GB2089808A

GB2089808A - 5 alpha - and 5 beta -androstane-17 beta - carboxylates and -thiocarboxylates

Info

Publication number: GB2089808A
Application number: GB8138530A
Authority: GB
Original assignee: Upjohn Co
Current assignee: Pharmacia and Upjohn Co
Priority date: 1980-12-22
Filing date: 1981-12-22
Publication date: 1982-06-30
Also published as: NL8105455A; JPS57131000A; DE3149475A1; BE891585A; IT8125692A0; FR2496668A1; IT1142142B; ZA817929B

Abstract

Compounds of the formula <IMAGE> wherein Q is O or S; R2 is hydrogen or methyl; R6 is hydrogen, fluorine or methyl; either R9 is hydrogen, fluorine or chlorine, R11 is beta -chlorine, beta -hydroxyl or oxo, and the 9,11-bond is a single bond, or R9 and R11 are each hydrogen and the 9,11-bond is a double bond; either R16 is hydrogen, hydroxy or methyl and R17 is COR17 alpha or R16 and R17 together form an acetonide; R17 alpha if present, is hydrogen, C1-4 alkyl, phenyl or p-tolyl; QR20 is hydroxyl, C1-4 alkoxy optionally substituted by 1 or 2 halogen atoms, benzyloxy, C5-7 cycloalkoxy, C6H11-CH2-O-, C6H11-CH2-CH2O-, HOCH2CH2O-, (C1-4 alkyl)-COOCH2CH2O-, PhCOOCH2CH2O-, C1-6 alkylthio, optionally ring-substituted phenylthio or optionally ring-substituted benzylthio, in which any ring substituent is selected from C1-4 alkyl, C1-4 alkoxy, fluorine, chlorine and bromine; and SIMILAR indicates alpha or beta configuration. Certain of the above compounds have antiinflammatory activity.

Description

SPECIFICATION 5a-androstane-1 7ss-carboxylates and 5ss-an- drostane-17ss-carboxylates US Patent Specifications Nos 3,828,080 and 3,856,828 disclose alkyl and haloalkyl esters of androstane 1 7ss-carboxylate which are useful as topical anti-inflammatory agents. The earlier Specification states that the steroids disclosed possess a ratio of anti-inflammatory action to undesired cortisone-like action which is generally good.

US Patent Specification No. 3,721,687 discloses 21-halo steroids which have enhanced activity and/or a favourable ratio of topical anti-inflammatory activity to systemic side effects. US Patent Specification No. 3,981,894 discloses 1 6-methyl-A15-steroid-1 7fi-carboxy- late esters which are useful as anti-inflammatory agents. US Patent Specification No.

3,636,010 discloses various 1 7ss-carboxylate esters having 1 7a-hydroxy (exemplified) or 1 7a-acyloxy (not exemplified)substitution. US Patent Specification No. 4,093,721 selects a narrow range of 1 7a-acyloxy 1 7-carboxylate esters having a good rate of topical antiinflammatory to undesired glucocorticoid activity.

Virtually all the cortical steroids disclosed for topical anti-inflammatory activity, including those discussed above, are A4 or #1.4 steroids.

US Patent Specification No. 3,055,922 discloses a series of 5a-steroids which are al leged to retain the topical anti-inflammatory activity of the corresponding #4 or #1.4 steroids, with minimal systemic activity. It has been established that these Sa" steroids are actually "5P"; this matter will be more fully discussed below.

The present invention provides novel Sa- androstane-1 7ss-carboxylates (of formula XV, XV' and XVIII) and 5fl-andrnstane-1 7fi-car- boxylates (XXIV and XXXII), as well as the corresponding 5a-androstane-1 7ss-thiocarboxylates (VIII, VIII' and XVII) and 5ss-andros- tane-1 7P-thiocarboxylates (XXVI and XXXIII).

The compounds can have utility an anti-inflammatory agents. Such agents are especially useful for topical and local administration because they can possess the unique combination, when applied locally, of high potency and low systemic activity, thus producing less unwanted systemic corticoid action for a given amount of topical/local anti-inflammatory acitivity relative to corticoids now employed therapeutically.

Intermediates (VI, VII, X-XIV, XVI, XXI XXIII, XXV, XXX and XXXI) useful in the production of the above identified anti-inflammatory agents are also disclosed, as are processes for producing them.

For the formulae given above, reference should be made to the subsequent Charts.

European Patent Publication No. 4741 discloses a process for the preparation of 1 7a- acyloxy-androsta-1 ,4-dien-3-one 17ss-thiocarboxylates which are of utility as starting materials for the various aspects of the present invention.

The 5α-#9(11)-corticoid starting material (I, IX) can be produced by classical hydrogenation of the corresponfing 54 or A1,4-sternid.

However, during the hydrogenation process, the majority of the reduced product produced is the 5flA9(llLcorticoid (XX), and the 5α-#9(11).

corticoid (I, IX) is only produced in small amounts. The preferred route to prepare the 5α-#9(11)-corticoid starting materials (I, IX) is not by hydrogenation of the corresponding #4- or #1.4-steroid, but rather by a stereoselective metal-amine reduction of a 4- or A1,4-steroid (such are known or can be readily prepared from known steroids by methods well known to those skilled in the art). The steroid is reduced with sodium in ammonia or lithium in ammonia or alkyl amines such as methylamine, ethylamine or ethylenediamine, preferably with lithium in liquid ammonia. Before performing the lithium-ammonia reduction the pregnane side chain of the #4- or A1,4-steroid starting material must be protected.The side chain is conveniently protected as a 17,20;20,21-bisdioxy (preferably bismethylenedioxy) derivative as is well-known to those skilled in the art (U.S. Patents 2,888,456 and 2,888,457).

The A4- or A1,4-steroid starting material in an inert organic diluent such as THF, diethyl ether or dioxane is added to a solution of lithium in liquid ammonia at-60 to -80 .

The reaction is monitored by TLC and when complete (about 1 hour), the reaction is worked up as is well-known to those skilled in the art. Following the stereospecific reduction, the side chain protecting group is removed, as is well-known to those skilled in the art, by acid hydrolysis. Acetic acid is a suitable acid.

Alternatively, the 5α-#9(11)-corticoid starting materials (I, IX) may be obtained from a sapogenin which possesses the desired Sa- configuration. For example, 3ss-hydroxy-5a- pregna-9(1 1), 1 6-dien-20-one 3-acetate derived from hecogenin is a versatile starting material for preparation of 5aA9(llLsternids (I, IX) of this invention as will be apparent to one skilled in the art. This intermediate has been converted to 17α,21-dihyroxy-16ss-methyl-5α- pregn-9(11)-ene-3,20-dione 21-acetate (I) by J. Attenburrow et al (J. Chem. Soc. 1961, 4547). See Preparations 1-4.

A number of Sa-sternids are known which would serve as starting materials for the present invention, see for example J. Chemo.

Soc., 1961, 4560 ibid., 1958, 4001, J.

Chem. Soc. Chem. Comm., 1976, 961 and British Patent 924,254.

The 5a-pregn-9(1 1 )-ene-21-acylate (I) and the 5a-pregn-9(1 1)-enel 7,21-dio (IX) are readily interchangeable as is well known to those skilled in the art. As disclosed in Charts A and B, one can begin with the 5a-pregn9(11)-ene 21-acylate (I) and first modify the C ring to the 9α-halo-11ss-hydroxy functionality and then convert the corticoid side chain at C17 to the 17ss-carboxylate ester (Examples 14-20) or 17ss-thiocarboxylate ester (Examples 14-19 and 21). Conversely, as disclosed in Charts C, D and E, the corticoid side chain at C17 can first be transformed to the desired 17ss-carboxylate ester or 17ss-thiocarboxylate ester and then the C-ring is modified (Examples 1-13).

Chart A discloses the first steps of the former sequence, namely the transformation of the 5α-pregn-9(11)-ene 21-acylate (1) to the corresponding 5α-bromohydrin (11) and then to the corresponding 913-1 113-epoxy-Sa-pregnane (III) and subsequently to the corresponding 5α-halohydrin (IV). The transformation of a #9(11)-steroid to the corresponding 9α-halo- 11 13-hydroxy steroid by the reaction disclosed in Chart A is well known to those skilled in the art.Chart B discloses the process whereby the ester at C2, is removed by known means to produce the 5a-pregnane-1 7,21-diol (V) which is then converted to the 17a-hydroxy- Sa-androstane 17ss-carboxylic acid (VI) by oxidation in a suitable solvent such as methanol with an agent such as periodate in water. See, for example, U.S. Patent 3,828,080, Method A. The reaction is preferably performed at 20-30 , but higher or lower temperatures are suitable. The 17a-hydroxy-5a-androstane 17ss-carboxylic acid (VI) is then acylated by known processes (see U.S. Patents 3,828,080 and 3,856,828) to form the 1 7a- acyloxy-5α-androstane 17ss-carboxylic acid (VII).The 17α-acyloxy-5α-androstane 17ss-carboxylic acid can then be esterified by known processes (see U.S. Patents 3,828,080 and 3,856,828) to form the desired 1 7a-acyloxy- Sa-androstane 17ss-carboxylate (XV) or to the desired 1 7a-acyloxy-5a-androstane 17ss-thiocarboxylate (VIII) by treating the steroid (VII) with a suitable base salt (preferably an alkali metal salt) of an appropriate alkyl, phenyl or benzyl sulfide. More particularly, a reactive derivative of the steroid (VII) is reacted with an excess (e.g. about 1.1 to 5 molar equivalents based on the steroid of alkali metal salt of a compound of the formula R20,,SH.

Representative alkali metal salts include, e.g., sodium methyl sulfide, sodium ethyl sulfide, sodium benzyl sulfide, sodium phenyl sulfide, potassium methyl sulfide, and the like. The alkali metal salt can be reacted directly with the reactive derivative of the 1 713-carboxylic acid, or the salt can be formed in situ by mixing an alkali metal hydride, such as sodium hydride or potassium hydride, with an alkyl, phenyl, or benzyl sulfide. The thioesterification reaction readily takes place at temperatures of about 10 to 100 (preferably at temperatures of about 20 -25 ) in a suitable inert solvent such as DMF, diethylformamide, dimethylacetamide, and the like.The reactive derivative of the 17ss-carboxylic acid may be an acid chloride, but is preferably a mixed anhydride, prepared by reacting a dialkyl (1-4 carbons) chlorophosphate (e.g. diethylchlorophosphate) or an N,N-dialkylphosphoramide dichloride with the appropriate 1 7ss-carboxylic acid (VII) in an inert solvent such as THF under an inert atmosphere (nitrogen).

