IL27745A - Ethers of 17beta-hydroxy-gona-4,9,11-trienes - Google Patents

Description

ETHERS of The present invention is concerned with new unsaturated steroid as well as processes for the preparation of these The invention is more particularly concerned with the of the general formula in which A represents an oxygen atom or an B represents an radical having 1 to 2 carbon C represents lower alkyl optionally by a lower lower alkylthio lower cycloalkyl alkoxy or carboxy alkenyl optionally stituted by a phenyl loner benzyl monocyclic saturated or unsaturated hydrocarbon group optionally lifaked to the oxygen atom through a lower alkyl represents a hydrogen atom where there be an oxygen B a methyl C the pyranyl and D a hydrogen The compounds of the general formula I have interesting physiological they considerable androgenic Thus the compounds for which the D represents hydropen or a ethyl or propyl radical are active on the metabolism of In a general the great advantage of the of the formula I resides in the fact that they are active orally because of are preferably used The preparation process for the trienes of general formula also an objective of the present are carried out by classical and good results are obtained by using particular processes of etherification adapted to obtention of specified categories of These specific processes of etherification are of course to be included in the object of the present The processes of preparation of the trienes of the general I are characterized by the fact that etherification is effected in a known manner either by the action of a corresponding chloromethyl ether on a in the presence or in the absence of a basic or by the action of a halogenated derivative of a hydrocarbon chosen from the group constituted by lower alkyl optionally substituted by a lower lower lower or carboxy alkenyl optionally substituted by a phenyl lower monocyclic saturated or unsaturated hydrocarbon group which latter may have a further lower alkyl group through which the group ie linked to the oxygen atom or n on the derivative of a or divalent metal of a if the formed to acid hydrolysis to obtain the ketonic or by the action of a mixture of dimethyl sulfoxide and an aliphatic anhydride on a to obtain a methylthiomethyl or by the action of a dialkyl ketal of a cyclo on a or by the action of a dihydropyran on a to obtain a The following examples characterize the invention without in any way limiting EXAMPLE I Preparation of Preparation dimethylformamide in the presence of lithium At room temperature and under an atmosphere nitrogen gm of were dissolved in 12 cc of cc of then gm of lithium carbonate were added and the mixture was agitated at room After about one two hours and three an addition of cc of methoxychloromethane and of gm of lithium carbonate was One hour after the last introduction of the that is to at the end of four hours of the reaction mixture was poured into an aqueous saturated solution of sodium The aqueous phase was extracted with methylene chloride and the extracts were The organic solution obtained was washed with dried over sodium sulfate and concentrated to dryness under reduced The residue was purified by chromatography through silica then by crystallization from and gm of 9 11 1 were r having a melting point of On the basis of a sample of this fied by from with a melting point of the following determinations were that first by then by recrystallization from of were The product had a melting point of Identical to that obtained in the first Preparation by action of the dimethylzinc in dimethyl ormamide While maintaining the internal temperature at to gm of in 30 of dimethylformamide were treated first with cc of a M dimethylzinc solution in then with 2 cc of The mixture was then allowed to stand for two hours at room 1 cc of methoxychloromethane was added to the tion which was allowed to stand first for six hours at room then 48 hours at about the reaction mixture was poured into water and extracted with methylene The organic phases were dried over sodium sulfate and tilled to In this gm of a raw product were which was then purified by tography through silica gel and by recrystallization from the was The product had a melting point of identical to the products obtained according to the preparations A and 5 EXAMPLE 4 Preparation of ll and n Preparation of estratriene Under an atmosphere of first m of the preparation of which is described then gm of a pension of sodium hydride in vaseline oil of were introduced into 17 co of The solution was agitated for 30 minutes at gm of allyl bromide were added and the reaction mixture was agitated for 20 hours at a temperature of the reaction mixture was cooled and into a saturated aqueous solution of sodium The aqueous phase was extracted with methylene chloride and the extracts were The organic solution obtained was washed with dried over sodium sulfate and concentrated to dryness under reduced The sultant residue was subjected to chromatography through silica gel and then crystallized from ethanol containing of thus obtaining gm of 4911 The product had a melting point of Example triene Stage At A quantity of of are dissolved in ml of and there ore added of a suspension of sodium hydride in oil the reaction mixture is heated to during 1 and 3 ml bromide are added and the reaction mixture stirred at during 16 hours cooled to ambient 10 ml water are added and the reaction mixture is into It is the phase washed with tilth an aqueous sodium chloride dried over magnesium sulfate and to dryness under reduced is obtained of crude which is used for This compound not described in the Stage g of the rlene are dissolved 100 ml methanol containing mg of citric acid are added and the stirred during 1 hour in an inert atmosphere and at ambient The reaction mixture is oured into estraoted under reduced The residue subjected to on silica and a of ben acetate and recrysta Hissed from obtained 100 of yellowish soluble in and in methylene Analysis calculated Found Spec tr am around This ootapound has cot been described the 6 Preparation of and gm of were introduced into cc of anhydrous Then at a temperature maintained below and within the space of about 30 cc of a solution of dimethylz nc in dimethylformamide were In cc of a M solution of dimethylzinc in diraethylformamide were Introduced into gm of bromoacetic and the solution was brought ί i up to a volume of 75 cc with This j thus prepared for immediate use was Introduced into reaction mixture over a period of about Next the reaction solution was agitated for 15 hours at a perature of about under an atmosphere of it was cooled to room then poured into a dilute aqueous solution of hydrochloric acid taining The aqueous phase was extracted with The methylene chloride extracts were j washed first with a saturated aqueous solution of sodium then with dried and concentrated to dryness under reduced The residue obtained sisted principally of The alkaline aqueous phases were combined and then After the whole was tracted with isopropyl The ethereal extracts were The organic solution obtained was washed with dried and then concentrated to dryness under reduced The residue was purified by chromatography through silica then recrystallized from In this one was having a melting point of with 20 a speclfio rotation in molecular weight C H Ultraviolet spectra at 238 mu inflection toward 270 mu at This product is not described in the j Preparation of gm of pyridine hydrochloride were ij into 60 cc of toluene and several cc of solvent were 9 11 jj gm of Δ then cc of the dimethyl ketal of cyclohexanone were jj added to the About 10 cc of solvent were ii within about 20 then 1 cc of the dimethyl ketal of jj cyclohexanone and gm of pyridine hydrochloride were The solvent was distilled at the rate of about 30 cc ij per jj After 30 15 cc of cc of the dimethyl ketal of cyclohexanone and gm of pyridine jj hydrochloride were and the distillation was continued for 15 minutes 35 cc of solvent were distilled therefrom over The solution thus obtained was admixed with cc of and then poured j into a saturated aqueous solution of sodium Ίjj The organic phase was separated by The aqueous phase was extracted with benzene and extracts were combined with the organic The organic solution obtained was washed first with then with salt dried and concentrated to dryness under reduced Jj The residue was purified by chromatography through silica The adsorption and elution were effected in the of In this gm of 1 7 one were jj Ultraviolet spectra at EXAMPLE 13 Preparation of Preparation of Over a period of one at a temperature of gm of ol and of 50 sodium hydride in vaseline oil were heated in of Then cc of benzyl bromide were added and the mixture was held at reflux for three the reaction mixture was returned to the temperature of and poured into a the reaction mixture was extracted with methylene The methylene chloride phases were washed with water and dried over of triethylamlne were added to the organic phase which was evaporated to The residue obtained was taken up in 5 cc of petroleum The solution was evaporated to and gm of raw product were which was purified by chromatography and recrystallization from gm of were The product occurred in the form of beige colored soluble in alcohol and and insoluble in It had a melting point of Analysis molecular weight C H Ultraviolet spectra at E 1 cm 175 inflection toward mu 100 1 cm inflection toward 260 E 100 1 cm inflection toward 284 mu E 1 cm at E 805 1 cm This compound is not described in the EXAMPLE l4 Preparation of A 4 Q 11 of Δ were suspended in 28 cc of dihydropyrane containing of phoric The solution obtained was agitated for two hours at room then cc of ether were added The ethereal phase was washed first with a saturated aqueous solution of sodium then with dried over magnesium and ated to dryness under gm of raw product were which was purified by successive tion from isopropyl ether containing one part per thousand of gm of were having a melting point of and a specific rotation molecular weight 7 C H Infrared spectra presence of at presence of at 657 to presence of at to Ultraviolet spectra inflection toward 97 at 341 E 819 1 cm were poured this which was then agitated for two hours at room again cc of were added After three hours of agitation at room the reaction mixture was poured into 200 cc of distilled water and 200 cc of a saturated aqueous solution of sodium The suspension was extracted four times with through a column of magnesium silicate and cluted with The useful dosology controlled between 8 and 400 per day in the animal or between and 25 per day for the adult according to the product utilized and as a function of the method of administration and therapeutic The pharmaceutical forms such as drinkable or injectable solutions or solutions for the transcutaneous coated sublingual and are prepared according to the usual processes or as indicated in the preceding The preceding specific embodiments are tive of the It is to be that other expedients known to those skilled in the art may be departing from the spirit of the j or the scope of the appended insufficientOCRQuality

