NO162926B - APPLIANCES FOR SELF-RIGHT OR DIRECTIVE DRILLING IN UNDERGRADUAL FORMS. - Google Patents
APPLIANCES FOR SELF-RIGHT OR DIRECTIVE DRILLING IN UNDERGRADUAL FORMS. Download PDFInfo
- Publication number
- NO162926B NO162926B NO851885A NO851885A NO162926B NO 162926 B NO162926 B NO 162926B NO 851885 A NO851885 A NO 851885A NO 851885 A NO851885 A NO 851885A NO 162926 B NO162926 B NO 162926B
- Authority
- NO
- Norway
- Prior art keywords
- ethyl
- formula
- carbon atoms
- benzamido
- methanol
- Prior art date
Links
- -1 phenylcyclopropyl Chemical group 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 235000013877 carbamide Nutrition 0.000 claims description 11
- 239000008280 blood Substances 0.000 claims description 10
- 210000004369 blood Anatomy 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000004434 sulfur atom Chemical group 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 8
- 229940112021 centrally acting muscle relaxants carbamic acid ester Drugs 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
- 125000004687 alkyl sulfinyl alkyl group Chemical group 0.000 claims description 4
- 150000001412 amines Chemical group 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 4
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000005358 mercaptoalkyl group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 230000002035 prolonged effect Effects 0.000 claims description 3
- 229940124530 sulfonamide Drugs 0.000 claims description 3
- 150000003456 sulfonamides Chemical class 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 239000005864 Sulphur Substances 0.000 claims description 2
- 230000010933 acylation Effects 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000006622 cycloheptylmethyl group Chemical group 0.000 claims description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 2
- 125000006623 cyclooctylmethyl group Chemical group 0.000 claims description 2
- 239000012948 isocyanate Substances 0.000 claims description 2
- 150000002513 isocyanates Chemical class 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 135
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 150000003672 ureas Chemical class 0.000 description 6
- WUESWDIHTKHGQA-UHFFFAOYSA-N cyclohexylurea Chemical compound NC(=O)NC1CCCCC1 WUESWDIHTKHGQA-UHFFFAOYSA-N 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000004202 carbamide Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000155 melt Substances 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-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
- 125000002252 acyl group Chemical group 0.000 description 2
- GHDLZGOOOLEJKI-UHFFFAOYSA-N benzenesulfonylurea Chemical class NC(=O)NS(=O)(=O)C1=CC=CC=C1 GHDLZGOOOLEJKI-UHFFFAOYSA-N 0.000 description 2
- 150000001714 carbamic acid halides Chemical class 0.000 description 2
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 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
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- UJYAZVSPFMJCLW-UHFFFAOYSA-N n-(oxomethylidene)benzenesulfonamide Chemical class O=C=NS(=O)(=O)C1=CC=CC=C1 UJYAZVSPFMJCLW-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 150000003585 thioureas Chemical class 0.000 description 2
- KUIYILOSSGJKHZ-UHFFFAOYSA-N 1,3-bis(benzenesulfonyl)urea Chemical compound C=1C=CC=CC=1S(=O)(=O)NC(=O)NS(=O)(=O)C1=CC=CC=C1 KUIYILOSSGJKHZ-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
- 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 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 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
- FUHMLQFYZRLAOA-UHFFFAOYSA-N COCOC(C=CC=C1)=C1C(NCC(C=C1)=CC=C1S(N)(=O)=O)=O Chemical compound COCOC(C=CC=C1)=C1C(NCC(C=C1)=CC=C1S(N)(=O)=O)=O FUHMLQFYZRLAOA-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 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
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001555 benzenes Chemical group 0.000 description 1
- 150000008331 benzenesulfonamides Chemical class 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
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical group OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000609 carbazolyl group Chemical class C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000008164 mustard oil Substances 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- ZFLIKDUSUDBGCD-UHFFFAOYSA-N parabanic acid Chemical group O=C1NC(=O)C(=O)N1 ZFLIKDUSUDBGCD-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- PFUVRDFDKPNGAV-UHFFFAOYSA-N sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 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
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 238000001308 synthesis method Methods 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
- 150000003560 thiocarbamic acids Chemical class 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- E—FIXED CONSTRUCTIONS
- E21—EARTH OR ROCK DRILLING; MINING
- E21B—EARTH OR ROCK DRILLING; OBTAINING OIL, GAS, WATER, SOLUBLE OR MELTABLE MATERIALS OR A SLURRY OF MINERALS FROM WELLS
- E21B17/00—Drilling rods or pipes; Flexible drill strings; Kellies; Drill collars; Sucker rods; Cables; Casings; Tubings
- E21B17/10—Wear protectors; Centralising devices, e.g. stabilisers
-
- E—FIXED CONSTRUCTIONS
- E21—EARTH OR ROCK DRILLING; MINING
- E21B—EARTH OR ROCK DRILLING; OBTAINING OIL, GAS, WATER, SOLUBLE OR MELTABLE MATERIALS OR A SLURRY OF MINERALS FROM WELLS
- E21B7/00—Special methods or apparatus for drilling
- E21B7/04—Directional drilling
- E21B7/06—Deflecting the direction of boreholes
- E21B7/068—Deflecting the direction of boreholes drilled by a down-hole drilling motor
-
- E—FIXED CONSTRUCTIONS
- E21—EARTH OR ROCK DRILLING; MINING
- E21B—EARTH OR ROCK DRILLING; OBTAINING OIL, GAS, WATER, SOLUBLE OR MELTABLE MATERIALS OR A SLURRY OF MINERALS FROM WELLS
- E21B7/00—Special methods or apparatus for drilling
- E21B7/04—Directional drilling
- E21B7/10—Correction of deflected boreholes
Landscapes
- Engineering & Computer Science (AREA)
- Geology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Mining & Mineral Resources (AREA)
- Physics & Mathematics (AREA)
- Environmental & Geological Engineering (AREA)
- Fluid Mechanics (AREA)
- General Life Sciences & Earth Sciences (AREA)
- Geochemistry & Mineralogy (AREA)
- Mechanical Engineering (AREA)
- Earth Drilling (AREA)
- Polyesters Or Polycarbonates (AREA)
- Biological Depolymerization Polymers (AREA)
Description
Fremgangsmåte til fremstilling av oralt anvendbare benzolsulfonylurinstoffer med sterk og protrahert blodsukkersenkende virkning. Process for the production of orally usable benzenesulfonylureas with a strong and prolonged blood sugar-lowering effect.
