IL27472A - Halogenated steroids of the androstane,norandrostane and pregnane series and their manufacture - Google Patents

Description

steroids the and preganne series their 2β05β RAN This invention relates to novel halogenated steroids and to a process for the manufacture The novel halo enated steroids of this invention are characterized in the A and B rings by the feature the following formula wherein is bromine or lower Q is oxo or of 4 carbon and represents the remaining portions of the A B as well as the C and Ώ rings of the steroid and corresponds to any one of the partial in is lower or lower alkyl is hydrogen or lower and each is independently hydrogen or lower lower alkyl or is hydrogen or is hydrogen or fluorineI is hydrogen or lower alkyl X is an unsaturation between the and io n is a whole integer from 0 to T is or 2 is or 0 when is when is may also be As used herein the terminology lower alkyl comprehends both straight and branched chain saturated hydrocarbon moieties having up to eight carbon such as or the Lower alkanoyl similarly comprehends residue of lower alkane such as or the like and of 2 to 4 carbon atoms comprehends moieties such as and the Preferred compounds are those wherein is fluorine or lower alkyl of up to four carbon Especially preferred are those compounds wherein is fluorine or Also preferred are compounds wherein is ethylenedioxy or the latter being particularly Steroidal compounds having the structure shown in formula I have been found to have valuable endocrinological Compounds of formula I in which K has the partial formula II wherein other than hydroxy are useful as progestational compounds of formula I in which has the partial fomula IY are useful as and agents and compounds of formula I in which has the partial formula III wherein is hydrogen and Y is or are useful as 0 anabolic agents when is hydrogen or lower and as progestational agents when is Compounds of formula I in which has the partial formula wherein is can be es and compounds of I in which has the partial formula III wherein lower alkanoyl can be converted the corresponding free hydroxy Time such compounds are useful as The process of this indention comprises treating a compound of the formula wherein and have the meaning as above with chlorine either in the presence of a proton acceptor or followed by the addition of a proton acceptor if converting the group into a The chlorination procedure according to this invention is suitably effected by intramixing chlorine and a reaction medium which contains the starting steroid of formula ferably in The treatment with the chlorine can be conducted in the presence of a proton for a heterocyclic base such as picoline or pyridine an such as formamide or a lower alkylene oxide such as ethylene oxide or propylene or the th proton acceptor can be added subsequent to the intramixing of the chlorine and starting material steroid of formula The proton acceptor can also serve as the solvent for the starting material steroid of formula and the reaction medium can contain other These solvents can be any convenient inert organic for ethers as lower alkyl for ethyl or lower alkanoic acids such as propionic acid or acetic chlorinated hydrocarbons such as chloroform or carbon or the The chlorine can be introduced into the reaction mixture by conventional or a solution taining the chlorine can be introduced into the reaction A lower alkanollc acid for chlorine in propionic is particularly suitable for this The treatment with chlorine is effected at a low preferably between about and room erature more advanta eousl between about and about When chlorination of those wherein n is it is preferable to conduct the chlorination in l Hydroxy groups present in the starting material comprehended by the moieties symbolized by can be esterified after the chlorination the chlorination procedure can be effected on starting materials containing ester When chlorinating Y or Z is it is preferable to protect the hydroxy group prior to for via acetylation to form the corresponding or After the chlorination the compound can be formula I in which has the generated by conventional Products artial III wherein is lower alkanoyl can be converted to ispondlng compounds wherein is hydrogen via if is followed by reduction with lithium aluminum hydride yielding compounds wherein is hydrogen and is The compound if can be deketalized conventional for treatment with mineral acid preferred to make the latter compounds directly formula V in which has the via chlorination of starting materials formulas III V wherein Rs is In addition to the other knovm techniques can be used to protect labile groups prior to chlorination The facile manner in which the ination procedure can be conducted and the good yields able therewith are notable inasmuch as conventional ination procedures with wherein has the same meaning as have failed to yield appreciable amounts of steroid The conversion