IL28034A - Benzenesulfonyl ureas and process for their manufacture - Google Patents

Description

C O H E N Z E D E K S P I S B A C H PAT E N T ATTO R N E YS LEVONTIN T E A V V P A T E N T S D E S I G N S O R D I N A N C E SPECIFICATION PROCESS FOR THEIR FA WEB KE HOECHST A KT GES E LLSCHA FT VOfiMA IS ME IS TEH LUCIUS a of Frankfurt am DO HEREBY DECLARE the nature of this invention and in what manner the same is to be performed to be particularly described and ascertained in and by the following statement and their The present invention relates to corresponding to the formula X CO phenylene NH CO NH R R which as such or in the form of their physiologically tolerable salts show hypoglycemic properties and are characterized by a strong and a long lasting In the represents lower lower nhenylalkyl or preferably a disubstituted with methyl and alkoxy containing 1 2 carbon of the formula 0 of the formula or X represents a phenyl carrying in any desired positions the Z and which may be identical or V Z represents lower phe phenyl lower tri represents lower alkoxyalkoxy or a tetrahydronaphthyl radical thienyl a radical which be or tuted by lower aryl or a tetra radical or a thenyl the meaning of X mentioned under being Y represents a hydrocarbon chain of 1 carbon preferably the grouping In the above and the following definitions always stands for an alkyl group containing 1 to carbon atoms in a straight or branched stands for an acyl radical acid containing up to carbon preferably a or branched alkanoyl radical of a corresponding of According to the definitions R may for compounds in which R represents hydrogen being Ring systems representing the member X in the mentioned for the 4 As examples for the bridge member Y there are 3 those binding the benzene nucleus with the carbonamide group over 2 carbon atoms are As the following radicals are or The formula by is preferably mono or by or lower π pni l p i n being The present invention also relates to processes for the preparation of said wherein benzenesul acid benzenesul acid acid halides or or semicarbazones substituted by the group X CO Y R are reacted with amines if the salts benzenesulfonamides of the formula X CO Y phenylene or their salts are reacted with correspondingly substituted benzenesul acids or acid amidines are hydrol in correspondingly substituted the sulfur atom is exchanged for an oxygen to correspondingly substituted water is corresponding or are in of the formula phenylene NH CO NH R the radical X CO is introduced by if desired in several correspondingly substituted are reacted with in correspondingly substituted or the sulfur atom or the sulfur atoms are exchanged by an oxygen atom or oxygen if R is compounds of the formula X C N phenylene S02 U or their parabanic acid derivatives or compounds of the ormula X C N phenylene S0 H C N u u wherein U represents alkyl or halogen are or unsaturated are hydrogenated and the reaction products are treated with alkaline if the formation of is According to the nature of the starting substances in particular of the member X one or the other method mentioned above for the preparation of certain individual compounds corresponding to the general formula may be unsuitable in some at least require measures for the protection of active Such cases which do not occur very often can easily be recognized by the expert and there will be no culty in applying in these cases one or the other methods of synthesis described Instead of the benzenesul there can wise be used reaction products of benzenesul with acid amides for as caprolacta or furthermore with weakly basic amines for as The acid esters or the acid esters may contain in the alcohol component a alkyl radical or a phenyl The same applies to carbamic acid esters or the corresponding thiocarbamic acid As carbamic acid halides there are above the The used as starting substances for the process of the invention may be unsubstituted at the side of the urea molecule opposite to the sulfonyl group or may be or Since these substituents are split off during the reaction with their nature can vary in wide Instead of substituted by an acyl heterocyclic there can likewise be used the benzenesulfon l which ma possible to treat such or h amines of the formula and to heat the salts so obtained to an elevated to a tempera ture above it is possible to start from ureas of the formula R or from such ureas which are in particular at the free nitrogen atom and to react these with substituted by the ing As such starting substances are R for or at the correspondingly in which case the phenyl radicals may be stituted and may be linked with one another directly or by means of a bridge member such as or or as well as the corresponding or and finally the ureas of formula Hydrolysis of the mentioned or sulfon ormic acid amidines is suitably carried out in an alkaline and can be hydrolysed successfully