Oppfinnelsen vedrører en fremgangsmåte til fremstilling av oralt anvendbare benzolsulfonylurinstoffer med sterk og protrahert blodsukkersenkende virkning og med den generelle formel The invention relates to a method for the production of orally usable benzenesulfonylureas with a strong and prolonged blood sugar-lowering effect and with the general formula
hvori in which
R betyr hydrogen, lavere alkyl eller lavere fenylalkyl, R means hydrogen, lower alkyl or lower phenylalkyl,
R<1> betyr a) alkyl, alkenyl eller merkaptoalkyl med 2-8 karbonatomer, R<1> means a) alkyl, alkenyl or mercaptoalkyl with 2-8 carbon atoms,
b) alkoksyalkyl, alkylmerkaptoalkyl eller alkylsulfinylalkyl med 4 til 8 karbonatomer, hvorav minst 2 tilhører alkylendelen av alkoksyalkyl, alkylmerkaptoalkyl resp. alkylsulfinylalkyl, b) alkoxyalkyl, alkylmercaptoalkyl or alkylsulfinylalkyl with 4 to 8 carbon atoms, of which at least 2 belong to the alkylene part of alkoxyalkyl, alkylmercaptoalkyl resp. alkylsulfinylalkyl,
c) lavere fenylalkyl, fenylcyklopropyl, c) lower phenylalkyl, phenylcyclopropyl,
d) lavere cykloheksylalkyl, cykloheptylmetyl, cykloheptyl-etyl eller cyklooktylmetyl, e) endoalkylencykloheksyl, endoalkylencykloheksenyl, endoalkylencykloheksylmetyl eller endoalkylencyklo-heksenylmetyl med 1 til 2 endoalkylenkarbonatomer, d) lower cyclohexylalkyl, cycloheptylmethyl, cycloheptylethyl or cyclooctylmethyl, e) endoalkylenecyclohexyl, endoalkylenecyclohexenyl, endoalkylenecyclohexylmethyl or endoalkylenecyclohexenylmethyl with 1 to 2 endoalkylene carbon atoms,
f) lavere alkylcykloheksyl, lavere alkoksycykloheksyl, f) lower alkylcyclohexyl, lower alkoxycyclohexyl,
g) cykloalkyl med 5 til 8 karbonatomer, g) cycloalkyl with 5 to 8 carbon atoms,
h) cykloheksenyl, cykloheksenylmetyl, h) cyclohexenyl, cyclohexenylmethyl,
i) en heterocyklisk ring med 4 til 5 karbonatomer og et i) a heterocyclic ring of 4 to 5 carbon atoms and et
oksygen- eller svovelatom såvel som inntil to etyleniske dobbeltbindinger, eller oxygen or sulfur atom as well as up to two ethylenic double bonds, or
k) en over en metylenrest til nitrogenatomet bundet heterocyklisk ring med 4 til 5 karbonatomer og et oksygen-eller svovelatom, såvel som inntil to etyleniske k) a heterocyclic ring with 4 to 5 carbon atoms and an oxygen or sulfur atom attached to the nitrogen atom via a methylene residue, as well as up to two ethylenic
dobbeltbindinger, double bonds,
X betyr hydrogen, halogen, lavere alkyl eller lavere alkoksy, Y betyr en hydrokarbonkjede med 1 til 4 karbonatomer, X means hydrogen, halogen, lower alkyl or lower alkoxy, Y means a hydrocarbon chain with 1 to 4 carbon atoms,
n betyr 1, 2 ,eller 3, n means 1, 2, or 3,
U betyr oksygen eller svovel, U stands for oxygen or sulphur,
Z betyr en me,ttet eller umettet, alifatisk eller cykloalifatisk Z means a saturated or unsaturated, aliphatic or cycloaliphatic
hydrokarbonrest med inntil 6 C-atomer, fenyl eller benzyl, hydrocarbon residue with up to 6 C atoms, phenyl or benzyl,
og fremgangsmåten ifølge oppfinnelsen er karakterisert véd at enten and the method according to the invention is characterized by either
a) med gruppen a) with the group
i p-stilling substituerte benzolsulfonylisocyanater, -karbaminsyreestere, -tio karbaminsyreestere, -karbaminsyrehalogenider eller p-substituted benzenesulfonyl isocyanates, -carbamic acid esters, -thiocarbamic acid esters, -carbamic acid halides or
-urinstoffer omsettes med aminer som er substituert med gruppen R"*" eller deres salter, eller -ureas are reacted with amines which are substituted with the group R"*" or their salts, or
b) sulfonamider med formel b) sulfonamides of formula
eller deres salter omsettes med isocyanater, karbaminsyreestere, tiokarbaminsyreestere, karbaminsyrehalogenider eller urinstoffer, som er substituert med gruppen R^, eller or their salts are reacted with isocyanates, carbamic acid esters, thiocarbamic acid esters, carbamic acid halides or ureas, which are substituted with the group R^, or
c) forbindelser med formel c) compounds with formula
hvori A betyr en isourinstoffeter-, isotiourinstoffeter- eller wherein A means an isourea ether-, isothiourea ether- or
parabansyre-gruppe og R, r\ U, X, Y, Z og n har den ovenfor angitte betydning, hydrolyseres eller parabanic acid group and R, r\ U, X, Y, Z and n have the above meaning, are hydrolyzed or
d) i til benzolsulfonylurinstoffer med formel (I) svarende benzolsulf onyl-tiourin-stof f er utveksles svovelatomet med et oksygenatom på d) in to benzenesulfonylureas with formula (I) corresponding to benzenesulfonyl-thioureas f is the sulfur atom is exchanged with an oxygen atom of
kjent måte, eller known way, or
e) benzolsulfinyl- resp. sulfenylurinstoffer som svarer til benzolsulf onylurinstof fer ■ med formel (I) oksyderes, eller e) benzenesulfinyl or sulphenylureas which correspond to benzolsulphonylureas ■ with formula (I) are oxidized, or
f) i benzolsulfonylurinstoffer med formel f) in benzenesulfonylureas of formula
innføres ved acylering, eventuelt trinnvis på kjent måte resten is introduced by acylation, possibly step by step in a known manner the remainder
eller or
g) benzolsulfonylhalogenider med formel g) benzenesulfonyl halides of formula
hvori R, U, X, Y, Z og n har de ovenfor angitte betydninger, omsettes in which R, U, X, Y, Z and n have the meanings given above, are converted
med urinstoffer med formel with formula ureas
og at eventuelt reaksjonsproduktene for saltdannelse behandles med alkaliske midler. and that, if necessary, the reaction products for salt formation are treated with alkaline agents.
I det ovennevnte og følgende definisjoner betyr "lavere alkyl" alltid et slikt med 1 til 4 karbonatomer i rettlinjet eller forgrenet kjede. In the above and following definitions, "lower alkyl" always means one with 1 to 4 carbon atoms in a straight or branched chain.
Tilsvarende de ovennevnte definisjoner kan R eksempelvis bety metyl, etyl, propyl, isopropyl, butyl, isobutyl, tert. butyl, benzyl, a- eller g-fenyletyl-, a-, g- eller yfenylpropyl. Forbindelser, hvori R er metyl eller benzyl og spesielt slike hvor R er hydrogen, er foretrukket. Corresponding to the above definitions, R can for example mean methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. butyl, benzyl, a- or g-phenylethyl, a-, g- or y-phenylpropyl. Compounds in which R is methyl or benzyl and especially those in which R is hydrogen are preferred.
R1 kan eksempelvis bety etyl, propyl, isopropyl, butyl, isobutyl, sek.butyl, rettlinjet eller forgrenet amyl (pentyl), heksyl, heptyl eller oktyl, de til de nevnte hydrokarbonrester tilsvarende rester med en etylenisk dobbeltbinding som allyl eller krotyl, videre slike alkyler med 2 til 8 karbonatomer, som dessuten har en merkapto-gruppe som 3-niérkaptoetyl eller høyere merkaptoalkyler. Videre kan R"<*>" f.eks. bety ynietoksypropyl, 6-metoksy-n-butyl, g-etoksyet|yl, y-etoksypropyl, 6-etoksybutyl eller høyere alkyloksyetyler, -propyler eller -butyler såvel som de tilsvarende grupper, som i stedet for oksygenatomet har et svovelatom eller leddet -SO-. Videre kommer det som R<1> på tale benzyl, a-fenyletyl, g<->fenyletyl, a-, g- eller yfenylpropyl eller fenylbutyler. R1 can for example mean ethyl, propyl, isopropyl, butyl, isobutyl, sec.butyl, linear or branched amyl (pentyl), hexyl, heptyl or octyl, those to the aforementioned hydrocarbon residues corresponding to residues with an ethylenic double bond such as allyl or crotyl, further such alkyls of 2 to 8 carbon atoms, which additionally have a mercapto group such as 3-niercaptoethyl or higher mercaptoalkyls. Furthermore, R"<*>" can e.g. means ynietoxypropyl, 6-methoxy-n-butyl, g-ethoxyet|yl, y-ethoxypropyl, 6-ethoxybutyl or higher alkyloxyethyls, -propyls or -butyls as well as the corresponding groups, which instead of the oxygen atom have a sulfur atom or the link - SO-. Furthermore, R<1> is mentioned as benzyl, a-phenylethyl, g<->phenylethyl, a-, g- or yphenylpropyl or phenylbutyl.
Spesielt foretrukket er innen oppfinnelsens ramme slike forbindelser som som R<1> inneholder en cykloalifatisk, eventuelt med alkyl resp. alkoksy substituert eller over alkylen til nitrogenatomet bundet hydrokarbonrest. Som slike rester kan eksempelvis nevnes cyklopentyl, cykloheksyl, cykloheptyl, cyklooktyl, metylcykloheksyl, etylcykloheksyl, propyl- og isopropylcykloheksyl, metoksycykloheksyl, etoksycykloheksyl, propoksy- og isopropoksycykloheksyl, id<t>et alkyl-resp. alkoksygruppen kan foreligge i 2-, 3- eller fortrinnsvis i 4-stilling, nemlig såvel i cis- som også i trans-stilling. Cyklo-heksylmetyl, a- eller g-cykloheksyletyl, cykloheksylpropyl, endo-metylencykloheksyl (2,2,1-tricykloheptyl), endoetylencykloheksyl, (2,2,2-tricyklooktyl), endometylencykloheksenyl, endoetylencyklo-heksenyl, endometylencykloheksylmetyl, endoetylencykloheksylmetyl, endometylencykloheksenylmetyl eller endoetylencykloheksenylmetyl, Particularly preferred within the scope of the invention are such compounds which as R<1> contain a cycloaliphatic, optionally with alkyl or Alkoxy substituted or hydrocarbon residue attached above the alkylene to the nitrogen atom. Such residues can be mentioned, for example, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclohexyl, ethylcyclohexyl, propyl- and isopropylcyclohexyl, methoxycyclohexyl, ethoxycyclohexyl, propoxy- and isopropoxycyclohexyl, id<t>et alkyl-resp. the alkoxy group can be present in the 2-, 3- or preferably in the 4-position, namely both in the cis- and also in the trans-position. Cyclohexylmethyl, a- or g-cyclohexylethyl, cyclohexylpropyl, endo-methylenecyclohexyl (2,2,1-tricycloheptyl), endoethylenecyclohexyl, (2,2,2-tricyclooctyl), endomethylenecyclohexenyl, endoethylenecyclohexenyl, endomethylenecyclohexylmethyl, endoethylenecyclohexylmethyl, endomethylenecyclohexenylmethyl or endoethylenecyclohexenylmethyl,
a- eller g-fenylcyklopropyl såvel i cis- Bom også i trans-form. a- or g-phenylcyclopropyl both in cis-Bom and in trans-form.
