NO158637B - DRIVE UNIT. - Google Patents
DRIVE UNIT. Download PDFInfo
- Publication number
- NO158637B NO158637B NO85854343A NO854343A NO158637B NO 158637 B NO158637 B NO 158637B NO 85854343 A NO85854343 A NO 85854343A NO 854343 A NO854343 A NO 854343A NO 158637 B NO158637 B NO 158637B
- Authority
- NO
- Norway
- Prior art keywords
- substituted
- nortricyclyl
- benzenesulfonyl
- carbamic acid
- salts
- Prior art date
Links
- 238000000034 method Methods 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 14
- -1 benzenesulfonic acid halides Chemical class 0.000 claims description 12
- 239000008280 blood Substances 0.000 claims description 11
- 210000004369 blood Anatomy 0.000 claims description 11
- 239000012948 isocyanate Substances 0.000 claims description 11
- 150000002513 isocyanates Chemical class 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- UJYAZVSPFMJCLW-UHFFFAOYSA-N n-(oxomethylidene)benzenesulfonamide Chemical class O=C=NS(=O)(=O)C1=CC=CC=C1 UJYAZVSPFMJCLW-UHFFFAOYSA-N 0.000 claims description 6
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 5
- 229940112021 centrally acting muscle relaxants carbamic acid ester Drugs 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000003170 phenylsulfonyl group Chemical class C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 2
- 150000001447 alkali salts Chemical class 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 150000001338 aliphatic hydrocarbons Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 235000013877 carbamide Nutrition 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 150000008331 benzenesulfonamides Chemical class 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 150000003672 ureas Chemical class 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-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
- 229920001615 Tragacanth Polymers 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- ALZKZGUTVJXYEF-UHFFFAOYSA-N benzenesulfonylcarbamic acid Chemical class OC(=O)NS(=O)(=O)C1=CC=CC=C1 ALZKZGUTVJXYEF-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- UGTNGGMJOOXGLY-UHFFFAOYSA-N (3-amino-4-methylphenyl)sulfonylurea Chemical compound NC=1C=C(C=CC1C)S(=O)(=O)NC(=O)N UGTNGGMJOOXGLY-UHFFFAOYSA-N 0.000 description 1
- RUTYWCZSEBLPAK-UHFFFAOYSA-N (4-methylphenyl)sulfonylurea Chemical compound CC1=CC=C(S(=O)(=O)NC(N)=O)C=C1 RUTYWCZSEBLPAK-UHFFFAOYSA-N 0.000 description 1
- YBLWHGQKHHKWRU-UHFFFAOYSA-N 1,3-bis-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 YBLWHGQKHHKWRU-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- LALCDSDHLXWTTL-UHFFFAOYSA-N 2-chloro-n-(oxomethylidene)benzenesulfonamide Chemical compound ClC1=CC=CC=C1S(=O)(=O)N=C=O LALCDSDHLXWTTL-UHFFFAOYSA-N 0.000 description 1
- MNURPFVONZPVLA-UHFFFAOYSA-N 2-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1Cl MNURPFVONZPVLA-UHFFFAOYSA-N 0.000 description 1
- HEBTZZBBPUFAFE-UHFFFAOYSA-N 2-methyl-n-(oxomethylidene)benzenesulfonamide Chemical compound CC1=CC=CC=C1S(=O)(=O)N=C=O HEBTZZBBPUFAFE-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- PQWRIGCASGGXIN-UHFFFAOYSA-N 3-(4-methylphenyl)sulfonyl-1,1-diphenylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)N(C=1C=CC=CC=1)C1=CC=CC=C1 PQWRIGCASGGXIN-UHFFFAOYSA-N 0.000 description 1
- HCZDHXMDYWZPPN-UHFFFAOYSA-N 3-amino-4-methylbenzenesulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1N HCZDHXMDYWZPPN-UHFFFAOYSA-N 0.000 description 1
- BUFPYFZTTSMGCN-UHFFFAOYSA-N 3-chloro-n-(oxomethylidene)benzenesulfonamide Chemical compound ClC1=CC=CC(S(=O)(=O)N=C=O)=C1 BUFPYFZTTSMGCN-UHFFFAOYSA-N 0.000 description 1
- JDQDSEVNMTYMOC-UHFFFAOYSA-N 3-methylbenzenesulfonic acid Chemical compound CC1=CC=CC(S(O)(=O)=O)=C1 JDQDSEVNMTYMOC-UHFFFAOYSA-N 0.000 description 1
- CSATVXJBGFVJES-UHFFFAOYSA-N 4-acetylbenzenesulfonamide Chemical compound CC(=O)C1=CC=C(S(N)(=O)=O)C=C1 CSATVXJBGFVJES-UHFFFAOYSA-N 0.000 description 1
- PCWITQSPDHVTKN-UHFFFAOYSA-N 4-acetyloxybenzenesulfonic acid Chemical group CC(=O)OC1=CC=C(S(O)(=O)=O)C=C1 PCWITQSPDHVTKN-UHFFFAOYSA-N 0.000 description 1
