DE2103118A1 - 4 (2-heterocyclylethyl) - benzenesulphonylureas - with hypoglycaemic activity - Google Patents
4 (2-heterocyclylethyl) - benzenesulphonylureas - with hypoglycaemic activityInfo
- Publication number
- DE2103118A1 DE2103118A1 DE19712103118 DE2103118A DE2103118A1 DE 2103118 A1 DE2103118 A1 DE 2103118A1 DE 19712103118 DE19712103118 DE 19712103118 DE 2103118 A DE2103118 A DE 2103118A DE 2103118 A1 DE2103118 A1 DE 2103118A1
- Authority
- DE
- Germany
- Prior art keywords
- ethyl
- salts
- benzenesulfonyl
- corresp
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 230000002218 hypoglycaemic effect Effects 0.000 title abstract 2
- -1 3-ethylcyclopentyl Chemical group 0.000 claims abstract description 76
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 150000007513 acids Chemical class 0.000 claims abstract description 6
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims abstract description 5
- 239000012948 isocyanate Substances 0.000 claims abstract description 4
- 150000002513 isocyanates Chemical class 0.000 claims abstract description 4
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 3
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 claims abstract description 3
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 235000013877 carbamide Nutrition 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000008280 blood Substances 0.000 claims description 8
- 210000004369 blood Anatomy 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 150000003672 ureas Chemical class 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- 229940112021 centrally acting muscle relaxants carbamic acid ester Drugs 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 4
- GHDLZGOOOLEJKI-UHFFFAOYSA-N benzenesulfonylurea Chemical compound NC(=O)NS(=O)(=O)C1=CC=CC=C1 GHDLZGOOOLEJKI-UHFFFAOYSA-N 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- VNMLVHLVBFHHSN-UHFFFAOYSA-N thiophen-2-ylcarbamic acid Chemical class OC(=O)NC1=CC=CS1 VNMLVHLVBFHHSN-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 150000001714 carbamic acid halides Chemical class 0.000 claims description 3
- 150000001718 carbodiimides Chemical class 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 150000002542 isoureas Chemical class 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- JEHKKBHWRAXMCH-UHFFFAOYSA-N benzene seleninic acid Natural products O[S@@](=O)C1=CC=CC=C1 JEHKKBHWRAXMCH-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 239000000460 chlorine Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- UJYAZVSPFMJCLW-UHFFFAOYSA-N n-(oxomethylidene)benzenesulfonamide Chemical group O=C=NS(=O)(=O)C1=CC=CC=C1 UJYAZVSPFMJCLW-UHFFFAOYSA-N 0.000 claims description 2
- 150000003455 sulfinic acids Chemical class 0.000 claims description 2
- 229940124530 sulfonamide Drugs 0.000 claims description 2
- 150000003456 sulfonamides Chemical class 0.000 claims description 2
- 150000001447 alkali salts Chemical class 0.000 claims 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 2
- 231100000252 nontoxic Toxicity 0.000 claims 1
- 230000003000 nontoxic effect Effects 0.000 claims 1
- 239000004202 carbamide Substances 0.000 abstract description 8
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 abstract description 7
- 238000006243 chemical reaction Methods 0.000 abstract description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 abstract description 5
- 150000001409 amidines Chemical class 0.000 abstract description 4
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 2
- 125000002947 alkylene group Chemical group 0.000 abstract 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 abstract 1
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 abstract 1
- 241001061127 Thione Species 0.000 abstract 1
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 abstract 1
- 150000004820 halides Chemical class 0.000 abstract 1
- UUFWPLHGJYIEBA-UHFFFAOYSA-N n-(iminomethylidene)benzenesulfonamide Chemical compound N=C=NS(=O)(=O)C1=CC=CC=C1 UUFWPLHGJYIEBA-UHFFFAOYSA-N 0.000 abstract 1
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 abstract 1
- 150000007659 semicarbazones Chemical class 0.000 abstract 1
- SSGGNFYQMRDXFH-UHFFFAOYSA-N sulfanylurea Chemical compound NC(=O)NS SSGGNFYQMRDXFH-UHFFFAOYSA-N 0.000 abstract 1
- 238000002844 melting Methods 0.000 description 38
- 230000008018 melting Effects 0.000 description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- QAXZWHGWYSJAEI-UHFFFAOYSA-N n,n-dimethylformamide;ethanol Chemical compound CCO.CN(C)C=O QAXZWHGWYSJAEI-UHFFFAOYSA-N 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- WWECJGLXBSQKRF-UHFFFAOYSA-N n,n-dimethylformamide;methanol Chemical compound OC.CN(C)C=O WWECJGLXBSQKRF-UHFFFAOYSA-N 0.000 description 8
- 239000000155 melt Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 4
- KQWGXHWJMSMDJJ-UHFFFAOYSA-N cyclohexyl isocyanate Chemical compound O=C=NC1CCCCC1 KQWGXHWJMSMDJJ-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229940100389 Sulfonylurea Drugs 0.000 description 3
- WUESWDIHTKHGQA-UHFFFAOYSA-N cyclohexylurea Chemical compound NC(=O)NC1CCCCC1 WUESWDIHTKHGQA-UHFFFAOYSA-N 0.000 description 3
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- CSDGNEKJWIEXAM-UHFFFAOYSA-N 1-(4-methylcyclohexyl)-3-[4-[2-(4-oxoquinazolin-3-yl)butyl]phenyl]sulfonylurea Chemical compound C1=NC2=CC=CC=C2C(=O)N1C(CC)CC(C=C1)=CC=C1S(=O)(=O)NC(=O)NC1CCC(C)CC1 CSDGNEKJWIEXAM-UHFFFAOYSA-N 0.000 description 1
- LGMGYAKLAALTTO-UHFFFAOYSA-N 1-cyclohexyl-3-[4-[2-(4-oxoquinazolin-3-yl)butyl]phenyl]sulfonylurea Chemical compound C1=NC2=CC=CC=C2C(=O)N1C(CC)CC(C=C1)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 LGMGYAKLAALTTO-UHFFFAOYSA-N 0.000 description 1
- SWSXEZOUBBVKCO-UHFFFAOYSA-N 1-isocyanato-4-methylcyclohexane Chemical compound CC1CCC(N=C=O)CC1 SWSXEZOUBBVKCO-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- IUYZNZCQHGNONW-UHFFFAOYSA-N 4-[2-(4-oxoquinazolin-3-yl)butyl]benzenesulfonamide Chemical compound C1=NC2=CC=CC=C2C(=O)N1C(CC)CC1=CC=C(S(N)(=O)=O)C=C1 IUYZNZCQHGNONW-UHFFFAOYSA-N 0.000 description 1
- PXYMACAYRGWCDC-UHFFFAOYSA-N 5-cyclohexyl-1h-imidazole-2-carboxamide Chemical class N1C(C(=O)N)=NC(C2CCCCC2)=C1 PXYMACAYRGWCDC-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 150000008331 benzenesulfonamides Chemical group 0.000 description 1
- ALZKZGUTVJXYEF-UHFFFAOYSA-N benzenesulfonylcarbamic acid Chemical class OC(=O)NS(=O)(=O)C1=CC=CC=C1 ALZKZGUTVJXYEF-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- ONENTOHJOJEWPH-UHFFFAOYSA-N n-(benzenesulfonyl)-1h-imidazole-2-carboxamide Chemical class N=1C=CNC=1C(=O)NS(=O)(=O)C1=CC=CC=C1 ONENTOHJOJEWPH-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000001272 nitrous oxide Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- PFUVRDFDKPNGAV-UHFFFAOYSA-N sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
- C07D239/96—Two oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Benzolsulfonylharnstoffe und Verfahren zu ihrer Herstellung Gegenstand der Erfindung sind Sulfonylharnstoffe der Formel die als Substanz oder in Form ihrer Salze blutzuckersenkende Eigenschaften besitzen und die sich durch eine starke und anhaltende Senkung des Blutzuckerspiegels auszeichnen.Benzenesulfonylureas and process for their preparation The invention relates to sulfonylureas of the formula which, as a substance or in the form of their salts, have blood sugar lowering properties and which are characterized by a strong and sustained lowering of the blood sugar level.
