLC analyses (HPLC = High Performance Liquid Chromatography) were performed on a Waters pBondapak C-jg column (300x3.9 mm internal diameter) with a flowrate of 1.0 ml/min and with ethanol-water in ratios between 50:50 and 60:40 as mobile phase, if not otherwise stated.

Example 1. This example sets forth a process for preparing (22RS)-, (22R)- and (22S)-116,16α, 17g, 21-tetrahydroxypregns-1,4-diene-3,20-dione 16a,17c-acetals.

Preparation of (22RS)-, (22R)- and (225)-16α„ 17o-butylidenedioxy-6osθαdi fl uoro- 116,21-dihydroxypregna-1„4-diene-3s20-di one.

A. To a suspension of 1.0 g of 6as9a-difluoro-116,16a,17(s,21-tetra30 hydroxypregna-1-4~diene-3,20-dione in 500 ml of methylene chloride 0.32 ml of freshly distilled n-butanal and 2 ml of 72% perchloric acid were added. Th® reaction mixture was.allowed to stand for 24 h at room temperature under stirring. The reaction mixture was washed with 10% aqueous potassium carbonate solution and water, dried over sodium sulphate end evaporated. The residue was dissolved in ethyl acetate and precipitated with petroleum ether leaving 883 mg of (22RS)-16e,17abutyl i denedi oxy-δα» 9o-di fluoro-11 β, 21 -di hydroxypregna-1,4-di ene-3,20di one. HPLC-analysis showed 99% purity and the ratio 16:84 between the 225- and 22R-epiaers. Molecular weight: 466 (calculated 466.5).

The (22RS) epimeric mixture was chromatographed on Sephadex LH-20 column (75x6.3 cm) using heptane:chloroform:ethanol, 20:20:1. as mobile phase. The fractions 12315-13425 ml (A) and 13740-15690 ml (8) were collected and evaporated and the residue dissolved in methylene chloride and precipitated with petr.-ether. Fraction A gave 62 mg of (22$)- and fraction B 687 mg of (22R)-16e21-dihydroxypregna-l,4"diene-3s20"dione. The (22S)-epimer: Molecular weight 466 (calculated 466.5), m.p. 196-200%.

The (22R)-epimer: Molecular weight 466 (calculated 466.5), m.p. 169-72%.

B. To a solution of 1.0 g of 6«, 9<>-di fluoro-116,21-di hydroxy-16<*,17«i[(1 -methylethylidene)bis(oxy)] pregna-1,4-diene-3,20-dione in 500 ml of methylene chloride was added 0.30 ml freshly distilled n-butanal and ml of 72« perchloric acid. The reaction mixture was allowed to stand for 24 h at 33% under stirring, extracted with aqueous potassium carbonate and water, dried over sodium sulphate and evaporated. The residue was dissolved in methylene chloride and precipitated with petr.-ether yielding 848 mg of (22RS) -16cs 1 /«-butyl idenedioxy-6 B'. To a suspension of 4.0 g of 6a,9ct-difluoro-ll J,2^-dihydroxy-16α,17o<ί (methylethylidene)bis(oxy)]pregna-l,4-diene~3s20-dione in 100 ml of heptane was added 1.2 ml of freshly distilled n-butanal and 3.8 ml of perchloric acid (72%). The reaction mixture was allowed to stand for 5 h at room temperature under vigorous stirring, extracted with aqueous potassium carbonate and water, dried over sodium sulphate and evaporated yielding 4.0 g of (22R$)-16cc517o‘-butylidenedioxy-6o4s,9ci"difluoro-l 1/?,21dihydroxypregna-l,4-diene-3,20-dione. HPLC-analysis showed 98.5« purity and the ratio 3/97 between the 22$- and 22R-epimers. After two recrystallisations from chloroform-petroleum ether 3.1 g of 22R-epimer was obtained, which contained only 1.1% of the 22S-epimer and 1.3« of other impurities.

C. Similarly, by following the procedure set forth in the example by substituting 6«, 9»~difluoro-11/3,16«, 17a, 21-tetrahydroxypregna-1,4-diene3,20-dione for 1lj, 1 6cs 17a,21 -tetrahydroxypregna-1,4’diene-3,20-dione, 9«-fluoro- and 6a-fluoro-ll/?,16csl7x,21-tetrahydroxypregna-l ,4-diene-3,20 dione or the corresponding 16os 17a-acetonides non-fluorinated and fluorinated non-sywietric (22RS)-, (22R)- and (22S)-llj,16a,17a,21-tetrahydroxypregna-l ,4-diene~3,20-dione 16osl7cx-acetals from acetaldehyde, propane!, butanal, isobutanal, pentanal, 3-methylbutanal, 2,2-dimethylpropane! , hexanal, heptanal, octanal „ nonanal and dodecanal are prepared.

