GB2108504A - New 6 alpha -fluoro-21-chloro steroids having antiinflammatory activity - Google Patents

Description

SPECIFICATION Dihalogenated steroids The present invention relates to novel dihalogenated steroids of the formula

in which X represents methylene or an a-oriented methyl group together with a hydrogen atom, and R represents an alkyl group having a maximum of 6 carbon atoms, and to the corresponding 1,2-dehyd 1 ,2-dehydro derivatives, in which the dotted line in the 1,2-position indicates an additional C-C bond, and to pharmaceutical preparations containing these steroids, and to processes for the manufacture thereof.

The radical characterised by the symbol Xis preferably methylene.

The alkyl group characterised by the symbol R may be branched, such as isopropyl, isobutyl or 1,1-dimethylethyl, but it is preferably a straight-chained alkyl group, such as methyl, propyl, butyl, pentyl or hexyl or, especially, ethyl.

For the manufacture of complicated poly-substituted steroid compounds from simple raw materials or industrially available intermediates a multi-stage synthetic sequence is necessary in which each individual functional group is introduced separately, and often a group that has already been introduced must later be temporarily protected against undesired further conversion. The sequence of the individual synthesis steps, which are mostly known perse from analogous processes, is often of decisive importance for the economy of the complete synthesis. For the synthesis strategy, that is to say when selecting the process variants and their sequence, in general attention is paid particularly to reducing to a minimum the synthesis steps required; also associated with this is the obvious consideration that a less complicated structure as a rule also requires fewer synthesis steps.Consequently, recently, contrary to the earlier tendency towards increasing the activity of basic compounds by additional substituents, an alternative research strategy has increasingly been pursued, that is, to simplify, by objective research, the structure of an existing complicated active substance whilst retaining its high activity. The compounds of the formula A according to the invention are the result of such action, as on the one hand thegy have a high anti-inflammatory activity but, on the other hand, owing to their simple structure, they can be produced by less expensive processes.

The novel compounds of the formula A are distinguished by valuable pharmacological properties, especially an excellent anti-inflammatory activity, as can be ascertained, for example when applied locally to inhibit inflammatory symptoms, and also by strikingly large dissociation between the anti-inflammatory effect and atrophogenic side-effects.For example, in a dermatitis inhibition test, i.e. the rat ear assay according to Tonelli, they exhibit a marked anti-inflammatory activity in the dosage range of from 10 to 250 llg/ml.21-Chloro-6a-fluoro-17a-hydroxy-16-methylene-pregn-4-ene-3,20-dione-17-propionate has, for exam- ple, an ED50 (effective dose that produces a 50% inhibition of the symptoms) of 25 Fg/ml, and 21-chloro-6a-fluoro-17a-hydroxy-16-methylene-pregna-1,4-diene-3,20-dione-17-propionate has an ED50 of 10 Fg/ml. Analogous 16a-methyl compounds have activities of the same order.

The anti-inflammatory activity of the novel compounds can also be demonstrated in the granuloma test in which, at doses of less than 1 9 per compressed cotton pellet, they exhibit significant inhibition of granuloma formation. At doses of up to 500 up per pellet no adverse effects on the thymus, the adrenals and body weight development can be detected in this impregnative foreign body granuloma test.

As a result of these properties, compounds of the formula A can be used successfully in indications for which the classic gluococorticoids are used successfully as anti-inflammatory agents, especially as topical agents, for example for the treatment of inflammatory dermatoses, such as eczemas and dermatides, or partially corticosteroid-resistant dermatoses, for example psoriasis.

In addition, the compounds of the formula A are valuable intermediates for the manufacture of other useful substances, especially other pharmacologically active steroids. In this connection they have, for example, a key position in the synthesis of topically administrable corticosteroids having a high anti-inflammatory activity, such as 21 -chlorn-6a-fluorn-9a-halo-1 1 p-hydroxy-1 6a-methyl-1 7a-propionyloxy- pregna-1 ,4-diene-3,20-diones and analogues thereof according to British Patent Specification 1 537 136.

Conversion into these valuable therapeutic agents requires merely conventional processes, such as the introduction of 110-hydroxy and 9-chloro or 9-fluoro.

Of the compounds of the formula A according to the invention, the 1,2-unsaturated derivatives are preferred.

Of the compounds of the formula A according to the invention, the 17-propionates are preferred.

There may be mentioned as especially preferred compounds of the formula A: 21-chloro-6a-fluoro-17a- hydroxy 6-methylene-pregn-4-ene-3,20-dione-1 7-propionate and 21-chloro-6α-fluoro-17α-hydroxy-16- methylene-pregna-1,4-diene-3,20-dione-17-propionate, as well as 21-chloro-6α-fluoro-17α-hydroxy-16α- methyl-preg n-4-ene-3,20-dione-1 7-propionate uoro-17a-hydroxy-16a-methyl-preg na-1,4- diene-3,20-dione-17-propionate.

The novel compounds of the formula A can be maufactured in accordance with the invention in a manner known perse by conventional processes of steroid chemistry.

The novel compounds of the formula A according to the invention are manufactured by, for example, converting the group R0 into a chlorine atom in a compound of the general formula

in which R, X and the dotted line in the 1,2-position have the meanings mentioned above and Ro represents a group that can be converted into a chlorine atom, and, if desired, introducing the 1,2-double bond into a resulting 1,2-saturated final product.

A group R0 that can be converted into a chlorine atom is, for example, the group -O-Rat in which Ra represents the acyl radical of an organic sulphonic acid; the exchange of the sulphonyloxy group -O-Ra for a chlorine atom is carried out in a manner known perse. The acyl radical Ra of an organic sulphonic acid is especially that of an aliphatic or carbocylic, optionally aromatic, sulphonic acid. Such acids are, interalla, optionally substituted, for example halogenated, lower alkanesulphonic acids, cycloalkanesulphonic acids in which the cycloalkyl radical may be mono- or poly-cyclic, or benzene-sulphonic acids optionally substituted by lower alkyl, for example methoxy, halogen, for example, chlorine or bromine, and/or nitro.There may be mentioned as typical examples of such acids trifluoromethanesulphonic acid, (+)-camphor-1 0-suiphonic acid, 4-bromobenzenesulphonic acid and 3-nitrobenzenesulphonic acid, especiallyp-toluenesulphonic acid and, above all, methanesulphonic acid.