In der Formel bedeuten R Wasserstoff, Chlor, Brom, Methoxy oder Methyl, -X-Y- -N=CH-, -NH-CH2-, -NH-CO-, wobei "Alkyl" ein solches mit 1 - 4 Kohlenstoffatomen bedeutet, R' Alkyl mit 3 - 6 C-Atomen, Cycloalkyl mit 5 - 8 C-Atomen, 3-Äthyl-cyclopentyl, Methyl-cyclopentyl, Dimethylcyclopentyl, 4-Alkyl-cyclohexyl mit 1 - 3 C-Atomen im Alkylrest, Cyclopentenyl, Cyclohexenyl, Cycloheptenyl, 4-Chlor-cyclohexyl, 4,4-Dimethylcyclohexyl, 3-Methylcyclopentenyl, 4-Methylcyclohexenyl, Endoalkylencyclohexyl, Endoalkylencyclohexenyl, Bicyclo(2. 2.l)hept-2-en-7-yl.In the formula, R denotes hydrogen, chlorine, bromine, methoxy or methyl, -XY- -N = CH-, -NH-CH2-, -NH-CO-, where "alkyl" means one with 1-4 carbon atoms, R 'alkyl with 3-6 carbon atoms, cycloalkyl with 5-8 carbon atoms, 3-ethyl-cyclopentyl, methyl-cyclopentyl, dimethylcyclopentyl, 4-alkyl-cyclohexyl with 1 - 3 carbon atoms in the alkyl radical, cyclopentenyl, cyclohexenyl, cycloheptenyl, 4-chloro-cyclohexyl, 4,4-dimethylcyclohexyl, 3-methylcyclopentenyl, 4-methylcyclohexenyl, endoalkylene cyclohexyl, endoalkylene cyclohexenyl, bicyclo (2. 2.l) heptenyl 2-en-7-yl.
Gegenstand der Erfindung sind ferner Verfahren zur Herstellung dieser Sulfonylharnstoffe. Diese sind dadurch gekennzeichnet, dass man a) mit der Gruppe in 4-Stellung substituierte Benzolsulfonyl-isocyanate, carbaminsäureester, -thiolcarbaminsäureester, -harnstoffe, -semicarbazide oder -semicarbazone mit einem Amin oder dessen Salzen umsetzt oder Sulfonamide der Formel oder deren Salze mit R'-substituierten Isocyanaten, Carbaminsäureestern, Thiolcarbaminsäureestern, Carbaminsäurehalogeniden oder Harnstoffen umsetzt, b) entsprechend substituierte Benzolsulfonyl-isoharnstoffäther, -isoharnstoffester, -isothioharnstoffäther, -parabansäuren oder -halogenameisensäureamidine verseift oder hydrolysiert, c) in entsprechend substituierten Benzolsulfonyl-thioharnstoffen aas Schwefelatom durch ein Sauerstoffatom ersetzt oder an entsprechend substituierte Carbodiimide Wasser anlagert, d) entsprechende Benzolsulfinyl- oder sulfenylharnstoffe oxydiert, e) in Benzolsulfonylharnstoffen der Formel gegebenenfalls stufenweise den Rest einführt, f) entsprechend substituierte Benzolsulfonylhalogenide mit R'-substituierten Harnstoffen oder deren-Alkalisalzen umsetzt oder entsprechend substituierte Benzolsulfinsäure-halogenide oder, in Gegenwart von sauren Kondensationsmitteln, auch entsprechend substituierte Sulfinsäuren oder deren Alkalisalze, mit N-R'-Nt-hydroxyharnstoff umsetzt und die Reaktionsprodukte gegebenenfalls zur Salzbildung mit alkalischen Mitteln behandelt.The invention also relates to processes for the preparation of these sulfonylureas. These are characterized by a) with the group benzenesulfonyl isocyanates substituted in the 4-position, carbamic acid esters, -thiolcarbamic acid esters, -ureas, -semicarbazides or -semicarbazones with an amine or its salts or sulfonamides of the formula or their salts are reacted with R'-substituted isocyanates, carbamic acid esters, thiol carbamic acid esters, carbamic acid halides or ureas, b) correspondingly substituted benzenesulfonyl isourea ethers, isourea esters, isothiourea ethers, -parabanic acids or -halogenoformic acid, correspondingly saponified benzene sulfonyl isoureaethers, -isothiourea ethers, -parabanic acids or -halogenoformic acid or) benzene-methylamylamylated-benzene sulphonamidines aas the sulfur atom is replaced by an oxygen atom or water is added to appropriately substituted carbodiimides, d) corresponding benzenesulfinyl or sulfenylureas are oxidized, e) in benzenesulfonylureas of the formula, if appropriate, in stages the rest introduces, f) correspondingly substituted benzenesulfonyl halides with R'-substituted ureas or their alkali metal salts or correspondingly substituted benzenesulfinic acid halides or, in the presence of acidic condensing agents, also correspondingly substituted sulfinic acids or their alkali metal salts, with N-R'-Nt-hydroxyurea and the reaction products are optionally treated with alkaline agents to form salts.
Die erwähnten Benzolsulfonyl-carbaminsäureester bzw. -thiolcarbaminsäureester können in der Alkoholkomponente einen Alkylrest oder einen Arylester oder auch einen heterocyclisdhen Rest aufweisen. Da dieser Rest bei der Reaktion abgespalten wird, hat seine chemische Konstitution keinen Einfluss auf den Charakter des Endproduktes und kann deshalb in weiten Grenzen variiert werden. Das gleiche gilt für die N-R-substituierten Carbaminsäureester bzw. die entsprechenden Thiolcarbaminsäureester.The benzenesulfonyl carbamic acid esters or thiol carbamic acid esters mentioned can be an alkyl radical or an aryl ester or also one in the alcohol component heterocyclic-hene Have remainder. Because this remainder in the reaction is split off, its chemical constitution has no influence on the character of the end product and can therefore be varied within wide limits. The same applies to the N-R-substituted carbamic acid esters or the corresponding thiol carbamic acid esters.
Als Carbaminsäurehalogenide eignen sich in erster Linie die Chloride.The chlorides are primarily suitable as carbamic acid halides.
Die als Ausgangsstoffe des Verfahrens infrage kommenden Benzolsulfonylharnstoffe können an der der Sulfonygruppe abgewandten Seite des Harnstoffmoleküls unsubstituiert oder.The benzenesulphonylureas which can be used as starting materials for the process can be unsubstituted on the side of the urea molecule facing away from the sulfony group or.
ein- oder insbesondere zweifach substituiert sein. Da diese Substituenten bei der Reaktion mit Aminen abgespalten werden, kann ihr Charakter in weiten Grenzen variiert werden. Neben alkyl-, aryl-, acyl- oder heterocyclisch substituierten Benzolsulfonylharnstoffen kann man auch Benzolsulfonylcarbamoylimidazole und ähnliche Verbindungen oder Bisbenzolsulfonyl -harnstoffe, die an eint3m der Stickstoffatome noch. einen weiteren Substitueten, z.B. Methyl, tragen können, verwenden. Man kann beispielsweise derartige Bis-(benzolsulfonyl)-harnstoffe oder auch N-Benzolsulfonyl-N'-acylharnstoffe mit R-substituierten Aminen behandeln und die erhaltenen Salze auf erhöhte Temperaturen, insbesondere solche oberhalb 1000C, erhitzen.be substituted once or in particular twice. Because these substituents be split off in the reaction with amines, their character can be within wide limits can be varied. In addition to alkyl, aryl, acyl or heterocyclic substituted benzenesulfonylureas one can also use benzenesulfonylcarbamoylimidazoles and similar compounds or bisbenzenesulfonyl -ureas, which are attached to one of the nitrogen atoms. another substituent, e.g. methyl. One can, for example, such bis (benzenesulfonyl) ureas or treat N-benzenesulfonyl-N'-acylureas with R-substituted amines and the salts obtained at elevated temperatures, especially those above 1000C, heat.
Weiterhin ist es möglich, von R'-substituierten Harnstoffen auszugehen oder von solchen R-substituierten Harnstoffen, die am freien Stickstoffatom noch ein- oder insbesondere zweifach substituiert sind, und diese mit in 4-Stellung substituierten Benzol- sulfonamiden umzusetzen. Als solche Ausgangsstoffe kommen beispielsweise infrage N-Cyclohexyl-harnstoff, die entsprechenden N'-Acetyl, N'-Nitro, N'-Cyclohexyl, N',N'-Diphenyl-(wobei die beiden Phenylreste auch substituiert sowie direkt oder auch über ein Brückenglied wie -CH2-, -NH-, -0- oder -5- miteinander berbunden sein können), N'-Methyl-N'-phenyl-, N' , N'-Dicyclohexylharnstoffe sowie Cyclohexyl-carbamoyl-imidazole, pyrazole oder -triazole sowie solche der genannten Verbindungen, die anstelle des Cyclohexyls einen anderen im Bereich der Definition fUr R liegenden Substituenten tragen.It is also possible to start from R'-substituted ureas or from those R-substituted ureas which are still mono- or, in particular, doubly substituted on the free nitrogen atom, and these with to implement benzene sulfonamides substituted in the 4-position. Possible starting materials of this type are, for example, N-cyclohexyl urea, the corresponding N'-acetyl, N'-nitro, N'-cyclohexyl, N ', N'-diphenyl- (where the two phenyl radicals are also substituted, either directly or via a Bridge members such as -CH2-, -NH-, -0- or -5- can be bonded to one another), N'-methyl-N'-phenyl-, N ', N'-dicyclohexylureas and cyclohexyl-carbamoyl-imidazoles, pyrazoles or -triazoles and those of the compounds mentioned which, instead of cyclohexyl, have another substituent lying in the range of the definition for R.
Di Hydrolyse der als Ausgangsstoffe genannten Benzolsulfonyl-parabansäuren, -isoharnstoffäther, -isothioharnstoffäther, -isoharnstoffester oder -hologenameisensäureamidine erfolgt zweckmässig in alkalischem Medium. Isoharnstoffäther und Isoharnstoffester können auch in einem sauren Medium mit gutem Erfolg hydrolysiert werden.Di hydrolysis of the benzenesulfonyl-parabanic acids mentioned as starting materials, -isourea ethers, -isothiourea ethers, -isourea esters or -hologoformic acid amidines it is best done in an alkaline medium. Isourea ethers and isourea esters can also be hydrolyzed in an acidic medium with good success.
Der Ersatz des Schwefelatoms in der Harnstoffgruppierung von entsprechend substituierten Benzolsulfonylthioharnstoffen durch ein Sauerstoffatom kann in bekannter Weise zum Beispiel mit Hilfe von Oxyden oder Salzen voll Schwermetallen oder auch durch Anwendung von Oxydationsmitteln, wie Wasserstoffperoxyd, Natriumperoxyd, salpetriger Säure oder Permanganten ausgeführt werden.The replacement of the sulfur atom in the urea grouping by corresponding substituted benzenesulfonylthioureas by an oxygen atom can be known in For example, with the help of oxides or salts full of heavy metals or also by using oxidizing agents such as hydrogen peroxide, sodium peroxide, nitrous oxide Acid or permangant.
Die T}iioharnstoffe können auch entschwefelt werden durch Behandlung mit Phosgen oder Phosphorpentachlorid. Als Zwwischenstufe erhaltene Chlorameinsensäureamidine bzw. Carbodiimide können durch geeignet te Maßnahmen wie Verseifen oder hnlaterung von Wasser in die Benzolsulfonylharnstoffe überführt werden.The thiioureas can also be desulfurized by treatment with phosgene or phosphorus pentachloride. Chloramic acid amidines obtained as an intermediate stage or carbodiimides can be prepared by suitable measures such as saponification or treatment converted by water into the benzenesulfonylureas.
Die Ausführungsformen des Verfahrens gemass der Erfindung können im allgemeinen hinsichtlich der Reaktionsbedingungen weitgehend variiert und den jeweiligen Verhältnissen angepasst werden. Beispielsweise können die Umsetzungen in Abwesenheit oder Anw.esenheit von Lösungsmitteln, bei Raumtemperatur oder bei erhöhter Temperatur durchgeführt werden.The embodiments of the method according to the invention can be in generally largely varied with regard to the reaction conditions and the respective Conditions can be adjusted. For example, the conversions can be absent or presence of solvents, at room temperature or at elevated temperature be performed.
Je nach dem Charakter der Ausgangsstoffe karm das eine oder andere der beschriebenen Verfahren in einzelnen Fällen einen gewünschten individuellen Benzolsulfonylharnstoff nur in geringen Ausbeuten liefern oder zu dessen Synthese nicht geeignet sein. In solcnen verhältnismässig selten auftretenden Fällen macht es dem Fachmann keine Schwierigkeiten, das gewünschte Produkt auf einem anderen der beschriebenen Verfahrenswege zu synthetisieren.Depending on the character of the raw materials, one or the other can be of the procedures described in individual cases a desired individual Provide benzenesulfonylurea only in low yields or for its synthesis Not be suitable. In such cases, which occur relatively seldom, makes there is no difficulty in finding the desired product on another for those skilled in the art to synthesize the process routes described.
Die blutzuckersenkende Wirkung der beschriebenen Benzolsulfonylharnstoffe kann dadurch festgestellt werden, dass man sie in Form der Natriumsalze in Dosen von 10 mg/kg an normal ernährte Kaninchen verfüttert und den Blutzuckerwert nach der bekannten methode von Hagedorn-Jensen oder mit einem Autoanalyzer über eine längere Zeitdauer ermittelt.The blood sugar lowering effect of the described benzenesulfonylureas can be determined by taking them in canned form of the sodium salts of 10 mg / kg fed to normally fed rabbits and checked the blood sugar level the well-known method from Hagedorn-Jensen or with an auto analyzer via a longer period of time determined.
Die beschriebenen Benzolsulfonylharnstoffe sollen vorzugsweise zur Herstellung von oral verabreichbaren Präparaten mit blutzuckersenkender Wirksamkeit zur Behandlung des Diabetes mellitus dienen und können als solche oder in Form ibrer Salze bzw. in Gegenwart von Stoffen, die zu einer Salzbildung führen, appliziert werden. Zur Salzbildung können beispielsweise alkalische Mittel wie Alkali- oder Erdalkalihydroxyde, -carbonate oder -bicarbonate herangezogen werden.The benzenesulfonylureas described should preferably be used for Manufacture of orally administrable preparations with blood sugar lowering effectiveness serve to treat diabetes mellitus and can be used as such or in other forms Salts or in the presence of substances that lead to salt formation, applied will. For salt formation, for example, alkaline agents such as alkali or Alkaline earth hydroxides, carbonates or bicarbonates are used.
Als medizinische Präparate kommen vorzugsweise Tabletten in Betracht, die neben den Verfahrenserzeugnissen die üblichen Träger- und Hilfsstoffe wie Talkum, Stärke, Milchzucker, Tragant oder Magnesiumstearat enthalten.The preferred medical preparations are tablets, which, in addition to the products of the process, the usual carriers and auxiliaries such as talc, Contain starch, lactose, tragacanth or magnesium stearate.
Ein Präparat, das die beschriebenen Benzolsulfonylharnstoffe als Wirkstoff enthält, z.B. eine Tablette oder ein Pulver tiiit oder ohne Zusätze, ist zweckmässig in eine geeignet dosierte Form gebracht. Als Dosis ist dabei eine solche zu wählen, die der Wirksamkeit des verwendeten Benzolsulfonylharnstoffes tmd dem gewünschten Effekt angepasst ist.. Zweck mässig beträgt die Dosierung je Einheit etwa 0,5 bis 500 mg, vorzugsweise mg, jedoch können auch darüber oder darunter liegende Dosierungseinheiten verwendet werden, die gegebenenfalls vor Applikation zu teilen bzw. zu vervielfachen -sind.A preparation which contains the benzenesulfonylureas described as active ingredient, for example a tablet or a powder with or without additives, is expediently brought into a suitably dosed form. The dose to be selected is one which is adapted to the effectiveness of the benzenesulfonylurea used and the desired effect. The dosage per unit is expediently about 0.5 to 500 mg, preferably mg, but dosage units above or below can also be used, which if necessary have to be divided or multiplied before administration.
Die nachfolgenden Beispiele zeigen einige der zahlreichen Verfahrensvarianten, die zur Synthese der erfindungsgemässen Sulfonylharnstoffe verwendet werden können. Sie sollen jedoch nicht eine Einschränkung des Erfindungsgegenstandes darstellen.The following examples show some of the numerous process variants, which can be used for the synthesis of the sulfonylureas according to the invention. However, they are not intended to represent a limitation of the subject matter of the invention.
Beispiel 1 N-[4-(ß-4-Chinazolinon-3-yl-äthyl)-benzolsulfonyl] N'-cyclohexylharnstoff 16,5g 4-(ß-4-Chinazolinon-3-yl-äthyl)-benzolsulfonamid (Schmp. 253-255°, hergestellt aus 4-(ß-2-Amino-benzamido-äthyl)-benzolsulfonamid und Ameisensäure) werden in 200 ml Aceton mit der Lösung von 2g Natriumhydroxyd in Wasser in Lösung gebracht. hierzu tropft man unter Rühren 6,5g Cyclohexylisocyanat und rührt 2 Stunden nach. Die Lösung wird mit Wasser versetzt, filtriert und amsesäuert. Man saugt den ausgefällten Niederscalag ab, fällt ihn aus 1proz. Ammoniak um und kristallisiert ihn aus Äthanol-Dimethylformamid um. Dor erhaltene N-[4-(ß-4-Chinazolinon-3-yl-äthyl) benzolsulfonyl] N'-cyclohexyl-harnstoff schmilzt bei 227-229°.Example 1 N- [4- (β-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] N'-cyclohexylurea 16.5 g of 4- (β-4-quinazolinon-3-yl-ethyl) -benzenesulfonamide (melting point 253-255 °, produced from 4- (ß-2-amino-benzamido-ethyl) -benzenesulfonamide and formic acid) are in 200 ml of acetone brought into solution with the solution of 2 g of sodium hydroxide in water. For this 6.5 g of cyclohexyl isocyanate are added dropwise with stirring and the mixture is stirred for a further 2 hours. The solution water is added, the mixture is filtered and acidified. The precipitated lower scalag is sucked from, it falls from 1 per cent. Ammonia recrystallizes it from ethanol-dimethylformamide around. The N- [4- (β-4-quinazolinon-3-yl-ethyl) benzenesulfonyl] N'-cyclohexylurea obtained melts at 227-229 °.