in an acid The sulfur atom in correspondingly substituted can be replaced by an oxygen in known for example with the aid of oxides or salts of heavy metals or likewise by applying oxidizing agents such as gen sodium peroxide or nitrous Thioureas may also be desulfurized by treating with phosgene or phosphorus acid amidines or carbodiimides obtained as intermediate products for as or addition of in molecule and unsaturated for example can be by hydration for example h molecular gen in the presence of a known hydration catalyst in the according to the present The acylation of may be carried out either in one for by reaction of a correspondingly substituted acid or it may be carried out in several One example of the numerous ties of stepwise acylation is the reaction of with chloride and sequent introduction of a halogen atom into the benzene nucleus of the benzamido The sulfur atoms in correspondingly substituted or thioureas can be replaced by oxygen atoms for with the aid of oxidizing agents as hydrogen sodium peroxide or other peroxide Instead of the the corresponding or acids or acid amidines can be desulfurized by treatment with oxidizing agents in an acid or alkaline medium whereby simultaneously a desulfurization and a hydrolysis forming the grouping occur and the are obtained in a Instead of the compounds of the formula u wherein U has the meaning given can be converted by treatment with oxidising agents in an acid or alkaline medium by simultaneous desulfuration and hydrolysis into the As regards the reaction the forms of realizing the process of the invention in vary within wide limits and can be adapted to each individual For the reactions can be carried out with the use of solvents either at temperature or at an elevated The hypoglycemic action of the derivatives described above could be determined by feeding them to rabbits for example in the form of sodium salt in doses of 10 and determining the blood sugar value according to the known method by or by means of an analyzer over a prolonged period of it was for that 10 gram of sulfonyl after 3 a lowering of the blood sugar by after 24 hours still amounts to 44 and which falls to zero only after 48 In the same 10 milligrams of provoke after 3 hours a blood sugar lowering of which after 24 hours even amounts to provoke after hours a lowering of the blood sugar of 22 after 24 hours still amounts to 19 whereas the known when administered lowering of the blood The rong hypoglycemic action of the ony of the invention becomes ev nt if the done further administered to rabbits in a dose of and benzamido yl is administered to rabbits in a dose of and the urea is administered to rabbits in a dose of a distinct lowering of the blood sugar can still be provoke after 3 hours a lowering of the sugar of after 24 hours still amounts to 28 and after 48 hours to 16 and falls to zero only after 72 that 10 of provoke after hours a lowering of the blood sugar of after 24 hours still amounts to 21 and falls to zero only after 48 10 of likewise provoke after 3 hours a lowering of the blood sugar of 25 after 24 hours even amounts to 33 after 48 hours to urea after 3 hours a of the blood sugar of 21 after 24 hours amounts to 23 and after 48 hours still to 17 10 of benzamido th 1 sugar of 25 after 24 hours amounts to and after 48 hours still to 12 When is ministered to rabbits in a dose of is administered to rabbits in a dose of is administered to rabbits in a dose of is administered in a dose of is administered to rabbits in urea is administered to rabbits in a dose of distinct lowering of the blood sugar can still be As regards the toxicity of the compounds the values are within the same range as those of for example urea and the of which amounts to or with oral It results therefrom that the products of the invention show a very strong hypoglycemic action accompanied by a good tolerabilit The described are preferably used for the manufacture of orally administrable pharmaceutical preparations for the lowering of the blood sugar level in the treatment of diabetes they may be used as such or in the form of their physiologically tolerable salts or in the en f ubst nces which cause such salt For agents such as alkali metal hydroxides or alkaline earth metal alkali metal carbonates or bicarbonates or alkaline earth metal carbonates or The pharmaceutical preparations are advantageously in the of tablets in addition to the products of the present the usual pharmaceutically suitable carriers such as tragacanth or magnesium A pharmaceutical preparation containing one of the said benzenesul as the active for a tablet or a with or without the aforesaid is advantageously into a suitable unit dosage The dose chosen should comply with the activity of the used and the desired the dosage per unit amounts to about to 100 preferably 2 to 10 but considerably higher or lower dosage units may