Патент USA US2404737код для вставки
Patented July 23, 1946 ’ 2,404,737 UNITED STATES PATENT OFFICE 2,404,737 SULPHANILYLSULPHANILADHDE DERIVATIVES‘ ‘ ‘ Maurice L. Moore, Detroit, Mich., assignor a Sharp & Dohme, Incorporated, Philadelphia, Pa., a corporation of Maryland No Drawing. Application July 5, 1943, Serial No. 493,578 20 ‘Claims. (Cl.260-239..6) ' 1 2 This invention relates to N4-carboxyacyl-sul of the radical T is ‘different from the radical M; and E, G, and ‘R1 are. each separately selected phanilylsulphanilamidothiazoles, in which the carboxyacyl group is the radica1 remaining when ‘ from hydrogen and alkyl, aralkyl and aryl rad the hydroxyl group is removed from only one of icals; and R2 and R3 may be separately hydrogen as well as an alkyl radical, saturatedlor unsatu the two or more carboxyl ‘groups of a polycar rated, for example, methyl, ethyl, propyl, butyl, amyl, allyl, hexyl, heptyl, octyl and the like, or boxylic acid, and the invention covers such prod ucts containing the remaining 'carboxyl group decyl, dodecyl, hexadecyl and the like, as well as anaralkyl radical as benzy1 and the like, as well or groups'unaltered as well as with the hydrogen in any of such remaining carboxyl groups replaced by a carboxylate-forming element or radical. The new products of this invention are in gen eral therapeutically useful in varying degrees and applications, for example, in treating ailments of theintestinal tract.‘ , The products of this invention may be repre sented by the general formula 10 as an aryl radical as phenyl, (unsubstituted as well, as substituted, for example, having nitro, amino, alkyl, carboxyl, sulphonic ‘acid, hydroxy, alkoxy with the alkyl saturated or unsaturated and straight or branched chain, phenyl, halogen 15 such as chlorine, and the like substituentaas well as the naphthyl and diphenylradicals, eachsim ilarly unsubstituted as well as substituted, and a‘ (...C00...),,...T nitrogen-containing radical as nitro and amino (unsubstituted and substituted as ‘acyl- and 20 alkyl—), and an oxygenated radical, for example, hydroxy, m in which M is selected from hydrogen and mono valent and polyvalent radicals capable of com‘ bining with a carboxyl radical to form arcar boxylate, such as the alkali metals sodium, potas sium, lithium and the like, the alkaline earths alkoxy such .as methoxy, ethoxy, propoxy, and carbalkoxy such as carbmethoxy, carboxyL- and halo-alkyl as chlorethyl and the like, and halogen, for example, chlorine and 2 bromine, , I In this speci?cation and its appending claims, the term “carboxylates” relates to the products as calcium, magnesium, barium and the like, an resulting when the acid formiof the products of timony, copper, gold, iron, bismuth and man the invention (that is, the form in which the ganese and the like, an alkyl radical, a nitrogen 30 carboxyl groups of thecompounds have not been base as ammonium and corresponding radicals neutralized) is converted to the carboxylate form of alkyl amines and alkanolamines and the like; by replacement of the hydrogen of the free car and R is the residue of a polycarboxylic acid, boxyl group or groups thereof by a mono-valent aliphatic, aromatic, as well as heterocyclic, metal or group, or by one of the valences of a stripped of its carboxyl groups; and T is selected 35 poly-valent metal as illustrated at column 1, lines from hydrogen and the M-monovalent radicals 23-32 above. , i and free valences 0f the M-polyvalent radicals not The carboxyacyl group (remaining group when satis?ed by the single carboxyl group shown di the hydroxy group is removed from only one of rectly linked to M; and n is selected from zero the at least two carboxyl groups of a polycar and any whole number up to four, whereby the 40 