In analoger Weise erhält man den N-[4-(ß-4-Chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-(4-methylcyclohexyl)-harnstoff vom Schmp. 184-186° (aus Wasser-Äthanol) N-[4-(ß-4-Chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-butylharnstoff vom Schmp. 221-223° (aus Äthanol) N-[4-(ß-4-Chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-(4-äthylcyclohexyl).harnstoff vom Schmp. 190-1920 (aus Äthanol) In analoger Weise erhält man aus dem 4-(ß-6-Chlor-4-chinazolinon-3-yl-äthyl)-benzolsulfonamid vom Schmp. 248.2490 den N-[4-(ß-6-Chlor-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-cyclohexyl-harnstoff vom Schmp. 225-227° (aus Äthanol) N-[4-(ß-6-Chlor-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-(4-methylcyclohexyl)-harnstoff vom Schmp. 219-221° (aus Äthanol) N-[4-(ß-6-Chlor-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-butyl-harnstoff vom Schmp. 237-239° (aus Äthanol-DMF) In analoger Weise erhält man aus dem 4-(ß-7-Methyl-4-chinazolinon-3-yl-äthyl)-benzolsulfonamid vom Schmp. 258-260° den N-[4-(ß-7-Methyl-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-cyclohexyl-harnstoff vom Schmp. 221-223° (aus Äthanol-DMF) N-[4-(ß-7-Methyl-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-4-methyl-cyclohexyl)-harnstoff vom Schmp. 205-207° (aus Äthanol) N-[4-(ß-7-Methyl-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-(4-äthylcyclohexyl)-harnstoff vom Schmp. 264.2060 (aus Äthanol) In analoger Weise erhält man aus dem 4-(ß-2-Methyl-4-chinazolinon-3-yl-äthyl)-benzolsulfonamid vom Schmp. 252.2540 den N-[4-(ß-2-Methyl-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-cyclohexyl-harnstoff vom Schmp. 253-254° (aus Äthanol-DMF) In analoger Weise erhält man aus dem 4-(ß-2-Äthyl-4-chinazolinon-3-yl-äthyl)-benzolsulfonamid vom 8chmp. 248.2500 den N-[4-(ß-2-Äthyl-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-cyclohexyl-harnstoff vom Schmp. 216.2180 (aus thanol-DMP) N-[4-(ß-2-Äthyl-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-(4-methylcyclohexyl)-harnstoff vom Schmp. 207-2090 (aus Äthanol-DMF) Beispiel 2 N-[4-(ß-1,2-Dihydro-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-cyclohexyl-harnstoff 8,3g 4-(ß-1,2-Dihydro-4-chinazolinon-3-yl-äthyl)-benzolsulfonamid (Schmp. 219-221°, hergestellt aus 4-(ß-2-Amino-benzamidoäthyl)-benzolsulfonamid und Formaldehyd) werden in 100ml Aceton, der Lösung von Ig NaOH in Wasser und 3 , 3,3g Cyclohexylisocyanat wie oben beschrieben umgesetzt und aufgearbeitet. Der erhaltene N-[4-(ß-1,2-Dihydro-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-cyclohexylharnstoff schmilzt nach Umkristallisieren aus Wasser-Äthanol bei 186-1880.The N- [4- (ß-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N '- (4-methylcyclohexyl) urea is obtained in an analogous manner of m.p. 184-186 ° (from water-ethanol) N- [4- (β-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N'-butylurea of melting point 221-223 ° (from ethanol) N- [4- (β-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N '- (4-ethylcyclohexyl) urea from melting point 190-1920 (from ethanol) 4- (β-6-chloro-4-quinazolinon-3-yl-ethyl) -benzenesulfonamide is obtained in an analogous manner of m.p. 248.2490 the N- [4- (β-6-chloro-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N'-cyclohexylurea of melting point 225-227 ° (from ethanol) N- [4- (β-6-chloro-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N '- (4-methylcyclohexyl) urea of melting point 219-221 ° (from ethanol) N- [4- (β-6-chloro-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N'-butylurea from melting point 237-239 ° (from ethanol-DMF) Received in an analogous manner from the 4- (ß-7-methyl-4-quinazolinon-3-yl-ethyl) -benzenesulfonamide of mp. 258-260 ° the N- [4- (β-7-methyl-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N'-cyclohexylurea of melting point 221-223 ° (from ethanol-DMF) N- [4- (β-7-methyl-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N'-4-methyl-cyclohexyl) -urea with a melting point of 205-207 ° (from ethanol) N- [4- (β-7-methyl-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N '- (4-ethylcyclohexyl) urea of melting point 264.2060 (from ethanol) In an analogous manner, 4- (β-2-methyl-4-quinazolinon-3-yl-ethyl) -benzenesulfonamide is obtained of mp 252.2540 the N- [4- (β-2-methyl-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N'-cyclohexylurea of melting point 253-254 ° (from ethanol-DMF) 4- (β-2-ethyl-4-quinazolinon-3-yl-ethyl) -benzenesulfonamide is obtained in an analogous manner from 8chmp. 248.2500 N- [4- (β-2-ethyl-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N'-cyclohexylurea of melting point 216.2180 (from ethanol-DMP) N- [4- (β-2-ethyl-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N '- (4-methylcyclohexyl) urea from m.p. 207-2090 (from ethanol-DMF) Example 2 N- [4- (β-1,2-dihydro-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N'-cyclohexylurea 8.3g 4- (ß-1,2-dihydro-4-quinazolinon-3-yl-ethyl) -benzenesulfonamide (melting point 219-221 °, made from 4- (ß-2-amino-benzamidoethyl) -benzenesulfonamide and formaldehyde) in 100 ml of acetone, the solution of Ig NaOH in water and 3.3 g of cyclohexyl isocyanate implemented and worked up as described above. The N- [4- (β-1,2-dihydro-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N'-cyclohexylurea obtained After recrystallization from water-ethanol, it melts at 186-1880.