- JGHDVROWMPBQSR-UHFFFAOYSA-N 4-chloro-n-(oxomethylidene)benzenesulfonamide Chemical compound ClC1=CC=C(S(=O)(=O)N=C=O)C=C1 JGHDVROWMPBQSR-UHFFFAOYSA-N 0.000 description 1
- HHHDJHHNEURCNV-UHFFFAOYSA-N 4-chlorobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(Cl)C=C1 HHHDJHHNEURCNV-UHFFFAOYSA-N 0.000 description 1
- ZPBSZCDTNNYFHY-UHFFFAOYSA-N 4-ethyl-n-(oxomethylidene)benzenesulfonamide Chemical compound CCC1=CC=C(S(=O)(=O)N=C=O)C=C1 ZPBSZCDTNNYFHY-UHFFFAOYSA-N 0.000 description 1
- RGVBEISMHCYSNF-UHFFFAOYSA-N 4-methoxy-n-(oxomethylidene)benzenesulfonamide Chemical compound COC1=CC=C(S(=O)(=O)N=C=O)C=C1 RGVBEISMHCYSNF-UHFFFAOYSA-N 0.000 description 1
- MSFQEZBRFPAFEX-UHFFFAOYSA-N 4-methoxybenzenesulfonamide Chemical compound COC1=CC=C(S(N)(=O)=O)C=C1 MSFQEZBRFPAFEX-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- GDIVONWUHRIALS-UHFFFAOYSA-N C(C)(=O)C1=CC=C(C=C1)S(=O)(=O)N=C=O Chemical compound C(C)(=O)C1=CC=C(C=C1)S(=O)(=O)N=C=O GDIVONWUHRIALS-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class 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
- 229920002472 Starch Polymers 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 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
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- GHDLZGOOOLEJKI-UHFFFAOYSA-N benzenesulfonylurea Chemical compound NC(=O)NS(=O)(=O)C1=CC=CC=C1 GHDLZGOOOLEJKI-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
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 150000001714 carbamic acid halides Chemical class 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- KWHXRPOBVUXTNC-UHFFFAOYSA-N ethyl N-(4-methoxyphenyl)sulfonyl-N-methylcarbamate Chemical compound COC1=CC=C(C=C1)S(=O)(=O)N(C(=O)OCC)C KWHXRPOBVUXTNC-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- CXLBYPJSAWOYSI-UHFFFAOYSA-N ethyl n-methyl-n-(4-methylphenyl)sulfonylcarbamate Chemical compound CCOC(=O)N(C)S(=O)(=O)C1=CC=C(C)C=C1 CXLBYPJSAWOYSI-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000003948 formamides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- XWQXWXZSAIORQC-UHFFFAOYSA-N methyl N-(3,4-dimethylphenyl)sulfonylcarbamate Chemical compound COC(NS(=O)(=O)C1=CC(=C(C=C1)C)C)=O XWQXWXZSAIORQC-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- FCMYFMSWNFVHAC-UHFFFAOYSA-N methyl n-(4-chlorophenyl)sulfonylcarbamate Chemical compound COC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 FCMYFMSWNFVHAC-UHFFFAOYSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- GPUWWYFDBGWKFK-UHFFFAOYSA-N n-(4-chlorophenyl)sulfonylcarbamoyl chloride Chemical compound ClC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 GPUWWYFDBGWKFK-UHFFFAOYSA-N 0.000 description 1
- PKOFBDHYTMYVGJ-UHFFFAOYSA-N n-(4-sulfamoylphenyl)acetamide Chemical compound CC(=O)NC1=CC=C(S(N)(=O)=O)C=C1 PKOFBDHYTMYVGJ-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical group 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])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
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- PFUVRDFDKPNGAV-UHFFFAOYSA-N sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000725 suspension Substances 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
- 150000003585 thioureas Chemical class 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 210000003462 vein Anatomy 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
- E21B19/00—Handling rods, casings, tubes or the like outside the borehole, e.g. in the derrick; Apparatus for feeding the rods or cables
- E21B19/16—Connecting or disconnecting pipe couplings or joints
-
- 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
- E21B19/00—Handling rods, casings, tubes or the like outside the borehole, e.g. in the derrick; Apparatus for feeding the rods or cables
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Description
Fremgangsmåte til fremstilling av oralt anvendbare benzolsulfonylurinstoffer. Process for the preparation of orally usable benzenesulfonylureas.
