NO145786B - WINCH. - Google Patents
WINCH. Download PDFInfo
- Publication number
- NO145786B NO145786B NO771605A NO771605A NO145786B NO 145786 B NO145786 B NO 145786B NO 771605 A NO771605 A NO 771605A NO 771605 A NO771605 A NO 771605A NO 145786 B NO145786 B NO 145786B
- Authority
- NO
- Norway
- Prior art keywords
- benzenesulfonyl
- alkylene
- compounds
- formula
- hydrazines
- Prior art date
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- 238000000034 method Methods 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 17
- 239000008280 blood Substances 0.000 claims description 13
- 210000004369 blood Anatomy 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 239000012948 isocyanate Substances 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 150000001555 benzenes Chemical class 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 150000002513 isocyanates Chemical class 0.000 claims description 5
- 150000007513 acids Chemical class 0.000 claims description 4
- LSNDGFYQJRXEAR-UHFFFAOYSA-N benzenesulfonamidourea Chemical class NC(=O)NNS(=O)(=O)C1=CC=CC=C1 LSNDGFYQJRXEAR-UHFFFAOYSA-N 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- JOMVGRRCEIJQFK-UHFFFAOYSA-N benzenesulfonylcarbamothioic s-acid Chemical class OC(=S)NS(=O)(=O)C1=CC=CC=C1 JOMVGRRCEIJQFK-UHFFFAOYSA-N 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical group OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims description 2
- UJYAZVSPFMJCLW-UHFFFAOYSA-N n-(oxomethylidene)benzenesulfonamide Chemical class O=C=NS(=O)(=O)C1=CC=CC=C1 UJYAZVSPFMJCLW-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- SBMSLRMNBSMKQC-UHFFFAOYSA-N pyrrolidin-1-amine Chemical compound NN1CCCC1 SBMSLRMNBSMKQC-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000155 melt Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- -1 benzenesulfonyl semi-carbazides Chemical class 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 235000013877 carbamide Nutrition 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 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
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
- TYMBLCCPQXGEHE-UHFFFAOYSA-N (3-methylphenyl)sulfonylurea Chemical compound CC1=CC=CC(S(=O)(=O)NC(N)=O)=C1 TYMBLCCPQXGEHE-UHFFFAOYSA-N 0.000 description 1
- ASRMWYDEZPXXBA-UHFFFAOYSA-N (sulfonylamino)urea Chemical class NC(=O)NN=S(=O)=O ASRMWYDEZPXXBA-UHFFFAOYSA-N 0.000 description 1
- YCMLQMDWSXFTIF-UHFFFAOYSA-N 2-methylbenzenesulfonimidic acid Chemical compound CC1=CC=CC=C1S(N)(=O)=O YCMLQMDWSXFTIF-UHFFFAOYSA-N 0.000 description 1
- BEXJGSYJZVGRLZ-UHFFFAOYSA-N 2-pentylbenzenesulfonamide Chemical compound CCCCCC1=CC=CC=C1S(N)(=O)=O BEXJGSYJZVGRLZ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- NKPXUYQIGKOBBX-UHFFFAOYSA-N 4-(3-methylbutyl)benzenesulfonamide Chemical compound CC(C)CCC1=CC=C(S(N)(=O)=O)C=C1 NKPXUYQIGKOBBX-UHFFFAOYSA-N 0.000 description 1
- CVLHGLWXLDOELD-UHFFFAOYSA-N 4-(Propan-2-yl)benzenesulfonic acid Chemical compound CC(C)C1=CC=C(S(O)(=O)=O)C=C1 CVLHGLWXLDOELD-UHFFFAOYSA-N 0.000 description 1
- BRIXOPDYGQCZFO-UHFFFAOYSA-N 4-ethylphenylsulfonic acid Chemical compound CCC1=CC=C(S(O)(=O)=O)C=C1 BRIXOPDYGQCZFO-UHFFFAOYSA-N 0.000 description 1
- QGCVBPONRAFDHS-UHFFFAOYSA-N 4-hexylbenzenesulfonamide Chemical compound CCCCCCC1=CC=C(S(N)(=O)=O)C=C1 QGCVBPONRAFDHS-UHFFFAOYSA-N 0.000 description 1
- VLJQDHDVZJXNQL-UHFFFAOYSA-N 4-methyl-n-(oxomethylidene)benzenesulfonamide Chemical compound CC1=CC=C(S(=O)(=O)N=C=O)C=C1 VLJQDHDVZJXNQL-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
- ARAHQDBOLBKARK-UHFFFAOYSA-N C(C)C1=CC=C(C=C1)S(=O)(=O)N(C(=O)OCC)C Chemical compound C(C)C1=CC=C(C=C1)S(=O)(=O)N(C(=O)OCC)C ARAHQDBOLBKARK-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 244000265913 Crataegus laevigata Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- YBHQCJILTOVLHD-YVMONPNESA-N Mirin Chemical compound S1C(N)=NC(=O)\C1=C\C1=CC=C(O)C=C1 YBHQCJILTOVLHD-YVMONPNESA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 150000008331 benzenesulfonamides Chemical class 0.000 description 1