of a reaction product obtained into a the preparation of compounds wherein is subsequent to chlorination can be effected via conventional for via reaction with a glycol in the presence of an acid catalyst such as For ethylene glycol can be used and yields a compound wherein is Free hydroxy groups present in a reaction product obtained can be esterified according to know techniques in a further reaction reaction products such as can be dehydrogenated by know means to give the corresponding unsaturated Particularly preferred compounds of this invention are those of the formula wh meaning as above and is lower or lower These compounds are marked by pronounced progestational activity and are useful as progestational Of the compounds of formula VI those wherein is chlorine are as are those wherein is and in compounds wherein is other than those where is methyl are The substituent can be in either the or Especially preferred those compounds wherein hydrogen or lower Another preferred embodiment of this Invention comprehends compounds of the formula wherein R Y and n each has the same meaning as and is hydrogen or lower These compounds are useful as androgenic and anabolic Especially preferred compounds of formula VII are wherein is methyl or compounds wherein is pre as are those wherein n is Yet another pref rred embodiment of this invention are compounds of the formula wherein R and Y each has the same meaning as These are useful as progestational Especially preferred are those compounds of formula wherein is Yet a referred of this invention is compounds of wherein Z and n each has the same meaning as These compounds are useful as and thymolytic Especially preferred compounds of formula are those wherein Rg is hydrogen or as well as those wherein Z is carbonyl or ylene those wherein is or and those wherein is Some of the starting materials which can be used in the process of the present invention are of the general formula wherein is hydrogen or lower is lower alkylj and a halogen of atomic weight less than The compounds of formula X can be prepared by a procedure starting f om compounds of the formula wherein each has the same meaning as In the first step of this the compound of formula XI is dehydrogenated according to methods known per for with to yield a compound a the formula wherein and s each has the same meaning as The compound of formula XII is then selectively once again according to known for with perphthalic to yield a compound of the formula XIII and each has the same meaning as Treatment of the compound of in acidic such as acetic with a hydrogen halide then yields the desired compound of formula In a like manner other starting materials of formula V can be Besides compounds of formulas XII and among other novel intermediate are those of the wherein is hydrogen or In addition to being useful as intermediates corresponding compounds of formula compounds of formula XIV are The compound of formula XIV wherein is hydrogen is useful as an anabolic and androgenic whereas the compound of formula XIV wherein is acetyl is useful as an antiandrogenic The latter compound can be into the former which can be prepared from the corresponding compound via with manganese dioxide or the like oxidizing In the same manner other one compounds of formula V can be prepared from corresponding compounds which in turn can be obtained from compounds via treatment of the latter The procedures described in this paragraph are known and can be conducted according to the known Compounds of formula VI wherein is hydrogen can be converted into compounds of formula VI where is In one procedure a compound of formula VI is hydrogen and oxo is treated with acetic anhydride and perchloric acid yielding the acetate compound of the ormula wherein and n have the same meaning as A compound of formula VI wherein hydroxy can then be obtained by treating the enol acetate of formula XV with unbuffere peracetic Via another procedure a compound of formula XV is treated with buffered peracetic acid yieldin a compound of the formula wherein X and n have the same meaning as Via acidic or basic hydrolysis a compound of formula XVI can be converted to a compound of formula VI wherein is The above procedures utilizing compounds of formulas XV and XVI as intermediates are known reaction procedures and can be conducte according to known The compounds of this invention are characterized by a high degree of endocrinological usefulness with a selectivity of action characterized by minimal side the useful compounds of this those of partial and complete and can be administered internall for orally or with dosage to individual in the conventional cal for they can be administered in ventional pharmaceutical solid or liquid such or the These pharmaceutical preparations can contain conventional pharma ceutical carriers and such corn polyalkylene emulsifying buffering agent agents for the adjustment of osmotic and the Though