Both the 1 7α-acyloxy-5α-androstane 1 713- thiocarboxylate (VIII) and the 1 7a-acyloxy-5aandrostane 1 7ss-carboxylate (XV) are 1 1ss-hy- droxy steroids. They can be converted to the corresponding 1 1-keto compounds (VIII' and XV'), as disclosed in Chart J, by means well known to those skilled in the art.

In the reaction sequence from the 5,-pregn9(11)-ene 21-acylate (I) starting material to the pharmacologically active 1 7,-acyloxy-Sa- androstane-17ss-thiocarboxylate (VIII) and 1 7a-acyloxy-5a-androstane 1 7ss-carboxylate (XV), the A9(11)-double bond of the C ring is first transformed to the desired 9a-halo-1 1ss- hydroxy functionality and then the corticoid side chain is modified to the desired 1 7aacylate- 1 713-(th io)carboxylate. Alternatively, the corticoid side chain can be modified first and then the functionality of the C ring can be changed as disclosed in Charts C, D and E.

More particularly, the same 1 7a-acyloxy-5aandrostane 1 7ss-carboxylate (XV) and the corresponding 1 1-keto compound (XV') can be produced by the process disclosed in Charts C and D (Examples 1-10). The 5a-pregn-9(1 1)- ene 21-acylate (I) is first hydrolyzed to the Sa- pregn-9(1 1 )ene 17,21-diol (IX) which is then oxidatively cleaved to the 1 7a-hydrnxy-5a- pregn-9(1 1 )ene 1 7ss-carboxylic acid (X) which is then acylated to form the 17α-acyloxy-5α- pregn-9(11)-ene 17ss-carboxylic acid (XI) which is then esterified at C20 to form the 1 7a-acyloxy-5a-pregn-9(1 1 )-ene 1 713-carboxy- late (XII).In this reaction sequence the corticoid side chain has been modified to the desired @/α-acylate-17ss-carboxylate 17-ester leaving the #9(11) C ring functionality the same as in the 5a-pregn-9(1 1)-ene 21-acylate (I) starting material. Next the #9(11) functionality of the C ring is modified (Chart D).The 1 7a acyloxy-5α-pregn-9(11)-ene 17ss-carboxylate (XII) is first converted to the Sa-androstane 1 713-carboxylate bromohydrin (XIII), next to the 9p,11 13-epoxy-5a-andrnstane 1 7ss-car- boxylate (XIV) and finally to the desired 1 7a acyloxy-5a-androstane 1 7ss-carboxylate (XV), all by means well known to those skilled in the art.

In addition, an alternate route (Charts D and E) offers the opportunity to prepare 9a-1 113- dichloro compounds which are pharmacologically active as anti-inflammatory agents. To prepare 1 7a-acyloxy-9a, 11 13-dichloro-Sa-an- drostane-1 713carboxylate (XVIII), the 1 7a-acy loxy-5a-pregn-9(11 )-ene 1 713-carboxylate (XII) is reacted with chlorine by known means, see Example 11 and Chart D.Similarly, Chart E discloses 17α-acyloxy-9α, 11ss-dichloro-5α-an- drostane 17ss-thiocarboxylate (XVII) is prepared from 17a-acyloxy-5a-pregn-9(11)-ene 1 713-carboxylic acid (Xl) by first converting it to 17α-acyloxy-5α-androst-9(11)-ene 17ss-thiocarboxylate (XVI) and then chlorinating that compound as described above.

The process of producing the 5ss-androstane 1 713-carboxylates of the present invention is set forth in Charts F thru I.

The 513-androstane starting materials (XX and XXVIII) are obtained from the corresponding A4- or A1,4-3-keto steroids (XIX and XXVI I), respectively, by hydrogenation and hydrolysis if R21 is not a hydrogen atom.

Some 5,-isomer is produced but the substantial majority is the 5ss-isomer.

The A4- or A14-steroid (XIX and XXVII) starting material is subjected to hydrogenation as is well-known to those skilled in the art.

The A4- or A1,4-steroid (XIX and XXVII) is dissolved in a suitable organic solvent such as ethyl acetate, acetone, THF, toluene and alcohols such as methanol or ethanol. Preferred solvents are ethyl acetate, THF and acetone.

The reaction is performed in the presence of a hydrogenation catalyst. These catalysts are well known to those skilled in the art and include, for example, heterogenous catalysts such as palladium-on-carbon, platinum-on-carbon, platinum dioxide, palladium-on-barium carbonate or palladium-on-calcium carbonate, rhodium-on-alumina, rhodium-on-carbon, palladium-on-barium sulfate or palladium-on-zinc oxide and the like. Soluble catalysts such as tris(triphenylphosphine) rhodium (I) chloride may also be employed. In addition, strong acid or strong base catalysts may optionally be used. Suitable strong acids include mineral acids such as hydrogen chloride or perchloric acid and organic acids such as p-toluene sulfonic acid or 2,4-dinitrobenzene sulfonic acid.

Suitable strong bases include inorganic bases such as sodium hydroxide or potassium hydroxide and organic bases such as triethylamine or 1 ,4-diazabicycle[2.2.2.]octane (Dabco).

The reaction is performed under hydrogen using a pressure of 1-10 atmospheres. One to two atmospheres is convenient. Higher pressure can be utilized if desired.

The reaction is performed at 20-25 until the desired uptake of hydrogen is complete.

Lower or higher temperatures are suitable, but room temperature is most convenient.

When the uptake of hydrogen is complete, the mixture is filtered and the filtrate is concentrated under reduced pressure. The concentrate contains a mixture of the 5a and 5ss isomers. The 5ss isomer is formed stereospecifically when R9 is fluorine. The 5ss isomer predominates when the C ring functionality is A9(11) This ratio is dependent on the experimental conditions and the specific structure of the hydrogenation substrate.

The mixture of 5ss and 5a isomers is separated by chromatography as is well known to those skilled in the art. Adsorbents such as silica gel, Florisil and alumina may be employed. Various organic solvents such as methanol, acetone, ethyl acetate, ether, methylene chloride, hexane, SSB and chloroform are used for elution either alone or in combination. Those fractions containing the steroid product with the 5ss configuration as determined by CMR are combined and concentrated to give the desired 5ss-propuct. If desired, further purification is achieved by crystallization from a suitable solvent.

If the A4- or A1,4-steroid (XIX or XXVII) is a 21-hydroxy steroid (R21 is a hydrogen atom), no further processing is required. However, it is generally preferred to purify 21-esters rather than the corresponding 21-hydroxy steroids. Therefore, usually for pratical reasons, the 1X4- and A1,4-steroid (XIX and XXVII) will be 21-esters (R2, is -COR21") rather than the 21-hydroxy analogue. Hydrolysis of the 21-ester to the corresponding 21-hydroxy compound is accomplished by means well known to those skilled in the art, see Examples 1 and 44.

When a A4- or a A14-steroid (XIX, XXVI I, XXXIV, or XXXV) is hydrogenated, two isomeric products, 5a and 5ss, can be and are formed. U.S. Patent 3,055,922 reported obtaining only the 5,-isomer analytically pure and in almost quantitative yield upon hydrogenation of 1X4- and A14-steroids with the appropriate noble metal catalyst. U.S. Patent 3,055,922 was filed in 1961. In 1972 J. L.

Gough, J. P. Guthrie and J. P. Stothers [J.

Chem. Soc. Chem. Comm. 1972, 979) reported a method of determining the stereochemistry of the A/B ring junction by CMR.

These authors reported that when the A/B ring junction is cis (5ss), the C19 carbon atom is less shielded by about 11-12 ppm. Based on this evidence and their own experimentation the applicants have determined that the predominate isomer produced when a A4- or A1,4-steroid is hydrogenated under the conditions set forth in this invention is 5ss and not 5a as reported in U.S. Patent 3,055,922. It is realized that at the time of filing of the patent application for U.S. Patent 3,055,922, CMR spectroscopy was not available.

Further, E. L. Shapiro et al. (J. Chem. Soc.

Chem. Comm. 1976, 961) reported that hydrogenation of A4- and ' 4-3-keto-9a-fluoro steroids gave exclusively the 5ss-isomers.

It is possible to prepare 5ss-starting materials from bile acid intermediates. For example, 11α,17α,21-trihydroxy-16ss-methyl-5ss-preg- nane-3,20-dione 21-acetate iE. P. Oliveto et al., J. Amer. Chem. Soc. 80, 6687 (1958)] may readily be converted to 17a,21-dihy- droxy-16ss-methyl-5ss-pregn-9(11)-ene-3,20-di one (XX).

European Patent Application 4,741, p.

18-19 discloses compounds within the scope of compounds of formula (XXXV) which also are starting materials for the present invention, in particular methyl and benzyl 6a,9a- difluoro-11ss-hydroxy-16α-methyl-17propiony- loxy-androst-1,4-dien-3-one 17ss-thiocarboxylate.

Chart H discloses the transformation of the 9α-fluoro-21-acylate (XXVII) to the reduced 9α-fluoro-5ss-pregnane-21-acylate (XXVIII), hydrolysis to the 5ss-pregnane-17,21-diol (XXIX), oxidative cleavage to the 17α-hydroxy-5ss-an- drostane 17ss-carboxylic acid (XXX) and its esterification at 17a to the 17α-acyloxy-5ssan- drostone 17ss-carboxylic acid (XXXI) which is then converted to either the 17α-acyloxy-5ss- androstane 17ss-carboxylate (XXXII) or the 17α-acyloxy-5ss-androstone 17ss-thicarboxylate (XXXII I), see Chart I, by means well known to those skilled in the art.Chart I also discloses that the pharmacologically active 17a-acyloxy- 5ss-androstane 17ss-carboxylate (XXXII) and 17α-acyloxy-5ss-androstane 17ss-thiocarboxylate (XXXIII) can also be made directly by hydrogenation of the corresponding androst-4en-3-one 17ss-carboxylate (XXXIV) and androst-4-en-3-one 17ss-thiocarboxylate (XXXV).

respectively, as well as the A1-analogues thereof.

By this procedure, modification of the C ring and C17 corticoid side chain takes place prior to hydrogenation of the #4 or #1,4 unsaturation in the A ring to give the 5ss reduced compound. Hence, it should be readily apparent to one skilled in the art that there are numerous pathways to make a given desired compound (XXIV, XXVI, XXXI I and XXXIII).

The means to produce these compounds are well known to those skilled in the art. The applicants' invention is in using the known processes to produce new and useful antiinflammatory agents.