- GHDLZGOOOLEJKI-UHFFFAOYSA-N benzenesulfonylurea Chemical class NC(=O)NS(=O)(=O)C1=CC=CC=C1 GHDLZGOOOLEJKI-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229940112021 centrally acting muscle relaxants carbamic acid ester Drugs 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- UTLABMWLBRDNAM-UHFFFAOYSA-N ethyl n-[(4-methylphenyl)sulfonylmethyl]carbamate Chemical compound CCOC(=O)NCS(=O)(=O)C1=CC=C(C)C=C1 UTLABMWLBRDNAM-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- HTHDATSBFYFYTK-UHFFFAOYSA-N hydrazinyloxymethanethioic S-acid Chemical class N(N)OC(O)=S HTHDATSBFYFYTK-UHFFFAOYSA-N 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- SBFRBCWEYRIGAS-UHFFFAOYSA-N n-(4-methylphenyl)sulfonylcarbamoyl chloride Chemical compound CC1=CC=C(S(=O)(=O)NC(Cl)=O)C=C1 SBFRBCWEYRIGAS-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 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
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B66—HOISTING; LIFTING; HAULING
- B66D—CAPSTANS; WINCHES; TACKLES, e.g. PULLEY BLOCKS; HOISTS
- B66D1/00—Rope, cable, or chain winding mechanisms; Capstans
- B66D1/02—Driving gear
- B66D1/14—Power transmissions between power sources and drums or barrels
Landscapes
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Earth Drilling (AREA)
- Gear Transmission (AREA)
Description
Fremgangsmåte til fremstilling av nye benzolsulfonylsemi-karbazider med blodsukkersenkende egenskaper. Process for the production of new benzenesulfonyl semi-carbazides with blood sugar-lowering properties.
Det er kjent at visse benzolsulfonyl-urinstoffderivater har blodsukkersenkende egenskaper og er egnet som pr. os admi-nistrerbare antidiabetika (sammenlign f. eks. «Arzneimittelforschung», bind 8 (1958), side 444—454). It is known that certain benzenesulfonyl urea derivatives have blood sugar-lowering properties and are suitable as per us administrable antidiabetics (compare e.g. "Arzneimittelforschung", volume 8 (1958), pages 444-454).
Oppfinnelsens gjenstand er nu en fremgangsmåte til fremstilling av benzolsulfonyl-semikarbazider med blodsukkersenkende egenskaper og som har den generelle formel The object of the invention is now a process for the production of benzenesulfonyl semicarbazides with blood sugar-lowering properties and which have the general formula
hvori X betyr en 1 til 6 karbonatomholdig alkylrest og -Z-Z'- betyr en 3 til 4 karbonatomholdig alkylenkjede som eventuelt kan være substituert med ytterligere lavmolekylære alkylrester, samt fremstilling av deres salter idet fremgangsmåten er karakterisert ved at man a) Omsetter forbindelser med formel hvori X har den angitte betydning, med tilsvarende N,N-alkylenhydraziner, idet det i stedet for benzolsulfonylisocyanater også kan finne anvendelse slike forbindelser som under reaksjonsforløpet danner slike isocyanater eller reagerer som slike isocyanater eller b) Omsetter forbindelser med formel hvori X har den angitte betydning og Y betyr en lavmolekylær alkylrest eller en arylrest resp. tilsvarende benzolsulfonyl-tiokarbaminsyreestere med N,N-alkylen-hydraziner eller c) Omsetter forbindelser med formel in which X means a 1 to 6 carbon-containing alkyl residue and -Z-Z'- means a 3 to 4 carbon-containing alkylene chain which may optionally be substituted with additional low molecular weight alkyl residues, as well as the production of their salts, as the method is characterized by a) reacting compounds with formula in which X has the given meaning, with corresponding N,N-alkylene hydrazines, since instead of benzenesulfonyl isocyanates such compounds can also be used which during the course of the reaction form such isocyanates or react as such isocyanates or b) Converts compounds of formula in which X has the stated meaning and Y means a low molecular weight alkyl residue or an aryl residue resp. corresponding benzenesulfonyl-thiocarbamic acid esters with N,N-alkylene hydrazines or c) Converts compounds of formula
med N,N-alkylen-hydrazino-N'-kullsyre-estere resp. med tilsvarende hydrazino-monotiokullsyreestere, som i esterkompo-nenten har en lavmolekylær alkylrest eller en arylrest eller with N,N-alkylene-hydrazino-N'-carbonic acid esters resp. with corresponding hydrazino-monothiocarbonic acid esters, which in the ester component have a low molecular weight alkyl residue or an aryl residue or
d) Omsetter forbindelser mel formel d) Converts compounds to formula
hvori X har den angitte formel med N,N-alkylen-hydraziner eller e) omsetter i benzolkjernen tilsvarende substituerte benzolsulfonylurinstoffer, som ved den side av urinstoffmolekylet som vender bort fra sulfonylgruppen er usub-stituert eller mono- eller disubstituert med lavmolekylære alkylrester eller arylrester med N,N-alkylenhydraziner eller f) omsetter i benzolkjernen tilsvarende substituerte N-benzolsulfonyl-N'-acylurin-stoffer resp. også bis-(benzolsulfonyl)-urinstoffer med tilsvarende N,N-alkylenhydra-ziner eller g) omsetter Ni,Ni-alkylensemikarbazider, som eventuelt ved nitrogenatom N4 kan være substituert. med en fortrinnsvis lavmolekylær alifatisk eller en aromatisk syre-rest eller med nitrogruppen med forbindelser med formel in which X has the indicated formula with N,N-alkylene hydrazines or e) reacts in the benzene nucleus with correspondingly substituted benzenesulfonylureas, which on the side of the urea molecule facing away from the sulfonyl group is unsubstituted or mono- or disubstituted with low molecular weight alkyl residues or aryl residues with N,N-alkylene hydrazines or f) reacts in the benzene nucleus correspondingly substituted N-benzenesulfonyl-N'-acylurines resp. also bis-(benzenesulfonyl)-ureas with corresponding N,N-alkylene hydrazines or g) reacts Ni,Ni-alkylene semicarbazides, which can optionally be substituted at nitrogen atom N4. with a preferably low molecular weight aliphatic or an aromatic acid residue or with the nitro group of compounds of formula
hvori X har den angitte betydning og eventuelt behandler de dannede fremgangsmå-téprodukter for fremstilling av ikke-toksiske salter med fysiologisk tfilbare baser eller syrer. in which X has the indicated meaning and optionally treats the formed process products for the production of non-toxic salts with physiologically compatible bases or acids.
Som utgangsstoffer kan det for fremgangsmåten ifølge oppfinnelsen anvendes o-, m- og p-alkylbenzolsulfonsyrederivater som tilsvarende amider, karbaminsyreeste-re, urinstoffer, tiourinstoffer og isocyanater. Eksempelvis kan det nevnes: o,m,p-metyl-benzolsulfonsyreamid, o,m,p-etylbenzolsulfonsyreamid, o,m,p- (n)-propyl-benzolsulfonsyreamid, o,m,p-isopropyl-benzolsulfonsyreamid, o,m,p-n-butyl-, o,m,p-isobutyl-, o,m,p-tert.butyl-benzolsulfonamid, p-pentyl-(3)-benzolsulfonamid, p-isoamyl-benzolsulfonamid, p-tert.amyl-benzolsulfonamid, p-n-hexyl-benzolsulfonamid, o,m,p-alkylbenzolsulfonyl-karbamin-syreester, o,m,p-alkyl-benzolsulfonylurin-stoff, o.m.p-alkyl-benzolsulfonyl-isocyanater. As starting materials for the method according to the invention, o-, m- and p-alkylbenzenesulfonic acid derivatives can be used as corresponding amides, carbamic acid esters, ureas, thioureas and isocyanates. Examples include: o,m,p-methyl-benzenesulfonic acid amide, o,m,p-ethylbenzenesulfonic acid amide, o,m,p-(n)-propyl-benzenesulfonic acid amide, o,m,p-isopropyl-benzenesulfonic acid amide, o,m ,p-n-butyl-, o,m,p-isobutyl-, o,m,p-tert.butyl-benzenesulfonamide, p-pentyl-(3)-benzenesulfonamide, p-isoamyl-benzenesulfonamide, p-tert.amyl-benzenesulfonamide , p-n-hexyl-benzenesulfonamide, o,m,p-alkylbenzenesulfonyl-carbamic acid ester, o,m,p-alkyl-benzenesulfonylurea, o.m.p-alkyl-benzenesulfonyl isocyanates.
For fremstilling av disse utgangsstoffer kan det anvendes forskjellige fra litte-raturen kjente metoder. Different methods known from the literature can be used for the production of these starting materials.
