NO163285B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE STEROIDS. - Google Patents

Description

The invention relates to an analogue method for the preparation of therapeutically active steroids selected from the basis consisting of a compound of formula (I)

where is C 2 -C 20 alkyl; C-1-C4 haloalkyl; or -CH 2 COOR 6 , where R 6 is C 1 -<C> 20 alkyl; or R ± is where Y is -S-, -SO 2 - or -O-, and R 8 is hydrogen or lower alkyl or R 1 is (where R 6 is as defined above), R 2 is C 1 -C 4 alkyl; which may be substituted with a halogen group, C3-C8 cycloalkyl, or R2 is benzyl; R 3 is hydrogen, α-methyl, β-methyl, or α- or

where R£ is lower alkyl,

R4 is hydrogen, fluorine or chlorine,

R5 is hydrogen, fluorine or chlorine,

Z is carbonyl or β-hydroxymethylene;

and the dotted line in ring A shows that the 1,2 bond is saturated or unsaturated.

Successful predictions on a rational basis of the biological activity of compounds leading to new drugs are the main goal of drug designers. This has usually been achieved by considering a known bioactive molecule as the basis for structural modifications, either design with the group or biofunctional parts or by changing the overall physico-chemical properties of the molecule. The main purpose has thus been to design, synthesize and test new compounds that are structurally analogous to the bioactive base molecule, which, however, have improved therapeutic and/or pharmacokinetic properties. Although "vulnerable" moieties have been identified as those whose role is to bioactivate or metabolically eliminate the drug after it has exerted its role, little or no attention has been paid to the drug-formation process for the rational design of the metabolic scheme of the medications. This has been the case despite the fact that the toxicity of a number of bioactive molecules is due to their increased elimination half-life, stability or other factors introduced during design to increase their activity. Medicines and especially their metabolic processes contribute to various toxic processes by forming active metabolites. The phenomenon of metabolic activation to reactive intermediates that covalently bind to tissue macromolecules is the initial step in cell damage. It is also clear that most toxic metabolites will not survive long enough to be excreted and identified, and studies of the stable metabolites can thus provide misleading information.

It is clear that, in order to prevent and/or reduce drug toxicity problems, the metabolic regulation of drugs should be considered at an early stage of the drug design process. This is especially the case when one considers that the body can attack and alter structures that are chemically completely stable, and that even if a drug is excreted 95% unchanged, the remaining small portion can, and most likely will, cause toxicity .

"Soft drugs" can be defined as biologically active chemical compounds (drugs) that may structurally resemble known active drugs (soft analogues) or they may be completely new structural types, but all are characterized by a predictable in vivo destruction (metabolism) to non-toxic parts, after they have exercised their therapeutic role. The metabolic arrangement of the soft drugs takes place at an adjustable rate in a predictable manner.

The present inventor has found 5 main classes of soft drugs. One of the most useful classes was called "inactive metabolite", and can be advantageously used to design particularly valuable "soft drugs". This practice begins with the use of a known inactive metabolite in a drug or class of drugs, followed by modification of the metabolite to structurally (isosterically and/or isoelectronically) resemble the active drug (ie, activation), and engineering the metabolism of the activated species so that it leads to the initial inactive metabolite after it has performed its desired therapeutic role, without the formation of toxic intermediates (ie, predictable metabolism). Exercising with the "inactive metabolite" allows further regulation of the metabolism rate and pharmacokinetic properties by molecular manipulation in the activation step. Also, if no useful inactive metabolite is known, one can be designed by introducing transfer groups into non-critical structural parts.

The present inventor has now applied his inactive metabolite to the area that includes natural and synthetic glucocorticosteroids, and has designed the soft steroidal anti-inflammatory agents according to the present invention, starting with the known inactive natural metabolites in the glucocorticosteroids. Thus, for example, in the case of hydrocortisone, one of its major inactive metabolites, cortic acid, i.e. 11(3,17a-dihydroxyandrost-4-en-3-one-173-carboxylic acid), has been used as a starting material and has been activated by the introduction of suitable non-toxic 17a and 173-substituents, which activated derivatives will be cleaved in vivo, after the exercise of their therapeutic role, to the initial inactive metabolites and other non-toxic parts..

The new steroids of formula (I) and their quaternary ammonium salts are very potent local anti-inflammatory agents, but due to the fact that their easy destruction in vivo leads only to the inactive steroidal metabolites, the compounds according to the present invention have invention far less systemic activity than the known glucocorticosteroids from whose inactive metabolites they are derived. In fact, many of the compounds of the present invention are completely free of systemic activity. Such minimal - or non-existent - systemic activity means that the compounds according to the present invention can be used for local (e.g. topical) treatment of inflammatory conditions without the serious systemic side effects that accompany the use of the known glucocorticosteroids.

With respect to the various groups covered by the general expressions used here and throughout the description, the following definitions and explanations are applicable: The alkyl groups can be linear or branched groups containing the number of carbon atoms indicated above. Likewise, the alkyl parts in the haloalkyl groups can be linear or branched.

Specific examples of relevant haloalkyl groups include chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1-chloroethyl, 2-chloroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 1,2-dichloroethyl, 1-chloropropyl, 3-chloropropyl, 1-chlorobutyl, 1-chloropentyl, 1-chlorohexyl, 4-chlorobutyl and the like.

Also, the term "C 3 -C 8 cycloalkyl" is used to refer to a cycloalkyl radical having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Although all the compounds comprised by formula (I) above essentially satisfy the purposes of the present invention, certain groups are nevertheless preferred. A "first" group of preferred compounds of formula (I) is listed below the summary of the invention above.

Another preferred group of compounds consists of those compounds of formula (I) where Z, Rx and R2 are as defined above, and the remainder of the structural variations are identical to those of hydrocortisone (ie R^ , R^ and R^ are each a hydrogen atom and the 1,2-bond is saturated) or to prednisolone (ie R3, and R,, are each a hydrogen atom and the 1,2-bond is unsaturated),

and most particularly when R and R, are as defined in connection with the "first" group of preferred compounds set forth above.

Another preferred group of compounds consists of

6a- and/or 9a-fluoro and 16a- or 160-methyl congeners of the compounds indicated in the preceding paragraph. Within this group are those compounds in which Z, R 1 and R 2 are as defined above,

and the remaining structural variables are identical to those of fludrocortisone, betamethasone and dexamethasone, particularly preferred, most particularly when R 1 and R 2 are as defined in connection with the

"first" group of preferred compounds as listed above. Other compounds of particular interest within this group are those where Z, R 1 and R 2 are as defined above and the remaining structural variables are identical to those of triamcinolone, flumethasone, fluprednisolone or paramethasone, especially when and R 2 are as defined in connection with the "first" group of preferred compounds indicated above.

Still further interesting compounds are those where Z, X,

R 1 and R 2 are as defined above, R 2 is

and they re-

being structurally variable are identical to those of triamcinolone, especially when R 1 and R 2 are as defined in connection with the "first" group of preferred compounds indicated above.

The compounds of formula (I) can usually be prepared

according to the invention in that

a) for the preparation of a compound of the formula

where Rj_, R2 , R3 , R4 . R 5 and Z, and the dotted line in the ring A is as defined in the preamble (I), with the proviso that R± and R 2 are not a sulfonyl-containing group, reacts a compound with the formula where R 2 , R 3 , R 4 , R 5 . Z and the dotted line in the ring A are as defined above, and M is alkali metal, alkaline earth metal/2, thallium or NH4, with a compound of the formula where R^ is as defined above, and W is halogen, or b) for the preparation of a compound with the formula: where R-L, R2, R4, R5, Z and the dotted line in ring A are as defined in alternative a) and R3 is as initially defined, a compound of formula where R 1 , R 4 , R 5 , Z and the dotted line in ring A are as defined above, and R 3 " is hydrogen, o-methyl, p-methyl-a-OCOCl or p-OCOCl with a compound of the formula wherein R 2 is as defined above, but equal to R2 when R3'' is a- or P-OC0C1 and M' is hydrogen or M as defined previously, or c) for the preparation of a compound of the formula:

where Ri, R2, R4, R5, Z and the dotted line in the ring A are

as defined in alternative a), and R3 is as defined in the preamble (I), a compound with the formula is reacted

where R]_, R4, R5, Z and the dotted line in ring A are as defined above, and R3' is hydrogen, cx-methyl, P-methyl, ot-OH or P-OH, with a compound of the formula where R2 is as defined above, but equal to R^ when R3 is α-OH or P-OH, X' is chlorine or bromine, or d) for the preparation of a compound of the formula where Rj_, R2 , R3 , R4 , R5 , Z and the dotted line in the ring A is as defined in the preamble (I), with the proviso that at least one of Rx and R2 is a sulfinyl- or sulfonyl-containing group, a compound of the formula where R3, R4, R5, Z and the dotted line in the ring A is as defined above, and ^ and R2 are as defined in the preamble (I), with the proviso that at least one of Rx and R2 is a sulfur-containing group, or e) for the preparation of a compound of the formula where Rlf R2, R3, r4, r5 and the dotted line in the ring A is as defined in the preamble (I), a compound with the formula is oxidized

where Rlt R2, R3, r4, r5 and the dotted line in ring A are as defined above.