In analoger Weise erhält man den N-[4-(ß-1,2-Dihydro-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-butyl-harnstoff vom Schmp. 188-1900 (aus Wasser-Äthanol) N-[4-(ß-1,2-Dihydro-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-(4-methyl-cyclohexyl)-harnstoff vom Schmp. 208-210° (aus Äthanol) rn analoger Weise erhält man aus dem 4-(ß-7-Methyl-1,2-dihydro-4-chinazolinon-3-yl-äthyl)-benzolsulfonamid den N-[4-(ß-7-Methyl-1,2-dihydro-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-cyclohexyl-harnstoff vom Schmp. 185-187° (aus Äthanol) N-[4-(ß-7-Methyl-1.2-dihydro-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-(4-methylcyclohexyl)-harnstoff vom Schmp. 206.2080 (aus Äthanol) N-[4-(ß-7-Methyl-1,2-Dihydro-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-(4-äthylcyclohexyl)-harnstoff vom Schmp. 200-202° (aus Äthanol) In analoger Weise erhält man aus dem 4-(ß-6-Chlor-1,2-dihydro-4-chinazolinon-3-yl-äthyl)-benzolsulfonamid vom Schmp. 208-209° den N-[4-(ß-6-Chlor-1,2-dihydro-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-cyclohexyl-harnstoff vom Schmp. 181-183° (aus Äthanol-DMF) N-[4-(ß-6-Chlor-1,2-dihydro-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-(4-methylcyclohexyl)-harnstoff vom Schmp. 190-192° (aus Äthanol) N-[4-(ß-6-Chlor-1,2-dihydro-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-butylharnstoff vom Schmp. 182-184° (aus Äthanol) ** In analoger Veise erhält man aus dem 4-(ß-2,2-Dimethyl-1,2-dihydro-4-chinazolinon-3-yl-äthyl)-benzolsulfonamid vorn Schmp. 234-235° den N-[4-(ß-2,2-Dimethyl-1,2-dihydro-4-chinazolinon-3-yl-äthyl)-benzolsulfonyl]-N'-(4-methylcyclohexyl)-harnstoff vom Schmp. 200-201° (aus Methanol-DMF) Beispiel 3 N'-cyclohexyl-harnstoff 8 ,65g 4~{ß-2,4(1H)-Chinazolindion 3-yl-Ethyl)-bonzolsulSonamid vom Schmp. 307-311°, hergestellt durch Zusammenschmelzen von 4-(ß-2-Amino-benzamidoäthyl)-benzolsulfonamid und Harnstoff) werden in 100ml Aceton, 1g Natriumhydroxyd und Wasser in Lösung gebracht. Dazu tropft man unter Rühren bei Raumtemperatur 3,3g Cyclohexylisocyanat, rührt 2 Stunden bei Raumtemperatur nach. Anschließend verdünnt man mit Wasser, filtriert und säuert das Filtrat an. Der ausgefällte N-[4-(ß-2,4(1H)-Chinazolindion-3-yl-äthyl)-benzolsulfonyl]-N'-cyclohexyl-harnstoff wird aus Äthanol-DMF umkristallisiert und schmilzt bei 250°C.N- [4- (ß-1,2-dihydro-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N'-butylurea is obtained in an analogous manner from melting point 188-1900 (from water-ethanol) N- [4- (ß-1,2-dihydro-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N '- (4-methyl-cyclohexyl) -urea with a melting point of 208-210 ° (from ethanol) in an analogous manner is obtained from 4- (β-7-methyl-1,2-dihydro-4-quinazolinon-3-yl-ethyl) -benzenesulfonamide the N- [4- (β-7-methyl-1,2-dihydro-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N'-cyclohexylurea from melting point 185-187 ° (from ethanol) N- [4- (ß-7-methyl-1,2-dihydro-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N '- (4-methylcyclohexyl) - urea of mp 206.2080 (from ethanol) N- [4- (β-7-methyl-1,2-dihydro-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N '- (4-ethylcyclohexyl) urea from melting point 200-202 ° (from ethanol) In an analogous way one obtains from 4- (ß-6-chloro-1,2-dihydro-4-quinazolinon-3-yl-ethyl) -benzenesulfonamide from Mp. 208-209 ° the N- [4- (β-6-chloro-1,2-dihydro-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N'-cyclohexylurea of melting point 181-183 ° (from ethanol-DMF) N- [4- (β-6-chloro-1,2-dihydro-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N '- (4th methylcyclohexyl) urea of melting point 190-192 ° (from ethanol) N- [4- (β-6-chloro-1,2-dihydro-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N'-butylurea from melting point 182-184 ° (from ethanol) ** In an analogous manner, 4- (β-2,2-dimethyl-1,2-dihydro-4-quinazolinon-3-yl-ethyl) -benzenesulfonamide is obtained from mp 234-235 ° den N- [4- (ß-2,2-dimethyl-1,2-dihydro-4-quinazolinon-3-yl-ethyl) -benzenesulfonyl] -N '- (4-methylcyclohexyl) -urea from melting point 200-201 ° (from methanol-DMF) Example 3 N'-cyclohexyl urea 8, 65g 4 ~ {ß-2,4 (1H) -quinazolinedione 3-yl-ethyl) -bonzenesulfonamide with a melting point of 307-311 °, produced by melting together 4- (ß-2-amino-benzamidoethyl) -benzenesulfonamide and urea) are dissolved in 100ml acetone, 1g sodium hydroxide and water. 3.3 g of cyclohexyl isocyanate are added dropwise with stirring at room temperature, and the mixture is stirred 2 hours at room temperature. Then it is diluted with water and filtered and acidifies the filtrate. The precipitated N- [4- (ß-2,4 (1H) -quinazolinedion-3-yl-ethyl) -benzenesulfonyl] -N'-cyclohexylurea is recrystallized from ethanol-DMF and melts at 250 ° C.
In analoger Weise erhält man den N-[4-(ß-2,4(1H)-Chinazolindion-3-yl-äthyl)-benzolsulfonyl]-N'-butyl-harnstoff vom Schmp. 230° (aus Äthanol-DMF) N-[4-(ß-2,4(1H)-Chinazolindion-3-yl-äthyl)-benzolsulfonyl]-N'-(4-methylcyclohexyl)-harnstoff vom Schmp. 245°C (aus Äthanol) In analoger Weise erhält man aus dem 4-(ß-7-Methyl-2,4(1H)-chinazolindion-3-yl-äthyl)-benzolsulfonamid vom Schmp. 303-304° den N-[4-(ß-7-Methyl-2,4(1H)-chinazolindion-3-yl-äthyl)-benzolsulfonyl]-N'-cyclohexyl-harnstoff vom Schmp. 313-314° (aus Äthanol-DMF) N-[4-(ß-7-Methyl-2,4(1H)-chinazolindion-3-yl-äthyl)-benzolsulfonyl]-N'-(4-methylcyclohexyl)-harnstoff vom Schmp. 260° (aus Äthanol-DMF) * N-[4-(ß-6-Chlor-2,4(1H)-chinazolindion-3-yl-äthyl)-benzolsulfonyl]-N'.cyclohexyl.harnstoff vom Schmp. 2500 (aus Äthanol-DMF) * In analoger Weise erhält inan aus dem 4-(ß-6-Chlor-2,4(1H)-chinazolindion-3-yl-äthyl)-benzolsulfonamid vom Schmp. 307-309° den Beispiel 4 N-[4-(ß-1,2,3-Benzotriaziazin-4-on-3-yl-äthyl)-benzolsulfonyl]-N'-cyclohexyl-harnstoff 8,25g 4-(ß-1,2,3-Benzotriazin-4-on-3-yl-äthyl)-benzolsulfonamid (Schmp. 232-234°, hergestellt aus 4-(ß-2-Aminobenzamidoäthyl)-benzolsulfonamid und salpetriger Säure) werden in 200ml Aceton mit 10g Kaliumcarbonat und 3,3g Cyclohexylisocyanat winter Rühren am Rückflußkühler gekocht. Man saugt nach Erkalten ab, löst in Wasser, filtriert und säuert das Filtrat an. Der ausgefällte N-[4-(ß-1,2,3-Benzotriaziazin-4-on-3-yl-äthyl)-benzolsulfonyl]-N'-cyclohexyl-harnstoff schmilzt nach Umkristallisieren aus Äthanol bei 213-215°.N- [4- (ß-2,4 (1H) -quinazolinedion-3-yl-ethyl) -benzenesulfonyl] -N'-butylurea is obtained in an analogous manner of m.p. 230 ° (from ethanol-DMF) N- [4- (β-2,4 (1H) -quinazolinedion-3-yl-ethyl) -benzenesulfonyl] -N '- (4-methylcyclohexyl) urea of melting point 245 ° C. (from ethanol) In an analogous manner, 4- (β-7-methyl-2,4 (1H) -quinazolinedione-3-yl-ethyl) -benzenesulfonamide is obtained of melting point 303-304 ° the N- [4- (β-7-methyl-2,4 (1H) -quinazolinedion-3-yl-ethyl) -benzenesulfonyl] -N'-cyclohexylurea of melting point 313-314 ° (from ethanol-DMF) N- [4- (ß-7-methyl-2,4 (1H) -quinazolinedion-3-yl-ethyl) -benzenesulfonyl] -N '- (4- methylcyclohexyl) urea of m.p. 260 ° (from ethanol-DMF) * N- [4- (β-6-chloro-2,4 (1H) -quinazolinedion-3-yl-ethyl) -benzenesulfonyl] -N'.cyclohexyl.urea from melting point 2500 (from ethanol-DMF) * In an analogous manner, 4- (ß-6-chloro-2,4 (1H) -quinazolinedione-3-yl-ethyl) -benzenesulphonamide is obtained of melting point 307-309 ° den Example 4 N- [4- (β-1,2,3-Benzotriaziazin-4-on-3-yl-ethyl) -benzenesulfonyl] -N'-cyclohexylurea 8.25g 4- (ß-1,2,3-benzotriazin-4-on-3-yl-ethyl) -benzenesulfonamide (melting point 232-234 °, made from 4- (ß-2-aminobenzamidoethyl) -benzenesulfonamide and nitrous acid) are winter in 200ml acetone with 10g potassium carbonate and 3.3g cyclohexyl isocyanate Stirring boiled on the reflux condenser. After cooling, it is filtered off with suction, dissolved in water and filtered and acidifies the filtrate. The precipitated N- [4- (ß-1,2,3-benzotriaziazin-4-on-3-yl-ethyl) -benzenesulfonyl] -N'-cyclohexylurea melts after recrystallization from ethanol at 213-215 °.