Til omsetning med de forannevnte utgangsstoffer kan det ved fremgangsmåten ifølge oppfinnelsen anvendes hydraziner med den generelle formel: For reaction with the aforementioned starting materials, hydrazines with the general formula can be used in the method according to the invention:
idet -Z—Z'- betyr en 3 til 4 karbonatomholdig alkylenkjede, som eventuelt kan ha ytterligere lavmolekylære alkylrester. Fortrinnsvis anvendes: N-amino-a,a-dimetyl-acetidin, N-amino-pyrrolidin, N-amino-a,a'-dimetyl-pyrrolidin. where -Z—Z'- means a 3 to 4 carbon-containing alkylene chain, which may optionally have further low molecular weight alkyl residues. Preferably used: N-amino-a,a-dimethyl-acetidine, N-amino-pyrrolidine, N-amino-a,a'-dimethyl-pyrrolidine.
Fremgangsmåten ifølge oppfinnelsen kan med hensyn til reaksjonsbetingelsene varieres innen vide grenser. Omsetningene kan eksempelvis gjennomføres under anvendelse av oppløsningsmidler ved værelse-temperatur eller ved forhøyet temperatur. The method according to the invention can be varied within wide limits with respect to the reaction conditions. The reactions can, for example, be carried out using solvents at room temperature or at an elevated temperature.
For å få fremgangsmåteproduktene renest mulig er det nødvendig med en best mulig adskillelse av de som utgangsstoffer anvendte eller under reaksjonen dannede benzolsulfonamider hvilket fortrinnsvis kan oppnås ved at man opptar fremgangsmåteproduktene i sterkt fortynnet ammoniakk, frafiltrerer uoppløste bestanddeler og gjenvinner de ønskede fremgangsmåte-produkter ved sur gjøring, fortrinnsvis ved hjelp av organiske syrer som fortynnet eddiksyre. In order to get the process products as pure as possible, it is necessary to have the best possible separation of the benzenesulfonamides used as starting materials or formed during the reaction, which can preferably be achieved by absorbing the process products in highly diluted ammonia, filtering out undissolved components and recovering the desired process products by acid making, preferably by means of organic acids such as dilute acetic acid.
De ved fremgangsmåten ifølge oppfinnelsen dannede benzolsulfonyl-semikarbazider er verdifulle legemidler, som spesielt utmerker seg ved god blodsukkersenkende virkning og med liten toksisitet. The benzenesulfonyl semicarbazides formed by the method according to the invention are valuable pharmaceuticals, which are particularly distinguished by their good blood sugar-lowering effect and low toxicity.
Således kunne det med 4-(4-metylben-zolsulf onyl) -1,1 - tetrametylen-semikarbazid fremstillet ifølge oppfinnelsen på kaniner ved en applikasjon på 100 ml/kg etter 6 timer iakttas en 30 pst.-ig blodsukkersenkning. Blodsukkerverdiene ble bestemt på vanlig måte etter Hagedorn/ Jensen. Den gode virkning av forbindel-sene fremstillet ifølge oppfinnelsen frem-trer spesielt tydelig ved en prøve i «Terskel-verdiområdet». Med «terskelverdi» forstår man da den virksomme stoffmengde i mg/ kg legemsvekt av forsøksdyrene som må tilføres intravenøst eller pr. os for å frembringe en markant blodsukkersenkning i sammenligning med kontrolldyr som er holdt samme måten. Det har nu vist seg at terskelverdien ligger meget lavt for benzolsulfonyl-semikarbazidene fremstilt iføl-ge oppfinnelsen. Således er det med 4- (4-metyl-benzolsulfonyl)-l,l-tetrametylen-semikarbazid ved intravenøs administrasjon på kaniner tilstrekkelig med 1,25 til 2,5 mg/kg ved peroral applikasjon og en dosering på 5 mg/kg, til å frembringe en blodsukkersenkning. Den under samme be-tingelser funne sammenlignings-terskelverdi for det kjente N-(4-metyl-benzolsulfonyl)-N'-n-butylurinstoff utgjør ved peroral administrasjon 35 mg/kg og ved intra-venøs applikasjon 20 mg/kg. Følgelig er Thus, with 4-(4-methylbenzenesulfonyl)-1,1-tetramethylene-semicarbazide produced according to the invention, a 30 percent drop in blood sugar could be observed on rabbits after 6 hours with an application of 100 ml/kg. The blood sugar values were determined in the usual way according to Hagedorn/Jensen. The good effect of the compounds produced according to the invention is particularly clear in a sample in the "Threshold value range". By "threshold value" is then understood the effective amount of substance in mg/kg body weight of the experimental animals that must be administered intravenously or per os to produce a marked lowering of blood sugar in comparison with control animals kept in the same way. It has now been shown that the threshold value is very low for the benzenesulfonyl semicarbazides produced according to the invention. Thus, with 4-(4-methyl-benzenesulfonyl)-1,1-tetramethylene-semicarbazide for intravenous administration to rabbits, 1.25 to 2.5 mg/kg is sufficient for oral application and a dosage of 5 mg/kg, to produce a lowering of blood sugar. The comparative threshold value found under the same conditions for the known N-(4-methyl-benzenesulfonyl)-N'-n-butylurea amounts to 35 mg/kg for oral administration and 20 mg/kg for intravenous application. Consequently is
4-(4-metylbenzolsulfonyl)-l-l-tetrametylen-semikarbazid ved pr. os administrering 4-(4-methylbenzenesulfonyl)-1-1-tetramethylene-semicarbazide at pr. us administration
syv ganger og ved intravenøs administrasjon åtte til seks ganger så virksomme som den kjente sammenligningsforbindelse. seven times and by intravenous administration eight to six times as effective as the known comparison compound.