Using the route disclosed in Chart H, only 9α-fluoro-11ss-hydroxy compounds can be produced, as 9α-chloro steroids may be unstable to the reaction conditions of the processes of Chart H, Examples 43 thru 46. If 9α-chloro steroids within the 5ss-series are desired, they can be produced by hydrogenation of the corresponding 4- or A1,4-3-keto steroids (XXXIV or XXXV) or by the process disclosed in Charts F and G. In the process of Charts F and G, the C17 corticoid side chain is modified first; the last step is chlorination of the A9(11)- double bond.Charts F and G disclose that following hydrogenation of the A9(11)-21-acy- late (XIX) and hydrolysis to the 5ss-pregn- 9(11)-ene-17,21-diol (XX), the C17 side chain is oxidatively cleaved to give the 17α-hydroxy- 5ss-androst-9(11)-ene 17ss-carboxylic acid (XXI) which is then esterifid at 17a to give 17a- acyloxy-5ss-androst-9(11)-ene 17ss-carboxylic acid (XXII) which is then esterified at C20 to give 17α-acyloxy-5ss-androst-9(11)-ene 17sscarboxylate (XXIII), which is chlorinated to give 17α-acyloxy-9α,11ss-dichloro-5ss-andros- tane 17ss-carboxylate (XXIV).Alternatively, the 17α-acyloxy-5ss-androst-9(11)-ene 17ss-carboxylic acid (XXII) can be transformed to 1 7a- acyloxy-9α,11ss-dichloro-5ss-androstane 17ssthiocarboxylate (XXVI) by first producing the 17α-acyloxy-5ss-androst-9(11)-ene 17ss-thio-carboxylate (XXV) intermediate and chlorinating that compound.

The steroids of the present invention have a number of variable substituents as is well known to those skilled in the art. It is preferred that R2 and R6 are hydrogen atoms. It is preferred that R9 is a fluorine or chlorine atom; it is more preferred that R9 is a fluorine atom. It is preferred that R11 is an oxygen atom or hydroxyl group; it is more preferred that R,t is a hydroxyl group. It is preferred that R,6 is a methyl group. It is preferred that R,7 is -COR,7a and R,7 is alkyl of 1 thru 4 carbon atoms or phenyl. It is preferred that R20 is alkyl of 1 thru 4 carbon atoms substituted with 0-1 fluorine or chlorine atoms.

The 17α-acyloxy-5α-androstane 17ss-carboxylate (XV), 17α-acyloxy-5α-androstane 17ss-thio carboxylate (VIII), 17α-acyloxy-9α,11ss-di- chloro-5α-androstane 17ss-carboxylate (XVIII), 17α-acyloxy-9α,11ss-dichloro-5α-androstane 17ss-thiocarboxylate (XVII), 17α-acyloxy-5ss- androstane 17ss-carboxylate (XXXII), 1 7a-acy- loxy-5ss-androstane 17ss-thiocarboxylate (XXX III), 1 7o'-acyloxy-9o', 11 ss-dichloro-5ss-andros- tane 17ss-carboxylate (XXIV) and 17α-acyloxy- 9α;,11ss-dichloro-5ss-androstane 17ss-thiocarboxylate (XXVI) as well as the 11 -keto analogues of (VIII and XV) which are (VIII') and (XV'), respectively, of the present invention are therapeutically useful anti-inflammatory agents when applied topically or administered locally to warm-blooded animals responsive to treatment with anti-inflammatory corticostero ids. These compounds are especially useful for topical and local administration because they possess the unique combination when applied locally of high potency and low systemic activity, thus producing less unwanted systemic corticoid action for a given amount of topical-local anti-inflammatory activity relative to corticoids now employed therapeuti cally.

They are administered topically to the infl amed skin, eyes, external ears and mucous membranes of the mouth, nose, respiratory tract, vagina, rectum and colon. They are applied or instilled to these areas as drug suspensions or solutions in the usual dosage forms such as solutions, lotions, creams, oint ments, gels, pastes, aerosols, bandages or tape, drops, enemas, suppositories, etc. For the therapy of asthma, allergic rhinitis and other inflammatory respiratory disorders, the usual dosage forms such as aerosols or powders, solutions and suspensions for inhalation are employed.

These compounds (VIII, VIII', XV, XV', XVII, XVIII, XXIV, XXVI, XXXI I and XXXIII) are also useful for local intralesional therapy by intracavity (e.g., intra-articular) or soft tissue injection of solution, suspension or solution-suspension dosage forms. Also useful for the therapy of secondarily infected and inflamed conditions, particularly of the skin, eyes, external ear canals, rectum and vagina, are combination dosage forms of these steroids and antifungal and/or anti-bacterial agents such as clotrimazole, dichloroxine, miconazole, neomycin, gentamycin, clindamycin, and valconazole, etc.

The concentration and dosage regimen of the dosage form used and the frequency of administration will depend upon the particular location and condition treated, the severity of the inflamed lesion, the potency of the particular steroid, the phase and natural course of the inflammation, the age and condition of the patient, and other factors known to practitioners skilled in the management of cutaneous and local inflammatory diseases.

The drug concentration ranges, and the dosage regimens of these 5a- and SP-andros- tane-1 713-carboxylates and 17ss-thiocarboxylates administered topically (locally) on inflammatory lesions of the skin, nostrils, vagina, rectum, colon and external ears are about 0.005% to about 2.5% with one to four daily applications. Generally preferred concentrations are from 0.010/o to 0.2%. These same concentration ranges are used in the eyes, but with one to eight daily applications or instillations, according to phase and disease severity.

For the therapy of asthma or other inflammations of the respiratory tract, two to three daily inhalations or sprays, each containing from 0.001 to 2.0 mg. of corticosteroid are used. From 1.0 to 100 mg. doses of the steroid are administered for intralesional inflammations of joints, tissue cavities and soft tissues. The volume and frequency of the injections are dependent primarily on lesion size, severity and response to treatment.

Some examples of inflammatory diseases where these steroids are useful topically and locally are (1) dermatoses such as psoriasis, atopic, neuro, contact and allergic dermatitis, lichen planus, alopecia areata and immune diseases; (2) pruritus ani, vulva and rectal or colonic inflammation; (3) conjunctivitis, superficial punctate keratitis and herpes zoster keratisis of the eyes; (4) contact, allergic and selected infective otitis of the external ear canal; and (5) allergic-inflammatory nasal and respiratory conditions such as rhinitis and asthma.

Some examples of conditions treated with these steroids by injection into local lesions are (1) rheumatoid arthritis, bursitis and peritendonitis and (2) alopecia areata, cycstic acne, keloids, hypertrophic scarring conditions and localized, treatment-resistant type dermatitic lesions.

DEFINITIONS The definitions and explanations below are for the terms as used throughout the entire patent application, including both the specification and claims.

All temperatures are in degrees Centigrade.

SSB refers to an isomeric mixture of hexanes.

IR refers to infrared spectroscopy (mineral oil mull).

CMR refers to 13C magnetic resonance spectroscopy in deutero-chloroform, chemical shifts of the C-19 methyl group are reported in ppm (6) downfield from TMS.

DMF refers to dimethylformamide.

P-TSA refers to p-toluenesul fonic acid.

THF refers to tetrahydrofuran.

PMR refers to proton magnetic resonance spectroscopy in deuterochloroform, chemical shifts are reported in ppm (8) downfield from TMS.

TMS refers to tetramethylsilane.

[o']D refers to specific optical rotation in dioxane.

Saline refers to a saturated solution of sodium chloride.

TLC refers to thin-layer chromatography.

R2 is a hydrogen atom or methyl group.

R6 is a hydrogen or fluorine atom or methyl group.

R9 is a hydrogen, fluorine or chlorine atom.

R" is a chlorine or oxygen atom or hydroxyl group; when R" is a chlorine atom or hydroxyl group.... between R" and C" is a single bond in the ss-configuration and when R" is an oxygen atom the. .. between R" and C" is a double bond.

R,6 is a hydrogen atom or hydroxyl or methyl group; the hydroxyl group can form an acetonide with R,7.

R,7 is COR17a or an acetbnide with R,6 when R,6 is hydroxyl.

R17 is a hydrogen atom, alkyl of 1 thru 5 carbon atoms, phenyl, or p-methylphenyl.

R20 is an alkyl group of 1 thru 4 carbon atoms substituted with 0-2 fluorine, chlorine, bromine or iodine atoms, benzyl, cycloalkyl of 5 thru 7 carbon atoms, -CH2-C6H", -CH2CH2 C6H", -CH2CH20H or -CH2CH20R.

R2oa is an alkyl group of 1 thru 6 carbon atoms or phenyl or benzyl optionally substituted with a substituent on the phenyl ring which is alkyl of 1 thru 4 carbon atoms, alkoxy where the alkyl portion is 1 thru 4 carbon atoms, or fluorine, chlorine, or bromine.

R is COR21,,.

R21α is alkyl of 1 thru 4 carbon atoms or phenyl.

indicates the attached group can be in either the a or ss configuration.

.... is a single or double bond.

When the term i̇'ky of ~ thru ~ carbon atoms" is used, it includes, the isomers thereof when they exist.

When solvent pairs are used, the ratio of solvents used are expressed as volume/volume (v/v).

EXAMPLES Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limiting of the preceding disclosure in any way whatsoever.

Preparation 1 1 7a,21-Dihydroxy-1 613-me- thylpregna-4,9(11)-diene- 3,20-dione A mixture of 17cr,21-dihydroxy-l GP-methyl- pregna-4, 9(11 )-diene-3,20-dione 21 -benzoate (U.S. Patent 3,725,392, 32 g.)in methanol (700 ml.) is stirred with potassium carbonate (5.3 g.) in water (50 ml.) at 20-25 for about 2 hours. The mixture is cooled, acidified with acetic acid (7 ml.), diluted with water (475 ml.) and concentrated under reduced pressure. The precipitate is collected, washed with water and dried to give the title compound, TLC, Rf = 0.70 (acetonemethylene chloride, 20/80).

Preparation 2 16ss-Methyl-17α,20:20,21- bismethylenedioxypregna 4,9(11 )dien-3-one A solution of hydrochloric acid (250 ml.) and formalin (35%, 250 ml.) prepared at 0 is aded to a stirred suspension of 17a,21dihydroxy-16ss-methylpregna-4,9(11)-diene3,20-dione (Preparation 1, 32 9.) in methylene chloride (900 ml.). The mixture is stirred for 16 hours at 20-25 and diluted with ice water (500 ml.). The organic layer is separated, washed successively with cold aqueous sodium carbonate and water and then is dried and concentrated under reduced pressure. The residue is column chromatographed on silica gel packed in methylene chloride. Elution is performed with acetone-methylene chloride mixture beginning with 0% acetone and increasing to 7%.The appropriate fractions are pooled and concentrated to give a solid which is crystallized from acetone-SSB to give the title compound, m.p. 232.5-237; [o']D -29; UV ax = 239.5 nm (e = 17,250).