The following description indicates further details of the production according to the invention through preceding intermediate products.

Thus, products of formula I where Z is p-hydroxymethylene are prepared from compounds

where R 4 , R 1 , and the dotted line in ring A are as previously defined and R 2' is hydrogen, α-methyl, Θ-methyl, α-OH, 0-OH or =CH 2 (and which can conveniently be prepared by treatment of the corresponding 21-hydroxypregnenolones of the formula where R^ , R^, R^' and the dotted line in ring A are as defined above, with NalO^ in a suitable organic solvent at room temperature or elevated temperature.) According to this method according to the invention, a starting material of formula (II) is reacted with R20C0C1 or R2OCOBr (formed by reacting R2OH with COC12 or COBr2, where R2 is as defined above), under anhydrous conditions, in a suitable inert organic solvent such as dichloromethane, chloroform or tetrahydrofuran, preferably in the presence of a suitable acid acceptor (eg triethylamine, pyridine, calcium carbonate or other suitable base). Time and temperature are not critical factors, but the reaction is conveniently carried out at a temperature between 0°C and room temperature for approx. 1 to 6 hours. The resulting new 173-carboxylic acid-17α-carbonate has the formula

where R2, R4, Rcj and the dotted line in ring A are as defined above and R3" is H, a-CH3, 3-CH3, cx-OC00R2 or B-OCOOR2

When R3' in the starting material with formula (II) is a-OH or 3-OH, sufficient R20C0C1 or R2OCOBr is usually used to ensure that formation of the carbonate group takes place in the 16-position and also in the 17-position [i.e. when R 3' in formula (II) is OH, R 3' in the resulting intermediate of formula (III) is a- or (3-OCOOR 2 ).

After the above-described introduction of the 17a-substituent, the resulting new intermediate of formula (III) is converted to its corresponding metal salt of the formula

where R2, R3", R4, R5, Z and the dotted line in ring A are as defined above, and M is a suitable metal, eg alkali metal (such as sodium or potassium), alkaline earth metal/2, or thallium or NH^. The new salt of formula (IV) is typically formed by reacting a steroid of formula (III) with a hydroxide (MOH) or alkoxide (MOR) in a suitable organic solvent, then

as ethyl ether or tetrahydrofuran, at a temperature of 0°C to room temperature, for 0.5 to 4 hours. Then the salt of formula (IV) is reacted with a compound of formula R^-W where R^ is as defined above and W is halogen, to give the desired final product of formula (I). This step in the reaction sequence can conveniently be carried out at room temperature for approx. 1 to 24 hours, or at the boiling point of the solvent (ie acetonitrile, THF, etc).

When it is desired to introduce a halogen-substituted R^ group into the steroid, e.g. a compound of formula (I) where R1 is chloromethyl, it has been found that the reaction proceeds well by using hexamethylphosphoramide as solvent at lower temperatures (0-10°C) and using a reactant R1-w where W is iodine (for example iodochloromethane). When in a) a non-halogenous R^ group is desired (e.g. R1 = alkyl or -CH^COORg where R& is alkyl, etc), it is not necessary to place any such restrictions on the reactant R^-W or on the solvent. W can thus be any halogen atom, preferably chlorine or bromine, and the usual organic solvents such as dimethylformamide, dichloromethane, acetonitrile, tetrahydrofuran or chloroform can, if desired, be used instead of hexamethylphosphoramide. When a compound of formula (I) is desired where R^ contains a sulfonyl group, such a group is usually not introduced via the reaction with R^-W, but is afterwards prepared from the corresponding thio-steroid, as described below.

The compounds of formula (I) where R 1 (or R 2 ) is a sulfonyl-containing group can be prepared in d) by oxidizing them. corresponding thio-steroids. Thus, for example, a compound of formula (I) where R^ is -CH-S-(lower)

R9

alkyl) [where Rg cr II, lower alkyl, or combined with it

lower alkyl group that is attached to S to form a cyclic

- system, as described above] is reacted with 1 equivalent of m-chloroperoxybenzoic acid at 0-25°C for 1 to 24 hours, in a suitable alkyl) [where Rg is H, lower alkyl, or combined with the lower alkyl group which is linked to S to form a cyclic system, as described above] is reacted with 2 equivalents of m-chloroperoxybenzoic acid to give the corresponding compound

of formula (I) where R^ is

Another method for preparing the compounds of formula (I) where Z is ω-hydroxymethylene and X is oxygen, uses the same 17α-hydroxy-17β-carboxylic acid starting materials of formula (II) as used in the synthesis core described supra, but involves formation of the 17P-C00R! group before, rather than after, the introduction of the 17a-OCOOR2 substituent. Essentially the same non-stereoidal reactants, reaction conditions, etc., as described above, are used for the introduction of each group. Thus, the starting material with formula (II) is first for d) reacted with MOH or MOR to form the corresponding intermediate with the formula. where R 3 , R 4 , R 5 and M and the dotted line in ring A are as above, which is then treated with R 1 W where R 1 and W are as above to give the corresponding 17P-carboxylate of the formula

where R-^ , R 4 , R 5 , Z and the dotted line in ring A are as indicated above, and R 3 is hydrogen, cx-methyl, P-methyl, a-OH or 3-OH, which in turn is reacted with R20C0C1 or R2OCOBr where

R 2 is as indicated above, to give the corresponding 17a-carbonate of formula (I). The various parameters of the process for converting (II) to (V) are the same as discussed in detail above in connection with the conversion of (III) to (IV). Likewise, the process parameters for conversion of (V) to (VI) are parallel to those discussed in detail in connection with the conversion of (IV) to (I). Likewise, the process parameters for the conversion of (VI) to (I) are essentially the same as those given above for the conversion of (II) to (III). Thus again, when the starting material contains a 16-hydroxy group, a 16,17-dicarbonate of formula (I) will be formed which can then be selectively hydrolyzed, if desired, to the corresponding 16-hydroxy-17-carbonate of formula (I ). And again, the compounds of formula (I) in which is a sulfonyl-containing group can conveniently be prepared by oxidation of the corresponding thio-containing compounds of formula (I) as described in detail above. Alternatively, the compounds of formula (I) where R

is a sulfonyl-containing group [e.g. when R^ is

SO2-(lower alkyl)] is prepared by oxidation, preferably with m-chloroperoxybenzoic acid, of the corresponding compounds of formula (VI) wherein R^ is a thio-containing group, followed by introduction of the 17ot-OCOOR2 substituent to give the resulting sulfonyl compound.

Another desirable method b) for preparing the compounds of formula (I) where Z is P-hydroxymethylene, consists in using the 17a-hydroxy-173-carboxylates of formula (VI) above. According to this method, an intermediate product of formula (VI) is reacted with phosgene, in a suitable organic solvent (e.g. toluene, benzene, CH2C12 or acetonitrile) at a low temperature (-20°C to room temperature, f . eg CC) for approx. 2 hours (or until turnover is complete). Evaporation to remove solvent and excess phosgene gives the desired new 17a-chlorocarbonyloxy-17B-carboxylate intermediate of the formula where , R4, R5, Z and the dotted line in ring A are as indicated above, R2''' is hydrogen, α-methyl, β-methyl, α-OCOCl or B-OCOCl. When <R>3 in the starting material of formula (VI) is hydroxy, sufficient phosgene is usually used to ensure formation of the chlorocarbonyloxy group in the 16-position and also in the 17-position [i.e. when R3 in formula (VI) is a-OH or P-OH, R3" in the resulting intermediate of formula (VII) is a- or P-OC0C1]. The intermediate of formula (VII) is then reacted with a compound of formula R2OM' where R2 and M' are as indicated above, in an inert solvent, preferably in the presence of an acid acceptor (e.g. triethylamine, to obtain the corresponding compound of formula (I). When R2OM' is an alcohol of formula R2OH, the reaction is carried out under the same conditions as in the reaction to convert compound (II) to compound (III). If, on the other hand, a compound of formula R2OM is used as R2OM', the reaction conditions are as described above for conversion of compound (VIII) to compound (I). When R<3>'' in formula (VII) is 0C0C1, sufficient R2OM' is usually used to be sure to measure conversion of both 16- and 17a -substituents of OCOOR2 groups in the final product.And again the 16-hydroxy and sulfonyl-containing compounds is of formula (I) most conveniently formed as a final step in the synthesis scheme.

