IL35432A - Esters and ethers of 6,16-dimethyl-3-hydroxy-4-pregnen-20-ones and process for their preparation - Google Patents

Description

vt8 4 3 Esters and Ethers of And Process For Their Preparation invention is concerned certain novel and with processes for their We have found that of formula acid of 1 to 7 carbon possibly substituted by or is the radical of the monoethyl ester of carbonic an alkoxy group of 1 to carbon atoms or a cycloalkoxy group of 5 or 6 carbon atoms and which may have an additional double bond in the valuable pharmacological In these compounds have and As a the ovulation inhibiting and fertility aotivitiee of the compounds of the invention are more pronounced than the same activities of the corresponding which are described already in the Israeli Patent For a compound of this exhibits a progestional activity which after oral administration is twice as high as that of mentioned in said Israeli patent the activity of the above mentioned is about per higher as that of said comparison And by the activity of there is caused a significant reduction of the pregnancies in treated Wistar rats with a dose of 1 whereas by there is produced any reduction of the number of Similar results were obtained with when it was compared with The compounds of formula I may therefore be used as drugs or as intermediate products for the preparation of other For the saponi ication of gives the strongly The compounds of formula I are novel and constitute aspect of the present The present invention also a composition comprising at least one compound of formula I and an physiiLogieally The present invention further comprises a process for the preparation of a compound of formula which comprises eaterifying or etherifying a of formula which bond be present in th or a derivative of such a which is reaotively in the by reaction with an esterifying or agent of the formula in which BO has the or with a reactive derivative of a compound of In a further process according to the a steroid which otherwise corresponds to formula I but has a functionally modified group is treated solvolytlcally to liberate the grou In formulae I sinuous lines in the and positions mean that the substituents may be in the or at these Among the compounds of formulae I and their those with a group are The esterlfied etherifled hydroxy group in the preferably has the When RO represents an esterlfied hydroxy the acid radicals are preferably derived from saturated aliphatic substituted or carboxylic acids in each a total of particularly 1 to 7 carbon suhh as formic acetic propionic butyric the valerianic such as acid or trlmethylace the caproic such as tertiary butylacetic acid or diethylaeetic oenanthlc halocarboxylie such as chloroacetlc acid and acid or the ester of the carbonic Esters containing a group imparting water such as a carboxy are particularly because they may be used for the preparation of aqueous These esters are derived from dicarboxylic acids for example As ty ester salts of the acid for example the of dibasic carboxylic there should be in alkali metal especially the sodium the ammonium salts and the and O may also represent an OH preferably alkoxy containing 1 to carbon such as secondary butoxy or tertiary butoxy or containing 6 carbon such as or In the esterifying or etherifying agents of formula a reactive derivative of such a accordingly represents an acid radical or an ether preferably the radical of a carboxylic acid or an The reaction of the compounds of formula II and or their reactive can be earried out by methods described in the literature in at temperatures between and The reaction times are between one minute and about The of formula II and their preparation are also described in the Their reactively esterified derivatives may be for by the methods indicated Esterifieation of the free hydroxy group in compounds of formula II can be effected by methods described in the As esterifying agents there may be for the mentioned acids that may be described by the formula formula and their bromides of the formula and their anhydrides of the formula Thus the of formula may be with the acids in question with or without the addition of such as sulphuric hydrochloric phosphoric aromatic sulphonic such as 10 to the boiling temperature of the acid in which is usually used in To influence the esterification equilibrium the reaction may be carried out in the presence of for example molecular sieves or anhydrous such as the sulphates of cobalt or The water formed on esterification may also be removed by azeotropic in which case such as benzene or or chlorinated such as chloroform or are advantageously added as solventSo Esterification reactions proceed under very mild conditions if the water of reaction is bound chemically by the addition of preferably in molar such as in inert such as benzene or ethylglycoldimethyl particularly in the presence of bases such as It is also possible similarly to the methods described in the literature to react the hydroxysteroids of formula II or their alkali metal the halides or anhydrides of the acids to be esterified with or without the addition of for example sodium potassium sodium potassium or an organic base such as collidine or triethylamine Suitable solvents for such reactions are inert organic such as tetrahydrofuran or Excess halide or anhydride or an excess of the base may also be used as the The esterification is advantageously carried out at a of from 0 to in from half an hour to Formic acid esters are obtained with acetic acid In a preferred procedure the hydroxysteroid of formula II is added to the halide or anhydride of the acid in a pyridine Esters of formula I are also obtained by treating hydroxysteroids of formula II with alkyl preferably lower alkyl of carboxylic acids according to the transesterification methods described in the The reaction is preferably carried out in the presence of basic such as sodium sodium ethylate or potassium tertiary when equilibrium is one reactant is preferably withdrawn from the equilibrium mixture by distillation0 For can be converted into with butyric acid methyl ester with removal of the methanol by Hydroxysteroids of formula II can also be esterified with keteneso It is preferable to carry out the reaction n an inert such as benzene or and with the addition of an acid such as sulphuric acid or for the corresponding acetate be prepared from 6 and Esters of formula I can also be formed by subjecting such as diazoacetone to transposition with separation of nitrogen in the presence of hydroxysteroids of formula II and in the presence of basic such as pyridine or Suitable reaction conditions for this method are described in the the corresponding is obtained from and The of of formula XI is preferably effected with alcohols of the formula and their reactive Such alcohols for eyclopentanol and cyclohexanol preferably methanol and Suitable reactive derivatives of these alcohols are such as their alkali metal preferably their sodium and potassium for example sodium potassium