SE202499C1

SE202499C1 -

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Publication number: SE202499C1
Authority: SE
Publication date: 1965-01-01

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Uppfinnare: G Korger, H Wagner, W Aumillier och H Rusehig Prioritet begord frein den 10 august! 1956 (Forbundsrepubliken Tgskland) Sasom vardefulla lakemedel med blodsockersankande verkan ha redan foreslagits sulfonylkarbamider med den allmanna formeln R—S02—NH—CO—NH—R, I vilken R betecknar en fenylgrupp, i vilken eventuellt en eller Iva vateatomer aro ersatta med alkyl- eller alkoxigrupper, vilkas alkylgrupp foretradesvis uppvisar upp till 8 kolatomer, eller med halogenatomer, eller i vilken R betecknar en allfatisk eller cykloalifatisk kolvategrupp med 3-8 kolatomer eller en naftalen-2-, en 5,6,7,8-tetrahydronaftalen-2- eller en 4-feno3d-fenylgrupp och R, en alkyl-, alkenyl-, cykloalkyl- eller cyldoalkylalkylgrupp med 2-8 kolatomer, avensom deras salter. Inventors: G Korger, H Wagner, W Aumillier and H Rusehig Priority requested on 10 August! 1956 (Federal Republic of Germany) As valuable blood sugar lowering drugs, sulfonylureas of the general formula R-SO 2 -NH-CO-NH-R have already been proposed, in which R represents a phenyl group in which optionally one or eleven hydrogen atoms are replaced by alkyl- or alkoxy groups, the alkyl group of which preferably has up to 8 carbon atoms, or with halogen atoms, or in which R represents an all-phase or cycloaliphatic carbonate group having 3-8 carbon atoms or a naphthalene-2-, a 5,6,7,8-tetrahydronaphthalene-2 or a 4-pheno3d-phenyl group and R, an alkyl, alkenyl, cycloalkyl or cyldoalkylalkyl group having 2-8 carbon atoms, in addition to their salts.

Man har nu funnit, att man kan erhalla blodsockersankande foreningar, vilka are bakteriostatiskt overksamma, om man omsatter sulfonylkarbamider med formeln R—SO 2—NH--C 0—NH—R a, i vilken Ra betecknar vate, en acylgrupp eller gruppen R—S0 a, och primara aminer med for-mein 11.„—NHa eller omvant, eventuellt i franvaro av ett losningsmedel, omsatter sulfonsyraamider med formeln R—S0 2—N112, och karbamider med formeln Dupl. kL 12 : R1—NH--00—NH—R,, i vilken R, betecknar vate, en nitrogrupp eller acetyl-, propionyl-, butyryl- eller bensoylgruppen, med varandra for bildning av sulfonylkarbamider med den allmanna formeln R—S02—NH—CO—NH—R1, I vilken formel R betecknar en fenylgrupp, i vilken eventuellt en eller tvã vateatomer are ersatta med alkyl- eller alkoxigrupper, vilkas alkylgrupp fdretradesvis uppvisar upp till 8 kolatomer, eller med halogenatomer, eller i vilken formel R betecknar en alifatisk eller cykloalifatisk kolvategrupp med 3-8 kolatomer, eller en naftalen-(2)-, 5,6,7,8- tetrahydronaftalen-(2)- eller en 4-fenoxi-fenyl- grupp, B1 gruppenC aFia (n = 2-4), och eventuellt overfor de erhallna foreningarna till motsvarande salter med hjalp av oorganiska eller organiska baser. It has now been found that blood sugar lowering compounds which are bacteriostatically inactive can be obtained by reacting sulfonylureas of the formula R-SO 2 -NH-C 0 -NH-R a in which Ra represents vate, an acyl group or the group R —SO a, and primary amines of the form 11. 11 - NHa or vice versa, optionally in the absence of a solvent, react sulfonic acid amides of the formula R — SO 2 —N112, and ureas of the formula Dupl. kL 12: R1 — NH - 00 — NH — R ,, in which R, denotes vate, a nitro group or the acetyl, propionyl, butyryl or benzoyl group, together to form sulfonylureas of the general formula R — SO2 - NH-CO-NH-R 1, in which formula R represents a phenyl group, in which optionally one or two hydrogen atoms are replaced by alkyl or alkoxy groups, the alkyl group preferably having up to 8 carbon atoms, or with halogen atoms, or in which formula R represents an aliphatic or cycloaliphatic piston group having 3-8 carbon atoms, or a naphthalene- (2) -, 5,6,7,8-tetrahydronaphthalene- (2) - or a 4-phenoxy-phenyl group, the B1 group C aFia (n = 2-4), and possibly to the obtained compounds to the corresponding salts with the aid of inorganic or organic bases.

De nya foreningarna utgora vardefulla lakemedel och utmarka sig under avsaknad av bakteriostatiska biverkningar i synnerhet for en kraftig och langvarig sankning av blodsockervardet avensom for en mycket ringa toxicitet. The new compounds constitute valuable drugs and stand out in the absence of bacteriostatic side effects, especially for a sharp and prolonged decrease in blood sugar levels, as well as for very low toxicity.

