IL38909A - Iodomethanesulfonamides,their preparation and x-ray contrast agents comprising them - Google Patents

Description

their preparation and contrast agents comprising them EPROVA 36949 The present invention relates to contrast processes for producing them and compositions which are in for portraying liquor spaces and as shadow forming a highly of the general formula in which R is a hydrogen atom or a methyl and is a hydroxylsopropyl a l Preferred components are the formula in which is as defined Individual components which are particularly ferred are For portraying these liquor spaces either negative gaseous contrast oxygen carbon dioxide o positive contrast agents consisting of esters or aqueous solutions of salts of certain in the been of these methods have been found to be icularly satisfactory see und 1 15 diagnostic value o air myelography has been found to be very limited because the absorption differences between the narrow air band of the subarachnoidal space and the massive amount of surrounding soft although better suited have the disadvantage that are virtually not that they can be removed only incompletely by mechanical means give ris in many cases to meningeal sometimes oil arachnoiditis and to the viscous oils which are not with the body liquors do not penetrate into all the fine hollow spacesi the quality of the myelograms being thus Myelography with acid ethyl ester as practised mainly countries has similar Better diagnostic results are achieved with aqueous salt These mix with th surrounding body liquor and are therefore able to penetrate into the finest gaps and to portray lar radicle structures and pathological forms within the spinal sac in detail on the contrast these contrast agents have always been found to Their aqueous solutions contain no It is now using these to prepare aqueous infection solutions contras agents which a su iciently high concentration and contain no charged they have no electric conductivity and fore a substantially red influence on the nervous transmitting system and a substantially reduced irritating effect on the nerve their osmotic pressure is reduced by or Their general compatibility is Their maximal compatibility with the CHS is The intracerebral and intracisternal toxicity of is found to be the lowest of all compounds hitherto The unusually high intracisternal compatibility of components within the present which is to be as times than that of the best control is particularly unusually loeal compatibility is a precondition for the extension of their application beyond the lumbar region the cervical sections of the subarachnoidal and even to the intrathecal spaces liquor It has already been proposed to use s or for similar Deutsche published of 7th 1971 especially pages 42 this proposal does not seem to have any practical These two compounds which appear to be the known derivatives share with the unsubstit ted iodo phonamide Binz et schrift 16 21 the disadvantage of having an solubility in water precludes them from used i aqueous solutions of contrast which has a solubility of only and with glucamine can give solution of not more than the minimal concentrations of iodine per volume unit required for contrast photography could not be For the spinal liquor could not made visible on the even when the highest tolerated volume of these substances was applied at the highest possible saturation concentration to the test animals these were no to be useful as trast The same applies to which is even substantially less Useful solutions of contrast have a minimum content of of contrast dilute solutions are not capable of giving contrast especially since they become diluted i the liquor space by mixing with the body have apparently hitherto been disclosed which have the required of at least Compounds within the invention have a solubility of about 45 over and meet an obvious practical In view of the very limited solubility of the known mentioned this high is striking and quite The following Table gives a comparison between some properties which are decisive for the intended application of the compounds according to the invention D and and the structurally most closely related known compounds H and of which the compound I can be regarded as the relevant standard preparation Arzneimittel well as with the contrast agent component which is used in practice but is not structurally The symbols a c acid Binz et Zeitschrift 16 21 thane enlegungsschrif published specification i od onyl thanolamine e published specification thane onate me li soph thalamic Intravenous Concentration injection solutions 300 rag Injection 20 Intracerebral 2 were always The concentrations Intracisternal Concentration of the 280 The concentrated aqueous solutions equired for a comparative investigation of the compounds and could not be prepared because of insufficient The value given for the compound P is approximative and not directly rabbits used each dose The animals were anaesthetised with mg kg 1 ml solution was used for every kg body Evaluation of the good still distinct weak maximal concentration obtainable because of limited The substantial improvement achieved with the compounds A E within the present and especially the compounds B and over the known compounds in respect of the suitability of heir aqueous solutions for is In the area of the central nervous the are substantially better tolerated than the previous Their intracistemal compatibility is many times Due to their high their osmotic pressure in their optimal intracistemal and intracerebral they can be used at high concentrations and in liquor preparations which have 10 hitherto not been accessible to photography by means of oontrast agents beoause insufficient The compounds G and are useless beoause of their insufficient i 15 The for the production of the of the general formula is characterised in that a reaotive derivative of the general formula 20 I CH2 S02 X is with a reaotive oompound of the in which X and Y are radicals reaotive to form the group