boxylic acid) may be derived from any desirable grouping (- - - COO - - ‘)n - - - T represents the carboxyl and the carboxylate groups over two from any polycarboxylic acid having more than two carboxyl groups, and m is a small number se polycarboxylic acid, for example, aliphatic, aro matic, and heterocyclic, such asthe aliphatic polycarboxylic acids as‘ the saturated aliphatic polycarboxylic acids such as the dicarboxylic acids, lected from the'class consisting of (A) one, in 45 oxalic and malonic acids and their methylene those compounds embraced herein in which all of non-substituted homologues, succinic, glutaric, the carboxyl groups in the carboxyacyl radical adipic, pimelic, suberic, azelaic and sebacic ‘acids satisfy all of the valences of any polyvalent rad and‘the like, and derivatives thereof exempli?ed icals represented by M and T, and (B) a small by malonic acid and its homologues, in any of number equal to the valences of M, in those com w which at least one of-the hydrogens of at least pounds embraced herein and selected from those one of ‘the available chain methylene groups is ‘re (a) in which n is zero, (12) in which each 00 placed by any desirable substituent, for example, currence of the radical T is selected from hy alkylisaturated as well as unsaturated) , hydroxy, drogen and any of the monovalent radicals repre amino, carboxyl, and the like.- O-fsrichderiva sented by T, and (0,)‘ in which each occurrence 55 tives, the saturated-alkyl-substituted-methylene 2,404,737 4 3 type is shown by the monoalkyl examples as ample, the dicarboxypyrazines, such as antipella inethyl-malonic, ethyl-malonic, butyl-malonic, pyrotartaric (methyl-succinic) and ethyl-succinic acids, and the saturated-dialkyls by dimethyl pyrazine and 2,6-dicar-boxyDyrazine, as well as the gric acid (2,3-dicarboxypyrazine), 2,5-dicarboxy-. malonicrand diethyl-malonic acids, and the un derivatives thereof substituted on the nucleus, for ' 5 example, those alkyl-substituted on the nucleus, saturated-alkyl by allyl-malonic acid. The hy droxy-substituted-methylene type is exempli?ed by tartronic (hydroxy-malonic) and malic (hy nuclear-monoalkyl derivatives, as 2,3-dicarboxy é-methyl-pyrazine, and the nuclear-dialkyl deriv droxy-succinia'in the three isomeric forms) acids atives as 2,3edicarboxy-5,6-dimethyl-pyrazine, as as the homologs of antipellagric acid such as the and the polyhydroxy-substituted by the dihydroxy 10 Well as 2-carboxy-3-methylu5-carboxy-?-methyl pyrazine, and also dicarboxypyridazines such as type shown by tartaric (dihydroxy-succinic) acid é,5-dicarboxypyridazine as well as the derivatives‘ and the tetrahydroxy example in talomucic acid. The amino~substituted-methylene type is demon thereof substituted on the nucleus, such as those strated by aspartic (aminosuccinic) and glutamic » alkyl substituted on the nucleus as 4.5-dicarboxy acids. The mixed-substituted-methylene type is 15 3,6-dimethyl-pyridazine, and also the dicarboxy pyrimidines such as e,5-dicarboxypyrimidine and 4,6-dicarboxy-pyrimidine. Also included are the thiazole polycarboxylic acids such as the dicar boxythiazoles, as well as the derivatives thereof type. Unsaturated aliphatic dicarboxylic acids from 20 substituted on the nucleus, such as 2-methyl-4,5 shown by citramalic (2-hydroxy-2-methyl-bu tanedioic) and citric acids, the latter serving also to point out the carboxylic-substituted-methylene which the carboxyacyl radical is derived corre spond to any of the above mentioned saturated examples having at least four carbon atoms and dicarboxythiazole. these N4-carboxyacylsulphanilylsulphanilamid othiazoles by heating the desired polycarboxylic further particularized by maleic and citraconic (methylmaleic) acids and their respective