GB1563595A - Halogenoprepnadienes and process for the manufacture thereof - Google Patents

Abstract

2,9 alpha -Dichloro-6 alpha -fluoro-16 alpha -methyl-11 beta ,17,21-trihydroxy- pregna-1,4-diene-3,20-dione compounds of the formula (I) <IMAGE> (R1, R2 = OR where R = H, acid residue) have antiinflammatory effects. They are prepared by reacting corresponding 2-dechloro compounds with chlorine and subsequently eliminating HCl from the 1,2-dichloro compounds obtained in this way.

Description

(54) NOVEL HALOGENOPREGNADIENES AND PROCESS FOR THE MANUFACTURE THEREOF (71) We, CIBA-GEIGY AG, a body corporate organised according to the laws of Switzerland, of Basle, Switzerland, do hereby declare the invention, forwhich we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement::- The invention provides 2,9a-dichloro- 6a - fluoro - 16a- methyl - ll,l7,2l - tri - hydroxy - pregna - 1,4 - diene - 3,20- dione compounds of the formula

wherein each of Rl and R2 represents a free or esterified hydroxyl group, whilst R, and R2 together can also represent a cyclic 17,21-diester group e.g. which is derived from an ortho-carboxylic acid or from carbonic acid, and a process for the manufacture of these compounds.

The esterified hydroxyl groups mentioned above are derived from acids which are customarily suitable as esterification compounds in hydroxy-steroids intended for therapeutic use, for example from unsubstituted or substituted organic carboxylic acids containing 1 to 18 carbon atoms, from sulphonic acids or from inorganic acids, Preferred carboxylic acids of the aliphatic series are in particular the lower aliphatic mono- or dicarboxylic acids containing 1 to 7 carbon atoms, for example acetic acid, propionic acid, the butyric acids, the valeric acids, the caproic acids, in particular trimethylacetic acid, n-caproic acid, dimethylethylacetic acid, malonic acid, succinic acid, glutamic acid. Suitable higher aliphatic carboxylic acids are, for example, capric or undecylenic acid, palmitic acid, oleic acid or stearic acid.

Examples of cycloaliphatic or cycloaliphatic-aliphatic monocarboxylic acids are cyclopropane-, cyclobutane-, cyclopentane- and cyclohexanecarboxylic acid and cyclopropyl- or cyclobutylmethanecarboxylic acid, or one of the cyclopentyl- or cyclohexylethanecarboxylic acids. Preferred substituted carboxylic acids are in particular the hydroxylated carboxylic acids, for example the malic acids, the lactic acids, the citric acids, glycollic or diglycollic acid, or alkoxycarboxylic acids, in particular lower alkoxycarboxylic acids, such as methoxy- or ethoxyacetic acid or methoxy- or ethoxypropionic acid.Aromatic carboxylic acids which are particularly suitable as esterification components are the monocyclic acids, such as benzoic acid and the derivatives thereof, or phthalic acid, and araliphatic carboxylic acids are monocycliclower aliphatic carboxylic acids, such as phenylacetic or phenylpropionic acid. The esterified hydroxyl groups can also however be derived from heterocyclic acids, for example from nicotinic or isonicotinic acid.

Suitable sulphonic acids are chiefly methanesulphonic acid or monocyclic aromatic sulphonic acids, for example benzene- or toiuenesulphonic acids, especially p-toluenesulphonic acid. Finally, the esterified group can be derived from inorganic acids, in particular sulphuric acid and ortho-, meta- or pyro-phosphoric acid. The esters of polybasic acids are generally in the form of the monoesters.

The ester groups can also be derived from orthocarboxylic acids, in particular lower aliphatic ortho-carboxylic acids containing 1 to 7 carbon atoms, such as orthoformic acid, orthoacetic acid or orthopropionic acid, or from carbonic acid. The esters of such acids are in the form of cyclic 17,21ortho-carboxylic acid esters or cyclic 17,21carbonates.

Water-soluble preparations of formula (I) can be obtained by advantageously preparing hemiesters of polybasic acids.

such as dicarboxylic acids, for example succinic or phthalic acid. or of sulphuric acids or of phosphoric acids, and then converting these into salts of organic bases, for example of simple aliphatic amines, such as trimethylamine, diethylamine, ethylamine, propylamine or isopropylamine, or of cyclic bases, such as piperidine, moropholine or pyrrolidine, or the homologues thereof. However, for the same purpose it is also possible to prepare esters which are derived from a carboxylic acid which contains amino groups, for example diethylamino-, piperidino- or morpholinoacetic acid, or any other known amino acid, and to quaternise the amino group in these esters, so that the watersoluble quaternary ammonium salts are formed.

