IL32699A - 6-substituted-13-polycarbonalkyl-18,19 dinorpregn-4-en-3-ones,their preparation and pharmaceutical compositions containing them - Google Patents

Description

their preparation and pharmaceutical compositions containing them AMERICAN HOME PROBITCTS CORPORATION This invention is concerned generally with novel steroid compounds and with processes for preparing and using the and with useful intermediates More particularly it relates to steroids of series and analogues and to intermediates and processes for producing The steroid compounds of this invention have the formula wherein R is an alkyl group of from 2 to 6 carbon X is or wherein is hydrogen or a groups Y is OH or OCOR 2 wherein R2 is a group and either rings A and B have the formula P wherein is a divalent radical of the wherein Z is bromo or fluoro and Z is chloro or provided that when X is and Y is is other than rings A and B have the formula where W is an alkoxy group and is CH20H CHO The term denotes hydrocarbon chains of from 1 to 6 carbon atomst both straight chain and and illustrative members of which are isopentyl and The term denotes containing from 2 to 6 carbon atoms and includes groups illustrated but excluding the methyl the ethyl group is The term denotes groups of the formula wherein is above acetyl is Special mention is made of a number of particularly valuable preferred compounds of the instant There compounds wherein R is alkyl of from 2 to 6 carbon X is or 1 2 wherein R is hydrogen or Y is OH or OCOR wherein is and is a divalent radical of the formulae 13 a compound of formula wherein R is X is Y is H and dione and the ester compounds of formula la wherein R is X is Y is OH or and is a compound of formula wherein R is X is Y is H and is Gl a compound of formula la wherein R is X is Y is H and is 6 7 a compound of formula wherein R is X is Y OCOCH and is CI 13 a compound of formula wherein R is X is Y is and is CI r 13 a compound of formula wherein R is X is Y is OH and is CI compounds of formula compound of formula wherein R is X is and Y is H compounds of formula wherein R is and Y1 is OH or OCOR2 wherein R2 is and a compound of formula Ic wherein R is X is and Y1 is The compounds of formula I wherein rings A and B have the formula except the compounds herein are valuable substances0 They have been found to be active in standard pharmacological tests in laboratory animals such as rats and rabbits and the and They are more active than many known compounds now used with these activities in possess a valuable separation of hormonal properties to a greater degree than many compounds presently used with these active substances are used in cases of infertility and more but without to delay estrus and ovulation in and active compounds are to counter the effects due to an excess of such as estrone and similar metrotropic agents0 The instant compounds are also of value in that field of use known as microdose They have an effect at considerably lower levels of administration than the levels used 1 to 100 on a daily The compounds of formula I and the compounds of formula I where rings A and B have the formula P are The compounds of formula I of this invention can be prepared by a general method for example by exchange hydrogenation with a able organic in the presence of a palladium on a compound of formula wherein X and Y are as hereinabove defined to give a compound of formula wherein X and Y are as hereinabove for example by heating with a weak sodium and a noble metal preferably a Pt or Pd Pt or in an inert ethanol9 a compound of formula II hereinabove to give the corresponding compound of formula wherein X and are as ere na ove e ne chlorinating or with an enol ester of formula Ills wherein X and Y are as above defined and to give a compound wherein Y and Z are as above directly by heating with a compound of formula If to give a compound of formula R i wherein Y and Z are as above or preferably reacting with a hydrogen namely dry hydrogen hydrogen bromide or hydrogen fluoride an epoxide of formula wherein X and Y are as hereinabove to give a compound formula wherein Y and Z are as above partially hydrolysing a compound of formula wherein Z is chloro or to give a compound of formula wherein R and are as defined in formula I hereinabove0 The partial hydrolysis may be carried out with dilute alkali metal methanolic potassium hydroxide0 The compound of formula Ik may be obtained by acylation of a compound of formula li with a reagent of the formulae or R C0C1 a mixture thereof in the presence of an acid binding an organic base such as morpholine selectively oxidising a compound of the formula to a compound of the formula wherein R and Y are as defined selectively hydrolysing a compound of the formula to give a compound of the formula wherein and Y are as defined to give a compound of the formula wherein hydrolysing a compound of the formula In as above defined to give a wherein the groups R R and W are as defined above