Fremgangsmåteproduktene er i sin blodsukkersenkende virkning tydelig over-legne overfor de fra Arzneimittelforschung, bind 8 (1958), side 447 kjente 4-(4-metyl-benzol-sulfonyl)-l,l-pentametylen-semikarbazid (I). The process products are clearly superior in their blood sugar-lowering effect to those known from Arzneimittelforschung, volume 8 (1958), page 447 4-(4-methyl-benzol-sulfonyl)-1,1-pentamethylene-semicarbazide (I).
Ved en dosering på 400 mg/kg pr. os på kaniner ble det for det ved fremgangsmåten ifølge oppfinnelsen fremstilte 4-(3-metyl-benzolsulfonyl)-l,l-tetrametylen-semikarbazid (II) sammenlignet med den kjente forbindelse I funnet de i følgende tabell oppførte verdier for den prosentuale blodsukkersenkning: At a dosage of 400 mg/kg per os on rabbits, for the 4-(3-methyl-benzenesulfonyl)-1,1-tetramethylene-semicarbazide (II) produced by the method according to the invention, compared to the known compound I, the values listed in the following table for the percentage lowering of blood sugar were found:
Også 4- (4-isopropylbenzolsulfonyl) - Also 4-(4-isopropylbenzenesulfonyl)-
1,1-tetrametylen-semikarbazid har en sterk overlegen virkning overfor den kjenté forbindelse I. Mens den kjente forbindelse I ved en dosering på 400 mg/kg pr. os på kaniner bare oppnår en maksimalverdi på 15 pst. blodsukkersenkning oppnås det med en dosering på bare 100 mg/kg av 4-(4-isopropyl-benzolsulf onyl) -1,1 - tetrametylen-semicarbazid en maksimalverdi på 40 pst. blodsukkersenkning. 1,1-tetramethylene-semicarbazide has a strong superior effect to the known compound I. While the known compound I at a dosage of 400 mg/kg per os on rabbits only achieves a maximum value of 15 per cent blood sugar reduction, a maximum value of 40 per cent blood sugar reduction is achieved with a dosage of only 100 mg/kg of 4-(4-isopropyl-benzenesulfonyl)-1,1 - tetramethylene-semicarbazide.
Fremgangsmåteproduktene har fordi de ikke har noen p-plasert aminogruppe i benzolkjernen, ingen effekt som er sam-menlignbar med sulfonamidene (som anvendes terapeutisk ved infeksjonssykdom-mer) således at man selv etter årelang administrasjon ikke behøver å f ryte noen resistent. Av samme grunn opptrer det heller ikke bireaksjoner som er å tilbake-føre på tarmfloraforstyrrelser. The process products, because they have no p-placed amino group in the benzene nucleus, have no effect comparable to the sulfonamides (which are used therapeutically in infectious diseases), so that even after years of administration there is no need to find any resistant ones. For the same reason, there are also no side effects that can be attributed to intestinal flora disturbances.
Fremgangsmåteproduktene skal fortrinnsvis tjene til fremstilling av oralt ad-ministrerbare preparater med hypogly-kemisk virkning til behandling av diabe-tes mellitus, idet sulfonyl-semikarbazidene kan anvendes som sådanne eller i form av deres salter med baser eller syrer eller i nærvær av stoffer som fører til en saltdannelse. For saltdannelse kan det eksempelvis anvendes: alkaliske midler som alkali- eller jordalkalihydroksyder, -kar-bonater-, bikarbonater, så vel som fysiologisk tålbare organiske baser, videre syrer som klorhydrogensyre, bromhydrogensyre, svovelsyre og amidosulfonsyre. The process products should preferably serve for the production of orally administrable preparations with hypoglycaemic action for the treatment of diabetes mellitus, as the sulfonyl semicarbazides can be used as such or in the form of their salts with bases or acids or in the presence of substances that lead to a salt formation. For salt formation, for example, alkaline agents such as alkali or alkaline earth hydroxides, carbonates, bicarbonates, as well as physiologically tolerable organic bases, further acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and amidosulfonic acid can be used.