The novel compounds of the formula (I) encompass the free 2,9a-dichloro-6a- fluoro - 16fr - methyl - 11A,17,21 - trihydroxy pregna-l,4-diene-3,20-dione (2,9a- dichloroparamethasone), the 17- and 21monoester and the 1 7,2 1 -diester thereof, in particular also the cyclic 17,21-diesters.

These compounds possess valuable pharmacological properties. By way of example, they have in particular a pronounced antiinflammatory action, as can be demonstrated in animal tests, for example on rats in the foreign body granuloma test. For example, when applied locally in the dosage range between 0.003 mg per cotton wool pellet and 0.03 mg per cotton wool pellet they exhibit a marked antiinflammatory action. An action on the thymus is observed in this mode of administration only from 0.03 mg per cotton wool pellet and action on adrenals and body weight occurs only at doses from 0.3 mg per cotton wool pellet.For example, in the indicated mode of administration and in the above mentioned test on rats, both 2,9adichloroparamethasone 21-pivalate and 2,9a - dichloroparamethasone 17,21 dipropionate exhibit an ED20~so from 0.001 mg per cotton wool pellet. The novel compounds can therefore be used as antiinflammatory agents, in particular in dermatology. However, they are also valuable intermediates for obtaining other useful substances, especially pharmacologically active compounds.

The compounds of the above formula (I) can be obtained in a manner known per se.

In particular, they can be obtained by (a) the addition of chlorine to the 1,2double bond in a compound of the formula

wherein R1 and R2 are as defined in formula (I), whilst optionally protecting the 11hydroxy group temporarily beforehand, and the dehydrochlorination of the resultant 1,2dichloro compound, or (b) treating a compound of the general formula

wherein Rl and R2 are as defined in formula (1), with hypochlorous acid or with a hypochlorous acid donor, or (c) treating a compound of the general formula

wherein R1 and R2 are as defined in formula (I), with hydrogen chloride or a hydrogen chloride donor, and/or, if desired, in compounds of the formula (I), in which at least one of the groups R1 and R2 is esterified, converting at least one esterified hydroxyl group into a free hydroxyl group., or in compounds of the formula (I), in which at least one of the groups R, and R2 represents a free hydroxyl group, whilst optionally protecting the 1 l-hydroxyl group temporarily, esterifying at least one free hydroxyl group, and/or, if desired, converting hemiesters of dicarboxylic acids or of polybasic inorganic acids into their metal salts or salts of organic bases.

According to method (a), chlorine is added to the 1,2-double bond in a manner known per se. to this end, preferably elementary chlorine is used and the chlorination is carried out in an inert organic solvent, for example an ether, such as dioxane or fetrahydrofurane, a halogenated hydrocarbon, for example methylene chloride, or an aliphatic carboxylic acid with up to 7 carbon atoms, such as acetic acid or propionic acid.

Instead of using carboxylic acids it is also possible to use derivatives thereof, such as acid amides, for example dimethyl formamide, or nitriles, such as lower alkylnitriles, for example acetonitrile.

Advantageously, mixtures of these solvents can also be used, in particular a mixture of an ether, such as dioxane, with one of the above mentioned lower aliphatic carboxylic acids. The process can be carried out with chlorine in an amount substantially in excess of the theoretical amount; but preferably the stoichiometric amount of chlorine is used. The chlorination is advantageously carried out at low temperature, approx. between -50" and- +30"C, for example between -20" and +10"C, and in the dark. The reaction time is normally several hours or days, for example up to 7 days.In a particularly preferred embodiment of the process, the starting steroid is dissolved in one of the solvents mentioned above, for example dioxane, and treated with a solution of the chlorinating agent, for example chlorine, in a lower aliphatic carboxylic acid, for example propionic acid, and this solution is then allowed to stand at the given temperature for several days.

However, the chlorination of the 1,2double bond can also be effected with mixtures of two different chlorinecontaining compounds one of which yields positive and the other negative chlorine.

Examples of suitable reagents which are able to set free positive chlorine are chlorinated acid amides or acid imides, such as chlorosuccinimide or chloroacetamide, and reagents which yield negative chlorine are, for example, hydrogen chloride and alkali metal chlorides. The above mentioned solvents can also be used for the addition of chlorine with these reagents.

If desired, the 1 1-hydroxyl group can be protected before the chlorination, preferably by esterification with trifluoroacetic acid. The trifluoroacetates are obtained by reacting the starting materials with trifluoroacetic chloride or anhydride in a manner known per se. It is known that this ester can be easily split off again by hydrolysis or solvolysis, for example by treatment with hydroxides, carbonates, bicarbonates or acetates of alkali metals or alkaline earth metals, for example in alcoholic or aqueous-alcoholic solution, for example in methanolic solution, or with alcohols alone.A particular method of carrying out the solvolysis of the 1 l-trifluoroacetate group is that described in German patent specification 1,593,519, which is chiefly suitable whenever it is a question of leaving the ester groups in 17- and/or 21-position intact. This method comprises treating the Il-ester in a lower alcohol with a salt of an acid whose pKa-value is in the range between about 2.3 and about 7.3, such as sodium or potassium azide or sodium or potassium formate. If appropriate, this salt can also only be used in catalytic amounts.