Preparation 3 16ss-Methyl-17α,20:20,21- bismethylenedioxy-5a-pregn- 9(1 1)en-3-one A solution o 1 613-methyl-1 7a,20:20,21-bis- methylenedioxypregna-4,9(11)dien-3-one (Preparation 2, 22.8 9.) in THF (290 ml.) is added slowly (3/4 hour) to a solution of lithium wire (2.28 g.) in liquid ammonia (1.1 1.) at -78 . The mixture is stirred for an additional one hour. Then ammonium chloride (17.7 g.) is added. The ammonia is allowed to evaporate on a steam bath and the mixture is concentrated under reduced pressure. The residue is stirred with acetone (600 ml.) and water (300 ml.), the pH is adjusted to 6 with hydrochloric acid and the mixture is further diluted with water (1.1 1.).The solid is collected, washed with water and dried at 60 under reduced pressure to give a solid which is recrystallized from aqueous acetone to give the title compound, m.p. 247-255 ; CMR 17-38 #; IR 2770, 1712, 1673, 1691, 1078, 1007 and 946 cm-'.

Preparation 4 17a,21-Dihydroxy-l GP-me- thyl-5a-pregn-9(11)-ene-3,20- dione (IX) A suspension of 16ss-methyl-17α,20:20,21- bismethylenedioxy-5α-pregn-9(11)-en-3-one (Preparation 3, 1 2.5 g.), acetic acid (375 ml.) and water (125 ml.) is heated under reflux for 2 hours. The mixture is then diluted with ice and water to 4 1. and stirred for about 20 minutes. The solid is collected, washed with water and suspended in acetone (750 ml.) and water (375 ml.). The mixture is neutralized with sodium hydroxide (1 N), diluted with ice water to 4 1., then refiltered. The product is collected and dried under reduced pressure to give the title compound TLC, Rf = 0.1 8 (acetone-methylene chloride 10/90).

Example 1 17a,21-Dihydroxy-16ss-methyl- 5o'-pregn-9(1 1 )-ene3,20-dione (IX) A solution of 17a,21-dihydroxy-16ss-methyl- 5α-pregn-9(11)-ene-3,20-dione 21-acetate (1, J. Chem. Soc. 1961, 4547, 4.89 9.) in methanol (225 ml.) and methylene chloride (38 ml.) was mixed with aqueous potassium carbonate (10%, 15.4 ml.) under an inert atmosphere. The reaction mixture is stirred at 20-25 for about 2 hours and then neutralized with acetic acid (2.1 ml.), eluted with water, and concentrated under reduced pressure. The concentrate is chilled and then filtered. The filter cake is dried under reduced pressure to give the title compound.

Example 2 17α-Hydroxy-16ss-methyl-5α-an- drost-9(1 1 )-en-3-one 1 7ss-car- boxylic acid (X) A solution of periodic acid (5.57 g.) in water (64 ml.) is slowly added to a solution of 17α,21-dihydroxy-16ss-methyl-5α-pregn- 9(1 1)-ene-3,20-dione (IX, Example 1, 4.1 g.) in methanol (255 ml.) at 23-28 . The mixture is stirred for about 1.5 hours at 20-25 , then is diluted with water, concentrated under reduced pressure, chilled and filtered. The filter cake is dried under reduced pressure to give the title compound.

Example 3 1 7a-Acetyloxy-1 6ss-methyl-5α-an- drost-9(11)-en-3-one 17-carboxy lic acid (XI) Following the general procedure of U.S.

Patent 3,856,828, a solution of 1 7a-hydroxy- 1 613-methyl-5,,-androst-9(1 1 )-en-3-one 1 7-carboxylic acid (X, Example 2, 3.6 g.) and methylene chloride containing triethylamine (4.9 g.) is cooled to 2 with stirring. Acetyl chloride (2.7 ml.) is slowly added. The mixture is stirred for an additional 0.8 hours at 2 and then diluted with methylene chloride (100 ml.). The mixture is washed successively with aqueous sodium bicarbonate, hydrochloric acid and water and then the mixture is filtered through sodium sulphate. The filtrate is concentrated under reduced pressure to give a solid. The solid is suspended in acetone (120 ml.) containing diethylamine (3.8 ml.) and stirred for 0.5 hours, then concentrated to dryness under reduced pressure.The residue is partitioned between aqueous hydrochloric acid (0.5 N, 260 ml.) and ethyl acetate. The organic extracts are washed with water, dried over magnesium sulfate, and concentrated to give the title compound.

Example 4 Chloromethyl 17α-acetyloxy-16ss methyl-5a-androst-9(1 1 )-en-3-one 1 7ss-carboxylate (XII) Step 1 Sodium 17a-acetyloxy-16ss-methyl- 5a-androst-9(1 1 )-en-3-one 1 7ss- carboxylate A solution of 1 7o'-acetyloxy-1 6ss-methyl-5α- androst-9(1 1 )-en-3-one 1 7ss-carboxylic acid (Xl, Example 3) in methanol (1 25 ml.) is titrated under an inert atmosphere with 1 N methanolic sodium hydroxide (phenolphthalein). The indicator color is discharged with a few drops of 0.1 N hydrochloric acid and the mixture is concentrated under reduced pressure.The residue is dried over phosphorus pentoxide under reduced pressure to give anhydrous sodium 17α-acetyloxy-16ss-methyl- 5o'-androst-9(1 1 )-en-3-one 1 713-carboxylate.

Step 2 Chloromethyl 17α-acetyloxy-16ss- methyl-5a-androst-9(1 l)-en-3-one 1 713-carboxylate (XII) A mixture of sodium 1 7,,-acetyloxy-1 6-me thyl-5α-androst-9(11)-en-3-one 17-carboxylate (Step 1, 5.4 g.) in hexamethylphosphoramide (20 ml.) is stirred with chloroiodomethane (5.5 ml.) under an inert atmosphere for about 5 hours at 20-25 . The reaction mixture is then diluted with ethyl acetate. The mixture is washed successively with water, aqueous potassium bicarbonate, water and saline, then dried (magnesium sulfate), filtered and the filtrate concentrated under reduced pressure.

The residue is column chromatographed on silica gel (600 g.) in acetone-methylene (5/95). Elution is performed with the same solvent mixture, the appropriate fractions are pooled and concentrated to give a residue which upon crystallization from acetonehexane gives the title compound, m.p. 231.8-232 , Example 5 Chloromethyl 17α-acetyloxy-9α- bromo-11P-hydroxy-l GP-methyl- 5a-androstan-3-one 1 713-carboxy late (XIII) A solution of chloromethyl 1 7o'-acetyloxy- 16ss-methyl-5α-androstan-9(11)-en-3-one 17sscarboxylate (XII, Example 4, 2.5 g.) in methylene chloride (8 ml.) and tert-butyl alcohol (34 ml.) is cooled to 20 and mixed with a solution of perchloric acid (70%, 7.3 ml.) in water (73 ml.).A solution of N-bromoacetamide (1.349. in 14 ml. of tert-butyl alcohol) is added and the mixture stirred for about 1 hour. A solution of the sodium sulfite (1.34 g.

in 14 ml. of water) is added, the mixture is diluted with water and concentrated under reduced pressure to give a gummy precipitate.

The precipitate is taken up in methylene chloride, washed with aqueous potassium bicarbonate, filtered through sodium sulfate and concentrated under reduced pressure to give the title compound, which is used without further purification.

Example 6 Chloromethyl 17a-acetyloxy 9,11-epoxy-16ss-methyl-5α-an- drostan-3-one 1 713-carboxylate (XIV) A solution of the bromohydrin (XIII, Example 5) in THF (45 ml.) is mixed with 1,8 diazabicyclo[5.4.0]undec-7-ene (0.96 ml.) and allowed to stand overnight at 5 . The mixture is diluted with water (185 ml.) and concentrated under reduced pressure to give a precipitate which is recovered and dissolved in methylene chloride. The methylene chloride solution is washed successively with aqueous potassium bisulfate, water and aqueous potassium bicarbonate.The mixture is then filtered through sodium sulfate and concentrated to give a foam which is chromatographed on silica gel (265 g.) packed in acetone-methylene chloride (2/98) and eluted with the same solvent mixture. The appropriate fractions are pooled and concentrated to give the title compound, PMR 0.96, 1.20, 1.41, 2.07 and 3.48 and 5.69 Example 7 Chloromethyl 17α-acetyloxy-9α- fluoro-11ss-hydroxy-16ss-methyl-5α- androstan-3-one 17ss-carboxylate (XV) A sample of chloromethyl 1 7,-acetyloxy- 9,11-epoxy-16ss-methyl-5-α;-androstan-3-one 17ss-carboxylate (XIV, Example 6, 0.5 g.) is added to a stirred mixture of hydrogen fluoride (5.28 gl), methylene chloride (2.25 ml.) and water (2.14 ml.) at -78 . The mixture is stirred for 1 hour at -30 , it is then re-cooled to -78 , diluted with THF (8 ml.) and poured into a cold mixture of aqueous potassium carbonate and THF. The aqueous phase is diluted with water and extracted with methylene chloride. The organic extracts are combined, washed with water, dried, and concentrated under reduced pressure to give 0.48 g.

of a foam, which is chromatographed on silica gel (100 g.). Appropriate fractions (TLC, Rf 0.37, acetone-methylene chloride, 5:95) are pooled and concentrated to give a solid which is crystallized from acetonehexane to give the title compound, m.p. 216.5"; PMR 1.02, 1.36, 1.42, 2.07, 4.25 and 5.7 #; [a]D -6 (C 0.96).

Example 8 Chloromethyl 1 7o'-acetyloxy-9o'- chloro-11ss-hydroxy-16ss-methyl 5α-androstan-3-one 17ss-carboxy late (XV) Hydrogen chloride is bubbled into a solution of chloromethyl 17α-acetyloxy-9,11- epoxy-l 68-methyl-5,-androstan-3-one 1 7Kcar- boxylate (XIV, Example 6, 0.53 g.) in chloroform (37 ml.) at 0 for 15 minutes. The mixture is washed with water until neutral, then is dried and concentrated to give a foam which is chromatographed on silica gel (50 g.).Elution is performed with acetone/methylene chloride (5/95), the appropriate fractions are pooled, concentrated and crystallized from acetone-hexane to give the title compound, m.p. 182-182.5 ; [a]D + 10 (C 1.01); PMR 1.03, 1.43, 1.50, 2.08, 4.5 and 5.69 #.