and being a lower alkyl hydrolysing a compound of the formula where K ation e by acid to a ethylenic and X is as defined above or may be a protected carbonyl or hydroxymethylene group to obtain a compound of formula Id the corresponding isomerising a compound of formula wherein is or to obtain a corresponding formylating a compound of formula where W is an alkoxy group accompanied by ethylenic bonds in the and or and if necessary with reconversion of the group Y or X to obtain a compound of formula Im 1 1 2 as defined the groups Z R R and being as defined above and being a lower alkyl The method of step hydrogenating a compound of formula II can be carried out by an exchange hydrogenation In this for a mixture of the compound with about 3 parts by weight of cyclohexene and about part by weight of a such as palladium on is refluxed in absolute ethanol for about to about The product of formula Id is recovered by any standard One useful method comprises adding filtering the adding a trace of mineral acid and evaporating off the solvent to leave the product as a It if be purified by lisation from The method of step rearranging a compound of formula II can be carried out by treating it with a weak base in the presence of a such as palladium on carbon and in an inert preferably at moderately elevated 75 to In one manner of the compound of formula II is suspended in about 300 parts by weight of an and there is added about parts by weight of sodium acetate and about parts of palladium on If the mixture is heated and refluxed for about 1 to 3 rearrangement to the compound of formula is substantially complete0 This can be recovered in any conventional way but a convenient means to cool the dilute it with filter wash with saturated aqueous sodium then with dry over anhydrous sodium and finally evaporate the solvents leaving the product as a It if be purified by recrystallisation from ether A useful series of compounds outside the scope of this the can be prepared by treating the corresponding compounds of formula Id wherein R is X is and Y is H with a standard oxidising the Jones 8N chromic until conversion to a corresponding compound wherein X is is stantially and recovering said which has valuable progestational and antiestrogenic properties0 Starting materials of formula II hereinabove may be obtained for example according to one of the pathways outlined as In the a is subjected to obtain the corresponding 0 Compound VI is as with potassium hydroxide in to the corresponding alcohol on treatment with a metal hydride reducing sodium borohydride in methanol mixed with affords the Treatment of compound VIII with a mineral acid such as dilute methanolic conveniently at about results in hydrolysis of the enol ether and concomitant elimination of water to give the of formula is as above defined and X is wherein is dimethylformamide and is In the above scheme the group is conveniently a methoxy group but other alkoxy groups may of course be used and this route provides access to the compounds In to compound VIII of the above In the the starting a 13 is treated with an acylating acetic anhyd ide and a trace of perchloric acid in ethyl acetate to obtain the corresponding which is then reacted with a potassium hydroxide in tetrahydrofuran to obtain the corresponding which in turn is reacted with methyl in dioxane containing acid to produce the corresponding which in turn is formylated with phosphorus oxychloride in formamide and ethylene dichloride to produce the corresponding which is reduced with lithium aluminum hydride in tetrahydrofuran to the corresponding and treatment of this with oxalic acid in methanol and water produces the desired acetate according to the following ethylene dichloride wherein R is as hereinabove is is acid and is methyl Of course other alkylating agents may be used in place of The method of step chlorinating an enol ester of formula III with a reagent such as or can be carried out by adding the enol ester to about 0 parts of a mixture of and which contains about parts of sodium acetate and parts of glacial acetic acid per part b weight of enol The mixture then is cooled to about and there is added about 6 to 8 parts of succinimide per part by weight of enol The formation of the product of formula If is complete in about 1 to about hours and it can be recovered by diluting the reaction mixture with then extracting with ether and evaporating to dryness leaving compound If as a instead of is there is obtained the corresponding compound of formula Starting materials of formula III hereinabove may be prepared starting with an enol ether of formula Vbs X and Y are as above by acid go with concentrated or of the corresponding cyclic acylating with an acid preferably acetic anhydride in the presence of a trace of perchloric acid and about parts by volume of ethyl acetate0 The reaction is quite being substantially complete in about Treatment with enough aqueous sodium bicarbonate to acetic