it is preferred the endocrinologicall useful compounds of this invention the cally useful compounds of this invention having those of formulas VI and or those of formula usefulness can also be administered topicall For this topical these compounds can be administered in conventional topical administration forms such as ointments or in combination with conventional topical carriers such as stearic acid or the Also compositions containing an active ingredient of this invention can be subjected to conventional pharmaceutical such sterilization or the the ceutical compositions of this invention can contain othe active the endocrinologically active compounds of formulas and XIV can be administered as feed and for this purpose can be admixed with conventional animal feed or conventional animal feed prefixes Though as indicated dosage of the useful compounds of this invention hould be adjusted to individual useful as those of formulas VI and can be administered internally in daily dosage regimens of from about to about per compounds useful as androgenic and anabolic those of formulas VII and can be administered internally in daily dosage regimens of from about to about per compounds useful as ant and thymolytic those of formula can be administered internally in daily dosage regimens of from about to about per Dosages can be administered in unit or divided dosage The following examples are illustrative of this invention but not limitative Most of the starting material compounds are known compounds or members of known classes of In any the starting materials can be prepared by known methods for those in certain in exemplified in the following All temperatures in the examples are stated in degrees Example To a cooled solution of in 20 of di and 10 of ether was added of a M solution of chlorine in propionic The mixture was allowed to stand at for 12 hours whereupon an additional of the chlorine solution was added and the mixture was then allowed to stand for an additional 2 hours at The reaction mixture was then poured into of water and the resulting mixture was extracted three times with methylene chloride mixture organic layers were washed once with sodium bicarbonate solution and once with The combined organic layers were then dried and evaporated under reduced The residual oil was triturated in the presence of ethyl acetate giving crude which upon further crystallization from acetate formed colorless crystals of According to the above yields yields yields rihyd yields Example 2 To a cold solution of of of alcohol free chloroform was rapidly added of a M solution of in dry carbon This solution was stored at for The solvent was then removed under reduced pressure and the residue was treated with 25 of heptane and the solvent was again removed under reduced This operation was repeated a second The residue was then treated with 4 of dry pyridine and the resulting solution was heated on a steam hath for The solution was then lowed to stand at room temperature overnight chloride precipitated from the reaction To the pyridin solution was then added chloroform and the resulting solution was twice each time with of hydrochloric The aqueous layer was then extracted with of The organic layers were dried over magnesium sulfate and evaporated under reduced The residue treated with 25 of heptane which was evaporated Sunder reduced This operation was repeated a second time giving crude dione which was recrystallized twice from methylene ethylacetate yielding Example To a cooled solution of in of dry dimethyl ormamide and 10 of ether was added of a M solution of chlorine in propionic The reaction mixture was allowed to stand at for 10 hours and then at room temperature for 5 The reaction mixture was then poured into 100 of water and was extracted with methylene The layer was washed twice with sodium bicarbonate solution and once with The organic solution was then dried over sodium sulfate and The residue was crystallized three times from methylene giving Example 4 To a cooled solution of of in 6 of and of ether was added of a M solution of chlorine in propionic The reaction mixture was allowed to stand at for 12 The reaction mixture was then diluted 100 of water and the mixture was i extracted three times with chloride mixture The organic layers were washed once with 5 sodium bicarbonate solution and once with The combined organic layers were dried and evaporated to dryness under The residual oil was triturated with giving crude which upon further crystallization from methylene formed colorless crystals of in According to the above yields 17 yields 17 yields The starting 17 was prepared as A solution of 25 of in 125 of anhydrous pyridine and 125 of acetic anhydride was heated under reflux for The reaction mixture was then cooled and diluted with 1 liter of chloride mixture The organic solution was then washed twice with 1 N hydrochloric acid twice with sodium bicarbonate solution and once