also be are divided or multiplied prior to their The followin Examples serve to illustrate the but they are not intended to limit it E x a m p l e 2 g of point I89 are suspended in 50 ml of dioxane and dissolved in 50 ml dioxane after addition of 2 g of acetate point by hydrogenation of the nucleus of of at and under a pressure of 250 atmospheres and heated for about 1 hour to in which process the methanol which has formed during the reaction is distilled After water is precipitates in crystalline form and it is recrystallized from methanol point 179 In analogous there is from meth lurethane point 178 melting point 159 from methylurethane point melting point 190 sulfony point melting point 177 from point 163 melting point from urethane point 1 melting point 184 f om me h point 178 melting point 191 point 175 h melting point 177 from 1 point melting point l8l from methylurethane point lbenzamid melting point l8l from me h lure hane point melting point 146 l point 193 h point melting point 171 point melting point E x a l e 2 benzenesul onyl point 175 are suspended in 75 of dioxane and 1 g of at under a pressure of 10 mm of obtained by hydrogenation of the nucleus of at at and atmospheres are The whole is heated for 1 hour to Then the is precipitated by means of The crystals melt after recrystallization from methanol at 172 In analogous there is from urethane point 173 from ho lure hane point 1 melting point 157 from urethane point melting point 168 urethane point 160 melting point 140 from methylurethane point melting point 173 from methylurethane point 197 melting point melting point 1 from h lurethane point 164 melting point 155 from point from hylurethane point 226 melting point 182 from onyl lurethane point 175 melting point 172 methanol urethane point mido melting point 166 from methylure hane point 178 melting point 213 point 175 melting point 110 lurethane point 197 melting point from meth point 189 melting point 112 ll from melting point E x a m p l e 5 g of point l60 are dissolved in 7 of 2N sodium hydroxide solution and ml of acetone and 4 g of at under a pressure of 10 mm of are added dropwise at 0 Then stirring is continued for 2 then the whole diluted with and any undissolved matter is filtered and the filtrate is acidified with dilute hydrochloric The precipitating in crystalline form melts at 125 after recrystallization from In analogous manner there is from point 225 melting point 209 me from point 197 h melting point from benzenesulfonamide point 173 melting point from onamide point 213 melting point 1 point 187 melting point 170 from point 1 melting point me E x a m p l e 4 A mixture of g of 300 ml of ml of hy1 g of glacial acetic acid and g of spiro boiling at 120 under is treated with alcohol and the crystals obtained of the are recrystallized from methanol point analogous manner there is om point melting point 207 E x p l e 5 benzenesulfonamide sodium and of point 125 are heated to for 5 minutes in 100 ml of Then the whole is poured into water and ammonia of 1 strength is Then it is filtered the filtrate is acidified and the precipitate obtained is once more b which precipitates in crystalline form melts at 179 after recrystallization from E a m p l e 6 g of point 151 cooled at room 20 ml of acetone are added and g of glacial acetic and 1 g of are added in After stirring for 2 hours at room temperature the whole is filtered off with the precipitate is treated with a solution of bonate and then i is precipitated from dilute hydrochloric acid The urea melts 179 after recrystallization from benzamido urea which has After recrystallization from it melts at 177 In analogous manner there is melting point melting point urethane point 17 melting point melting point from urethane point 159 melting point 100 urethane point l60 melting point from melting point 162 from h point 1 melting point l80 and melting point I98 methylurethane point melting point 159 from me point 175 melting 110 and melting point from point melting point point melting point 179 and melting point 202 20 from urethane point l67 melting point 1 l from point 226 sulfo melting point 200 from point melting point l86 from urethane point 200 melting point 179 from methylurethane point melting point 1 4 from urethane point melting point 17β After addition of water and tion of the precipitating product from amide there is obtained in good yield the melting at 177 E x a m p l e 9 A mixture of S of point 171 500 ml of ml of g of glacial acetic acid g of are heated under reflux for 5 Then the whole is concentrated in vacuo and the residue is treated with The obtained as crude product melts at after recrystallization from a p l e 1 0 g of zenesulfonamide g of point 115 l and 100 ml dimethyl are heated to for Then the whole and E p e g point 151 are heated under reflux for 2 hours with g of sodium hydroxide and ml of Then the whole is cooled to room 