SE201888C1

SE201888C1 -

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Publication number: SE201888C1
Authority: SE
Publication date: 1965-01-01

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KLASS INTERNATIONELLSVENSK C07 c12o:17/03 PAT ENT- OCH REGISTRERINGSVERKET Ans. 1973/1958 inkom den 28/2 1958 uttagd den 17/5 196 FARBWERKE HOECHST AG VORMALS MEISTER LUCIUS & BRUNING, FRANKFURT A.M., FORBUNDSREPUBLIKEN TYSKLAND Forfarande for framstallning av bakteriostatiskt overksamma, blodsockersilnkande sulfonylkarbamider Uppfinnere: H Wagner, W Aumilller, H Ruschig och G Korger Prioritet begtird !ran den 26 maj 1956 (ForbimdsrepubIiken TyskIand) Patentet 171 652 avser framstallning av nya blodsockersankande, icke bakteriostatiskt verksamma sulfonylurinamnen av den allmanna formeln B—S 2—NH—C 0 —NH—R dar R betecknar en fenylgrupp, i vilken en eller tva vateatomer kunna vara substituerade med foretradesvis lagmolekylara alkyl- eller alkoxiradikaler och/eller med halogenatomer, eller en. alifatisk resp. cykloalifatisk kolvategrupp med 3-8 kolatomer och R, beLecknar en alifatisk eller cykloalifatisk kolvategrupp med 28 kolatomer, avensom av deras salter darigenom, att man ornsatter sulfonylurinamnen av formeln R—S 02—NH—C 0—NH med aminder av formeln R1--N1-12 eller omvant omsatter sulfonamider av formeln R—S02.—NH2 med urinamnederivat av formeln Ri—NH—00NE12, dar och R, ha den angivna betydelsen och eventuellt med hj alp av oorganiska eller organiska baser overfor de erhallna foreningarna till motsvarande salter. CLASS INTERNATIONAL SWEDISH C07 c12o: 17/03 PAT ENT AND REGISTRATION AGENCY Ans. 1973/1958 was received on 28/2 1958 taken on 17/5 196 FARBWERKE HOECHST AG VORMALS MEISTER LUCIUS & BRUNING, FRANKFURT AM, FEDERAL REPUBLICEN GERMANY Procedure for the production of bacteriostatic inactive, blood sugar silks Wagner Sulfur gum, Korger Priority filed May 26, 1956 (Federal Republic of Germany) Patent 171,652 relates to the preparation of novel blood glucose lowering, non-bacteriostatically active sulfonylurea names of the general formula B — S 2 — NH — C 0 —NH — R where R represents a phenyl group, in which one or two hydrogen atoms may be substituted by preferably lower molecular weight alkyl or alkoxy radicals and / or by halogen atoms, or one. aliphatic resp. cycloaliphatic piston group having 3 to 8 carbon atoms and R, represents an aliphatic or cycloaliphatic piston group having 28 carbon atoms, in addition to their salts by reacting the sulfonylureas of the formula R-S O 2 -NH-C 0 -NH with amines of the formula R N1-12 or, conversely, sulfonamides of the formula R — SO2. —NH2 react with urea derivatives of the formula R1-NH-00NE12, dar and R .

Enligt foreliggande uppf inning har man nu funnit, att foreningar av den allmanna formeln R—S 02—NH—C 0 —NH—R„ dar R betecknar en alifatisk eller cykloalifatisk kolvategrupp med 3-8 kolatomer och R, en mattad eller omattad, oppenkedjig eller ringformad, syre eller svavel innehallande alifatisk kolvategrupp med 3-8 kolatomer, och salterna av dessa foreningar vid ringa tocicitet utmarka sig fOr en kraftig blodsockersankande verksamhet. According to the present invention, it has now been found that compounds of the general formula R-S O 2 -NH-C 0 -NH-R 2, where R represents an aliphatic or cycloaliphatic carbon group having 3 to 8 carbon atoms and R openkedjig or ring-shaped, oxygen or sulfur containing aliphatic carbon group with 3-8 carbon atoms, and the salts of these compounds at low toxicity mark for a strong blood sugar lowering activity.

Foreliggande uppfinning avser framstallning av dylika blodsockersankande foreningar utan bakteriostatisk verksamhet darigenom, att man ornsatter sulfonylurinamnen av formeln R—S02-- NH—CO—NH2 med aminer av formeln R1—NH2 eller omvant omsLtter sulfonamider av formeln R—S02—N1-12 med urinamnederivat av formeln 1:11.—NH—00—NH-13.2, dar R och R, ha den angivna betydelsen och R2 kan beteckna vate, en acylgrupp eller nitrogrupp, och eventuellt med hj alp av oorganiska eller organiska baser overfor de erhallna foreningarna till motsvarande salter. The present invention relates to the preparation of such blood glucose lowering compounds without bacteriostatic activity by reacting the sulfonylureas of the formula R-SO 2 -NH-CO-NH 2 with amines of the formula R 1 -NH 2 or conversely reacting sulfonamides of the formula R-SO 2 -N1-12 with urea derivatives of the formula 1: 11. — NH — 00 — NH-13.2, where R and R, have the indicated meaning and R 2 may represent vate, an acyl group or nitro group, and optionally with the aid of inorganic or organic bases opposite the obtained compounds to the corresponding salts.

