[1]United States Patent Offi @@202@680 @3,202,680 NEW BE4 NZENESULFONYL UREAS AND PROCESS FOR THEIR MANUFACTURE Gerbard ICorger, Franlifurt am Main, and Walter Au. miiller, Kelkheim, Taunus, Germany, assignors to Farb- .5 werke Hoechst Alitiengeselischaft vormals Meister Lucius & Briining, 'Franidurt am Main, Germany, a corporation of Germany No Drawing. Ffled July 17, 1962, Ser. No. 210,579 Claims priority, application Germany, July 28, 1961, 10 F 34@554 9 Claims. (Cl. 260-347.2) The present invention relates to new benzeilesul-f-onyl ureas of the formula 15 t R-o-x-o-e "I@-S 02-NH-CO-NH-Ri in w-hich R represent@s a low alkyl group havin.- froni I to 6 carbon aton-is, X represents an alkyleiie group having from 2 to 3 carbon atoms and RI stands for a saturated 2 0 or unsaturated, aliphat@ic or alicyclic hydrocarbon radical havin.- from 2 to 8 carbon atoms-in the case of cyclic compounds fr@bm 3 to 8 carbon ato-tns-wh,-reby these radioals, if they contai-@i from 3 to 8 carb@on atoms, may be int.-rrup-ted by lan oxygen or sulfur a'Lbm; or RI rep25 resents a beqzyl or g@phenyl-ethyl group and th,-, salts thereof, which exliibi@L hypoolyceniic properties and which because of their strong blood sugar reducing activity are suitable as oral antidiabetic dru,@s. The present invention likewis-. rela-tes to the preparat@ion -, 0 of said benzenesulfonyl ureas. For the manufacture of the new compounds those processes enter in considera@- tion that are usually applied for the pr@paration of sulfo-iiyl ureas. icorrespondin.-ly substituted benzenestilfonyl isocya- 5 nates ca-@l be reacted, for examp'le, with ami-iies of the f ormula RI-NI -12- Instead of these amines there m,,iy ,also be used the derivatives thereof, for example, ainines -,vhich a-re formylated correspondingly, @and t-he products thus obtained caq be converted by hydrolysis into the de@10 sire-d products. The liew benzenesi-ilfonyl ur@-as may also be obtained in,a reverse reac-tion, by reacting isocyanates -of the formula RI--NCO with correspondingly substituted b-.nzenesulfonic acid amides, adiantageous][Y with t,he salts theteof. Instead the benzenesulfonyl isocya- 4- of a iiates as well as of the isocyanates -of the formula RI-NTCO compounds as in there nay generally be used also such 50 the course of the reaction form those isocyanates or as ,react lilce such isocyanates. B--nzenesulf6nyl carbamic acid esters wl-iic@h !are su-bstit,,jted correspondingly and which have a low molecular alkyl group or a phenyl radical in the ester componen@l, 5 5 ,and/or the corresponding benzenesulfonyl monothiocarbamic acid esters can be reacted wiih @amines of the formula RI-NH2; or vice versa, carbamic acid esters of the for@mula RI--NH-COOR2, wherein R2 represents a low molecular alkyl group or a phenyl radical, and/or mono60 thiocarbamic acid esters can be reacted wit-h correspondingly substituted benzenesulfonic acid amides. Also carbamic hali-Jes can be used with the same success. The desired compounds c@,n be obtained from cor- 1 respondingly substituted benzenesulfbny@l carbamic acid 65 halides and arnines of th6 fofm@ula RI-NH2, or vice ver.sa, fro-m carbamic agid halides of t@he formula RI-NH-CO-Hal Ce' Paiented Aug. 24,1965 2 stituted on the side ;of the urea molecule apposit-, to the sulfonyl group or wh@ich are substituted once or twice by other alkyl groups or aryl radicals, can be converted in-to the desired compounds by the reaction with amines of the formula R@NH2, if desired in the form -of the corresponding salts. Ins-tead of the above-mentio.,ied benzenesulfonyl ureas there may -be used t-he correspondin.@ Nb@-nzenesulfonylN'-acyl ureas @and/,or also bis-(benzenesulfonyl)-ureas. Thbse -bis-(benzenesulfonyl)- ureas or =enesulfonyl-N'-;acyl uroas can, for example, be with @anlines of the formula RI-NH2 aildthe salts thus o@btained can b-- heat-,d to temderatures a-bove 100' C. It is, furthermore, possible to start from ureas of the formula RI-NH-CO-NH2, or from acylated ureas of formula Rl--NH-CO-NH-acyl, wherein "acyl" repres,,nts a preferably low iriolecular al@iphatic or aromatic ae-id rad,cal or 4the n-itro -roup, or from diphe-nyl ureas of the formula RI --- 4NH-CO-N,(C6H5)2 and to react.said ureas with correspondingly @substituted