Example 9 Chloromethyl 17α-acetyloxy-9α- fluoro-l GP-methyl-Sa-androstane- 3,11 -dione 17ss-carboxylate (XV') Jones reagent (chromium trioxide-aqueous sulfuric acid 1.3 ml.) is added to a solution of chloromethyl 17α-acetyloxy-9α-fluoro-11ss-hy- droxy-16ss-methyl-5-α-androstan-3-one 17sscarboxylate (XV, Example 7, 2 g.) in acetone (50 ml.). The mixture is stirred for 30 minutes at 20-25 . Isopropyl alcohol (1.3 ml.) is added, followed by slow addition of ice water (600 ml.). The precipitate is collected, washed with water and dried. The crude produce is column chromatographed on silica gel eluting with acetone-methylene chloride (5/95).The appropriate fractions (TLC) are pooled, concentrated under reduced pressure and crystallized to give the title compound.

Example 10 Chloromethyl 17α-acetyloxy-9α- chloro-1 613-methyl-5o'-andros- tane-3, 11 -dione 1 713-carboxy- late (XV') Following the general procedure of Example 9 and making noncritical variations but starting with chloromethyl 17α-acetyloxy-9α- chloro-11ss-hydroxy-16ss-methyl-5α-androstan- 3-one 1 713-carboxylate (XV, Example 8), the title compound is obtained.

Example ii Chloromethyl 17α-acetyloxy-9α,11ss-di- chloro-16ssmethyl-5α-androstan-3-one 17sscarboxylate (XVIII) A solution of chloromethyl 17a-acetyloxy- 16ss-methyl-5α-androst-9(11)-en-3-one 17sscarboxylate (XII, Example 4, 0.44 9.) in chloroform (35 ml.) containing pyridine (0.3 ml.) is cooled to -10 and treated with chlorinecarbon tetrachloride solution (1.2 eq., 3.2 ml.). The reaction mixture is washed with cold aqueous potassium bisulfate, water and aqueous potassium bicarbonate. The organic extract is dried and concentrated under reduced pressure to give a foam which is chromatographed on silica gel (50 g.). Elution is performed with acetone/methylene chloride (5/95), the appropriate fractions are pooled and concentrated to give a material which is crystallized from acetonehexane to give the title compound, m.p. 178-180 ; (o']D + 17 (C 1.01); PMR 1.08, 1.44, 2.09, 4.74 and 5.69 #.

Example 12 Methyl 17α-acetyloxy-16ss-me- thyl-5α-androst-9(11)-en-3-one 17ss-thiocarboxylate (XVI) To a solution of 1 7o'-acetyloxy-1 613-methyl- 5a-androst-9(11)-en-3-one 1 713-carboxylate (Xl, Example 3, 1.0 g.) in THF (14 ml.) containing triethylamine (0.4 ml.) stirred at 20-25 under an inert atmosphere is added slowly a solution of diethylchlorophosphate (0.5 g.) in THF (14 ml.). The mixture is stirred overnight and then filtered. To the filtrate is added 5 ml. of a solution previously prepared from DMF (20 ml.), sodium hydride (1.03 g., 55% in mineral oil) and methanethiol (1 ml.).

The reaction mixture is stirred for 7 hours then is diluted with ethyl acetate, washed with water and saline. The organic extract is dried and concentrated under reduced pressure to a residue which is column chromatographed on silica gel (100 g.) packed in acetone-methylene chloride (5/95). Elution is performed with the same solvent mixture. The appropriate fractions are pooled and concentrated to give the title compound.

Example 13 Methyl 17α-acetyloxy-9a, 11 ss- dichloro-16ss-methyl-5α-andros- tan-3-one (1 713-thiocarboxylate (XVII) Following the general procedure of Example 11 and making noncritical variations but starting with methyl 17α-acetyloxy-16ss-methyl-5α- androst-9(11)-en-3-one 17ss-thiocarboxylate (XVI, Example 12), the title compound is obtained.

Example 14 9α-Bromo-11ss,17α,21-trihy- droxy-l GP-methyl-Sa-preg nane- 3,20-dion 21-acetate (II) Following the general procedure of Example 5 and making non-critical variations but starting with 17a,21-dihydroxy-l GP-methyl-Sa- pregn-9(11 )-ene-3,20-dione 21-acetate (I, J.

Chem. Soc. 1961, 4547), the title compound is obtained.

Example 15 9,11-Epoxy-l 7cu,21-dihydroxy- 16ss-methyl-5α-pregnane-3,20- dione 21-acetate (Ill) Following the general procedure of Example 6 and making non-critical variations but starting with 9o'-bromo-1 113,1 7o',21-trihydroxy- 16ss-methyl-5α-pregnane-3,20-dione 21-acetate (II, Example 14), the title compound is obtained.

Example 16 9α-Fluoro-11ss,17α,21-trihy- droxy-l Gpmethyl-ScY-pregnane- 3,20-dione 21-acetate (IV) Following the general procedure of Example 7 and making non-critical variations but starting with 9,11-epoxy-17α,21-dihydroxy-16ss- methyl-5α-pregnane-3,20-dione 21-acetate (III, Example 15), the title compound is obtained.

Example 17 9α-Fluoro-11ss,17α,21-trihy- droxy-16ss-methyl-5α-pregnane- 3,20-dione (V) Following the general procedure of Example 1 and making non-critical variations but starting with 9α-fluoro-11ss,17α,21 -trihydroxy 16ss-methyl-5α-pregnane-3,20-dione 21-acetate (IV, Example 16), the title compound is obtained.

Example 18 9α-Fluorol-11ss-17α,dihydroxy- 16ss-methyl-5a-androstan-3-one 1 713-carboxylic acid (VI) Following the general procedure of Example 2 and making non-critical variations but starting with 9α-fluoro-11ss,17α,21-trihydroxy- 1 GP-methyl-Sa-pregnane-3,20-dione (V, Example 17), the title compound is obtained.

Example 19 17α-Acetyloxy-9α-fluoro-11ss-hydroxy-16ss- methyl-5α-androstan-3-one 17ss-carboxylic acid (VII) Following the general procedure of Example 3 and making non-critical variations but starting with 9α-fluoro-11ss,17α-dihydroxy-16ss- methyl-5a-androstan-3-one 1 713-carboxylic acid (VI, Example 18), the title compound is obtained.

Example 20 Chloromethyl 17α-acetyloxy-9α- fluoro-11ss-hydroxy-16ss-methyl 5α-androstan-3-one 17ss-car boxylate (XV) Following the general procedure of Example 4 and making non-critical variations but starting with 1 7r-acetyloxy-9cr-fluoro- 11P-hydroxy- 16ss-methyl-5α-androstan-3-one 17ss-carboxylic acid (VII, Example 19), the title compound is obtained.

Example 21 Methyl 17a-acetyloxy-9a-fluoro- 11P-hydroxy-l GP-methyl-Sa-an- drostan-3-one 17ss-thiocarboxy late (VIII) Following the general procedure of Example 12 and making non-critical variations but starting with 17α-acetyloxy-9α-fluoro-11ss-hy- droxy-16ss-methyl-5α-androstan-3-one 17sscarboxylic acid (VII, Example 19), the title compound is obtained.

Example 22 Methyl 17α-acetyloxy-9α-fluoro- 16ss-methyl-5α-androstane- 3,11-dione 17ss-thiocarboxylate (VIII') Following the general procedure of Example 9 and making non-critical variations but start ing with methyl 17α-acetyloxy-9α-fluoro-11ss- hydroxy-16ss-methyl-5α-androstan-3-one 17ss thiocarboxylate (VIII, Example 21), the title compound is obtained.

Example 23 Methyl 9α-fluoro-11ss-hydroxy- 1 GP-methyl-l 7cr-propionyloxy- 5ss-androstan-3-one 17ss-car boxylate (XXXII) A solution of methyl 9α-fluoro-11ss-hydroxy- 16ss-methyl-17α-propionyloxyandrosta-1,4- dien3-one-l 7P-carboxylate (XXXIV, U.S. Pa tent 3,828,080, 2 g.) in acetone (100 ml.) and triethylamine (1 ml.) is hydrogenated in the presence of palladium-on-carbon (5%, 0.22 g.) catalyst under 2 atmospheres pres sure until the uptake of is complete. The product is isolated by filtration and concentra tion of the filtrate under reduced pressure.

The residue is column chromatographed on silica gel and eluted with acetone-methylene chloride mixtures. The appropriate fractions are pooled and concentrated. The concetrate is crystallized from acetone-SSB to give the title compound, m.p. 193-193.5 ; IR 3486, 1749, 1730, 1691, 1274, 1241, 1046, 1035 and 1016 cm-1, CMR 27.08 # and [o']D + 4 ( C 0.83).

Example 24 Chloromethyl 9α-fluoro-11ss-hy- droxy-16ss-methyl-17α-acety loxy-5ss-androstan-3-one 17ss- carboxylate (XXXII) Chloromethyl 9α-fluoro-11ss-hydroxy-16ss- methyl-17α-acetyloxyandrosta-1,4-dien-3-one 17ss-carboxylate (XXXIV, Ger. Offen.

2,904,614, 1.50 g.) in acetone (150 ml.) is hydrogenated in the presence of paladium-oncarbon (5%, 1.1 g.) under 2 atmospheres of pressure until the uptake of hydrogen is com plete. The crude product is recovered in the usual manner and column chromatographed on silica gel (150 g.) packed in acetone methylene chloride (5/95). Elution is per formed with the same solvent system. The appropriate fractions are pooled and concen trated to give a material which is crystallized from acetone-hexane to give the title com pound, m.p. 205.5 (decomp.); CMR 27.06 #; [α]D -2 (1.04).

Example 25 Methyl 9α-fluoro-11ss-hydroxy- 16α-methyl-17α-propionyloxy- 513-androstan-3-one 17ss-car boxylate (XXXII) Following the general procedure of Example 23 and making non-critical variations but starting with methyl 9,,4luoro-1 113-hydroxy- 16α-methyl-17-proprionyloxyandrosta-1,4- dien-3-one 1 713-carboxylate (U.S. Patent 3,828,080, Example 21), the title compound is obtained.