iso mers, ,fumaric and mesaconic (methyl-fumaric) acids. ' , i acid, its anhydride,» or an ester, such as an ‘alkyl ester, or a monohalide, such as the monochloride or a monochloride of the ester, or acid chloride ' Other aliphatic polycarboxylic acids from which the carboxyacyl radical may be derived are the tribasic, saturated as Well as unsaturated, acids exempli?ed respectively by tricarballylic ' The invention also includes the preparation of 36 such as the di-acid chloride, thereof with, for example, any desired sulphanilylsulphathiazole, either merely together or in an inert reaction me dium such as an inert solvent, and as in'the lat ter case'separating the desired end product or, and aconitic acids and derivatives thereof as as in the'case of the use of the ester or the acid those in which anyof the methylene or chain hy~ chloride, liberating the end product by hydrolysis, drogens is replaced by any desirable substituent (as pointed out in relation to the dicarboxylic 35 and in any case, where necessary, subjecting it to puri?cation as by recrystallization. Thus, for acids) illustrated by citric acid. example, with the aliphatic dicarboxylic acids " The aromatic=>'(aryl) polycarboxylic acids from which ,the-carboxyacyl radical may be derived having less than four carbon atoms in the chain. the alkyl diester vof the dicarboxylic acid is re may be anaryl dicarboxylic acid or .aryl tricar boxylic acid as trimellitic acid as, well as‘pne V40 acted with the sulphamlylsulphathiazole selected. With the aliphatic acids having four and ?ve car containing up to six carboxyl groups, as mellitic acid, and > those having replaceable hydrogen bon atoms in the chain and with the aromatic polycarboxylic acids ‘having two carboxyl groups ' atoms may or may not have other substituents on the aromatic nucleus. Those having no substit- ,. orthoto each other, the desired anhydride is uents on the aromatic nucleus are illustratedjby '“ taken as the starting material, While with the ali the aryl dicarboxylic. acids, such as the isomeric phatic acids having. over ?ve carbon atoms in the phthalic acids, phthalic (ortho), isophthalic (meta) and terephthalic (para). In those ‘having other substituents on the nucleus, such substit“ uents may be illustrated by alkyl (mono- and di-), alkoxy, hydroxy, halo,'nitro and other common groups, for example, xylidic (or uvitic, 5-methyl— chain vwith the‘ aromatic acids ‘having no carboxyl group in ortho position to another car boxyl group, the free acid may be heated directly with the selected .sulphanilylsulphathiazole. If desired,- the monohalide of the est-er of any of the acids may be used as the starting material. 1,-3-dicarboxylicbenzene), cumidic (dimethyl The invention may be illustrated by, but not phthalic), hemipic' (dimethoxy-phthalic), and restricted to, the following: coccinic (hydroXy-methyl-phthalic) acids, While 55 ExampZc.—-N4-succinyl -N1 -4- (2 ethiazolyl the above speci?cally named aromatic acids illus sulphamyl) ephenylsulphanilamide ' trate the mononuclear or phenyl-polycarboxylic acid type, these aromatic polycarboxylic acids in 25.5 grams vof sulphathiazole was dissolved by clude also those of the polynuclear type such as warming in 200 cc. of dry pyridine. To this was the naphthyl polycarboxylic acids as naphthalic 60 added, in portions with stirring, 34.0 grams of (naphthalene-1,8-dicarboxylic acid), naphtha p-acetylamino-benzene sulphonyl chloride. The lene-1,2-dicarboxylic acid, naphthalene-2,3-di reaction mixture after standing overnight was carboxylic acid, 50 naphthalene-1,4-dicarb0xylic poured into a mixtureof crushed ice and hydro chloric acid. vThe resulting precipitated solid was The-heterocyclic polycarboxylic acids from which 65 collected