In analoger Weise erhält man den N-[4-(ß-1,2,3-Benzotriazin-4-on-3-yl-äthyl)-benzolsulfonyl]-N'-(4-methylcyclohexyl)-harnstoff vom Schmp. 212-214° (aus Äthanol) N-[4-(ß-1,2,3-Benzotriazin-4-on-3-yl-äthyl)-benzolsulfonyl]-N'-butyl-harnstoff vom Schmp. 211-213° (aus Äthanol) Beispiel 5 N-[4-(ß-1,3-Benzoxazin-2,4-dion-3-yl-äthyl)-benzolsulfonyl]-N'-(4-methylcyclohexyl)-harnstoff 7, 5g 4-(ß-1,3-Bensoxazin-2,}+-dion-3-yl-äthyl)-bonFolnalSonamid (Schmp. 266-267°) werden mit 6g gemahlener Pottasche in 250ml aceton 3 Stunden gekocht. Anschließend gibt man 3,2g trans-4-methylcyclohexylisocyanat zu und kocht unter Rühren weitere 8 Stunden. Nach Erkalten saugt man ab, gibt den Niederschlag in Wasser und säuert an. Das abgeschiedene Produkt wird aus Methanol-DMF umkristallisiert. Der erhaltene N-[4-(ß-1,3-Benzoxazin-2,4-dion-3-yl-äthyl)-benzolsulfonyl]-N'-(4-methylcyclohexyl)-harnstoff schmilzt bei 220-221° cyclohexyl)-harnstoff schmilzt bei 220-221 In analoger Weise oder entsprechend Beispiel 1 erhält man den N-[4-(ß-1,3-Benzoxazin-2,4-dion-3-yl-äthyl)-benzolsulfonyl]-N'-cyclohexylharnstoff vom Schmp. 227-228° (aus Methanol-DMF) In analogor Weise erhält man aus dem 4-(ß-6-Methyl-1,3-benzoxazin-2,4-dion-3-yl-äthyl)-benzolsulfonamid vom Schmp. 242.2430 den N-[4-(ß-6-Methyl-1,3-benzoxazin-2,4-dion-3-yl-äthyl)-benzolsulfonyl-N'-cyclohexyl-harnstoff vom Schmp. 218.2200 (aus Methanol-DMF) N-[4-(ß-6-Methyl-1,3-benzoxazin-2,4-dion-3-yl-äthyl)-benzolsulfonyl]-N'-(4-methylcyclohexyl)-harnstoff vom Schmp. 222-223° (aus Methanol-DMF) N-[4-(ß-6-Methyl-1,3-benzoxazin-2,4-dion-3-yl-äthyl)-benzolsulfonyl]-N'-butyl-harnstoff vom Schmp. 200-201° (aus Methanol-DMF) aus dem 4-(ß-6-Chlor-1, 3.benzoxazin-2, 4.dion.3.yl.äthyl) -benzolsulfonamid vom Schmp. 259.2610 den N-[4-(ß-6-Chlor-1,3-benzoxazin-2,4-dion-3-yl-äthyl)-benzolsulfonyl]-N'-cyclohexyl-harnstoff vom Schmp. 221-223° (aus Methanol-DMF) N-[4-(ß-6-Chlor-1,3-benzoxazin-2,4-dion-3-yl-äthyl)-benzolsulfonyl]-N'-(4-methyl-cyclohexyl)-harnstoff vom Schmp. 235-237° (aus Methanol) aus dem 4-(ß-6-Methoxy-1,3-benzoxazin-2,4-dion-3-yl-äthyl)-benzolsulfonamid vom Schmp. 245-2470 den N-[4-(ß-6-Methoxy-1,3-benzoxazin-2,4-dion-3-yl-äthyl)-benzolsulfonyl]-N '-cyclohexyl-harnstoff vom Schmp. 194.1960 N-[4-(ß-6-Methoxy-1,3-benzoxazin-2,4-dion-3-yl-äthyl)-benzolsulfonyl]-N'-(4-methylcyclohexyl)-harnstoff vom Schmp. 205° (aus Methanol-DMF)The N- [4- (ß-1,2,3-benzotriazin-4-on-3-yl-ethyl) -benzenesulfonyl] -N '- (4-methylcyclohexyl) urea is obtained in an analogous manner of m.p. 212-214 ° (from ethanol) N- [4- (β-1,2,3-benzotriazin-4-on-3-yl-ethyl) -benzenesulfonyl] -N'-butylurea from mp. 211-213 ° (from ethanol) Example 5 N- [4- (β-1,3-Benzoxazin-2,4-dion-3-yl-ethyl) -benzenesulfonyl] -N '- (4-methylcyclohexyl) -urea 7.5g 4- (ß-1,3-Bensoxazin-2,} + - dion-3-yl-ethyl) -bonFolnalSonamid (melting point 266-267 °) are boiled for 3 hours with 6g of ground potash in 250ml of acetone. Afterward 3.2 g of trans-4-methylcyclohexyl isocyanate are added and more is boiled with stirring 8 hours. After cooling, it is filtered off with suction, the precipitate is poured into water and acidified at. The deposited product is recrystallized from methanol-DMF. The received N- [4- (β-1,3-Benzoxazin-2,4-dion-3-yl-ethyl) -benzenesulfonyl] -N '- (4-methylcyclohexyl) -urea melts at 220-221 ° (cyclohexyl) urea melts at 220-221 in an analogous manner or according to Example 1, N- [4- (β-1,3-benzoxazin-2,4-dion-3-yl-ethyl) -benzenesulfonyl] -N'-cyclohexylurea is obtained of melting point 227-228 ° (from methanol-DMF) In an analogous manner, 4- (β-6-methyl-1,3-benzoxazin-2,4-dion-3-yl-ethyl) -benzenesulfonamide is obtained of melting point 242.2430 the N- [4- (β-6-methyl-1,3-benzoxazin-2,4-dion-3-yl-ethyl) -benzenesulfonyl-N'-cyclohexylurea of melting point 218.2200 (from methanol-DMF) N- [4- (ß-6-methyl-1,3-benzoxazin-2,4-dion-3-yl-ethyl) -benzenesulfonyl] -N '- (4- methylcyclohexyl) urea of melting point 222-223 ° (from methanol-DMF) N- [4- (β-6-methyl-1,3-benzoxazin-2,4-dion-3-yl-ethyl) -benzenesulfonyl] -N'- butyl urea from melting point 200-201 ° (from methanol-DMF) from the 