Example 2 A. Prednacinolon Ifes 17<*~acetonide (250 mg;0,6 mmol) was dissolved in 75 ml of CH^Cl^. n-Butanal (130 mg; 1,8 mmol and 70% perchloric acid (0,025ml) were added. The solution was stirred at 33°C for 15 hours.

The yellow solution was washed with 2x10 ml of 10% K^COg end H^O, dried and evaporated. Yield: 257 mg (97,7%). HPLC gave 91,1% purity. Unreacted acetonide consists of 7,4% of the impurities. Epimer ratio 14,6/85,4. 8. Triamcinolon 16ος 17 C. Fluocinolon 16 Example 3. This example sets forth a process for preparing ll^-hydroxy16ot,17«x- [(1-methyl ethylidene)bis(oxy)] - and (20RS)-, (20R)~ and (20S)11(7-hydroxy-16a, 1 Tfe-alky lmethylenedioxyandrosta-1,4-diene-3-one-l 7^-carboxylic and -4-ene-3-one-17p-carboxylic acids.

Preparation of 6α, 9a-difluoro-116-hydroxy-16as17a-[ (1-methyl ethy li dene )bis(oxy)]androsta~l,4-diene-3-one-176-carboxylic acid.

A. To a solution of 1.99-g of fluocinolone 16α,1/a-acetonide in 120 ml of methanol 40 ml of 20¾ aqueous potassium carbonate was added. A stream of air was bubbled through this solution for about 20 h under stirring at room temperature. Th® methanol was evaporated and 200 si of water was added to the residue. The solution was extracted with methylene chloride. The aqueous phase was acidified with diluted hydrochloric acid. The precipitate formed was collected by filtration and dried to yield 1.34 g of 6a,9a-difluoro-l l£-hydroxy-16a,17a-i (1-methy 1 ethyl idene)bis(oxy) ]androsta-l ,4-diene-3-one-17fe-carboxylic acid, melting point 2S4-68eC, molecular weight 438. The purity determined by HPLC was 94.0%. The aqueous phase was extracted with ethyl acetate. After drying the solvent was evaporated leaving another 0.26 g portion of acid.

Purity: 93.7%.

B. Periodic acid (15.1 g) in 16.5 ml of water was added to a solution of fluocinolone 16a,17a~acetonide (5.0 g) in 55 ml dioxane. The reaction mixture wss stirred at room temperature for 20 h, neutralized with saturated aqueous sodium hydrogen carbonate and evaporated. The residue was dissolved in 200 ml of methylene chloride and washed with 8 x 100 ml 10% aqueous potassium carbonate. The aqueous phase was acidified with cone, hydrochloric acid and extracted with 6 x 100 ml of ethyl acetate.

After drying the solvent was evaporated. Th® residue was dissolved in 400 ml of ethyl acetate and precipitated with petroleum ether yielding 3.96 g of 6as9a-difluoro-116-hydroxy-16a,17a-ill-eiethylethylidene)bis(oxy) Jandrosta-l ,4-diene-3-one-175-carboxylic acid. The purity determined by HPLC was 99.5%.

C. Sisilarly, by following the procedure set forth in tine example by substituting fluocinolone 16α, Ua-acetonide for 116,16a,17©,21-tetrahydroxypregna-1,4-diene-3,20-dione, 6a-fluoro-11Bs 16as17a,,21-tetrahydroxypregna-Ί3diene-3s20-diones and triamcinolone 16a, 17a-acetonide 116-hydroxy-16a, 17a- ((1 -methyl ethyl i dene) bi s (oxy) ] sndrosta-1,4-di ene3*one~176-carboxy1ic acids are prepared. By substituting the 16c,17aacetonide group for 16a, 17c-acetals between 16a-hydroxyprednisolone 6o-f1uor-16a-hydroxyprednisolone, triamcinolone and fluocinolone and acetaldehyde, propanal, butanal, isobutanal, pentanal, 3-methylbutanal, 2,2-dimethylpropanal 9 hexanal, heptanal, octanal, nonanal and dodecanal and their 21-esters (20RS)- (20R)- and (20S)-11B-hydroxy-16a,17Q-alkylmethylenedioxyandrosta-l,4-diene- and 4-ene-3-one-176-carboxylic acids are prepared.

Example 4. 1 '-Ethoxycarbonyloxyethyl 6ct,9a-dif luoro-118-hydroxy-16a,17ct[(1-methylethylideneIbis(oxy))sndrosta-l,4-diene-3-one-176-carboxy1ate.

