IL28465A - 6-halo-21-fluoro-1alpha,2alpha-methylene-17alpha-hydroxy-pregna-4,6-diene-3,20-dione 17 esters - Google Patents

Description

Invention new and their facture The present provides piregnadienes of the general formula chlorine atom ysiologically The present invention also provides a process for the of the compounds as comprises either esterifying the corresponding 9 or treating the appropriate ester of with of the formula in which X has the meaning given ting water from the resulting ound by means of a strong preferably hydrochloric the ring has this ring by means of an organic base or of aluminium The acids from which the residues represented b R derived are preferably those oontainin up to 15 carbon especially the lower and medium cular weight aliphatic earboxylic Furthermore the acids also be polybasio or substituted in the for by droxyl or amino groups or halogen Also suitable are cycle mixed or which may be substituted in suitable Further possible are the usual acids such for phosphoric according to method may be carried by known Special mention should be o with acid anhydrides the presence of an the action with desired acid presence of fluoracetic The reaction of the acid of formul accordin place a which is know per Dependin on the meaning of the in final is reacte with hydrochloric or hydrofluoric acid the presence of at a high or low reaction preferably a temperature within range from abou and especially a room As inert may be for carboxylic acids such as acetic hydrocarbons such as carbons such as methylene chloride o as dloxan also especially suitable a solvent for opening of the by means of s initially are with a strong for example hydrochloric a in acetic in order to eliminate water and thereby form the In the where a is introduced the epoxide and the elimination of water by means of hydrochloric according to place in During the reaction with hydrochloric acid acid may also be added to the whereupon the corres onding compound In order to the cyclopropane ring primary product so is subsequently treated with an organic fo o The of the cyclopropane ferably takes place at the boiling point of the The desired ring closure to give the 192 methylene compound also be by filtration of the solved organic through aluminium rendering the use of temperatures The new esters of the present invention a sur strong especially afte oral Table 1 shows the iori of the new com ounds takin as an is the hitherto structurally ver similar ver A gestagenic effect b the Clauberg It a advantage of the new esters that they show prac icall no effect which is a very interfering of very many effec tested on male castrated rats weighing 100 Beginning on week after the test substance was istered in graduated doses durin course of 7 Durin the of animals received mg of testosterone propionate They were killed on the eight day and the weights of the seminal vesicles and prostates were The value determined as the daily dose which the organ weight by testosterone alon to one TABLE 1 Substance Gestagenic Effec Threshold value Effect Seminal vesicle Prostate I i 3 mg mg The main field of application of the active stances of present invention is in the treatmen of the following gynaecological primary amenorrhoea and secondary amenorrhoea of prolonged disturbances wit inadequate yellow body endomsstriosis uterus complaints and dose administered corresponds to the severity of the case of the In general between 5 and 100 mg of active substance should be administered the presen invention further vides pharmaceutical preparations which comprise new esters in admixture or with a ceutically suitable The preparations are prepared in the usual by combining the active substances with suitable exclpients and flavou capsules and solutions particularly for oral Example 9 to 11 below describe preferred ceutical preparations containing the new The manufacture of starting materials used in Examples 1 to 8 which are included within the present is described in the following The new can manufactured in g according to German Patent Specification 1 g of were dissolved in 250 ml of absolute tetrahydrofuran and 250 ml of 37 g of calcium oxide were added and of an iodine prepared of 100 of absolute tetrahydrofuran and 100 ml of absolute methanol was added dropwise while 30 the remaining of the iodine solution were added and g of calcium oxide were twice added at 30 minute a total time of hours the oaloium oxide was separated o and thoroughly washed with methylene The was wit sodium tion and dried over sodium sulphate and ted to dryness in The crude 46 obtained was dissolved in 500 ml mixed with 143 ml of triethylamine and 93 ml glacial acetic acid and for 2 hours under then kept for 2 hours at room Thereafter the mixture was into ice water and resultin ate was filtered taken methylene chloride and over sodium The residue mained after evaporation to dryness was silica gel and g of obtained in the form of an This was dissolved in 150 ml of mixed at 0 with a solu of chloride with water and drie over sodium residue remained after tion dryness was from ethyl g tate g of meltin poin to were 17 g of the so obtained in 100 ml of absolute puridine mixed with a solution o ml of sulphonyl chloride in 10 ml of while stirring and cooling ice and stirred for a further 3 excess acid chloride wit ice The solution was diluted with ed with dilute hydrochloric acid and water and dried over sodium After evaporating to dryness and triturating vith dllsopropyl ether g of 3 of melting point 173 to were This was for 18 hours at with g of potassium ge fluoride in ml of The mixture was stirred into ice water extracted methylene chloride washed with dried sodium sulphate d evaporated to dryness which remained is chromatographed on silica gel and g of ing poin to were The whic hitherto not been described in the relevant literature can tured the foilowin tetrahydrofuran ml o absolute 55 g of calcium oxide were added and of an iodine solutio prepared from 46 g of 150 ml of absolute fura and 150 ml of absolute methanol was ed dropwise while After 30 minutes the remaining of the sol were added and g of oxide wer twic 30 minute After a reaction of 4 hours the calcium oxide separated thoroughly organic phase was with ha e solution and wate dried over sulphate and to dryness in resulting crude was dissolved in 750 ml of acetone mixed with 215 m of triethylamlne and 140 ml of acetic heated 2 hours under and was then kept at room temperature for 2 The mixture was then stirred into ice water and the precipitate formed taken up in chloride dried sodium residue remaining evaporatio dryness chromatographed on were obtained In the form an was dissolved in 225 ml of methylene chloride and 225 of mixed at with solution of of potassium hydroxide in 90 ml of methanol and stirred for 80 After neutralisation glacial acetic the mixture was diluted with methylene washed with water and dried sodium 4 6 g of the so were in 150 of absolute while stirring and cooling in with a solution of 6 ml of sulphonyl chloride in ml and stirred for a further The excess acLd chloride then decomposed by means of ice The was diluted with washed with hydrochloric acid and water and dried over sodium After evaporating to g o 1 mesylate were This was stirred for 18 hours at with 1 of potassium hydrogen luoride ml of The mixture stirred into ice extracted sodium sulphate and to dryness in vacuo The residue which was chromatographed on gel and g of 4 of melting point 251 20 This compound was subsequently rifled in the by known g of 9 t in 250 ml of dioxan were with g of 50 ml of wate and 5 ml of strength perchloric acid while After a reaction tim of minutes at room temperature the reactio solutio was mixed with water containing sodium sulphite the resulting precipitate was filtered off wit water The so obtained was dissolved in 40 ml of methanol mixed with a solution of g of potassium carbonate in 4 ml wate and heated 1 hour under reaction solutio was then neutralised acid and extensively vacuo precipitatin with ice resulting precipitate was o Δ dissolved in 60 ml of ethylene chloride while a of 12 g of acid in 35 ml of The reaction mixture was allowed to for 5 days at room was then diluted with methylene and the phase i washed with ferrous sulphate solution in a little sulphuric dilute sodium ate and After drying and evaporatin in about 9 of 3 were The following Examples illustrate the Exam ί t at e 700 of were stirred for 17 hours at room temperature wit 350 mg of acid in 14 ml of acetic The ture was the stirred into ice and the resulting precipitate was taken up in methylene chloride and washed with dilute hydrochloric sodium bicarbonate solution and After drying over sulphate and to the product was crystallised from ethyl acetate and mg of of melting point 193 to were 2 2r 100 mg of were stirred for days at with 50 mg of aoid in 1 of propionic aoid After subsequen distillation and extraction with organic phase was dried over sodium sulphate and orated to The residue was reqrystallised sopropyl ethe 81 of propionate of melting point 170 were 100 m of were for 3 days at with 50 mg of i 1 ml of butyric acid After in 2 recrystallisation from Example 4 for 4 da s at with 50 of acid 1 ml of caproic acid anhydride After as cribed in was i the form of an 17 Example 5 acetic The solution was saturated wit hydrogen chloride gas at temperature and allowed to stand for 16 hours room It was then cipitated with ice water and the precipitate was filtered off and taken up in methylene chloride The organic phase was washed with sodium bicarbonate tion and water until neutral and evaporated to in vacuo The crude A acetate so obtained was taken up in 20 of collidine and was heated at the boiling point under nitrogen for minutes After diluting with ether the tion was washed and was dried over sodium sulphate to dryness vacuo The residue was chromatographed on silica Using 289 mg of tate was obtained after retfrystallisation from Example 6 300 tag of point 240 was dissolved in 15 ml of glacial acetic The solution was saturated with hydrogen chloride gas and was allowed to stand for 20 hours room It was the precipitated with ice precipitate was filtered off and dissolved in methylen chloride and the solution was with sodium hie onate solution and dried over sodium sulphate and the solvents evaporated in vacuo The crude 4 so was i 10 ml of and stirred for 24 hours under nitrogen with g o aluminium oxide of II activity aluminium oxide was then filtered off and washed with the filtrate was evaporated vacuo the crude was of 173 mg of 100 m of p r at unde the ditions specified in Exampl Example 8 100 mg of ted into under the described in Example 57 Example 9 Gelatine capsules of 5 Composition of 1 capsule 5 of 7 micronised ally 200 mg of DAB substance was filled into hard gelatine fit capsules in the usual 10 15 mg Composition of mg of micronised particle j occasionally 16 mg of lactose USP XVI rag of corn starch USP XVI mg of talc DAB USP mg of white DAD 6 of sodium lauryl sulphate USP XVI mg of methyl DAB USP mg of propyl DAB USP insufficientOCRQuality