20 ml of acetone are added and g of glacial acetic and g of are added in portions and stirring is continued for 1 The tate if filtered off with stirred with bicarbonate solution and from The obtained melts at E p l e 1 5 g of sulfonamide point 185 are dissolved in 7 of 2N sodium hydroxide solution and 50 ml of acetone and g of are added dropwise while ring at 0 Then stirring is continued for 2 the whole is diluted with water and and any undissolved matter is filtered off and the filtrate is acidified with hydrochloric The melts at after recrystallization from In analogous manner there is melting point l80 from point 148 melting point 147 from sulfonamide point melting point 177 E a m p l e 1 of acid point 222 are suspended in 50 ml benzene and heated under reflux for 2 hours with g of and 1 g of The solvent is the remaining oil is treated with and the undlssolvable residue is from The acid melts at 179 g of the compound is heated in a vapor bath for 45 minutes in of dioxane and 10 ml of IN sodium hydroxide Then water is acidified and recrystallized from There is obtained the E x a m l e 1 urea 1 g of point is dissolved in 100 ml of methanol to which 10 ml of dioxane are 1 g of mercury peroxide are added and stirring is continued for hours at After tion from the mercury the whole is concentrated in The methyl ether melts at 125 after recrystallization from dilute 1 g of the product obtained according to is pended in 2 ml dioxane and 10 ml concentrated hydrochloric Then the whole is heated for 5 minutes in a vapor water is added and the precipitate is filtered off with suction and crystallized from The E a m p l e 1 of point is dissolved in ml 2N sodium hydroxide and 10 ml of hydrogen peroxide of strength are Then the whole is heated 20 minutes in a vapor cooled and A precipitate is obtained which is filtered off with and treated with highly diluted After filtration it is The g of sulfonamide are dissolved in ml of g of ground potassium carbonate are added the whole is heated under reflux for 2 while Then a solution of is added dropwise in benzene by thermal of the ponding acid and stirring is continued for 5 hours at boiling The cooled solution is poured into and the precipitate is filtered off with suction and recrystallized twice from Melting point 188 In analogous manner there is 186 melting at E x a m p l e 1 7 g of are heated for hours in a reflux condenser while stirring in 150 ml of acetone with g of potassium Then 3 5 g of point of 72 obtained in usual manner from carboxylic are added and stirring is continued for 8 hours at boiling The solvent is and the residue is treated with filtered and the filtrate is The l filtered off with is recrystallized from dilute ethanol and melts at 195 In analogous manner there is from point 214 melting point from point melting point 1 from point 161 melting point 147 from point 220 melting point 201 point 187 melting point l60 from point 162 melting point 178 from point 148 melting point melting point 188 from melting point l80 from point I82 melting point 172 from point point l4 melting point 158 E x a m p l e 1 8 g of hane point are heated to while in ml dioxane with point at under a pressure of 10 mm of prepared from by saponification with acetic acid of during this process methanol which has formed is distilled Then dioxane is evaporated to a large extent under reduced pressure and water is added to the The product which precipitated is filtered off with suction and recrystallized from dilute The melts at Ιβθ E x a m l e 1 9 P 4 J g of zenesulfonamide are dissolved in 250 ml then 1 g ground potassium carbonate are added and the whole is heated for 2 hours under Then a solution of in benzene is added by thermal transposition of the corresponding acid and stirring is continued for 5 hours at boiling The cooled solution is given into the precipitate is filtered off with and stallized twice from Melting point l88 E x a m p l e 2 0 g of point 189 are in ml dioxane and g of cyclohexylamine point at under a pressure of 6 mm of melting point are Then the whole is heated to for 1 hours while and the methanol which has formed during the reaction is distilled When adding a small amount of water the crystallizes and melts after recrystallization from methanol at 170 In analogous manner there is melting point 177 melting point and melting point 17 methylmethane point 203 melting point 1 melting point 158 and melting point from point 171 melting point 175 melting point l80 melting point 196 from meth lure hane melting point 1β7 from hane point 197 l melting point 204 e h melting point and melting point 202 from methylurethane point melting point 164 from point 173 melting point 157 on melting point and melting point 142 from methylurethane point 164 melting point 138 from urethane point melting point 197 melting point 169 point 179 and melting point l88 urethane point 159 melting