A. 6a,9a-Di f1uoro-11β-hydroxy-Ί 6α, 17a-[(1-methyl ethyli dene) bi s(oxy)]androsta-1,4-diene-3-one-17B-carboxylic acid (600 mg) and potassium hydrogen carbonate (684 mg) were dissolved in 45 ml of dimethyl formamide. 1-Bromoethyl ethyl carbonate (2 ml) was added and the reaction mixture stirred at room temperature overnight. Mater (200 ml) was added and the mixture was extracted with methylene chloride. The combined extracts were washed with 5% aqueous sodium hydrogen carbonate and water, and the residue purified by chromatography on a Sephadex LH-20 column (72x6.3 cm) using chloroform as mobil phase. The fraction 1515-2250 ml was collected and evaporated yielding 480 mg of 1'-ethoxycarbonyloxyethyl 6a,9a~dif1uoro-11β-hydroxy-16a, 17a-[(1-methyl ethyli dene)bis(oxy)]androsta-1,4-diene-3-one~176~carboxylate. The purity determined by HPLC was 98.1% and the ratio epimer A/B, 48/52. Melting point: 218-27°C. - +63.2C (c=0.214; CH^Cl^) · The molecular weight was 554.

The 1’-ethoxycarbonyloxyethyl 6a,9a-dif1uoro-115-hydroxy-16α,17a-(1 methylethylidene)bis(oxy)]androsta-1,4-diene-3-one-176-carboxylate (480 mg) was chromatographed on a Sephadex LH-20 column (76x6.3 cm) using heptane:chloroform:ethanol, 20:20:1, as mobile phase. The fraction 2325-2715 ml was collected, evaporated and the residue dissolved in methylene chloride and precipitated by petroleum ether giving 200 mg of a compound (A) of purity 97.3% (determined by HPLC analysis). Melting point: 246-50°C. - +100.5° (cs0.214; CH^Clg). The molecular weight was 554..

The fraction 4140-5100 ml yielded 250 mg of a compound (B) with purity 99.0%. Melting point: 250-55’C. [α)θ5 = +28.5° (c=0.246; CH^Cl^). The nolecular weight was 554. The nethine signal froa the ester group is shifted 0.13 ppm downfield in H-HMR spectrum of 8 compared to A, while the rest of the spectra are nearly identical. The electron impact mass spectra of A and B are identical apart from the intensities of the mass peaks. These spectroscopic differences and similarities indicate that A and B are epimers due to the chiral centre in the ester group.

B. &x5 Sx-Di f 1 uoro-11 β-hydroxy-117e- [(1 -methyl ethyl i dene) bi s (oxy )j androsta-1,4-diene-3-one-l78-carboxylic acid (200 mg) was dissolved in 25 ml of dimethylformamide. l-Chloroethyl ethyl carbonate (100 mg), potassium hydrogen carbonate (70 mg) and 18-crown-6-ether were added.

The reaction mixture was stirred at 80°C for 3 h, cooled, extracted with methylene chloride after addition of 150 ml of water, dried and evaporated. The crude product was purified in the same way as in procedure A leaving 207 mg of 1'-ethoxycarbonyloxyethyl 6«,9®-di fluoro-11 β-hydroxy-1 Sou, 1 /ex- [(1 -methyl ethyl idene)bi s {oxy)3 androsta-1,4-diene-3-one-l78-carboxylate. The purity (HPLC) was 98.4% and the ratio epimer A/B, 54/46.

C. δα,9%-Dif 1 uoro -118-hydroxy -16% 1/©- j( 1 -methylethyl idene)bi s(oxy)j androsta-1,4-diene-3-one-178-carboxylic acid (200 mg) and Γ "ΐ 1s5-diazabicyclo (5.4.0; undecene-5 (140 mg) were suspended in 25 ml of benzene and warmed to reflux. A solution of 1-bromoethyl ethyl carbonate (175 mg) in 5 ml of benzene was added and the mixture was refluxed for 2 1/2 h. After cooling 50 ml of methylene chloride was added and the solution was washed with water, dried and evaporated. The crude product was purified in the same way as in procedure A, yielding 207 mg of Γ-ethoxycarbonyloxyethyl 6 difluoro-118-hydroxy-16 9. To a solution of 6«, 9®rdi fluoro-11 β-hydroxy-IS®, 17ei- [(1-methyl ethyli dene) bis (oxy )3 androsta-1 „4-diene-3-one-l 78-carboxyl ic acid (100 mg) in 25 ml of acetone 175 mg of -bromodiethylcarbonate and 45 mg of anhydrous potassium carbonate were added. The mixture was heated for 6 h at reflux. The cooled reaction mixture was poured into 150 ml of water and extracted with methylene chloride. The extract was washed with water, dried over sodium sulphate and evaporated yielding 65 mg of solid 1'-ethoxycarbonyloxyethyl 6ος 9o<-dif luoro-1lB-hydroxy-16<\ 17a, f(1-methylethyl idene)bi s(oxy)] androsta-1,4-diene-3-one-176-earboxylate.