Yid omsattning av sulfonamider med enkelt alifatiskt eller cykloalifatiskt sub stituerade urinamnen kan det vara av sarskild fordel att insatta sulfonamides i form av deras alkalisalter och urinamnederivaten i form av motsvarande acylerade eller nitrerade foreningar och uppvarma komponenterna i franvaro av losningsmedel till hogre temperatures, foretradesvis 130-160° C. By reacting sulfonamides with simple aliphatic or cycloaliphatically substituted ureas, it may be of particular advantage to insert sulfonamides in the form of their alkali salts and the urea derivatives in the form of corresponding acylated or nitrated compounds and to heat the components in the absence of solvents. 160 ° C.

Sasom utgangsmaterial ifragakomma vid forfarandet enligt uppfinningen exempelvis foljande sulfonylfOreningar: alkyl-, cykloalkyl- eller cykloalkylalkylsulfamider, vllka sasom alkylradikaler kunna uppbara t. ex. en propyl-, butyl-(1)-, butyl-(2)-, 2-metyl-propyl-(1)-, pentyl-(1)-, pentyl-(2)-, pentyl-(3)-, 3-metyl-butyl-(1)-, 2-metyl-butyl-(1)-, hexyl-(1)-, hexyl-(2)-, 4-metyl-pentyl-(2)-, (2)- etyl-butyl-(1)-, heptyl-(1)-, heptyl-(2)-, heptyl-(4)-, 2,4-dimetyl-pentyl-(1)-, 2,4-dimetyl-pentyl-(3)-, oktyl-(1)- och oktyl-(2)-radikal, sasom cykloalkylradikaler t. ex. en cyklohexyl- och cykloheptyl-. As starting materials in the process according to the invention, for example, the following sulfonyl compounds: alkyl, cycloalkyl or cycloalkylalkylsulfamides, which such alkyl radicals can bear e.g. and propyl-, butyl- (1) -, butyl- (2) -, 2-methyl-propyl- (1) -, pentyl- (1) -, pentyl- (2) -, pentyl- (3) -, 3-methyl-butyl- (1) -, 2-methyl-butyl- (1) -, hexyl- (1) -, hexyl- (2) -, 4-methyl-pentyl- (2) -, (2) - ethyl-butyl- (1) -, heptyl- (1) -, heptyl- (2) -, heptyl- (4) -, 2,4-dimethyl-pentyl- (1) -, 2,4-dimethyl- pentyl (3), octyl (1) and octyl (2) radicals, such as cycloalkyl radicals e.g. a cyclohexyl and cycloheptyl.

Dupl. kl. 12 o: 2 radikal och sasom cykloalkyl-alkylradikaler exempelvis en cyklohexylmetyl- och cyklohexyletylradikal. Vidare kunna motsvarande alkyl-, cykloalkyl- eller cykloalkylalkylsulfonylurinamnen namnas. Dupl. at 12 o: 2 radical and such as cycloalkyl-alkyl radicals, for example a cyclohexylmethyl and cyclohexylethyl radical. Furthermore, the corresponding alkyl, cycloalkyl or cycloalkylalkylsulfonylurea names can be named.

For omsattningen med de ovannamnda sulfonylurinamnena kunna enligt uppfinningen folj an-de primara aminer anvandas: metchd-propylamin, etwd-propylamin, propoxi-propylamin, propoxietylamin, etwd-etylamin, etoxi-etylenoxi-etylamin, metoxi-etylenoxi-etylamin, a-tetrahydrofurfurylmetylamin, 6-propyl-dioxan-(1,3)-amin(4), /3,fl-dietoxi-etylamin, metylmerkaptopropylamin och etyl-merkapto-propylamin. I stallet for dessa aminer kunna fOr omsattningen med sulfonamiderna de urinamnen anvandas, vilka kunna liarledas frau dessa aminer. For the reaction with the above-mentioned sulfonylurea names, the following primary amines can be used according to the invention: methd-propylamine, ethd-propylamine, propoxy-propylamine, propoxyethylamine, ethd-ethylamine, ethoxy-ethylenoxy-ethylamine, methoxy-ethylfurin-amyl-furamyl-amyl-furamyl-amyl-furamyl-amyl-furamyl-amyl-furamyl-amyl-furamin , 6-propyl-dioxane- (1,3) -amine (4), β, β-diethoxyethylamine, methylmercaptopropylamine and ethylmercapto-propylamine. Instead of these amines, the urea names which can be derived from these amines can be used for the reaction with the sulfonamides.

