IL21826A - Steroid ketones and their derivatives - Google Patents

Description

Steroid ketones and their derivatives This invention relates to steroid ketones having alkynyl to certain of their processes for preparing the ketones and their and pharmaceutical compositions containing The steroid ketones of the invention are those of structure R ig up less than 6 carbon is a saturated alkyl group having from 2 to 6 carbon R 2 is a group trans to R1 and having less than 6 carbon O is hydroxy1 or an ether or acyloxy is a methylene or ethylene the substituents at the tertiary carbon atoms in ring C are in the and ring A contains an ethylenic bond in the or These compounds are thus having an ethylenic bond either in the or in the The invention also includes modifications or derivatives of indicated the group X is an protected oxo group which contains an organic radical linked to ring A by sulphur or accompanied by an ethylenic bond e minatin at the osition without a second eth lenic The invention also includes modifications or derivatives of the above ketone having the structure ion of ring C are as indicated ring A an ethylenic bond in the or position and Y is hydrogen or an The terra as used broadly in this specification includes both straight or branched chain alkyl it includes a substituted alkyl group having the aliphatic character of an alkyl a group R is an alkyl preferably it is a methyl or ethyl 1 2 R preferably an or R is a halogenoalkynyl having its acetylenic linkage at the carbon nearest to the steroid ring Examples of halogenoalkynyl groups are chloroethynyl bromoethynyl fluoroethynyl and trifluoromethy ethynyl OR can be an ether which is alkyl or or an acyloxy for instance an acetyl or preferably has less than 20 carbon Particularly valuable are those compounds in which each group R is or only one group R in the molecule is an alkyl group 1 and this is a methyl those in which R is an ethyl those in which is a chloroethynyl those in which O is and athose in Y is an acetyl In the compounds of structure the group which is at the in the steroid contains an organic radical linked to ring A by sulphur or The organic hydrocarbon X can thus be an alkoxy group in which the alkyl portion is substituted or unsubstituted a methoxymethoxy or ypropyloxy alkylthio group in which the alkyl portion is substituted or unsubs an ethylthio or a tertiary amino group a dialkylamino group or an and alkylenedioxy group an ethylene dioxy or an alkylenedithio or alkyenethiooxy The unsaturation present ring A or ring B which is associated with the group X in such a way as to form an arrangement of atoms so that acid hydrolysis can covert the compound containing the arrangement to a can consist of a single ethylenic bond terminating at the that it can be in the the or the The unsaturation can also take the form of two ethylenic one of which terminates at the that it can be in the or and the other at the such ethylenic bonds can be or The compounds with one ethylenic bond are ones in which two hetero atoms are attached to the carbon at the and are exemplified by and all representing derivatives of a The compounds with two ethylenic bonds are those having only one hetero atom attached to the carbon atom at the and these are exemplified by enol enol and tertiary amino representing derivatives of the enol form of a Typical arrangements of the unsaturation and X are to be found in mixtures of ethers from s ethers of esters from mixtures of and ketals from ketals of and tertiary enaraines from Particularly important are those derivatives in which X is an alkoxy group and ring A has ethyienic bonds in the and those where X is an ethylenedioxy group and rings A and B have an ethyienic bond in either the or the those where X is an alkoxy group and rings A and B have ethyienic bonds in the or A process for preparing a steroid compound of structure above is one in which a corresponding compound of structure is alkynylated at the or position with introduction of the 2 halogenalkynyl group By alkynylation as used in this specification is meant the attachment of the halogenoalkynyl group to the or carbon atom consequent formation of a tertiary Starting materials of structure can be obtained from the pentaene compounds described in Israeli Patent by a suitable sequence of for catalytic hydrogenation to form a 1 or Birch reduction of this tetraene to give a or and selective to form a corresponding or Suitable s starting materials of structure above are also described in Israel Patent 16027 and British Patent Specification or can be obtained from the compounds there described by introducing the appropriate group at the for can be prepared by reaction with pyrrolidine under dehydrating The ethylene ketal of can be prepared from the latter by heating it in solution with ethylene glycol and and the corresponding can then be obtained by oxidation with chromic acid or under Oppenauer to give monoketal suitable as a starting material for an process of this An ethylene can be prepared by reacting with the appropriate using acid as a and oxidising the resulting under Oppenauer conditions to the ketone A ether can be converted into the corresponding compound by heating it with ethylene glycol and A can be prepared by reacting the appropriate with anhydrous alcohol and ethyl orthoformate in refluxing benzene in the presence of pyridine hydrochloride as catalyst and submi ting the product to Oppenauer A can be obtained by the selective acylation of a The alkynylation process can be carried out using as alkynylating reagent a suitable organornetallic compound containing the 2 alkynyl group which it is desired to The compound can be a Grignard reagent example trifluoropropynyl magnesium or an alkali metal acetylide for example a lithium halogenoalkynylation ca be carried out by the action of lithium chloroacetyiide0 The alkyjation reaction is carried out at reaction temperature i suitable inert example ether or process of the invention preparing steroid ketone of structure above is one in which there is hydrolysed corresponding derivative of structure The hydrolysis ca be carried out by bringing the starting material into contact with and water at a suitable Where the starting material contains an ethylenic bond in the ketones of the invention can be obtained under conditions of mild as with aqueous alcoholic oxalic acid at and belo under more vigorous acid as aqueous hydrochloric at isomerisation to the ketones is and the product recovered is the conjugated one0 Where the starting material does not contain an ethylenic bond in the hydrolysis proceeds with formation of the ketone with conjugated some example where X is an acyloxy th hydrolysis reactio can be carried out by use of a for instance sodium aqueous In many instances hydrolysis with water is and all that is required is a hydroxylie for example an alcohol or carboxylic Steroid ketones of the inventio having an ethylenic bond the ca also be obtained by the isomerisation of the corresponding compounds with an ethylenic bond at the This isomerisation can be carried basic as or with sodium alkoxide in an alcohol at 60 Vigorous acid such as heating in methanol with concentrated hydrochloric can also be The process proceeds with the appearance on the hydrogen atom at the to that at the In a further a steroid of structure where is a hydroxy group is etherified at the or for instance by reaction with to give a hydropyranyl A of structure where is an acyloxy can be obtained by the acylation of a of structure where is and the acylate group can then be preferentially hydrolysed ive a of structure O is an In yet a further process of the invention a steroid alcohol of structure where Y is is prepared by the reduction of the corresponding steroid ketone of structure using a suitable reducing for example sodium borohydride or lithium aluminium butoxide The product of this reduction can then be acylated at the to give a compound structure where Y is an acyl for example an acetyl using suitable methods for esterification of a secondary carbinol conditions for of compounds containing a tertiary carbinol group should be used in order to avoid dehydration of the or In the above structures to the and compounds not separately In the product of a total synthesis which has not included a suitable resolution stage the 13β and forms will be present in equimolecular mixture or racemate Preferably the starting material in a process of the invention is a resolved The invention the enantiomers having the group in the presence or absence of their 13 so that it includes the resolved compounds and the forms in admixture with the corresponding especially racemic The compounds of this invention are useful either as pharmaceuticals having progestational pituitary gonadotropic inhibitory or other valuable steroidal hormone or as intermediates for such It has been discovered that in general the properties of the alkyl pharmaceutical compounds are superior or different from those of the corresponding compounds having a The difference in properties between the compounds of this invention and the corresponding compounds not only a difference of but also a qualitative In general the compounds of the invention with a group are useful as intermediates for other In it has been observed that homologation with one additional carbon atom at the a generally results in retention and enhancement of the valuable properties of the corresponding 1 Compounds of the invention with or at the in general show less but are still valuable because they show a separation of activities different from that by the corresponding isolated by means of ether and purified by taking it up in benzene and chromatographing the resulting solution on an activated Elution with benzene containing a small proportion of ether and isolation of the product followed by recrystallisation from a mixture of ethyl acetate and hexane gave C EXAMPLE 9 suspended in methanol containing 5 dioxan 1 5 water and concentrated hydrochloric acid and the mixture stirred under nitrogen for 45 The resulting clear solution was poured into brine and the product isolated by means of recrystallisation a mixture of ethyl acetate and hexane gave 240 221 5 1 requires EXAMPLE 10 was added to 2 containing benzene and acid monohydrate and the mixture heated to boiling point and maintained at that temperature until solution was complete The solution was then allowed to cool to room temperature and kept for 16 a er which it was diluted with ether saturated aqueous sodium followed by water and then by brine Evaporation of the dried solution and crystallisation the residue from hexane gave requires EXAMPLE 7 acetic anhydride acetyl chloride and pyridine were heated under reflux for 2 The remaining acylating agent and solvent were evaporated under reduced pressure and the residue partitioned between water and a mixture of benzene and the organic phase was dried and evaporated to give crude crystalline A sample trituration with cold filtration and washing with had 236 EXAMPLE 12 To dissolved in methanol and tetrahydrofuran under nitrogen and cooled to was added a solution of methanolic caustic potash and the mixture stirred at 1 The solution was then poured into the tetrahydrof was added lithium aluminium hydride After standing overnight at room temperature water was added and the suspended solids filtered Evaporation of the filtrate gave o as a gum EXAMPLE n ta oylox o e dissolved in methanol and an excess of sodium borohydride addedo After stirring at room temperature for two aqueous acetic acid was the mixture poured into brine and the product isolated ether as epta o loxygo EXAMPLE 25 To a clear solution of o pyridine was added succinic anhydride The pharmaceutical preparations the invention are ones comprising a compound of the invention of structure or i association with a pharmaceutically acceptable carrier0 Accordingly such a preparation is prepared by a process in which a pharmaceutical compound of the invention is mixed or otherwise brought into association with a pharmaceutically acceptable The p harmaceutically acceptable carrier can either solid or Solid form preparations include dispersible cachets