on a ?lter-and'washed with water. The the carboxyacyl radical may be derived may be crude acetyl derivative, ' '‘ acid and naphthalene-1,5-dicarboxy1ic acid. any desirable heterocyclic polycarboxylic acid, for example, the pyridine polycarboxylic acids as the dicarboxypyridines such as quinolinic acid (2.3 dicarboxypyridine), lutidinic acid (2,5i-dicar 70 ' . r I 011,0 ONHGSOzNHOSOzNHC ‘ 1 t - " 1! \ on / N .. . boxypyridine), 2,5r-dicarboxypyridine, cinchome ronic, acid; t('3,4'-dicarboxypyridine), dipicolinic thus obtained'was heated in a mixture of 400 cc. of 6N hydrochloric acid and 50 cc. of ethyl alcohol. acid (2,6-dicarboxypyridine), and dinicotinic acid After about 30 minutes heating, the‘ deep red (3,5-dicarboxypyridine) , also the diazine polycar boxylio acids as the dicarboxydiazines, for ex 75 solution. which. resulted was decolorized with’ . 2,404,737 5 6 charcoal, cooled slightly, and the solid sulphanilyl thiazole with a substantial excess of ethyloxalate on a, hot plate at around 130-150” C. for about two hours with occasional stirring and then wash ing the reaction mixture with dilute hydrochloric acid and water and directly or after intermediate sulphathiazole, puri?cation, for example, ‘by recrystallizations such as from dilute alcohol, placing the reaction precipitated by adding 200 cc. of concentrated product in approximately 150 cc. of a 2.5% solu ammonia, melted at 168° C. 11.82 grams of this tion of sodium hydroxide and heating on the hot intermediate was suspended in 100 cc. of dry dioxan, heated to re?ux, and 8.0 grams of suc 10 plate for around a half hour at 95-100” 0., and then decolorizing the solution with charcoal and cinic anhydride added with stirring. The reac making it slightly acid by the addition of con tion mixture was re?uxed further for 20 minutes, centrated hydrochloric acid, there results N4 during which period, all of the material went oxalyl-sulphanilylsulphathiazole. By replacing into solutionand a solid subsequently started crystallizing out. The cooled reaction mixture 15 the ethyl oxalate by ethyl malonate, there results N4-malonyl-N1—4- (2-thiazolylsulphamyl) —phenyl was ?ltered and washed with dilute hydrochloric sulphanilamide. The corresponding carboxyacylsulphanilylsul acid, yielding 12.18 grams of N4-succinyl-N1-‘l (2.-thiazolylsulphamyl) -phenylsulphanilamide, S—CH I II 110 o 0 011201120 ONHOSOZNHOsOENHQ \ /o11 phathiazoles from the transform succinic acid 20 derivatives may be obtained by replacing the ethyl oxalate or malonate in the immediately pre ceding procedure by an equivalent quantity of a monochloride-ester of such succinic acid deriva tive or unsaturated isomer and with little or no N which crystallized from a water-dioxan mixture as needles decomposing at 233° C. ‘By replacing the succinic anhydride in this 25 heating, for example, with the equivalent quan tity of the moncchloride of the ethyl'ester of, for example by the equivalent quantity of the possible example, fumaric or mesaconic acid. These compounds and those from the amino inner anhydrides of other succinic acid deriva tives, such as pyrotartaric, ethylsuccinic, maleic and hydroxy-substituted derivatives of succinic and citraconic acid anhydrides and the like or by glutaric anhydride, or by phthalic, cumidic or 30 acid are exempli?ed by: Nt-malylsulphanilyh sulphathiazole, N4 - aspartylsulphanilylsulpha hemipic anhydride, or the anhydride of diphenic thiazole, N4-citramalylsulphanilylsulphathiazole, acid or of naphthalic acid, corresponding N4 N4- tartarylsulphanilylsulphathiazole, N4- fum carboxyacylsulphanilylsulphathiazoles are ob tained, for example: ‘ 35 N4; pyrotartaryl-N1- 4 -(2 - thiazolylsulphamyl) - phenylsulphanilamide, N4-ethylsuccinyl - N1‘- 4 -(2-thiazolylsulphamyl) phenylsulphanilamide, ' ‘ N4-maleyl-N1- 4 -(2-thiazolylsulphamyl) éphenyl sulphanilamide, 40 nitylsulphanilylsulphathiazole, phanilylsulphathiazole, ‘ ‘ N4-glutary1-N1—4- (2-thiazolylsulphamyl) -phenyl sulphanilamide, ‘ Né- phthalyl - N1- 4 -(2 - thiazolylsulphamyD - phenylsulphanilamide, N4-cumidyl-N1-4- (Z-thiazolylsulphamyl) -pheny1 sulphanilamide, N4-hemipyl-N1-4— (2-thiazoly1sulphamy1) —pheny1_ sulphanilamide, ' By heating separate 10 gram portions of sul 45 phanilylsulphathiazole separately with an equi-‘ molecular weight of adipic acid, pimelic acid, suberic acid, azelaic acid and sebacic acid, at around 130-150° C. for at least twenty minutes and then treating the respective reaction mix 50 tures separately with a suitable quantity, for ex ample, 60 cc. of 10% sodium carbonate solution,‘ N4- diphenoyl - N1- 4 -(2 - thiazolylsulphamyl) phenylsulphanilamide, and ‘ ?ltering off the insoluble, undesired ‘by-Products, and neutralizing the ?ltrate with dilute hydro chloric acid, there results the corresponding: ' N4-naphthaloyl - N1- 4 -(2 - thiazolylsulphamyl) phenylsulphanilamide. ‘ N4 - mellitylsul N4-coccinylsulphanilyl sulphathiazole and N4-(4-hydroxy-3-carboxyl benzoyl) -sulphanilylsulphathiazoleQ N4- citraconyl - N1- 4 -( 2 - thiazolylsulphamyl) phenylsulphanilamide, ‘ arylsulphanilylsulphathiazole and N4-mesaconyl sulphanilylsulphathiazole. Similarly, there is obtained N4-citrylsulphanil ylsulphathiazole, N4-glutamylsulphanilylsulpha thiazole, N4-talomucylsulphanilylsulphathiazole, N4-tricarballylsulphanilylsulphathiazole, N4-aco— 65 Similarly, by separately replacing the succinic N4-adipyl-N1-4-(2 - thiazolylsulphamyl) -phenyl- ' sulphanilamide, N4-pimelyl-N1-4 - (2-thiazolylsul phamyl) -phenylsulphanilamide, N4-suberyl-N1-4 ‘anhydride by the equivalent quantity of ‘2,3 (2 - thiazolylsulphamyl) - phenylsulphanilamide, dicarboxy-pyrazine anhydride, and the anhydride N4-_azelay1-N1-4- (2- thiazolylsulphamyll -phenyl of 2,3-dicarboxy-5,6-dimethyl-pyrazine andxof 2,3-dicarboxy-S-methyl-pyrazine, there results 60 sulphanilamide, and N4-sebacy1-N1-4-(Z-thiazol ylsulphamyl)-phenylsulphanilamide. the corresponding: N4- (B-carboxy-pyrazinoyl) N1- 4 -( 2 - thiazolylsulphamyl) -phenylsulphanil amide, N4-(3-carboxy-5,6—dimethyl-pyrazinoy1) N1- 4 -(2 - thiazolylsulphamyl) — phenylsulphanil- , amide, and N4-(3-carboXy-5-methyl-pyrazinoyl) - ‘ ' By heating sulphanilylsulphathiazole with ap proximately a 15% excess over an equimolecular 65 portion of respectively lutidinic acid, dinicotinic acid, and 'dipicolinic acid, in intimate mixture to a fusion temperature around between 160-190° C. in a sand bath for about between an hour and amide. Likewise, with the corresponding stoi an hour and a half with occasional manual stir chiometric equivalent of respectively quinolinic ring, then cooling the melt and taking it up in acid anhydride, cinchomeronic acid anhydride and of 2-methyl-4,5-carboxythiazole anhydride,‘ 70 dilute alkali, around 5%, and precipitating with a slight excess of hydrogen chloride, and then there results: N4-quinolinoyl-sulphanilylsulpha— ?ltering off the precipitate and treating it with thiazole, cinchomeronoyl- and (2,-rnethyl-5 cool sodium bicarbonate solution and ?ltering oil“ carboxythiazole-4-carboxylyl) -N1-4-(2-thiazolyl the ‘soluble residue, and then making this ?ltrate sulphamyl) -phenylsulphanilamide. . slightly acid with hydrogen chloride, there result By heating 5 grams of sulphanilylsulpha N1- 4 —(2 - thiazolylsulphamyl) - phenylsulphanil 2,404,737 the iollowine ‘corresponding products, which may be further puri?ed by, forexample, reprecipita therein Within the scope of the depending claims tion: N4-lutidinoyl-Nl-4- (‘Z-thiazolylsulphamyl) - as limited by the state'of the art. tions, extensions or substitutions may be made ‘ " ' phenylsulphanilamide, N4-dinicotinoyl-N1-4-(2 What is claimed is: thiazolylsulphamyl)ephenylsulphanilamide, and 5 1. N4 - carboxyacyl - N1 - [4 - (2 - thiazolyl N‘l-dipicolinoyl - N1 - 4 -(2 - thiazolylsulphamyl) - phenylsulphanilamide. By adding an equimolecular stoichiometric equivalent of sulphanilylsulphathiazole in small ~ ; r _ sulphamyl) -phenyl] -sulphanilamides having the general formula V. (...Q00..,),,...T ' ‘ S_.