anhydride and evaporation of the organic layer to provides Compound III as a The method of step dehydrogenation of a compound of formula If to introduce a double bond between and can be carried out with a reagent such as chloranil0 In one manner of compound If can be suspended in 25 parts by volume of a such as ethyl containing about 5 parts by volume of acetic acid and about 2 parts by weight chloranil per part by weight of If is If the mixture is refluxed under nitrogen for about 2k conversion to compound Ig is substantially complete and it may be for by cooling the washing it with 10 sodium hydroxide then with drying it over anhydrous sodium sulphate evaporating to leaving Ig as a The method of step treatment of the epoxide of formula IV with a halogen acid to provide the of formula Ih can be carried out with dry hydrohalic In one manner of the epoxide be suspended in about 50 parts by volume of glacial acetic The mixture is cooled to about the freezing point of glacial acetic and a slow stream of gaseous hydrogen hydrogen bromide or hydrogen iodide is passed After about 2 to 6 the formation of the compound of formula Ih is substantially complete and the product for be recovered by pouring the mixture into ice water and extracting with a such as a mixture of benzene and ether0 The organic layer is washed free of with dilute sodium dried and evaporated to leave compound Ih as a Starting materials of formula IV the epoxides may be prepared by halogen elimination in the or compound of formula to provide the followed by epoxidation thereof to provide compound IV according to the wherein Y and Z are as hereinabove defined and is diraethylformamide0 The dehalogenation is for by suspending compound If in about parts by volume of formamide or pyridine and adding about 3 psirts by weight of calcium carbonate based on parts by weight of Refluxing under nitrogen for about 1 filtering off the pouring the filtrate into extracting with ether and evaporation of the ether leaves the IX as a residue0 This is for by suspending it in about parts by volume of chloroform and treating the mixture with 1 part by weight of a such as perbenzoic and or preferably monoperphthalic per part by weight of for about hours about The epoxide IV is then for by washing the organic phase with saturated sodium then with drying it over sodium sulphate and evaporating the solvent to leave IV as a The method of step selectively hydrolysing a compound of formula Ii including preparation of the diacylate is preferably carried out first with an appropriate acyl acetic or an acyl acetyl chloride or acetyl preferably mixtures in the presence of an acid binding such as an organic preferably to form the corresponding enol In one manner of compound Ii is treated with an excess of acetic anhydride and acetyl chloride in pyridine and the mixture is warmed o to about a ew minutes then kept at about C about 67 The enol ester is recovered by pourin the mixture into a large volume of water and extracting the organic layer with drying and evaporating the ether leaves the enol ester as a This is selectively hydrolysed with a dilute base0 In one manner of the enol acetate is suspended in methanolic potassium hydroxide and the mixture is stirred at until partial hydrolysis is substantially Cooling and neutralising the reaction evaporating to extracting the residue with ether and evaporating the leaves compound as a The selective oxidation of step can be carried out with Jones reagent where Y is hydrogen or and with dimethylsulphcxide in acetic acid where Y is The compounds described herein may also be made by processes for analogous Starting material for all of the compounds can be obtained from compounds described in UK Patent tion or UK Patent Specification or can be prepared from similar startin mater 3 26 2 the above mentioned patent ications by analogous processes to those described in the specifica ions The pounds of these ecifications or analogues thereof can be obtained by applying in earlier steps methods of total synthesis described by Siddall and Smith and by Jr0 and Watson If starting materials the product a total synthesis which has included a suitable resolution stage the compounds of the invention will be present as racemateso if a resolved starting material used for example by resolving at an earlier stage in the the products of the processes described herein will of course be the resolved resolved Intermediates for startin materials of the are described in the Jo Cherao 1 Using a convention approved by Fieser and 1959 the compound designated as the forms are the corresponding in configuration at to that of the natural hormone corresponding enantiomorphs are consequently designated the and the racemates the structural formulas show only the enantiomorphs of the uration but it will of course be understood that the racemates are included in the The time and temperature ranges used in carrying out the above mentioned processes are not particularly