with The organic layer was dried and was then concentrated under reduced residue was then passed through a short column of synthetic gel Plorisil the product being with The benzene eluate was concentrated under reduced giving in A slow stream of hydrogen chloride was bubbled for about 10 seconds through a solution of of in 150 of anhydrous In a separate a slow stream of anhydrous hydrogen chloride was bubbled for about 10 seconds through a solution of of in 130 of anhydrous The two dloxane solutions were then mixed together and hydrogen chloride was bubbled through the mixture for about 0 The reaction mixture was then allowed to stand at room temperature for and was then filtered from the resulting The filtrate was concentrated to about 5 under reduced pressure and was then diluted with 1 liter of chloride mixture The organic solution was washed twice with dilute sodium hydroxide 1 solution and once with The organic layer was dried and evaporated under reduced The residue was filtered through a short column of synthetic gel being elute with benzene and ethyl The eluates were combined and The residue was crystallized from methylene ether giving in To a solution of of in of methylene chloride and 225 of ether was added 125 of a molar solution of perphthalic acid in The reaction mixture was allowed to stand at room temperature for and was then diluted with 1A liters of The organic layer was washed twice with sodium carbonate with water and twice with The organic layer was dried and was then concentrated under reduced The residue was crystallized from methylene giving crude whic upon further crystallization from methylene melted at Hydrogen chloride was bubbled for 10 minutes through a solution of 17 in 110 of glacial acetic The solution was then allowed to stand at room temperature for an additional 5 and was then diluted with 700 of The resulting mixture was extracted three times chloride mixture The organic layers washed twice with sodium bicarbonate once with and once with The combined organic layers were dried and concentrated under reduced The residue was chrom ographed on 50 of synthetic gel The column was eluted with acetate and the resulting product was crystallized from methylene giving which upon crystallization from melted at 1 Example To a cooled solution of of in 21 of dimeth and of ether was added of a solution of chlorine in propionic The reaction mixture was then allowed to stand at for hours and then at for The resulting mixture was poured into 200 of water and was extracted three times with chloride mixture The organic layers were washed once with sodium bicarbonate solution and once with The combined organic layers were dried and evaporated under reduced The residue was crystallized twice from methylene giving which upon further purification by crystallization from methylene melted at Example A solution of of acid and 2 of ethylene glycol in 15 of dry benzene was distilled slowly over a hour An additional of 8 of benzene and of acid was then added and slow distillation was carried out for an additional two The cooled reaction mixture was then diluted with 20 of ether and 40 of sodium bicarbonate The two phases were separated and the organic layer was washed once with sodium bicarbonate solution and once with The organic layer was dried over sodium trated and the residue crystallized on the addition of The resulting solid was crystallized twice from methylene in i 7 To a cooled solution of of in 10 of chloroform was added of a molar solution of chlorine in dry carbon The reaction mixture was allowed to stand at for 18 The solvent then removed under reduced pressure and the residue was treated with 25 of The solvent was again removed under reduced pressure and the solid residue was dissolved in 2 of dry After 24 hours at room temperature the pyridine solution was treated with 25 of 1 N hydrochloric acid and the product was extracted with The chloroform solution was then washed each time with 10 of 1 N hydrochloric acid and the combined aqueous layers were extracted with 50 of The organic layers were combined and dried over magnesium The solvent was removed under reduced pressure and the residue was crystallized from methylene acetate yielding Evaporation of the mother liquor and recrystallization of the residue yielded further Example 8 To a stirred suspension of of in 15 of hexanoic acid was added of trifluoroacetic The solid rapidly went into solution and stirring was continued at room temperature of cold sodium bicarbonate solution and the resulting mixture extracted three times with chloride mixture j The organic layers were washed twice with N sodium hydroxide once with brine and were then over sodium sulfate and ί 1 The residue was dissolved in 2 and was then chromatographed on 1 of synthetic gel The product was eluted with ethyl and finally with ethyl The eluents were evaporated and the residues were crystallized by trituration with The resulting solids were combined and crystallized from methylene giving crystals of 17 which upon one further crystallization from the same system formed 5 in Example 9 To a cooled solution of of in of dry formamide and 5 of ether was added of a solution of chlorine in propionic The reaction mixture was allowed to stand at for reaction mixture was then diluted with 100 of water and the resulting mixture extracted three times with chloride mixture The organic layers were washed once with sodium bicarbonate and once with The combined organic layers were dried and evaporated to dryness under reduced The oil was dissolved benzene and chromatographed on a column of s nthetic ma el Florisil benzene and ethyl acetate eluates were combined and evaporated to To a cooled solution of the residue in 6 of dry and 5 of ether was added 2 of a solution of chlorine in propionic The reaction mixture was allowed to stand at for 12 hours and was then diluted with 100 of The mixture was extracted three with chloride mixture and the organic layers were washed once with sodium bicarbonate solution and once with The combined organic layers were dried and evaporated to dryness under reduced The residue on trituration with giving crude which upon further crystallization from methylene formed colorless in Example 10 To a solution of of dione in 50 of dichloromethane and 250 of ether cooled to and protected from atmospheric moisture was added of a chlorine in propionic acid The solutions were mixed thoroughly and allowed to stand at Benzene 100 was added and the solution was concentrated unde vacuum to about 200 Pyridine was then added and the resultant solution was heated at for 5 and poured into The organic layer and an ether extract of the aqueous layer were combined and washed with 2N hydrochloric sodium bicarbonate and finally with dried over sodium sulfate and The residue was dissolved in 2C benzene in hexane and adsorbed onto 12 silica Earl benzene eluted some less polar material and later benzen fractions eluted crystalline These crystalline fractions were combined and crystallized from ethanol and hexane giving colorless crystals which upon one further recrystallization gave Example 11 A solution of of dione in 10 of carbon tetrachloride protected from atmospheric moisture was cooled to and a mixture of of perchloric acid and 2 of acetic anhydride was added over 10 After stirring for an additional hour at the solution was diluted with 100 of ether and washed with sodium bicarbonate and then with The solution was dried over sodium sulfate and concentrated to an oil containing sufficiently pure for subsequent To a stirred solution of 17 from of according to the above in benzene was added of 40 peracetic After 4 5 of 10 sodium sulfite was added and the mixture was stirred The reaction mixture was diluted with washed with dried and The residue was adsorbed onto silica gel from benzene solution and eluted with in lization from ether gave Example 12 A solution of from of according the procedure of Example in of benzene was added with stirring over 5 minutes to a mixture of of peracetic acid and 80 of sodium After the reaction mixture had been stirred at room temperature for 15 10 of ice water followed by 20 of sodium sulfite was The organic layer was then diluted with washed with dried and evaporated to an oil containing sufficiently pure for subsequent A solution of 4 from of 17 according to the above procedure in 15 of tetrahydrofuran and of 1 N chloric acid was stirred at room temperature for 6 hours and poured into ice The amorphous precipitate was collected by filtration and adsorbed onto synthetic gel from benzene The later benzene eluates upon evaporation and crystallization from ether gave Example 13 A mixture of from of apcording to the procedure carbonate monohydrate was stirred at room temperature 2 hours Ice water was added and after stirring for an additional minutes the resultant solid was Recrystallization from ether gave Example 14 To a cooled solution of of in 15 of dry dimethyl ormamide and 10 of ether was added of solution of chlorine in propionic The mixture was allowed to stand at for 24 hours and then at for 12 The reaction mixture was then poured into 100 of cold water and the resulting mixture was extracted three times with chloride mixture The organic layers were washed once with sodium bicarbonate solution and once with The combined organic layers were dried over sodium sulfate and evaporated under reduced The residue was dissolved in benzene and chromatographed on 15 of synthetic gel The benzene and ethyl acetate eluates were evaporated and the residue was crystallized once from methylene and three times from methanol giving The starting material was prepared as To a stirred solution of of of of acetate in 60 of The resulting mixture was cooled to and of was added over a 5 minute followed by the rapid addition of of glacial acetic The reaction mixture was then allowed to stir at