As a variation of the procedure described immediately above, a stereoidal 17α-hydroxy-17B-carboxylic acid starting material of formula (II) can be reacted with phosgene as described above to give a 17α-chlorocarbonyloxy-17B-carboxylic acid intermediate of the formula

where 1*3'', R4, R5 and the dotted line in ring A are as indicated above, which can then be reacted with R2OM' as described above, to give the corresponding compound of formula (III) above. The new intermediate can then be converted into a corresponding compound of formula (I) as described above. And again, the 16-hydroxy and sulfonyl derivative is best prepared as a final step. In yet another method c) for preparing the compounds of formula (I) where Z is P-hydroxymethylene, the 17a-hydroxy-17B-carboxylates of formula (VI) above are used. In accordance with this method, an intermediate of formula (VI) is reacted with an excess of a carbonate of the formula (which can conveniently be prepared by reacting phosgene with 2 equivalents of R 2 OH) in the presence of an acid catalyst, to obtain the corresponding compound with formula (I). Depending on the nature of the R2 group may also

the reactant acts as a solvent at the boiling point of the carbonate reactant, or at the boiling point of the corresponding R2OH (which can be conveniently removed in this way from the reaction mixture, bringing the reaction to completion), or the reactants can be mixed together in a suitable inert organic solvent (f .eg an aromatic compound such as benzene or toluene, or a halogenated hydrocarbon such as dichloromethane or chloroform). Again, the 16-hydroxy and sulfonyl compound of formula (I) may conveniently be prepared as a final step in this process, although the intermediate of formula (VI) in which R 2 contains a sulfur atom may be oxidized first, and the resulting sulfonyl compound of formula (VI) then becomes

traded with

Other methods of preparing selected compounds of formula (I) will be readily apparent to those skilled in the art. For example, a compound of formula (I) wherein vor or R 2 is halogen-substituted can be subjected to a halogen exchange reaction to replace the halogen with a different halogen in accordance with the order of reactivity Cl<Br<I. For example, reaction of a chloroalkyl-17p-carboxylate of formula (I) with an alkali metal iodide, e.g. sodium iodide, give the corresponding iodoalkyl-17P-carboxylate. Similarly, a bromide salt (eg, lithium bromide) can be reacted with a chloroalkyl-173-carboxylate to give the corresponding bromoalkyl-170-carboxylate. A suitable solvent for each reaction may be selected from the group consisting of hexamethylphosphoramide, acetone, ethanol, methyl ethyl ketone, dimethylacetamide, dimethylformamide and acetonitrile.

In a similar way, a halogen-exchange reaction based on relative solubilities can be used to convert a chloroalkyl-17(5-carboxylate or an iodoalkyl-170-carboxylate of formula (I) into the corresponding fluoroalkyl derivative. Silver fluoride can be used in this reaction which is carried out in a suitable organic solvent (e.g. acetonitrile) and which is particularly useful in the preparation of compounds in which is fluoromethyl or fluoroethyl.

The 21-hydroxypregnenolones from which the steroidal starting materials of formula (II) are prepared can be obtained commercially or prepared by known methods. Likewise, the non-steroidal starting materials used in the various methods discussed above are commercially available or can be produced by known chemical processes.

A starting material of formula (II) above can also be reacted with a compound of formula R 2 OCOCl or R 2 OCOBr where R 2 is as indicated above to give an intermediate of the formula where R 2 , R 3 , R 4 , R 5 and the dotted line in ring A are as indicated above, which can be converted to the corresponding intermediate of formula (III) above by partial hydrolysis, with or without isolation of the compound of formula (XI).This reaction of a starting material of formula (II) with R 2 OCOCI or R 2 OCOBr can be carried out under the same conditions as the reaction of a compound of formula (II) with R 2 O C 0 C 1 or R 2 OCOBr as described above, except that R 2 O C 0 C 1 or R 2 OCOBr is used in an amount of 2 mol or more to one mol of the compound of formula (II). The partial hydrolysis of the resulting compound of formula (XI) can be carried out in an inert solvent in the presence of a catalyst Examples of suitable catalysts include tertiary alkylamines such as triethylamine, trimethylamine e ller similar; aromatic amines such as pyridine, 4,4-dimethylaminopyridine, quinoline or the like; secondary alkylamines such as diethylamine, dimethylamine or the like; and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium bicarbonate or the like. Pyridine or potassium bicarbonate is preferably used. Examples of suitable inert solvents for use in the hydrolysis include water; lower alcohols such as ethanol, methanol or the like: ethers such as dimethyl ether, diethyl ether, dimethoxyethane, dioxane, tetrahydrofuran or the like; halogenated hydrocarbons such as dichloromethane, chloroform or the like; tertiary amines such as pyridine, triethylamine or the like; or a mixture of two or more of the above solvents. The reaction is usually carried out at a temperature of from approx. 0 to 100°C, preferably at room temperature to 50°C, for 1 to 48 hours, preferably for 2 to 5 hours.

In yet another aspect e) the present invention provides new compounds of the formula

where , , R^, R^, R,, and the dotted line in ring A is as indicated in connection with formula (I) above. The 11-keto compounds of formula (IX) can be prepared by the methods described above for the preparation of the corresponding lip-hydroxy compounds of formula (I). Thus, a starting material corresponding to formula (II), but having an 11-keto group, is reacted with R20COCl or R-jOCOBr, to give the corresponding new intermediate of formula (III) having an 11-keto group.

This intermediate is then converted to its metal salt, which corresponds to formula (IV) except for the presence of an 11-keto group instead of a hydroxy group, and the metal salt is then reacted with RjW to give the corresponding compound with formula (IX). All reaction conditions are as previously described in connection with the corresponding methods for preparing the corresponding compounds of formula (I). Also the production of the compounds of formula (IX) in which R^ is a sulfone-containing group or in which R3 is hydroxy, usually takes place as a final step in the synthesis scheme in an analogous manner to that used for the corresponding compounds of formula (I) .

Furthermore, all of the above-described alternative methods for the preparation of the compounds of formula (I) are equally applicable to the preparation of the compounds of formula (IX) by simply substituting a 11-oxo starting material in place of the corresponding 11-hydroxy steroids used here, e.g. substitute

The 11-hydroxy group in the formulas (V), (VI), (VII), (X) and (XI)

with an 11-oxo group and otherwise proceed as described above for the reactions (11)-—» (V) > (VI) > (I); (III)

(IN); (VI) > (VII) > (I); <") (X) (I)

(VI) > (i) , etc.

The compounds of formula (IX) can also be prepared by reacting the corresponding compounds of formula (I) in which Z is e-hydroxymethylene as in e) with an oxidizing agent. The oxidation of a compound of formula (I) to convert it to the corresponding compound of formula (IX) is usually carried out using an oxidizing agent in a suitable solvent. The solvent can be any conventional solvent, e.g. water, an organic acid (e.g. formic acid, acetic acid, trifluoroacetic acid), another alcohol (e.g. methanol, ethanol), a halogenated hydrocarbon (e.g. chloroform, dichloromethane) or the like. The oxidizing agent may also be any conventional agent effective to oxidize a hydroxy group to a carbonyl group, e.g. pyridinium chlorochromate, chromium trioxide in pyridine, hydrogen peroxide, dichromic acid, dichromates (e.g. sodium dichromate, potassium dichromate), permanganic acid, permanganates (e.g. sodium permanganate, potassium permanganate) or the like. The oxidizing agent is usually used in an amount of 1 mol or more, preferably 1 to 3 mol, per moles of the compound of formula (I). The reaction is usually carried out at a temperature

of 0 to 40°C, preferably at around room temperature, for approx. 6 to 30 hours.

The new compounds of formula (IX) are useful as mild steroidal anti-inflammatory agents and also precursors in vivo or in vitro for the corresponding HB-hydroxy compounds.

It is typical that microbiological reduction is advantageous for carrying out the desired conversion, although chemical reduction is also possible. Furthermore, the compounds of formula (IX) can be formulated into suitable dosage forms (e.g. enema-retention) for the treatment of conditions such as ulcerative colitis. In such dosage forms, it is thought that the compounds of formula (IX) are microbiologically reduced by bacteria in the body (e.g. in the colon) to the highly active HB-hydroxysteroids, which elicit the desired anti-inflammatory response.

The preferred compounds of formula (IX) are those which are precursors of the preferred compounds of formula (I) where Z is P-hydroxymethylene, namely corresponding to the 11-keto compounds of formula (IX). A particularly preferred group of compounds of formula (IX) consists of those where X, Rx and R2 are defined as above in connection with formula (I) and the remaining structural variations are identical to those of cortisone (ie R3, R4 and R5 are each hydrogen atoms and the 1,2 bond is saturated), for prednisone (ie R3, R4 and R5 are each hydrogen and the 1,2 bond is unsaturated) or for 6a- and/or 9a-fluorine and 16a- or 16B -methyl congeners thereof, especially when R 1 and R 2 are as defined in connection with the "first" group of preferred compounds indicated above. Most particularly preferred of these derivatives are those where X is oxygen, R 2 is C 2 -C 8 -alkyl and R 3 is -C 1 -C 6 -alkyl, C 1 -C 6 -(monohalo)alkyl [especially chloromethyl] or -CH 2 -Y -(C1-C6 alkyl) [especially -CH2-Y-CH3].