I detalj kan R exempelvis beteckna fOljande grupper: fenyl och substituerade fenylgrupper, sa.som metyl-fenyl, i synnerhet p-metylfenyl, etylfenyl, propylfenyl, butylfenyl, pentylfenyl och. hexylfenyl. Substituenterna kunna vara saval rak.kedjiga som aven grenade; forutom i p-stallning kan substituenten aven yam bunden till andra stallen, i synnerhet i m-stallning, av fenylgruppen. Vidare ifragakomma fOr R halogenfenyl- 2 grupper, sasom klorfenyl och bromfenyl. Vidare ma disubstituerade fenylgrupper namnas, sasom dialkyl-, dialkoxi- eller alkyl-alkoxifenylgrupper. Dessutom kunna aven fenylgrupper adores, vilka innehalla saval en alkyl- eller en alkmdgrupp som aven en halogenatom samtidigt, exempelvis metyl-ldor-fenyl. Substituenterna kunna befinna sig i godtycklig stallning vid bensenkarnan. R kan aven beteckna en difenyleter-, naftalen- eller tetrahydronaftalengrupp. Slutligen kan R beteckna alkylgrupper, exempelvis en propyl-, butyl-, pentyl-, hexylgrupp, cykloalkylgrupper, exempelvis cyklohexylgruppen, och cykloalkylalkylgrupper, exempelvis hexahydrobensylgruppen. I den man det darvid är fraga oin alifatiska grupper, kunna dessa vara saval rakkedjiga som aven grenade. In detail, R may, for example, represent the following groups: phenyl and substituted phenyl groups, such as methylphenyl, in particular p-methylphenyl, ethylphenyl, propylphenyl, butylphenyl, pentylphenyl and. hexylphenyl. The substituents can be as straight-chain as they are branched; in addition to the β-position, the substituent may also be attached to other positions, especially in the m-position, of the phenyl group. Furthermore, R halogenphenyl groups such as chlorophenyl and bromophenyl are suitable for R. Furthermore, disubstituted phenyl groups are named, such as dialkyl, dialkoxy or alkyl alkoxyphenyl groups. In addition, phenyl groups may also be adored, which contain either an alkyl or an alkamide group as well as a halogen atom at the same time, for example methyl-la-dor-phenyl. The substituents can be in any position at the benzene core. R may also represent a diphenyl ether, naphthalene or tetrahydronaphthalene group. Finally, R may represent alkyl groups, for example a propyl, butyl, pentyl, hexyl group, cycloalkyl groups, for example the cyclohexyl group, and cycloalkylalkyl groups, for example the hexahydrobenzyl group. In the case of aliphatic groups, these can be saval straight-chain as well as branched.

Vid forfarandet enligt uppfinningen kan det vara av sarskild fordel vid omsattningen av sulfonsyraamiderna med enkelt alifatiskt eller cykloalifatiskt substituerade karbamider att anvanda karbarniderna i form av motsvarande acylerade, t. ex. acetyl-, propionyl-grupper, eller bensoylerade eller nitrerade foreningar och varma komponenterna i franvaro av losningsmedel till hOgre temperaturer, foretradesvis 130-160° C; aven omvant kan enligt uppfinningen gruppen Rs i sulfonylkarbamider med formeln R—SO 2—NH—CO—NH---R3 exempelvis med hj alp av primara aminer med for-mein. R1—NI-12 ersattas med gruppen R1. Istallet for N'- icke-substituerade sulfonylkarbamider kunna aven de med acylgrupper, sasom acetyl-, propionyl-, hutyryl- eller bensoylgruppen substituerade sulfonylkarbamiderna anvandas. In the process of the invention it may be of particular advantage in the reaction of the sulfonic acid amides with simple aliphatic or cycloaliphatically substituted ureas to use the carbarnides in the form of corresponding acylated, e.g. acetyl, propionyl groups, or benzoylated or nitrated compounds and the hot components in the absence of solvents to higher temperatures, preferably 130-160 ° C; Conversely, according to the invention, the group Rs in sulfonylureas of the formula R-SO2-NH-CO-NH-R3 can be used, for example, with the aid of primary amines with formine. R1 — NI-12 is replaced by the group R1. Instead of the N'-unsubstituted sulfonylureas, the sulfonylureas substituted by acyl groups, such as the acetyl, propionyl, hutyryl or benzoyl group, can also be used.

De for framstallningen av forfarandeprodukterna lampliga metoderna kunna varieras i stor utstrackning med avseende pa sina reaktionsbetingelser och anpassas efter de aktuella forhallandena. Exempelvis kunna omsattningarna i manga fall genomfOras vid forhojd temperatur genom enkel uppvarmning av komponenterna, men aven under anyandande av losningsmedel, sasom toluen, xylen och klorbensen. For att erhalla forfarandeprodukterna i ren form foretager man lampligen en sa fullstandig separering som mojligt av de sasom utgangsmaterial anvanda eller Mom loppet av reaktionen bildade sulfonamiderna, vilken lampligen kan uppnas darigenom, att man behandlar forfarandeprodukterna med utspadd ammoniak, i vilken sulfonylkarbamiderna Oro relativt latt losliga och ater faller nt dem ur losningarna genom surgoring med organiska eller oorganiska syror. The methods suitable for the preparation of the process products can be varied widely with respect to their reaction conditions and adapted to the current conditions. For example, in many cases the reactions can be carried out at elevated temperature by simply heating the components, but also using solvents such as toluene, xylene and chlorobenzene. In order to obtain the process products in pure form, the sulfonamides used as completely as possible are separated as completely as possible from the starting materials used in the course of the reaction, which can be conveniently achieved by treating the process products with dilute ammonia, in which the sulfonylureas are relatively soluble. and again they fall out of the solutions by acidification with organic or inorganic acids.

Som alkylgrupper, vilka kunna upptrada en eller tvà ganger sasom substituenter i fenylgruppen, eventuellt Over en syrebindning, ifragakomma foretradesvis grupper med lag molekylvikt. As alkyl groups which may occur once or twice as substituents in the phenyl group, optionally over an oxygen bond, low molecular weight groups are preferably preferred.