for 75 minutes and was then dilutee with 750 of The mixture was extracted 3 times each time with chloride mixture The organic layers were washed once with sodium bicarbonate solution and once with The combined organic layers were dried over sodium sulfate and The residue was dissolved in benzene and a column of synthetic gel The benzene and ethyl acetate eluents were combined and The residue was lized from giving which is sufficiently pure for the next To a stirred solution of of 6 in 25 of dry dioxane was added of and of sulfonic The reaction mixture stirred at room temperature for 80 minutes and was then diluted with a solution comprising 50 of water and 2 of The mixture was then stirred at room temperature for 5 minutes and the resulting was then washed with water and crystallized from acetone 20 containing 1 of giving in 2 liters of tetrachloride was added 810 of a solution of prepared by the method of Heusler and 289 in carbon followed by 8l of acetic The resulting mixture was heated under reflux for 12 A solution of of oxalic acid in 2 liters of water was then added to the cooled and an exothermic reaction occurred while the mixture was stirred for 2 The cooled reaction mixture was then extracted with 5 liters of chloroform and the organic layer was separated and washed once with once with sodium carbonate solution and once with The organic layer was dried over sodium sulfate and The residue was dissolved in benzene and chromatographed on 1 of synthetic silica gel The product was eluted with liters of 10 ethyl and liters of ethyl The combined fractions were evaporated and the residue was crystallized from ethyl acetate giving which upon tion from ethyl acetate melted at in Example 1 To a cooled solution of of in 15 of dry formamide and 10 of ether was added of solution of chlorine in propionic The mixture was allowed to stand at for 12 hours and at 5 and was extracted three times with chloride mixture The organic layers were washed twice with sodium bicarbonate solution and once with The organic layers were then dried over sodium sulfate and The residue was crystallized three times from methylene giving which further crystallization from the same solvent system melted at This compound occasionally crystallized as a polymorphic The starting material was prepared as To a stirred solution of of lithium aluminum hydride in 1 liter of ether was rapidly added a solution of of in liters of The reaction mixture was stirred at for 10 minutes and was then allowed to warm to room temperature over a 1 hour The mixture was then again cooled to after which 100 of ethyl acetate was added over a 10 minute followed by the addition of 250 of saturated sodium sulfate The reaction mixture was to room temperature and filtered through a bed of filter The precipitate was washed with ether and methylene The filtrate was washed with dried over sodium sulfate and evaporated to give a colorless solid which was dissolved in 250 of dry To the with was added a suspension of 20 of in 210 of dry dioxane and the resulting mixture was stirred at temperature for 1β The resultant precipitate was rated to The residue was dissolved in 1 liter of methylene chloride and was washed 5 times with sodium hydroxide solution 5 The organic layers were dried over sodium sulfate and The residue was dissolved in benzene and chromatographed on 200 of synthetic gel The column was eluted with 500 of 20 ethyl and of ethyl The eluents were combined and The residue was crystallized methylene giving Additional was recovered from the mother Upon recrystallization from ethanol melted at Example To a stirred solution of of in 110 of alcohol was added of seienious acid and of acetic anhydrid and the resulting mixture was heated under An additional of seienious acid was added over a 48 hour After heating under reflux for a total of the reaction mixture was diluted with chloroform and The filtrate was washed once with sodium bicarbonate with 1 hydrochloric acid solution and once with The organic layer was dried over sodium sulfate and The residue in benzene was chromatographed on a column of synthetic gel The column was eluted with then evaporated and the residue was crystallized from methylene giving which upon further crystallization from the same solvent system melted at D in Example 17 To a cooled solution of of in a mixture of of over calcium and 55 of ether was added of a solution of chlorine in propionic The mixture was allowed to stand at for 14 hours and then at for 6 The reaction mixture was then poured into 3 liters of water and was extracted three times with chloride mixture The organic ere washed twice with II liters of 5 sodium bicarbonate solution and once with 2 liters of The combined organic layers were dried over sodium sulfate and evaporated under reduced The residual oil was dissolved in and tographed on 1100 of synthetic gel The column was eluted with 2 liters of 1 liter benzene 1 liter 2 ethyl benzene 