The results of various activity studies of representative species according to the invention, discussed in detail below, clearly show the powerful anti-inflammatory activity and the minimal systemic activity/toxicity of the soft steroids of formula (I). On the basis of this desirable separation of local and systemic activities, the compounds according to the invention can be used in the treatment of topical or other localized inflammatory conditions without causing the serious systemic side effects that typically occur with the known natural and synthetic glucocorticosteroids such as cortisone, hydrocortisone , hydrocortisone-17a-butyrate, betamethasone-17-valerate, triamcinolone, betamethasone dipropionate and the like.

THYMUS INVOLUTION TEST

The test animals were female Sprague/Dawley rats weighing approximately 40-45 grams each. One side of each ear of each rat was treated with a total of 25 microliters of a solution (ethanol/isopropyl myristate or acetone/isopropyl myristate, 90/10) containing the amount of test compound indicated below. Animals treated identically, except that the test compound was omitted, served as comparisons (controls). After 24 hours, all rats were sacrificed and weighed, and their thymi were removed and weighed. The results are listed in Table I below, the weights of thymi being expressed as mg/100 g rat.

The change in thymi weight is a measure of systemic activity and, consequently, toxicity. The lower the weight of the thymi, the greater the systemic activity. As can be seen from the above data, even hydrocortisone, the natural glucocorticoid, causes a marked decrease in thymus weight compared to the control. The reduction caused by equal doses of representative species according to the invention is much less evident, and this shows that such compounds have much less systemic activity than hydrocortisone.

BLEACH STUDIES

McKenzie-type bleaching studies were conducted in humans to study the bleaching effect of a representative test compound of the invention, chloromethyl-17a-ethoxycarbonyloxy-11(3-hydroxyandrost-4-en-3-one-173 ~carboxylate The ability of a compound to cause bleaching in humans has been found to correlate closely with its anti-inflammatory activity.

The test compound was dissolved in ethanol/isopropyl myristate (90/10 or 70/30) at concentrations of 0.03, 0.01, 0.003, 0.001 and 0.0003 M. Aliquots of 50 microliters of each solution were applied on separate gas parts of a bandage of the type usually used in allergy testing, and the bandage was put on the forearm. After 6 hours of occlusion, the bandage was removed.

After 1 to 5 hours after removal of the dressing, bleaching was observed even with the lowest concentrations of test compound.

When hydrocortisone was tested according to the above procedure to compare it directly with the test compound,

no bleaching was observed at concentrations of hydrocortisone below 0.03 M. Furthermore, it was noted that 0.03 M hydrocortisone caused approximately the same degree of bleaching as that resulting from the use of 0.001 M chloromethyl-17a-ethoxy-carbonyloxy- 113-Hydroxyandrost-4-en-3-one-173-carboxylate.

EAR EDEMA TEST

The test animals were Sprague/Dawley rats weighing approximately 150 grams each. When treating groups, selected amounts of the test compound were dissolved in acetone containing 5% croton oil,

and 50 microliters of the solution applied to the inner surface of the right ear of the rats. A control group was treated identically

with only excipients, i.e. 5% croton oil in acetone. 6 hours after the croton oil challenge, a constant region of each ear was removed by dissection under anesthesia. Then, 48 hours after the steroid treatment, the animals were sacrificed, and the thymi and adrenals were removed and weighed. The test results showing the inhibitory effect of topically applied steroids on the ear swelling induced with croton oil are summarized in Table II below.

As can be seen in Table II above, the representative compound of the present invention, namely, chloromethyl-17a-ethoxycarbonyloxy-11(5-hydroxyandrost-4-en-3-one-170-carboxylate), substantially inhibited the swelling (and consequently increased weight) of the ear caused by croton oil, that is, the compound exhibited significant anti-inflammatory activity. On the other hand, in contrast to the effect caused by betamethasone-17-valerate, the representative compound according to the invention did not significantly decrease degree the thymus weight in relation to the control, i.e. it did not show any clear degree of .. systemic activity.

GRANULOMA FORMATION TEST

The test compound was dissolved in acetone and aliquots of varying concentrations were injected into cotton pellets. The pellets were dried, and then one pellet was implanted under the skin of each test animal. Six days later, the animals were killed, and the granulation tissue (granuloma) that had formed in and around the implanted pellet was removed, dried and weighed. In addition, thymi and adrenals were removed and weighed. The ability of a compound to inhibit granuloma formation in this test is a direct indication of local anti-inflammatory activity. Thus, the lower the weight of granulation tissue, the better the anti-inflammatory activity. On the other hand, a clear decrease in thymus weight indicates a clear systemic activity; and conversely, when a test compound does not produce a significant reduction in thymus weight compared to the control, this is an indication of a lack of (or very minimal) systemic side effects.

The results are listed in Tables III, IV and V-a and V-b below.

The test data in Tables III, IV and V-a and V-b above clearly show that the representative compounds according to the present invention exhibit a significant anti-inflammatory activity at lower doses than in the steroids known in the art, hydrocortisone-17-butyrate and betamethasone- 17-valerate. On the other hand, all the steroids previously known in the art very dramatically reduce the weight of thymi, and thus show very strong systemic activity, while the representative compounds according to the invention either do not provide any significant reduction in thymi weights or only minimally reduce thymi- the weights. The present compounds thus have a much greater therapeutic index, i.e. separation of local anti-inflammatory activity from systemic activity, than the steroidal anti-inflammatory agents previously known in the industry.

The test data in Table V-b above also show that the representative compounds according to the present invention exhibit a significant local anti-inflammatory activity.

From the results listed in Tables IV and V-b, the values for ED4q» ED5o°9 ED60°^ ^e re^atlve powers of the representative compounds according to the invention were calculated, and are shown in Table VI below. One of the compounds according to the invention, namely chloromethyl-11-hydroxy-17-isopropoxy-carbonyloxyandrost-4-en-3-one-17-carboxylate, has been given a power value of 1 at each ED level, and the powers until the other compounds are expressed in relation to this. The values for ED^q, ED^q and EDg0 are the doses required to achieve respectively

40%, 50% and 60% reduction in the weight of the granulation tissue.

THYMUS INHIBITION TESTING

Several additional studies were conducted to determine the effects of selected compounds of the invention on thymi weights in rats when the drugs were systemically administered. In each of these studies, male Sprague-Dawley rats were used. (Regarding the average weight of rats for each study, see the tables that follow.) The test compounds were suspended in 0.5% CMC (carboxymethyl cellulose) and injected subcutaneously once a day for three days. On the fifth day (48 hours after the last treatment), the animals were sacrificed and the thymi weights were recorded. Gain in body weight was measured 24 hours after the last treatment. The test results are shown in Tables VII, VIII and IX below. The values for TED^q and TED^q (thymolytically effective doses or doses required to achieve 40% and 50% inhibition of thymi weight, respectively) and relative potencies for representative compounds according to the invention and reference steroids are shown in Table X below. In Table X, the TED^0 and TED^Q of the reference steroid betamethasone-17-valerate are each given a value of 1, and the potencies of the other compounds are expressed relative to this. It is clear that the higher the inhibition of thymus activity at a given dose, the more toxic the compound.

PURE- COTTON- PELLET- GPvANULOMA- SAMPLE

A further test was conducted to determine the thymolytic activity of a representative compound of the invention in comparison with betamethasone-17-valerate. In this test, the drugs were administered intravenously to rats using a pure cotton pellet -granuloma sample Male Sprague-Dawley rats, each weighing approx.

185 grams (166-196 grams) was used. Two cotton pellets, each weighing 30 mg and containing no test compounds, were sterilized and implanted subcutaneously in the back of each test animal. This day was considered day 0 at implantation. Test compounds suspended in 0.8% polysorbate 80 were administered intravenously once a day for 3 consecutive days beginning with day 1. On day 5, the animals were sacrificed and the two pellets with their respective granulomas were removed, dried , overnight in an oven at 50°C and weighed (dry granuloma weight).' Thymi weights and final body weights were also ■ recorded. The results are set out in Table XI below.

In the preceding tests, the deactivation was determined for the representative compounds of the present soft steroids administered intravenously to rats. The ratio between the powers of the tested steroids and betamethasone-17-valerate against local anti-inflammation was 283:0.7, as shown in Table VI. This means that the test compounds exhibit a local anti-inflammatory activity that is approximately 400 times as high as the activity of betamethasone-17-valerate. The test compounds were administered intravenously to rats to check the test compounds also for systemic anti-inflammatory activity compared to betamethasone-17-valcrat. The test compounds were found to give lower inhibition of granulation tissue formation and also lower thymic involution activity than betamethasone-17-valerate. From the test results, it is assumed that the compounds that will not be easily exposed to metabolism (deactivation) have a systemic anti-inflammatory activity, as in the case of betamethasone-17-valerate.

The values for ED^0 calculated for the local cotton pellet granuloma test (as shown for example in Table VI above) and for TED^q calculated on the basis of the thymus inhibition testing (as shown for example in Table X above) was used to arrive at a relative potency and a therapeutic index for the representative compounds of the invention compared to steroids previously known in the industry. See Table XII below which clearly demonstrates the potent anti-inflammatory activity and minimal systemic toxicity of the compounds of the present invention.

The compounds of formula (I) can be combined with suitable non-toxic pharmaceutically acceptable carriers to provide pharmaceutical preparations for use in the treatment of topical or other localized inflammations. It is obvious, on the basis of their lack of systemic activity, that the compounds according to the present invention are not intended for the treatment of conditions where systemic adrenocortical therapy is indicated, e.g. adrenocortical insufficiency. As examples of inflammatory conditions that can be treated with pharmaceutical preparations containing at least one compound according to the invention and one or more pharmaceutical carriers, the following can be mentioned: dermatological disorders such as atopic dermatitis, acne, psoriasis, or contact dermatitis; allergic conditions such as bronchial asthma; ophthalmic and otic diseases involving acute and chronic allergic and inflammatory reactions; respiratory diseases; ulcerative colitis; and anorectal inflammation, pruritus and pain associated with hemorrhoids, proctitis, cryptitis, fissures, postoperative pain and pruritus ani.

Such preparations can also be applied locally as a prophylactic agent against inflammation and tissue rejections that occur in connection with transplants.

It is obvious that the choice of carrier(s) and dosage forms will vary with the particular condition for which the preparation is administered.

Examples of different types of preparations for topical/local administration include ointments, solutions, creams, powders, drops (eg eye or ear drops), sprays (eg nasal or throat), suppositories, retention enemas , chewable or suckable tablets or pellets (eg for the treatment of aphthous ulcers) and aerosols. Ointments and creams can, for example, be formulated against an aqueous or oily base by adding suitable thickeners and/or gelling agents and/or glycols. Such a base may for example include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a glycolic solvent such as propylene glycol or 1,3-butanediol. Thickening agents which may be used according to the nature of the base include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycols, wool fat, hydrogenated lanolin and beeswax and/or glyceryl monostearate and/or nonionic emulsifiers.

The solubility of the steroid in the ointment or cream can be increased by incorporating an aromatic alcohol such as benzyl alcohol, phenylethyl alcohol or phenoxyethyl alcohol.

Solutions can be formulated with an aqueous or oily base and will usually also include one or more of the following, namely emulsifiers, dispersants, suspending agents, thickeners, solvents, dyes and perfumes. Powders can be formed using any suitable powder base, e.g. talc, lactose or starch. Drops can be formulated with an aqueous base which also comprises one or more dispersing agents, suspending agents or solubilizing agents etc. Spray preparations can for example be formulated as aerosols using a suitable propellant, e.g. dichlorodifluoromethane or trichlorofluoromethane.

The amount of active ingredient in the preparations according to the invention will vary with the precise compound used, the type of formulation being prepared and the particular condition for which the preparation is administered. The formulation will usually contain from approx. 0.0001 to approx. 5.0% by weight of the compound of formula (I). Topical preparations will usually contain 0.0001 to 2.5, preferably 0.01 to 0.5%, and will be administered once a day, or as needed. The compounds according to the invention can also, generally speaking, be incorporated into topical and other local preparations formulated essentially like such preparations which are currently available and which contain known glucocorticosteroids, against approximately the same (or in the case of the most potent compounds according to to the invention, proportionally lower) dosage amounts as known, highly active agents, such as methyl-prednisolone acetate and beclomctason dipropionate, or with considerably lower dosage amounts compared to less active, known agents such as hydrocortisone.

Thus, for example, an inhalation formulation suitable for use in the treatment of asthma can be prepared as a metered-dose aerosol unit containing a representative compound according to the invention such as chloromethyl-17a-ethoxy-carbonyloxy-110-hydroxyandrost- 4-ene-3-one-170-carboxylate, according to methods well known to those skilled in the art

pharmaceutical industry. Such an aerosol unit can contain a microcrystalline suspension of the aforementioned compound in a suitable propellant (eg trichlorofluoromethane and dichlorodifluoromethane), together with oleic acid or other suitable dispersant. Each unit typically contains 10 mg of the aforementioned

active ingredient, as approximately 50 micrograms of it is released with each use. When one or more of the more powerful compounds according to the invention, for example chloromethyl-17a-ethoxycarbonyloxy-9a-fluoro-110-hydroxy-16a-methy1androsta-1,4-dien-3-one-170 -carboxylate, is used, each unit typically contains 1 mg of the active ingredient and releases approx

5 micrograms with each use.

Another example of a pharmaceutical preparation

is a foam suitable for the treatment of a wide variety of inflammatory anorectal diseases, to be applied anally or perianally, comprising 0.1% of a compound of formula (I), such as chloromethyl-17a-ethoxycarbonyloxy-110 -hydroxyandrost- 4-en-3-one- 17(3-carboxylate, and 1% with local anesthetic, such as pramoxine hydrochloride, in a mucoadhesive foam base of propylene glycol, ethoxylated stearyl alcohol, polyoxyethylene-10-stearyl ether , cetyl alcohol, methylparaben, propylparaben, triethanolamine and water, with inert propellants. When a more potent compound according to the invention is used, less active ingredient is usually used, eg 0.05% of chloromethyl-9a-fluorine -11|3-hydroxy-17a-methoxy-carbonyloxy-16a-methylandrosta-1,4-dicn-3-one-170-carboxylate.

Yet another pharmaceutical formulation.

is a solution or suspension suitable for use as a retention enema, a single dose thereof typically containing 40 mg of a compound according to the invention, such as chloromethyl-17a-ethoxycarbonyloxy-110-hydroxy-androst-4-ene -3-one-170-carboxylate (or 20 mg of a more potent compound according to the invention, such as chloromethyl-90-fluoro-110-hydroxy-17a-isopropoxycarbonyloxy-160-methylandrosta-1,4-dien-3-one -170-carboxylate or chloromctyl-9a-fluoro-110-hydroxy-16a-methyl-17a-propoxycarbonyloxyandrosta-1,4-dien-3-one-170-carboxylate) together with sodium chloride, polysorbate 80 and from 31.1 to 186 .6 grams of water (the water is added shortly before

reversal). The suspension can be administered as a retention enema. Or by continuous drips several times a week in the treatment of ulcerative colitis.

It is assumed that a person skilled in the industry without further processing, by using the preceding description, can utilize the present invention to the widest extent. The following examples should therefore only be regarded as illustrative and not limiting the description and claims in any way.

Example 1 (Intermediate product)

To a solution of hydrocortisone (15 g, 0.04 mol) in 120 ml

tetrahydrofuran and 30 ml of methanol at room temperature, a warm (approximately 50°C) solution of sodium metaperiodate (25.7 g, 0.12 mol) in 100 ml of water is added. The reaction mixture is stirred at room temperature for 2 hours, and is then concentrated under reduced pressure to remove tetrahydrofuran and methanol. The solid is finely divided with 50 ml of water, separated by filtration, washed with water and dried in vacuum at 50°C for 3 hours. The product, 113, 17α-dihydroxyandrost-4-en-3-one-173-carboxylic acid

(ie cortienic acid), which melts at 231-234°C, is obtained in a yield of approximately 96% (13.76 g) and can be represented by the structural formula

Example 2 (Intermediate product)

A 50% (wt/ volume) solution of methyl chloroformate (3.9 mol) in dichloromethane. The reaction mixture is allowed to warm to room temperature for a period of

2 hours. The triethylamine hydrochloride precipitate that forms is removed by filtration, and the filtrate is washed successively with 3% sodium bicarbonate, diluted (-1%) hydrochloric acid and water. The organic layer is separated, dried with magnesium sulfate and filtered. The filtrate is concentrated in vacuo to a foam. The foam is used in the next step (e.g. example 3 below) or chromatographed and crystallized to be analyzed. The product, 113-hydroxy 17a-methoxycarbonyloxyandrost-4-en-3-one-170-carboxylic acid, melts at 198-204°C after chromatography and crystallization; ir (KBr) 3000-2800 { C- H), 1750, 1735, 1720 (C=0), 1650, 1640 (C=C-C=0)era"1. The product can be indicated with the structure formula

Using an equivalent amount of ethyl chloroformate instead of methyl chloroformate used above, and substantially repeating the preceding procedure, gives 17α-ethoxy-carbonyloxy-1 ip -hydroxyandros t-4-cn-3-one-17 [3- carboxylic acid melting at 192-195°C, after chromatography and crystallization;

ir (KBr) 3500 (113-02!!), 3000-2800 (C-H), 1740 (C=0), 1630

(C=C-C=0) cm<_1>;

nmr (CDCl-j) 66.4 (1, b, CO0I1) , 5.67 (1, s, C-CH) , 4.43 (1, b, CH01I) , 4.13 (2, q, J = 7.5l!z, OCn_2CH3);

Anal. calculated for C23l,32°7: C 65.69, H 7.67.