Forfarandeprodukterna utgora vardefulla lakemedel, vilka sarskilt utmarka sig fOr en kraftig blodsockersankande verksamhet och mycket ringa toxicitet. Genom den senare egenskapen synas de yam sdrskilt lampliga for anvandning shsom perorala antidiabetika, eftersom dylika for behandling av sockersjuka lampliga foreningar i vissa fall mdste ingivas under manga dr. Foreningarna kunna finna anvandning som sadana eller i form av sina alkalisalter resp. i narvaro av Amnen, vilka fora till en saltbildning. For saltbildningen kunna exempelvis foljande nananas: alkali- eller jordalkalihydroxider, alkalikarbonater eller -bikerbonater, vidare fysiologiskt fordragbara organiska baser. The process products constitute valuable drugs, which in particular stand out for a strong blood sugar lowering activity and very low toxicity. Due to the latter property, they appear to be particularly suitable for use as oral antidiabetics, since such compounds suitable for the treatment of diabetic lamps must in some cases be administered in many cases. The associations can find use as such or in the form of their alkali salts resp. in the presence of the Amnen, which lead to a salt formation. For the salt formation, for example, the following nananas: alkali or alkaline earth hydroxides, alkali carbonates or biker carbonates, or physiologically tolerable organic bases.

Vid djurforsok kan verkningen ph blodsockerspegeln exempelvis p0 kaniner pdvisas. Om man ph normalt utfodrade kaniner administrerar foreningar av den foreliggande strukturen i en engangsdos av i genomsnitt 400 mg/kg i exempelvis bikarbonatalkalisk lOsning, iakttager man en snabbt insattande sankning av blodsockerspegeln, som mom 3-4 tim uppnar ett maximum av c:a 30 % av utgangsvardet. Exempelvis sanker den angivna dosen av N-(3-metyl-butan-(1)-sulfony1)- N'-(3'-metoxipropy1)-urinamne blodsockret efter 2 tim c:a 30 %; verkan varar c:a 6 tim. Om man anvander N-(3-metyl-butan-(1)-sulfony1)-N'-(3- etoxipropy1)-urinamne, erhaller man efter 2 tim en blodsockersankning av 20 %, som efter 6 tim fortfarande utgor 16 %. Om man anvander N-cyklohexansulfonyl-N'-(3'-metoxipropy1)-urinam-ne, utgor sankningen av blodsockret efter 1 tim c:a 30 %; denna sankning hAller i sig utover 6 tim. Om man anyander N-cyklohexyl-metansulfonylN'-(3'-metoxipropy1)-urinamne, utgor blodsockersankningen efter 2 tim 40 % och efter 6 tim alum 35%. In animal experiments, the effect on the blood sugar level, for example on rabbits, can be demonstrated. If ph normally fed rabbits are administered compounds of the present structure in a single dose of an average of 400 mg / kg in, for example, bicarbonate alkaline solution, a rapid insertion of the blood sugar level is observed, which at a 3-4 hour time reaches a maximum of about 30 % of the initial value. For example, the indicated dose of N- (3-methyl-butane- (1) -sulfonyl) -N '- (3'-methoxypropyl) -urine name lowers blood sugar after 2 hours about 30%; the effect lasts about 6 hours. If N- (3-methyl-butane- (1) -sulfonyl) -N '- (3-ethoxypropyl) -urine name is used, a blood sugar drop of 20% is obtained after 2 hours, which after 6 hours is still 16%. If N-cyclohexanesulfonyl-N '- (3'-methoxypropyl) -urinamine is used, the accumulation of blood sugar after 1 hour is about 30%; this collection lasts for more than 6 hours. If one mixes N-cyclohexyl-methanesulfonylN '- (3'-methoxypropyl) -urine name, the blood sugar drop after 2 hours is 40% and after 6 hours alum 35%.

Blodsockervardena kunna bestammas genom analyser varje timme enligt Hagedorn-Jensen. Blodsockersankningen bestammes genom jamforelse med blodsockervArdena av likartat Mina, icke behandlade kontrolldjur. The blood sugar values can be determined by analyzes every hour according to Hagedorn-Jensen. The blood sugar lowering is determined by comparison with the blood sugar values of similar Mina, untreated control animals.