1 liter ethyl 500 ethyl Further elution with of litersof ethyl a 1 liter of ethyl The combined solids were crystallized twice from methylene giving which upon crystallization from the same solvent system melted at Example To a suspension of of i in of glacial and 270 of acetic anhydride was added of The reaction mixture was stirred until all solid went into solution and was then allowed to stand at room temperature for a total of β The mixture was poured into 7 liters of water and after 50 minutes the precipitate was filtered and washed well with wate The resulting wet product was dissolved in about 1 liter of methylene dried over sodium sulfate and evaporated under reduced pressure to about 200 This solution was transferred to an flask and the hot solution was concentrated with the simultaneous addition of ethyl acetate 1 The product precipitated out of the boiling solution final giving which upon one further crystallization from the same solvent system melted at 2 was obtained from the mother Example 19 An ointment the following formulation is prepared as described Per Kilo White 999 1 The white petrolatum was placed in a suitable jacketed mixing kettle and heated to approximately with constant slow The which was first ground to a fine powder in a small ball was then addea slowly to the melted petrolatum and the mixture stirred until thoroughly Cool water was then circulated through the jacketed kettle and the cooling continued until the temperature reached about mixture was then passed into an Eppenbach colloid mill at a setting of 20 The preparation was then packaged in opal glass If aluminum or tin ointment tubes can be substituted for the glass Example 20 Capsules containing the formulation are prepared as described Per Capsule Lactose Corn starch Talc The was mixed with the lactose and corn starch in a suitable The mixture was further blended by passing through a suitable minuting a Fitzpatrick Comminuting Machine with a 1A screen with knives The blended powder was then returned to the the talc added and the resultant mixture blended It was then filled into hard shell capsules on a capsulating Example 21 Tablets of the following formulation are prepared as described Per Tablet spray dried Corn Calcium stearate Total Weight The corn starch and calcium stearate were blended in a suitable The powder was then compressed on a heavy duty tablet compressing machine and yielded tablet slugs of about diameter and The tablet slugs were passed through a suitable comminuting machine and yielded granules of approximately 1β mesh with a minimum of The granulation was on a tablet compressing machine using a standard concave punch to an average tablet weight of 100 22 A for animal feed of the following compositio is prepared as described diene 125 Corn germ meal 831 Drew Oil Total Weight 1000 i The corn germ meal was placed in a suitable mixer and while the Drew Oil OO was slowly added and thoroughly mixing continuously the was slowly added and mixed until the mixture was This premix was then added to a commercial poultry feed at the ratio of 2 to yield a ratio of and thoroughly This was used in the mash and it was also pelleted on a pellet the Waldron Pellet Amounts of the above premix can be added to the commercial feed to yield medicated levels ranging from to The commercial feeds to which this premix is added can be free of other medicaments or can contain other Drew Oil 1400 is a mixture of glyceryl triesters of lower molecular weight fatty Example 23 A for animal feed of the following composition is prepared as described Grams Corn germ meal Drew Oil 1400 Total Weight 1000 The corn germ meal was placed in a suitable mixer and while the Drew Oil 1400 was slowly added and thoroughly While mixing continuously the was slowly added and mixed until the mixture was This premix was then added to a commercial poultry feed at the ratio of 2 to yield a ratio of and thoroughly This medicated feed was used in the mash and it was also pelleted on a pellet the Waldron Pellet Amounts of the above premix can be added to the commercial feed to yield medicated levels ranging from to The commercial feeds to which this premix is be free of other medicaments or can contain other Example 24 A cream of the following formulation is prepared as scribed Stearic acid Light mineral oil Sorbitan monostearate Methyl Propyl Sorbitol Polysorbate 60 polyoxyethylene 20 sorbitan Distilled Water ad pH The stearic light mineral sorbitan methyl and propyl were placed in a suitable jacketed and the mixture melted and heated to The was then added with To a separate jacketed kettle were added the and polysorbate and this mixture was then heated to The water phase was added to the oil phase with mixture agitated for 15 minutes at cooled to brought to final volume with distilled water and cooled to room temperature with good Example A liquid concentrate of the following formulation is prepared as described Per Kilo 