Example 26 Methyl 1 7o'-butyryloxy-9o'- fluoro-11ss-hydroxy-16α-methyl- 5ss-androstan-3-one 17ss-car boxylate (XXXII) Following the general procedure of Example 23 and making non-critical variations but starting with methyl 1 7o'-butyryloxy-9o'-fluoro- 11ss-hydroxy-16α-methylandrosta-1,4-dien-3- one 1 713-carboxylate (U.S. Patent 3,828,080, Example 22), the title compound is obtained.

Example 27 Ethyl 9α-fluoro-11ss-hydroxy- 16ss-methyl-17α-propionyloxy- 5ss-androstan-3-one 17ss-car boxylate (XXXII) Following the general procedure of Example 23 and making non-critical variations but starting with ethyl 9,,-fluoro-1 1ss-hydroxy-16ss- methyl-l 7cu-propionyioxyand rosta-1,4-dien-3- one 1 713-carboxylate (U.S. Patent 3,828,080, Example 9), the title compound is obtained.

Example 28 Methyl 17αl-acetoxy-9α-fluoro- 11ss-hydroxy-16ss-methyl-5ss-an drostan-3-one 1 713-carboxylate (XXXII) Following the general procedure of Example 23 and making non-critical variations but starting with methyl 17α-acetoxy-9α-fluoro- 11ss-hydroxy-16ss-methylandrost-1,4-dien-3one 17ss-carboxylate (U.S. Patent 3,828,080, Example 5), the title compound is obtained.

Example 29 Methyl 17α-acetoxy-9α-fluoro-16ss-methyl- 5ss-androstane-3,11-dione 17ss-carboxylate (XXXII) Following the general procedure of Example 23 and making non-critical variations but starting with methyl 17α-acetoxy-9α-fluoro- 16ss-methylandrost-1,4-diene-3,11-dione 17sscarboxylate (U.S. Patent 3,828,080, Example 14), the title compound is obtained.

Example 30 Methyl 17α-acetoxy-9α-fluoro- 11ss-hydroxy-16α-methyl-5ss-an- drostan-3-one 1 713-carboxylate (XXXII) Following the general procedure of Example 23 and making non-critical variations but starting with methyl 1 7o'-acetoxy-9o'-fluoro- 11ss-hydroxy-16α-methylanbdrost-1,4-dien-3- one 1 713-carboxylate (U. S. Patent 3,828,080, Example 20), the title compound is obtained.

Example 31 Methyl 17α-butyryloxy-9α- fluoro- 11 13-hydroxy- 1613-methyl- 5ss-androstan-3-one 17sscarboxy late (XXXII) Following the general procedure of Example 23 and making non-critical variations but starting with methyl 17a-butyryloxy-9a-fluoro- 11ss-hydroxy-16ss-methylandrost-1,4-dien-3one 17ss-carboxylate (U.S. Patent 3,828,080, Example 7), the title compound is obtained.

Example 32 Methyl 9α-fluoro-11ss-hydroxy- 16ss-methyl-17α-propionyloxy- 5ss-androstan-3-one 17ss-car boxylate (XXXII) Following the general procedure of Example 23 and making non-critical variations but starting with methyl 9α-fluoro-11ss-hydroxy- 16ss-methyl-17a-propionyloxyandrost-4-ene-3one 1 713-carboxylate (U.S. Patent 3,828,080, Example 46), the title compound is obtained.

Example 33 Chloromethyl 9α-fluoro-11ss-hy- droxy-16ss-methyl -17α-propio- nyloxy-5ss-androstan-3-one 1 713- carboxylate (XXXII) Following the general procedure of Example 24 and making non-critical variations but starting with chloromethyl 9α-fluoro-11ss-hy- droxy-l GP-methyl-l 7a-propionyloxyandrost- 1,4-dien-3-one 1 713-carboxylate, the title compound is obtained.

Example 34 Fluoromethyl 9α-fluoro-11ss-hy- droxy-16ss-methyl-17α-propio nyloxy-5ss-androstan-3-one 17ss- carboxylate (XXXII) Following the general procedure of Example 24 and making non-critical variations but starting with fluoromethyl 9α-fluoro-11ss-hy- droxy-16ss-methyl-17α-propionyloxyandrost- 1,4-dien-3-one 17ss-carboxylate, the title compound is obtained.

Example 35 2'-Fluoroethyl 9α-fluoro-11ss-hy- droxy-16ss-methyl-17α-propio- nyloxy-5ss-androstan-3-one 17ss carboxylate (XXXII) Following the general procedure of Example 24 and making non-critical variations but starting with 2'-fluoroethyl 9α-fluoro-11ss-hy- droxy-16ss-methyl-17α-propionyloxyandrost- 1,4-dien-3-one 17ss-carboxylate, the title compound is obtained.

Example 36 Chloromethyl 9a-chloro-1 113-hy- droxy-16ss-methyl-17α-propio- nyloxy-5ss-androstan-3-one 17ss carboxylate (XXXII) Following the general procedure of Example 24 and making non-critical variations but starting with chloromethyl 9α-chloro-11ss-hy- droxy-l GP-methyl-l 7,-propionyloxyandrost- 1,4-dien-3-one 17ss-carboxylate, the title compound is obtained.

Example 37 Chloromethyl 9α-fluoro-11ss-hy- droxy-16α-methyl-17α-propiony loxy-513-androstan-3-one 1 713- carboxylate (XXXII) Following the general procedure of Example 24 and making non-critical variations but starting with chloromethyl 9α-fluoro-11ss-hy- droxy-16α-methyl-17α-propionyloxyandrost- 1,4-dien-3-one 17ss-carboxylate, the title compound is obtained.

Example 38 Fluoromethyl 9α-fluoro-11ss-hy- droxy-16α-methyl-17α-propionyl loxy-5p-androstan-3-one 1 7Kcar- boxylate (XXXII) Following the general procedure of Example 24 and making non-critical variations but starting with fluoromethyl 9α-fluoro-11ss-hy- droxy-16α-methyl17α-propionyloxyandrost- 1,4-dien-3-one 17ss-carboxylate, the title compound is obtained.

Example 39 Fluoromethyl 9α-fluoro-11ss-hy- droxy-16ss-methyl-17α-propio nyloxy-5ss-androstan-3-one 17ss- carboxylate (XXXII) Following the general procedure of Example 24 and making non-critical variations but starting with fluoromethyl 9α-fluoro-11ss-hy- droxy-16ss-methyl-17α-propionyloxyandrost- 1,4-dien-3-one 17n-carboxylate, the title compound is obtained.

Example 40 Chloromethyl 9α-fluoro-16ss-me- thyll 7,-propionyloxy-SP-andros- tane-3,11-dione 17ss-carboxy late (XXXII) Following the general procedure of Example 24 and making non-critical variations but starting with chloromethyl 9α-fluoro-16ss-me- thyl-17α-propionyloxyandrost-1,4-diene-3,11- dione 1 713-carboxylate, the title compound is obtained.

Example 41 Hexyl 17a-acetyloxy-9a-fluoro- 1 113-hydroxy-1 16ss-methyl-5ss-an- drostan-3-one 17ss-thiocarboxy late (XXXIII) Following the general procedure of Example 23 and making non-critical variations but starting with hexyl 17a-acetyloxy-9a-fluoro- 11ss-hydroxy-16ss-methylandrosta-1,4-dien-3one 17ss-thiocarboxylate (XXXV) the title com pound is obtained.

Example 42 Chloromethyl 1 7o'-acetyloxy-9a- fluoro-1 1 13-hydroxy-1 613-methyl- 5ss-androstan-3-one 17ss-thio carboxylate (XXXIII) Following the general procedure of Examples 23 and 24 and making non-critical variations but starting with chloromethyl 17α-ace- tyloxy-9α-fluoro-11ss-hydroxy-16ss-methylan- drost-4-en-3-one 17ss-thiocarboxylate (XXXV) the title compound is obtained.

Example 43 9α-Fluoro-11b,17α,21-trihydroxy-16ss-me- thyl-5ss-pregnane-3,20-dione 21-acetate (XXVIII) A mixture of 9α-fluoro-11ss,17α21-trihy- droxy- 1 613-methyl-pregna-1 ,4-diene-3,20-dione 21 acetate (XXVII, 20 g.) in acetone (200 ml.) is hydrogenated in the presence of palladium on carbon (5%, 1 g.) until the uptake of hydrogen is complete. The mixture is filtered and the filtrate is concentrated under reduced pressure. The concentrate is column chromatographed on silica gel (200 g.) packed in acetonemethylene chloride (10/90). Elution is performed with the same solvent system. The appropriate fractions are pooled and concentrated to give the product which upon crystallization from acetone-SSB gives the title compound.

Example 44 9α-Fjuoro-11ss,17α,21-trihy- droxy-l GP-methyl-SP-pregnane- 3,20-dione (XXIX) 9α-Fluoro-11ss,17α,21-trihydroxy-16ss-me- thyl-5ss-pregnane-3,20-dione 21-acetate (Example 43, 21.6 g.) in methanol (680 ml.) and aqueous potassium carbonate (10%, 75 ml.) is stirred for 0.5 hours under a nitrogen atmosphere. The mixture is then acidified with acetic acid (6 ml.), diluted with water and concentrated under reduced pressure. The mixture is cooled and the solid collected, dried and successively crystallized from aqueous acetone and acetone to give the title compound.

Example 45 9α-Fluoro-11ss,17α-dihydroxy- 16ss-methyl-5ss-androstan-3-one 17ss-carboxylic acid (XXX) Following the general procedure of Example 2 and making non-critical variations but starting with 9α-fluorol-11ss,1 7o',21-trihydroxy- 16ss-methyl-5ss-pregnane-3,20-dione (XXIX, Example 44), the title compound is obtained.

Example 46 1 7α-Acetyloxy-9α-fluoro-1 113-hy- droxy-16ss-methyl-5ss-androstan 3-one 1 713-carboxylic acid (XXXI) Following the general procedure of Example 3 and making non-critical variations but start ing with 9o'-fluoro-1 1ss,17α-dihydroxy-16ss- methyl-5ss-androstan-3-one 17ss-carboxylic acid (XXX, Example 45), the title compound is obtained.

Example 47 Chloromethyl 17α-acetyloxy-9α- fluoro-11ss-hydroxy-16ss-methyl 5ss-androstan-3-one 17ss-car boxylate (XXXII) Following the general procedure of Example 4 and making non-critical variations but starting with 1 76acetyloxy-9,-fluoro-l 1 P-hydroxy- 16ss-methyl-5ss-androstan-3-one 17ss-carboxylic acid (XXXI, Example 46), the title compound is obtained.