Furthermore, the hydrolysis of the 11trifluoroacetate group can also be effected by treatment with other basic reagents, for example with amines, in particular heterocyclic bases, such as pyridine or collidine. Finally, the saponification by treatment with silica gel according to the process described in DT-OS 2,144,405 is also possible.

The ll-hydroxyl protective group can be removed immediately after the addition of chlorine te the 1,2-double bond or, if appropriate, simultaneously with dehydrochlorination by treatment with a base to be carried out, according to the process, after the chlorination. However, if desired, the protective group can be removed not until after the removal of hydrogen chloride by treatment with a base.

The dehydrochlorination of the 1,2dichloro compounds obtained by the addition of chlorine in the 1,2-double bond can advantageously be accomplished with a base. Suitable bases are, for example, tertiary organic nitrogen bases, such as the lower aliphatic amines, for example triethylamine, or heterocyclic bases, such as pyridine and homologues thereof, for example collidine, or aromatic bases, such as N,N-dialkylanilines. However, it is also possible to use inorganic bases, such as in particular the alkali metal and alkaline earth metal salts also used for removing the above mentioned I l,B-hydroxyl protective group, for example potassium or sodium acetate or potassium or sodium bicarbonate, in aqueous-alcoholic solution, and the corresponding hydroxides.The dehydrohalogenation is preferably carried out in the temperature range between approx. 200 and 100"C and over the course of half an hour up to approx. 30 hours, depending on whether the reaction is carried out at elevated or low temperature.

Preferably, an excess of the dehydrohalogenating agent is used.

According to method (b), the elements of hypochlorous acid are added in a manner known per se to the 9,1 I-double bond of the compounds of the formula (III) by, for example, treatment with aqueous hypochlorous acid or with hypochlorous acid donors, such as N chlorocarboxamides or N chlorocarboximides (cf. US patent specification 3,057,886), in the presence of water and/or an inert solvent, such as a tertiary alcohol, for example butanol, an ether, for example diethyl ether, methyl isopropyl ether, dioxane, or a ketone, such as acetone, optionally in the presence of a strong acid. An advantageous method of carrying out this process is the reaction with tert.-butylhypochlorite in an inert waterimmiscible solvent, for example a nitrosubstituted hydrocarbon, in the presence of perchloric acid (cf. German patent specification 2,011,559).

According to method (c), the 9p, 11,5- oxido group of the starting compounds of the formula (IV) is treated in a manner known per se with hydrogen chloride and the process can be carried out in aqueous medium or in an inert organic solvent.

According to the process, esterified hydroxyl groups in the 17- and/or 21position can, if desired, be converted into free hydroxyl groups. This conversion can be accomplished in a manner known per se, for example preferably by alkaline saponification with the hydroxides, carbonates or bicarbonates of alkali metals, in particular of sodium or potassium, for example in aqueous or aqueous-alcoholic solution. The use of an aqueous solution of sodium bicarbonate in methanol or ethanol is preferred.

The selective saponification of the 21ester group in 17,21-esters can be effected in a manner known per se by, for example, treating these esters with a solution of a strong acid, such as perchloric acid, in an alcohol, for example methanol, preferably at room temperature, to yield in this way the 17-monoesters. Another method of obtaining 17-mono-esters comprise treating the cyclic 17,21-orthoesters of a carboxylic acid with a weak organic acid, for example oxalic acid.

If desired, according to the process of this invention free hydroxyl groups can be esterified in the 17-and/or 21-position. The esterification is again carried out in a manner known per se, for example by treating the steroid alcohol with a reactive functional derivative of the acid in question, for example an organic acid, in particular a carboxylic acid. In particular the chlorides or the anhydrides of these acids are used, preferably in the presence of a tertiary base, such as pyridine or collidine.If it is desired to esterify both groups in 17,21-dihydroxy compounds, or also the 17cr-hydroxy group in 21-esters, then acylation is carried out with the indicated reactive functional acid derivatives in the presence of a strong acid, in particular an aromatic sulphonic acid, for example p-toluenesulphonic acid, which acts as catalyst, It is advantageous to protect the ll-hydroxyl group temporarily before these esterification reactions, for example by conversion into the trifluoroacetate, because under the conditions in which the 17-hydroxy group is esterified, the 11hydroxyl group is also easily acylated. As described above, the trifluoroacetoxy group can be selectively reconverted into the free hydroxyl group.It is known that orthoesters can be obtained advantageously by reacting a 17,21-steroid-diol with an orthoester of the R'-C(OR")3 type, wherein R' represents a hydrogen atom or an alkyl group and R" represents an alkyl group. in the presence of a strong acid, for example p-toluenesulphonic acid, in an inert organic solvent, for example an aromatic hydrocarbon, such as benzene or homologues thereof, Chiefly orthoacetates and orthopropionates are prepared.