The purity determined by HPLC was 97.6% and the ratio epimer A/B, 49/51.

E. 5«,9erDifluoro-11B-hydroxy-lSes4-diene-3-one-17B-carboxylic acid (500 mg) and tetrabutylammonium hydrogen sulphate (577 mg) were added to 3 ml of IM sodium hydroxide.A solution of 435 mg of 1-bromoethyl ethyl carbonate in 50 ml of methylene chloride was added. The mixture was refluxed with stirring overnight. The two layers were separated. The organic layer was washed with 2x10 ml of water, dried and evaporated. The crude product was purified by chromatography on a Sephadex LH-20 column (72x6.3 cm) using chloroform as mobile phase. The fraction 1545-1950 ml was collected and evaporated and the residue precipitated from methylene chloride - petroleum ether leaving 34Ί mg of 1'-ethoxycarbonyloxyethyl &*,9o-dif 1 uoro-1 IB-hydroxy-16^, 17®·- {(1 -methylethyl idene) -bis(oxy)] androsta-1,4-diene-3-one-17B-carboxylate. The purity determined with HPLC was 99.2% and the ratio epimer A/B, 56/44.

F. 6«>,S'*-Dif 1 uoro-1 IB-hydroxy-16$ς 17ct- Γ( 1 -methyl ethyl idene) bi s(oxy)J androsta-1s4-diene-3-one-178-carboxylic acid (200 mg) and tricaprylmethylammonium chloride (200 mg) were added to 5 ml of saturated aqueous NaHCO^. A solution of 100 mg of 1-bromoethyl ethyl carbonate in 10 ml of methylene chloride was added. The mixture was stirred at AS’C for 20 h, diluted with 10 ml of methylene chloride and isolated and purified in the same way as in procedure E yielding 254 mg of 1'-ethoxycarbonyloxyethyl S^-difluoro-ΠΒ-hydroxy-16^17^- f( 1-methyl ethyl i dene) hi s( oxy )j - androsta-l,4-diene-3-one-17B-carboxylate. The purity (HPLC) was 97.4% and the ratio epimer A/8, 60/40. 6. 6ος91-ethoxycarbonyloxyethyl 6e-s9a-difluoro-11 β-hydroxy-16Csl7®<" [(1-methylethylidene)bis(oxy)Ί androsta-Ί ,4-diene-3-one~176-carboxylate. The purity (HPLC) was 97.8% and the ratio epimer A/B, 48/52.

Example 5 1'-Acetoxyethyl 6 6«,9^-Difluoro-1 18-hydroxy-16cg 17s4-diene-3-one-17B-carboxylic acid (500 mg) and potassium hydrogen carbonate (575 mg) were dissolved in 40 ml of dimethylformamide. l-chloroethyl acetate (1 ml) was added and the reaction mixture was stirred at room temperature for 40 h. The reaction mixture was poured into 50 m! of water and extracted with methylene chloride. The extract was washed with aqueous sodium hydrogen carbonate and water, dried and evaporated. The residue was chromatographed on Sephadex LH-20 column (72x6.3 cm) using chloroform as mobile phase. The fractions 1755-2025 and 2026-2325 ml were collected and evaporated.

The solid product from fraction 1755-2025 ml was further purified by chromatography on a sephadex LH-20 column (76x6.3 cm i.d.) using a mixture of heptane-chloroform-ethanol, 20:20:1, as mobile phase. The fraction 2505-2880 ml was collected and evaporated, the residue was ( dissolved in methylene chloride and precipitated with petroleum ether leaving 167 mg of solid product (A). The purity determind by HPLC was 99.1%. Melting point 238-59°C. = +94° (c=0.192; CH^). The { molecular weight was 524.

The solid product from fraction 2026-2325 ml above was further purified by chromatography in the same way as above. The fraction 5100-5670 ml was collected and evaporated. The residue was dissolved in methylene chloride and precipitated with petroleum ether yielding 165 mg of solid product (8). The purity determined with HPLC was 99.4%. Melting point 261-65°C. = +34° (c=0.262; CH^CI?). The molecular weight was 524. 3S The ^H-NMR spectra of A and 8 are nearly identical with the exception of the methine quartet from the ester group which is shifted 0.16 ppm downfield in compound B compared to A. The fragmentation patterns of A and B in electron impact mass spectra are identical apart from the intensities of the mass peaks. These spectroscopic properties of A and B indicate that they are epimers due to the chiral centre in the ester group.

Examples 6-88 The substance given in Table 1-3 below were prepared, isolated and purified in a manner analogous to that described in Examples 4 and 5.

