IL32814A - Water soluble 16alpha-methyl-11beta,21-dihydroxy-pregna-1,4-diene-3,20-dione 21-esters - Google Patents

Description

Water soluable The present 1s concerned with new and with their manufacture and The present Invention provides compounds of the general formula CH20Y or Inorganic represents 2 or and and each representing a lower alkyl group or and together the N to which they are attached representing a or a In Israeli patents 12 12 11 249 and 1n German Patent the preparation of salts of esters of cortlcold steroids which dissolve water are described however said patents do not teach or suggest the subject matter of the present In the endotoxin shock test the new compounds are superior to the known used as standard as as in the eosinophHene as 1B shown 1n the following a En t a n c e I Sodium meth 1000 2400 6ooo sulphate hemisulphate II 200 14o III 20 40 IV 14 25 chloride The activity on the endotoxin shock was determined by a modification of the experiment described by Brooke y page in the following each weighin 100 to 120 were adrenalectomized and on the following day given g of bodywelght of endotoxin intravenously under a light ether Immediately after the injection the cortlcoid was administered through the same and the dose was established after the administration of which the rats survived for 24 The eoslnophllene test according to Speirs and Meyer the modified was also carried out on adrenalectomized having determined the number for each it was given subcutaneously g of bodywelght of the solution under after the injection blood was taken from the tall vein and the eosinophilene number was and compared with the previously found starting The dos which lowered the eosinophilene numbe by results summarized the Table clearly shown that the activity on the endotoxin shock and the lowering effect upon eosinophilene very much more distinct with the oompounds II to IV of the present Invention than with the control substance A from 14 to of the new compounds achieved the same effect as 1000 to of the control The new active compounds can be administered in an aqueous solution parenterally or Aqueous solutions of the preparations are always preferred when is necessary for the administered substance to as quickly and intensively as By virtue of their excellent pharmacological properties the followin Indications are suitable for parenteral Shock after an failure of blood circulation afte heart infarct lung for the treatment of serious and allergic Status trouble caused by contrast agents and the The active compounds can also be used with advantage Inflammation inhibitors aqueous nose and ear where the otherwise indispensable oily solution promoters often produce undesirable side the present Invention also provides pharmaceutica preparations comprise compounds of the general formula admixture conjunction with a pharmaceutically suitable The present invention provides also a process for the manufacture of the oompounds of the general formula wherein the corresponding compounds are a known maimer likewise a known the resulting esters are then converted into salts tolerable bases or To manufacture the metal salts compounds of the general formula in which represents an the corresponding compounds are converted in a known especially by reaction with a trloxide the acid sulphuric acid esters and the latter are the likewise in a known salts thereof with physiologically tolerable alkali As such physiologically tolerable there may mentioned the hydroxide butylate like of an alkali especially of The acid metal salts of the present Invention compounds of the general formula which Y represents a are likewise manufactured a known for the corresponding hydroxy compounds may be first converted with a preferably in pyridine into the heating the 21isulphonates with an alkali metal Iodide in acetone the compounds are obtained whic are then heated wit phosphoric acid in the of an organic base in an whereby the are The organic base used for the reaction with phosphoric acid may be an alkylated for example Suitable inert solvents a for example dimethyl sulphoxlde or For manufacture of the alkali metal salts the phosphoric acid monoesters are mixed with an alkali an alcoholic solutio until a of 11 been The ealt precipitated from the solution ether and isolated h be manufactured by known methods from the corresponding 2 hydroxy compounds for the corresponding compounds concerted with a derivative of a for example chloroacetic bromoacetyl bromide or in the presence of an organic for example into the It is advantageous to carry out the reaction in the presenoe of an inert for in at first while cooling and then it is completed at room The halogenoacylate then cted with an amine of the general formula to form the amine there is preferably for a secondary aliphatic o for example pipera or an or The reaction of with the amine carried out b simply mixing and heating the two excess amine serves as solvent during the In the reaction can also be performed in a dilute The thus obtained can be converted by known methods acids the corresponding acid addition salts The addition salts may be formed with those ally tolerables acids normally with organic nitrogen o acids for nicotinic acid The following Examples the 1 40 ml yridine were cooled to and 59 ml of freshly distilled sulphur trioxide were stirred in dropwlse at such a rate that the internal temperature did not rise above Then 20 g of were added to this solution while flushing ml of The reaction mixture was stirred for minutes at room diluted 400 ml f stirred for a further 30 minutes and adjusted to a of with ml of hydroxide The pyridine was removed by extraction with methylene The e of the aqueous solution was readjusted to 8 with sodium hydroxide and the solution was under vacuum at a bath residue was dissolved ml of the sodium dulphate was filtered off and the filtrate was evaporated under vacuum and to yield sodium melting at with Ultraviolet of the Example 2 A solution of g of 10 ml of pyridine was stirred with 0 g of adduot 12 hours at room The reaction solution was then mixed with ml of stirred for 2 hours and added dropwlse to 100 ml of The precipitate formed was filtered off washed with ether dissolved in 15 ml of absolute The solution was adjusted to with was filtered off The filtrate was concentrated with the precipitate formed was filtered off with suction and dried under vaccum at to yield pregnadl sulphate melting at with Example 3 A solution of 8 m in 10 ml of pyridine with g of adduct was stirred for 12 hours at room temperature under The reaction solution was then mixed ml of stirred for 2 hours and added dropwise to 100 ml of dry The precipitate formed was filtered off washed ether and dissolved in 15 ml of absolute The solution adjusted to a alue of with left to stand for 16 adjusted to a pH value of and the precipitated sodium sulphate was filtered off with The filtrate was concentrated and mixed precipitate formed was filtered off with suction and The resulting sodium melted at with of the theoretical Example 4 20 ml of thane sulphonyl chloride was stirred dropwise into a cooled solution 20 g of 200 ml of After a reaction time of 30 minutes the reaction solution was poured into and the precipitated was filtered Grams of the resulting were dissolved in 500 ml of g of sodium iodide in 400 ml of acetone were added and the whole was heated for 15 minutes at the The filtered reaction solution was evaporated under residue was stirred with diluted sodium thiosulphate filtered with washed with dissolved 300 ml of acetone and while being heated precipitated wi th 120 of After g of thy decomposed at 157 160 were Grams of the compound were dissolved in ml of acetonltrlle and refluxed for 3 hours with 1 ml of orthophosphorlc acid and 42 ml of trie thy The reaction solution then concentrated under the residue taken up i methanol and the solution was adjusted to alue of 11 with sodium hydroxide The was filtered the filtrate evaporated under vacGum the residue was taken up in 70 ml of and the salt was precipitated by adding The dlsodium jsalt can be purified by repreclpitation from methanol with g of dlsodium Ultraviolet χ Example 5 3 Grams of f were reacted and worked up as described Example to g of dlsodium c 1 in Example 6 then coo ed to room diluted with ch oroform evaporated under The residue was taken up chloroform and washed with dilute bicarbonate solution and The solution was dried over sodium sulphate and evaporated under to yield g of as a viscid oil was taken up in 300 ml of clarified by through and ethereal hydrochloric acid was added until an acid reaction to Congo red had been of After purification b reprecipitation from a methanolic solution with ether the pure hydrochloride melted at 227 Example A 1 of as described in Example in 20 ml of dioxan was mixed with a solution of ml of plperldlne in 2 of dioxan and the whole was stirred for 24 hours at The residue was filtered off with suction he filtrate was evaporated under The residue was stirred for about 15 minutes with 50 ml of the filtered off suction and washed with to yield g of after from melted at 232 with Gram of the above compound w suspended in ml of methanol ethereal hydrochloric acid was to yield g of hydrochloride melting at 242 with Example 9 Gram of Exampli was reacted with ml of morphollne and worked up as described in Example to yield g of converted into the as described in Example Melting point 211 c with E of at 132 When 4 g of the above compound were treated with ethereal acid as described Example there w re obtained g of hydrochloride melting at 221 Example 12 A solution of g of in 50 ml of absolute dloxan was mixed with ml of pyridine then a solution Of g of in 25 ml fo abso lute ether was added dropwise the whole was stirred for 24 hours room then diluted with and the organic phase was repeatedly Washed with water dried over sodium sulphate and After recrystallizatlon from ethyl acetate hexane there Composition of eyedrops g of sodium f of sodium mercurlthloaalicylate g of g of sodium hydroxide and of sodium chloride were dissolved in of distilled water filtered und er sterile and bottled under aseptiiS conditions 14 Composition of eyedrop of sodium f 3 benzoic methyl g of propyl ester g of citric g of sodium hydroxide and g of sodium chloride were dissolved in g of disti lled water fi ltered under sterile conditions and bottled under conditions Example 15 Composition of a sprayj g of sodium 6 16 of an aliphatic polyglycol g of paraffin oil of g of stearyl alcohol g of c acid methyl of acid propyl g of perfume oil g of water grama The spray was manufactured in the usual Example 16 Composition of an i g of sodium meth g of white petroleum jelly g of paraffin oil g of white of a mixed ester of high molecular from ra materials close to natual products g of perfume oil g of paraffin oil white petroleum g of glycerin and g of stea l g of hydro acid methyl g of acid propyl g of perfume g of of paraffin oil g of white petroleum Jelly g of glycerin and g of a old methyl of b acid propyl of perfume g of water grams insufficientOCRQuality