Example 48 Chloromethyl 17α-acetyloxy-9α- fluoro-11ss-hydroxy-16ss-methyl 5ss-androstan-3-one 17ss-thiocar boxylate (XXXIII) Following the general procedure of Examples 12 and 21 and making non-critical variations but starting with 17α-acetyloxy-9α- fluoro-11ss-hydroxy-16ss-methyl-5ss-androstan3-one 1 713-carboxylic acid (XXXI, Example 46, the title compound is obtained.

Example 49 17a,21 -Dihydroxy- 613-methyl- 5ss-pregn-9(11)-ene-3,20-dione (XX) Following the general procedure of Examples 23 and 1 and making non-critical variations but starting with 17α,21-dihydroxy-16ss- methyl-pregna-1,4,9(11)-triene-3,20-dione 21-acetate (XIX), the title compound is obtained.

Example 50 17 α-Hydroxy-16ss-methyl-5ss- androst-9(11)-en-3-one 17ss-car boxylic acid (XXI) Following the general procedure of Example 2 and making non-critical variations but starting with 17α,21-dihydroxy-16ss-methyl-5ss- pregn-9(1 1 )-ene-3,20-dione (XX, Example 49), the title compound is obtained.

Example 51 1 7,,-Acetyloxy-1 6ss-methyl-5ss-an- drost-9(11)-en-3-one 17ss-car boxylic acid (XXII) Following the general procedure of Example 3 and making non-critical variations but starting with 1 7a-hydroxy-1 6ss-methyl-5ss-androst- 9(11 )-en-3-one 17ss-carboxylic acid (XXI, Example 50), the title compound is obtained.

Example 52 Methyl 17α-acetyloxy-16ss-me- thyl-5ss-androst-9(11)-en-3-one 17ss-carboxylate (XXIII) Following the general procedure of Example 4, substituting methyl iodide for chloromethyl iodide, and making non-critical variations but starting with 17α-acetyloxy-16ss-methyl-5ss-an- drost-9(11)-en-3-one 17ss-carboxylic acid (XXII, Example 51), the title compound is obtained.

Example 53 Methyl 1 7a-acetyloxy-9o', 11ss- dichloro-16ss-methyl-5ss-andros tan-3-one 1 713-carboxylate (XXIV) Following the general procedure of Example 11 and making non-critical variations but starting with methyl 1 7o'-acetyloxy-1 613-me- thyl-5ss-androst-9(11)-en-3-one 17ss-carboxylate (XXIII, Example 52), the title compound is obtained.

Example 54 Methyl 1 7o'-acetyloxy-1 6ss-me- thyl-513-androst-9(1 1)-en-3-one 1 713-thiocarboxylate (XXV) Following the general procedure of Example 12 and making non-critical variations but starting with 17α-acetyloxy-16ss-methyl-5ss-an- drost-9(11)-en-3-one 17ss-carboxylic acid (XXII, Example 51), the title compound is obtained.

Example 55 Methyl 1 7α-acetyloxy-9α,1 113- dichloro-16ss-methyl-5ss-adnros tan-3-one 1 7-thiocarboxylate (XXVI) Following the general procedure of Example 13 and making non-critical variations but starting with methyl 17α-acetyloxy-1 613-me- thyl-5ss-androst-9(11)-en-3-one 17ss-thiocarboxylate (XXV, Example 54), the title compound is obtained.

Example 56 6α,9α-Difluoro-11ss,17α,21- trihydroxy-16ss-methyl-5ss-preg nane-3,20-dione 17,21-diace tate A solution of 6α,9α-difluoro-11ss,17α,21- trihydroxy-16ss-methylpregna-1,4-diene-3,20dione 17,21-diacetate (U.S. Patent 3,980,778, 7 g) in acetone (100 ml) is hydrogenated in the presence of palladium-oncarbon (5%, 0.25 g). The product is purified by chromatography on silica gel and crystallized from aqueous acetone to give the title compound, m.p. 225 ; CMR 27.24 #; [o']D + 28 (C 1.12).

Example 57 6α,9α,-Difluoro-11ss,17α,21- trihydroxy-l GP-methyl-SP-preg- nane-3,20-dione (XXIX) Following the general procedure of Example 44 and making non-critical variations but starting with 6α,9α-difluoro-11ss,17α,21-trihy- droxy-16ss-methyl-5ss-pregnane-3,20-dione 1 7,21-diacetate (Example 56), the title compound is obtained.

Example 58 6a,9a-Difluoro-11 1ss,17α-dihy- droxy-16ss-methyl-5ss-androstan 3-one 17ss-carboxylic acid (XXX) Following the general procedure of Example 2 and making non-critical variations but starting with 6α,9α,difluoro-11ss,17α,21-trihy- droxy-16ss-methyl-5ss-pregnane-3,20-dione (XXIX, Example 57), the title compound is obtained.

Example 59 17α-Acetyloxy-6α,9α-difluoro- 11ss-hydroxy-16ss-methyl-5ss-an drostan-3-one 17ss-carboxylic acid (XXXI) Following the general procedure of Example 3 and making non-critical variations but starting with 6a,9a-difluoro-11 1113,1 7o'-dihydroxy 16ss-methyl-5ss-androstan-3-one 17ss-carboxylic acid (XXX, Example 58), the title compound is obtained.

Example 60 Chloromethyl 17α-acetyloxy- 6α,9α-difluoro-11ss-hydroxy 16ss-methyl-5ss-androstan-3-one 17ss-carboxylate (XXXII) Following the general procedure of Example 4 and making non-critical variations but starting with 17α-acetyloxy 6α,9α-difluoro-11ss-hy- droxy-16ss-methyl-5ss-androstan-3-one 17sscarboxylic acid (XXXI, Example 59), the title compound is obtained.

Example 61 Chloromethyl 1 7o'-acetyloxy- 6α,9α-difluoro-11ss-hydroxy- 16ss-methylandrosta-1,4-dien-3 one 17ss-carboxylate (XXXIV) 17α-Acetyloxy-6α,9α-difluoro-11ss-hydroxy- 16ss-methylandrosta-1,4-dien-3-one 17ss-carboxylic acid is converted to the sodium salt.

The salt is mixed with hexamethylphospho ramide (45 ml) and chloromethyl iodide (7.25 ml) and stirred at 25-30 . After a short period, the reaction mixture set to a thick gel which is allowed to stand for about 1 hour.

The mixture is shaken with ethyl acetate (100 ml) and water (100 ml). The phases are separated and the organic extract is washed with potassium carbonate (1 N), water and saline. The dried extract is concentrated to a solid which is chromatographed on silica gel (500 g) packed in 5% acetone-methylene chloride. Elution is performed with 5% and 10% acetone-methylene chloride collecting 200 ml fractions. The appropriate fractions are pooled and concentrated to give a solid which is crystallized from acetone-hexane to give the title compound, m.p. 213-213.5 ; PMR 1.07, 1.45, 1.53, 2.03, 4.4, 6.3-6.4, 7.0-7.2 S; UV #max = 236 nm (e 17,150); [α]D + 29 (C 0.95).

Example 62 Chloromethyl 1 7o'-acetyloxy- 6α,9α-difluoro-11ss-hydroxy- 16ss-methyl-5ss-androstan-3-one 1 713-carboxylate (XXXII) Chloromethyl 1701-acetyloxy-6cu, Sar-difluoro- 11ss-hydroxy-16ss-methylandrosta-1,4-dien-3one 1 713-carboxylate (XXXIV, Example 61, 1.95 g) in acetone (100 ml) is hydrogenated in a Parr shaker at 2 atmospheres in the presence of palladium-on-carbon (5%, 0.1 g).

The rate of hydrogenation was slow and additional catalyst (0.2 g) is added. After 18 hours, the reaction was still not complete. the sample was recovered, dissolved in ethyl acetate (100 ml) and hydrogenated in the presence of palladium-on-carbon (5%, 0.4 g) and p-TSA (16 mg) for 20 hours. The mixture is filtered and the filtrate washed with saline, dried and concentrated. The concentrate is chromatographed on silica gel (200 g) eluting with 10% acetone-methylene chloride. The appropriate fractions are pooled and concentrated. The concentrate is crystallized from acetone-hexane to give the title compound, m.p. 214-214.5 ; PMR 1.02, 1.30, 1.45, 2.08 and 5.0 #.

CHART A

CHART B

CHART C

(I) ow 0 Rv C: I Rie 0+ (z) d=cOH O > OH R2 RIB o == (x) R6 OqzOX R2xv ('I) CHARLIE K6 6820 6 | o%/OR20 R2 I R1e H Rs (I CHART D

CHART E

CHART F

CHART G

CHART H

CHART I

CHART

Claims

1. A compound of the formula

where Q is O or S; R2 is hydrogen or methyl; R6 is hydrogen, fluorine or methyl; either R9 is hydrogen, fluorine or chlorine, R" is s-chlo- rine, 13-hydroxyl or oxo, and the 9,11-bond is a single bond, or R9 and R" are each hydrogen and the 9,11-bond is a double bond; either R,6 is hydrogen, hydroxyl or methyl and R,7 is COR17α' or R,6 and R,7 together form an acetonide;R17,,, if present, is hydrogen, C1-4 alkyl, phenyl or Rtolyl; QR20 is hydroxyl, C1-4 alkoxy optionally substituted by 1 or 2 halogen atoms, benzyloxy, C5-7 cycloalkoxy, C6 H"-Ch2-O, C6H11-CH2-CH2O-, H0CH2CH2O-, (Cr~4 alkyl)-COOCH2CH2O-, PhCOOCH2CH2O-, C16 alkylthio, optionally ring-substituted phenylthio or optionally ring-substituted benzylthio, in which any ring substituent is selected from C14 alkyl, C1-4 alkoxy, fluorine, chlorine and bromine; and # indicates α or ss configuration.