Med sarskild fordel anvander man grupper med 1-6 kolatomer. Man kan aven anvanda grupper med upp till 8 kolatomer, men darutover gar forfarandeprodukternas verksamhet kraftigt tillhaka. I stallet for de eventuellt med alkyl- eller alkoxigrupper substituerade bensensulfonylforeningarna kan man a.ven anvanda sadana aromatiska foreningar, som i fenylgruppen Oro substituerade en eller tva ganger med halogenatomer, foretradesvis med klor eller brom, eller med en halogenatom jamte en alkyl- eller alkoxigrupp. De enskilda metoderna fOr framstallningen av de onskade sulfonylkarbamiderna aro aven vid halogensubstituerade bensensulfonylforeningar desamma som ovan beskrivits. With special advantage, groups with 1-6 carbon atoms are used. It is also possible to use groups with up to 8 carbon atoms, but in addition the activity of the process products is greatly increased. Instead of the benzenesulfonyl compounds optionally substituted by alkyl or alkoxy groups, it is also possible to use such aromatic compounds which in the phenyl group Oro substituted once or twice with halogen atoms, preferably with chlorine or bromine, or with a halogen atom and an alkyl or alkoxy group. . The individual methods for the preparation of the desired sulfonylureas are also the same with halogen-substituted benzenesulfonyl compounds as described above.

I ovanstaende beskrivning har sarskilt hanvisats till bensensulfonyl-foreningar sasom utgangsmaterial. Vid forfarandet enligt uppfinningen kunna emellertid aven alifatiska och cykloalifatiska sulfonylforeningar med 3 till 8 kolatomer anvandas som utgangsforeningar. Aven fOr framstallningen av sulfonylkarbamiderna med den angivna allmanna formeln, i vilken R betecknar en difenyleter-, naftalen- eller tetrahydronaftalengrupp, kunna de namnda utforingsformerna anforas. In the above description, particular reference has been made to benzenesulfonyl compounds as starting materials. However, in the process of the invention, aliphatic and cycloaliphatic sulfonyl compounds having 3 to 8 carbon atoms can also be used as starting compounds. Also for the preparation of the sulfonylureas of the indicated general formula, in which R represents a diphenylether, naphthalene or tetrahydronaphthalene group, the mentioned embodiments can be mentioned.

Vid de vid forfarandet enligt uppfinningen anvanda utgangsmaterialen är det ofta fraga om fOreningar, som aro kanda fran litteraturen. Exempelvis ma namnas: bensensulfamid, 4-metylbensensulfamid, 4-etyl-bensensulfamid, 4-n-propyl-bensensulfamid, 4-isopropylbensensulfamid, 4- n-butyl-bensertsulfamid, 4-tert.-butyl-bensensulfamid, 4-n-hexyl-bensensulfamid, 4-metoxi-bensensulfamid, 4-etoxi-bensensulfamid och 4-n-butoxibensensulfamid. Likaledes kunna aven de motsvarande sulfonylkarbamiderna anvandas och i stallet for sadana foreningar, vilka aro substituerade i bensenkarnan i 4-stallning, kunna aven de motsvarande 1 2- eller battre 3-stallning substituerade foreningarna anvandas. In the case of the starting materials used in the process according to the invention, it is often a question of compounds which are known from the literature. Examples are: benzenesulfamide, 4-methylbenzenesulfamide, 4-ethyl-benzenesulfamide, 4-n-propyl-benzenesulfamide, 4-isopropylbenzenesulfamide, 4-n-butyl-benzenesulfamide, 4-tert-butyl-benzenesulfamide, 4-n-hexyl -benzenesulfamide, 4-methoxy-benzenesulfamide, 4-ethoxy-benzenesulfamide and 4-n-butoxybenzenesulfamide. Likewise, the corresponding sulfonylureas can also be used, and instead of such compounds which are substituted in the benzene nucleus in 4-position, the corresponding 1- or better 3-positioned substituted compounds can also be used.

Vidare ifragakomma sasom utgangsmaterial halogenbensensulfonylkarbamider, fOretradesvis klor- och bromforeningarna, varvid halogenatomen kan befinna sig i godtycklig stallning i bensenkarnan, och pa motsvarande sad substituerade bensensulfonsyraamider. Furthermore, as starting material, there are halobenzenesulfonylureas, in particular the chlorine and bromine compounds, the halogen atom being able to be in any position in the benzene nucleus, and correspondingly substituted benzenesulfonic acid amides.

Vidare kunna sa.som utgangsmaterial disubstituerade halogenbensensulfonsyraamider och motsvarande disubstituerade bensensulfonylkarbamider anvandas, varvid halogenatomerna kunna befinna sig i godtycklig staining vid bensenkarnan. Furthermore, as starting material, disubstituted halobenzenesulfonic acid amides and the corresponding disubstituted benzenesulfonylureas can be used, the halogen atoms being able to be in any staining at the benzene nucleus.

Likasa kunna som utgangsmaterial anvandas exempelvis dimetylbensensulfonyl-foreningar i form av amider och karbamider eller aven de motsvarande dimetoxi-bensensulfonylfbreningarna eller alkyl-halogen-bensen-, alkoxi-halogen-bensen- och alkcod-alkyl-bensensulfonylderivaten. Vi-dare ifragakomma; alkyl-, cyldoalkyl-, cykloalkylalkyl-, naftalen-(2)-, 5,6,7,8-tetrahydronaftalen- 3 (2)- och 4-fenmdfenyl-sulfonsyraamider eller — sulfonylkarbamider. Sasom alkyl-, cykloalkyl- och cykloalkylalkylsulfonylfOreningar ma namnas sulfonamider, vilka exempelvis innehalla foljande grupper: propyl, butyl-(1), butyl-(2), 2-metylpropyl-(1), pentyl-(2), pentyl-(3), 3-metyl-butyl(1), 2-metylbutyl-(2), hexyl-(1), cyklohexyl, cyklohexylmetyl. Givetvis kunna aven de motsvarande karbamiderna anvandas. Similarly, dimethylbenzenesulfonyl compounds in the form of amides and ureas or, for example, the corresponding dimethoxybenzenesulfonyl compounds or the alkyl-halo-benzene, alkoxy-halo-benzene and alkcode-alkyl-benzenesulfonyl derivatives can be used as starting materials. Vi-dare ifragakomma; alkyl, cyldoalkyl, cycloalkylalkyl, naphthalene- (2) -, 5,6,7,8-tetrahydronaphthalene-3 (2) - and 4-phenylphenylsulfonic acid amides or sulfonylureas. As alkyl, cycloalkyl and cycloalkylalkylsulfonyl compounds, sulfonamides may be named which contain, for example, the following groups: propyl, butyl- (1), butyl- (2), 2-methylpropyl- (1), pentyl- (2), pentyl- (3) ), 3-methyl-butyl (1), 2-methylbutyl- (2), hexyl- (1), cyclohexyl, cyclohexylmethyl. Of course, the corresponding ureas can also be used.