The exchange reaction is usually carried out by treating the starting material of the formula I with an alkali metal chlorine of the formula MCI, in which M represents an alkali metal, in the presence of an aprotic organic solvent, the dielectric constant of which is 29 or higher. There comes into consideration as alkali metal M preferably lithium.There may be used as aprotic organic solvents especially di-lower alkyl sulphoxides, for example dimethyl sul phoxide, N,N-di-lower alkylamides of lower aliphatic carboxylic acids, for example N,N-dimethylformamide or N,N-dimethylacetamide, lower alkanenitriles, for example acetonitrile, hexa-lower alkyl phosphoric amides, for example hexamethyl phosphoric amide, or also ketones, especially aliphatic or cycloaliphatic ketones having from 3 to 10 carbon atoms, such as corresponding alkanones, for example acetone, 2-butanone, or 3-pentanone, 2-hexanone or 4-decanone, or cycloalkanones having 5 or 6 ring carbon atoms, for example cyclo-pentanone or cyclohexanone, or mixtures of such solvents.

The reaction is advantageously carried out between room temperature and the boiling temperature of the reaction mixture, at least one equivalent of the alkali metal chloride being used for the reaction.

A further group R0 that can be converted into a chlorine atom is a free hydroxy group, which can be exchanged for chlorine by reaction with a conventional halogenating agent, such as thionyl chloride, phosphorus trichloride or phosphorus oxychloride, the reaction usually being carried out with excess halogenating agent and in the presence of an organic base, such as, especially, pyridine, and with dilution by an inert organic solvent, such as a halogenated lower alkane, especially methylene chloride or chloroform, at a temperature of below 80 C. A preferred variant comprises treating the corresponding starting material of the formula I in which R0 represents a free hydroxy group with a phosphine, such as a tri-lower alkylphosphine or preferably triphenyl phosphine, and carbon tetrachloride. This operation is preferably carried out in a dipolar aprotic medium, for example in the presence of a corresponding solvent of the amide type, such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone or hexamethylphosphoric amide, while cooling or heating, for example in a temperature range of from approximately 1 00C to approximately 1250C and, if necessary, under elevated pressure and/or in an inert gas atmosphere.

Afurther group that can be exchanged for chlorine is a radical that the group R0 forms together with the group -OCOR, that is to say the grouping of a 17,21-orthoester derived from a lower alkanecarboxylic acid RCOOH and having the partial formula

in which R has the meaning given above and Rb represents lower alkyl, for example methyl or ethyl.The exchange for chlorine in the 21-position with the formation of the esterified hydroxy group -OCOR in the 17a-position is carried out in a manner kown per se, for example by treatment with a chlorine-transferring agent, such as a trihydrocarbylsilyl chloride (for example an optionally substituted triphenylsilyl chloride, especially triphenylsilyl chloride or tri-p-tolylsilyl chloride, or preferably a tri-lower alkylsilyl chloride, especially trimethylsilyl chloride) or triphenylmethyl chloride in organic solvents in which the two reactants are soluble and which are inert with respect to the halogenating agent.There come into consideration as such solvents especially aliphatic and cyclic ethers (such as 1,2-dimethoxyetha ne, 2,5,7-trioxanonane, tetrahydrofuran and dioxan) and especially halogenated aliphatic hydrocarbons (such as carbon tetrachloride, chloroform, dichloroethane and, especially, methylene chloride), and appropriate combinations thereof.

The reaction is carried out preferably at the boiling temperature of the reaction mixture, for example a solution in methylene chloride, especially under anhydrous conditions and, if desired, under an inert atmosphere, for example under nitrogen or argon.

The starting materials of the formula I are known or can be manufactured in a manner known peruse; for example, compounds of the formula in which R0 represents organic sulphonyloxy can be manufactured by treating a corresponding 6a-fluoro-1 7a,21 -dihydroxy-1 6-X-pregn-4-ene-3,20-dione-1 7-monoester or a corresponding 1-dehydro derivative having a free 21-hydroxy group with a reactive derivative of an organic sulphonic acid of the formula Ro-OH, especially with a corresponding sulphonic acid chloride of the formula Ro-CI, in the presence of a base, for example pyridine. 17,21-Orthoesters of the formula I in which R0 and -OCOR together form a group of the formula la are produced, for example, by treating a 6a-fluoro-17a,21- dihydroxy-1 6-X-pregn-4-ene-3,20-dione compound or a corresponding 1 -dehydro derivative with a suitable ortho-lower alkanecarboxylic acid ester (for example ortho-lower alkanecarboxylic acid triethyl ester, such as, especially, orthopropionic acid triethyl ester) in the presence of a strong acid, for example p-toluenesulphonic acid, and advantageously with the removal of the alcohol liberated, for example by azeotropic distillation.

The novel compounds of the formula A can also be obtained by epimerising the 6ss-fluorine atom to a fluorine atom in a corresponding GBfluoro-compound of the formula

in which R, X and the dotted line in the 1,2-position have the meanings given above and, if desired, introducing the 1,2-double bond into a resulting 1,2-saturated final product.

The epimerisation is carried out in a manner known peruse, especially as an acid-catalysed isomerisation, by treating the compound of the formula II with a catalytic amount of a strong acid in an inert organic solvent. The acid used is either an inorganic acid, for example sulphuric acid, perchloric acid or a hydrohalic acid, such as especially hydrogen chloride or hydrogen bromide, or a strong organic acid, for example a sulphonic acid, such as especiallyp-toluenesulphonic acid. There come especially into consideration as solvents, for example, liquid carboxylic acids, especially lower aliphatic monocarboxylic acids, such as glacial acetic acid or propionic acid, and halogenated hydrocarbons, such as chloroform and methylene chloride, and mixtures thereof. The reaction temperature is usually approximately between 0 and room temperature.The reaction is carried out especially in a chloroform solution with dry gaseous hydrogen chloride at approximately 0".