The starting materials necessary for carrying out the above process methods are known or they can be obtained in a manner known per se.

The present invention also provides pharmaceutical preparations which contain as active ingredient a compound according to the invention of the formula (I) or a salt of such a compound with salt-forming properties, together with a pharmaceutical carrier.

Suitable pharmaceutical preparations are primarily ones for topical application, such as creams, ointments, pastes, foams, tinctures and solution, which contain approx. 0.005% to approx. 0.1 ' of active compound, and also preparations for oral administration, for example tablets, coated tablets and capsules, and those for parenteral administration.

Creams are oil-in-water emulsions which contain more that 50% of water. Fatty alcohols are chiefly used as oleaginous base, for example lauryl, cetyl or stearyl alcohol, fatty acids, for example palmitic or stearic acid, liquid to solid waxes, for example isopropyl myristate, wool wax or bees-wax, and/or hydrocarbons, for example petroleum jelly (petrolatum) or paraffin oil.

Suitable emulsifiers are surface-active substances with primarily hydrophilic properties, such as corresponding non-ionic emulsifiers, for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters of polyoxyethylene sorbitan fatty acid esters (Tweens Registered Trade Mark): polyoxyethylene fatty alcohol ethers or esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulphates, for example sodium lauryl sulphate, sodium cetyl sulphate or sodium stearyl sulphate, which are customarily used in the presence of fatty alcohols, for example cetyl alcohol or stearyl alcohol.

Additives to the water phase include agents which reduce water loss through evaporation, for example poly-alcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, as well as preservatives, perfumes etc.

Ointments are water-in-oil emulsions which contain up to 70If) preferably however approx. 20% to about 50%, of water or aqueous phase. The oleaginous phase comprises chiefly hydrocarbons, for example petroleum jelly, paraffin oil and/or hard paraffins, which contain preferably hydroxy compounds suitable for improving the water-absorption, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohols, or wool wax.

Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans Registered Treade Mark), for example sorbitan oleate and/or sorbitan isostearate. Additives to the water phase include humectants, such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, and preservatives, perfumes etc.

Greasy ointments are anhydrous and contain as base in particular hydrocarbons, for example paraffin, petroleum jelly and/or liquid paraffins, furthermore natural or partially synthetic fat, for example coconut fatty acid triglycerides, or preferably hardened oils, for example hydrated ground nut or castor oil, and also fatty acid partial esters of glycerol, for example glycerol mono- and distearate, and, for example, the fatty alcohols, emulsifiers and/or additives for increasing the water-absorption mentioned in connection with the ointments.

Pastes are creams and ointments containing powdered ingredients which absorb secretions, such as metal oxides, for example titanium oxide or zinc oxide, and talc and/or aluminium silicates whose- purpose it is to bind moisture or secretion present.

Foams are administered from pressurised dispensers and are liquid oil-in-water emulsions in aerosol form, with halogenated hydrocarbons, such as chlorofluoro-lower alkanes, for example dic hlorodifl uoromethane and dichlorotetrafluoroethane being used as propellants. For the oleaginous phase there are used, inter alia, hydrocarbons, for example paraffin oil, fatty alcohols, for example cetyl alcohol, fatty acid esters, for example isopropyl myristate, and/or other waxes. As emulsifiers there are used, inter alia. mixtures of those emulsifiers with primarily hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those with primarily lipophilic properties, such as sorbitan fatty acid esters (Spans). In addition, the conventional additives are used, such as preservatives etc.

Tinctures and solutions generally have an - aqueous ethanolic base to which are added, inter alia, polyalcohols, for example glycerol, glycols, and/or polyethylene glycol, as humectants for reducing water loss, and fat-restoring substances, such as fatty acid esters with lower polyethylene glycols, i.e. lipophilic substances which are soluble in the aqueous mixture as substitute for fatty substances which are taken from the skin with the ethanol, and, if necessary, other assistants and additives.

The pharmaceutical preparations for topical application are obtained in known manner, for example by dissolving or suspending the active substance in the base or in a part thereof, if necessary. When processing the active substance in the form of a solution, it is usually dissolved in one of the two phases before the emulsification, and when processing the active substance in the form of a suspension, it is mixed with a part of the base before the emulsification and then added to the remainder of the formulation.