R and one of the symbols X and Y is one of the halogen atoms bromine or iodine or an alkyl or halogen substituted alk grou as EXAMPLES OF PROCESS AND COMPOUNDS 1 A solution of g honic acid chloride in 600 ml of dried tetrahydro uran is added dropwise in the coures of 2 to 3 hours to g ml of dried THF at to mixture is subsequently stirred for a further 2 to 3 thus precipitated and the is then filtered off with The filtrate is evaporated in a The residue after evaporation is taken up with 1 litre of water and extracted with diethyl in order to remove the The aqueous solution is filtered clear and freed the residual in a column charged with a cation exchanger The eluate is neutralised with a 0 sodium hydroxide solution and completely evaporated in a The residue after evaporation is dissolved in 100 ml et anol and 500 ml chloroform and passed through a chromatography column charged with silica The eluate is freed from the solvent The residue is recrystallised twice from isopropanol 122 of Melting Boiling mm Hg soluble in 2 parts of water at slightly 0 3 parts soluble in benzene and C C Thin layer chromatogram on silica flow ha 10 2 oxyeth by the reaction of acid anhydride with 0 acid anhydride 2 g sodium are stirred 5k ml of concentrated o Common salt is this is filtered off with The residue is mixed portionwise with g The reaction mixture is heated at slightly boiling temperature for 3 to hours and then completely evaporated in a The residue of g of is recrystallised from dry diethyl Melting l The acid anhydride is very sensitive to heat and Reaction of with an g in ml of free chloroform 30 ml THP are mixed mol The resultant is isolated with the aid of an ion exchange resin after removal of the Melting Example od o c a c r ox th ox thy g aminoethox in 300 ml THF are reacted with g acid chloride in ml THP and then worked up according to the method described in Example The final product is crystallised from hot ethanol g of Melting 53 soluble in 2 parts of water at very eadily soluble in lower slightly soluble in G 1 S C S on silica flow chlorof Example g in isopropanol are mixed at about dropwise with a solution of g acid chloride in 80 ml while The surface layer chloride of 1 separates as is surface layer The reaction mixture with the residue is taken up water and extracted with ethyl The aqueous phase is freed from the hydrochloride on a cation exchanger the eluate is neutralised with a sodium hydroxide solution and graphed on silica gel with 1 The resultant product is recrystallised from g of Melting 78 soluble in parts of water at very readily soluble in methanol and soluble in C 3 G on silica flow od by protecting Preparation hydroxy1 functions propylamide ioxolane g acid chloride in 30 ml THF are added dropwise to g in ml of dry while The resultant hydrochloride crystallises it is filtered off with suction and can reconverted into the starting The filtrate is the residue taken up with the solution is washed with dried and completely Id 33 g of The is a viscous very readily soluble in lower ether and on silica flow heating in about 27 ml of hydrochloric The solution is neutralised a sodium hydroxide solution and completely evaporated in a The residue is recrystallised from a little 17 19 g of in g 80 C ϊ S G I s The oxolane 7 required as starting material for is prepared as 100 g dioxolane 1 chimica Acta are dissolved in 1150 ml mixed with 2 g hydrazine hydrate and stirred at temperature for 6 The resultant precipitate is filtered off suction and the filtrate is The residue after filtration and the residue after evaporation are mixed with 80 ml of a sodium hydroxide and the mixture is heated at 50 for is precipitated and filtered off with filtrate is extracted with The chloroform extract is carefully concentrated through a and the residue is fractionally Boiling 0 mm g of ca C G 6 onic by the reaction of iod with 1 g ome thane are dissolved in 200 ml of a sodium hydroxide g are and the mixture is heated to 6o while after about 3 the mixture is allowed to cool to room temperature while stirring is The resultant precipitate is filtered off wit It melts at 180 consists of unchanged filtrate is the residue is dissolved in 750 ml chloroform and ml freed from the precipitated sodium chloride by and chromatographed through a column charged with silica gel under chlorof 3 The eluate which shows only one spot in the thin layer is separated and The residue is recrystallised from g of Melting 79 on silica gel flow chlorof 7 in ml are reacted with g acid chloride ml The hydrochloride of thin surface layer separates as The whole reaction is evaporated in a The residue is dissolved in 3OO ml of The solution is extracted with ethyl The aqueous phase is freed from the hydrochloride on a column charged with a cation exchanger The eluate is neutralised with a sodium hydroxide evaporated and purified simplified chromatography on a column charged with silica as described in Example The resultant product is recrystallised from 2 g of Melting 75 soluble in parts of very readily soluble in methanol and in ethyl C S C I S on silica flow 10 1 8 ihyd rox is o e A solution g iod ome acid chloride in 175 is added dropvise at about in the course of 3 hours ith stirring to in ml The out isopropyla ine as a y The reaction mixture is the residue is taken up βθθ ml of water and extracted ethyl The aqueous phase is filtered clear and freed from the amine ide and the unreacted amine on a column charged a cation exchanger resin 550 ml Dowex acidic eluate is continuously neutralised a sodium hydroxide solution and completely evaporated in a The residue after evaporation is dissolved in 300 ml of dry ethanol and the precipitated sodium chloride is filtered 1320 ml chloroform are added to the filtrate which is passed through a chromatography column charged with 500 g silica gel under ethanol The eluate which shows in the thin layer on a silica gel plate with ethanol flow agent only one spot is separated and evaporated to dryness in a The residue is recrystallised