The 6ss-fluoro-compound used as starting material of the formula II can also be formed direction in situ in the reaction mixture and epimerised immediately without being isolated. In an especially advantageous variant of the above process, instead of the above-mentioned 4,5-unsaturated 6ss-fluoro-compound of the formula II, one of its possible starting materials, namely 21-chlorn-6-fluorn-5a,17a-bis-(lower alkanecarbonyloxy)-16-X-pregnane-3,20-dione of the formula Ill

in which X and R have the meanings given above, is treated under the above-described reaction conditions with a catalytic amount of a strong acid in an inert organic solvent. - If desired the reaction can, however, also be carried out in two stages: in the first stage the esterified Sa-hydroxy group in the compound of the formula Ill is eliminated by treatment with acid to form the 4,5-double bond conjugated with the 3-oxo group and, in the second stage, the 6ss-configuration of the fluorine atom in the resulting isolated compound of the formula II is converted to the thermodynamically more stable 6a-configuration by acid-catalysed isomerisation. Since, for the ss-elimination of the 5-positioned lower alkanecarbonyl-oxy group, already the low acidity of a carboxylic acid is sufficient, liquid carboxylic acids, serving simultaneously also as solvents, are known to be especially suitable for this purpose, and among these especially lower aliphatic monocarboxylic acids, such as, in particular, glacial acetic acid and propionic acid.In this case the p-elimination is preferably carried out at an elevated temperature of from approximately 50" to the boiling temperature of the reaction mixture and in the absence of a stronger acid.

Starting materials of the formula II saturated in the 1,2-position can be manufactured in a manner known perse also by an alternative method by converting a corresponding 21-chloro-17a-lower alkane carbonyloxy-16-X-pregn-4-ene-3,20-dione compound that is unsubstituted in the 6-position, by treatment with a lower alkyl orthoformate (for example especially ethyl or methyl orthoformate) with acid catalysis, to form the corresponding 3-enol ether (i.e. 3-lower alkoxy-3,5-diene), and reacting the latter in a manner known perse with perchloryl fluoride.

Those starting materials of the formula Ill in which X represents methylene can be obtained especially advantageously from corresponding 21 -chlo ro-6ss-fl uoro-3ss,5a, 1 7a-trihydroxy-1 6-methylene-pregnan-20- one-3-lower alkanoyl-5,1 7-bis(lower alkanecarbonyl) esters, which are described in European Patent Application 81810152.9.In this process, in the 21-chloro-6ss-fluoro-3ss,5a,17a-trihydroxy-16-methylene- pregnan-20-one-3-lower alkanoyl-5,1 7-di-lower alkanecarbonyl ester of the formula IV

in which R has the meaning given above and Ac represents a lower alkanoyl radical, in the first place the esterified 3hydroxy group is freed by solvolysis (and thus the corresponding 5,17-di-lower alkanecarbonyl ester is formed), and then is oxidised to the 3-oxo group.The selective liberation by solvolysis of the secondary 3hydroxy group in the presence of analogously esterified tertiary hydroxy groups in the 5a- and 17a-positions is carried out in a manner known perse by acid catalysis, for example in a lower alkanol, such as methanol, ethanol or isopropyl alcohol in the presence of a mineral acid, such as hydroxhloric acid or sulphuric acid. If the 3-hydroxy group in the starting material of the formula (IV) is present as a formate, the selective liberation is especially smooth and can also be carried out with weakly basic agents, for example with one equivalent of an alkali metal bicarbonate, such as sodium or potassium bicarbonate, at room temperature. Also, the subsequent oxidation (dehydrogentation) of the free 3ss-hydroxy group to the oxo group ot form 21 -chloro-6B-fluoro-5cl,l 7a-di-lower alkanecarbonyloxy-1 6-methylene-pregnan-3,20-dione of the formula Ill (X = CH2) is carried out in the conventional generally known manner, advantageously, for example, with a compound of hexavalent chromium (such as chromium trioxide or chromaic acid and alkali metal salts thereof), there being used as reaction medium lower alkanecarboxylic acids, such as acetic or propionic acid, or a ketone, such as acetone, optionally with dilution by a halogenated lower alkane, such as methylene chloride or chloroform, and the reaction temperature preferably being maintained below room temperature.A preferred variant is oxidation with a solution of chromium trioxide in aqueous sulphuric acid (Jones regent) which is usually carried out in acetone at a temperature of between approximately -10 and approximately 25", preferably in the region of Q .

The above-mentioned radical Ac is a lower alkanoyl radical having from 1 to 7 carbon atoms, for example one that is derived from the alkyl radical R defined hereinbefore, but is especially the acetyl or formyl radical.

(In order to differentiate therefrom, throughout the description the similar radical R.CO- which, however, according to the definition given at the beginning contains from 2 to 7 carbon atoms, this is referred to as the loweralkanecarbonyl radical).

The novel compounds of the formula A can also be obtained by esterifying the free 17a-hydroxy group with the above-defined radical RCO- of a lower alkane-carboxylic acid in a corresponding 17a-hydroxycompound of the formula V

in which X and the dotted line in the 1,2-position have the meanings given above and the 6-fluorine atom may be a- or B-oriented, and, at the same time, epimerising an optionally present 6fluorine atom to a 6a-fluorine atom and, if desired, introducing the 1,2-double bond into a resulting 1,2-saturated final product.