Besides the pharmaceutical preparations which can be applied topically, other suitable preparations are those for enteral, for example oral, and parenteral administration to warm-blooded animals and which contain the pharmacologically active substance as sole ingredient or together with a pharmaceutically acceptable carrier. These pharmaceutical preparations contain about 0.01% to about 10% of active substance and are in dosage unit form, such as coated tablets, tablets, capsules, suppositories or ampoules. They are obtained in known manner, for example by conventional mixing, granulating, coating, dissolving or lyophilising methods.

The dosage of active substance depends on the species of warm-blooded animal, the age, and the individual condition as well as on the mode of application.

The present invention also relates to the use of the novel compounds of the formula I and of the salts of such compounds with salt-forming properties, preferably for treating inflammations, chiefly as antiinflammatory glucocorticoids for local application, normally in the the form of pharmaceutical preparations, especially in the form of pharmaceutical preparations for topical application.

The compounds of the present invention can also be used as additives to animal feeds.

The following Examples describe the invention in more detail.

Example I 700 ml of tert.-butyl alcohol are poured over 34.57 g of 2-chloro-6(z-fluoro-16a- methyl- 1 7a,2 1 -dihydroxy-pregna- 1,4,9(11)- triene-3,20-dione 21-acetate in a flask of 2000 ml capacity and, under nitrogen and with stirring, 35 ml of a 10% solution of perchloric acid and finally 10 ml of tert.

butylhypochlorite are added thereto. The steroid has completely dissolved after stirring for a further 2 hours; but after 5 hours, a crystalline material precipitates again. Then 360 ml of water are added, stirring is continued for a time, and then the precipitate is collected by filtration with suction. The filter cake is washed firstly with 200 ml of methanol-water (1:1) and then thoroughly with water and dried in vacuo.

The concentrated mother liquors are extracted with ethyl acetate and the extract is dried over sodium sulphate. The dry product is dissolved in acetone and treated at elevated temperature with animal charcoal. Toluene is then added to the filtered solution and the acetone is evaporated in vacuo. The precipitated crystals are collected with suction, washed with toluene and dried in a vacuum exsiccator. The product is 2,9-di-chloro- - - fluoro - 16 - methyl - l lA,17a,21 - tri - hydroxy-pregna-l ,4-diene-3,20-dione 21 acetate (2,9dichloroparamethasone 21acetate), which melts at 1240C. UV absorption spectrum A max. 249 nm (E= 12952).

The starting material can be prepared as follows: 35 g of 2-chloroparamethasone 21-acetate are dissolved in 70 ml of pyridene and 210 ml of dimethyl formamide. The solution is cooled to15 to -200C and treated dropwise with stirring in the course of approx. 15 minutes, at a temperature of -10" to -15"C, with 22 ml of a solution prepared from 3 g of sulphur dioxide and 90.4 g of mesyl chloride (methanesulphonyl chloride). The mixture is stirred for a further 20 minutes at the same temperature and then water is added dropwise with caution (especially at the start), while the temperature is kept at 0 to -50C. The mixture is then poured into 1500 ml of water and stirred for 30 minutes.After this time, the precipitate which has formed is collected with suction and washed with water. The filter cake is then dissolved in 700 ml of boiling methanol and, at boiling temperature, 210 ml of water are added, whereupon a thick crystalline precipitate falls out of the solution. After cooling to 0 C, the precipitated crystals are collected with suction, washed with methanol/water (1:1) and dried in an exsiccator. The product is 2-chloro-6cw-fluoro- 16cr-methyl-17a,21 - dihydroxy - pregna - 1,4,9(1 1)triene - 3,20 - dione 21-acetate, which melts at 1300-- 148"C.

Example 2 - 10 g of 2,9a-dichloro-paramethasone 21acetate (2,9a-dichloro-6-fluoro- 16- methyl-11p,17a 21-trihydroxy-pregnadiene- 3,20-dione 21-acetate) are dissolved in 250 ml of methanol and the solution is cooled to OOC under nitrogen. To this solution is added dropwise at 0 C and in the course of 15 minutes a solution prepared from 5 g of potassium carbonate, 70 ml of water and 70 ml of methanol and which has been freed from oxygen by introducing nitrogen. The mixture is then stirred for 45 minutes at OOC.

The solution is then adjusted with 10 ml of 50 /n acetic acid to a slightly acid reaction.

The methanol is evaporated completely in vacuo and the resultant suspension is filtered with suction. The filter cake is washed with water and then sharply filtered with suction. The residue is dissolved in acetone and the solution is concentrated in vacuo and the residue dried to constant weight. Crystallisation from acetonetoluene yields pure 2,9n-dichloro- paramethasone, which melts at 2400-- 250"C (with decomposition).