point 185 melting point 170 methylurethane point melting point 19 from hylure hane point 163 melting point l8l from point meltinfe point g of point 178 are dissolved in 9 ml of 2N sodium hydroxide solution and 40 ml of aoetone and 5 g of point at I08 under a pressure of 11 mm of obtained by reaction of point at 95 boiling point with are added dropwise while stirring at 0 Stirring is continued for 2 3 hours at room the whole is diluted with water and then the whole is filtered from the precipitating in crystalline form melts after recrystallization from methanol at 186 In analogous manner there is from point 151 melting point point melting point 191 and melting point point 187 melting point melting point 201 from onamide point 168 from point 1 ony melting point 168 from point 128 melting point 164 and melting point 190 from sulfonamide point l6l sul melting point from point 190 melting point 210 from melting point 167 melting point 148 from point 187 melting point 178 from onamide melting point l4l from point melting point 202 point 145 melting point 185 and melting point 169 from melting point 175 from point 177 melting point 168 from sulfonamide point melting point 181 E x a m p l e 2 2 g of point 171 are suspended in 1 0 ml of dioxane and heated under reflux for 1 hour after addition of g of Then the solvent is distilled off in vacuo and water is added are recrystallized from formamide and melt at 200 E x a m p l e with are heated under reflux for hours together with g of and g of amine in 100 ml Then the whole is filtered off while hot from the undissolved and the crystals which are obtained while cooling the are boiled out with After recrystallization from the 1 acid melts at g of the parabanic acid is heated in a vapor bath in 5 ml of dioxane 10 ml of hydroxide solution for After water is acidified and the N obtained is recrystallized from methanol point 177 E x a m p l e 2 4 1 g of pared by reaction of isothiocyanic acid benzenesulfonamide with cyclohexyl oil in acetone in the presence of potassium melting point 175 and are dissolved in 250 ml An aqueous solution of g sodium nitrite is added and while stirring is continued at 15 ml of 5N acetic acid are added After stirring for 2 hours acetone is distilled The residue is dissolved in dilute sodium hydroxide the solution is clarified with charcoal and There is obtained a crystalline precipitate of and recrystallized from dilute The substance melts at g of are dissolved in 5 ml dioxane and 250 ml Then g of mercury peroxide are and stirring is continued 4 hours at The mercury sulfide formed is filtered and the filtrate is half concentrated and water is After standing over a crystalline precipitate has which is filtered off with suction recrystallized from dilute The methylether thus obtained melts at g of isourea ether obtained according to the method are dissolved in 5 ml After addition of 20 ml 2N sodium hydroxide the whole is heated in a vapor bath for 5 By there is obtained a crystalline precipitate of melting at after recrystallization from dilute E x a m p l e 2 5 g of sodium and g of acid methyl ester are well The substance is introduced into an Erlenmeyer flask having a content of 300 ml so that the botton of the flask is Then the flask is put to an oil bath to After a few minutes the mass starts to after another 5 minutes solidification can be is acidified with 2N hydrochloric There is obtained a crystalline precipitate of which is dissolved once more in dilute ammonia and which precipitates by acidi ication with chloric The substance melts after filtration with tion and recrystallization at and g of the obtained according to method are suspended in 100 ml g of are added while stirring and salt formation can be Then the whole is heated to boiling ture for 1 hour while after a few minutes the pension has changed into a clear The whole is concentrated in the residue is treated with ammonia of about 1 strength and then it is The filtrate gives by acidification a crystalline precipitate of The substance melts after recrystallization from methanol at E x a m p l e 2 6 N sulfonamide sodium and 16 g of are heated for 7 hours in an oil bath to in of Then the whole is water to and alkalies are added to the reaction mixture is extracted with amine which has The aqueous phase is treated with charcoal and the filtrate is The obtained is reorystallized from and melts at In analogous manner there is melting point melting point melting point melting point and et melting point E a m p l e 2 7 g of are dissolved in 250 ml of S of finely ground potassium carbonate are added and the whole is heated to boil for 2 hours while g of are added dropwise while continuing to Stirring and heating is continued for 8 mass the whole1 poured into water and The stalline precipitate obtained is filtered off with and The whole is dissolved in methanol is added and thus a crystalline mass is obtained of melting at l6l insufficientOCRQuality