and A solid carrier can be one or more substances which may also act as flavourin suspending or agentss it also be an encapsulating In powders the carrier is a finely divided solid which is in admixture with the finely divided the tablets the compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape size desiredo The powders and tablets preferably contain from 10 to of the active ingrediento Suitable solid carriers are magnesium magnesium tragacanthj methyl sodium carboxymethyl a melting The is include the formulation the with a in which the compound without is surrounded by which is thus in association with are cachets and capsules can be used for Liquid form preparations include and dissolved in aqueous propylene glycol solutions for parenteral They can also be formulated in solution in aqueous solutions of polyethylene glycol of molecular weight Aqueous suspensions suitable for oral use can be made by dispersing the finely divided compound in water with sodium carboxymethyl cellulose as agents suspensions can be prepared by dispersing compound in arachis Preferably the pharmaceutical preparation is in unit dosage In the preparation is unit doses containing appropriate quantities of compounds dosage form can be a packaged the containing discree quantities example packeted powders or vials or ampouleso unit dosage form can be a cachet or tablet itselfs or be the appropriate number of any of these in packaged The quantit of compound in a unit dose preparation may be varied or adjusted to within the range of to 25 according particular application and the potency the active ingredient The invention is further illustrated by the following Examples describing pharmaceutical 25 A pharmaceutical tablet for use as an oral progestational agent consists of the following This is prepared by mixing the powder ingredients in the correct proportions and filling into hard gelatine capsules such that each capsule contains 2 mgo of active ingrediento insufficientOCRQuality

Claims (1)

1. WHAT I CLAIM A steroid ketone of structure is wh of less than 6 carbon R is a saturated group having from 2 to 6 carbon R is a ynyl group trans to and having less than 6 carbon O or an ether or acyloxy Q is a methylene or ethylene the substituents at the tertiary carbon atoms in ring C are in the trans and ring A contains an ethylenic bond in the or steroid ketone derivative of structure where ring G are as indicated in Claim the group X is an hydrolysable protected group which contains an organic radical linked to ring A by sulphur or accompanied by an ethylenic bond terminating at the with or without a second ethylenic bond terminating at the A steroid ketone derivative of structure C is as indicated in Claim Y is hydrogen or an group and ring A contains an ethylenic bond in or A steroid according to any preceding claim having a in the presence or absence of its A steroid according to any preceding claim where each group R is A steroid according to any preceding claim in which is an ethyl A steroid according to any preceding claim in R 1 is an A steroid according to any preceding where Q is a methylene A steroid according to any one of Claims 1 to where Q is ethylene A steroid according any where R is a chloroethynyl A steroid according to any preceding where is h drox A steroid according to any one of Claims 1 to is a tetrahydropyranyloxy A steroid according to any one of Claims 2 and to 12 and having the structure where X is an alkoxy group and ring A contains ethylenic bonds at the and A steroid according to any one of Claims 2 and to 12 and having the structure X is an acyloxy group and ethylenic bonds are present in the d A steroid according to any one of Claims 1 and to having the structure where ring A contains a ethylenic A steroid according to any one of Claims 1 and to having the structure where ring A contains a ethylenic 17a 3 17 n 17 o n l7 17 17a The or steroid substantially as described in any one of Examples 1 to 10 and The steroid substantially as described in any one of Examples 13 16 to 18 and 20 to A process for preparing a steroid ketone derivative according to any one of Claims 11 13 33t 39 and kO and having the structure as defined in Claim 2 where OR is in a corresponding steroid of structure where X is as defined in Claim 2 is alkynylated at the or with introduction of the 2 alkynyl group A process according to Claim in alkynylation is effected with lithium A process for preparing a steroid ketone according to any one of Claims 1 to 11 16 17 18 20 31 32 and 33 and having the structure in which there is hydrolysed a corresponding derivative of structure as defr in Claim A process according to Claim k in which the product is the rocess accordin t Claim k A process for preparing a steroid ketone according to any one of to 15 and lo and having the structure where is an ether in which the corresponding compound of structure where is hydroxyl is A process according to Claim in which etherification with is A process for perparirig a steroid ketone according to Claim where is an acyloxy in which a corresponding compound where is hydroxyl is to give a of structure as defined in Claim where is an acyl and the acylate group is then preferentially A process for preparing a steroid ketone derivative according to any one of Claims 3 19 and and having the structure in which the corresponding steroid ketone of structure is reduced at the carbonyl and if required then A process according to Claim which the acylating agent used is an acetylating A process for preparing compound of the formula II or III as defined in Claim 2 or substantially as described in any one of Examples 1 to and for preparing a steroid compound the formula II or III as defined in Claims 2 or substantially as described in any one of Examples 11 to 16 to 18 and 20 to A pharmaceutical preparation comprising a steroid according to any one of Claims to to or 53 having the structure or in is association with a pharmaceutically acceptable A pharmaceutical preparation as claimed in Claim substantially as described in 25 or Example For the insufficientOCRQuality