Found: C 65 , 76, I! 7.74.

In a similar way, it is achieved by using an equivalent amount of butyl chloroformate instead of methyl chloroformate

used in the first section of this example, and essentially repeating in detail the procedure there, 17α-butoxycarbonyloxy-113-hydroxyandrost-4-en-3-one-173_carboxylic acid. The final product, after crystallization from tetrahydrofuran-hexane, melts at 164-166°C.

Similarly, by using an equivalent amount of isopropyl chloroformate in place of the methyl chloroformate used in the first paragraph of this example, and repeating in detail the procedure there, 11[3-hydroxy-17a-isopropoxycarbonyloxy-androst-4-en-3 -one-173-carboxylic acid. The final product,

after crystallization from tetrahydrofuran-hexane, melts at 144.5-146.5°C.

Example 3

11(3-hy droc sy-17 a-me tok syk arbony loxy andros t-4-en-3-one-17(3-carboxylic acid is mixed together with an equivalent amount of 1N sodium monohydroxide in methanol, and that solution is diluted to 100 times its original volume with ethyl ether. The resulting suspension is cooled for 1 hour. Then the crystals that form are recovered by filtration, dried in an evacuated desiccator, and dissolved in hexamethylphosphoramide (10% w/v). A portion of resulting solution containing 1 mole of the acidic salt, i.e., sodium 11[3-hydroxy-17ci-methoxycarbonyloxyandrost-4-en-3-one-17[3-carboxylate, is mixed together with 4 moles of chloromethyl iodide. is kept at room temperature for 3 hours, and then diluted to 10 times its original volume with ethyl acetate. The diluted reaction mixture is washed successively with 5% sodium thiosulfate, 3% sodium bicarbonate and water. The organic layer is separated, dried with magnesium sulfate and filtered The filtrate is concentrated in vacuo to a foam. The foam is purified by crystallization from a suitable solvent (ethyl ether or tetrahydrofuran/hexane). Thus, chlormcty 1-113-hydroxy-17a-methoxycarbonyloxy-androst-4-en-3-one-17(i-carboxylate is obtained, which melts at 171-173°C after crystallization;

ir (KBr) 3000-2800 (C>H) , 1760, 1748 (C=0) , 1650 (C=C-C=0)enf<1>; nmr (CDC13) 6 5.67 (s, 1, C=CH), 5.82, 5.62 (ABq, J=5.5Hz, 2, 0CH2Cl1) , 4.4 7 (b, 1, C1I0II) ;

Anal. calcd for C23H31C10: C 60.72, H 6.87, Cl 7.79. Found: C 60.50, H 7.06, Cl 7.50. The product is characterized by the structural formula

Using an equivalent amount of 17α-ethoxycarbonyl-oxy-113-hydroxyandrost-4-en-3-one-173-carboxylic acid instead of the steroidal acid used above, and substantially repeating the preceding procedure, gives, as a intermediate salt, sodium 17a-ethoxycarbonyloxy-113-hydroxyandrost-4-en-3-one-173-carboxylate, and, as the final product, chloromethyl-17a-ethoxycarbonyloxy-113-hydroxyandrost-4-en-3 -one-173-carboxylate, which melts at 197-200°C after crystallization; ir (KBr) 3600-3200(0-11), 3000-2800(C^H), 1763, 1740 (C=0), 1650 (C=C-C=0) cm"<1>; nmr (CDCl-j ) 6 5.7 (s, 1, C=CH), 5.81, 5.62 (ABq, J=5Hz, 2, -OHCH 2 Cl);

Anal. calcd for C24H33C107: C 61.46, H 7.09.

Found: C 61.58, H 7.08

Similarly, using an equivalent amount of 17α-butoxycarbonyloxy-113_hydroxyandrost-4-en-3-one-173-carboxylic acid in place of the steroidal acid used in the first paragraph of this example, and in all substantially detailed repetition of the process wherein, as an intermediate salt, sodium 17a-butoxycarbonyloxy-113-hydroxyandrost-4-en-3-one-173-carboxylate, and, as the final product, chloromethyl 17a-butoxycarbonyloxy-113~hydroxyandrost-4- en-3-one-173-carboxylate, which melts at 98-100°C after crystallization;

ir (KBr) 3600-3300 (0ZH), 3000-2800 (C-H), 1765 (02C=0), 1735

(0C=0), 1650 (C=C-C=0) cm"<1>;

nmr (CDCl 3 ) 6 5.80, <5 5.60 (2, ADq, J=4.5Hz, -OHCH 2 Cl ) , 5.67

(1, s, C=CH) , 4.45 (1, b, CHOII) , 4.08 (2, t, J=6Hz, 02COCH2-CH2) ;

Anal. calcd for C26H37C107: C 62.77, H 7.44, Cl 7.14.

Found: C 62.88, H 7.23, Cl 7.30.

In a similar manner, using an equivalent amount of α 110 -hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-170-carboxylic acid in place of the steroidal acid used in the first section of this example, and in total substantially detailed repetition of the procedure in which, as an intermediate salt, sodium 110-hydroxy-17a-isopropoxycarbonyloxyandrost-4-en-3-one-170-carboxylate, and, as the final product, chloro-methyl-11Ø-hydroxy- 17α-Isopropoxycarbonyloxyandrost-4-en-3-one-<i>' 170-carboxylate, which melts at 183.5-184.5°C after recrystallization from tetrahydrofuran-hexane.

In a similar manner, an equivalent amount of 17α-ethoxy-carbonyloxy-11β-hydroxyandrost-4-en-3-one-170-carboxylic acid is used in place of the steroidal acid, and an equivalent amount of butyl chloride is used in place of chloromethyiodide used in the first paragraph of this example, and the procedure there is repeated in substantial detail, except that the washing step with 5% sodium thiosulphate is eliminated. In this way, the intermediate salt, sodium 17a-ethoxycarbonyloxy-110-hydroxyandrost-4-en-3-one-170-carboxylate, and the final product, butyl-17a-ethoxycarbonyloxy-110-hydroxyandrost-4-en- 3-one-170-carboxylate. After crystallization from acetone, the final product melts at 148-149°C, after chromatography and crystallization, ir (KBr) 3600-3200 (O^H), 3000-2800 ( C- H),

1750 (2 C=0) , 1670 (C=C-C=0) cm"<1>;

nmr (CDCl 3 ) δ 5.64 (s,l, -C=CH) , 4.46 (b, 1, CHOH) , 4.32-4.95

(m, 4, COOCIi2CII3<+>, COOCI]2CII2-) ;

Anal. calculated for C27H40°7: C 67'99' H 8.39.

Found: C 67.76, H 7.74.

Example 4

17a-e toxycarbonyloxy-110-hydroxyandrost-4-en-3-one-170-carboxylic acid (3 g, 7.13 inmol) is treated with 7.13 mL of 1M methanolic sodium hydroxide solution, and 500 mL of ethyl ether is then added to achieve precipitation. The precipitate is separated by filtration and dried in an evacuated desiccator overnight, and this gives 2.71 g (6.12 mmol) of the desired salt, i.e. sodium--a- e toxycarbonyl loxy- 110- hy dr ok sy an drost- 4 - en-3-one-170-carboxylate, as a yellow powder. The salt is dissolved in 40 mL of hexamethylphosphoramide, and chloromethyl methyl sulfide (2.36 g, 24.5 mmol) is slowly added. A precipitate of sodium chloride is formed in

the reaction mixture within 1 minute. The reaction mixture is stirred at room temperature for 1 hour, then diluted with ethyl acetate to a total volume of 200 ml and washed successively with 3% sodium bicarbonate and water. The organic layer is separated, dried with magnesium sulfate and filtered. The filtrate is concentrated in vacuo to an oil and the oil is chromatographed from silica gel using ethyl acetate, chloroform and acetic acid as eluents. The chromatographed product is crystallized from a mixture of ethyl ether and hexane to give white powdery crystals of methylthiomethyl-17a-ethoxycarbonyloxy-11|3-hydroxyandrost-4-en-3-one-17[3-carboxylate which melts at 133-136° C. This product is characterized by the structural formula

To a solution of methylthioinethyl~17α-ethoxycarbonyloxy-113_ hydroxyandrost-4-cn-3-one-173-carboxylate (0.48 g, 1 mmol) in 2 ml of dichloromethane is added rn-chloropcroxybenzoic acid (0.4 g = 0 .34 g of peracid, 2 mmol). An exothermic reaction occurs, which quickly subsides. The reaction mixture is stirred at room temperature for 1 hour. The precipitate which forms is removed by filtration and the filtrate is concentrated in vacuo to give, as a white foam, methylsulfonylmctyl-17a-ethoxycarbonyloxy-113-hydroxyandrost-4-en-3-one-173-carboxylate. This product has the structural formula