Table 1, f .,25 Example X^ % a5 R^e Epimer Mp 6C ic*Q,2 in Molecular weight Retention no. CHgClg) calc, found volume (ml) S 7 δ « H Η H F H Phenyl Phenyl CK(CH3)2 H H H CH, CT; CH, A B A 242 (dee) 22) (dee) +798 +89* +1020 550/7 550.7 534,6 550 550 534 1665-189013 1891-217513 .2325-25801 * 9 F 11 cmcf?3)?. H C«3 8 - +40e 534,6 534 3165-3^5513 a a 10 F H Phenyl H CII3 A 249 (dec) +73° 568,6 568 2040-2355 ' 11 F fi Phenyl If CII3 B 238 (dec) +75® 568.6 568 2895-328513 12 F F ch3 8 C(CHj)3 A 262-70 +87® 566,6 566 2190-2S0511 13 F F «13 H CUh3)3 β 268=?? +50° 566,6 566 3525-399013 (continued) [α] χ1 X 2 *4 *5 Epimer Mp °C (c=0.2 in CH2Ct2) Molecular weight Retention volume (m calc. found F F CHg H Phenyl A 224-30 +95° 586.6 586 2325-2625 F F ch3 H Phenyl 8 259-67 +48° 586.6 586 4350-4875 F F ch3 ch3 ch3 - 130-42 +61° 538.6 538 1965-2220 F Η ch3 H Oc(GH3)3 A 184-87 +98° 564.7 564 235-280 F. Η ch3. H 0C(CH3)3 8 >300 +30° 564.7 564 525-630 Η F ch3 H 0CH(CH3)2 A 250-53 +109° 550.6 550 1530-1770 Η F ch3 H OCH(CH3)2 8 230-35 +58° 550.6 550 2295-2850 F F ch3 H och3 A 235-42 -si 02° 540.6 540 590-690 F F ch3 H och3 B 225-33 +31° 540.6 540 395-430 F F C«3 H 0{CH?)?CH^ A 224-31 +106° 568.6 568 410-495 F F CH3 H 0{CH?)?CH? 6 227-30 +28° 568.6 568 690-900 F F ch3 H 0CH(CH3)2 A+8 205-28 -)-59° 568.6 568 1365-1560 F F ch3 H 0CH(CH3)2 A 210-25 4-95° 568.6 568 400-475 t F F ch3 H 0CH(CH3)2 3 242-47 -)-31° 568.6 568 625-780 F F ch3 H 0CH(CH2CH3)2 A 226-28 4-95° 596.7 596 1785-2085 F F ch3 H OCH(CH?CH^)? 8 183-97 -)-30° 596.7 596 3150-3600 F F ch3 H 0CH?CH(CH?CHg)2 A 217-21 +89° 610.7 610 1725-1980 F F ch3 H och2ch(ch2ch3)2 8 207-10 +30° 610.7 610 3120-3480 i1} )1} 3) 2) »υ )1} 2) 3) 2) 2) )5) 2) 2) i]) )1} )Ί) J) Table 1. (continued) r ,25 ialD Example no. ^4 «5 R6/YR6 Epimer Mp °C (c=0.2 in Molecular weight Retention ch2ci2) calc. found volume (ml) 32 F F CH3 H °c{CH3)3 A+B 170-78 +65° 582.6 582 1290-1920 33 F F ch3 H 00(0)3)3 A 177-79 +100° 582.6 582 255-310 34 F F ch3 H 00(0)3)3 β 190-92 +27° 582.6 582 650-800 : 35 F F ch3 11 och2c(ch3)3 A+B 208-36 +60° 596.7 596 1605-1995 36 F F CK3 H OCH2C(CH3)3 A 248-56 +98° 596.7 596 1845-2130 37 F F ch3 H 0CH2C(CH3)3 8 226-28 +28° 596.7 596 3270-3750 38 F F CH, CH, 00),01, - - - 568.6 568 405-460 1) 2) 3) 4) ) On a Sephadex LH-20 column On a Sephadex LH-20 column On a Sephadex LH-20 column On a Sephadex LH-20 column On a Sephadex LH-20 column (76x6.3 cm) using chloroform-heptane-ethanol (20:20:1) as mobile phase. (87.5x2.5 cm) using chloroform-heptane-ethanol (20:20:1) as mobile phase. (85x2.5 cm) using chloroform as mobile phase. (72x6.3 cm) using chloroform as mobile phase. (71.5x6.3 cm) using chloroform as mobile phase. *4,9 Table 2.