-C-';[?;iv portions over a forty minute period to a solution of a given amount of the di-acid chloride of 4,6 dicarboxypyrimidine in a suitable quantity of a solvent such as dioxan (for example, .006 mol of N_- my and the carboxylates thereof, in which R is the residue of a polycarboxylicra'cid stripped of'its carboxyl groups; nris selected from zero and any whole number less than five; E, G and R1 are each separately and independently a 'memb'er‘of each reactant in about 50 cc. of solvent) and per mitting the mixture to stand at room temperature for about at least ten minutes after the addition is completed, and then pouring the mixture into the class consisting of hydrogen and alkyl, aral a suitable quantity (approximately 100 cc.) of kyl and aryl radicals; and the thiazole ring‘ to dilute sodium bicarbonate solution, ?ltering. o? the insoluble portion after the effervescence dis 20 gether with R2 and R3 attachedto that ring rep resent a member of the 'class consisting of thi continues, then clarifying the ?ltrate with char azole radicals. ' ' l coal and after the removal of the latter making 2. N4 - carboxyacyl - N1 - [4 - (2 - thiazolyl the ?ltrate acid with hydrogen chloride and chill ‘ sulphamyl) -phenyll-sulphanilamides, in which . ing it, there results N4-(6-carboxy-pyrimidine-4 carboxylyl) -sulphanilylsulphathiazole. ’ 25 The carboxylate form of any of the compounds of the invention may be prepared, for example, “Z-thiazolylsulphamyl” represents a thiazolyl nu cleus linked through its carbon atom in the 2-po sition to the sulphonamido nitrogen and having by adding to a small amount of water an excess its carbon atoms in the four and five positions of the compound over its solubility in water and linked to one another by a double bond, dissolving the excess by stirring in a su?icient 30 ' 3. N4 - carboxyacyl - N1 - [4 - (2 - thiazolyl ‘ quantity of, for example, anhydrous sodium car sulphamyl) -phenyl'] -sulphanilamides, in ' which bonate. The solution is preferably ?ltered and from the ?ltrate the highly soluble sodium salt “2-thiazolylsulphamyl” represents . a thiazolyl nucleus linked through its carbon atom in the , can be isolated, for example, by adding an equal Z-position to, ' the sulphonamido nitrogen ‘and volume of alcohol and pouring the resulting so 35 having its carbon atoms in the four and ?ve po sitions linked to one ‘another by a double bond, lution into about 10 volumes of acetone. ‘The in which the carboxyacyl group is ‘aliphatic. ‘ substance thrown out of solution is permitted to 4. N4 - carboxyacyl - N1 .- [4 .- (2.- thiazolyl settle and the supernatant liquid withdrawn and sulphamyl) -phenyll-sulphanilamides,r in’ which the residue preferably treated several times with fresh acetone. After decanting the acetone from 40 “Z-thiazolylsdlphamyl” represents a: thiazolyl nucleus linked through its carbon atom in‘ the the last treatment, the resulting desired sodium 2-position to the sulphonamido nitrogen and salt may be dried preferably under vacuum. having its carbon atoms in the-four and '?ve po Other metal carboxylate salts of the com sitions linked to one another by a double bond, pounds such as the copper, gold, iron and bismuth salts and the like may be obtained by reacting 45 in which the carboxyacyl group is aromatic. 