Endelig er det dessuten egnet heterocykliske ringer Finally, heterocyclic rings are also suitable
som R"*" som foruten H til 5 karbonatomer dessuten kan inneholde et oksygen- eller svovelatom og inntil 2 dobbeltbindinger og kan eventuelt være bundet til det naboplaserte nitrogenatom gjennom en metylengruppe. Eksempler på slike heterocykliske ringer er: as R"*" which, in addition to H to 5 carbon atoms, may also contain an oxygen or sulfur atom and up to 2 double bonds and may optionally be bound to the neighboring nitrogen atom through a methylene group. Examples of such heterocyclic rings are:
Som eksempler for broleddet Y kan nevnes: As examples for the bridge link Y can be mentioned:
-CH2-, -CH2-CH2-, -CH(CH3)-5 -CH2-CH2-CH2, CH(CH3J-CHg-, CH2-CH(CH;5)-, -C(CH:5)2-J -CH2-CH2-CH2-CH2-, -CH( CE^ )-CH2-CH2-, -CH2-CH(CH5)-CH2-, -CH2-CH2-CH(CH3)-J -CH(CH3)-CH( CE^)-, -C(CH^)-CHg-, -CH2-, -CH2-CH2-, -CH(CH3)-5 -CH2-CH2-CH2, CH(CH3J-CHg-, CH2-CH(CH;5)-, -C(CH:5)2- J -CH2-CH2-CH2-CH2-, -CH( CE^ )-CH2-CH2-, -CH2-CH(CH5)-CH2-, -CH2-CH2-CH(CH3)-J -CH(CH3) -CH(CE^)-, -C(CH^)-CHg-,
-CH2-C(CH3)2-} -CH(C2H5)-, -C(CH3)(C2H5)-. -CH2-C(CH3)2-} -CH(C2H5)-, -C(CH3)(C2H5)-.
Den i formelen med -fenylen- betegnede fenylenrest er fortrinnsvis usubstituert. Den kan imidlertid også være en eller flere ganger substituert med halogen, lavere alkyl eller lavere alkoksy. Den kan ha de resterende deler av molekylet i o-, m- eller p-stilling til hverandre, idet p-stillingen er foretrukket. The phenylene residue denoted by -phenylene- in the formula is preferably unsubstituted. However, it can also be substituted one or more times by halogen, lower alkyl or lower alkoxy. It can have the remaining parts of the molecule in the o-, m- or p-position to each other, the p-position being preferred.
Alt etter naturen av leddene Depending on the nature of the joints
vil i enkelte tilfelle den ene eller andre av de nevnte fremgangs-måter være uegnet for fremstilling av enkelte under den generelle formel fallende individuelle forbindelser. Slike forholdsvis skjeldent opptredende tilfelle kan lett erkjennes av fagfolk og det byr ikke på vanskeligheter i slike tilfelle å anvende med resultat en annen av de omtalte syntesemetoder. in some cases, one or the other of the aforementioned methods will be unsuitable for the production of certain individual compounds falling under the general formula. Such relatively rare occurrences can be easily recognized by professionals and it does not pose any difficulties in such cases to use another of the mentioned synthesis methods with results.
I stedet for benzolsulfonyl-isocyanater kan man også anvende omsetningsprodukter av benzolsulfonylisocyanater med syre-amider som kaprolaktam eller butyrolaktam, videre med svakt basiske aminer som karbazoler. Instead of benzenesulfonyl isocyanates, one can also use reaction products of benzenesulfonyl isocyanates with acid amides such as caprolactam or butyrolactam, further with weakly basic amines such as carbazoles.
De nevnte benzolsulfonyl-karbaminsyreestere, resp. The mentioned benzenesulfonyl-carbamic acid esters, resp.
-tiokarbaminsyreestere kan i alkoholkomponenten ha en lavmolekylær -thiocarbamic acid esters can have a low molecular weight in the alcohol component
alkylrest eller en f enylrest. Det samme gjelder for de R"<1>"-substituerte karbaminsyreestere resp. de tilsvarende monotio-karbaminsyreestere..Med en lavmolekylær resp. lavere alkylrest innen oppfinnelsens ramme skal det i alle tilfelle forstås en slik med ikke mer enn h karbonatomer. alkyl radical or a phenyl radical. The same applies to the R"<1>"-substituted carbamic acid esters or the corresponding monothio-carbamic acid esters..With a low molecular resp. lower alkyl residue within the scope of the invention shall in all cases be understood as one with no more than h carbon atoms.
Som karbaminsyrehalogenider egner det seg i førBte As carbamic acid halides, it is suitable in the first place
rekke kloridene. series of chlorides.
De som utgangsstoffer for fremgangsmåten angjeldende benzolsulfnnylurinstoffer kan på den side av urinstoffmolekylet som vender bort fra sulfonylgruppen være usubstituert eller være en-eller to ganger substituert, fortrinnsvis med lavere alkylrester eller arylrester. I stedet for på slik måte substituerte benzolsulf onylurinstof f er kan det også anvendes tilsvarende N-benzolsulfonyl-N'-acyl-urinstoffer (acyl = lavere alifatiske acyl som acetyl, propionyl eller butyryl, imidlertid også benzoyl) og også bis-(benzolsulfonyl)-urinstoffer. Man kan eksempelvis behandle slike bis-(benzolsulfonyl)-urinstoffer eller N-benzolsulfonyl-N'-acyl-urinstoffer med aminer R^NH^ og oppvarme de dannede salter til forhøyede temperaturer, spesielt slike over 100°C. The benzenesulfonylureas used as starting materials for the method may, on the side of the urea molecule facing away from the sulfonyl group, be unsubstituted or be substituted once or twice, preferably with lower alkyl residues or aryl residues. Instead of benzenesulfonyl ureas substituted in this way, corresponding N-benzenesulfonyl-N'-acyl ureas can also be used (acyl = lower aliphatic acyl such as acetyl, propionyl or butyryl, however also benzoyl) and also bis-(benzenesulfonyl) - urea substances. One can, for example, treat such bis-(benzenesulfonyl) ureas or N-benzenesulfonyl-N'-acyl ureas with amines R^NH^ and heat the formed salts to elevated temperatures, especially those above 100°C.
Videre er det mulig å gå ut fra urinstoffer med formel R1-NH-CO-NH2 eller acylerte urinstoffer med formel R<1->NH-CO-NH-acyl, hvori acyl betyr en fortrinnsvis lavmolekylær alifatisk eller aro-matisk syrerest eller nitrogruppen, resp. fra fenylurinstoffer med formel R1-NH-CO-NH-C^Hir eller fra dif enylurinstof f er med formel R -NH-CO-lsKCgH,-^, idet fenylrestenekan være substituert såvel som direkte eller også over et broledd som -CH"2-, -NH-, -0- eller -S-forbundet med hverandre eller fra N,N'-disubstituerte urinstoffer med formel R<1->NH-C0-NH-R<1> og å omsette disse med X-CONH-Y-substituerte benzolsulfonamider. Svovelatomets erstatning med et oksygenatom i de tilsvarende substituerte benzolsulfonyl-tiourinstoffer kan eksempelvis utføres ved hjelp av oksyder eller salter av tungmetaller eller også ved anvendelse av oksydasjonsmidler som hydrogenperoksyd, natriumperoksyd eller salpetersyrling»Furthermore, it is possible to start from ureas with the formula R1-NH-CO-NH2 or acylated ureas with the formula R<1->NH-CO-NH-acyl, in which acyl means a preferably low molecular weight aliphatic or aromatic acid residue or the nitro group , respectively from phenylureas with the formula R1-NH-CO-NH-C^Hir or from diphenylureas with the formula R -NH-CO-lsKCgH,-^, the phenyl residues can be substituted as well as directly or also via a bridge link such as -CH" 2-, -NH-, -0- or -S-connected with each other or from N,N'-disubstituted ureas of formula R<1->NH-C0-NH-R<1> and to react these with X- CONH-Y-substituted benzenesulfonamides. The replacement of the sulfur atom with an oxygen atom in the correspondingly substituted benzenesulfonyl-thioureas can for example be carried out with the help of oxides or salts of heavy metals or also by using oxidizing agents such as hydrogen peroxide, sodium peroxide or nitric acid."
Tiourinstoffene kan også avsvovles ved behandling med fosgen eller fosforpentaklorid. Som mellomtrinn dannede klormaur-syreamidiner resp. -karbodiimider kan ved egnede forholdsregler som forsåpning eller tilleiring a<y> vann overføres i benzolsulfonylurin-stof f ene. The thioureas can also be desulphurised by treatment with phosgene or phosphorus pentachloride. As an intermediate step, chlorformic acid amidines resp. -carbodiimides can be transferred into benzenesulfonylureas by suitable precautions such as saponification or addition of water.
v 1 w 1
Analogt tiourinstoffene forholder isotiourinstoffeterene seg som innen oppfinnelsens ramme er likestillet som utgangsstoffer for avsvovlingsreaksjonene. Analogously to the thioureas, the isothiourea ethers are treated as starting materials for the desulphurisation reactions within the framework of the invention.
Utførelsesformene av fremgangsmåten ifølge oppfinnelsen kan generelt variere sterkt med hensyn til reaksjonsbetingelser og tilpasses de eventuelle forhold. The embodiments of the method according to the invention can generally vary greatly with regard to reaction conditions and can be adapted to any conditions.
Eksempelvis kan omsetningen gjennomføres under anvendelse av oppløsningsmidler ved vasrelsetemperatur eller forhøyet temperatur. For example, the reaction can be carried out using solvents at vat temperature or elevated temperature.
Som utgangsstoffer anvender man på den ene side slike forbindelser som inneholder en med gruppen As starting materials, on the one hand, such compounds are used which contain a with group
substituerte benzolrest. Som eksempler for bestanddelen av denne formel kan' uten krav på fullstendighet følgende nevnes: substituted benzene residue. As examples of the constituents of this formula, the following can be mentioned without claiming completeness:
De omtalte benzolsulfonyl-urinstoff-derivaters blodsukkersenkende virkning kunne fastslås ved at man foret dem i doser på 10 mg/kg på kaniner og bestemte blodsukkerverdien etter den kjente metode av Hagedorn-Jensen eller med en"autoanal5»zer'J over et lengere tidsrom. The blood sugar-lowering effect of the mentioned benzenesulfonyl urea derivatives could be determined by feeding them in doses of 10 mg/kg to rabbits and determining the blood sugar value according to the known method of Hagedorn-Jensen or with an "autoanalyzer" over a longer period of time.
Således ble det eksempelvis fastslått at 10 mg/kg N-/_ 4-(8-<2-metoksy-metoksybenzamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl-urinstoff etter 3 timer bevirker en blodsukkersenkning på 19%, som etter 24 timer sågar utgjør 33$ og først etter 48 timer igjen synker til nullverdien. På samme måte bevirker 10 mg N-/_ 4-(3-<2-3-metoksyetoksy-benzamido>-etyl)-benzolsulfonyl7-N'-(4-metylcykloheksyl)-urinstoff, etter 3 timer en blodsukkersenkning på 31%, som etter 24 timer ennå utgjør 20%, mens det kjente N-/_ 4-metyl-benzolsulfonyl-N'-butyl-urinstoff ved en dosering på mindre enn 25 mg/kg på kaniner ikke mer frembringer noen senkning av blodsukkerspeilet. Thus, for example, it was determined that 10 mg/kg N-/_ 4-(8-<2-methoxy-methoxybenzamido>-ethyl)-benzenesulfonyl7-N'-cyclohexyl-urea after 3 hours causes a blood sugar lowering of 19%, which after 24 hours even amounts to 33$ and only after 48 hours again drops to the zero value. In the same way, 10 mg of N-/_ 4-(3-<2-3-methoxyethoxy-benzamido>-ethyl)-benzenesulfonyl7-N'-(4-methylcyclohexyl)-urea, after 3 hours, causes a blood sugar lowering of 31%, which after 24 hours still amounts to 20%, while the known N-/_ 4-methyl-benzenesulfonyl-N'-butyl urea at a dosage of less than 25 mg/kg in rabbits no longer produces any lowering of the blood sugar level.
Den sterke virkning av de omtalte benzolsulfonyl-urinstof f er blir spesielt tydelig når man ytterligere nedsetter dosen. Administrerer man N-/ 4-($-<2-metoksy-metoksybenzamido>-etyl)-benzolsulfonyl/-N'-(4-metylcykloheksyl)-urinstoff i en dosering på 0,05 mg/kg på kaniner så fastslås stadig en tydelig blodsukkersenkning. The strong effect of the mentioned benzolsulfonylureas becomes particularly evident when the dose is further reduced. If N-/ 4-($-<2-methoxy-methoxybenzamido>-ethyl)-benzenesulfonyl/-N'-(4-methylcyclohexyl)-urea is administered in a dosage of 0.05 mg/kg to rabbits, a constant clear blood sugar lowering.
De omtalte benzolsulfonylurinstoffer skal fortrinnsvis tjene til fremstilling av oralt administrerbare preparater med blodsukkersenkende virkning for behandling av diabetes mellitus og kan appliseres som sådanne eller i form av deres salter, resp. i nærvær av stoffer som fører til en saltdannelse. Por saltdannelse kan det eksempelvis anvendes: alkaliske midler som alkali- eller jordalkalihydroksyder, -karbonater eller -bikarbonater. The mentioned benzenesulfonylureas are preferably used for the production of orally administrable preparations with blood sugar-lowering effects for the treatment of diabetes mellitus and can be applied as such or in the form of their salts, resp. in the presence of substances that lead to salt formation. For salt formation, for example, alkaline agents such as alkali or alkaline earth hydroxides, carbonates or bicarbonates can be used.
Som medisinske preparater kommer det fortrinnsvis i betraktning tabletter, som ved siden av fremgangsmåteproduktene inneholder.de vanlige hjelpe- og bærestoffer som talkum, stivelse, melkesukker, tragant eller magnesiumstearat. Tablets are preferably taken into consideration as medicinal preparations, which, in addition to the process products, contain the usual auxiliary and carrier substances such as talc, starch, milk sugar, tragacanth or magnesium stearate.
Et preparat som inneholder de omtalte benzolsulfonyl-urinstof f er som virksomt stoff, f.eks. en tabfeftt eller et pulver med eller uten de nevnte tilsetninger, er hensiktsmessig bragt i en egnet dosert form. Som dose er det da å velge en slik som er tilpasset virkningen av det anvendte benzolsulfonylurinstoff og den ønskede effekt. Hensiktsmessig utgjør doseringen pr. enhet ca. 0,5 til 100 mg, fortrinnsvis 2 til 10 mg, imidlertid kan det også anvendes betraktelig høyere eller lavereliggende doseringsenheter, som eventuelt før applikasjon må deles eller mangfoldiggjøres. A preparation containing the mentioned benzolsulfonylureas as active ingredient, e.g. a tab fat or a powder with or without the aforementioned additives, is suitably brought into a suitable dosed form. The dose is then to choose one that is adapted to the effect of the benzenesulfonylurea used and the desired effect. Appropriately, the dosage per unit approx. 0.5 to 100 mg, preferably 2 to 10 mg, however, considerably higher or lower dosage units can also be used, which may have to be divided or multiplied before application.
Eksempel 1. Example 1.
N-/~~4-($-< 2-metoksy-etoksy-benzamido>-etyl)-benzolsulfonyl7-N* - cykloheksyl-urinstoff. a) 2,6 g N-/~4-($-<2-metoksy-etoksy-benzamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl-tiourinstoff (fremstilt av N-4-6-<2-metoksy-étoksy-benzamido>-etyl)-benzolsulfonamid og cyklo-heksylsennepolje, smep. 116-118°C), oppløses i ca. 20 ml 2-n natronlut. Man tilsetter ca. 5 g 35%-ig H202, hvorpå det inntrer sterk oppvarmning. Etter noen henstand avkjøler man og surgjør med fortynnet eddiksyre. Den dannede utfelling av N-/~4-(B-<2-metoksy-etoksy-benzamido>-etyl)-benzolsulfonyl7-N<*->cykloheksylurinstoff suges fra og omkrystalliseres fra metanol, smp. l60-l62°C. b) 2',6 g N-/~4-( g-<2-metoksy-etoksy-benzamido>-étyl)-benzolsulfonyl7-N'-cykloheksyl-tiourinstoff oppløses i 30 ml metanol. N-[~4-($-< 2-Methoxy-ethoxy-benzamido>-ethyl)-benzenesulfonyl7-N*-cyclohexyl-urea. a) 2.6 g of N-/~4-($-<2-methoxy-ethoxy-benzamido>-ethyl)-benzenesulfonyl7-N'-cyclohexyl-thiourea (prepared from N-4-6-<2-methoxy- ethoxy-benzamido>-ethyl)-benzenesulfonamide and cyclo-hexyl mustard oil, smep. 116-118°C), dissolves in approx. 20 ml 2-n caustic soda. Add approx. 5 g of 35% H202, after which strong heating occurs. After some delay, it is cooled and acidified with diluted acetic acid. The formed precipitate of N-/~4-(B-<2-methoxy-ethoxy-benzamido>-ethyl)-benzenesulfonyl7-N<*->cyclohexylurea is sucked off and recrystallized from methanol, m.p. 160-162°C. b) 2'.6 g of N-[4-(g-<2-methoxy-ethoxy-benzamido>-ethyl)-benzenesulfonyl-7-N'-cyclohexyl-thiourea are dissolved in 30 ml of methanol.
Etter tilsetning av CH-j I i lite overskudd oppvarmes det i 45 min. After addition of CH-j I in small excess, it is heated for 45 min.
på dampbad under tilbakeløp. Etter avdestillering av metanol og overskytende metyljodid forblir det tilbake et oljeaktig residuum av N-/<->4-(3-<<>2-metoksy-etoksy-benzamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl-isotiourinstoff-metyleter som man oppløser, i 5 ml dioksan og blander med 10 ml 2-n natronlut. Etter 1 times oppvarmning helles det ut i vann og surgjøres. Den dannede utfelling av 4-(g-<2-metoksy-etoksy-benzamido>-etyl)-benzolsulfonyl7-N'-cykloheksylurinstoff smelter etter frasugning og omkrystallisering fra metanol ved 160-162°C. c) 2j6 g N-/<->4-(g<-><2-metoksy-etoksy-benzamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl-tiourinstoff oppløses i 50 ml metanol. on a steam bath under reflux. After distilling off methanol and excess methyl iodide, an oily residue of N-/<->4-(3-<<>2-methoxy-ethoxy-benzamido>-ethyl)-benzenesulfonyl 7-N'-cyclohexyl-isothiourea methyl ether remains which is dissolved in 5 ml of dioxane and mixed with 10 ml of 2-n caustic soda. After 1 hour of heating, it is poured into water and acidified. The formed precipitate of 4-(g-<2-methoxy-ethoxy-benzamido>-ethyl)-benzenesulfonyl7-N'-cyclohexylurea melts after extraction and recrystallization from methanol at 160-162°C. c) 2j6 g of N-[<->4-(g<-><2-methoxy-ethoxy-benzamido>-ethyl)-benzenesulfonyl-7-N'-cyclohexyl-thiourea are dissolved in 50 ml of methanol.
Man tilsetter 1,1 g HgO og noe K2C0-j og oppvarmer under samtidig omrøring i 5£,time ved 45°C. Etter frafiltrering av dannet HgS inndampes det i vakuum. Det blir tilbake et oljeaktig residuum av N-/~4-(g-<2-metoksy-etoksy-benzamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl-isourinstoff-metyleter, som man oppløser i 5 ml dioksan. Man tilsetter ca. 10 ml 2-n natronlut og oppvarmer i 1 time på dampbad. Etter innhelling i vann surgjøres. Den dannede utfelling av N-/~4-(g-<2-metoksy-etoksy-benzamido>-etyl)-benzolsulfonyl/-N'-cykloheksyl-urinstoff suges fra og omkrystalliseres fra fortynnet metanol. Smp. l60-l62°C. 1.1 g of HgO and some K2C0-j are added and heated with simultaneous stirring for 5 hours at 45°C. After filtering off the formed HgS, it is evaporated in a vacuum. An oily residue of N-[4-(g-<2-methoxy-ethoxy-benzamido>-ethyl)-benzenesulfonyl-7-N'-cyclohexyl isourea methyl ether remains, which is dissolved in 5 ml of dioxane. Add approx. 10 ml 2-n caustic soda and heat for 1 hour in a steam bath. After pouring in water, it is acidified. The formed precipitate of N-[4-(g-<2-methoxy-ethoxy-benzamido>-ethyl)-benzenesulfonyl/-N'-cyclohexyl urea is sucked off and recrystallized from dilute methanol. Temp. 160-162°C.
Eksempel 2. Example 2.
N-/~4-(3-<2-metoksymetoksy-benzamido>-etyl)-benzolsulfonyl/-N'-(4-metylcykloheksyl)-urinstoff (trans). N-/~4-(3-<2-Methoxymethoxy-benzamido>-ethyl)-benzenesulfonyl/-N'-(4-methylcyclohexyl)-urea (trans).
9J. g 4-( g-<2-metoksymetoksy-benzamido>-etyl)-benzolsulf onamid (smp. 169-170°C) oppløses i 12,5 ml 2-n natronlut og 30 ml aceton og blandes ved 0-5°C under omrøring dråpevis med 3,6 g trans-4-metylcykloheksylisocyanat. Man lar det etteromrøre i 3 timer, fortynner med vann og metanol, filtrerer fra uoppløst og surgjør filtratet med fortynnet eddiksyre. Det i form av krystaller dannede N-/~4-(3-<2-metoksymetoksybenzamido>-etyl)-benzolsulfonyl7-N'-(4-metyl-cykloheksyl)-urinstoff (trans) smelter etter omkrystallisering fra metanol ved l62-l63°C. 9J. g 4-(g-<2-methoxymethoxy-benzamido>-ethyl)-benzenesulfonamide (m.p. 169-170°C) is dissolved in 12.5 ml of 2-n caustic soda and 30 ml of acetone and mixed at 0-5°C while stirring dropwise with 3.6 g of trans-4-methylcyclohexyl isocyanate. It is left to stir for 3 hours, diluted with water and methanol, filtered from undissolved and the filtrate acidified with dilute acetic acid. The N-/~4-(3-<2-methoxymethoxybenzamido>-ethyl)-benzenesulfonyl7-N'-(4-methyl-cyclohexyl)-urea (trans) formed in the form of crystals melts after recrystallization from methanol at l62-l63 °C.
På analog måte får man: N-/~4-(3-<2-metoksymetoksy-benzamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl-urinstoff med smp. 152-154°C (fra metanol) av 4-(3-<4-metoksymetoksy-benzamido>-etyl)-benzolsulfonamid (smp. 196-197°C): N-/~4-(B-<4-metoksymetoksy-benzamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl-urinstoff med smp. 175-176°C fra metanol/dimetylform-amid og N-/~4-( B-<4 -metoksymetoksy-benzamido>-etyl)-benzolsulf onyl7-N' - (4-metylcykloheksyl)-urinstoff (trans) med smp. l80-l8l°C fra metanol/dimetylformamid: av 4-(3-<3-B-metoksyetoksy-benzamido>-etyl)-benzolsulfonamid (smp. 134-136°C): N-/~4-(3-<3-3-metoksyetoksy-benzamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl-urinstoff med smp. 132-133°C (fra metanol) og N-/~4-(3-<3-3-metoksyetoksy-benzamido>-etyl)-benzolsulfonyl/-N'-(4-metylcykloheksyl)-urinstoff (trans) med smp. 157_159°C In an analogous manner, one obtains: N-[4-(3-<2-methoxymethoxy-benzamido>-ethyl)-benzenesulfonyl7-N'-cyclohexyl-urea with m.p. 152-154°C (from methanol) of 4-(3-<4-methoxymethoxy-benzamido>-ethyl)-benzenesulfonamide (m.p. 196-197°C): N-/~4-(B-<4-methoxymethoxy -benzamido>-ethyl)-benzenesulfonyl7-N'-cyclohexyl-urea with m.p. 175-176°C from methanol/dimethylformamide and N-/~4-(B-<4-methoxymethoxy-benzamido>-ethyl)-benzenesulfonyl7-N'-(4-methylcyclohexyl)-urea (trans) with m.p. . 180-181°C from methanol/dimethylformamide: of 4-(3-<3-B-methoxyethoxy-benzamido>-ethyl)-benzenesulfonamide (m.p. 134-136°C): N-/~4-(3-< 3-3-Methoxyethoxy-benzamido>-ethyl)-benzenesulfonyl7-N'-cyclohexylurea with m.p. 132-133°C (from methanol) and N-/~4-(3-<3-3-methoxyethoxy-benzamido>-ethyl)-benzenesulfonyl/-N'-(4-methylcyclohexyl)-urea (trans) with m.p. . 157-159°C
(fra metanol): (from methanol):
av 4-(3-<4-3-metoksyetoksy-benzamido>-etyl)-benzolsulfonamid (smp. 212-2l4°C): N-/<->4-(3-<4-3-metoksyetoksy-benzamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl-urinstoff med smp. 200-201°C (fra metanol/dimetylformamid), N-/~4-(3-<4-3-metoksyetoksy-benzamido>-etyl)-benzolsulfonyl/-N'-butyl-urinstoff med smp. 197-198°C (fra metanol/dimetylformamid) og N-/~~4-(3-<4-3-metoksyetoksy-benzamido>-etyI)-benzolsulfonylT-N'-(4-metylcykloheksyl)-urinstoff (trans) med smp. 208-209°C of 4-(3-<4-3-methoxyethoxy-benzamido>-ethyl)-benzenesulfonamide (m.p. 212-214°C): N-/<->4-(3-<4-3-methoxyethoxy-benzamido> -ethyl)-benzenesulfonyl7-N'-cyclohexylurea with m.p. 200-201°C (from methanol/dimethylformamide), N-/~4-(3-<4-3-methoxyethoxy-benzamido>-ethyl)-benzenesulfonyl/-N'-butyl urea with m.p. 197-198°C (from methanol/dimethylformamide) and N-[~4-(3-<4-3-methoxyethoxy-benzamido>-ethyl)-benzenesulfonyl T-N'-(4-methylcyclohexyl)-urea (trans) with m.p. 208-209°C
(fra metanol/dimetylformamid), (from methanol/dimethylformamide),