4- (ß-6-chloro-1, 3.benzoxazin-2, 4.dione.3.yl.ethyl) -benzenesulphonamide of melting point 259.2610 denotes N- [4- (β-6-chloro-1,3-benzoxazin-2,4-dion-3-yl ethyl) benzenesulfonyl] -N'-cyclohexyl urea of melting point 221-223 ° (from methanol-DMF) N- [4- (β-6-chloro-1,3-benzoxazin-2,4-dion-3-yl-ethyl) -benzenesulfonyl] -N'- (4-methyl-cyclohexyl) urea of melting point 235-237 ° (from methanol) from 4- (β-6-methoxy-1,3-benzoxazin-2,4-dion-3-yl-ethyl) -benzenesulfonamide of m.p. 245-2470 denotes the N- [4- (β-6-methoxy-1,3-benzoxazin-2,4-dion-3-yl-ethyl) -benzenesulfonyl] -N '-cyclohexylurea of m.p. 194.1960 N- [4- (β-6-methoxy-1,3-benzoxazin-2,4-dion-3-yl-ethyl) -benzenesulfonyl] -N' - (4-methylcyclohexyl )-urea with a melting point of 205 ° (from methanol-DMF)
Claims (4)
Priority Applications (21)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19712103118 DE2103118A1 (en) | 1971-01-23 | 1971-01-23 | 4 (2-heterocyclylethyl) - benzenesulphonylureas - with hypoglycaemic activity |
| ES398959A ES398959A1 (en) | 1971-01-23 | 1972-01-18 | Benzene sulphonyl ureas and process for their manufacture |
| NL7200696A NL7200696A (en) | 1971-01-23 | 1972-01-18 | |
| CH1339775A CH580085A5 (en) | 1971-01-23 | 1972-01-19 | |
| CH1339675A CH580601A5 (en) | 1971-01-23 | 1972-01-19 | |
| CH1339975A CH580602A5 (en) | 1971-01-23 | 1972-01-19 | |
| CH1339875A CH588472A5 (en) | 1971-01-23 | 1972-01-19 | |
| CH727176A CH584694A5 (en) | 1971-01-23 | 1972-01-19 | |
| CH79072A CH580084A5 (en) | 1971-01-23 | 1972-01-19 | |
| CH727076A CH580086A5 (en) | 1971-01-23 | 1972-01-19 | |
| CH1339575A CH580600A5 (en) | 1971-01-23 | 1972-01-19 | |
| CA132,892A CA989835A (en) | 1971-01-23 | 1972-01-21 | Benzene sulfonyl ureas and process for their manufacture |
| AT50172A AT323752B (en) | 1971-01-23 | 1972-01-21 | PROCESS FOR THE PRODUCTION OF NEW BENZENE SULFONYL UREAS AND THEIR SALTS |
| AU38159/72A AU3815972A (en) | 1971-01-23 | 1972-01-21 | Benzene sulfonyl ureas |
| ZA720427A ZA72427B (en) | 1971-01-23 | 1972-01-21 | Benzene sulfonyl ureas and process for their manufacture |
| BE778421A BE778421A (en) | 1971-01-23 | 1972-01-24 | BENZENE-SULFONYL-UREES AND MEDICINAL PRODUCTS CONTAINING THESE SUBSTANCES |
| GB323872A GB1379973A (en) | 1971-01-23 | 1972-01-24 | Benzene sulphonyl ureas and process for their manufacture |
| FR7202187A FR2122612B1 (en) | 1971-01-23 | 1972-01-24 | |
| US05/489,103 US3962244A (en) | 1971-01-23 | 1974-07-17 | Benzene sulfonyl ureas |
| AT804674A ATA804674A (en) | 1971-01-23 | 1974-10-07 | PROCESS FOR THE PREPARATION OF NEW ACYLAMINOATHYL BENZOLSULFONYL URITES AND THEIR SALTS |
| AT804574A AT335463B (en) | 1971-01-23 | 1974-10-07 | PROCESS FOR THE PRODUCTION OF NEW BENZENE SULFONYL UREAS AND THEIR SALTS |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19712103118 DE2103118A1 (en) | 1971-01-23 | 1971-01-23 | 4 (2-heterocyclylethyl) - benzenesulphonylureas - with hypoglycaemic activity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2103118A1 true DE2103118A1 (en) | 1972-08-24 |
Family
ID=5796696
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19712103118 Pending DE2103118A1 (en) | 1971-01-23 | 1971-01-23 | 4 (2-heterocyclylethyl) - benzenesulphonylureas - with hypoglycaemic activity |
Country Status (2)
| Country | Link |
|---|---|
| DE (1) | DE2103118A1 (en) |
| ZA (1) | ZA72427B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4379785A (en) | 1979-12-19 | 1983-04-12 | Hoechst Aktiengesellschaft | Heterocyclic substituted sulfonyl ureas, and their use |
-
1971
- 1971-01-23 DE DE19712103118 patent/DE2103118A1/en active Pending
-
1972
- 1972-01-21 ZA ZA720427A patent/ZA72427B/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4379785A (en) | 1979-12-19 | 1983-04-12 | Hoechst Aktiengesellschaft | Heterocyclic substituted sulfonyl ureas, and their use |
| EP0031058B1 (en) * | 1979-12-19 | 1984-04-04 | Hoechst Aktiengesellschaft | Sulfonyl ureas, processes for their preparation and pharmaceutical compositions containing these compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA72427B (en) | 1973-03-28 |
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