COOCOCR ί Η - O^r^R2 -θΧ CH3 Epimer 8 r ,25 Example no.K1 x2 r2 % VYR6 Epimer Mp °C (c=0.2 in ch2ci2) Molecular weight Retention volume (ml) calc. found 39 H H ch3 H C(CH3)3 - 189-92 +78° 502.6 502 1290-166511 1110-126011 1245-144011 1485-180011 1200-139511 320-400 21 225-285 21 1410-154511 1620-217511 40 H H (CH2J2CH3 H ch3 - 63-70 +79° 488.6 488 41 H H (CH2)2CH3 H C(CH3)3 - 192-96 +74° 530.7 530 42 F H (CH?)2CB3 H C(CH3)3 - 254-58 +64° 548.7 548 43 H H (Ch?)2CH3 H O(CH2)3CH3 - 40-46 +70° 546.7 546 44 H H (ch2)2ch3 H OC(CH3)3 - 155-58 +67° 546.7 546 45 H H (CH2)2CH3 ch30CH2CH3 A+B 163-75 +53° 532.6 532 45 F H (CH2)2CH3 ch3 och2ch3 A+B 138-60 - 550.6 550 47 F F (CH2)2CH3 ch3 och?ch3 A+8 160-87 - 568.6 568 On a Sephadex LH-20 column (72x6.3 cm) using chloroform as mobile phase. - in on cm) usjng chloroform as mobile phase. able 3.

Epimer A xampleX1 x2 R] RgR5 Rg/YR 6 no. 48 H H ch3 h H H C(CH3) 3 49 H H H CH3 H H C{CH3) 3 50 F K {CH2)2CH3 h H H C(CH3) 3 51 F H H 2)2CH3 H H C(CH3) 3 52 F H (CH?)pCH3 H ch3 H ch3 53 F H (CH?)?CK3 K ch3 H ch3 54 F H H ch3 HCiS 55 F H H (CH2)2CH3 ch3 H Cfi3 56 F H H (CH2)2CH3 CH(CH3)2 H CH3 57 F H H (CK2)?CH3 CH(CH3)2 H ch3 ("Id5 Epimer Mp °C (c=0.2 in CHgClg) Molecular calc. weight found Retention volume (ml) — 192-97 467° 502.6 502 1650-199511 - 196-200 +87° 502.6 502 1305-156031 - 261-67 469° 548.7 548 1950-210011 - 255-59 +63° 548.7 548 2145-237011 A 226-31 4 101° 520.6 520 1905-217511 8 232-38 435° 520.6 520 3300-372011 A 176-88 4104° 520.6 520 430-490 21 8 214-19 446° 520.6 520 630-715 21 A 133-35 4 110° 548.7 548 2100-240011 8 210-12 444° 548.7 ,548 2850-322511 (continued) Ια)*5 x, X2R1 R2 % *5R6/VR8 Epimer Mp °C (c=0.2 in ch2ci2) Molecular calc. weight found Retention volume (ml) F H H (CH?)?CH3 fenyl H ch3 A 235-40 +75° 582.7 582 2100-2400^ F H H {CH"}"CH3 fenyl H cb3 8 157-82 +75° 582.7 1582 2760-30751J 1) Η H (ch?)2ch3 h H H OC(CB3)3 140-42 +77° 546.7 546 1500-1665 1 ) Η H H · (CH2)2CH3 H H 0C(CH3)3 - 160-65 +69° 546.7 546 1620-1785 F H 2)2ch3 h H H °c(CH3)3 171-73 *65° 564.7 564 250-295 H 4) F H H {CH2)2CH3 H H 0C(CB3)3 - 161-64 +720 564.7 564 245-290 ά) F F H (CK2)2CH3 B H · 0CH2CH3 - 203-11 +99° 554.6 554 325-370 11 F F H (CH?)2CH3 H H 0CH(CH3)2 - 196-209 +70° 568.6 568 2235-2550 2) H H(CH2}2CH3 H ch3 H och2ch3 A+B 138-52 +102° 532.6 532 300-370 9) H H H (CH2)2CH3 ch3 H och2ch3 A+B 158-91 +33° 532.6 532 400-460 F H H (CH2)2CH3 ch3 K0CH2CH3 A 196-98 +110° 550.7 550 405-475 a F H H (CH2)2CH3 ch3 H OCH2CH3 B 212-14 4 36 550.7 550 585-670 a F H (ch2)2ch3 h ch3 H OC(CH3)3 A 154-57 +92° 578.7 578 345-400 u F H (CH2)?CK3 h cb3 H 00(ΟΗ3)3 B 161-58 427° 578.7 578 485-565 α 9 1 F H H (CH2)2CH3 ch3 H 0CH(CH3)2 A 221-24 +107° 554.7 564 355-425 a o\ F H H UB?)2CB3 ch3 H OCH(CH3)2 B 212-15 4-35° 564.7 564 535-635 9 1 F H H (CH2)2CH3CH3 H 0C(CB3)3 A 168-71 +103° 578.7 578 485-570 £' c 1 F H H (CH2)2CH3 ch3 H OC(CH3)3 8 174-79 +31° 578.7 578 255-310 Table 3. (continued) Example no.X1 x2R, *2R4R5R6/YR6 76 F H C(CH3I3 H ch3 H OCH?CH, 77 F H c(ch3)3 H ch3 H OCH?CH^ 78 F H H C!CH3)3 ch3 H OCH^CH^ 70 F H H c(ch3)3 ch3 H och?ch3 80 F F (CH? )/11^ H ch3 H OCHpCH-, 81 F F (CH?)?CH3 H CK3 H OCHpCH^ 82 F F H (CH?)?CHq ch3 H OCH?CHq 83 F F H (CH^CH·, ch3 H OCH?CH^ 84 F F H (CH?)j,CH^ ch3 H OCH?CHq 85 F F H (CHp)?CH3 ch3 H och(ch3) 86 F F H (CH?)?CH? ch3 H OCH(CH3) 87 F F H (CH?)?CHq ch3 H OCH(CH3) 88 F F H(CH2}2CH3 ch3 CH3 och2ch Epimer Mp °C (c=0.2 in Molecular weight Retention ch2ci2) calc. found volume (ml) A 220-22 +95° 564.7 564 380-430 21 8 227-37 418° 564.7 564 540-630 21 A 229-32 4-115° 554.7 564 385-455 7 2) 7 8 8 8 246-51 434° 564.7 564 565-695 21 A 167-70 495° 568.6 568 300-330 51 B 188-90 426° 568.6 .563 365-395 51 A+B 178-96 468° 568.6 568 3720-415511 A 217-21 4105° 568.6 568 290-340 51 8 211-15 432° 568.6 568 341-395 51 A+B 198-210 467° 582.6 582 2190-39001) A 232-37 496° 582,6 582 2190-23551 1 8 225-32 437° 582.6 582 3630-390011 - - - 582.6 582 385-440 21 1) 2) 3) 4) ) On a Sephadex LH-20 column On a Sephadex LHr2O column On a Sephadex LH-20 column On a Sephadex LH-20 column On a Sephadex LH-20 column (75x6.3 cm) using heptane-chloroform-ethanol (20:20:1) as mobile phase (87.5x2.5 cm) using heptane-chloroform-ethanol (20:20:1) as mobile phase (72x6.3 cm) using chloroform as mobile phase (80x2.5 cm) using chloroform as mobile phase (81.5 x2.5 cm) using chloroform as mobile phase The following non-limitative examples illustrate formulations intended for different topical forms of administration. The amount of active steroid in the percutaneous formulations are ordinarily 0.001-0.2% (w/w preferably 0.01-0.1% (w/w).

