IL32973A - 18-methyl-17beta-hydroxy-17alpha-ethynyl-4,6-dichloro-delta 4,6-oestradien-3-one and derivatives thereof - Google Patents

Description

drox Δ and derivatives thereof The present 1s concerned new 4 6 and their manufacture and The present invention provides racemic optically active 4 6 ones of the general formula I OR in which R represents a hydrogen an alkyl or a tetrahydropyranyi group of an acyl group selected from the group consisting of benzoyl or a straight or branched chain aikanoyl group of up to 15 carbon atoms optionally substituted by carboxy or Preferred for forming the acyl residue are for acetic propionic caprolc enanthic undecyclic trimethyl acetic di cyclopentyl propionic phenyl propionic phenyl acetic dialkylamino acetic succinic benzoic acid As alkyl groups represented by there may especially be mentioned propyl and butyl The new compounds of the general formula I display a surprisingly strong progesterone The strong activity of the compounds could not have been foreseen since it has been known the literature that active steroids lose much of their activity when chlorinated in the Journal of Chemistry page and Chemistry and Industry page 548 The main sphere of application of the active compounds of the present invention is in the treatment of the following dlsturbancess Primary araenorrhoea and secondary amenorrhoea of long cyclus troubles by a corpus uterus premenstrual progressive mamma carcinoma and The dose depends on the seriousness of the individual In between 5 and 100 mg of active substance should be given Severe menstruation irregularities can be for by a treatment with daily doses of 10 mg of active With some for example dysfunctional bleeding or a conception inhibition induced by the the active compound can be administered in combination with an oetrogenlc for example the present invention also provides a pharmaceutical preparation which comprises a compound of the general formula admixture or conjunction with a maceutically suitable carrie The pharmaceutical preparations are manufactured the usual manner by making up the active compounds together with the vehicles and flavourings normally used galenic pharmacy the desired form of for or solutions The concentration of active substance n the preparations thus formulated depends on the form of for example a tablet preferably contains from to 10 mg of active substance example of such a tablet being described n Example 6 whereas a solution for parenteral admi istration from 1 to 20 mg per ml of The present Invention further provides a process for the manufacture of a racem c or an optically active of the general formula I wherein a of the general formula II in which R represents a hydrogen an or a hydeopyranyl group or an 1s reacted with a chlorinating agent capable of liberating a positively charged chloride Ion and a negatively charged chloride 1on and the resul ting trichloro product treated wi th a base if desired 1n the resulting depending on the desired final meaning of any hydroxyl group is hydrolysed or any free hydroxyl group is By a there to be understood herein at least one compound or at least one element or a mixture thereof capable of a positively charged chloride ion and a negatively charged chloride Positive and negative chlorine may be liberated during the reaction by a of suitable taining compounds Positive chlorine for by and preferably and and also by for example tertiary agents that furnish negative there may be mentioned preferably elementary chlorine may be split to yield positive and negative The process of the present process may be carried for as steroid is dissolved in acetic acid and reacted lithium chloride and the presence of a strong anhydrous for example hydrogen chloride in o tetrahydrofu By of the bond the corresponding is formed and then dehydrochlorinated with a preferably organic Simultaneously with the dehydrochlorlnation a chlorine atom migrates into the The chlorlnation and are performed under mild preferably at about room tempe The optional subsequent and hydrolysis reactions may be carried out by known For the esteriflcatlon there may be mentioned the reaction with an acid anhydride or hallde in the presence of an acidic or basic agent and the reaction the desired acid in the presence of To hydrolyse the acid treated with for example with a hydroxide alcoholate or carbonate of an alkali the presence of sol ution To manufacture ethers the y compounds be reacted with in the presence of an for example The with an group is preferably out with an hallde in the presence of a condensing for example silver The compounds of the general formula II used as starting materials in the process of the present invention may be manufactured by known for example as 4 6 4 Δ is reacted with formic acid ethyl ester the presence of concentrated sulphuric acid at room The resulting 175 brominated in the position with and the resulting 6 4 is dehydrobrominated in dimeth the presence of lithium bromide and lithium to yield melting at To introduce the chlorine atom into the the formed by treatment with chloroperbenzolc treated with hydrogen chloride in is converted the ate with methanesulphonyl chloride in When the mesylate is heated in pyridine the presence of sodium it furnishes at 203 nat h one converted ether as described under A Bromlnation y dehydrobroml produces 4 6 nat Ultraviolet 26 For Introducing the chlorine Into the the epoxlde formed by treatment with treated wi th hydrogen chloride in acetic acid and for introducing bond the resulting hydroxy compound reacted as described under section A first with methane sulphonyl chloride and then with sodium acetate to yield 4 6 melting at 214 215 which cdntalns the ultraviolet an extinction of The following Examples illustrate 1 A solution of g of rac 4 in 200 ml of acetic acid was mixed successively 7 of lithium l 4 g of and of dloxan saturated wi th hydrogen chloride gas After a reaction of 7 minutes at room temperature the reacti on product was stirred and the precipitate formed was fi ltered off wi th suction and taken up in methylene chloride The methylene chloride phase washed with sodium bicarbonate solution and water dried over sodium sulphate and evaporated to dryness under vacuum The residue was dissolved 5 ml of and kept for 16 hours at room temperature then taken up in ether with dilute hydrochloric acid and water dried and evaporated to dryness under The residue was ehromatographed on silica and then from to yield of th melting at 210 to with Example 2 4 6 was reacted and worked up as described in Example to yield Ultraviolet spectrum 18 Example 3 A so luti on of 8 h Δ in 300 ml of acetic was mixed successively with 10 g of lithium chloride g of and ml dioxan saturated hydrogen chloride gas After a reaction time of 7 minutes at room temperature the batch was up as described in Example The isolated product was dissolved 5 ml of pyridine and kept for 16 hours at room temperature then taken up in washed with dilute hydrochloric acid and with water dried and evaporated to dryness under The residue was ehromatographed on silica gel and melting at 216 to Ultraviolet spectrum Example 4 A solution of g of in 100 ml of aeetic acid mixed g lithium chloride 1 g of and ml of dloxan saturated hydrogen chloride gas After a reaction time of 7 at room temperature the batch was worked up as described Example 1 and then treated and chromatographed on silica to yield 350 mg of 4 6 hep no t Δ as an Ultraviolet Example 5 A mixture of 500 mg of 4 ml of methanol and 500 mg of was heated for 24 hours while being allowed to distil off then diluted with washed water and evaporated dryness under vacuum from ace yielded one melting at 215 to Ultraviolet Example 6 having the following compositi on were mg of hyny 2 8 some up to mg lactose mg of corn starch mg of talcum mg of white O mg of sodium laurylsulphate mg of acid methyl ester 3rd supplement stands for Deutsches 6th edition and stands fo United States 16th Example A mixture of g of ml 5 ml methyl iodide and 10 g silver oxide was refluxed for 4 Chromatography on silica gel yielded g Ultraviolet 1 Example 8 Δ solution of 500 mg of 46 in 10 ml of tetrahydrofuran was mixed with 1 ml of dihydropyran and ml of phosphorous oxide The mixture was kept for 3 hours at room then diluted with washed with a saturated solution of sodium hydrogen carbonate and dried and evaporated to dryness under thus yielding 530 mg an Ultraviolet insufficientOCRQuality