av 4-(B-<2-y-fenoksypropoksy-benzamido>-etyl)-benzolsulfonamid (smp. 168-.I70°C): N-/-4-( $-<2-y-f enoksypropoksy-benzamido>-etyl) -benzolsulf onyl7-N' - cykloheksyl-urinstoff med smp. l48-l49°C (fra metanol), N-/~~ 4-( 8-<2-y-f enoksypropoksy-benzamido>-etyl)-benzolsulf onyl^7-N' - butyl-urinstoff med smp. l42-l44°C (fra metanol/dimetylformamid) og N-/—<4>-( 3-<2-y-fenoksypropoksy-benzamido>-etyl)-benzolsulfoir<y>l/-N'-(4-metylcykloheksyl)-urinstoff (trans) med smp. 169-170°C of 4-(B-<2-y-phenoxypropoxy-benzamido>-ethyl)-benzenesulfonamide (m.p. 168-.170°C): N-/-4-( $-<2-y-phenoxypropoxy-benzamido>-ethyl )-benzenesulfonyl7-N'-cyclohexyl-urea with m.p. 148-149°C (from methanol), N-/~ 4-(8-<2-y-phenoxypropoxy-benzamido>-ethyl)-benzenesulfonyl^7-N'-butyl-urea with m.p. 142-144°C (from methanol/dimethylformamide) and N-/-<4>-(3-<2-y-phenoxypropoxy-benzamido>-ethyl)-benzenesulfoir<y>1/-N'-(4-methylcyclohexyl )-urea (trans) with m.p. 169-170°C
(fra metanol), (from methanol),
av 4-(3_<2-fenylmerkaptometoksy-benzamido>-etyl)-benzolsulfonamid (smp. 152-153°C): N-/<->4-(3_<2-fenylmerkaptometoksy-benzamido>-etyl)-benzolsulfonyl7-N'-cykloheksylurinstoff med smp. 136-138°C (fra metanol), of 4-(3_<2-phenylmercaptomethoxy-benzamido>-ethyl)-benzenesulfonamide (m.p. 152-153°C): N-/<->4-(3_<2-phenylmercaptomethoxy-benzamido>-ethyl)-benzenesulfonamide7- N'-cyclohexylurea with m.p. 136-138°C (from methanol),
a<y> 4-(3-<2-8-metoksyetoksy-5-metyl-benzamido>-etyl)-benzolsulfonamid (smp. 156-158°C): N-/—4-( 3-<2-3-metoksyetoksy-5-metyl-benzamido>-etyl)-benzolsulf onyl7-N'-cykloheksyl-urinstoff med smp. l6l-l63°C (fra metanol) og N-/_ 4-(3-<2-3-metoksyetoksy-5-metyl-benzamido>-etyl)-benzolsulfonyl/- N'-(4-metylcykloheksyl)-urinstoff (trans) med smp. 157-158°C a<y> 4-(3-<2-8-methoxyethoxy-5-methyl-benzamido>-ethyl)-benzenesulfonamide (m.p. 156-158°C): N-/—4-( 3-<2-3 -methoxyethoxy-5-methyl-benzamido>-ethyl)-benzenesulfonyl7-N'-cyclohexyl-urea with m.p. 161-163°C (from methanol) and N-/_ 4-(3-<2-3-methoxyethoxy-5-methyl-benzamido>-ethyl)-benzenesulfonyl/- N'-(4-methylcyclohexyl)-urea ( trans) with m.p. 157-158°C
(fra metanol), (from methanol),
av 4-(3-<2-3-metoksyetoksy-5-klor-benzamido>-benzolsulfonamid (smp. 161-162°C): N-/-4-(3-<2-3-metoksyetoksy-5-klor-benzamido>-etyl)-benzolsulfonyl7-N<1->cykloheksyl-urinstoff med smp. 151-153°C (fra metanol) og N-/~~4-(3-<2-3-metoksyetoksy-5_klor-benzamido>-etyl)-benzolsulfonyl/- N'-(4-metylcykloheksyl)-urinstoff (trans) med smp. l45-l47°C of 4-(3-<2-3-methoxyethoxy-5-chloro-benzamido>-benzenesulfonamide (m.p. 161-162°C): N-/-4-(3-<2-3-methoxyethoxy-5-chloro -benzamido>-ethyl)-benzenesulfonyl7-N<1->cyclohexyl-urea with m.p. 151-153°C (from methanol) and N-/~~4-(3-<2-3-methoxyethoxy-5_chloro-benzamido >-ethyl)-benzenesulfonyl/- N'-(4-methylcyclohexyl)-urea (trans) with mp 145-147°C
(fra metanol), (from methanol),
av 4-(3-<3-3-metoksyetoksy-5-metoksy-benzamido>-etyl)-benzolsulfonamid (smp. 177-178°C): N-_/ 4-( 3-<2-3-metoksyetoksy-5-metoksy-benzamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl-urinstoff med smp. 140-142°C .(fra metanol) og N-/ 4-(8-<2-3-metoksyetoksy-5-metoksy-benzamido>-etyl)-benzolsulfonyl7-N'-(4-metylcykloheksyl)-urinstoff (trans) med smp. 163-165°C (fra metanol), of 4-(3-<3-3-methoxyethoxy-5-methoxy-benzamido>-ethyl)-benzenesulfonamide (m.p. 177-178°C): N-_/ 4-(3-<2-3-methoxyethoxy- 5-methoxy-benzamido>-ethyl)-benzenesulfonyl 7-N'-cyclohexyl-urea with m.p. 140-142°C .(from methanol) and N-/ 4-(8-<2-3-methoxyethoxy-5-methoxy-benzamido>-ethyl)-benzenesulfonyl7-N'-(4-methylcyclohexyl)-urea (trans ) with m.p. 163-165°C (from methanol),
På analog måte får man av 4-(2-metoksymetoksy-benzamido-metyl)-benzolsulfonamid (smp. 176-178°C): N-/_—4-( 2-metoksymetoksy-benzamidometyl)-benzolsulf onyl7-N' -cyklo-heksylurinstof f med smp. 191-193°C, av 4-(0-<2-metoksy-metoksybenzamido>-etyl)-benzolsulfonamid (smp. 169-170°C): N-/—4-(3-<2^metoksymetoksybenzamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl-urinstoff med smp. 151-153°C (fra metanol), av 4-(8-<4-B-etoksyetoksybenzamido>-etyl)-benzolsulfonamid (smp. 200-202°C): N-/_ 4-(B-<4-B-etoksyetoksybenzamido>-etyl)-benzolsulfonyl7-N'-(4-metylcykloheksyl)-urinstoff (trans) med smp. l82-l84°C In an analogous manner, one obtains from 4-(2-methoxymethoxy-benzamido-methyl)-benzenesulfonamide (m.p. 176-178°C): N-/_—4-(2-methoxymethoxy-benzamidomethyl)-benzenesulfonyl7-N' - cyclohexylurea f with m.p. 191-193°C, of 4-(0-<2-methoxy-methoxybenzamido>-ethyl)-benzenesulfonamide (m.p. 169-170°C): N-/—4-(3-<2^methoxymethoxybenzamido>-ethyl)-benzenesulfonyl7-N' -cyclohexyl urea with m.p. 151-153°C (from methanol), of 4-(8-<4-B-ethoxyethoxybenzamido>-ethyl)-benzenesulfonamide (m.p. 200-202°C): N-/_ 4-(B-<4- B-ethoxyethoxybenzamido>-ethyl)-benzenesulfonyl 7-N'-(4-methylcyclohexyl)-urea (trans) with m.p. 182-184°C
(fra metanol), (from methanol),
av 4-(3-<2-B-etoksyetoksy-5-metylbenzamido>-etyl)-benzolsulfonamid (smp. 132-134°C): of 4-(3-<2-B-ethoxyethoxy-5-methylbenzamido>-ethyl)-benzenesulfonamide (m.p. 132-134°C):
N-/~4-($-<2-B-etoksyetoksy-5-metylbenzamido>-etyl)-benzolsulfony 17-N'-cykloheksyl-urinstoff med smp. 121-123°C (fra metanol) og N-/_"~4-(8-<2-3-etoksyetoksy-5-metylbenzamido>-etyl)-benzolsulfonyl7-N-(4-metylcykloheksyl)-urinstoff (trans) med smp. ll8-119°C (fra metanol), av 4-(8-<2-metoksymetoksy-5-metylbenzamido>-ety1)-benzolsulfonamid (smp. 225-228°C): N-_/ 4-( B-<2-metoksymetoksy-5-metylbenzamido>-etyl)-benzolsulfonyl7-N'-cykloheksylurinstoff med smp. 224-226°C (fra metanol/dimetyl-formamid) og N-/~4-($-<2-metoksymetoksy-5-metylbenzamido>-etyl)-benzolsulfonyl7-N'-(4-metylcykloheksyl)-urinstoff (trans) med smp. 199-201°C (fra metanol/dimetylformamid), av 4-(B-<2-B-metoksyetoksy-5-fluorbenzamido>-etyl)-benzolsulfonamid (smp. 154-155°C): 4-( 3-<2-3-metoksyetoksy-5-fluorbenzamido>-etyl)-benzolsulf onyl/- N'-cykloheksyl-urinstoff med smp. 132-134°C (fra metanol), N-/~4-(8-<2-3-metoksyetoksy-5-fluorbenzamido>-ety1)-benzolsulfonyl7-N'-(4-metylcykloheksyl)-urinstoff (trans) med smp. l6l-l63°C N-/~4-($-<2-B-ethoxyethoxy-5-methylbenzamido>-ethyl)-benzenesulfony 17-N'-cyclohexylurea with m.p. 121-123°C (from methanol) and N-/_"~4-(8-<2-3-ethoxyethoxy-5-methylbenzamido>-ethyl)-benzenesulfonyl7-N-(4-methylcyclohexyl)-urea (trans) with m.p. 118-119°C (from methanol), of 4-(8-<2-methoxymethoxy-5-methylbenzamido>-ethyl)-benzenesulfonamide (m.p. 225-228°C): N-_/ 4-( B-<2-methoxymethoxy-5-methylbenzamido>-ethyl)-benzenesulfonyl7-N'-cyclohexylurea with m.p. 224-226°C (from methanol/dimethyl-formamide) and N-/~4-($-<2- methoxymethoxy-5-methylbenzamido>-ethyl)-benzenesulfonyl7-N'-(4-methylcyclohexyl)-urea (trans) with mp 199-201°C (from methanol/dimethylformamide), of 4-(B-<2-B -methoxyethoxy-5-fluorobenzamido>-ethyl)-benzenesulfonamide (m.p. 154-155°C): 4-(3-<2-3-methoxyethoxy-5-fluorobenzamido>-ethyl)-benzenesulfonyl/- N'-cyclohexyl -urea with m.p. 132-134°C (from methanol), N-/~4-(8-<2-3-methoxyethoxy-5-fluorobenzamido>-ethyl)-benzenesulfonyl7-N'-(4-methylcyclohexyl)- urea (trans) with mp 161-163°C
(fra metanol) og (from methanol) and
N-/~4-(3-<2-3-metoksyetoksy-5-fluorbenzamido>-etyl)-benzolsulfonyl7-N'-(4-etylcykloheksyl)-urinstoff (trans) med smp. 156-158°C N-[4-(3-<2-3-methoxyethoxy-5-fluorobenzamido>-ethyl)-benzenesulfonyl7-N'-(4-ethylcyclohexyl)-urea (trans) with m.p. 156-158°C
(fra metanol)« (from methanol)«
Eksempel 3. Example 3.