Oppfinnelsen vedrører en fremgangsmåte for fremstilling av oralt anvendbare The invention relates to a method for the production of orally applicable
benzolsulfonylurinstoffer med forsterket benzenesulfonylureas with enhanced
blodsukkersenkende virkning og med formel blood sugar-lowering effect and with formula
som som stoff eller i form av deres salter har blodsukkersenkende egenskaper, og som i deres virkning overtreffer det kjente N-( 4-metyl-benzol-sufonyl )-N'-n-bu-tylurinstoff med det mangedobbelte. I formelen betyr R og R' hydrogen, halogen, alkoksy, acyl med 1—4 C-atomer, eller en mettet eller umettet eventuelt med halogen, en amino- eller hydroksylgruppe substituert, alifatisk hydrokarbonrest, med 1—4 C-atomer. I det ovennevnte og i de følgende de-finisjoner betyr «alkyl» eller «alkoksy» alltid en slik med 1—4 karbonatomer i rettlinjet eller forgrenet kjede. «Acyl» betyr en acylrest (organisk syrerest) med inntil 4 karbonatomer spesielt en rettlinjet eller forgrenet alkanoylrest av tilsvarende kjedelengde. R og R' kan eksempelvis bety metyl, etyl, propyl, isopropyl, butyl, isobutyl, sec. butyl med de til nevnte hydrokar-bonrester tilsvarende rester med en etyl-enisk dobbeltbinding som allyl eller cro-tyl, videre slike alkyler med 2—4 karbonatomer som som substituenter har halogen som fluor, brom eller jod eller fortrinnsvis klor, f. eks. klormetyl, brom-metyl, /3-klormetyl, y-klorpropyl. Endelig skal det som eksempler for R og R' nevnes halogener som fluor, brom, jod eller fortrinnsvis klor, lavere alkoksyrester som metoksy, etoksy, propoksy, isopro-poksy, butoksy og acylrester som acetyl, propionyl. Oppfinnelsens gjenstand' er altså en fremgangsmåte for fremstilling av disse benzolsulfonylurinstoffer respektive av deres salter, og fremgangsmåten er karakterisert ved at man enten a) omsetter R,R'-substituerte benzolsulfonylisocyanater, -karbaminsyreestere, -tiokarbaminsyreestere, -karbaminsyrehalogenider eller -urinstoffer med amino-nortricyklen eller dets salter, eller b) omsetter benzolsulfonamidet med formel which as a substance or in the form of their salts have blood sugar-lowering properties, and which in their effect surpass the known N-(4-methyl-benzol-sufonyl)-N'-n-butylurea by many times. In the formula, R and R' mean hydrogen, halogen, alkoxy, acyl with 1-4 C atoms, or a saturated or unsaturated optionally with halogen, an amino or hydroxyl group substituted, aliphatic hydrocarbon residue, with 1-4 C atoms. In the above and in the following definitions, "alkyl" or "alkoxy" always means one with 1-4 carbon atoms in a straight or branched chain. "Acyl" means an acyl residue (organic acid residue) with up to 4 carbon atoms, in particular a straight or branched alkanoyl residue of corresponding chain length. R and R' can for example mean methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl with the residues corresponding to the aforementioned hydrocarbon residues with an ethylenic double bond such as allyl or crotyl, further such alkyls with 2-4 carbon atoms which have halogen as substituents such as fluorine, bromine or iodine or preferably chlorine, e.g. chloromethyl, bromo-methyl, /3-chloromethyl, y-chloropropyl. Finally, as examples for R and R', halogens such as fluorine, bromine, iodine or preferably chlorine, lower carboxylic acid residues such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and acyl residues such as acetyl, propionyl are to be mentioned. The object of the invention is therefore a process for the production of these benzenesulfonylureas and their salts, and the process is characterized by either a) reacting R,R'-substituted benzenesulfonyl isocyanates, -carbamic acid esters, -thiocarbamic acid esters, -carbamic acid halides or -ureas with amino- nortricyclene or its salts, or b) reacts the benzenesulfonamide of formula