For omsattningen med de ovannamnda foreningarna kunna enligt uppfinningen fi-fenyletylaminer, y-fenylpropylaminer och y-fenylbutylaminer anvandas. For the reaction with the above-mentioned compounds, according to the invention, phenylethylamines, γ-phenylpropylamines and γ-phenylbutylamines can be used.

I stallet far de namnda aminerna kunna vid forfarandet enligt uppfinningen aven de motsvarande och ur dessa aminer framstallbara karbamiderna, acylkarbamiderna och nitrokarbamiderna anvandas far omsattning med de ovannamnda sulfonylderivaten. In the process, the said amines can also be used in the process according to the invention for the corresponding ureas, acyl ureas and nitrocarbamides which can be produced from these amines before reaction with the above-mentioned sulfonyl derivatives.

De vid forfarandet enligt uppfinningen erhallbara foreningarna utmarka sig for hog stabilitet. I forhallande till de aminobensensulfonamider, vilka Mtt betydelse Mom kemoterapin, är i synnerhet deras bestandighet gentemot oxiderande inflytanden anmarkningsvard. The compounds obtainable by the process according to the invention are characterized by high stability. In relation to the aminobenzenesulfonamides, which Mtt importance Mom chemotherapy, in particular, their resistance to oxidizing influences is noteworthy.

Forfarandeprodukterna aro vardefulla lakemedel oeli ha i synnerhet en avsevard blodsockersankande verkan. De skilja sig fran de kanda aminobensensulfonamiderna framfar alit aven darigenom, att de pa grund av avsaknad av en pstallning befintlig aminogrupp ej aga flagon med sulfanilamiderna jamforbar kemoterapeutisk verkan. Salunda influeras exempelvis ej tarmfloran och vidare har ej iakttagits nagot vanjande av patogena organismer, vilket yore att befara vid langvarigt bruk. De nya foreningarna kunna tramstallas pa ett enklare Batt On de kanda aminobensensulfonylkarbamiderna. The prodrugs are valuable drugs and in particular have a significant blood sugar lowering effect. They differ from the known aminobenzenesulfonamides in that they also do not have a chemotherapeutic effect comparable to the sulfanilamides due to the lack of an existing amino group. Salunda, for example, does not influence the intestinal flora and furthermore, no habituation of pathogenic organisms has been observed, which is to be feared during long-term use. The new compounds can be trampled on a simpler Batt On the known aminobenzenesulfonylureas.

Farmakologiska fors& pa kaniner ha visat, att exempelvis utfodringen av 400 mg N-cyklohexansulfonyl-N'-(19-fenylety1)-karbamid i form av natriumsaltet per kg och per os Astadkommer en sank-fling av blodsockerspegeln av i genomsnitt 45 %. Efter utfodring av exempelvis N-(3,4-dimetylbensensulfony1)-N'-(8-fenylety1)-karbamid iakttager man en sankning av blodsockerspegeln av i genomsnitt 40 %. De pa kaninen gjorda iakttagelserna kunde bekraftas genom undersokningar pa andra fOrsoksdjur. Utfordrar man exempelvis den vid forfarandet enligt uppfinningen erhallbara N(4-metyl-bensensulfony1)-N' -(-fenylety1)-karbamiden i en dos av 100 mg per kg och per os pa fastande hund, iakttager man foljande sankningar av blodsockervardet uttryckt i %: 33 % efter tva timmar 37 % efter tre timmar 37 % efter sex timmar 15-20 % efter 24 timmar 0 % efter 48 resp. 72 timmar Vidare leder exempelvis N-(naftalen-2-sulfony1)- N7-(f3-fenylety1)-karbamiden has kaninen till en blodsockersankning av 45 %, N-(4-isopropyl-bensensulfony1)-N'-(fi-fenylety1)-karbamiden till en blodsockersankning av likaledes 45 %, N-(4- metyl-bensensulfony1)-N'-(3'-fenylpropy1)-karbamiden till en blodsockersankning av 40 % och N(3-klor-4-metyl-bensensulfony1)-N7-(-feny1ety1)- karbamiden till en blodsockersankning av 35%.. Pharmacological tests on rabbits have shown that, for example, the feeding of 400 mg of N-cyclohexanesulfonyl-N '- (19-phenylethyl) -urea in the form of the sodium salt per kg and per os results in a decrease in the blood sugar level of an average of 45%. After feeding, for example, N- (3,4-dimethylbenzenesulfonyl) -N '- (8-phenylethyl) -urea, a decrease in blood sugar level of an average of 40% is observed. The observations made on the rabbit could be confirmed by examinations of other experimental animals. If, for example, the N (4-methyl-benzenesulfonyl) -N '- (- phenylethyl) -urea obtainable in the process according to the invention is challenged at a dose of 100 mg per kg and per os on a fasting dog, the following decreases in the blood sugar value expressed in %: 33% after two hours 37% after three hours 37% after six hours 15-20% after 24 hours 0% after 48 resp. 72 hours Furthermore, for example, the N- (naphthalene-2-sulfonyl) -N7- (β-phenylethyl) -urea has the rabbit lead to a blood sugar decrease of 45%, N- (4-isopropyl-benzenesulfonyl) -N'- (β-phenylethyl) ) -urea to a blood sugar drop of likewise 45%, N- (4-methyl-benzenesulfonyl) -N '- (3'-phenylpropyl) -urea to a blood sugar drop of 40% and N (3-chloro-4-methyl-benzenesulfonyl) ) -N7 - (- phenylethyl) - urea to a blood sugar drop of 35% ..