Example 3 With stirring, 2 g of 2,9ez- dichloroparamethasone are dissolved in 10 ml of pyridine and the solution is treated with a solution obtained by mixing 4 ml of trimethylacetyl-chloride and 10 ml of pyridine at OOC. The mixture is then allowed to stand for I hour at 200 C. After addition of ice, the mixture is extracted with ethyl acetate and the extract is washed with 2N hydrochloric acid and then with water, dried and concentrated. The residue is filtered through a column of 30 g of aluminium oxide of activity II and the residue obtained from the filtrate is recrystallised from methanol/water to yield 2,9(r-dichloroparamethasone 21-pivalate (trimethylacetate), which melts at 2610-- 262"C with decomposition.

Example 4 11.92 g- of 2,9-dichloroparamethasone are dissolved in 50 ml of tetrahydrofurane and the solution is treated at 200C with 12 ml of triethyl orthopropionate and 500 mg of p-toluenesulphonic acid and allowed to stand for 1 hour at 200 C. Then 4 ml of pyridine are added, the batch is slightly concentrated in vacuo and the reaction product is taken up in ethyl acetate. The ethyl acetate extract is washed 5 times with water, dried and concentrated. The residue is then dissolved in approx. 150 ml of methylene chloride, freshly distilled isopropyl ether is added and the mixture is concentrated to some extent by heating. As the batch cools the ethyl 17e,21-ortho propionate of 2,9a-dichloroparamethasone precipitates, is collected with suction, washed with isopropyl ether, and dried.

Melting point: 223-2370C (with decomposition).

Example 5 A solution of 1.5 g of 2,9- dichloroparamethasone 17-propionate in 10 ml of pyridine is treated at OOC with 5 ml of propionic anhydride and the mixture is allowed to stand for 1 hour at 00C. After this time ice is added and the mixture is again allowed to stand for I hour and then extracted with ethyl acetate. The extract is washed with 2N hydrochloric acid, water, potassium hydrogen carbonate and water, dried and concentrated.

The residue is crystallised from methanol to yield 2,9a-dichloroparamethasone 17,21dipropionate, which is still further purified as follows: The obtained amount of ester is chromatographed through a column of 50 g of silica gel with methylene chloride as eluant. Fractions 4-13 are combined and recrystallised from acetone-methanol. The purified ester melts at 1350C.

The starting material can be prepared as follows: A solution of 5 g of 2,9a-dichloro paramethasone 17,21-ethyl-orthopropionate in 220 ml of methanol and a solution of 1.4 g of oxalic acid (dihydrate) in 12 ml of water are stirred at 500C and after 5 minutes a clear solution results. After 1 hour water is added, and the mixture is concentrated in vacuo and extracted with 500 ml of ethyl acetate. The extract is washed twice with 100 ml of 2N potassium hydrogen carbonate and three times with water, dried and concentrated. The residue is dissolved in acetone and toluene is added to the solution. The mixture is heated, so that the acetone distills off, then cooled to yield 2,9a-dichloroparamethasone 17propionate, which melts at 239O2480C (with decomposition).

Example 6 A solution, cooled to 0 C, of 1 g of 2,9a dichloro-6a-fluoro-16cr-methyl-1 l,B 17,21- trihydroxy-pregna- 1 ,4-diene-3,20-dione in 5 ml of pyridine is treated with 2 ml of valeric anhydride and the reaction mixture is allowed to stand for 2 hours at OOC. After addition of ice, the mixture is stood for 15 minutes at 200C and extracted with ethyl acetate. The combined ethyl acetate extracts are washed with 2N hydrochloric acid and water, dried, and filtered through a column of 30 g of aluminium oxide of activity II and washed.The residue of the evaporated filtrate is recrystallised from acetone-isopropyl ether to yield the 21valerate of 2,9ex-dichloro-6tx-fluoro- 16a- methyl- 11 ,17a,21 -trihydroxy-pregna- 1,4diene-3,20-dione (2,9a-d~ichloro- paramethasone 21-valerate), which melts at 1880-1910C.

WHAT WE CLAIM IS: I. A process for the manufacture of 2,9a- dichloro - - fluoro - 16a - methyl - I 17,21 - trihydroxy - pregna - 1,4 - diene - 3, 20 - dione compounds of the formula

wherein each of R1 and R2 represents a free or esterified hydroxyl group, whilst R1 and R2 together can also represent a cyclic 17,21-diester group which process comprises (a) the addition of chlorine to the 1,2double bond in a compound of the formula

wherein R1 and R2 are as defined in formula (I), whilst optionally protecting the 11hydroxyl group temporarily beforehand, and the dehydrochlorination of the resultant 1,2-dichloro compound, or (b) treating a compound of the general formula

wherein R1 and R2 are as defined in formula (I), with hypochlorous acid or with a hypochlorous acid donor, or (c) treating a compound of the general formula

wherein R1 and R2 are as defined in formula (I), with hydrogen chloride or a hydrogen chloride donor, and/or, if desired, in compounds of the formula (I), in which at least one of the groups R, and R2 is esterified, converting at least one esterified hydroxyl group into a free hydroxyl group, or in compounds of the formula (I), in which at least one of the groups R1 and R2 represents a free hydroxyl group, whilst optionally protecting the 1 l-hydroxyl group temporarily. esterifying at least one free hydroxyl group, and/or, if desired, converting hemiesters of dicarboxylic acids or of polybasic inorganic acids into their metal salts or salts of organic bases.