critical will be readily apparent to those skilled in the will be selected to carry out the reaction ia minimum of time without undue difficulty0 reaction temperatures below those exemplified can be but then the reaction time is On the other reaction temperatures higher than those exemplified can be used with a concomitant decrease in reaction although purity of the product may be somewhat As is mentioned the compounds of formula I wherein rings A and B have the formula P have progestational and estrogenic and they are useful to prepare compounds with these activities0 The progestational activity is illustrated by standard pharmacological tests in lower animals0 In one such the Clauberg immature female rabbits are primed with for six days0 The primed rabbits then receive graded doses of the compound daily for five days before autopsy on the sixtho Progestational activity is assessed by histological evaluation of uterine glandular proliferation according to Elton and o The antiestrogenic activity also is illustrated by standard pharmacological tests in blooded lower animalso In one such the estrogen moust uterine growth 100 of estriol is administered simultaneously with graded doses of the test compound over three At autopsy on day the uteri are removed and weighedo Active materials inhibit the metrotropic effect of as illustrated by Edgren and The products of formula I of this invention wherein rings A and B have the formula P above can be used for the above pharmacological purposes in association with a They can be formulated in liquid or solid for instance as dispersible and the like by combining them with conventional carriers0 Such conventional carriers include magnesium carbonate or methyl sodium methyl low melting wax and cocoa flavouring suspending binders or agents can be used0 Powders or tablets preferably contain 5 10 to of the active The active steroid can be formulated with an encapsulating material with or without other carriers0 Liquid preparations such as suspensions or emulsions can also be Such preparations include dispersions in a toxic carrier such as arachis oil or sterile preferably containing a nonionic surface active agent such as fatty acid esters of polyhydroxy sorbit aqueous starch in sodium cellulose aqueous propylene glycol or ethylene glycol0 Thus a water propylene glycol solution can be used for parenteral injection and aqueous suspensions suitable for oral use can be made by utilising natural or synthetic methyl cellulose or other well known suspending The composition can be administered to the lower animals in unit dose form in which the dose unit is for from about Ool to about 200 mg0 of each active steroido The unit dose form can be a packaged packeted or ampules for in the form of cachets or tablets or any number of these in packaged The compositions can also consist substantially solely of the active steroid when this is in unit dose When used for the purposes stated the dosage of the compounds will vary with the conditions being but in general will be in the range established for progesterone Seventh Description of the Preferred The following examples are given by way of illustration and are not to be construed as ations of this variations of which are possible without departing from the scope and spirit thereof0 76 EXAMPLE 1 To a solution of distilled dimethylformamide in distilled ethylene dichloride at is added a solution of distilled phosphorus oxychloride in ethylene dichloride over minuteso After stirring an additional 10 minutes at pyridine is added and then a solution of in ethylene dichloride containing pyridine is added all at once0 After stirring the red solution at for 1 hour a solution of sodium acetate in water is added and the mixture is stirred vigorously for 10 minutes0 The mixture is poured into extracted with the organic layer washed with water until the washings are dried over anhydrous sodium sulphate and stripped in vacuo0 Trituration of the residue with methanol affords go of m0p0 from 220 321 mu dl To a of formate in tetrahydrofuran under nitrogen at about is added all at once a solution of potassium hydroxide in methanol Stirring at room temperature is continued for the mixture is poured into saturated aqueous sodium bicarbonate and extracted with benzeneo The benzene extracts are washed with dried over anhydrous sodium sulphate and stripped in Trituration of the residue with ether affords l of yellow coloured n po 2 0 322 To a solution of in methanol and hydrofuran at room temperature is added sodium borohydride all at The mixture is stirred at about for 15 poured into water and extracted with benzeneβ The organic layer is washed with dried over anhydrous sodium sulphate and stripped in vacuo0 Trituration of the residue with ether affords To a stirred slurry of in methanol at room temperature is added a trace of 8N sulphuric acido Solution occurs immediately on adding the and reprecipitation occurs after 2 minuteso After minutes