25 Polysorbate polyoxyethylene 20 sorbitan 400 Propylene glycol 575 The polysorbate and propylene glycol were well mixed in a suitable size glass and the was slowly added with constant This concentrate of the drug was packaged in a glass container for shipment and use the concentrate is diluted by addition to a molasses based liquid protein supplement to give a concentration of from one to ten of drug per pound of liquid protein This is then added to the final grain carrier in amounts sufficient to give the desired dosage of drug per day per 26 g of dlone in 200 ml of dimethylformamide and 100 ml ether was cooled to about To this was added 53 ml of a molar solution of chlorine in propionic acid over 10 The mixture was allowed to remain overnight at 0 to 6 hours at room temperature and then it was diluted with Water and tracted with an chloride mixture The organio phase was washed with aqueous sodium hydrogen carbonate solution and dried over sodium 25 g crude The crude product was then chromatographed on 1250 g of Plorisil and eluated with benzene and acetate An early fraction acetate afforded g of a mixture rioh in The later fractions afforded g of the major The g fraction was on 96 g of silica using the same solvent system above and g of crude product was Trituration with ether yielded g of insoluble white Crystallization from methylene afforded as colorless and sintering Example 27 g of in 0 ml of glaoial acetic acid was treated at room temperature over 10 minutes with ml of a molar solution of chlorine in acetic acid and allowed to react overnight at room The crude product was isolated by dilution with water and extraction with methylene chloride in the usual g of crude Chromatography on 129 g of silica with afforded from the early fractions g of solid A sample was crystallized from methylene and melted at g of and g of lithium chloride in 25 ml of formamide were refluxed for 0 under The reaction mixture was poured into water and extracted with methylene The organic phase was washed with dried over and the solvent removed in The residue was chromatographed on 30 g of alumina activity using benzene and and the crude product was crystallized once from methylene g of ταμ and 308 insufficientOCRQuality

Claims (1)

1. CLAIMS Compounds of the general M wherein is bromine or lower is oxo or of 2 to 4 carbon and represents the remaining portions of the A and B as well as the C and D rings of the steroid and corresponds to any one of the partial in which formulae is lower alkanoyloxy or lower is hydrogen or lower and each is independently hydrogen or lower is lower alkyl or is hydrogen or is hydrogen or is hydrogen or lower X is an unsaturation between the and n is a whole integer from 0 to Y is or 2 is or when is 0 when is hydrogen Z may also be Compounds of the general formula wherein X and n each has the same meaning as in Claim 1 and is lower alkanoyloxy or lower A wherein is fluorine or 45 dione 4 Compounds of the general formula wherein and Y each has the same meaning as in Claim and hydrogen or lower Compounds of the general formula 46 wherein and Y each has the same meaning as in Claim 7 Compounds of the general formula wherein Z and n each has the same meaning as in Claim 4 A process for the manufacture of steroids of formula I in Claim which comprises treating a compound of the general formula M wherein and M have the same meaning as in Claim at 47 either in the presence of proton acceptor or followed the addition of a proton acceptor if converting the compound of formula I thus obtained in which Q is the group into a corresponding 1 A process according to Glaira wherein hydroxy groups present in reaction product are in a further reaction A process according to 16 or the action 4 or is in position in a further reaction process according to Claim 16 or wherein a reaction product of the formula VI wherein is hydrogen and X and n have the same meaning as in is converted in a further reaction step into a compound of the formula wherein is Processes for the preparation of steroids of formula I in Claim 1 as hereinbefore particularly especially with reference to the foregoing Process for the manufacture of preparations having hormonal properties9 characterised in that a compound of the 43 therapeutically compatible solid or liquid commonly used in such Compositions having containing a compound of the formula I in Claim 1 and a A of the formula I in Claim 1 pared by a process according to any one of Claims 16 to A compound of the formul in Claim 29 whenever pared by a process according to any one of Claims 16 to 18 and A compound of the formula VII in Claim whenever prepared by a process according to any one of Claims 17 and A compound of the formula VIII in Claim whenever prepared by a process according to any one of Claims 17 compound of the formula IX in Claim whenever prepared by a process according to any one of Claims 16 to 18 and the C AMD insufficientOCRQuality