IL23909A - Benzenesulfonyl-ureas and process for preparing them - Google Patents

Description

E G PAT AT TO RN EYS LEVONTIN 1169 T E L A V I V P A T E S D E S I G N S O R D I N A C E SPECIFICATION AND PR0CE33F0R PREPARING THEM HOECHST Lucius a of Frankfurt am REBY 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 Pile The present invention relates to ureas corresponding to in which Ί X represents naphthalene or indene which may be or wholly hydrogenated in one ring and which may be linked to the adjacent carbonyl group by a lower alkylene or lower or Z represents lower with 1 to 4 carbon lower alkoxy with 1 to 4 carbon hydroxy or lower represents lower alkyl with 1 to 4 carbon atoms or lower alkoxy with 1 to 4 carbon Y represents a saturated aliphatic hydrocarbon group containing 1 to 5 carbon atoms and represents alkyl of 2 to 8 carbon cycloalkyl with 5 to 8 carbon lower alk or lower alkyl having 7 to 9 carbon atoms of which 6 to 8 belong to the cycloalkyl an or hexenylmethyl group containing 1 or 2 carbon atoms in the endoalkylene In the above and following definitions Slower always means radicals with 1 to carbon atoms in a straight or branched stands an radical anic acid having up to 4 carbon preferably a straight chain or branched alkanoyl radical of the indicated chain may fo straight o branched or Within the scope of the invention there are icularly preferred compounds containing as a cycloalkyl or cycloalkenyl hydrocarbon may be stituted by alkyl or alkoxy or linked to the nitrogen atom by means of Said radicals cyclooctyl and and The alkyl or alkoxy groups may stand or preferably well as in Cyclic systems which enter into consideration as basic skeleton for the member X of the general formula are particularly those with 8 to 10 carbon for instance or the correspondin systems which are partially or wholly hydrogena ed in one such as tetrahydronaphthalene among the partially ring systems there are preferred those in which an aromatic and a saturated cycloallphatic nucleus are linked with one The ring system may be to the adjacent earbonyl group any In the case of partially hyd ogenated systems the linkage may in the aromatic as as in the hydrogenated part of the ring a linkage to the aromatic part being Linkage may likewise be effected via a lower alkylene for or or furthermore via group The substituents Z and may be likewise linked to the rin system X any for one stltuent the to the earbonyl group being As examples for the bridge member Y there are File As examples for the Z or there are or butyl as well as the ponding alkoxy bromine or chlorine being the preferred It may contain the remaining parts of the molecule o in or to one the being The present invention furthermore relates to a process for preparing the said The cess is characterized in that acid acid acid or ureas carrying the substituent are reacted with amines if their if are used in which Z OH this radical protected by benzylation or esteri benzenesulfonamides of the formula ZZ H2 or their salts are reacted with carbamic acid acid carbamic acid halides or ureas or correspondingly substituted benzenesulfonyl are reacted with or parabanic acids and the benzenesul or acids obtained this way or by another method are in correspondingly substituted thioureas the sulfur atom is replaced by an oxygen corresponding benzenesulfonyl ureas or are one or several reaction the radical is introduced by of formula in of the in which Z is a hydroxy group protected by or etheri the hydroxy group is split of by catalytic genation or and the products obtained are treated with alkaline if Instead of the there may also be used reaction products of isocyanates with acid amides such as caprolactam or or with weakly basic amines such The acid esters or zenesul acid esters may carry in the alcohol component a low molecular weight alkyl radical or a phenyl The same applies to the stituted carbamic acid esters or the corresponding monothiocarbamic acid As carbamic acid halides the chlorides are used the first The to be used as starting substances may be unsubstituted at the sid of the urea opposite to sulfonyl group or may be stituted once or twice by alkyl radicals or Instead of benzenesul substituted in this manner there be used corresponding and this case acyl stands for an phatic carboxylic acyl group with up to carbon atoms or a benzoyl It is possible for to treat such or with amines of the mula R 1 and to heat the salts obtained to elevated temperatures especially a temperature above It is likewise possible to start from ureas of the formula or from acylated ureas of the formula wherein represents an aliphatic or aromatic carboxylic acid radical preferably of molecular or the nltro or from of the formula R or from of the formula wherein the phenyl radicals may be substituted and may be linked with one another directly or by means of a bridge member such as or or from ureas of the formula and to react the said compounds with tuted In the correspondingly substituted benzenesulfonyl thioureas the sulfur atom can be replaced by an ozygen for example with the aid of oxides or salts of heavy metals or by the use of oxidizing agents such as hydrogen peroxide sodium peroxide or nitrous The can likewise be desulfurized by treatment with phosgene or phosphorus acid amidines or chloroformic acid obtained as ates can be converted into the by an appropriate for instance by hydrolysis or addition of When the products of the invention are prepared from intermediates the hydroxy group of which is benzylated or the final products obtained may be converted into the claimed by a conventiona The groups may be split off by catalytic hydrogenation and ester groups may be split off by acid or alkaline As regards the reaction the forms of realizing process of the invention in vary within wide limits and can be adapted to each vidual For the reactions can be carried out with the use of at room temperature or at elevated As starting substances there are on the one compounds containin a benzene radical substituted NH by the group As examples for the ponent of the said formula there are mentioned without the enumeration being the following radicals The lowerin action of the urea derlTatives according to the invention could be by feeding to rabbits in a dose of 10 milligrams kilogram and determining the blood sugar value according to the known method of or by means of an autoanalyzer over a roloned eriod of V it was for that 10 of provokes after 3 hours a lowering of the blood sugar of while the known has no blood sugar lowering properties to rabbits in a dose of less than 25 The products according to the invention are ably destined for the manufacture of orally preparations showing blood sugar lowering action in the treatment of diabetes melli us and can be applied as such or in the form of their salts or in the presence of stances causing salt For the formation of salts there can be for alkaline agents such as alkali metal hydroxides alkaline earth metal alkali metal carbonates or alkaline earth metal carbonates or As pharmaceutical parations there enter into consideration preferably tablets in addition to the products of the the usual adjuvants and carriers such as or magnesium A preparation containing the abovementioned active for instance a tablet or a with or without the aforesaid is advan ageously brought into a suitable dosage unit 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 ably higher or lower dosage units may likewise be if are divided or multiplied prior to their The following examples serve to illustrate the invention but they are not intended to limit it Example 1 15 Grams of sulfonamide point were while in 130 milliliters of acetone and 22 milliliters of 2N NaOH while grams of were dropped The dropwise addition being the temperature was allowed to rise slowly and the reaotion mixture was stirred at room temperature for 3 hours The reaotion mixture filtered with the acetone was removed under reduced pressure in a rotary evaporator at room ature and the residue was crystallized from methyl Melting 225 In analogous manner there were meltin oint from methanolwater melting point from a large amount of ethanol o dimethyl melting point from from point the melting point from the melting point from from point the melting point 195 from melting point 190 from methanol and melting point 170 from from amide point the melting point 183 from from ethanol and melting point from from s lfonamide point the melting point from from point the melting point from In an analogous manner there From point the point 208 C from the o point 203 the point 13 5 Grams of were while to 22 grams of point in 120 milliliters temperature was raised to whereby reaction set in with splitting off of The reaction mixture was cooled after about 30 the precipitated urea was filtered off with suction recrystallized from It had a of Example 3 Grams of 2 ether pared by reacting 2 benzenesulfonyl with mercury oxide in melting point 114 and 30 milliliters of concentrated hydrochloric acid were heated for 5 minutes on the steam The precipitate which solidified on cooling was recrystallized from melting point The mixed melting point with the substance pared by a different method showed no Example 4 Grams of 2 by reacting 2 sulfonamide with oil in the presence of potassium acetone and dimethyl ing point 137 after reorganization from acetic NaOH and hydrogen peroxide of strength was was for a short time on the steam it allowed to filtered and the filtrate was The precipitated was from It had a melting point of Example 5 Grams of sodium point of the free fonamide 173 and 22 grams of in 40 milliliters of dimethyl formamide were maintained for 7 hours at The reaction mixture was water was added and the ture was rendered alkaline by means of 2N The phenylamine formed was extracted with the aqueous phase was treated with coal and The precipitate was extracted with of acidified and reorystallized from The product obtained had a melting point 167 Example 12 Grams of point 201 350 milliliters of grams of glacial acetic acid and grams cyclohexylamine were stirred for 3 hours at The reaotion mixture was concentrated under reduced pressure and the residue Was treated with ammonia of the extract was acidified and the reaction product was recrystallized from had a Example 7 10 Grams of sodium were thoroughly mixed with 5 grams of ground potassium carbonate and 10 grams of cyclohexyl carbamio acid ester point and while stirring occasional the whole is heated for 3 hours at C on oil After water and the excess carbamio acid ester is removed by shaking out with The aqueous solution is then filtered with suction and crystallized from Melting point 17 In an analogous manner to Example 2 there were obtainedι Prom o ethyl 187 the point from and the point 169 from from urethane point the point from and the point from from point the point from and point from insufficientOCRQuality