5. N4 - carboxyacyl - N1 - [4 - (2 - thiazolyl the alkali metal salts, preferably in aqueous solu sulphamyl) -phenyl] -sulphanilamides, in- ‘which tion, with a suitable soluble salt of the metal, “2-thiazolylsulphamyl‘»’ represents a thiazolyl the carboxylate salt of which is desired. The de nucleus linked through its carbon atom in the sired carboxylate salt is obtained by resulting double decomposition. ' 50 2-position to the sulphonamido nitrogen. and having its carbon atoms in the four and ?ve, po The compounds of the invention, applicable in sitions linked to one another by a double bond; treating ailments of the intestinal tract, exhibit in which the carboxyacyl group is heterocyclic. such activity by the introduction to the various 6. N4 - carboxyacyl - N1 - [4 - (2 - thiazolyl nuclear portions of the individual compound; of sulphamyl)-phenyl]-sulphanilamides, in which substituents, the introduction of which into the "2-thiazolylsulphamyl” represents a thiazolyl basic nucleus leaves the compound substantially nucleus linked through its carbon atom in the non-toxic so that it would cause no permanent‘ 2-position to the sulphonamido nitrogen and injury to the subject when administered in the having its carbon atoms in the four and ?ve po necessary therapeutic dosage. The metallic ele ment in the compounds used as in preparations 60 sitions linked to one another by a double bond, and in which the carboxyacyl group is saturated for treating intestinal ailments are such that aliphatic. ' their inclusion in the compound introduces simi 7. N4 - carboxyacyl - N1 .- [4 - (2 ,-'thia_zolyl larly no unduly toxic characteristics. Thus, for example, as withv N4-succinylsulphanilylsulpha— multaneously high blood level.» sulphamyl)-phenyll-sulphanilamides, in which 05 “2-thiazolylsulphamyl” represents a thiazolyl nucleus linked through its carbon atom in the thiazole, it is possible to build up a high con .centration in the intestinal tract Without a- si ‘ 2-position to the sulphonamido nitrogen and having its carbon atoms in the four and ?vepo-v The'various compounds, used in the treatment of intestinal ailments are administered orally, sitions linked to one another by a double bond, either in the form of tablets, capsules or powders 70 and in which the carboxyacyl group is saturated aliphatic and is free of substituents on the meth of the solid material, or as solutions of any suit able concentration thereof. ' lyene carbons of its chain. ' ‘ While the compounds constituting the inven 8. N't- carboxyacyl - Nl - [4 - (2 - thiazolyl tion have been described by reference to certain sulphamyl) -phenyllesulphanilamides, in which speci?c embodiments thereof, other modi?ca 76 "2-thiazolylsulphamyl”r represents a thiazolyl 2,404,737 10 in which the carboxyacyl group is ‘derived from a mononuclear aryl dicarboxylic acid having its nucleus linked through its carbon atom in the 2-position to the sulphonamido nitrogen and carboxy groups in ortho position to one another. having its carbon atoms in the four and ?ve po sitions linked to one another by a double bond, and in which the carboxyacyl group is aliphatic and has four carbon atoms in its carbon chain. 