Claims (1)

1. HAVING NOW pax tic alar ly described and ascertained the nature of oar said invention and in what manner the same is to be perx'ormed, we declare that What we claim is: Benzenesulfonyl-ureas corresponding to the formula X-CO-N-Y½henylene-S0o-NH-CO- H-R R in which R represents lower alkyl, lower phenylalkyl, or preferably hydrogen, R1 (a) a cyclohexyl-disubstituted with methyl and alkoxy containing 1 - 2 carbon atoms, (b) chlorocyclohexyl, (c) spiro-(5,5)undecyl-(3) of the formula 2 h (d) exo-tricyclo-(5,2, 1,0. * )octane of the formula (e) -methylcyclohexenyl, (f) dimethyl- or .4-diethylcyclohexyl, a) represents a phenyl radical, carrying in any desired positions the substituents Z and Z' which may be identical or different, Z represents hydrogen, halogen, lower alkyl, alkenyl, alkoxy, alkenoxy, halogen-alkoxy, alkoxyalkoxy, phenai- koxy, phenylalkyl, cycloalkoxy, phenyl, phenoxy, lower acyl, benzoyl, trifluorornethyl, hydroxy, lower acyloxy,—™CN, -NOg, Z' represents hydrogen, halogen, lower alkyl, alkoxy, alkoxyalkoxy or acyloxy, hydroxy, b) a naphthyl radical which may be mono- or di substituted by halogen, lower alkyl. lower alkoxy. or hyd oxy , c) a tetrahydronaphthyl radical or an indanyl radioa!L., thienyl - disubstituted. by lower alkyl, phenylalkyl, alkoxy, alkoxyalkoxy, alkenoxy, phenylalkoxy, aryl or halogen, e) a tetramethylene-thenyl radical or a trimethylene- thenyl radical, the meaning of X mentioned under a) being preferred, Y represents a hydrocarbon chain of 1 - 3 carbon atoms, preferably the grouping -CH2~CH - and their salts. A process for the manufacture of benzenesulfonyl-ureas as claimed in claim 1, in which a) benzenesulfonyl-isocyanates, benzenesulfonyl-carbamic acid esters, benzenesulfonyl-thiocarba ic acid esters, benzenesulfonyl-ureas, benzenesulfonyl-semicarbazides or benzenegulfonyl-semicarbazones substituted by the group X - CO - N - Y · are reacted with R^-substituted amines or, if desired,' the salts thereof, b) benzenesulfonamides of the formula X - CO - N - Y-p- phenylene - S0g - NH2 or, if desired *, the,ir salts are reacted with R1-substituted isocyanates, carba ic acid esters, thio- carbamic acid esters, carbamic acid halides or ureas, c) correspondingly substituted benzenesulfonyl-isourea ethers, benzenesulfonyl-isothiourea ethers, benzene- sulfonyl-isourea esters, benzenesulfonyl-parabanic acids or benzenesulfonyl-haloformic acid amidines are hydrolyzed, d) in correspondingly substituted benzenesulfonyl- thioureas the sulfur atom is exchanged for an oxygen e) to correspondingly substituted carbodiimides water is added, f) corresponding benzenesulfonyl-ureas or benzenesul- fenyl-ureas are oxidized, g) in benzenesulfonyl-ureas of the formula HN - Y - phenylene - S0 - NH - CO - NH - R R the radical X - CO - is introduced by acylation, if desired in several stages, h) correspondingly substituted benzenesulfonyl-halides are reacted with R-substituted ureas, i) in correspondingly substituted thioamidoalkyl- benzenesulfonyl-ureas or benzenesulfonyl-thioureas the sulfur atom or the sulfur atoms are exchanged by an oxygen atom or oxygen atoms, or k) if R is K, compounds of the formula X - C = N - U phenylene - SOgNHCONH-R1 or their parabanic acid derivatives or compounds of the formula X - C = N - Y - phenylene - S0 - C = N - R u u wherein U represents one of the groups, -0- roproocnto lower alkyl, -S- represpnts lower alkyl or halogen (preferably chlorine) are saponified, 1) corresponding benzenesulfonyl-ureas containing in the molecule unsaturated bonds, are hydrated, and the reaction products are treated with alkaline agents, if the formation of salts is desired. 3) Process for preparing pharmaceutical compositions which have hypoglycemic action and are suitable for oral administration in the treatment of diabetes mellitus, which comprises bringing into a pharmaceutically suitable dosage unit form benzenesulfonyl-ureas as claimed in claim 1 or a salt of such a compound, if desired in admixture or conjunction with a pharmaceutically suitable carrier. 4) Pharmaceutical compositions having hypoglycemic action, which are suitable for oral administration in the treatment of diabetes mellitus, essentially consisting of a compound as claimed in Claim 1 or of a physiologically tolerable salt thereof. > 7 Method Tor lo erin the blood sugar lovol i the frreati- merib of diabetes mellitus, which comprises orally administering to the patient an effective amount of a compound as claimeMkin Claim 1 or of a physiologically ulerable salt thcrocftE.. έ) ^'N-^-CS-^ -methoxy^- luorobenzamido^-ethyl) -benzene- sulfony]L7-N' -(4.4-dimethylcyclohexyl) -urea. -benzene sulfonyl7-N' -(3.4-dimethylcyclchexyl) -urea. β) 7. N- 5-(fl-^-methoxy-5-chlorobenzamido^ethyl) -benzene- DATED THIS 23ra P.O.BOX llo9, Tfi'L-AVIV Attorneys x'or Applicants