Example 5A (Intermediates)

By using an equivalent amount of one of the starting materials listed below instead of the hydrocortisone used in example 1, and by essentially repeating the procedure there in detail, the specified products are obtained:

Example 6A (Intermediates)

By following the general procedure in example 2 and introducing the appropriate reactants, the following new intermediates are obtained according to the present invention:

Compounds 6A-1 to 6A-15 above can be named in the following manner: 6A-1: 17a-benzyloxycarbonyloxy-110-hydroxyandrost-4-en-3-one-170-carboxylic acid

6A-2: 17a-ethoxycarbonyloxy-9a-fluoro-110-hydroxyandrost-4-en-3-one-1-70-carboxylic acid

6A-3: 17a-ethoxycarbonyloxy-9a-fluoro-110-hydroxy-163-methylandrosta-1,4-dien-3-one-170-carboxylic acid

6A-4: 17α-ethoxycarbonyloxy-9α-fluoro-110-hydroxy-16α-methylandrosta-1,4-dien-3-one-173-carboxylic acid

6A-5: 9a-fluoro-110-hydroxy-17a-isopropoxycarbonyloxy-16a-methy1androsta-1,4-dien-3-one-173-carboxylic acid

6A-6: 113-hydroxy-17a-isobutoxycarbonyloxyandrost-4-en-3-one-173-carboxylic acid

6A-7: 9a-fluoro-113_hydroxy-17a-isopropoxycarbonyloxy-163-methylandrosta-1,4-dien-3-one-173-carboxylic acid

6A-8: US-hydroxy-17a-propoxycarbonyloxyandrost-4-en-3-one-170-carboxylic acid

6A-9: 9a-fluoro-113-hydroxy-16a-methyl-17u-propoxycarbonyloxy-androsta-1,4-dien-3-one-173-carboxylic acid

6A-10: 17α-cyclohccxyloxycarbonyloxy-11Ø-hydroxyandrost-4-en-3-one-170-carboxylic acid

6A-11: 9a-fluoro-110-hydroxy-17a-methoxycarbonyloxy-16a-methylandrosta-1,4-dien-3-one-170-carboxylic acid

6A-12: 17a-n-pentyloxycarbonyloxy-9a-fluoro-110-hydroxy-16a-methylandrosta-1,4-dien-3-one-170-corboxylic acid

6A-13: 17a-ethoxycarbonyloxy-6a,9a-difluoro-110-hydroxy-16a-methylandrosta-1,4-dien-3-one-170-carboxylic acid

6A-14: 17a-phenoxycarbonyloxy-9a-fluoro-110-hydroxy-1Ga-methyl androsta-1,4-dien-3-one-17O-carboxylic acid

6A-15: 17α-(2-chloroethoxycarbonyloxy)-9α-fluoro-110-hydroxy-16α-methylandrosta-1,4-dien-3-one-170-carboxylic acid

Example 7A

By following the general procedure in example 3 and inserting the appropriate reactants, the following compounds are obtained:

The preceding compounds can be named as follows: 7A-I: chloromethyl-17a-ethoxycarbonyloxy-9a-fluoro-110-hydroxyandrost-4-en-3-one-173-carboxylate

7A-2: chloromethyl-17a-ethoxycarbonyloxy-9a-fluoro-110-hydroxy-163-methylandrosta-1,4-dien-3-one-173-carboxylate

7A-3: chloromethyl-17a-ethoxycarbonyloxy-9a-fluoro-110-hydroxy-16a-methylandrosta-1,4-dien-3-one-170-carboxylate 7A-4: chloromethyl-17a-ethoxycarbonyloxy-110-hydroxy- androsta-1,4-dien-3-one-173-carboxylate

7A-5: chloromethyl-110-hydroxy-17a-isopropoxycarbonyloxy-androsta-1,4-dien-3-one-170-carboxylate

7A-6: chloromethyl-17a-ethoxycarbonyloxy-9a-fluoro-110-hydroxyandrosta-1,4-dien-3-one-170-carboxylate

7A-7: chloromethyl-9a-fluoro-113-hydroxy-17a-isopropoxycarbonyloxy-16a-methylandrosta-1,4-dien-3-one-170-carboxylate

7A-8: chloromethyl-9a-fluoro-113-hydroxy-17a-isopropoxy-carbonyloxy-163-methylandrosta-1,4-dien-3-one-173-carboxylate

7A-9: chloromethyl-113-hydroxy-17a-isobutoxycarbonyloxy-androst-4-en-3-one-170-carboxylate

7A-10: chloromethyl-17a-cyclohexyloxycarbonyloxy-110-hydroxyandrost-4-en-3-one-173-carboxylate

7A-11: chloromethyl-110-hydroxy-17a-propoxycarbonyloxy-androst-4-cn-3-one-170-carboxylate

7A-12: chloromethyl-9a-fluoro-110-hydroxy-16a-methyl-17a-propoxycarbonyloxyandrosta-1,4-dien-3-one-170-carboxylate

7A-13: methyl 1-110-hydroxy-17a-isopropoxycarbonyloxyandrost-4-en-3-one-17 3-carboxylate

7A-14: ethoxynrety1-110-hydroxy-17a-isopropoxycarbonyloxy-androst-4-nn-3-one-L70-carboxylate

7A-15: chloromethyl-17a-benzyloxycarbonyloxy-110-hydroxy and rost-4-cn-3-one-173-carboxylate

7A-16: 1-chloroctyl-10-hydroxy-17a-isopropoxycarbonyloxy-androst-4-cn-3-one-170-carboxylate

7A-17: ethoxycarbonylmcty1-110-hydroxy-17a-isopropoxy-carbonyloxyandrost-4-en-3-one-170-carboxylate

7A-18: 1-chloroethyl-9a-fluoro-110-hydroxy-17a-isopropoxycarbonyloxy-16O-methylandrosta-1,4-dien-3-one-170-carboxylate

7A-19: chloromethyl 1-9a-fluoro-17a-isopropoxycarbonyloxy-160-methylandrosta-1,4-diene-3,11-dione-17-carboxylate 7A-20: chloromethyl 1-9a-fluoro-17a-isopropoxycarbonyloxy-16a-methylandrosta -1,4-diene-3,11-dione-17-carboxylate

7A-21: chloromethyl 1-9α-fluoro-113-hydroxy-17α-me toxycarbonyloxy-16α-methylandrosta-1,4-dien-3-one-173-carboxylate

7A-22: fluoromethyl-113-hydroxy-17a-isopropoxycarbonyloxy-androst-4-en-3-one-173-carboxylate

7A-2 3: chloromethyl-9a-fluoro-113-hydroxy-16a-methyl-17a-pentyloxycarbonyloxyandrosta-1,4-dien-3-one-173-carboxylate

7A-24: chloromethyl 1-16a,17a-di(ethoxycarbonyloxy)-6a-fluoro-113-hydroxyandrosta-1,4-dien-3-one-173-carboxylate 7A-2 5: fluoromethyl-17a-ethoxycarbonyloxy-9a- fluoro-113-hydroxy-16a-methylandrosta-1,4-dien-3-one-173-carboxylate 7A-26: acetoxymethyl-17a-ethoxycarbonyloxy-113-hydroxy-androst-4-en-3-one-173-carboxylate

7A-2 7: chloromethyl-17a-ethoxycarbonyloxy-6a,9a-difluoro-113-hydroxy-16a-methylandrosta-1,4-dien-3-one-173~ carboxylate

7A-28: 2-chloroethy1-17a-ethoxycarbonyloxy-9a-fluoro-113-hydroxy-16a-methylandrosta-1,4-dien-3-one-173-carboxylate

7A-29: methyl 17a-ethoxycarbonyloxy-9a-fluoro-113-hydroxy-16a-methylandrosta-1,4-dien-3-one-173-carboxylate

7A-30: 2-chloroethyl-17a-isopropoxycarbonyloxy-113_hydroxy-androst-4-en-3-one-173~carboxylate

Example 8 (Intermediate product)

An equivalent amount of 113/17a-dihydroxyandrost-4-en-3-one-173-carboxylic acid is used in place of the 113-hydroxy-17a-methoxycarbonyloxyandrost-4-en-3-one-173-carboxylic acid starting material used in Example 3, and the procedure in the first paragraph of that example is essentially repeated. There is thus obtained, as intermediate salt, sodium 113»17a-dihydroxyandrost-4-en-3-one-173_carboxylate, and, as the final product, chloromethyl-113,17a-dihydroxyandrost-4-en-3-one- 170-carboxylate, which melts at 184-186°C (recrystallization from tetrahydrofuran-ether-hexane).