2. A compound as claimed in claim 1, of formula XXXII herein.

3. A compound as claimed in claim 1, of formula XV herein.

4. A compound as claimed in claim 1, of formula XV' herein.

5. A compound as claimed in claim 1, of formula XXIV herein.

6. A compound as claimed in claim 1, of formula XVIII herein.

7. A compound as claimed in claim 1, of formula XXXII I herein.

8. A compound as claimed in claim 1, of formula VIII herein.

9. A compound as claimed in claim 1, of formula VIII' herein.

10. A compound as claimed in claim 1, of formula XXVI herein.

11. A compound as claimed in claim 1, of formula XVII herein.

12. A compound as claimed in claim 1, of formula VI herein.

13. A compound as claimed in claim 1, of formula VII herein.

14. A compound as claimed in claim 1, of formula X herein.

15. A compound as claimed in claim 1, of formula Xl herein.

16. A compound as claimed in claim 1, of formula XII herein.

17. A compound as claimed in claim 1, of formula XVl.herein.

18. A compound as claimed in claim 1, of formula XXI herein.

19. A compound as claimed in claim 1, of formula XXII herein.

20. A compound as claimed in claim 1, of formula XXIII herein.

21. A compound as claimed in claim 1, or formula XXV herein.

22. A compound as claimed in claim 1, of formula XXX herein.

23. A compound as claimed in claim 1, of formula XXXI herein.

24. A compound as claimed in any preceding claim, wherein R2 is hydrogen or methyl.

25. A compound as claimed in claim 24, wherein R2 is hydrogen.

26. A compound as claimed in any preceding claim, wherein R6 is hydrogen.

27. A compound as claimed in any pre ceding claim, wherein R9 is fluorine or chlorine.

28. A compound as claimed in claim 27, wherein R9 is fluorine.

29. A compound as claimed in any preceding claim, wherein R1, is oxo or ss-hy- droxyl.

30. A compound as claimed in claim 29, wherein R,1 is ss-hydroxyl.

31. A compound as claimed in any preceding claim, wherein R,6 is methyl.

32. A compound as claimed in any preceding claim, wherein R,6 is in the ss-configu- ration.

33. A compound as claimed in any of claims 1 to 31, wherein R,6 is in the a- configuration.

34. A compound as claimed in any preceding claim, wherein R,7 is COR17α as defined in claim 1.

35. A compound as claimed in claim 34, wherein R17ss is C1-4 alkyl or phenyl.

36. A compound as claimed in any preceding claim, wherein QR20 or OR20, if present, is C1-4 alkyl optionally substituted by a fluorine or chlorine atom.

37. A compound as claimed in any of claims 1 to 35, wherein QR20 or SR20α' if present, is C1-4 alkylthio or phenylthio.

38. A compound according to claim 1 which is methyl 9α-fluoro-11ss-hydroxy-16ss- methyl-17α-propionyloxy-5ss-androstan-3-one 1 713-carboxylate.

39. A compound according to claim 1 which is chloromethyl 9α-fluoro-11ss-hydroxy- 16ss-methyl-17ss-acetyloxy-5ss-androstan-3-one 1 713-carboxylate.

40. A compound according to claim 1 which is methyl 9α-fluoro-11ss-hydroxy-16α- methyl-17α-propionyloxy-5ss-androstan-3-one 1 713-carboxylate.

41. A compound according to claim 1 which is methyl 1 7o'-butyryloxy-9o'-fluoro- 11ss-hydroxy-16α-methyl-5ss-androstan-3-one 17ss-carboxylate.

42. A compound according to claim 1 which is ethyl 9α-fluoro-11ss-hydroxy-16ss-me- thyl-17α-propionyloxy-5ss-androstan-3-one 17carboxylate.

43. A compound according to claim 1 which is methyl 1 7ar-acetoxy-9a-fluoro- 1 1 P- hydroxy-l GP-methyl-SP-androstan-3-one 17ss- carboxylate.

44. A compound according to claim 1 which is methyl 17α-acetoxyl-9α-fluoro- 16ssmethyl-5ss-androstane-3,11-dione 17sscarboxylate.

45. A compound according to claim 1 which is methyl 17α-acetoxy-9α-fluoro-11ss- hydroxy-16α-methyl-5ss-androstan-3-one 17sscarboxylate.

46. A compound according to claim 1 which is methyl 17α-butyryloxy-9α-fluoro-1 113-hy- droxy-l GP-methyl-SP-androstan-3-one 17ss- carboxylate.

47. A compound according to claim 1 which is chloromethyl 9a4luoro-i 113-hydroxy- 16ss-methyl-17α-propionyloxy-5ss-androstan-3- one 17ss-carboxylate.

48. A compound according to claim 1 which is fluoro methyl 9α-fluoro-11ss-hydroxy- 16ss-methyl-17α-propionyloxy-5ss-androstan-3- one 17ss-carboxylate.

49. A compound according to claim 1 which is 2'-fluororethyl 9α-fluoro-11ss-hy- droxy-16ss-methyl-17α-propionyloxy-5ss-an- drostant-3-one 1 713-carboxylate.

50. A compound according to claim 1 which is chlorormethyl 9α-chloro-11ss-hy- droxy-16ss-methyl-17α-propionyloxy-5ss-an- drostan-3-one 1 713-carboxylate.

51. A compound according to claim 1 which is chloromethyl 9α-fluoro-11ss-hydroxy- 16ss-methyl17α-proplonyloxy-5ss-androstan-3- one 1 713-carboxylate.

52. A compound according to claim 1 which is fluoromethyl 9o'-fluoro-i 113-hydroxy- 16α-methyl-17α-propionyloxy-5ss-androstan-3- one 1 713-carboxylate.

53. A compound according to claim 1 which is fluoromethyl 9α-fluoro-11ss-hydroxy- 16ss-methyl-17α-propionyloxy-5ss-androstan-3- one 17ss-carboxylate.

54. A compound according to claim 1 which is chloromethyl 9α-fluoro-16ss-methyl- 17α-propionyloxy-5ss-androstane-3,11-dione 1 713-carboxylate.

55. A compound according to claim 1 which is chlorormethyl 17α-acetyloxy-9α- fluoro-11ss-hydroxy-16ss-methyl-5α-androstan- 3-one 1 713-carboxylate.

56. A compound according to claim 1 which is chloromethyl 17α-acetyloxy-9α- chloro-11ss-hydroxy-16ss-methyl-5α-andros- tan-3-one 17ss-carboxylate.

57. A compound as claimed in claim 1 which is chloromethyl 17α-acetyloxy-9α- fluoro-16ss-methyl-5α-androstane-3,11-dione 1 713-carboxylate.

58. A compound according to claim 1 which is chloromethyl 17α-acetyloxy-9α- chloro-16ss-methy-5α-androstane-3,11-dione 17ss-carboxylate.

59. A compound according to claim 1 which is methyl 17α-acetyloxy-9α,11ss-di- chloro-l GP-methyl-SP-androstan-3-one 17ss- carboxylate.

60. A compound according to claim 1 which is chloromethyl 17α-acetyloxy-9α,11ss- dichloro-16ss-methyl-5α-androstan-3-one 17sscarboxylate.

61. A compound according to claim 1 which is methyl 9α-fluoro-11ss-hydroxy-16ss- methyl-17α-propionyloxy-5ss-androstan-3-one 17ss-thiocarboxylate.

62. A compound according to claim 1 which is chloromethyl 17α-acetyloxy-9α- fluoro-11ss-hydroxy-16ss-methyl-5ss-androstan3-one 17ss-thicarboxylate.

63. A compound according to claim 1 which is methyl 17α-acetyloxy-9α-fluoro-11 ss- hydroxy-16ss-methyl-5ss-androstan-3-one 17ssthiocarboxylate.

64. A compound according to claim 1 which is methyl 17α-acetyloxy-9α-fluoro-16ss- methyl-5α-androstane-3,11-dione 17ss-thiocarboxylate.

65. A compound according to claim 1 which is methyl 1 7o'-acetyloxy-9a, 1 1ss-di- chloro-16ss-methyl-5ss-androstan-3-one 17ssthiocarboxylate.

66. A compound accoridng to claim 1 which is methyl 17α-acetyloxy-9α-1 1 13-di- chloro-16ss-methyl-5ss-androstan-3-one 17sscarboxylate.

67. A compound according to claim 1 which is 9α-fluoro-11ss,17α-dihydroxy-16ss- methyl-5ss-androstan-3-one 17ss-carboxylic acid.

68. A compound according to claim 1 which is 17α-acetyloxy-9α-fluoro-11ss-hydroxy- 16ss-methyl-5α-androstan-3-one 17ss-carboxylic acid.

69. A compound according to claim 1 which is 17α-hydroxy-16ss-methyl-5α-androst- 9(11)-en-3-one 1 713-carboxylic acid.

70. A compound according to claim 1 which is 17α-acetyloxy-16ss-methyl-5α-an- drost-9(11)-en-3-one 17ss-carboxylic acid.

71. A compound according to claim 1 which is chloromethyl 17α-acetyloxy-16ss-me- thyl-5α-androst-9(11)-en-3-one 17ss-carboxylate.

72. A compound according to claim 1 which is methyl 17α-acetyloxy-16ss-methyl-5α- androst-9(11)-en-3-one 17ss-thiocarboxylate.

73. A compound according to claim 1 which is 17α-hydroxy-16ss-methyl-5ss-androst- 9(11)-en-3-one 17ss-carboxylic acid.

74. A compound according to claim 1 which is 17α-acetyloxy-16ss-methyl-5ss-an- drost-9(11)-en-3-one 17ss-carboxylic acid.

75. A compound according to claim 1 which is methyl 17α-acetyloxy-16ss-methyl- 5ss-androst-9(11)-en-3-one 17ss-carboxylate.

76. A compound according to claim 1 which is methyl 17α-acetyloxy-16ss-methyl- 513-androst-9(1 1 )-en-3-one 17ss-

77. A compound according to claim 1 which is 9α-fluoro-11ss,17α-dihydroxy-16ss- methyl-5ss-androstan-3-one 17ss-carboxylic acid.

78. A compound according to claim 1 which is 17α-acetyloxy-9α-fluoro-11 13-hydroxy- 16ss-methyl-5ss-androstan-3-one 17ss-carboxylic acid.

79. A compound according to claim 1 which is methyl 9α-fluoro-11ss-hydroxy-16ss- methyl-17ss-propionyloxy-5ss-androstan-3-one 17ss-carboxylate.

80. A compound according to claim 1 which is chloromethyl I 7α-acetyloxy-6α,9α- difluoro-11ss-hydroxy-16ss-methyl-5ss-androstan-3-one 17ss-carboxylate.

81. A compound of the formula

wherein R2, R6, R,6, R,7, R20 and - are defined in claim 1.

82. A compound of the formula

where R2, R6, R,6, R,7, R20 and ~ are defined in claim 1.

83. A compound according to claim 81 or claim 82 wherein R2 is hydrogen and R,6 is methyl.

84. A compound according to claim 81 which is chloromethyl 17α-acetyloxy-9α- bromo-11ss-hydroxy-16ss-methyl-5ss-androstane-3-one 17ss-carboxylate.

85. A compound according to claim 82 which is chloromethyl 17a-acetyloxy-9,11 - epoxy-16ss-methyl-5ss-androstan-3-one 17sscarboxylate.

86. A compound substantially as herein described.

87. A pharmaceutical composition comprising a compound as claimed in any preceding claim, in association with a physiologically acceptable excipient.