There are used for this conversion conventional methods, known per se, for the esterification of tertiary hydroxy groups that are difficult to esterify, for example treatment of the compound of the formula V that has such a hydroxy group in the 17a-position with a symmetric anhydride of a suitable lower alkane-carboxylic acid, for example with propionic an hydride, catalysed by means of a strong mineral acid, such as, especially, perchloric acid, or an organic sulphonic acid, such as p-toluenesulphonic acid. There is, however, especially used as esterifying agent a reactive mixed anhydride of the corresponding lower alkanecarboxylic acid, especially one with trifluoroacetic acid, for example the mixed propionictrifluoroacetic acid anhydride.The reaction is carried out usually at room temperature with the exclusion of water in an inert organic solvent, such as an optionally halogenated hydrocarbon, for example benzene, toluene, cyclohexane, or chloroform or methylene chloride, or an ether, such as diethyl ether, dioxan or tetrahydrofuran, with excess esterifying agent. This is prepared in the reaction mixture advantageously directly before the reaction by mixing the corresponding lower alkanecarboxylic acid with an approximately equivalent amount of trifluoroacetic anhydride, optionally while cooling, and allowing them to react at room temperature for 30 to 60 minutes.

Starting materials of the formula V can be manufactured in a manner known per se. Thus, for example, compounds of the formula V in which X represents methylene can be obtained by acid-catalysed isomerisation of the corresponding 21 -chloro-1 6a,1 7a-epoxy-(6a- or 6ss-)-fluoro-16ss-methyl-pregn-(4-ene or 1,4-diene)-3,20-dione of the formula VI defined below.

The novel compounds of the formula A in which X represents methylene can also be obtained by subjecting the 16-methyl-16,17-epoxy grouping to an acid-catalysed acylating isomerisation with ring opening in a corresponding 16ss-methyl-16a,17a-epoxide of the formula VI

in which the dotted line in the 1,2-position indicates the additional C-C bond of the 1,2-dehydro derivative and the fluorine atom may be a- or B-oriented (and, if necessary, simultaneously epimerising any fluorine atom) and, if desired, introducing the 1,2-double bond into a resulting 1,2-saturated final product.

By means ofthe acylating epoxide ring opening, the 16ss-methyl-16a,17a-epoxygrouping is directly converted to the desired 16-methylene-17a-lower alkane-carbonyloxy grouping in one process step. The direct conversion is carried out in a manner known perse by reacting the epoxide compound of the formula VI with an acylating agent derivated from a lower alkanecarboxylic acid RCOOH in an anhydrous medium in the presence of a strongly acidic catalyst. As acylating agent there is preferably used a reactive derivative of the lower alkanecarboxylic acid, such as an anhydride and, especially, a symmetric anhydride of the formula (RCO-)2O, in which R has the meaning given hereinbefore.A strongly acidic catalyst is preferably an oxygen-containing acid, such as sulphuric acid, perchioric acid or an organic sulphonic acid, for example p-toluenesulphonic acid,p-bromobenzene-sulphonic acid or benzenesulphonic acid; there may be used as solvents lower alkanecarboxylic acids, especially those corresponding to the acylating agent, and it is also possible to carry out the reaction with advantage in aprotic solvents, for example hydrocarbons, especially aromatic hydrocarbons, such as benzene ortoluene, or in halogenated aliphatic hydrocarbons, such as, especially, chloroform and methylene chloride, temperatures of approximately from 0 to the boiling temperature of the reaction mixture, preferably room temperature, being employed.

The starting materials of the formula VI can be obtained by known analogous processes, for example by treating a 21 -chloro-(6a- or 6ss)-fluoro-16-methyl-pregna-4,16-diene-3,20-dione with a conventional epoxidising agent, especially with a peroxycarboxylic acid, such as perbenzoic acid, phthalic-monoperoxy acid and, especially, m-chloroperbenzoic acid. The last-mentioned steroid-4,1 6-diene can be obtained, for example, from the corresponding 6-unsubstituted pregna-4,1 6-diene-3,20-dione compound by conventional introduction of the fluorine atom in the 6-position (for example by conversion into a 3-enol ether, especially a 3-lower alkoxy-3,5-diene, treatment thereof with perchloryl fluoride and optionally acid-catalysed epimerisation of the introduced ss-oriented 6-fluorine atom).

The novel compounds of the formula A can also be obtained by removing the protecting group to liberate the oxo group in a corresponding 1,2-saturated compound having a protected 3-oxo group and, if a 1,2-dehydro compound is desired, introducing the 1,2-double bond into a resulting 1,2-saturated end product.

There come into consideration as compounds having a protected 3-oxo group, for example, 3-ketals and 3-thioketals. The former are derived preferably from lower alkanols, such as methanol or ethanol, and especially from a- or ss glycols, such as 1,2for 1,3- propanediol, 1,2-, 2,3-or 1,3-butanediol and, especially, ethylene glycol; thioketals are derived preferably from analogously constituted thiols and dithiols, the corresponding 3,3-ethylenethioketal being especially preferred.In the 3-ketals the double bond is usually shifted into the 5,6-position, whereas in the case of 3-thioketals as a rule the original 4,5-position is retained; to achieve liberation of the 3-oxo group, this position of the double bond is, however, of no importance, since during the liberation the double bond in each case migrates into conjugation with the 3-oxo group.

There come into consideration as compounds having a protected 3-oxo group especially 3-substituted 3,5-diene compounds, such as 3-enamines, 3-enol ethers and 3-enol esters, and above all compounds of the formula VII

in which R and X have the meanings given above and Y represents a group that can be removed by solvolysis.

The group Y that can be removed by solvolysis is, for example, a tertiary amino group such as, especially, the pyrrolidino group or, above all, an etherified or esterified hydroxy group, such as, especially, a lower alkoxy group (for example methoxy or ethoxy) or a lower alkanecarbonyloxy group -OCOR with the meaning given bove.