Claims (1)

1. File WHAT IS CLAIMED A of the general formula in which X represents naphthalene or indene which may be partially or wholly hydrogenated in one ring and which may be linked to carbonyl group by a lower alkylene or lower or Z represents lower with 1 to 4 carbon lower alkoxy with 1 to 4 carbon hydroxy or represents lower alkyl with 1 to 4 carbon atoms or lower alkoxy with 1 to 4 carbon T represents a saturated aliphatic hydrocarbon group containing 1 to carbon atoms and represents alkyl of 2 to 8 carbon cycloalkyl with 5 to 8 carbon lower or alkyl having 7 to 9 carbon atoms of which 6 to 8 belong to the cycloalkyl an or hexenylmethyl group containing 1 or 2 carbon atoms in the endoalkylene A physiologically tolerable salt of a A process for preparing blood sugar lowering pharmaceutical preparations are suitable for oral treatment of diabetes which comprises processing as claimed in Claim 1 or if in admixture with pharmaceutically acceptable adjuvants and a dosage unit Blood sugar lowering pharmaceutical preparations suitable for the oral treatment of containin one of the defined in 1 or as the active of the formula 23 Fw 4531 B 6 of the formula of the formula 8 2 l of the formula 2 the formula Pw 4531 B ethyl N of the DATED SHIS 6th day of COHEN SPISBACH 1169 TEL AVIV Attorneys fo insufficientOCRQuality