2. A process according to claim 1(a), wherein the starting material is treated in an inert organic solvent with elementary chlorine.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (39)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   The residue is crystallised from methanol to yield 2,9a-dichloroparamethasone 17,21dipropionate, which is still further purified as follows: The obtained amount of ester is chromatographed through a column of 50 g of silica gel with methylene chloride as eluant. Fractions 4-13 are combined and recrystallised from acetone-methanol. The purified ester melts at 1350C.

   The starting material can be prepared as follows: A solution of 5 g of 2,9a-dichloro paramethasone 17,21-ethyl-orthopropionate in 220 ml of methanol and a solution of 1.4 g of oxalic acid (dihydrate) in 12 ml of water are stirred at 500C and after 5 minutes a clear solution results. After 1 hour water is added, and the mixture is concentrated in vacuo and extracted with 500 ml of ethyl acetate. The extract is washed twice with 100 ml of 2N potassium hydrogen carbonate and three times with water, dried and concentrated. The residue is dissolved in acetone and toluene is added to the solution. The mixture is heated, so that the acetone distills off, then cooled to yield 2,9a-dichloroparamethasone 17propionate, which melts at 239O2480C (with decomposition).

   Example 6 A solution, cooled to 0 C, of 1 g of 2,9a dichloro-6a-fluoro-16cr-methyl-1 l,B 17,21- trihydroxy-pregna- 1 ,4-diene-3,20-dione in 5 ml of pyridine is treated with 2 ml of valeric anhydride and the reaction mixture is allowed to stand for 2 hours at OOC. After addition of ice, the mixture is stood for 15 minutes at 200C and extracted with ethyl acetate. The combined ethyl acetate extracts are washed with 2N hydrochloric acid and water, dried, and filtered through a column of 30 g of aluminium oxide of activity II and washed.The residue of the evaporated filtrate is recrystallised from acetone-isopropyl ether to yield the 21valerate of 2,9ex-dichloro-6tx-fluoro- 16a- methyl- 11 ,17a,21 -trihydroxy-pregna- 1,4diene-3,20-dione (2,9a-d~ichloro- paramethasone 21-valerate), which melts at 1880-1910C.

   WHAT WE CLAIM IS: I. A process for the manufacture of 2,9a- dichloro - - fluoro - 16a - methyl - I 17,21 - trihydroxy - pregna - 1,4 - diene - 3, 20 - dione compounds of the formula

   wherein each of R1 and R2 represents a free or esterified hydroxyl group, whilst R1 and R2 together can also represent a cyclic 17,21-diester group which process comprises (a) the addition of chlorine to the 1,2double bond in a compound of the formula

   wherein R1 and R2 are as defined in formula (I), whilst optionally protecting the 11hydroxyl group temporarily beforehand, and the dehydrochlorination of the resultant 1,2-dichloro compound, or (b) treating a compound of the general formula

   wherein R1 and R2 are as defined in formula (I), with hypochlorous acid or with a hypochlorous acid donor, or (c) treating a compound of the general formula

   wherein R1 and R2 are as defined in formula (I), with hydrogen chloride or a hydrogen chloride donor, and/or, if desired, in compounds of the formula (I), in which at least one of the groups R, and R2 is esterified, converting at least one esterified hydroxyl group into a free hydroxyl group, or in compounds of the formula (I), in which at least one of the groups R1 and R2 represents a free hydroxyl group, whilst optionally protecting the 1 l-hydroxyl group temporarily. esterifying at least one free hydroxyl group, and/or, if desired, converting hemiesters of dicarboxylic acids or of polybasic inorganic acids into their metal salts or salts of organic bases.
2. 2. A process according to claim 1(a), wherein the starting material is treated in an inert organic solvent with elementary chlorine.
3. 3. A process according to either of claims