the precipitate is filtered giving of colourless products and 6o30 265 A mixture of cyclohexene and Pd C 130 in absolute ethanol heated at reflux for minutes0 mixture is diluted with ether and filtered through A trace of concentrated hydrochloric acid is added and the solution is stripped in Recrystallisation of the solid residue from ether o affords O0605 of colourless 6o23 has at ppm0 17H at ppm 6a at l0l8 ppm J 2 and 21 at lo07 ppm J 2 Calcdo for EXAMPLE 2 13 To a solution of in acetone at is added dropwise over 5 minutes Jones reagent chromic Stirring at is continued for 10 more minutes and excess propanol is The mixture is diluted with filtered through with saturated aqueous sodium dried over anhydrous sodium sulphate and stripped in The solid residue is recrystallised from ether giving 0o37 of white coloured Z l NMR has H at ppm J 6 Calcdo for EXAMPLE 3 A mixture of sodium acetate and 15 in absolute ethanol is heated at reflux for The mixture is cooled to about diluted with filtered through washed with saturated aqueous sodium dried over anhydrous sodium sulphate and stripped in The solid residue is recrystallised from ether giving 22 of s less m0p0 20 20 NMR has vinyl protons at and 17H at 75 at ppm and 21 at ppm acetate A solution of in ethyl acetate containing acetic anhydride and perchloric acid is stirred at room temperature for minutes0 The resulting yellow solution is diluted with washed with saturated aqueous sodium dried over anhydrous sodium sulphate and stripped in Crystallisation of the gummy residue from methanol gives go of colourless and max EtOH no hydroxy 1 has vinyl protons at 7 ppm and 5 two acetate methyls at 2011 ppm and methyl To a solution of in tetrahydrofuran and methanol is added under nitrogen at a solution of potassium hydroxide in methanol Stirring at is continued for The mixture is poured into saturated aqueous sodium bicarbonate extracted with and the organic layer washed with dried over anhydrous sodium sulphate and stripped in giving a colourless fiecrystallisation from ethyl acetate hexane gives g0 of colourless fl To a of acetate in dioxane 9 at room temperature is added methyl ortho ormate ml0 and a solution containing acid l6 and methanol in dioxane 75 The steroid dissolves after stirring 5 minutes and stirring is continued for another 55 Pyridine is added and the mixture diluted with ethe Washing with drying over anhydrous sodium sulphate and stripping in vacuo gives a Crystallisation from methanol containing trace of pyridine gives l08l go of colourless 5o To a solution of distilled formamide 25 and distilled ethylene dichloride 0 ml at is added a solution of distilled phosphorus oxychloride in ethylene dichloride 0 over 30 minutes0 After stirring an additional 10 minutes at pyridine is added and a solution of acetate lo 70 in ethylene dichloride containing pyridine is added all at once0 After stirring the red solution at for 1 hour a solution of sodium acetate in water is added and the mixture stirred vigorously for 10 minuteso The mixture is extracted with ethyl The organic layer is washed with saturated aqueous sodium water until the washings are dried over anhydrous sodium sulphate and stripped in vacuo0 Trituration of the resulting gum with hexane gives le29 of yellow coloured 6o02 19 6028 220 322 acetate s To a solution of form acetate in tetrahydrofuran under nitrogen at room temperature is added a solution of lithium aluminum hydride go in tetrahydrofuran o The mixture is stirred for 20 minutes at room temperature and poured into Dilution with washing the organic layer with saturated aqueous sodium drying over anhydrous sodium sulphate and stripping in vacuo gives a Crystallisation from affords of and 6o22 mu 18 To a solution of acetate and oxalic acid dihydrate go in methanol is added water at room After 5 minutes a precipitate begins to After minutes at room temperature the mixture is poured into saturated aqueous sodium extracted with the extract washed with dried over anhydrous sodium sulphate and stripped in vacuo0 The residue is triturated with 3 g o giving of 226 252 C 266 dl l8 Using the same conditions as for Example step the compound of this step is converted to the title o compound which had EXAMPLE 5 Following the procedure for Example is converted to the title 6 acetate and acetate is hydrolysed in a mixture of concentrated respectively for one hour with The product is filtered off directly and washed with After the crude has shows μ and This material is suspended in a mixture of acetic anhydride ethyl acetate perchloric acid and stirred for The excess acetic anhydride is destroyed by shaking with saturated sodium bicarbonate solution and the organic layer evaporated giving the title acetate is added to a mixture of acetone water sodium acetate and acetic acid The mixture is cooled to then treated with go of After hours water is added and the product extracted with The organic layer is evaporated and the product is obtained as