Example 8¾ . Pharmaceutical Preparations Formu 1 at i on 1, Oi ntment Steroid, micronized Liquid paraffin White soft paraffin 0.025 g 10.0 g ad 100.0 g Formulation 2, Ointment Steroid Propylene glycol Sorbitan sesquioleate Liquid paraffin White soft paraffin 0.025 g 5.0 g 5.0 g .0 g ad 100.0 g Formulation 3, Oil in water cream Steroid Cetanol Glyceryl monostearate Liquid paraffin Cetomacrogol 1000 Citric acid Sodium citrate Propylene glycol Water 0.025 g 5.0 g 5.0 g 10.0 g 2.0 9 0.1 g 0.2 g .0 g ad 100.0 g Formulation 4, Oil in water cream Steroid, micronized White soft paraffin 0.025 15.0 9 9 5 Liquid paraffin 5.0 9 Cetanol 5.0 9 Sorbiraacrogol stearate 2.0 9 Sorbitan monostearate 0.5 9 Sorbic acid 0.2 g 10 Citric acid 0.1 9 Sodium citrate 0.2 9 Water ad 100.0 9 Formulation 5, Water in oil cream 15 Steroid 0.025 s White soft paraffin 35.0 9 Liquid paraffin 5.0 9 Sorbitan sesquioleate 5.0 g 20 Sorbic acid 0.2 9 Citric acid 0.1 9 Sodium citrate 0.2 9 Water ad 100.0 g 25 Formulation 6, Lotion Steroid 0.25 mg Isopropanol 0.5 Carboxyvinyloolywer 3 s»g 30 NaOH q.s. Water ad KO 9 Formulation 7, Suspension for injection Steroid, micronized Sodium carboxymethylcellulose HaCl Polyoxyethylene (20) sorbitan monoleete Phenyl carbinol Water, sterile 0.05-10 mg 7 mg mg 0.5 rag mg ad 1.0 ml Formulation 8, Aerosol for oral and nasal inhalation Steroid, micronized Sorbitan trioleate Trichlorofluoromethane Di chiorotetrafluoromethane Dichlorodifluoromethane 0.1 % w/w 0.7 % w/w 24.8 % w/w 24.8 % w/w 49.6 % w/w Formulation 9, Solution for atomization Steroid 7.0 rag Propylene glycol 5.0 g Water ad 10.0 g Formulation 10, Powder for inhalation A gelatin capsule is filled with a mixture of Steroid, micronized 0.1 mg Lactose 20 rag The powder is inhaled by means of an inhalation device.