   I or 2, wherein either, a halogenated hydrocarbon or an aliphatic carboxylic acid with up to 7 carbon atoms, or a mixture thereof, is used as inert organic solvent.
4. 4. A process according to claim 3, wherein a solution of the starting material in dioxane is treated with a solution of chlorine in propionic acid.
5. 5. A process according to any one of claims 1 to 4, wherein the reaction is carried out at low temperature and in the dark.
6. 6. A process according to claim 1(a), wherein the starting material is treated with a mixture of two compounds one of which yields negative chlorine and the other positive chlorine.
7. 7. A process according to claim 6, wherein a chlorinated acid amide or acid imide is used in the presence of hydrogen chloride or an alkali metal chloride.
8. 8. A process according to either of claims 6 or 7, wherein the reaction is carried out in one of the solvents referred to in claims 3 to 4.
9. 9. A process according to any one of claims 1 to 8, wherein the l lA-hydroxy group is protected by esterification with trifluoroacetic acid before the addition of chlorine to the 1,2-double bond.
10. 10. A process according to any one of claims 1 to 9, wherein hydrogen chloride is split off by treatment with a base from the 1,2-dichlorosteroids obtained by the addition of chlorine.
11. 11. A process according to claim 10, which comprise the use of tertiary organic nitrogen bases.
12. 12. A process according to claim 11, which comprises the use of pyridine or the homologues thereof or of a N,N-dialkylaniline.
13. 13. A process according to claim 10, which comprises the use of hydroxides, carbonates, bicarbonates or acetates of alkali metals or alkaline earth metals as bases.
14. 14. A process according to claim 13, which comprises the use of potassium or sodium acetate in aqueous-alcoholic solution.
15. 15. A process according to any one of claims 10 to 14, wherein a l l,B- trifluoroacetoxy group is reconverted by hydrolysis or solvolysis into the 1 1-hydroxyl group before, or simultaneously with, the dehydrochlorination.
16. 16. A process according to claim 15, wherein the hydrolysis is carried out with hydroxides, carbonates, bicarbonates or acetates of alkali metals or alkaline earth metals in aqueous, alcoholic or aqueousalcoholic solution.
17. 17. A process according to claim l(b), wherein the starting materials are treated with N-chlorocarboxamides or Nchlorocarboximides in the presence of water and/or an inert solvent, optionally in the presence of a strong acid.
18. 18. A process according to claim 1(b), wherein the starting materials are treated with tert.-butylhypochlorite in an inert water-immiscible solvent in the presence of perchloric acid.
19. 19. A process according to claim 1(c), wherein the starting materials are treated with hydrogen chloride in aqueous medium or in an inert organic solvent.
20. 20. A process according to any one of claims 1 to 19, wherein esterified hydroxyl groups in the 17-position and/or 21-position are converted into free hydroxyl groups by alkaline saponification.
21. 21. A process according to claim 20, wherein an alkali metal carbonate or alkali metal bicarbonate in aqueous or aqueousalcoholic solution is used as saponifying agent.
22. 22. A process according to any one of claims I to 19, wherein a 17,21-diester is saponified with a solution of strong acid in an alcohol to hydrolyse the 21-ester group selectively to form a 17-monoester.
23. 23. A process according to any one of claims I to 19, wherein a cyclic 17,21orthoester of a carboxylic acid is saponified with a weak organic acid to hydrolyse the 21-ester group selectively to form a 17monoester.
24. 24. A process according to any one of claims I to 19, wherein the esterification of resultant compounds with at least one free hydroxyl group in the 17- and 21-position is carried out by treating said compounds with a reactive functional derivative of an acid.
25. 25. A process according to claim 24, wherein the 1 1-hydroxyl group is protected before the esterification by converting it into the trifluoroacetoxy group.
26. 26. Compounds of the formula

    wherein each of R1 and R2 represents a free or esterified hydroxyl group, whilst R, and R2 together can represent a cyclic 17,21diester group and metal salts or salts of organic bases of hemiesters of dicarboxylic acids or of polybasic inorganic acids of these compounds.
27. 27. Compounds according to claim 26, wherein esterified hydroxyl groups are derived from carboxylic acids containing 1 to 18 carbon atoms.
28. 28. Compounds according to claim 26, wherein esterified hydroxyl groups are derived from lower aliphatic carboxylic acids containing 1 to 7 carbon atoms.
29. 29. Compounds according to claim 26, wherein esterified hydroxyl groups are derived from ortho-, meta- or pyrophosphoric acid or from sulphuric acid.
30. 30. Compounds according to claim 26, wherein a cyclic 17,21-diester is derived from an ortho carboxylic acid or from carbonic acid.
31. 31. 2,9a-Dichloroparamethasone 21acetate.
32. 32. 2,9a-Dichloroparamethasone 21pivalate.
33. 33. The ethyl 17,21-orthopropionate of 2,9a-paramethasone.
34. 34. 2,9a-Dichloroparamethasone 17monopropionate.
35. 35. 2,9a-Dichloroparamethasone 17,21dipropionate.
36. 36. 2,9-Dichloroparamethasone 21valerate.
37. 37. A compound as claimed in claim 26 when prepared by a process claimed in any one of claims 1 to 25.
38. 38. A pharmaceutical preparation which contains a compound according to claim 26, together with a pharmaceutical carrier.
39. 39. A pharmeaceutical preparation according to claim 40, which contains one of the compounds claimed in any one of claims 27 to 38.