benzenesulfonic acid amides. It @'s also possiblet@o,react basified urea derivatives, for exa,mple, :,@uanidines, isourea ethexs or salts;of mono-Rlstibstittited parabanic acids with ter-tiary amines, with correspondiilgly substituted benzenesulfonic acid halides and to conv-,rt 'the sulfonyl-isourea ethets iand/,o-r sulfonylparabanic acids so @obtained by hydrolysis into .the desired benzenesulfoiiyl ureas. It is, furthermore, possible to prepare the correspondingly substituted benzenesulfonylthioure,as and @,to exchan,-e, from these compounds the sulftir atom or the thiourea -rotip in usual manner, against an oxygen atom, fo,r e,-am,ple by means cif oxides orsalts of heavy metals, or by the use of oxidizinagents such as hydrogen peroxide, sodium- peroxide and nitrous acid. The desixed benzenesulfunyl ureas can finally be obtained by oxidizing the COrrCSDonding stilfenyl- and sulfinyl-ureas. t As starting siibs ances for t,'@q-- process of the preserit invention there are used on the one hand such benzenesulfanic ac-id halides, amides, isocyana-tes, urethanes, areas, isolirea et@hers, guanidines, thioureas, parabani.c , c-id ete. as carry an. allcoxy-alkoxy group in para position to the sulfonyl group, for exa@mple, p-@nethoxyethoxy, P-eth@oyy-ethoxy, 0-propoxy-ethG-xy, @-@N-batoxyathoxy, p-isobutoxy-cthoxy 6-amyloxy-eth oxy,,e-hexyloxyethoxy, P-methc)-Yy-propox@, p-,th.y-propoxy y-niet hoxy-propcxy, I y-ethocy-propoxy and th-- likp-@ For the preparation of p-alkoxy-alkoxy benzene sulfonic acid derivatives it is advantageous to start from the corresponding alkoxy-alkoxy benzenp-s and to react them in the melt according to known methods viith amidosulfuric acid to p-alkoxyalkoxy benzenesulfonic acid, fro-tn which the corresponding sulfonic acid halides cgn be obtained accordin@ to usual methods. From the siilfonic acid chlorides @and/or halides further benzenesulfc)nic acid derivatives (such as, for example, carbamic acid esters, ureas, isourea ether etc.) serving-if desired@as starting substances, can be prepared according to known methods. As reactan ts with the above mentioned sulfonyl compounds, amines of th-- formula RINH2 are used, for example ethylam-ine, n-propylamirie, isopropylariine, bU7 tylamine(I), but3rlamine-(2), 2-methyl-propylamine(1), 2-methyl-p.@7opylamine-(2), pentylamine-(I), pentylamine-(2), p@-ntylamine-(3), 3-methylbutylamine-(I), hexylami--@ies such as hexylamine-(I) and 2-methylpentylamine-(I), beptylam;nes such as heptylan-line-(l), heptylamine-(4), oetylamines such as oetylamine-(l). ' As alkenylamines there may further be mentioned, for example allylamine and crotylamine, as cycloalkylarqines, cyand correspondingly substituted benzenesulfonic acid 7( clopentenyl-,imine, cyclopentylamine, cyclohexylamine$ arpides. cyclohexenylamine, cyclolieptylamire, 4-methyl-cycloFt@.r,therniOTe, benzoneslilfonyl ureas, wliioh are unsu-b- hexylamine and 2,5-endomethylenecyclohexylamine, and
[2]3 as cycloalkylalkylamines cyclohexylmethylamine and cyclohexylethylamine. As aliphatic or cycloaliphatic compounds interrupted by an oxygenor sulfur atom, there enter into consideration, for instance: 3-methoxy-propylamine, 3-ethoxy-propylamil-ic, 4-methoxybutyl-amine, tetrahydro - a - furfurylamine, 3 - methyl-mercaptopropylamine and 3-ethylmereapto-propylamine. As aralkylamines be mentioned, for instance 2-phenyl-ethylamine(1) and benzylamine. Instead of the aforementioned amines, the carbamic acid esters, carbamic acid halides, ureas, isourea ethers and parabanic acids prepared from said amines can be used for the reaction with suitable benzenesulfonyl compounds. The forms of operation of the process accordir,- to th-. invention may, generally be varied to a large extent and adapted to the conditions of each individual case. The reactions may be carried out, for instance, while using solvents, at room temperature or at an elevated temperature. In order to obtain the products in a form as pure as possible, they are suitably completely separated from the benzene sulfamides used as starting substances or formed in the cours.- of the reaction. This separation may be favorably effected by taking up the product according to the invention in considerably diluted ammonia, filterin.