The affinity of the mew androstane-178-carboxylie acid esters to the glucocorticoid receptor All steroids according to formula I are physiologically active compounds. The affinity of the novel androstane-17S~carboxylic acid esters to the glucocorticoid receptor has been, used as a model for determination of the anti-inflammatory potency.

Their receptor affinities have been compared to budesonide ([2 2 R, S]-16g,17a-buty1idenedioxy~11β,21-dihydroxypregna-1,4diene~3,20~dione) a highly active glucocorticoid with a. favourable ratio between local and systemic effects (Thalen and Brattsand, Arzneim.-Forsch.29, 1687-90 (1979)).

Male Sprague-Dawley rats, one to two months of age, were used throughout the investigation. The thymus was removed and put into ice-cold saline. The tissue was homogenized in a Potter Elvehjem homogenizer in 10 ml of a buffer containing 20 mM Tris, pH 7.4, 10% (w/v) glycerol, 1 mM EDTA, 20 m« h'aMoOd, 10 mM mercaptoethanol. The homogenate was centrifuged for 15 rain at 20,000 x g. Portions of the 20,000 x g supernatant (230 ul) were incubated for about 24 h at 0°C with 100 ul phenylmethylsulphonylfluoride (an esterase inhibitor, final cone. 0.5 rnM), 20 ul unlabelled competitor and 50 ul labelled dexamethasone (final cone. 3 nH). Bound and free steroid were separated by incubating the mixture with 60 ul 2.5% (w/v) charcoal and 0.25% (w/v) dextran T70 suspension in 20 mH Tris, ¢5 7.4, 1 mH EDTA, aad 20 mH NaMoO^ for 10 min at (PC. Following a centrifugation at 500 x g for 10 min, 230 ul of the supernatant was counted in 10 nal Insta-Gel in a Packard scintillation spectrophotometer. The supernatants were incubated with a) ( H]dexamethasone alone, b) [ H]dexamethasone plus 1000 fold excess of unlabelled dexamethasone and c) ( H]dexamethasone plus 0.03-300 fold ’’excess" of competitor. The nonspecific binding was determined when 1000 fold excess of unlabelled dexamethasone was added to [^H]-labelled dexamethasone.

The radioactivity bound to the receptor in the presence of competitor divided by the radioactivity bound to the receptor in the absence of competitor multiplied by 100 gives the percentage specific binding of labelled dexamethasone. For each concentration of a competitor the percentage specifically bound radioactivity is plotted against the log of concentration of competitor. The curves are compared at the 50% specific binding level and referenced to budesonidewhich is assigned a relative binding affinity (RBA) of 1.

Table 4. Table summarising relative binding affinities (R3A) to the glucocorticoid receptor of some of the investigated componds.

Compound according to Ex. No. RBA Budesonide 1 4 epimer 3 0.30 5 epimer 3 0.17 27 0.50 38 0.04 55 0.20 54 0.05 67 0.04 69 0.44 84 1.03 87 0.63

Claims (4)

1. A process for the preparation of a compound of the formula: or a stereoisomer thereof, in which formula the 1,2-position 5 is saturated or is a double bond; Xj is hydrogen, fluorine,, chlorine or bromine; X 2 is hydrogen,, fluorine, chlorine or bromine; R 2 is a straight or branched hydrocarbon chain having 1-10 carbon atoms and 10 R 7 is hydrogen or an acyl group with 1-10 carbon atoms arranged in a straight or branched chain, which process comprises reaction of a compound of the formula 0-s. c ^ CH 3 ^ch 3 with a compound of the formula wherein Xj, X 2 , R 2 , R 7 an< ^ have the meanings given above, in the presence of an acid catalyst.

2. A process according to claim 1 wherein a compound of formula D, wherein X, is hydrogen, X 2 is hydrogen, R 2 is a straight hydrocarbon chain having 3 carbon atoms, R 7 is hydrogen and the 1,2-position is a double bond, is prepared.

3. A process according to claim 1 substantially as described with reference to the Examples.

4. A compound of the formula D prepared by the process claimed in any one of claims 1 to 3.