a The procedure of step is repeated substituting for the chloro compound and the named product is EXAMPLE 7 acetate and The product of Example step is refluxed in dimethylformamide with 3 of calcium carbonate for 1 hour under The solid is filtered off and the filtrate poured into water and extracted with Evaporation of the solvent gives the title acetate in chloroform is treated with monoperphthalic acid mlo of for hours at room temperature The organic phase is washed with saturated sodium bicarbonate then and dried over sodium Evaporation of the solvent gives the title and acetate suspended in glacial acetic acid A slow stream of dry hydrogen chloride is passed through the mixture at a temperature close to the freezing point of acetic acid After the mixture is poured into ice water and extracted with benzene ether The organic layer is washed free from then dried and evaporated to give the title Treatment of this material with methanolic potassium hydroxide yields the corresponding alcohol at An alternative procedure for preparation of the title compound is to take the acetate of Example step in ethyl acetate acetic acid and reflux with chloranil for 2k hours under nitrogen0 The mixture is washed with sodium hydroxide solution then and driedo Evaporation gives 13 The procedure of this step is repeated substituting dry hydrogen bromide and hydrogen for hydrogen chlorideo There are obtained acetate and and acetate EXAMPLE 8 acetate Using the same conditions as for Example step is converted to the title compoundo Using the same conditions as Example step is converted to the producto EXAMPLE 9 13 and 19 The product of Example step is heated with dimethylformamide and calcium carbonate according to the procedure of Example step and the named compound is Using the same conditions as for Example step converted to the title acetate and Using the same conditions as for Example step acetate is converted to the title The had 283 mu Calcdo for using the conditions of the second method in Example step acetate is converted to the title The group in the compound of this Example is hydrolysed with methanolic potassium hydroxide accordin to Example 7 and the is following the procedure of Example the corresponding acetate and and acetate and are EXAMPLE 10 The procedure of Example step is substituting for the stoichiometrical amounts of the following X H H H OCOCHj CH2CH5 OH H There are obtained the following Y Y H H H OCOCHj OH OCOCHj CH2CH H EXAMPLE 11 The procedure of Example 3 repeated substituting for the 13 stoichiometrical amounts of the corresponding compounds of Example There are obtained the following R X H H H OH H By the same 13 is rearranged to 13 EXAMPLE 12 The procedure of Example 6 steps and are substituting for the stoichiometrical amounts of the following Y R X Y H H OH CH2CH3 The following compounds are R X Y CHiHiOCOCHj H Cl H Br H H H H Br CH2CH3 OH Br OCOCHj Cl Br The procedure of Example step the chloranil is substituting for the stoichiometrical amounts of the products of Example There are obtained the following R X Y C H 01 H Br H 01 H Br H 01 H Br H 01 OH 01 OH Br 01 OCOCHj Br EXAMPLE The procedure of Example step the opening of the ring with hydrogen hydrogen bromide and hydrogen is substituting for stoichiometrical amounts of the following Y X I H H OH There are obtained the following R X Y Z H CI H Br H F H CI H Br H CI CH2CH3 H F OH Br OH F OCOCHj CH EXAMPLE 15 acetate To a solution of acetate in tetrahydrofuran 20o0 under nitrogen at room temperature is added a solution of lithium hydride in tetrahydrofuran all at After 20 minutes at room ature the mixture is poured into Extraction with washing the organic layer with saturated aqueous sodium drying over anhydrous sodium sulphate and stripping in vacuo provides a Crystallisation from hexane affords of slightly yellow coloured and To a solution of oxalic acid dihydrate in methanol is added acetate Water is added and the mixture is stirred at room temperature for The mixture is poured into saturated aqueous sodium extracted with ether and the extracts washed with brine and dried over anhydrous sodium sulphateo Evaporation in vacuo yields a solid which is triturated with ether to give go of light yellow coloured a previously prepared 226 mu A mixture of acetate mgo and sodium acetate go in absolute ethanol is heated at reflux for minutes after which time a sample shows UV absorption at 287 mu and no 266 rm After cooling to room temperature the mixture is filtered through filter aid and diluted with Washing with saturated aqueous sodium sulphate and stripping in vacuo yields a Column chromatography on Qrade III Woelm neutral alumina using benzene as eluant affords of colourless product on crystallisation from 5o μ 5 has methyl singlets at and ppm and vinyl protons at 93 for 9 The compounds of this invention may also be prepared by hydrolysis of a compound of the wher in rings A and or B indicated by dotted lines is by acid to a oxo are