Som medisinske preparater kan det fortrinnsvis anvendes tabletter som ved siden av de i mengder fra ca. 0,05 til 0,5 g pr. administreringsenhet inneholdte frem-gangsmåteprodukter inneholder vanlige hjelpe- og bærestoffer som talkum, stivelse, melkesukker, tragant, magnesiumstearat. As medicinal preparations, tablets can preferably be used which, in addition to those in amounts from approx. 0.05 to 0.5 g per method products contained in the administration unit contain common excipients and carriers such as talc, starch, milk sugar, tragacanth, magnesium stearate.
Eksempel 1. Example 1.
4-( 3- metyl- benzolsulfonyl)- 1, 1- tetrametylensemikarbazid. 4-(3-methyl-benzenesulfonyl)-1,1-tetramethylenesemicarbazide.
19,3 g 3-metylbenzolsulfonamid-natri-um og 13 g 1,1-tetrametylensemikarbazid blandes godt med hverandre og oppvarmes i to timer ved 120 til 130°C idet ammoniakk unnviker. Reaksjonsproduktet opp-løses i vann og filtreres over kull. Ved filt-ratets surgj øring med iseddik fås krystal-ler som renses ved gjenutfelling med 1 pst.-ig ammoniakk/eddiksyre. Etter omkrystallisering fra metanol får man 4-(3-metyl-benzolsulfonyl)-1,1-tetrametylensemikarbazid med smeltepunkt 161—163°C. 19.3 g of 3-methylbenzenesulfonamide sodium and 13 g of 1,1-tetramethylenesemicarbazide are mixed well with each other and heated for two hours at 120 to 130°C while ammonia escapes. The reaction product is dissolved in water and filtered over charcoal. When the filtrate is acidified with glacial acetic acid, crystals are obtained which are purified by reprecipitation with 1% ammonia/acetic acid. After recrystallization from methanol, 4-(3-methyl-benzenesulfonyl)-1,1-tetramethylenesemicarbazide is obtained with a melting point of 161-163°C.
Eksempel 2. Example 2.
4- ( 2- metyl- benzolsulfonyl) - 1, 1- tetrametylensemikarbazid. 4-(2-methyl-benzenesulfonyl)-1,1-tetramethylenesemicarbazide.
9 g N,N-tetrametylenhydrazin-N'-kull-syremetylester blandes med 15,5 g 2-metyl-benzolsulfonamid og 9,5 g kaliumkarbonat og oppvarmes etter tilsetning av 30 ml tri-glykol under omrøring i 1 time ved 90°C 9 g of N,N-tetramethylenehydrazine-N'-carbonic acid methyl ester are mixed with 15.5 g of 2-methyl-benzenesulfonamide and 9.5 g of potassium carbonate and heated after the addition of 30 ml of tri-glycol while stirring for 1 hour at 90°C
og 8 timer ved 110°C. Etter tilsetning av and 8 hours at 110°C. After the addition of
100 ml vann surgj øres med saltsyre utfel-lingen suges fra og innføres i 150 ml 10 pst.-ig natriumbikarbonatoppløsning under omrøring. Man suger fra uoppløst residuum og utfeller med syre. Etter rensning over ammoniumsaltet og omkrystallisering fra dimetylformamid smelter 4-(2-metylben-zolsulfonyl)-1,1-tetrametylensemikarbazid ved 190°C. 100 ml of water is acidified with hydrochloric acid, the precipitate is sucked off and introduced into 150 ml of 10% sodium bicarbonate solution while stirring. One sucks from undissolved residue and precipitates with acid. After purification over the ammonium salt and recrystallization from dimethylformamide, 4-(2-methylbenzenesulfonyl)-1,1-tetramethylenesemicarbazide melts at 190°C.
Eksempel 3. Example 3.
4- ( 4- metyl- benzolsulfonyl) - 1, 1-( a, a- dimetyl- trimetylen)- semikarbazid. 4-(4-methyl-benzenesulfonyl)-1,1-(a,a-dimethyl-trimethylene)-semicarbazide.
10 g N-aminortt,a-dimetyl-azetidin 10 g of N-amino acid, α-dimethyl-azetidine
oppløses i ca. 50 ml absolutt eter og blan- dissolves in approx. 50 ml of absolute ether and mix
des under avkjøling og omrystning por- during cooling and shaking por-
sjonsvis med oppløsningen av 20 g p-tolu-olsulfonylisocyanat i omtrent absolutt eter. tionwise with the solution of 20 g of p-toluenesulfonyl isocyanate in approximately absolute ether.