All of the protecting groups mentioned can be removed in a manner known perse, for example by solvolysis; usually removal is carried out under the general conditions for acid catalysis and in the presence of water (i.e. acid-catalysed hydrolysis). Acid-catalysis indicates here treatment in the presence of an inorganic acid (for example an oxygen-containing acid, such as sulphuric or perchloric acid, or a hydrohalic acid, such as hydrochloric, hydrobromic or hydriodic acid), an organic sulphonic acid (such as, especially, p-toluenesulphonic acid or benzene-sulphonic acid) or a stronger carboxylic acid (such as trifluoroacetic acid, chloroacetic acid, oxalic acid or formic acid). In special cases, such as for the removal of more labile protecting groups (for example enamine or enol ether groups), it is also possible to use weaker carboxylic acids (such as benzoic or acetic acid) for the catalysis.

The hydrolytic removal is carried out usually in a neutral organic solvent, preferably one that is at least partially miscible with water, for example in a lower alkanol (such as, especially, methanol, ethanol or isopropyl alcohol), an open-chained or cyclic ether (for eample diethyl ether, 1,2-dimethoxyethane, dioxan or tetrahydrofuran), or an aliphatic ketone (such as acetone), and optionally, especially to increase the solubility, with admixture of a halogenated lower alkane (such as, especially, chloroform or methylene chloride); the reaction temperature is between approximately -10 C and the boiling temperature of the reaction mixture, especially between 0 C and room temperature.

In the case of thioketals, preferably a sulphur-binding compound (for example a metal salt, such as cadmium carbonate, and/or a heavy metal salt, such as mercury (II) chloride) may be added. Since the latter agent itself has a strongly acidic reaction in the presence of water, no additional acid is required as catalyst when it is used.

Enol acylates of the formula VII in which Y represents lower alkanecarbonyloxy -OCOR can be removed especially also by acid-catalysed alcoholysis, especially in an an hydros lower alkanol, such as methanol, ethanol or isopropyl alcohol, in the presence of a mineral acid (such as, especially, hydrogen chloride or sulphuric acid), the tertiary 17a-lower alkanecarbonyloxy group remaining intact. The removal of enol acylates can, finally, also be carried out by base-catalysed hydrolysis; this reaction is carried out especially with weakly basic inorganic reagents, for example with one equivalent of an alkali metal bicarbonate (such as sodium bicarbonate or potassium bicarbonate) and under mild reation conditions, for example at or below room temperature.

The derivatives having a protected 3-oxo group used as starting materials, such as those of the formula VII, can be obtained according to conventional processes of steroid chemistry, for example from corresponding 6ss-fluoro-derivatives having a free 3-oxo group using the generally known processes of ketalisation, thioketalisation, enolacylation and the formation of enol ethers and enamines. (These processes are generally characterised by the acid-catalysed treatment of the 3-oxo compound with a corresponding alcohol, glycol, dithiol, acid anhydride, lower alkanol orthoester or secondary amine with the exclusion or elimination of water).Enol acylates of the formula VII in which Y represents the above-defined group -OCOR can also be formed, for example, by carrying out the above-described acylation reactions of the starting materials of the formula V or VI under vigorous conditions (for example, elevated temperature, extended reaction time and higher concentrations of reactants and, especially, of catalyst).

The subsequent optional introduction of the 1,2-double bond into the 1,2-saturated compounds to form corresponding 1,2-dehydro derivatives is carried out in a manner known peruse, for example by dehydrogenation. Forthis purpose biological dehydrogenating processes can be used, for example using the micro-organisms Corynebacterium simplex or Septomyxa affinis or their enzyme systems, or treatment with selenium dioxide in an organic solvent, for example tert.-butyl alcohol, can be carried out.Preferably, however, 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone is allowed to act on the 1,2-saturated compounds at approximately reflux temperature for several, for example from 6 to 24, hours; customary solvents are used, for example aromatic hydrocarbons, such as benzene or xylene, lower aliphatic alcohols, such as ethanol, propyl alcohol or tert.-butyl alcohol, lower aliphatic ketones, such as acetone or 2-butanone, aliphatic esters, such as ethyl acetate, or cyclic ethers, such as dioxan or tetrahydrofuran.

In the above-described processes according to the invention, the reactants and intermediates used are preferably those that result in the specially emphasised, more especially the specifically mentioned, final products and intermediates; the reactions are, however, preferably carried out with 1,2-saturated intermediates and the 1,2-double bond is introduced in the last step.

Unless specifically defined to the contrary, throughout the description the term "lower" used in connection with a hydrocarbon radical relates to such a radical having a maximum of 7 carbon atoms.

The invention relates also to those embodiments of the above processes in which a compound obtainable as intermediate at any stage is used as starting material and the remaining steps are carried out, or in which a starting material is formed under the reaction conditions.

The present invention relates also to pharmaceutical preparations for humans and mammals that contain the novel above-described compounds of the formula A in a therapeutically effective amount as active ingredient together with a pharmaceutical carrier, and to their manufacture. There are used as carriers organic or inorganic substances that are suitable for enteral, especially oral, and intrauterine, parenteral, or topical administration. For formation ofthe same there come into consideration those substances that do not react with the novel compounds, such as, for example, water, gelatine, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohol, gum, polyalkylene glycols, petroleum jelly, cholesterol and other known medicament carriers.The pharmaceutical preparations may be in solid form, for example in the form of tablets, drawees or capsules, or in liquid or semi-liquid form as solutions, suspensions, emulsions, ointments or creams. If necessary these pharmaceutical preparations are sterilised and/or contain adjuncts, such as preservatives, stabilisers, wetting agents, emulsifiers, salts for altering the osmotic pressure, or buffers. They may also contain other therapeutically valuable or biologically active ingredients.

There come into consideration especially topically administrable pharmaceutical preparations, such as creams, ointments, pastes, foams, tinctures and solutions, that contain from approximately 0.001 % to approximately 0.5%, preferably from appoximately 0.005% to approximately 0.05% of the active ingredient.