Claims (1)

1. The tablets were manufactured on a tablet press in the usual l mm a braking notch thickness mm approximately 4 kg Stokes hardness disintegration in water at approximately 30 Example 11 Preparations for application 1 ml 2 of active substance 1 ml 30 35 Composition for 100 ml 200 rag of 9 20 ml of 25 ml of propylene glycol ad 100 ml of water doubly particularly desorlbed and ascertained the nature of our said invention in what manner the same to be performed we declare that what we claim is A of the general formula which X a om and R represents residue of a physiologically able 4 6 A process for the manufacture of a of the general formula t in represents fluorine or chlorine atom residue of which comprises esterifying the corresponding treating the appropriate ester of a ft dione with an acid of the formula in which X has the given eliminating water from the resulting compound by means of strong if the ring has been by means of organic base or of aluminium A process as in Claim wherei the eliminatio water is carried out with hydrochloric A process as claimed in Claim wherein the treatmen of the and the elimination of water is carried in step with hydrochloric acid in acetic A process as claimed in Claim and as in any one of Examples 1 to Θ A pharmaceutical preparation which comprises a compound of the general formula in which X chlorine atom and represents the of a physiologically in admixture or conjunction a ceutically suitable A preparation claimed Claim which is in a form suitable oral A pharmaceutical preparation having a position substantially as described in arar one insufficientOCRQuality