- off any undissolved matter and precipitatina the desired N(benzenesulfonyl)-urea by acidification. The benzenesulfonyl ureas obtained according to the process of the present invention are valuable medicaments which, at a low toxicity, are characterized, in particular by a strong hypoglycemic action. For example, the N-[4-(p-methoxyethoxy)- benzenesulfonyll-N'-cyclohexyl urea when tested in the form of the sodium salt on rabbits and applied in a dose of 400 mg./kg. of body weight administered per os effects a lowering of the blood sugar level by 40/ maximum. The same maximum lowering of the blood sugar on rabbits is obtained, when administering 400 mg./kg. of body weight of the sodium salt of N-[4-(p-methoxyethoxy)-benzenesulfon yl]-N'-isobutyl urea. The oral application of 400 mg./ kg. of body weight of sodium salt of N-[4-(p-methoxyethoxy)- benzenesulfonyll-N'-n-butyl urea on rabbits effects a lowering of the blood sugar level by 50% maximum. Since they do not contain an amino group in para-POsition in the benzene nucleus, the products of the invention do not show an action which could be compared with that of sulpha drugs (which are used therapeutically with infectious diseases), so that they do not catise a development of resistance even when applied for years. For the same reason there do not occur any side effects which result in injuries of the intestinal flore. The products of the invention are preferably used for the production of preparations to be orally admiiiistered in the treatment of diabetes mellitus and showing hypoglycemic action. They can be used as such or in the form of their salts or of substances that cause salt formation. For the salt formation may be used, e.g. alkaline agents such as alkali metal or alkaline earth metal hydroxides, carbonates orbicarbonates, furthermore, physiologically compatible organic bases. As medical preparations there enter into consideration preferably tablets containing in addition to the products of the invention the usual adjuvants and carriers, such as tale, starch, lac@ tose, tragacanth, ma.-nesium stearate and the like. The following examples serve to illustrate the invention but they are not intended to limit it thereto: EXAMPLE I N-[4-(p-inethoxy-ethoxy)-beizzeiiesulfoityl]-N'-cyclohex3,1 urea. 16.2 grams of 4-(p-methoxyethoxy)-benzenesulfonamide are dissolved in 200 cc. of acetone and after addition of 19.5 grams of ground potassium carbonate are heated 3,202,(:-,so 4 -at the boil for one hour. 10 grams of cyclohexylisocyanate are @hen added thereto, and the mixture is stirred at 56' C. i'Or a furlher 20 hours. The potassium salt thus formed is filtered with suction, dissolved in 800 cc. of water, the solu'Lion is filtered, clarified with charcoal, and the filtrate is ac@.dified with hydrocliloric acid. The separated precipitate is filtered with suction, washed with water and recrystallized from 200 cc. of methanol. There are obtained 19.1 grams of N-[4-(,g-methoxy-ethoxy)- 10 berizenesulfonyl]-N'-cyclohexyl urea melting at 155-157' C. The 4-(,(3-methoxy-ethoxy)-benzenesulfonamide serving as startin.- substance, can for example, be prepared as follows: 425 -rams of p-methoxy-ethoxy benzene are heated at 15 180' C., and while stirring, 500 grams of finely ground amidosulfonic acid are added thereto. Thereby the temperature rises to 215' C. The mixture thus formed is stirred for a further 21/2 hours at 185-200' C. and the so@lid substance obtained after cooling is dissolved by the 20 introduction of steam. The aqueous solution is clarified with charcoal, and potassium chloride is added in the heat to tb@- filtrate until it is saturated. After cooling at 5' C., the potassium salt of the 4-(p-me thoxyethoxy)berizene-sulfonic acid is fil@tered with suction, dried and 25 ruiverized finely. The yield amounts to 600 grams. 600 grams of potass@@Um salt and 275 grams of phosphorus pelitachloride are mixed in portions while being stirred, whereby liquefaction occurs with the rising temperature. The mixture thus formed is heated for a fur30 ther 2 hours on the steam bath apd then poured on ice. The oil that has precipitated in said proce,@s is taken up in ether, the ether solution is shaken out three times with water and the ether is distilled off. '380 grams of 4-(Pmethoxyethoxy)-benzenesulfonic acid chloride are ob35 tain-.d. 300 grams of the acid chloride obtained are heated for three hours on the steam bath wtih 1 liter of concentrated amnionia. After cooling, the whole is acidified with conceiitrated hydrochloric acid, the separated precipitate is 40 filtered with suction, dissolved in 2n-sodium hydroxide soli.,.tion, the solution is filtered with suction through a layer of coal and the filtrate is ac,',dified again. After filtering with suction, washin.- with water and dryin.-I there are obtain,-d 200 grams of 4-(,e-methoxyethoxy)- 45 benzenesulfonamide melting at 154-156' C. After recrystallization from water the melting point is 159161' C. EXAMPLE 2 50 N-[4-(p-methoryethoxy)-henzeneszilfoiiyl]-N',cyclooetyl urea 26 grams of N-[4-(,e-methoxyethoxy)-benzenesulfonyll-carbamic acid ester [prepared by the reactioii of 4-(/3m-,thoxyethoxy)- benzenesuli'onamide with chloroorniic 55 acid methyl ester in the presence of acetone and ground potassium carbonate] are mixed with 10.2 grams of cyclooctylamire and heated for I hour at 130' C. The melt thus formed is treated with 4 liters of dilute ammo-Tiia (1:25), the solution is filtered and the filtrate is acdified 60 with h@,drochloric acid. The precipitate is filtered' with suction, washed with water and recrystallized twice from methanol. Thus, there is obtained the N-[4-(P-methoxyethoxy)-benzenesulfonyl l-N'-cyclooctyl urea melting at 154-156' C. 65 When reacting 26 grams of N-[4-(,e-methoxylethox y)ben-7enesulfonyll-carbamic acid methyl ester and 5.9 grams of n-propylamine there are obtained in analogous manner 21 grams of N-[4-(,6-methoxyethoxy)-benzene70 sulfonyl]-N'-n-propyl urea melting at 123-125' C. after recrystallization from methanol. When using a-tetrahydrofurfurylamine there is obtained in the same manner the N-[4-(p-methoxyethoxy)b--nzenesulfonyl]-N'-a-tetrahydrofurfuryl urea melting at 75 110-1 13' C. (from methanol).
[3]EXAMPLE 3 .N-[4-(P-methoxyethoxy)-benzenesulfonyll-N'-n-hexyl urea 24 grams of 4-(p-methoxyethoxy)-benzenesulfonamide are reacted and worked up according to the clirection given in Example I with 12.7 grams of n-hexylisocyanate in 250 cc. of acetone -and in the presence of 20 grarns of ground potassium carbonate. There are obtained 20 grams of N-[4-(#- methoxyethoxy)-benzenesulfonyl]-N'n-hexyl urea melting at 113-115' C. (from methanol). With the use of n-butylisocyanate there is obtained in analogous manner the N-[4-(p-methoxyethoxy)-benzenesulfonyll-N'-n-butyl area melting at 116-118' C., and with the use of is obutylisocyanate there is obtained the N-[4-(,6-methoxyethoxy)-benzenesulfonyllN-'isobutyl urea melting at 119-121' C. EXAMPLE 4 N-[4-(p-methoxyethoxy)-benzenesulfonyll-N'cycloheptyl urea 20 grams of N-[4-(P-methoxyethoxy)-benzenesulfonyl)-N'-cycloheptyl thiourea [prepared by the reaction of 4-(,3- methoxyethoxy)-benzenesulfonamide with cycloheptyl mustard oil in the presence of acetone and ground potassium carbonate melting at 119-IZI' C from methanol] are dissolved in acetone. The solution' is cooled at +5' C. and mixed successively with a solution of 4.2 grams of sodium nitrite in 5 cc. of water and 32 cc. of 5-n-acetic acid, while being stirred. After stirring for 2 hours, the larger patt of acetone is distilled off under reduced pressure, the residue is liberated by ffltration from the elementary sulfur formed during the reaction, and the filtrate is mixed with water. The precipitated product is separated, washed with water and recrystallized from methanol. The N-[4-(#-methoxyethoxy)- benzene sulfonyll-N'-cyclo-heptyl urea so obtained melts,at 153- 156' C. EXAMPLE 5 N-[4-(p-ethoxyethoxy)-benzenesulfonyl]-N'- cyclohexyl urea 15 grams of 4-(,e-ethoxyethoxy)-benzensulfonamide [prepared according to Example 1 with the use of 6ethoxyethoxy benzene as starting material; melting point of the amide 125-127' C.] and 7.6 grams of cyclohexyl isocyanate are reacted -,according to the direction given in Example 1 - in 200 cc. of acetone and in the presence of 16.5 grams of ground potassium carbonate. The product thus obtained is recrystallized from aqueous methanol. The N-[4-(p-ethoxyethoxy)-benzenesulfonyl)-N'-cyclohexyl urea so obtained melts at 148-151' C. (from aqueous methanol). We