Creams are oil-in-water emulsions that contain more than 50% of water. As oily base there are used especially fatty alcohols, 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 beeswax, and/or hydrocarbons, for example petroleum jelly (petrolatum) or paraffin oil.As emulsifiers there come into consideration surface-active substances having predominantly hydrophilic properties, such as correspond ing non-ionic emulsifiers, for example fatty acid esters of polyalcohols, or ethylene oxide adducts thereof, such as polyglycerine fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), also polyoxyethylene fatty alcohol ethers or polyoxyethylene fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulphates, for example sodium lauryl sulphate, sodium cetyi 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 aqueous phase are, inter alia, agents that reduce the drying out of the creams, for example polyalcohols, such as glycerine, sorbitol, propylene glycol and/or polyethylene glycols, and also preservatives and perfumes.

Ointments are water-in-oil emulsions that contain up to 70%, but preferably from approximately 20% to approximately 50%, of water or aqueous phase. As fatty phase there come into consideration especially hydrocarbons, for example petroleum jelly, paraffin oil and/or hard paraffins, which, in order to improve the water-binding capacity, preferably contain suitable hydroxy compounds, 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), for example sorbitan oleate and/or sorbitan isostearate. Additives to the aqueous phase are, inter alia, humectants, such as polyalcohols, for example glycerine, propylene glycol, sobitol and/or polyethylene glycol, and also preservatives and perfumes.

Fatty oitments are an hydros and contain as base especially hydrocarbons, for example paraffin, petroleum jelly and/or liquid paraffins, and also natural or partially synthetic fats, for example coconut fatty acid triglyceride, or preferably hardened oils, for example hydrogenated ground nut oil or caster oil, and also fatty acid partial esters of glycerine, for example glycerine mono- and di-stearate, and also, for example, the fatty alcohols which increase the water-absorbing capacity, emulsifiers and/or additives mentioned in connection with the ointments.

Pastes are creams and ointments containing powder ingredients that absorb secretions, such as metal oxides (for example titanium dioxide or zinc oxide, and also talc and/or aluminium silicates), the purpose of which is to bind any moisture or secretions present.

Foams are administered from pressurised containers and are liquid oil-in-water emulsions in aerosol form, halogenated hydrocarbons, such as chlorofluoro-lower alkanes (for example dichloro-difluoromethane and dichlorotetrafluoroethane) being used as propellants. For the oily 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 having predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those having predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans). I addition, there may be used customary additives, such as preservatives.

Tinctures and solutions generally have an aqueous ethanolic base to which there are added, inter alia, polyalcohols, for example glycerine, glycols, and/or polyethylene glycol, as humectants for reducing evaporation, and fat-restoring substances, such as fatty acid esters with lower polyethylene glycols, that is to say lipophilic substances that are soluble in the aqueous mixture, to replace the fatty substances that are taken from the skin by the ethanol, and, if necessary, other adjuncts and additives.

The pharmaceutical preparations for topical application are manufactured in a manner known perse, for example by dissolving or suspending the active ingredient in the base or, if necessary, in a partthereof.

When processing the active ingredient in the form of a solution, it is usually dissolved in one of the two phases before emulsification; when processing the active ingredient in the form of a suspension, it is mixed with a part of the base after emulsification and then added to the remainder of the formulation.

Dosage of the active ingredient for example of the above specially mentioned compounds, is in principle carried out analogously to that of acknowledged topical anti-inflammatory agents of the corticoid type; it depends, however, also, on the one hand, on the species, body weight, age and individual condition of the warm-blooded animal and, on the other hand, on the method of administration; a suitable dose can be ascertained in a known manner by a routine test for each individual case.

The invention relates also to a method of alleviating or eliminating pathological inflammatory conditions of the body, and especially of the skin, of a warm-blooded animal, especially a human, which is characterised by treating that body or body part, preferably by topical application, with an anti-inflammatorily effective amount of a compound of the formula A, alone or in the form of a pharmaceutical preparation. By the expression "an anti-inflammatorily effective amount" there is to be understood that amount of the active ingredient which is sufficient to cause significant inhibition of the inflammation.

The following Examples illustrate in further detail how the present invention is carried out in practice, without the scope of the invention being limited in anyway. The temperatures hereinbefore and hereinafter are given in degrees Centigrade; unless specifically indicated otherwise, solvent mixtures are in % by volume or in vol.:vol.ratio, and solutions of solids are in % by weight, that is to say are quoted as the weight of the solid substance (in grams) in 100 parts by volume (in ml) of the solution.

Example 1 Hydrogen chloride is passed through a solution of 3.4 g of 21 -chloro-6(34luoro-5a,1 7a-dihydroxy-1 6- methylene-pregnane-3,20-dione dipropionate in 340 ml of chloroform for 6 hours while cooling with ice. The solution is poured into water, extracted into methylene chloride, washed with 3% strength sodium bicarbonate solution, and dried and concentrated by evaporation in vacuo. The residue is chromatographed over 100 g of silica gel. With toluene, mixtures of 21-chloro-6ss-fluoro-17a-hydroxy-16-methylene-pregn-4- ene-3,20-dione-propionate and 21 -chloro-6a4luoro-1 7a-hydroxy-1 6-methylene-pregn-4-ene-3,20-dione- propionate are eluated at first. Subsequently, the pure 6a-fluoro-compound is obtained, which after crystallisation from methylene chloride/ether, melts at 175-178.5".The starting material can be produced as follows: A mixture of 4.7 g of 21-chloro-6ss-fluoro-3ss,5a,17a-trihydroxy-16-methylene-pregnan-20-one-3-acetate- 5,17-dipropionate and 235 ml of methanol and 31 ml of a 3.85N solution of hydrogen chloride in isopropanol is stirred at room temperature for four hours, poured into saturated sodium bicarbonate solution and extracted with methylene chloride. The organic solutions are washed with dilute sodium chloride solution, dried and concentrated by evaportion in vacuo.