N-/-4-( 8-<2-8-metoksyetoksy-benzamido>-etyl)-benzolsulf onyl7-N' - cykloheksyl-urinstoff. N-/-4-(8-<2-8-Methoxyethoxy-benzamido>-ethyl)-benzenesulfonyl7-N'-cyclohexyl-urea.
8,7 g N-/<->4-(B-<2-8-metoksyetoksy-benzamido>-etyl)-benzolsulfonyl7-metyluretan (smp. 123-125°C) suspenderes i 90 ml xylol og blandes ved 80°C med 2 g cykloheksylamin. Man oppvarmer til 8.7 g of N-/<->4-(B-<2-8-methoxyethoxy-benzamido>-ethyl)-benzenesulfonyl-7-methylurethane (m.p. 123-125°C) are suspended in 90 ml of xylene and mixed at 80° C with 2 g of cyclohexylamine. One warms up
l40-150°C og avdestillerer den ved omsetningen dannede metanol. Etter ca. 30 minutter lar man det avkjøle, frasuger reaksjons-produktet og vasker det med metanol og eter. Det rå N-_/—4-CS-<2-3-metoksyetoksy-benzamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl-urinstof f smelter etter omkrystallisering fra metanol ved l60-l62°C. l40-150°C and distills off the methanol formed during the reaction. After approx. It is allowed to cool for 30 minutes, the reaction product is sucked off and washed with methanol and ether. The crude N-_/—4-CS-<2-3-methoxyethoxy-benzamido>-ethyl)-benzenesulfonyl-7-N'-cyclohexyl-urea melts after recrystallization from methanol at 160-162°C.
På analog måte får man: N-/—4-(g-<2-B-metoksyetoksy-benzamido>-etyl)-benzolsulfonyl7-N'-(4-metylcykloheksyl)-urinstoff (trans) med smp. 153-155°C ( fra metanol), In an analogous manner, one obtains: N-/-4-(g-<2-B-methoxyethoxy-benzamido>-ethyl)-benzenesulfonyl7-N'-(4-methylcyclohexyl)-urea (trans) with m.p. 153-155°C (from methanol),
Eksempel 4. Example 4.
N-/~4-(B-<2-metoksyetoksybenzamido>-etyl)-benzolsulfonyl/-N'-cykloheksyl- urinstof f. ; 13 g N-/—4-(g-<2-metoksyetoksy-benzamido>-etyl)-benzolsulfonyl7-urinstoff (fremstilt av det tilsvarende sulfonamid med kaliumcyanat, smp. 84°C) blandes i rekkefølge med 350 ml toluol, 2,15 g iseddik og 3,7 g cykloheksylamin og omrøres deretter, i 3 timer ved 120°C. Etter inndampning i vakuum behandles residuet med l#-ig ammoniakk, utfelles og krystalliseres fra metanol, smp. l60-l62°C. Eksempel 5. N-/-4-(B-<2-g-metoksyetoksy-5-klor-benzamido>-etyl)-benzolsulfonyl7- . N'- cykloheksyl- urinstoff. a) 1,4 g cykloheksylurinstoff oppløses i 15 ml pyiridin; ved innføring av 4-(3-<2-g-metoksyetoksy-5-klor-benzamido>-etyl)-benzolsulfinylklorid (fremstilt av 4 g 4-(6-<2-g-metoksyetoksy-5-klor-benzamido>-etyl)-benzolsulfinsyre og tionylklorid) opptrer lett oppvarmning. Den klare oppløsning has etter 10 minutter i en blanding av isvann og fortynnet saltsyre, den dannede utfelling fra-suges og utrøres med 1%- ig ammoniakk. Etter omkrystallisering av residuet fra metanol får man N-/~4-(g-<2-g-metoksy-etoksy-5-klor-benzamido>-etyl)-benzolsulfinyl7-N'-cykloheksyl-urinstoff med smp. 130°C. b) 1 g av ovennevnte urinstoff oppløses i 20 ml dimetyl-formamid og tilsettes varmt en vandig kaliumpermanganatoppløsning N-[4-(B-<2-methoxyethoxybenzamido>-ethyl)-benzenesulfonyl/-N'-cyclohexyl- urea f. ; 13 g of N-/—4-(g-<2-methoxyethoxy-benzamido>-ethyl)-benzenesulfonyl7-urea (prepared from the corresponding sulfonamide with potassium cyanate, m.p. 84°C) are mixed in sequence with 350 ml of toluene, 2, 15 g of glacial acetic acid and 3.7 g of cyclohexylamine and then stirred for 3 hours at 120°C. After evaporation in a vacuum, the residue is treated with l# ammonia, precipitated and crystallized from methanol, m.p. 160-162°C. Example 5. N-[-4-(B-<2-g-methoxyethoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl7-. N'-cyclohexyl urea. a) 1.4 g of cyclohexylurea is dissolved in 15 ml of pyridine; by introducing 4-(3-<2-g-methoxyethoxy-5-chloro-benzamido>-ethyl)-benzenesulfinyl chloride (prepared from 4 g of 4-(6-<2-g-methoxyethoxy-5-chloro-benzamido>- ethyl)-benzenesulfinic acid and thionyl chloride) slightly heating occurs. The clear solution is obtained after 10 minutes in a mixture of ice water and dilute hydrochloric acid, the formed precipitate is suctioned off and stirred with 1% ammonia. After recrystallization of the residue from methanol, one obtains N-[4-(g-<2-g-methoxy-ethoxy-5-chloro-benzamido>-ethyl)-benzenesulfinyl7-N'-cyclohexyl-urea with m.p. 130°C. b) 1 g of the above-mentioned urea is dissolved in 20 ml of dimethylformamide and hotly added to an aqueous potassium permanganate solution
i overskudd. Etter brunstenens frafiltrering blandes med vann og fortynnet saltsyre og den dannede utfelling omkrystalliseres fra metanol. Man får N-/—4-(g-<2-metoksyetoksy-5-klorbenzamido>Tetyl)-benzolsulfonyl7-N'-cykloheksylurinstoff med smp. 152-153°C. in surplus. After the brownstone has been filtered off, it is mixed with water and dilute hydrochloric acid and the formed precipitate is recrystallized from methanol. One obtains N-/-4-(g-<2-methoxyethoxy-5-chlorobenzamido>Tetyl)-benzenesulfonyl7-N'-cyclohexylurea with m.p. 152-153°C.