Example 9

The procedure in each section of Example 2 is substantially repeated using an equivalent amount of each of the following starting materials in place of the steroids used therein: chloromethyl-113,17a-dihydroxyandrost-4-en-3-one-173-carboxylate ; and methyl thioniethyl 113,17α-dihydroxyandrost-4-en-3-one-173~carboxylate. The following mild anti-inflammatory agents of formula (I) are obtained:

Example 10

Chloromethyl-113,17a-dihydroxyandrost-4-en-3-one-17f3-carboxylate (0.01 mol) is dissolved in toluene (100 ml) and the solution is cooled to approximately 0°C. Phosgene is then bubbled into the solution, while the reaction mixture is kept at a low temperature, until the reaction is complete (approximately 2 hours). The solvent and excess phosgene are removed by evaporation to leave the crude 17α-chlorocarbonyloxy compound of the formula

Example 11

The procedure in the first paragraph of Example 12 is repeated, except that an equivalent amount of 110,17a-dihydroxyandrost-4-en-3-one-170-carboxylsyrc is used instead of chlormethyl ty 1-1 lo, 17a-dihydroxyandrost- 4-en-3-one-170-carboxylate. The crude intermediate thus obtained has the formula

The intermediate is then subjected to the procedure in the second section of Example 12 to give 17α-ethoxycarbonyloxy-110-ethoxycarbonyl-17α-ethoxycarbonyloxy-110-hydroxyandrost-4-en-3-one-170rcarboxylate, which melts at 158-159°C .

Example 12

Chloromethyl-110,17α-dihydroxyandrost-4-en-3-one-170-carboxylate (0.02 mol) is mixed with diethyl carbonate (0.2 mol) containing 20 mg of p-toluenesulfonic acid. The reaction mixture is kept at room temperature for 4 hours, and then heated to approx. 80 to 85°C. The remaining ethanol that is formed is removed by distillation under reduced pressure. As an impure residue, chloromethyl-17a-ethoxycarbonyloxy-110-hydroxyandrost-4-en-3-one-170-carboxylate is obtained, which melts at 197-200°C, after crystallization.

Using an equivalent amount of methylthiomethyl-110,17a-dihydroxyandrost-4-en-3-one-170-carboxylate instead of chloromethyl-110,17a-dihydroxyandrost-4-en-3-one-170-carboxylate used above, and substantially repeating the preceding procedure, gives methylthiomethyl-17a-ethoxycarbonyloxy-110-hydroxy-androst-4-en-3-one-170-carboxylate, which melts at 133-136°C. This compound can then, if desired, be converted into the corresponding sulfonyl or sulfinyl compound as described in example 4.

Example 13 (Intermediate product)

By following the general method described in example 17, and inserting the appropriate reactants, the following compounds are obtained:

Example 14 (Intermediate product)

A solution of 13.2 g of n-propyl chloroformate is added dropwise to a solution of 8.7 g of 11(3,17a-dihydroxyandrost-4-en-3-one-170-carboxylic acid and 10 g of triethylamine in 100 ml of dichloromethane in 20 ml of dichloromethane over 1 - 1.5 hours under ice-cooling.The reaction mixture is allowed to warm to room temperature

for a period of 2 hours, and then washed successively with 3% aqueous sodium bicarbonate, IN hydrochloric acid and water, and dried over anhydrous sodium sulfate. The solvent is concentrated under reduced pressure. Crystallization from a mixture of ether and n-hexane gives 10.5 g of propoxycarbonyl-11(3-hydroxy-17a-propoxycarbonyloxy-androst-4-en-3-one-17|3-carboxylate, which is dissolved in 40 ml pyridine. To this solution is added dropwise 300 ml of water over a period of 1 to 1.5 hours. The mixture is stirred for 1 hour and adjusted to pli 2 to 2.5 by adding concentrated hydrochloric acid under ice-cooling. The mixture becomes then extracted with chloroform, washed successively with 1N hydrochloric acid and water, and then dried over sodium sulfate.The solvent is concentrated under reduced pressure, and the residue is recrystallized from a mixt.

of acetone and tetrahydrofuran, and this gives 7.7 g of 110-hydroxy-17a-propoxycarbonyloxyandrost-4-en-3-one-170-carboxylic acid melting at 156-157°C

Example 15

By following in detail the general procedure of Example 19, but using the appropriate starting materials and reaction conditions, the remaining compounds of Example 6A are obtained.

Example 16

Chloromethyl 1-17a-ethoxycarbonyloxy-9a-fluoro-110-hydroxy-16a-methylandrosta-1,4-dien-3-one-170-carboxylate (2 g) is dissolved in anhydrous dichloromethane (200 ml), and pyridinium chlorochromate ( 3.5 g) is added at room temperature, while stirring. The resulting mixture is stirred for 24 hours, and then the solvent is concentrated under reduced pressure at approx. 10 to 20°C. The residue is subjected to column chromatography on silica gel

(silica gel 60) using chloroform as the eluting solvent, followed by crystallization from a mixture of tetrahydrofuran and isopropyl ether, and this gives chloromethyl-17a-ethoxycarbonyl-oxy-9a-fluoro-16a-methylandrosta-1,4-diene -3,11-dione-170-carboxylate, with a yield of 1.7 g, and which melts at 138-140°C.

Example 17

By a similar method to that described in example 21, chloromethyl-9a-fluoro-17u-isopropoxycarbonyloxy-160-methylandrosta-1,4-diene-3, 11-dione-170-carboxylate is obtained, which melts at 200-201°C .

Example 18

By applying the general procedure in example 3, but by inserting the appropriate reactants, methyl-17a-(2-chloro-ethoxy)carbonyloxy-9a-fluoro-110-hydroxy-16a-methylandrosta-1,4-diene is obtained 3-one-170-carboxylate. After recrystallization from isopropanol, this product melts at 223-227°C.

Example 19

By the same general procedure as in example 3, 2-chloroethyl-17u-ethoxycarbonyloxy-9a-fluoro-110-hydroxy-16a-methylandrosta-1,4-dien-3-one-170-carboxylate is obtained. After recrystallization from tetrahydrofuran-hexane, this product melts at 243-245°C.

Claims (1)

Analogous process for the preparation of therapeutically active steroids selected from the group consisting of a compound with formula (I) where R 1 is C 1 -C 10 alkyl; C 1 -C 10 haloalkyl; or -CH 2 COOR 6 where R6 is C1-C10 alkyl or R1 is (lower alkyl) where Y is -S-, -SO2- or -O-, and R9 is hydrogen or lower alkyl or Ri is (where Rs is as defined before), R 2 is C 1 -C 10 alkyl, which may be substituted with a halogen group, C 3 -C 6 cycloalkyl, or R 2 is benzyl; R 3 is hydrogen, α-methyl, β-methyl, or α- or where R 2 is lower alkyl, R4 is hydrogen, fluorine or chlorine, Rs is hydrogen, fluorine or chlorine, Z is carbonyl or p-hydroxymethylene; and the dotted line in ring A shows that the 1,2 bond is saturated or unsaturated, characterized in that a) for the preparation of a compound with the formula where Rlf R2/ R3 . R4i R5 and 2 and the dotted line in the ring A is as defined in the preamble (I), with the proviso that and R2 is not a sulfonyl-containing group, reacts a compound with the formula where R2, R^ , , R^, Z and the dotted line in ring A are as defined above, and M is alkali metal, alkaline earth metal/2, thallium or NH4, with a compound of the formula where R^ is as defined above, and W is halogen, or b) for the preparation of a compound of the formula: where R^ , R2, R^, R^, z and the dotted line in the ring A are as defined in alternative a) and P>3 is as initially defined, a compound is reacted with the formula where R^, R^, R^, Z and the dotted line in ring A are as defined above, and R3"' is hydrogen, c-methyl, p-methyl, a-OCOCl or P-OCOCl with a connection with the formula where 1*2 is as defined above, but equal to R2 when R3- is a-or 0-OCOCl and M' is hydrogen or M as defined previously or c) for the preparation of a compound with the formula where <R>^, R2> R^, r z and the dotted line in the ring A are as defined in alternative a), and R^ is as defined in the preamble (I), a compound is reacted with the formula where R^, R^, r,., z and the dotted line in ring A are as defined above, and R^' is hydrogen, α-methyl, Ø-methyl, α-OH or 3-OH, with a compound with the formula where R 2 is as defined above, but equal to R 2 when R 3 ' is o-OH or 0-OH, X' is chlorine or bromine, or d) for the preparation of a compound of the formula where R^, , R^, R^, R^, Z and the dotted line in ring A are as defined in the preamble (I), with the proviso that at least one of R^ and R., is a sulfinyl or sulfonyl -containing group, a compound with the formula is oxidized where R3, R4, R5, Z and the dotted line in ring A are as defined above, and R-^ and R2 are as defined in the preamble (I), with the proviso that at least one of R and R2 is a sulfur-containing group, or e) for the preparation of a compound of the formula where R^, > < R4 > R5» ol3 ^a dotted line in the ring A is as defined in the preamble (I), a compound with the formula is oxidized where p r r R oq the dotted line in the ring A where R^, R3• K41 K5 y is as defined above.