4.4 ml of an 8N solution of chromic acid in sulphuric acid/water (Jones reagent) are added, while stirring and cooling with ice, to the solution of the resulting crude 21-chloro-GP-fluoro-3P,5cr-1 7a-trihydroxy-l 6- methylene-pregnan-20-one-5,1 7-dipropionate in 32 ml of methylene chloride and 128 ml of acetone. After 30 minutes a solution of 4.1 g of sodium acetate in 130 ml of water is added and the mixture is extracted with methylene chloride. The organic solutions are washed with sodium bicarbonate solution and dilute sodium chloride solution, dried and concentrated by evaportation in vacuo.Crystallisation of the residue from ether yields 3.57 g of 21 -chlorn-64luorn-5a,1 7a-dihydroxy-l 6-methylene-pregnan-3,20-dione-dipropionate having a melting point of 179-183 .

Example 2: A solution of 500 mg of 21 -chlo ro-6a-fl uoro-l 7a-hydroxy-l 6-methylene-pregn-4-ene-3,20-dione- propionate and 625 mg of recrystallised 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone in 20 ml of dioxan is refluxed for 23 hours. 125 ml of saturated sodium bicarbonate solution are added to the cooled reaction solution. After stirring for 30 minutes, the whole is extracted with methylene chloride, washed with dilute sodium chloride solution, dried and concentrated in vacuo.The residue is separated by thin layer chromatography over silica gel in the system toluene/acetone (4:1). The resulting 21 -chloro-6a-fluoro-17a- hydroxy-1 6-methylene-pregna-1 ,4-diene-3,20-dione-propionate melts, after crystallisation from methylene chloride/ether, at 158-159.5".

Example 3: 2.5 ml of methanesulphonyl chloride are added at -10" to a solution of 5.2 g of 6a4luoro-17a,21- dihydroxy-16a-methyl-pregn-4-ene-3,20-dione-17-propionate in 20 ml of pyridine. After leaving to stand for 16 hours at 0 , the mixture is poured, while stirring, into a mixture of 25 ml of concentrated hydrochloric acid and 200 ml of ice-water. 30 minutes later the whole is filtered with suction, washed with water, dissolved in methylene chloride, dried and concentrated by evaporation in vacuo. The residue is stirred with a mixture of 50 ml of dimethylformamide and 10 g of lithium chloride for 16 hours at a bath temperature of 95" in a nitrogen atmosphere. The cooled reaction mixture is poured into 500 ml of water.After stirring for 30 minutes, the whole is filtered with suction, washed with water, dissolved in methylene chloride, dried and concentrated by evaporation in vacuo. By chromatography of the residue over 150 g of silica gel, the 21 -chloro-6a4luoro-1 7a-hydroxy-1 6a-methyl-pregn-4-ene-3,20-dione-propionate is eluted with toluene/ ethyl acetate (49:1); on crystallation from methylene chloride/ether, a product having a melting point of 226-227" is obtained.

The 17a-propionate used as starting material can be obtained as follows: A mixture of 2 g of 6a-fluoro-1 7a,21 -dihydroxy-1 6a-methyl-pregn-4-ene-3,20-dione, 10 ml of dimethylformamide, 2 ml of orthopropionic acid ethyl ester and 100 mg of p-toluenesulphonic acid is stirred for 1 1/2 hours in an argon atmosphere. It is then poured into ice-water containing 1 ml of pyridine, filtered with suction and washed with water. The residue is dissolved in chlorofrom, water is separated and the solution is dried and concentrated by evaporation in vacuo. The residue is recrystallised from ether/pentane. A solution of 278 mg of oxalic acid in 3 ml of water is added to a solution of 1 g of the resulting crystallisate in 50 ml of alcohol. After stirring for 1 1/2 hours at 50" the mixture is poured into 50 ml of water and the alcohol is evaporated off in vacuo at 40".The resulting mixture is then filtered with suction, washed with water, dissolved in methylene chloride, dried and concentrated by evaporation in vacuo. After recrystallisation of the residue from methylene chloride/ether, the resulting 6a-fluoro-1 7a,21 -dihydroxy-1 6a-methyl-pregn-4- ene-3,20-dione-1 7-propionate melts at 112-122".

Example 4: A mixture of 500 mg of 21-chloro-6a-fluoro-17a-hydroxy-16a-methyl-pregn-4-ene-3,20-dione-propionate, 20 ml of dioxan and 625 mg of recrystallised 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone is refuxed for 22 hours. The cooled reaction solution is stirred with 125 ml of saturated sodium bicarbonate solution. After stirring for 30 minutes the material is extracted into methylene chloride, washed with dilute sodium chloride solution, dried and concentrated by evaporation in vacuo. The residue is separated by thin layer chromatography over silica gel in the system tolune/acetone (9:1). The resulting 21-chloro-6a-fluoro-17a hydroxy-1 6a-methyl-pregna-1 ,4-diene-3,20-dione-propionate melts at 212-222" after crystallisation from methylene chloride/ether.

Example 5 An ointment containing 0.1% of 21 -chloro-6a4luoro-1 7a-hydroxy-1 6-methylene-pregna-1 ,4-diene-3,20- dione-17-propionate can be produced as follows: Composition 21 -ch loro-6a-fl uoro-17a-hydroxy-16-methylene preg na-l ,4-diene-3,20-dione-1 7-propionate 0.1% petroleum jelly 45.0% paraffin oil 19.6% cetyl alcohol 5.0% beeswax 5.0% sorbitan sesquioleate 5.0% p-hydroxybenzoic acid ester 0.2% perfume 0.1% water 20.0% The fatty substances and emulsifiers are melted together. The preservative is dissolved in water and the solution is incorporated in the fatty melt by emulsification at an elevated temperature. After cooling, a suspension of the active ingredient in a part of the fatty melt is incorporated into the emuision and perfume is then added.

Claims (28)

1. Acompound oftheformula

in which X represents methylene or an a-oriented methyl group together with a hydrogen atom, and R represents an alkyl group having a maximum of 6 carbon atoms, and in which the dotted line in 1,2-position indicates an additional double bond of the corresponding 1,2-dehydro derivative.