Man hensetter i kort tid ved værelsetem- It is provided for a short time at room temp-
peratur, suger fra reaksjonsproduktet og omkrystalliserer det fra etanol, 4-(4-me-tylbenzolsulfonyl)-l,l-(a,a-dimetyltrime-tylen)-semikarbazider smelter ved 175— perature, suction from the reaction product and recrystallizing it from ethanol, 4-(4-methylbenzenesulfonyl)-1,1-(a,a-dimethyltrimethylene)-semicarbazides melt at 175—
177°C. 177°C.
Eksempel 4. 4- ( 4- isopropyl- benzolsulfonyl)- 1, 1-tetrametylen- semikarbazid. Example 4. 4-(4-isopropyl-benzenesulfonyl)-1,1-tetramethylene-semicarbazide.
26 g 4-isopropyl-benzolsulfonyl-metyl- 26 g 4-isopropyl-benzenesulfonyl-methyl-
uretan oppvarmes med 8,6 g N-amino-pyrroliden i oljebad ved 115°C. Fra den godt gjennomblandede smelte unnviker metanol. Deretter stivner reaksjonsproduk- urethane is heated with 8.6 g of N-amino-pyrrolidene in an oil bath at 115°C. Methanol escapes from the well-mixed melt. The reaction product then solidifies
tet. Man omkrystalliserer etter avkjøling fra etanol-vann og får 4-(4-isopropyl-benzolsulfonyl ) -1,1 - tetrametylen-semikarb- tight. It is recrystallized after cooling from ethanol-water and 4-(4-isopropyl-benzenesulfonyl)-1,1-tetramethylene-semicarb-
azid med smeltepunkt 174—175°C. azide with melting point 174-175°C.
På analog måte får man fra 4-metyl-benzolsulfonylmetyluretan og N-amino- In an analogous way, one obtains from 4-methyl-benzenesulfonylmethylurethane and N-amino-
pyrrolidin 4- (4-metyl-benzol-sulfbnyl) - 1,1-tetrametylen-semikarbazidet med smel- pyrrolidine 4-(4-methyl-benzenesulfnyl)-1,1-tetramethylene-semicarbazide with melting
tepunkt 180 til 182°C (fra metanol/dimetylformamid) og fra 4-etylbenzolsulfonyl-metyluretan og N-amino-pyrrolidin får man 4-(4-etyl-benzolsulfonyl)-l,l-tetrametylen-semikarbazid med smeltepunkt 165—166,5°C (fra metanol). tea point 180 to 182°C (from methanol/dimethylformamide) and from 4-ethylbenzenesulfonyl-methylurethane and N-amino-pyrrolidine one obtains 4-(4-ethyl-benzenesulfonyl)-1,1-tetramethylene-semicarbazide with melting point 165-166, 5°C (from methanol).
Eksempel 5. Example 5.
4- ( 4- tert.- butyl- benzolsulfonyl) - 1, 1- tetrametylen- semikarbazid. 4- ( 4- tert.- butyl- benzenesulfonyl)- 1, 1- tetramethylene- semicarbazide.
35 g 4-tert.-butyl-benzolsulfonyl-me- 35 g of 4-tert.-butyl-benzenesulfonyl-me-
tyluretan blandes godt med 10,3 g N-amino-pyrrolidin og oppvarmes i oljebad i 20. mi- tylurethane is mixed well with 10.3 g of N-amino-pyrrolidine and heated in an oil bath for 20 mi-
nutter ved 130°C. Etter ca. 5 minutter star- nuts at 130°C. After approx. 5 minutes star-
ter metanolutviklingen som er avsluttet etter ytterligere 5 minutter, deretter blir produktet fast. Man behandler etter av- ter the methanol evolution which is finished after a further 5 minutes, after which the product becomes solid. It is treated according to
kjøling med 1 pst.-ig ammoniakk, filtrerer og surgj ør med eddiksyre. Det således dan- cooling with 1 per cent ammonia, filter and acidify with acetic acid. It thus
nede 4- (4-tert.-butyl-benzolsulfonyl) -1,1-tetrametylen-semikarbazid smelter etter omkrystallisering fra isopropanol ved 186— down 4-(4-tert-butyl-benzenesulfonyl)-1,1-tetramethylene-semicarbazide melts after recrystallization from isopropanol at 186—
187°C. 187°C.
Eksempel 6. Example 6.
4- ( 3- metyl- benzolsulfonyl) - 1, 1-tetrametylen- semikarbazid. ' 5 g 3-metyl-benzolsulfonyl-urinstoff oppvarmes med 4,3 g N-amino-pyrrolidin i 4-(3-methyl-benzenesulfonyl)-1,1-tetramethylene-semicarbazide. ' 5 g of 3-methyl-benzenesulfonyl urea is heated with 4.3 g of N-amino-pyrrolidine in
50 ml dioksan under tilbakeløp til koking. 50 ml of dioxane under reflux to boiling.