Det är redan kant, att N-(4-amino-bensolsu1fony1)-N'-n-butyl-urinamne uppvisar blodsockershnkande egenskaper. Vidare Or det kant, att denna forening ph grund av sin sulfanilylkaraktar Oven Or kemoterapeutiskt verksam. Eftersom for anvAndningen som oralt antidiabetikum en standig dosering under en lang tidsrymd Or erforderlig, Or det emellertid onskvart, att den applicerade foreningen ej ham flagon sulfanilylkaraktar och foljaktligen Ar sh. fri som mojligt frau olikartade verkningar for att utesluta eventuella skador, exempelvis ph tarmfloran, dvensom allergi och resistensbildning av patogena organismer gentemot sulfonanilylamider. It is already true that N- (4-amino-benzenesulfonyl) -N'-n-butyl-urea name exhibits blood sugar lowering properties. Furthermore, it is known that this compound is chemotherapeutically active due to its sulfanilyl character. Since for the use as an oral antidiabetic a steady dosing for a long period of time is required, it is, however, unavoidable that the applied compound does not have sulfonilyl character and consequently Ar sh. free as possible from various effects to exclude any damage, such as the intestinal flora, allergy and the formation of resistance of pathogenic organisms to sulfonanilylamides.

Exempel 1. N-cyklohexansulfonyl-N'-(3'-metoxipropy1)-urinamne. 9,3 g cyklohexansulfonamid-natrium och 8,7 g N-(3-metoxipropy1)-N'-acetyl-urinamne med smaltpunkten 92-94° C (framstallt av 3-rnetoxipropylurinamne och atiksyraanhydrid genom uppvarmning ph angbad) blandas val och uppvarmes i oljebad under 1 1/2 tim till 140-150° C. Efter smaltans avsvalnande behandlar man reaktionsblandningen med 1-procentig vattenhaltig ammoniak, avfiltrerar frau ringa mangder °lost och erhaller genom surgoring av filtratet med utspadd saltsyra i gott utbyte en kristallin fallning av N-cyklohexansulfonyl-N'-(3'-metoxipropy1)-urinamne, som efter omkristallisationen ur etanol smalter vid 129-130° C. Example 1. N-Cyclohexanesulfonyl-N '- (3'-methoxypropyl) urea name. 9.3 g of cyclohexanesulfonamide-sodium and 8.7 g of N- (3-methoxypropyl) -N'-acetyl-urea name with a melting point of 92-94 ° C (prepared from 3-methoxypropyl urea name and acetic anhydride by heating ph ang bath) are mixed and heated in an oil bath for 1 1/2 hours to 140-150 ° C. After the melt has cooled, the reaction mixture is treated with 1% aqueous ammonia, filtered from small amounts and lost by acidifying the filtrate with dilute hydrochloric acid in good yield a crystalline precipitate of N-cyclohexanesulfonyl-N '- (3'-methoxypropyl) urea, which melts at 129-130 ° C after recrystallization from ethanol.

Exempel 2. N-cyklohexansulfonyl-N'-(3'-metoxipropy1)-urinamne. 20,6 g N-cyklohexansulfonyl-urina.mne forshttes med 9 g 3-metoxi-propylamin. Man uppvarmer det bildade saltet under 1 1/2 tim till 130-140° C. Efter avsvalnandet behandlas smaltan med c:a 1- procentig ammoniak, varvid losning intrader. 'Man klarar med kol och surgor filtratet med saltsyra. Den erhdllna fallningen avfiltreras, tvdttas med vatten och omkristalliseras ur etanol. Man erhaller ph sh satt N-cyklohexansulfonyl-N'-(3'- meto)dpropy1)-urinamne med smaltpunkten 129130° C. Example 2. N-Cyclohexanesulfonyl-N '- (3'-methoxypropyl) urea name. 20.6 g of N-cyclohexanesulfonylurea are reacted with 9 g of 3-methoxypropylamine. The salt formed is heated for 1 1/2 hours to 130-140 ° C. After cooling, the melt is treated with about 1% ammonia, whereupon solution is introduced. 'You can handle with carbon and acidify the filtrate with hydrochloric acid. The resulting precipitate is filtered off, washed with water and recrystallized from ethanol. N-cyclohexanesulfonyl-N '- (3'-metho) dpropyl) urea with a melting point of 129130 ° C is obtained.

Claims

Patent claim:

1. To prepare blood glucose-lowering compounds which are bacteriostatically inactive, it may be claimed that the sulfonylureas of the formula R-S0 2 -NH-C0-NH2 and amines of the formula R1-NH2 or converted sulfonamides of the formula R- SO 2 —Nl 2 and urea derivatives of the formula 111 — NH — 00 — NH — R 2 to react with each other to form the sulfonylureas of the general formula 11 — SO 2 NH — CO — NH — R 1, in which formulas R represent an aliphatic or cycloaliphatic piston group having 3 to 8 carbon atoms, R, a matte or unsaturated, open-chain or annular oxygen or sulfur-containing sliphatic carbonate group having 3 to 8 carbon atoms, and Ra the sulfonylurea names obtained to the corresponding salts.

SRL according to claim 1, can be characterized in that the compounds of the formula 11-80, -NH, are reacted in the form of their alkali metal salts. Request publications: