IL25534A - Benzene-sulfonyl semicarbazides and process for preparing them - Google Patents

Description

E PA TENT ATT O R N EYS LEVONTIN 1169 T E L AV I 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 NEW LFQ L AND PROCESS FOR PREPARING THEM HOECHST LUCIUS a German 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 The present invention provides compounds of the formula wherein R represents a phenyl radical which may be substituted twice or three times by lower lower lowe lower lower alkosyalkoxy or furthermore by or a thienyl radical which may be substituted once or twice by lower lower lower lower lower or or by a polymethylene chain linked with its two ends to the thiophene which chain contains from 3 to carbon a radical which may be substituted by methyl or a phenyl radical bound via an alkylene or alkenylene chain containing from 1 to carbon atoms which may be branched and contain an oxygen atom instead of one the phenyl radical being substituted if by lower alkyl or lower alkoxy or a or cyclohexenyl an alkyl radical containing 1 to 11 carbon Y represents a represents an from to 7 carbon atoms wherein the chain may be substituted by 2 to methyl groups or by or containing up to 3 carbon it may contain an alkylene group having from 1 to 3 carbon atoms and which may be substituted by lower lower or containing The radical wherein and stand for lower also and the which are valuable medicaments which are distinguished by a strong and particularly lowering The present invention further relates to a process for preparing said benzenesulfonyl As modes of preparation there may be mentioned the Reaction of preferably in the form of their with ccarbamic acid acid or containing as imino radical the group reaction hydrazines of the formula or their salts with benzenesulfonyl benzenes lfonyl carbamic acid yl thiocarbamic acid carbamic acid halides or reaction of with hydrolysis of isothlosemicarbazide ethers or parabanic exchange of the sulfur atom for an oxygen in zenesulfonyl of the formula introduction of the radical in one or several i azides of the ormula by The benzenesulfonyl semicarbazides obtained may then be if into their salts by treatment with line agents or with physiologically tolerable inorganic As semicarbazides or for the syntheses tioned under there are suitable compounds of the formula H2 acylated compounds of the formula acyl wherein acyl represents an aliphatic or aromatic acid preferably of lower molecular or diphenyl semicarbazides of the formula wherein the phenyl radicals may be substituted or may be linked to each other directly or by means of a bridge stituted carbohydrazides of the formula Especially suitable as benzenesulfonyl carbamic acid halides are the corresponding benzenesulfonyl ureas which may be unsubstituted at the terminal nitrogen or tuted once or twice by alk 1 or aryl may be converted into the final products by reacting them with hydrazines of the formula if in the form of their Instead these benzenesulfonyl ureas there may be used the corresponding ureas or Said compounds may be treated with hydrazines of the formula and the salts obtained may be heated to elevated preferably to at least The acid esters or benzenesulfonyl carbamic acid esters mentioned as well as the corresponding thioesters contain in the ester component preferably an alkyl radical of The benzenesulfonyl isosemicarbazide semicarbazide ethers or acids used as starting may be obtained by reacting corresponding carbazide isothiosemicarbazide ethers or parabanic acids with corresponding fonyl isosemicarbazide ethers are also in the first by desulfurizing benzenesulfonyl thiosemicarbazides in methanolic They are subsequently converted into benzenesulfonyl semicarbazides by Depending on the nature of the member in some the one or the other of the previously described methods may prove unsuitable for preparing the individual compounds falling under the general or at least will make it necessary for active groups to be Such rare cases can easily be recognized by the and there is no difficulty in cessfully applying another one of the syntheses As regards the reaction the embodiments of the process of the present invention in vary within wide limits and may be adapted to each individual For the reactions can be effected with the use of at room temperature or at an elevated As starting substances there are as one pounds containing a benzene radical substituted by the group As radical R may be for the following CI may for example The derivatives obtainable ing to the present are valuable medicaments which are distinguished by a strong and particularly long lasting action of lowering the blood sugar This in to such compounds in which R represents a phenyl radical carr in an rou in The blood be for in by administering the compounds in a dose of 10 and by determining the blood sugar over a prolonged period of according to the known method of The following table comprises the blood sugar lowering activities of some of the compounds obtained according to the process of the present Compound Lowering of the Limit amount blood sugar causing rabbits after ing of the ministering 10 blood sugar per os after level in o s rabbits 24 48 1 propionamido carbazide 26 22 me azide semicarbazide 32 20 semicarbazide 28 22 31 chlorobenzamido 26 29 35 benzamido 25 ethoxy benzamido benzenesul semicarbazide In contradistinction the known as antidiabetic and used as cament shows no lowering of the blood sugar level when stered in a dose of 25 in a comparative It is preferable to process the products of the present invention into orally administerable preparations which have blood sugar lowering action and which can accordingly be used in the treatment of diabetes mellitusj they can be employed as such or in the form of their salts or in the presence of substances causing salt For such salt formation there can be for alkaline agents such as alkali metal alkaline earth metal alkali metal alkaline earth metal alkali metal carbonates and alkaline earth metal bicarbpnates and ically tolerated The pharmaceutical preparations are preferably in the form of tablets which in addition to the compounds of the present the usual adjuvants and carriers such as nesium stearate and the The following Examples serve to illustrate the present but they are not intended to limit it Example 1 10 Grams of were suspended in 100 ml of dioxane and grams of zine were added while The mixture was heated to 120 for an hour while the methanol formed during the reaction was off together with a little amount of When being cooled the l l entameth precipitating it with dilute acetio After ation from methanol and dimethyl the semicarbazide melted at 229 In analogous manner there were hexamet 207 and 112 from 213 pen y car az 220 dimethyl and 195 dimethyl from methyl 1 and 208 from 2D0 24l and 209 dimethyl from 17 157 155 and 172 dimethyl from and 207 from 1 157 from sulfony h 175 from 137 from 178 209 and 201 from 226 202 and l8l from Ill and from 142 5 148 167 10 and l80 15 from cinnamoylamido 1 8 cinnamoylamido 198 0 h l 5 and 184 from from 184 186 210 and 200 dimethyl from y 210 and from 215 I63 from 163 159 and 152 from 173 237 from 172 17 1 and au 139 C from 159 171 189 164 and l6l from 178 177 from sulfon 1 from 165 pentameth 207 177 dimethyl and 224 from 155 and 176 from sulf l l and from l6j and from 1 170 from l60 from 121 106 from 179 and from 128 l6l and from 149 and earba 168 from benzenesul ony 187 161 me ha from 155 203 175 213 In analoguous manner there were from the corresponding e ethane 185 β thylene ce 205 s ntamethylene thylene thylene hylene l zene thylene 157 c thylene 1 180 t thylene sulfonyl hylene cw thylene 166 thylene thylene a ethylene 145 thyl 196 205 thyl 198 thylene Example 2 semicarbazide Grams of were suspended with grams of the sodium salt of sulfonamide in 100 ml of dimethyl amide and the whole was heated to for 3 After formed was removed by shaking it out three times with The aqueous phase was filtered and acidified with glacial aceti The precipitating in crystalline melted at 217 after having been recrystallized from dimethyl formamide and In analogous manner there was obtained dimethyl Example Grams of h acid were suspended in 240 ml of After addition of grams o trimethyl amine the mixture was dissolved and 7 grams of were added while The whole was refluxed for then cooled and decanted from the smeary This residue was digested with water in order to remove the hydrochloride and was made to recrystallize by trituration with alcohol and The acid thus obtained was purified by boiling it with methanol and it melted at Gram of the parabanic acid derivative obtained in the manner described was heated with 5 ml of sodium hydro xide solution the steam bath for 10 After a little while the salt of 1 crystallized It yielded the free acidification with dilute acetic 4 Grams of 1 were refluxed at the boil in 100 ml of dioxane with 5 grams of After a limpid solution had been the solvent was evaporated at reduced the residue was treated with about after filtration the filtrate was acidified with dilute acetic The which had was from water and dimethyl formamide and it melted at 220 Example Grams of benzenesulfonamide sodium were heated to with 1 grams of in a oil bath for 10 to 15 The mixture became pasty and then solidified After having been cooled it was treated with after filtration the filtrate was acidified with acetic acid and the reaction product was crystallized from The carbazide at 204 In analogous manner there were and from and 146 Example 6 mol of were heated to 110 while in of toluene with mol of The methyl alcohol forming was distilled After heating for 2 3 the whole was allowed to cool and the residue was filtered off with it was dissolved and from and The carbazide obtained melted at In analogous manner there were 229 l87 Example 7 semicarbazide arba d ol sis o 198 was heated to in 15 ml of chloroform with of pyridine and ml of benzoyl for The residue was filtered off with suction and dissolved and from and This compound melted at 216 Example 8 Mol of were in mol of 2N NaOH and mol of chloride was added wise while For complete reaction the whole was heated to for 2 The substance which had precipitated was filtered off with suction and the residue was dissolved and reprecipitated from and The substance melted at In analogous manner there were 187 Example 9 Mol of 187 being prepared by hydrolysis of was added to 10 ml of pyridine and mol of chloride was added While the reaction took cooled onto the precipitate was filtered off with dissolved and reprecipitated from and The pure substance melted at In analogous manner there were Pile 15250 of from there is obtained of from there is obtained dilute insufficientOCRQuality

Claims (1)

1. WHAT IS CLAIMED of formula represents a phenyl radical which may be substituted twice or three times by lower lower alkenyl lower lower lower or furthermore by dioxy or a thienyl radical which may be substituted once or twice by lower lower lower lower lower alkoxyalkox or or by a chain linked with its two ends to the thiophene which chain contains from 3 to carbon a radical which may be substituted by methyl or a phenyl radical bound via an alkylene or alkenylene chain containing from 1 to carbon atoms which may be branched contain an oxygen atom Instead of one the phenyl radical being if by lower alkyl or lower alkoxy or a cyclohexyl or cyclohexenyl an alkyl radical containing from 1 to 11 carbon atoms Y represents a or 1 represents an radical containing from 3 to 7 carbon atoms wherein the alkylene chain may be containing up to carbon it it may contain an endoalkylene group having from 1 to carbon atoms and which may be substituted by lower alkyl or a containing and stand for lower also representing and physiologically tolerable salts semicarbazide Physiologically tolerable salts of any one of the pounds claimed in claims 2 15 A pharmaceutical preparation effective against diabetes mellitus which comprises a semicarbazide as claimed in claim 1 or a physiologically tolerable salt thereof in admixture or conjunction with a pharmaceutically suitable Process for the lowering of blood sugar in the treatment of diabetes mellitus which comprises administerin to an individual an effective amount of a pharmaceutical tion havin as the essential ingredient a benzene sulfonyl a physiologically tolerable salt THIS 2 of insufficientOCRQuality