sodium ethylate and potassium and also the corresponding for example methyl for example methyl for example methyl for example dimethyl and sulphonic acid particularly the honic and honic acid such as methylmethane methylbenzene sulphonate and methyl in the present the corresponding such as diazomethane and The reaction of compounds of formulae II and the alcohol or their reactive derivatives can he effected according to methods described in the literature and depend on the nature of the starting materials For one of the two reactants may be introduced into the reaction in the form of a reactive ester or sulphonic acid and the other in the form of the free alcohol or an for example the appropriate sodium alcoholate or potassium alcoholate to pare a a or steroid that otherwise corresponds to formula preparable for from the corresponding and or or the acid ester of a steroid of formula may be reacted with methanol and catalytic quantities of an such as or wit sodium The sodium compound of a of formula II can also be reacted with methyl methyl or methyl ester of sulphonic If an of agent the such as methanol or is not used as a the reaction is generally carried out in the presence of an inert solvent suitable solvents for hydrocarbons such as benzene or or such as diethyl or diisopropyl tetrahydrofuran or The reaction is suitably carried at a temperature of from and the boiling point of the solvent The reaction time as a from 1 to According to another a of formula II reacted with a such as in the presence of a Lewie such as aluminium chloride or boron Ethers such as those mentioned above are in particular as two reactants II and can also be reacted each other the form of the free alcohols in the presence of a strong such as hydrochloric sulphuric tolueneeulphonie ecid or oxalic and an inert A particularly preferred method is to solve the hydrox steroid II in an excess of an alcohol or cycloalkyl and to leave the solution to stand for from 12 to hours at room temperature in the present of toluenesulphonic As reactive derivatives of the alcohols suitable for effecting there may be the corresponding particularly those that are formed from tertiary alcohols by for example The addition of these hydroxysteroids to the olefins advantageously effected the presence of an acid for example mineral perchloric sulphonyl chlorides or BP In many cases basic such as alkali metal aleoholatee are An excess of the olefin may be used as a solven in general such as benzene or are also A preferred reaction temperature is the boiling temperature of the solvent in The compounds of formula I are from the resulting The compounds of formula I are used in human or veterinary medicine in admixture with liquid semisolid excipientSo Suitable excipients are organic or inorganic substances that are suitable for enteral or topical application and do not react with the novel for example vegetable polyethylene magnesium petroleum jelly or preferably oily or aqueous and emulsions or are suitable for parenteral Tablets or dragees are suitable for enteral administration and creams or which may be sterilized or to which there may be added such as stabilizing or wetting or salts to influence the osmotic or buffer are suitable for topical Suitable doses of the novel compounds are from to and preferably to when the ceutical compositions are in dosage unit each dosage unit preferably contains these quantities of the active compoundso In order that the invention may be more fully the following examples are given by way of In the examples the temperatures are indicated in degrees the optical rotations were measured in chloroform unless otherwise Example 1 1 g of was left to stand overnight at room temperature with 10 ml of acetic anhydride and 10 ml of The reaction mixture was then stirred in the precipitated was filtered off and was 22 from D Instead of acetic acetyl chloride or acetyl bromide may be used and instead of triethyl or By reacting the corresponding with the corresponding acid anhydrides or the following may be obtained similarlyt 3 3 3 3 3 3 6 22 D acid athyl 22 D Example 2 g were heated to for 2 hours with 10 g succinic acid anhydride and 35 The reaction mixture was then stirred in watert acidified with hydrochloric acid and extracted with The ethereal solution was washed with dried over sodium sulphate and and the resulting 6 was recrystalllzed 22 from D The sodium salt of this compound is obtained by dissolving the hemleuccinate in ethanollc caustic soda solution and Example 3 1 g of was left to stand at room temperature for 20 hours with 100 of sulphonic acid in 100 ml of absolute The whole was poured into saturated bicarbonate solution and extracted with the ether solution was with water until dried over sodium sulphate and evaporated fco give Evaporation of the mother and chromatography of the residue on neutral aluminium oxide gave The following may be obtained similarly with the corresponding alcohols in the presence of benzenesulphonic acid or 22 D 6 thy β po 6a th dime t pre i o 6 dime t hy one obuto dime t dime dime t ho 6 dime t hy 1 re one 1 thy 6a dime dime thyl r a dimethyl t ho d t hy 1 16 Example of and g of oxalic aoid to stand at room temperature for hours ml of The reaction mixture was neutralized with water was and after suction the resulting was from Example 5 1 g of in ml of dimethyl was added slowly drop by with at to a suspension of 1 g of NaH 10 ml of dimethyl The whole was stirred for 20 of in 3 o dimethyl formamide was then added drop by and the whole was overnight at room After the usual working was Example 6 g of ate was dissolved in 10 ml of dimethyl and g of sodium methylate was added with The whole was stirred overnight at room the greater part of the solvent was water and ether wwre and was obtained from the aqueous V insufficientOCRQuality

Claims (1)

1. designates a residue of a or dibasic aliphatic acid of 1 to 7 carbon possibly substituted by or is the radical of the taonoethyl ester of carbonic acidi group of to carbon or a cycloalkoxy group of to 6 carbon atoms and which may have an additional A of any of formulae la to A process for the preparation of a of X specified in claim wfafch comprises etherifying a of formula XI n which an additional double bond If be present In the or a derivative of such a which is reaetlvely the by reaction an eeterifying or agent of formula which HO has the meaning specified in or with a reactive derivative of a oompound of formula A process for the preparation of a of formula I specified in claim which comprises subjecting a steroid which otherwise corresponds to formula I but has a functionally modified to solvolysis to liberate the A pharmaceutical composition comprising least one compound as claimed any of claims 1 to and an physio logically A pharmaceutical composition according to claim 11 in which each dosage contains from to 50 mg of A process for the preparation of a of formula I specified in claim 1 substantially as herein described any of the Attorney for Applicant insufficientOCRQuality