Etter ca. 15 minutter er det dannet en klar oppløsning. Man avdemper oppløsnings- After approx. After 15 minutes, a clear solution has formed. One dampens the resolution
middel under nedsatt trykk, behandler re- agent under reduced pressure, treats re-
siduet med 1 pst.-ig ammoniakk, filtrerer og surgj ør filtratet med fortynnet eddik- sided with 1 per cent ammonia, filter and acidify the filtrate with dilute vinegar
syre. 4- (3-metyl-benzolsulfonyl)-1,1-tetrametylen-semikarbazidet omkrystalliseres fra metanol og smelter ved 161—163°C. acid. The 4-(3-methyl-benzenesulfonyl)-1,1-tetramethylene-semicarbazide is recrystallized from methanol and melts at 161-163°C.
Eksempel 7. Example 7.
4- ( 4- metyl- benzolsulfonyl)- 1, 1- tetrametylen- semikarbazid. 4-( 4- methyl- benzenesulfonyl)- 1, 1- tetramethylene- semicarbazide.
11.7 g 4-metyl-benzolsulfonyl-karb-aminsyreklorid oppløses i ca. 50 ml dioksan. 11.7 g of 4-methyl-benzenesulfonyl-carbamic acid chloride is dissolved in approx. 50 ml dioxane.
Hertil setter man under avkjøling og ryst- To this end, under cooling and shaking,
ing 9 g N-amino-pyrrolidin, hensetter reaksjonsblandingen i to timer ved værelse-' temperatur, oppvarmer kort på dampbad og avdestillerer dioksanet deretter under nedsatt trykk. Residuet behandles med vann og noe saltsyre, det uoppløste pro- ing 9 g of N-amino-pyrrolidine, leave the reaction mixture for two hours at room temperature, heat briefly on a steam bath and then distill off the dioxane under reduced pressure. The residue is treated with water and some hydrochloric acid, the undissolved pro-
dukt suges fra og omkrystalliseres fra eta- duct is sucked off and recrystallized from eta-
nol/vann, Det dannede 4-(4-metyl-benzol- nol/water, The formed 4-(4-methyl-benzene-
sulf onyl ) -1,1 -tetrametylen-semikarbazid smelter ved 180—182°C. sulfonyl)-1,1-tetramethylene-semicarbazide melts at 180-182°C.
Eksempel 8. Example 8.
4- ( 4- metyl- benzolsulfonyl)- 1, 1-tetrametylen- semikarbazid. 4-(4-methyl-benzenesulfonyl)-1,1-tetramethylene-semicarbazide.
36.8 g bis-(p-toluolsulfonyl)Mirinstoff blandes godt med 8,6 g N-amino-pyrrolidin, oppvarmes i oljebad i 1% time ved 120— 36.8 g of bis-(p-toluenesulfonyl)mirin substance are mixed well with 8.6 g of N-amino-pyrrolidine, heated in an oil bath for 1% hour at 120—
130°. Man behandler reaksjonsblandingen etter avkjøling med 1 pst.-ig ammoniakk, frafiltrerer det dannede p-toluolsulfon- 130°. After cooling, the reaction mixture is treated with 1% ammonia, the p-toluenesulfone formed is filtered off
amid og surgj ør filtratet. Det i et utbytte på 22,4 g dannede 4-(4-metyl-benzolsulfonyl ) -1,1 -tetrametylen-semikarbazid smelter etter omkrystallisering fra etanol/ amide and acidify the filtrate. The 4-(4-methyl-benzenesulfonyl)-1,1-tetramethylene-semicarbazide formed in a yield of 22.4 g melts after recrystallization from ethanol/
vann ved 180—182°C. water at 180-182°C.
Claims (1)
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CA275,451A CA1056806A (en) | 1977-04-04 | 1977-04-04 | Winch |
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NO771605L NO771605L (en) | 1978-10-05 |
NO145786B true NO145786B (en) | 1982-02-22 |
NO145786C NO145786C (en) | 1982-06-02 |
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NO771605A NO145786C (en) | 1977-04-04 | 1977-05-06 | WINCH |
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AT (1) | AT352341B (en) |
CA (1) | CA1056806A (en) |
NO (1) | NO145786C (en) |
-
1977
- 1977-04-04 CA CA275,451A patent/CA1056806A/en not_active Expired
- 1977-05-06 NO NO771605A patent/NO145786C/en unknown
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AT352341B (en) | 1979-09-10 |
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NO145786C (en) | 1982-06-02 |
NO771605L (en) | 1978-10-05 |
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