2. A 1,2-unsaturated compound according to claim 1.

3. A compound according to claim 1 in which X represents methylene.

4. A compound according to claim 1 in which R represents ethyl.

5. A compound according to claim 1, which is 21 -chloro-6a4luoro-1 7a-hydroxy-1 6-methylene-pregn-4- ene-3,20-dione-17-propionate.

6. A compound according to claim 1, which is 21-chloro-6a-fluoro-17a-hydroxy-16-methylene-pregna-1, 4-diene-3,20-dione-17-propionate.

7. A compound according to claim 1, which is 21 -chloro-6a-fl uoro-1 7a-hydroxy-1 6a-methyl-pregn-4-ene- 3,20-dione-17-propionate.

8. A compound according to claim 1, which is 21 -chloro-6afl uoro-l 7a-hydroxy-1 6a-methyl-pregna-1 ,4- diene-3,20-dione-17-propionate.

9. Process for the manufacture of a compound of the formula

in which X represents methylene or an a-oriented methyl group together with a hydrogen atom, and R represents an alkyl group having a maximum of 6 carbon atoms, in which the dotted line in the 1,2-position indicates an additional double bond of a 1,2-dehydro derivative, characterised in that a) in a compound of the general formula

in which R, X and the dotted line in the 1,2-position have the meanings given above and R0 represents a group convertible into a chlorine atom, the group R0 is converted into a chlorine atom, or b) in a corresponding 6ss-fluoro-compound of the formula

in which R, X and the dotted line in the 1,2-position have the meanings given above, the 6fluorine atom is epimerised to the 6fluorine atom, or c) in a corresponding 17a-hydroxy-compound of the formula V

in which X and the dotted line in the 1,2-position have the meanings given above and the 6-fluorine atom may be a- or ss-oriented, the free 17a-hydroxy group is esterified with the above-defined radical RCO- of a lower alkanecarboxylic acid and, at the same time, an optionally present 6fluorine atom is epimerised to a 6fluorine atom, or d) for the manufacture of compounds of the formula A in which X represents methylene, in a corresponding 1 6-methyl-1 6,1 7-epoxide of the formula VI

in which the dotted line in the 1,2-position indicates the additional C-C bond of the 1,2-dehydro derivative and the 6-fluorine atom may be a- or B-oriented, the 16-methyl 16,17-epoxy grouping is subjected to acid-catalysed acylating isomerisation with ring opening and, at the same time, an optionally present 6fluorine atom is subjected to epimerisation, or e) in a compound that corresponds to a 1,2-saturated compound of formula A but carries the 3-oxo group in a protected form, the protecting group is removed to liberate the oxo group, or, optionally f) for the manufacture of a 1,2-dehydro compound of formula A, the 1,2-double bond is introduced into a resulting 1,2-saturated final product.

10. Process according to claim 9, variant a), characterised in that a compound of formula I in which R0 represents a group -O-Ral wherein Ra represents the acyl radical of an organic sulphonic acid, is treated with an alkali metal chloride of the formula MCI, in which M represents an alkali metal, in the presence of an aprotic organic solvent of which the dielectric constant is 29 or higher.

11. Process according to claim 9, variant a), characterised in that a compound of formula i in which R0 and -OCOR together represent a grouping of the formula

in which R has the meaning given in claim 9 and Rb represents a lower alkyl group, is treated with a trihydrocarbylsilyl chloride or triphenylmethyl chloride as chlorine-transferring agent in an inert organic solvent.

12. Process according to claim 9, variant b), characterised in that the 6ss-fluoro-starting material of formula I is produced in situ by treating a compound of the formula

in which X and R have the meanings given in claim 9, with a catalytic amount of a strong acid in an inert organic solvent.

13. Process according to claim 9, variant e), characterised in that, in a compound of the formula

in which R and X have the meanings given in claim 9 and Y represents a group that can be removed by solvolysis, the group Y is removed by acid-catalysed solvolysis.

14. Process according to claim 13, characterised in that a compound of formula VII in which Y represents a tertiary amino group or an etherified hydroxy group is hydrolysed by acid catalysis.

15. Process according to claim 13, characterised in that a compound of formula VII in which Y represents a lower alkanecarbonyloxy group -OCOR, R representing an alkyl group having a maximum of 6 carbon atoms, is treated with a mineral acid in a lower alkanol.

16. Process according to any one of claims 9-15, characterised in that one of the compounds characterised in claims 2-8 is manufactured.

17. A pharmaceutical preparation containing one of the compounds defined in claims 1-8 together with a pharmaceutical carrier.

18. Process for the manufacture of pharmaceutical preparations according to claim 17, characterised in that at least one of the active ingredients defined in claims 1-8 is processed with at least one pharmaceutical carrier.

19. Use of a compound according to any one of claims 1 to 8 as an anti-inflammatory agent.

20. Use of a compound according to any one of claims 1 to 8 as an intermediate for the synthesis of 6,9,21 -trihalogenated corticosteroids.

21. A compound according to any one of claims 1 to 8 as an anti-inflammatory agent.

22. Therapeutic method for alleviating or eliminating pathological inflammatory conditions in a warm-blooded animal, characterised by administration to that warm-blooded animal of a compound according to any one of claims 1 to 8, on its own or in theform of a preparation according to claim 17, in amounts that are effective for alleviating or eliminating the inflammation in the warm-blooded animal.

23. Method according to claim 22, in which an inflammation of the skin or mucous membrane is treated by topical administration of the active substance.

24. Method according to claim 22 or 23, for use on humans.

25. A process for the production of a compound of formula A substantially as described with reference to any of Examples 1 to 4.

26. Compounds of formula A when produced by a process according to claims 9 to 16 and 25.

27. Compounds of formula A substantially as described with reference to any of Examples 1 to 4.

28. The novel compounds mentioned in the description.