Claims (1)

1. What we claim A compound of the general formula representing a physiologically tolerable organic or rerpesenting 2 or and and each representing a lower alkyl group or and together with the N to which they are attached representing a or a A compound as claimed in claim wherein represents Sodium phate 1 thy pharmaceu ical y su tab e A pharmaceutical preparation which comprises the compound claimed any of claims 3 to admixture or conjunction with a pharmaceutically suitable A pharmaceutical preparation a Bubstantially as described in any of Examples 13 to A process for the manufacture a as claimed in tolerable process for the of a compound as claimed in claim 1 in which Y represents an wherein the corresponding converted into an acid sulphuric acid and the acid sulphuric acid ester is then converted into a thereof a physiologically alkali A process as claimed in claim wherein the conversion of th into the acid sulphuric acid ester is carried out by treatmen ith a A process for the manufacture of a compound as claimed claim 1 in which Y represents a wherein correspondlns compound is in the with the resulting converted the corresponding compound with an metal iodide in the resulting iodo compound is reacted with phosphoric acid the presence of an organic base and the resulting phosphoric acid monoester converted into a alkall metal salt thereof by means of A process for the manufacture of a compound as claimed represents a or wherein the correspondi g compound a derivative of a acid presence of an organic the resulting a addition salt thereof a physiologically tolerable A process claimed wherei the organic base is process for the manufacture of a compound as claimed conducted substantially as described i any one of Examples 1 to 12 Bregman and insufficientOCRQuality