Eksempel 6. N-/~4-(g-<2-B-metoksyetoksy-5-klorbenzamido>-etyl)-benzolsulfonyl7-N'- cykloheksyl- urinstoff. Example 6. N-[4-(g-<2-B-methoxyethoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl7-N'-cyclohexylurea.
16,3 g N-/~4-(8-aminoetyl)-benzolsulfonyl7-N'-cyklo-heksylurinstof f oppvarmes i kloroform med 9 g pyridin og 12,5 g 2-B-metoksyetoksy-5-klorbenzoylklorid i 6 timer under omrøring ved 40°C. Etter inndampning i vakuum uttrekkes residuet med 0, 5%- ig ammoniakk. Den ammoniakkalske oppløsning surgjøres og utfellingen omkrystalliseres fra metanol. Man får N-/<->4-($-<2-6-metoksyetoksy-5-klorbenzamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl-urinstoff av smp. 152-153°C. 16.3 g of N-/~4-(8-aminoethyl)-benzenesulfonyl7-N'-cyclohexylurea are heated in chloroform with 9 g of pyridine and 12.5 g of 2-B-methoxyethoxy-5-chlorobenzoyl chloride for 6 hours under stirring at 40°C. After evaporation in a vacuum, the residue is extracted with 0.5% ammonia. The ammoniacal solution is acidified and the precipitate is recrystallized from methanol. One obtains N-[<->4-($-<2-6-methoxyethoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl7-N'-cyclohexyl-urea of m.p. 152-153°C.
Eksempel 7-N-/-4-($-<2-g-metoksyetoksy-5-klorbenzamido>-etyl)-benzolsulfonyl7-N'- cykloheksyl- urinstoff. Example 7-N-/-4-($-<2-g-Methoxyethoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl 7-N'-cyclohexylurea.
7,1 g cykloheksylurinstoff oppvarmes i 150 ml benzol med 1,2 g natriumhydrid i 2 timer ved 50°C. Ved værelsetemperatur tildryppes en oppløsning av 10,4 g 4-($-<2-&-metoksyetoksy-5-klor-benzamido>-etyl)-benzolsulfoklorid i benzol og etteromrøres deretter i 3 timer ved 80°C. Etter tilsetning av noen dråper metanol ekstra-heres urinstoffet med 1%- ig natronlut og den alkaliske oppløsning surgjøres. Utfellingen renses ved oppløsning i ammoniakk og surgjøring og omkrystalliseres fra metanol. Man får N-/ 4-(g-<2-8-metoksyetoksy-5-klorbenzamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl-urinstof f av smp. 152-153°C 7.1 g of cyclohexylurea is heated in 150 ml of benzene with 1.2 g of sodium hydride for 2 hours at 50°C. At room temperature, a solution of 10.4 g of 4-($-<2-&-methoxyethoxy-5-chloro-benzamido>-ethyl)-benzenesulfochloride in benzene is added dropwise and then stirred for 3 hours at 80°C. After adding a few drops of methanol, the urea is extracted with 1% caustic soda and the alkaline solution is acidified. The precipitate is purified by dissolution in ammonia and acidification and recrystallized from methanol. One obtains N-/ 4-(g-<2-8-methoxyethoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl7-N'-cyclohexyl-urea f of m.p. 152-153°C
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843417743 DE3417743C1 (en) | 1984-05-12 | 1984-05-12 | Apparatus for alternative straight or directional drilling in underground rock formations |
| DE19843423465 DE3423465C1 (en) | 1984-06-26 | 1984-06-26 | Devices for alternative straight or directional drilling in underground rock formations |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO851885L NO851885L (en) | 1985-11-13 |
| NO162926B true NO162926B (en) | 1989-11-27 |
| NO162926C NO162926C (en) | 1990-03-07 |
Family
ID=25821161
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO851885A NO162926C (en) | 1984-05-12 | 1985-05-10 | APPLIANCES FOR SELF-RIGHT OR DIRECTIVE DRILLING IN UNDERGRADUAL FORMS. |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0163946B1 (en) |
| CA (1) | CA1235686A (en) |
| NO (1) | NO162926C (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5094304A (en) * | 1990-09-24 | 1992-03-10 | Drilex Systems, Inc. | Double bend positive positioning directional drilling system |
| CA2234495C (en) * | 1998-04-09 | 2004-02-17 | Dresser Industries, Inc. | Adjustable gauge downhole drilling assembly |
| US6328119B1 (en) | 1998-04-09 | 2001-12-11 | Halliburton Energy Services, Inc. | Adjustable gauge downhole drilling assembly |
| US9523244B2 (en) | 2012-11-21 | 2016-12-20 | Scientific Drilling International, Inc. | Drill bit for a drilling apparatus |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB636879A (en) * | 1946-07-12 | 1950-05-10 | Rolen Arcenjevitch Joannesjan | Improvements in or relating to the drilling of deep wells |
| US3260318A (en) * | 1963-11-12 | 1966-07-12 | Smith Ind International Inc | Well drilling apparatus |
| US3380543A (en) * | 1966-01-19 | 1968-04-30 | Pan American Petroleum Corp | Directional well-drilling apparatus |
| FR1593999A (en) * | 1968-12-04 | 1970-06-01 | ||
| JPS5248921B2 (en) * | 1973-03-08 | 1977-12-13 | ||
| US3938853A (en) * | 1974-05-01 | 1976-02-17 | Christensen Diamond Products Company | Shrink-fit sleeve apparatus for drill strings |
| US3993127A (en) * | 1974-08-08 | 1976-11-23 | Viktor Gavrilovich Chepelev | Apparatus for positioning a working implement in a borehole |
| US4059164A (en) * | 1976-05-19 | 1977-11-22 | Farris Ralph J | Self-stabilizing drilling tool |
| US4108256A (en) * | 1977-05-12 | 1978-08-22 | Continental Oil Company | Sliding stabilizer assembly |
| US4185704A (en) * | 1978-05-03 | 1980-01-29 | Maurer Engineering Inc. | Directional drilling apparatus |
| BE886147A (en) * | 1980-11-13 | 1981-03-02 | American Coldset Corp | DRILLING STABILIZER. |
-
1985
- 1985-05-02 EP EP85105353A patent/EP0163946B1/en not_active Expired
- 1985-05-03 CA CA000480696A patent/CA1235686A/en not_active Expired
- 1985-05-10 NO NO851885A patent/NO162926C/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO162926C (en) | 1990-03-07 |
| EP0163946A1 (en) | 1985-12-11 |
| EP0163946B1 (en) | 1989-04-05 |
| CA1235686A (en) | 1988-04-26 |
| NO851885L (en) | 1985-11-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US3507961A (en) | Benzenesulfonyl ureas as anti-diabetic agents | |
| NO159136B (en) | Panty liners. | |
| NO159166B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE BENZOAZEPINE DERIVATIVES. | |
| NO162257B (en) | PROGRESS TEA FOR LIQUIDIZATION OF NATURAL GAS AND THEREOF. | |
| NO159754B (en) | PROCEDURE FOR DETERMINING CARINO EMBRYONAL ANTIGEN (CEA). | |
| IE50635B1 (en) | Sulfonyl ureas,process for their manufacture,pharmaceutical formulations containing them and their use | |
| NO155188B (en) | MOVING FOOT STEPS FOR A VEHICLE. | |
| NO171025B (en) | Roofing sheet | |
| NO167442B (en) | A spiral. | |
| NO162926B (en) | APPLIANCES FOR SELF-RIGHT OR DIRECTIVE DRILLING IN UNDERGRADUAL FORMS. | |
| NO159998B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF A NEW THERAPEUTIC ACTIVE SULPHONAMIDE DERIVATIVE. | |
| NO123644B (en) | ||
| NO171182B (en) | VERY APPLICABLE MIXTURE SUITABLE FOR SELECTIVE PERMEABILITY MODIFICATION OF UNDERGROUND LAYER BY HYDROCARBON EXTRACTION | |
| US3494936A (en) | Benzenesulfonyl-ureas with hypoglycemic activity | |
| US3449346A (en) | Benzenesulfonyl ureas | |
| NO165846B (en) | VINYL CHLORIDE MATERIAL, AND PROCEDURE FOR THE PREPARATION OF SUCH A. | |
| NO122920B (en) | ||
| NO122923B (en) | ||
| US3705151A (en) | Benzene-sulfonyl semicarbazides and process for preparing them | |
| NO168334B (en) | JOINT CONNECTION WITH CONTROLLED MOVEMENT FOR SUPPORT OF CHAIRMAN AND CABLE | |
| NO122416B (en) | ||
| NO117362B (en) | ||
| US3754030A (en) | N - (4-(beta-<2-methoxy-5-chloro-benzamido>-ethyl) - benzenesulfonyl)-n'-cyclopentyl-urea and process for its manufacture | |
| IE45782B1 (en) | 1-(n-acylcarbamoyl)-2-cyanoziridines | |
| NO124726B (en) |