15. N4 - carboxyacyl-N1-[4-(2-thiazolylsulph ‘amyl) -phenyl]-sulphanilamides, in which “2 9. N4 - carboxyacyl - N1 — [4 - (2 ‘- thiazolyl - thiazolylsulphamyl” represents a thiazolyl nu cleus linked through its carbon atom in the 2 sulphamyl)-phenyl]-su1phanilamides, in which “2-thiazolylsu1phamyl” represents a thiazolyl ing its carbon atoms in the four and ?ve posi position to the sulphonamido nitrogen and hav nucleus linked through its carbon atom in the 10 tions linked to one another by a double bond, and in which the carboxyacyl group is-derived 2-position to the sulphonamido nitrogen and from a mononuclear aryl dicarboxylic acid hav having its carbon‘ atoms in the four and ?ve po ing ‘its aryl radical free of substituents on the sitions linked to one another by a double bond, remaining nuclear carbons. and in which the carboxyacyl group is saturated 16. N4 - phthalyl - N1 - [4-(2-thiazolylsulph aliphatic and has four carbon atoms in its car amyl) ~pheny1l-su1phanilamide in which the 2 bon chain. ‘ i thiazolylsulphamyl group is the radical 10. N4 - carboxyacyl - N1 - [4 - (2 - thiazolyl - sulphamyl)-phenyl]-sulphanilamides, in which “Z-thiazolylsulphamyl” represents a thiazolyl nucleus linked through its carbon atom in the 20 2-position to the sulphonamido nitrogen and having its carbon atoms in the four and ?ve po 17. N“1 - carboxyacyl - N1-[4-(2-thiazoly1sulph sitions linked to ‘one another by a double bond, amyl)-phenyl]-sulphanilamides, in which “2-. and in which the carboxyacyl group is saturated thiazolylsulphamyl” represents a thiazolyl nu aliphatic and has four carbon atoms in its car 25 cleus linked through its carbon atom in the 2- ‘ bon chain and is free of substituents on the position to the sulphonamido nitrogen and hav methylene carbons of its chain. . ing its carbon atoms in the four and ?ve posi 11. N4-succinyl-N1- [4- (Z-thiazolylsulphamyl) tions linked to one another by a double bond, and phenyll-sulphanilamide, in which the 2-thia in which the carboxyacyl group is derived from a 30 dicarboxypyridine. zolylsulphamyl group is the radical , 18. N4 - carboXyacyl-N1-[4-(Z-thiazolylsulph i'—‘ W‘ ~—S_OzNH-C C—H amyl) -phenyl]-sulphanilamides, in which “2 thiazolylsulphamyl” represents a thiazolyl nu cleus linked through its carbon atom in the 2 N position to the sulphonamido nitrogen and hav ing ‘its carbon atoms in the four and ?ve posi 12. N4 - carboXyacyl-N1-[4-(2-thiazolylsulph amyl)-pheny1]-sulphanilamides, in which “2— tions linked to one another by a double bond, and in which the carboxyacyl group is derived from a thiazolylsulphamy ” represents a thiazolyl nu cleus linked through its carbon atom in the 2 position to the sulphonamido nitrogen and hav~> ing its carbon atoms in the four and ?ve positions linked to one another by a double bond, and in which the carboxyacyl group is derived from an aryl dicarboxylic acid. 13. N4 _ carboxyacy1-N1-[4-(2-thiazolylsulph amyl) -phenyll-sulphanilamides, in which "2 thiazolylsulphamyl” represents a thiazolyl nu cleus linked through its carbon atom in the 2 position to the sulphonamido nitrogen and hav ing its carbon atoms in the four and ?ve posi tions linked to one another by a double bond, and in which the carboxyacyl group is derived from a mononuclear aryl dicarboxylic acid. 14. N4 - carboxyacyl-Nl-[4-(2-thiazolylsulph Mv dicarboxypyridine having its carboxy groups in ortho position to one another. . 19. N4 - carboXyacyl-N1-[44(2-thiazoly1su1ph amyl)-phenyl]-sulphani1amides, in which “2 thiazolylsulphamyl” represents a thiaz'olyl nu cleus linked through its carbon atoms in the 2 position to the sulphonamido nitrogen and hav ing its carbon atoms in the four and ?ve posi tions linked to one another by a double bond, and in which the carboxyacyl group is derived from a dicarboxypyridine free of substituents on the remaining nuclear atoms. ' 20. N4 _ quinolinyl - N1-[4-(2-thiazo1y1su1ph amyl) -phenyll-sulphanilamide, in which the 2 thiazolylsulphamyl group is the radical amyl)-pheny1]-sulphanilamides, in which thiazolylsulphamyl” represents a thiazolyl nu cleus linked through its carbon atom in the 2 position to the sulphonamido nitrogen and hav ing its carbon atoms in the four and ?ve posi tions linked to one another by a double bond, and ' MAURICE L. MOORE.