De ovannamnda vardena faststalldes genom jamforelse med blodsockervarden hos likartat hallna, joke behandlade kontrolldjur. Blodsockervardena kunna enligt Hagedorn-Jensen bestammas genom analyser varje timme. The above values were determined by comparison with the blood sugar levels in similarly treated, joke-treated control animals. According to Hagedorn-Jensen, blood sugar levels can be determined by analyzes every hour.

De enligt foreliggande uppfinning erhallbara produkterna am mycket ringa toxiska. Salunda uppgar exempelvis LD pa vita moss fin' den vid forfarandet enligt uppfinningen erhallbara N-(4- metyl- b ensensulf ony1)- N' - -fenyletyl) -karbamir den till 5,5-6 gikg. The products obtainable according to the present invention are very low toxic. Thus, for example, LD on white moss fin the N- (4-methyl-benzenesulfonyl) -N'--phenylethyl) -carbamide obtainable in the process according to the invention amounts to 5.5-6 g / g.

Forfarandeprodukterna skola foretradesvis artvandas f Or framstallningen av oralt administrerbara preparat med blodsockersankande verkan for behandling av Diabetes mellitus. De kunna darvid anvandas sasom sadana eller i form av sina salter eller i narvaro av amnen, som leda till en saltbildning. For saltbildningen kunna exempelvis naronas: ammoniak, alkaliska medel, sasom alkali- eller jordalkalihydrmdder, alkalikarbonater eller -bikarbonater, vidare fysiologiskt fordragbara organiska baser. The process products should preferably be used in the preparation of orally administrable preparations having a blood glucose lowering effect for the treatment of Diabetes mellitus. They can then be used as such or in the form of their salts or in the presence of the substances, which lead to a salt formation. For the formation of salt, for example, ammonia, alkaline agents, such as alkali or alkaline earth hydrides, alkali carbonates or bicarbonates, or physiologically tolerable organic bases can be used.

I det brittiska patentet 604 259 beskrives sal- fonylkarbamider av den allmanna formeln X / \—S02—NHCO NHaryl, dar X betecknar en aminogrupp eller en i en amir nogrupp overforbar grupp och aryl betecknar en substituerad eller icke substituerad bensylgrupp. Provningen av dessa foreningar, i synnerhet av N(4-aminobensen-sulfony1)-N'-bensyl-karbamiden, har givit till resultat, att flagon analog blodsockersankande verkan av det slag, som foreningarna enligt foreliggande uppfinning uppvisa pa ett entydligt satt, icke kommer dam till del. British Patent 604,259 discloses sulfonylureas of the general formula X 1 -SO 2 -NHCO NHaryl, wherein X represents an amino group or a group which is transferable in an amirogroup and aryl represents a substituted or unsubstituted benzyl group. The test of these compounds, in particular of the N (4-aminobenzenesulfonyl) -N'-benzylurea, has resulted in a flawed analogous blood sugar lowering effect of the kind which the compounds of the present invention clearly show, not ladies will benefit.

Darfor hade man icke vantat, att de foreliggande forfarandealstren skulle erhalla en sa god antidiabetisk verkan. Framfer alit hade man ej raknat med att de foreliggande foreningarna trots narvaron av en arylalkylgrupp skulle ha en sa ringa toxicitet. Therefore, it had not been expected that the present procedures would have such a good antidiabetic effect. Framfer alit, it had not been anticipated that the present compounds, despite the presence of an arylalkyl group, would have such low toxicity.

Exempel 1. N-(4-metyl-bensensulfony1)-N'-(2'- fenylety1)-karbamid. 21,4 g p-toluensulfonyl-karbamid och 14,5 g j9-fenyletylamin blandas val med varandra och upphettas 4 tim vid 130° C. Den erhallna reaktionsblandningen varmes med 1-procentig ammoniak pa angbad och den efter avkylningen kvar- 4 -blivande olosta aterstoden avsuges. Det ammoniakaliska filtratet surgores med utspadd saltsyra -cell far sta flera timmar. De utfallda kristallerna avsugas och omkristalliseras ur etanol. Man er-hailer pa sa satt 0,96 g N-(4-metyl-bensensulfo.ny1)-N'-(2'-fenylety1)-karbamid av smaltpunkten -145-147° C. Example 1. N- (4-methyl-benzenesulfonyl) -N '- (2'-phenylethyl) -urea. 21.4 g of p-toluenesulphonylurea and 14.5 g of .beta.-phenylethylamine are optionally mixed with each other and heated for 4 hours at 130 DEG C. The resulting reaction mixture is heated with 1% ammonia in a steam bath and the residue after cooling. the unloaded residue is sucked off. The ammoniacal filtrate is acidified with dilute hydrochloric acid cell for several hours. The precipitated crystals are sucked off and recrystallized from ethanol. 0.96 g of N- (4-methyl-benzenesulfonyl) -N '- (2'-phenylethyl) -urea of the melting point of -145-147 ° C are obtained.

Exempel 2. N-(4-metyl-bensensulfony1)-N'-(2'- fenylety1)-karbamid. 12,8 g N-p-toluensulfonyl-N'-acetyl-karbamid och 6,05 g 13-feny1etylamin blandas v5.1 och varmes -11/2 tim vid 130-140° C. Efter avsvalnandet varInes reaktionsgodset med 1 lit 1-procentig ammoniak pa angbad och avsuges efter avkylningen fran olosliga delar. Filtratet surgores med saltsyra och den utfallande fallningen omkristalliseras efter avsugningen ur metanol. Man erhaller 0,5 g N-(4- metyl-bensensulfony1)-N'-(2'-fenylety1)-karbamid av smaltpunkten 145-147° C. Example 2. N- (4-methyl-benzenesulfonyl) -N '- (2'-phenylethyl) -urea. 12.8 g of Np-toluenesulfonyl-N'-acetyl-urea and 6.05 g of 13-phenylethylamine are mixed in v5.1 and heated to -11/2 hours at 130-140 ° C. After cooling, the reaction material was washed with 1 liter of 1% ammonia on steam bath and sucked off after cooling from insoluble parts. The filtrate is acidified with hydrochloric acid and the precipitate is recrystallized after suctioning from methanol. 0.5 g of N- (4-methyl-benzenesulfonyl) -N '- (2'-phenylethyl) -urea of the melting point 145-147 ° C are obtained.

Exempel 3. N-(4-metyl-bensensulfony1)-N'-(2'- fenylety1)-karb amid. 12,8 g N-(p-toluensulfony1)-N'-acetyl-karbamid loses i 500 crn3 etylacetat och forsattes med 6 g flfenyletylamin, som tidigare Mists i 100 crn3 etylacetat. Det utfallda saltet avsuges, tvattas med etylacetat och torkas. Man erhaller 17,5 g /3- fenyl-etylamin-salt av N-(p-toluensulfony1)-N'- acetyl-karbamiden av smaltpunkten 162-164° C. Detta salt varmes 1 tim, narmare bestamt fOrst en kort tid vid 170° C och vidare vid 130° C. Efter avsvalnandet Wanes den sega massan med 1- -procentig ammoniak och varmes darefter 15 min pii angbadet. Man avkyler och avfiltrerar fran ringa mangder olosliga delar. Den efter surgoringen med saltsyra i ett utbyte av 10,4 g erhallbara raa sulfonylkarbamiden uppvisar en smaltpunkt av 134-135° C. Efter omkristallisationen ur etanol erhaller man 7,8 g av den namnda sulfonylkarbamiden av smaltpunkten 145-147° C. Example 3. N- (4-methyl-benzenesulfonyl) -N '- (2'-phenylethyl) -urea. 12.8 g of N- (p-toluenesulfonyl) -N'-acetyl-urea are dissolved in 500 ml of ethyl acetate and continued with 6 g of phenylethylamine, as previously Mists in 100 ml of ethyl acetate. The precipitated salt is filtered off with suction, washed with ethyl acetate and dried. 17.5 g / 3-phenyl-ethylamine salt of the N- (p-toluenesulfonyl) -N'-acetyl-urea are obtained, m.p. 162 DEG-164 DEG C. This salt is heated for 1 hour, more specifically only for a short time at 170 ° C and further at 130 ° C. After cooling, the tough mass is washed with 1% ammonia and then heated for 15 minutes in the steam bath. You cool and filter off small amounts of insoluble parts. After the acidification with hydrochloric acid in a yield of 10.4 g of the crude sulfonylurea obtainable, there is a melting point of 134-135 ° C.

Exempel 4. N-(4-metyl-bensensulfony1)-N'-(2'- fenylety1)-karbamid. 18,4 g bis-N,N'-(4-metyl-bensensulfony1)-karbamid och 6,05 g fl-fenyletylamin blandas viii och -det darvid bildade saltet upphettas 1 tim vid 130° C. Efter avsvalnandet upphettas reaktions-godset med 1 lit 1-procentig ammoniak kort lid pa angbadet. Efter avkylningen avsuges fran .oltista delar och det ammoniakaliska filtratet sur-gores med saltsyra. De kristaller, som, sedan de fatt sta flera timmar, blivit utfallda, avsugas och omkristalliseras ur utspadd etanol. Man erhaller .9,7 g (61 % av det teoretiska) N-(4-metylbensensulfony1)-N'-(2'-fenylety1)-karbamid av smalt-punkten 145-147° C. Example 4. N- (4-methyl-benzenesulfonyl) -N '- (2'-phenylethyl) -urea. 18.4 g of bis-N, N '- (4-methyl-benzenesulfonyl) -urea and 6.05 g of fl-phenylethylamine are mixed viii and the salt thus formed is heated for 1 hour at 130 ° C. After cooling, the reaction material is heated with 1 liter of 1% ammonia briefly on the steam bath. After cooling, it is filtered off with suction and the ammoniacal filtrate is acidified with hydrochloric acid. The crystals which, after standing for several hours, have been precipitated, sucked off and recrystallized from diluted ethanol. 9.7 g (61% of theory) of N- (4-methylbenzenesulfonyl) -N '- (2'-phenylethyl) urea are obtained, m.p. 145 DEG-147 DEG.

Exempel 5. N-(4-metyl-bensensulfony1)-N'-(2'- fenylety1)-karbamid. 9,65 g p-toluensulfonamid-natrium och 7,6 g pfenyletyl-karbamid blandas viii och upphettas flarefter 4 tim vid 150° C. Efter avsvalnandet forforsattes reaktionsgodset med 1 lit 1-procentig ammoniak, varmes 20 mm pa angbadet och avsuges efter fornyad avkylning Iran olosta delar. Filtratet klaras med kol och surgores med attiksyra. Efter avsugningen och omkristallisationen ur etanol erhaller man N-(2-metyl-bensensulfony1)-N'-(2'-fenylety1)-karbamid av smaltpunkten 144 146° C i ett utbyte av 9 g. Example 5. N- (4-methyl-benzenesulfonyl) -N '- (2'-phenylethyl) -urea. 9.65 g of p-toluenesulfonamide-sodium and 7.6 g of p-phenylethyl-urea are mixed viii and then heated for 4 hours at 150 ° C. After cooling, the reaction material is pre-charged with 1 liter of 1% ammonia, heated 20 mm on the steam bath and filtered off with suction. cooling Iran unresolved parts. The filtrate is clarified with carbon and acidified with acetic acid. After the suction and recrystallization from ethanol, N- (2-methyl-benzenesulfonyl) -N '- (2'-phenylethyl) -urea of the melting point 144 DEG-146 DEG C. is obtained in a yield of 9 g.

Exempel 6. N-(4-metyl-bensensulfony1)-N'-(2'- fenylety1)-karbamid 9,65 g p-toluensulfonamid-natrium och 20,6 g N-acetyl-N'-p-fenyletyl-karbamid (framstalld genom omsattning av f3-feny1etyl-karbamid med attiksyraanhydrid; smaltpunkt 128-130° C) blandas viii och varmes 4 tim vid 144 150° C. Efter avkylningen varmes med 1 lit 1-procentig ammoniak 30 mm pa angbadet. avkyles pa nytt och avsuges fran olosta delar. Filtratet surgores med saltsyra och den erhallna fallningen omkristalliseras efter avsugningen ur etanol. Man erhaller pa sii satt N-(4-metyl-bensensulfony1)-N'-(2'-fenylety1)-karbamid i ett utbyte av 7,2 g och av smaltpunkten 145-147° C. Example 6. N- (4-methyl-benzenesulfonyl) -N '- (2'-phenylethyl) -urea 9.65 g of p-toluenesulfonamide-sodium and 20.6 g of N-acetyl-N'-p-phenylethyl-urea (prepared by reacting β-phenylethyl urea with acetic anhydride; m.p. 128-130 ° C) is mixed for 1 hour and heated for 4 hours at 144 DEG-150 DEG C. After cooling, heat with 1 liter of 1% ammonia 30 mm in the steam bath. Re-cool and aspirate unresolved parts. The filtrate is acidified with hydrochloric acid and the resulting precipitate is recrystallized after suctioning from ethanol. N- (4-methyl-benzenesulfonyl) -N '- (2'-phenylethyl) -urea is thus obtained in a yield of 7.2 g and of the melting point 145-147 ° C.

Exempel 7. N-(4-klor-bensensulfony1)-N'-(2-fenyl-ety1)-karb amid. 27,6 g N-(4-klor-bensensulfony1)-N'-acetyl-karbamid med smaltpunkten 158-160° C (framstalld genom omsattning av 4-klor-bensensulfonamid med attiksyraanhydrid i narvaro av koncentrerad svavelsyra som katalysator) blandas viii med 12 g 2-fenyletylamin, varefter det resulterande saltet varmes 1 1/2 tim vid 130-140° C. Efter avkylning varmes reaktionsgodset pa angbad med 1-proc. ammoniak, och den erhallna losningen klaras med kol. Den vid filtratets surgOring med utspadd saltsyra utfallna fallningen omkristalliseras ur vattenhaltig metanol. Den erhallna substansen, N-(4- klor-bensensulfony1)-N'-(2'-fenyl-ety1)-karbamid, smalter vid 146-148° C. Example 7. N- (4-Chloro-benzenesulfonyl) -N '- (2-phenyl-ethyl) -urea. 27.6 g of N- (4-chloro-benzenesulfonyl) -N'-acetyl-urea, m.p. 158-160 ° C (prepared by reacting 4-chloro-benzenesulfonamide with acetic anhydride in the presence of concentrated sulfuric acid as catalyst) are mixed viii with 12 g of 2-phenylethylamine, after which the resulting salt is heated for 1 1/2 hours at 130-140 ° C. After cooling, the reaction material is heated on a steam bath with 1%. ammonia, and the resulting solution is clarified with carbon. The precipitate which precipitates on acidification of the filtrate with dilute hydrochloric acid is recrystallized from aqueous methanol. The resulting substance, N- (4-chloro-benzenesulfonyl) -N '- (2'-phenyl-ethyl) -urea, melts at 146-148 ° C.

Exempel 8. N-(4-etyl-bensensulfony1)-N'-(2'- fenyl-ety1)-karb amid. 18,5 g 4-etyl-bensensulfonamid blandas viii i form av sitt torra och finpulvriserade natriumsalt med 20,6 g N-acetyl-N'-(2'-fenyl-ety1)-karbamid med smaltpunkten 128-130° C och varmes 3 tim vid 140-155° C. Efter avkylning varmes 30 min pa angbad med utspadd ammoniak (1: 50), kyles ater och avsuges Iran olosta bestandsdelar. Filtratet surgores med saltsyra, den utfallna fallningen avsuges och omkristalliseras ur etanol. Den erhallna substansen, N-(4-etyl-bensensulfony1)-N'- (2'-fenyl-ety1)-karbamid, smatter vid 159-161° C. Example 8. N- (4-ethyl-benzenesulfonyl) -N '- (2'-phenyl-ethyl) -urea. 18.5 g of 4-ethyl-benzenesulfonamide are mixed viii in the form of its dry and finely powdered sodium salt with 20.6 g of N-acetyl-N '- (2'-phenyl-ethyl) -urea having a melting point of 128-130 ° C and heated 3 hours at 140-155 ° C. After cooling, heat for 30 minutes in a steam bath with diluted ammonia (1:50), cool again and aspirate Iran's undissolved constituents. The filtrate is acidified with hydrochloric acid, the precipitated precipitate is filtered off with suction and recrystallized from ethanol. The resulting substance, N- (4-ethyl-benzenesulfonyl) -N'- (2'-phenyl-ethyl) -urea, melts at 159-161 ° C.

Exempel 9. N-(4-metoxi-bensensulfony1)-N'-(2'- fenyl-ety1)-karb amid. 27,2 g N-(4-metoxi-bensensulfony1)-N'-acetylkarbamid med smaltpunkten 130-132° C (framstand genom omsattning av N-(4-metoxi-bensensulfony1)-karbamid med attiksyraanhydrid) omsattes med 12 g 2-fenyletylamin enligt den i exempel 7 angivna foreskriften. Den efter upparbetning pa med exempel 7 analogt satt erhallna sulfonylkarbamiden med den i rubriken angivna formeln visar efter omkristallisation ur metanol smaltpunkten 143-144° C. Example 9. N- (4-Methoxy-benzenesulfonyl) -N '- (2'-phenyl-ethyl) -urea. 27.2 g of N- (4-methoxy-benzenesulfonyl) -N'-acetylurea, m.p. 130-132 ° C (prepared by reacting N- (4-methoxy-benzenesulfonyl) -urea with acetic anhydride) were reacted with 12 g of 2- phenylethylamine according to the procedure set forth in Example 7. The sulfonylurea obtained after working up by analogy to Example 7, with the formula given in the title, shows, after recrystallization from methanol, the melting point of 143-144 ° C.

Exempel 10. N-bensensulfonyl-N'-(2'-fenylety1)-karbamid. 24,2 g N-bensensulfonyl-N'-acetyl-karbamid med smaltpunkten 157-158° C (framstalld genom omsattning av N-bensensulfonylkarbamid med attiksyraanhydrid) omsattes med 12 g 2-fenyletylamin pa det i exempel 7 beskrivna sattet. Den efter upparbetning ph det i exempel 7 angivna sattet erhallna foreningen med den i rubriken angivna formeln visar efter omkristallisation ur etanol smaltpunkten 130-132° C. Example 10. N-Benzenesulfonyl-N '- (2'-phenylethyl) -urea. 24.2 g of N-benzenesulfonyl-N'-acetylurea, m.p. 157-158 ° C (prepared by reacting N-benzenesulfonylurea with acetic anhydride) are reacted with 12 g of 2-phenylethylamine in the manner described in Example 7. The compound obtained after work-up according to the procedure given in Example 7 with the title formula shows, after recrystallization from ethanol, a melting point of 130-132 ° C.

Exempel 11. N-(3,4-dimetoxi-bensensulfony1)- N'-(2'-f enyl-ety1)-karb amid . 21,7 g 3,4-dimetmd-bensensulfonamid blandas i form av sitt kaliumsalt val med 22 g N-(2-fenylety1)-N'-propionylkarbamid. Efter 3 tim varmning av blandningen vid 140-150° C upparbetas reektionsprodukten analogt med det i exempel 6 angivna arbetssattet. Den darvid utvunna substansen, N-(3,4-dimetoxi-bensensulfony1)-N'-(2'-fenylety1)-karbamid, visar efter omkristallisation ur vattenhaltig etanol smaltpunkten 159-161° C. Example 11. N- (3,4-Dimethoxy-benzenesulfonyl) -N '- (2'-phenyl-ethyl) -urea. 21.7 g of 3,4-dimethylbenzenesulfonamide are mixed in the form of their potassium salt choice with 22 g of N- (2-phenylethyl) -N'-propionylurea. After heating the mixture for 3 hours at 140-150 ° C, the reaction product is worked up analogously to the procedure set forth in Example 6. The substance thus obtained, N- (3,4-dimethoxy-benzenesulfonyl) -N '- (2'-phenylethyl) -urea, shows, after recrystallization from aqueous ethanol, the melting point 159-161 ° C.

Pa analogt satt framstaller man med anvandning av motsvarande utgangsmaterial foreningen N-(naftalen-2-sulfony1)-N'-(p-fenyl-ety1)-karbamid med smaltpunkten 167-169° C (ur 80-proc. etanol), N- (p entan - 3 - sulfony1)-N' - (p - fenyl-etyl) -karb - amid med smaltpunkten 81° C (ur diisopropyleter), N-(4-fenoxi-bensensu1fony1)-N'-(16-feny1-ety1)- karbamid med smaltpunkten 110-112° C (ur etanol). In an analogous manner, using the corresponding starting material, the compound N- (naphthalene-2-sulfonyl) -N '- (p-phenyl-ethyl) -urea with a melting point of 167-169 ° C (from 80% ethanol), N - (pentane - 3-sulfonyl) -N '- (p-phenyl-ethyl) -urea with melting point 81 ° C (from diisopropyl ether), N- (4-phenoxy-benzenesulfonyl) -N'- (16- phenyl-ethyl) -urea having a melting point of 110-112 ° C (from ethanol).

Claims

1. Patent claim: Set to produce blood sugar lowering compounds which are bacteriostatically inactive, characterized in that sulfonyl ureas of the formula R-SO 2 -NH-CO-NH-R 2 in which R 3 represents vate, an acyl group or the group R-SO 2 are reacted , And primary amines of the form 11.1-NH2 or ornvant, optionally in the absence of a solvent, react sulfonic acid amides of the formula R-S02-NH2 and ureas with the formula in which R4 represents hydrogen, a. nitro group or the acetyl, propionyl, butyryl or benzoyl group, with each other forming sulfonyl ureas of the general formula R-SO 2 -NH-CO-NH-R 1, in which formulas R represents a phenyl group, in which optionally one or two hydrogen atoms are substituted by alkyl or alkoxy groups, the alkyl group preferably having up to 8 carbon atoms, or having halogen atoms, or R represents an aliphatic or cycloaliphatic carbonate group having 3-8 carbon atoms or a naphthalene- (2) -, 5,6,7, 8-tetrahydronaphthalene (2) - or a 4-phenoxy-phenyl group, R1 group - (C1-12) .— C, H6 (n = 2-4), and optionally transfer the obtained compounds to the corresponding salts with helped by inorganic or organic bases. Require publications: Agent: Ing. S Penderud, Stockholm & tocicholm 1966. Rune. Boktr. P. A. Norsteclit & SiMer. 660006