Claims (1)

1. 32973/3 / What we claim 1s:- 1. A racemlc or an optically active 4,6-d1chloro-17a-ethynyl -4,6-oestrad1ene-3-one of the general formula I OR In which R represents a hydrogen atom, an al kyl or a tetrahydropyranyl group or ah acyl group selected from the group consi sting of benzoyl or a straight or branched cSain al kanoyl group of up to 15 carbon atoms optional ly substituted by halogen , cycloalkyl , phenyl , carboxy or dl al kyl ami no* 2. A product according to cl aim 1 which is a racemlc 4,6-d1chioro-170- A a acetoxy-18-methyl-17ce-ethynyl -A ' -oestradi en~3-one. 3. A product according to claim 1 which is an optical ly active isomer of 4 ,6-di chl oro-17g-acetoxy-l 8-methyl -17a-ethynyl -Δ -oestradi en-3-one . 4. A product according to claim 1 which Is an optical ly active isomer of 4„6-dichloro-l 70-hydroxy-l8-methyl-l7 -ethynyl-A4 ,6-oestrad1en-3-one. 5. A product according to claim 1 which 1s an optically active isomer of 4 6 4,6-d1chloro-l70-heptanoyloxy-l8-methyl -l7ai¾ethynyl -A -oestradi en-3-one» 6. A pharmaceutical preparation which comprises ai^oestradiene as claimed In claim 1 , In admixture or conjunction with a pharmaceutically suitable carrie 7. A pharmaceutical preparation which comprises the oestradi ene claimed In claim 2 or 3, in admixture or conjunction with a pharmaceutically suitable carrier. 8. A pharmaceutical preparation which comprises the oestradi ene claimed in claim 4 or 5, In admixture or conjunction with a pharmaceutically suitable carrier. 9. A pharmaceutical preparation as claimed in any one of claims 6 to 8, wherein the preparation 1s in the form of a tablet containing 0.1 to 10 mg of the oestradi ene. 32973/2 10. A pharmaceutical preparation as claimed in any one of claims 6 to 8, wherein the preparation is In the form of a sol ution suitable for parenteral admini stration containing 1 to 20 mg of the oestradiene per ml of solution . 11. . A pharmaceutical preparation as cl aimed in any one of claims 6 to 10 , wherein the preparation also contains an oestrogenic compound component. 12. A pharmaceutical preparation having a composition substantially as described 1n Example 6 herein. 13. A process for the manufacture of a racemic or an optical ly 4 6 acti ve 4,6-dichloro- ' -oestradiene-3-one of the general formula I in which R represents a hydrogen atom, an al kyl or a tetrahyd pyranyl group or an acyl group according to claim 1 , wherein 6-chl oro- ,6-oestradi ene of the general formula II 1n which has the meaning given above, is treated with a chlorinating agent, as hereinbefore defined , capable of l iberating a positi vely chargec chl oride ion and a negatively charged chloride ion and the resulting trichloro 32973/2 product is treated with a base and , if desired, in the resulting compound any esterlfied hydroxy! group Is hydrolysed or any free chlorosucclnimlde or N-chloroacetam1de. 16. A process as claimed in claim 14 or 15, wherei;n the compound capable of liberating a negatively charged is l ithium chloride. 17. A process as claimed in any one of claims 13 the base is an organic base. 18. A process as claimed in claim 17, wherein the organic base is pyridine. 19. A process as claimed In claim 13, conducted substantial ly as described in Example 1 or 2 herein. 20. A process as claimed in claim 13, conducted substantially as described in any one of Examples 3 to 5 herein, f r the Applicant Wolff , Bregman and Goller By: >