from ethyl acetate with the of ethyl ether or from 68 g of Melting 87 soluble in parts of water at very readily soluble in readily slightly soluble in soluble ether and C S S on silica flow Preparation of isopropylaraide the reaction of 22 are dissolved in 100 ml of a sodium hydroxide are and the mixture is heated at 75 for 7 while After the resultant precipitate is off with g of The filtrate is the residue is dissolved in 1 and graphed on silica The eluate which shows only one spot on the thin layer chromatogram is evaporated and recrystallised from ethyl g of Melting after drying in a high vacuum on silica flow Example 10 Preparation of by the reaction of acid chloride with and subsequent partial hydrolysis of the resultant intermediate 23 g 150 ml mixed at to with a solution of 269 g sulphonic acid chloride while After at for 2 the precipitated hydrochloride of is filtered off with 191 g of melting 1 The filtrate is concentrated by evaporation and the residue is recrystallised from 1300 ml 330 g of Melting 137 0 S 0 I S found C I S very readily soluble in ethyl acetate and little soluble in isopropanol very sparingly soluble in water and on silica flow amide g are suspended in 1700 ml hydrochloric acid and briefly heated to while stirring whereupon a solution is This is cooled to room temperature and adjusted to pH 6 by means of ml of a sodium hydroxide The solution is then filtered clear and concentrated in a rotary evaporator at a bath temperature of The residue which crystallises slowly is dissolved in 4000 ml of hot ethyl The precipitated sodium chloride is filtered the filtrate is concentrated by evaporation and the recrystallised from ethyl ether or from Yield g of Melting 0 S S found C I S Solubility in water at a saturated solution contains 85 sulphonamide per 100 g the specific weight of this solution is The required as starting material for is obtained by catalytic hydrogenation of dioxan et 1175 in ethanol in the presence of sodium acetic acid and palladium 25 Boiling 70 mm Hg Melting 39 Equivalent The new of the formula are predomi antly used in the form of thei aqueous solutions The solutions may one or two of the relevant Dependent upon the intended there are used solutions at a concentration of about 20 to over with a content of about 100 to about Concentrated solutions are For and radiculography the solutions are instilled after lumbar or suboccipital For ventriculography the ventricles are directly 5 15 3 5 1 2 Preparation of solutions of the contrast agents is For the pure obtained according to the preceding Examples 1 10 dissolved under sterile conditions in the desired amount of The resultant solutions are filtered sterile and filled under sterile into serum bottles or sodium bicarbonate bidistilled water to make up a total volume of 100ml The acid amide derivative is dissolved at under nitrogen in a little The solution is adjusted to pH 7 the addition of sodium bicarbonate and then filtered through a filter with a pore diameter of adjusted to a volume of exactly 100 ml and filled under sterile conditions into stab bottles of 10 and 20 mi Iodine rag ainide 63g sodium bicarbonate bidistilled water to make up a volume of 100ml in analogy with iodine 280 iod omethane l 66g sodium bicarbonate bidistilled water to make up a volume in analogy with iodine iod omethane amide salt of tetraacetic acid disodium phosphate bidistilled water to make up a volume of 100ml as pH is adjusted with For this solution is lyophilised and is immediately before insufficientOCRQuality

Claims (1)

1. WHAT WE CLAIM of the R N in which R represents hydrogen or a methyl and represents a β β or of the general formula in which has the meaning defined in Claim of the formula OH OH amide of the formula of the formula of the formula A composition of contrast agent which is particularly suitable for the portrayal of the liquor as a readily of the general formul given and defined in Claim A composition of contrast agent which is particularly suited for the portrayal of the liquor spaces as a readily of the general formula in claim A composition of contrast agent for the portrayal of the liquor especially for radiculography and containing the highly and readily tolerated sulphonic of the formula OH OH which is capable of forming aqueous A composition of contrast agent for the portrayal of the liquor especially for and containing the highly and readily tolerated of the formula which is capable of forming aqueous Process for the production of a sulphonamide of the formula given and defined in claim 1 which includes reacting a reactive sulphonic acid derivative the general S02 X with a reactive compound of the formula Y reactive to 29 N and of the symbols X and Y represents one of the halogens bromine or or means an alkyl or halogen substituted or group while the other means a group which R means hydrogen or and represents the or wherein the hydrogen atom of each of the hydroxyl groups is optionally replaced by a protective and if a protective group is liberating the hydro groups b hydrolysis or selective Process according to Claim characterized in that a reactive iodomethane acid derivative of the formula in which Z is one of the halogen bromine or iodine or an sttlphonyloxy group is reacted with an amlnoalkano or of the formula R in which R and are as in Claim roceas according to Claim wherein Z is a group of the formula 30 Process according to Claim wherein an of the formula R in which R is hydrogen atom or a methyl reacted in the presence of a basic condensation agent with a halide or sulphonic acid ester of the general formula A in which A is a halogen atom or a sulphonic acid group and is as defined in Claim Process according to anyone of claims 11 to wherein the reaction of the compound of the formula with the compound of the formula is carried out in a basic Compositions according to Claim substantially as herein described and Processes according to Claim substantially as herein described and For the COM AND PARTNERS insufficientOCRQuality