Claims (1)

1. WHAT IS CLAIMED IS The of the general formula B in which A represents an oxygen atom or an ethylenedioxy B represents an alkyl radical having 1 to 2 carbon C represents lower alkyl optionally substituted by a lower lower lower cycloalkylalkoxy or optionally substituted by a phenyl lower monocyclic saturated or unsaturated hydrocarbon group optionally linked to the oxygen atom through a lower alkyl D represents a hydrogen there cannot be A an oxygen B a methyl radical and C a and D a hydrogen The of the general in which R re re e The of the general in which represents lower alkyl optionally substituted by a lower lower lower cycloalkylalkoxy or carboxy optionally substituted by a phenyl lower alkynyl cyclic saturated or unsaturated hydrocarbon 9 9 l 9 3 9 9 9 9 9 Processes for the preparation of compounds according to Claim 1 characterized by the fact than an etheri ication is carried out in a known ther by the action of a corresponding chloromethyl ether on 17 in the presence or in the absence of a basic or by the action of a halogenated derivative of a lower alkyl optionally substituted by a lower lower lower cycloalkyl alkoxy or carboxy alkenyl optionally substituted by a phenyl lower benzyl saturated or unsaturated hydrocarbon group optionally linked to the oxygen atom through a lower alkyl tetrahydropyranyl on the alcoholate derived from a or divalent metal and from a and if subjecting the 17 ether formed to an acid hydrolysis to obtain the corresponding or by the action of a mixture of the dimethyl sulfoxide and an aliphatic anhydride on a to obtain a methylthiomethyl or by the action of a dialkyl ketal of a cycloalkanone on a or by the action of dihydropyran on a to obtain The therapeutic compositions comprising at least one compound of general formula according to Claim 1 and a harmaceutical insufficientOCRQuality