well known in steroid chemistry and suitable starting materials can be prepared from known the gonatrienes described in British Patent Specification Preferred starting materials for the above process are in which K is an alkoxy group or in which K is an acyloxy X may be when carbonyl by a ketal The product of the above reaction predominantly has the group iut may accompanied by the l compoundo Thus starting materials for the above process where X is hydroxymethylene and is hydrogen may be prepared from described in British following The starting material is ethynylated standard method followed by of resulting by acylation and treatment with give a debromination with zinc and acetic acid to give a acetoxy compound which is subjected to Birch reduction to give a which is then hydrolysed according to the above of the The preparation of the starting material is by the following schemes Other starting materials for the hydrolysis process may be for by selective oxidation of the intermediate prior to giving a compound where X is carbonylo A starting material where K is an alkoxy group accompanied by ethylenic bonds in the 2 and and Y is hydroxyl or acyl may be prepared by the following procedures A obtained for example by oxidation including of compound is converted to the corresponding compound 1 either by treatment with potassium in in the presence of oxygen or by treatment with an acid 1 1 anhydride where R is a lower group in perchloric acid and ethyl acetate to give compound which on treatment with a peracid followed by potassium hydroxide in methanol yields the compound Compound is ketalised by standard e0g0 ethylene glycol in benzene with sulphonic acid as to give the ketal which reduced by a Birch reduction reaction Li in liquid ammonia in the presence of to give compound which is a starting material for the process to Upon hydrolysis with HC1 in compound is obtained wherein X is Y is hydroxy compound The corresponding compound where Y is acyl may be obtained by acylation of compound to give the corresponding partial hydrolysis of which gives A compound of the invention which has a bond in ring A and no unsaturation in ring B can be produced by using standard of the corresponding compound with a ethylenic The latter can be obtained for example by treatment of a under mild hydrolysis conditions as with oxalic acido 44a EXAMPLE A tablet is prepared from the following 2Q ione acetate Carboxymethylcellulose 15 Lactose powder 25 Redried corn starch 25 Magnesium powder 4 Calcium silicate powder 200 EXAMPLE A capsule for use orally in sulating the d acetate 10 Finely divided silica lubricant 5 Magnesium stearate powder 5 Powdered corn starch 113 Lactose powder insufficientOCRQuality

Claims (1)

1. CLAIMS A compound of the formula: wherein S is an alkyl group of from 2 to 6 carbon atoms; X is C=0 1 1 or C(H)OR wherein R is hydrogen or a, (lower)alkanoyl group; Y is 2 2 H, OH or OCOR wherein R is a (lower) alkyl group; and either rings A and B have the formula: wherein -C.-C-- is a divalent radical of the formulae: provided or rings A and B have formula: where W is an alkoxy group i and V !ie CH^OH or GH0o 2. A compound as claimed in Claim 1, wherein rings A and B have the ormula P» and where a 6-methyl group is present in a saturated ring B this has the a-con iguration. 3o A compound as claimed in Claim 2, wherein R is an ethyl group. . A compound as claimed in Claim 2 or Claim 3» wherein R1 is an acetyl group. 5. A compound as claimed in any one of Claims 2 to wherein R is a methyl group. 6. A compound of the formula: wherein R is an alkyl group of from 2 to 6 carbon atoms; X is C=0 or CiHjOR1 wherein R^" is hydrogen or a flower)alkanoyl group; is 2 2 Ht OH or OCOR wherein R is a (lower)alkyl group; and -Cg-C^- is a divalent radical of the formulae: A f 8. A wherein R is an alkyl group of from 2 to 6 carbon atoms; and Y is H, OH or OCOR 2 wherein R2 is a '(lower)alkyl group. 9. A compound of wherein R is an alkyl group of from 2 to 6 carbon atoms; X is C=0 or C(H)OH; and Y1 is OH or OCOR2 wherein R2 is a (lower)alkyl group. 10. A compound as claimed in any one of Claims 6, 8 or 9 wherein R is an ethyl group. 11. 13P-Ethyl-20j-hydroxy-6-methyl-l8,19-dinorpregna-it,6-dien-3-one. 12. ^-Ethyl-6-methyl-l8, lg-dinorpregna-J ,6-dien 3,20-dione ^-Ethyl-17a-hydroxy-6-methyl-l8,19-dinbrpregna-1 ,6-diene- »20-dione. Ik. The 17-acetate ester of the compound of Claim 13« 13p-Ethyl-6a-chloro=l8,19-dinorpregn- -en-3-on-20-ol, acetate« AHP-*7"6Vc fl l6." 13p~-Ethyl-6-chloro-l8,^-dinorpregna-^ ,6-dien-3-on-20-ol, acetate. 17» 13 -Ethyl-6 -chloro-l8,19-dinorpregn- -en-3r20-dion-17a-ol,. acetate, 18. 13β-Ethyl-6-chloΓO-l8,lg-dinorpregna-i ,6-dien-3,20-dion-17cc-ol, acetateo 19. 13P-Ethyl-6-chloro-17a-hydroxy-l8,19-dinorpregna- ,6-dien-3,20-dione. 20. 13P-Ethyl-20£-hydroxy-6a-methyl-l8, 19-dinbrpregn-4-en-3-one. 21. 13P-Ethyl-17a-hydroxy-6a-methyl-l8,19-dinorpregn-4-ene-3,20-dione, acetate. 22. 13 -Ethyl-17a-hydroxy-6-hy