eller eventuelt deres salter med nortricyklyl-isocyanat, -karbaminsyreestere, -tiokarbaminsyreestere, -karbaminsyrehalogenider eller -urinstoffer, eller or optionally their salts with nortricyclyl isocyanate, -carbamic acid esters, -thiocarbamic acid esters, -carbamic acid halides or -ureas, or
c) omsetter alkalisalter av R,R'-substituerte benzolsulfonsyrehalogenamider c) reacts alkali salts of R,R'-substituted benzenesulfonic acid haloamides
med nortricyklylformamid, eller with nortricyclylformamide, or
d) omsetter R,R'-substituerte benzol-sulfonylhalogenider med nortricyklyl-urinstoff, eller e) hydrolyserer N-( R,R'-substituerte benzolsulfonyl)-N'-nortricyklyl-isourin-stoffetere, -isotiourinstoffetere, -guanidi-ner eller -parabansyrer, eller f) utveksler i N-(R,R'-substituerte benzolsulf onyl )-N'-nortricyklyl-tiourinstoffer svovelatomet med et oksygenatom, eller g) oksyderer N-( R,R'-substituerte benzolsulfinyl-respektive benzolsulfenyl )-N'-nortricyklylurinstoffer, og behandler fremgangsmåteproduktene eventuelt med basiske midler for saltdannelse. d) reacts R,R'-substituted benzenesulfonyl halides with nortricyclylurea, or e) hydrolyzes N-(R,R'-substituted benzenesulfonyl)-N'-nortricyclylisourea ethers, -isothiourea ethers, -guanidines or -parabanic acids, or f) exchanges in N-(R,R'-substituted benzenesulfonyl)-N'-nortricyclyl-thioureas the sulfur atom with an oxygen atom, or g) oxidizes N-(R,R'-substituted benzenesulfinyl or benzenesulfenyl) -N'-nortricyclyl ureas, and optionally treat the process products with basic agents for salt formation.
Alt etter naturen av leddene R og R' vil i enkelte tilfeller den ene eller andre av de nevnte fremgangsmåter være min-dre egnet for fremstillingen av de under den generelle formel fallende individuelle forbindelser eller i det minste nødvendig-gjøre forholdsregler for beskyttelse av aktive grupper. Slike forholdsvis sjeldent opptredende tilfeller kan lett erkjennes av fagfolk, og det byr ikke på noen van-skeligheter i slike tilfeller med resultat å benytte en av de andre beskrevne syn-tesemåter. Depending on the nature of the links R and R', in some cases one or the other of the aforementioned methods will be less suitable for the preparation of the individual compounds falling under the general formula or at least necessitate precautions for the protection of active groups . Such relatively rarely occurring cases can be easily recognized by professionals, and it does not pose any difficulties in such cases to use one of the other described synthesis methods.
Istedenfor benzolsulfonylisocyanater kan man også anvende slike forbindelser som kan oppfattes som avarter av slike benzolsulfonylisocyanater. Instead of benzenesulfonyl isocyanates, one can also use such compounds that can be perceived as variants of such benzenesulfonyl isocyanates.
Avarter av slike isocyanater er også de såkalte «maskerte» isocyanater. Som «maskerte» isocyanater anses som be-kjent omsetningsproduktene av isocyanater med termisk forholdsvis lett igjen avspaltbare komponenter, eksempelvis med fenoler, bisulfit, malonestere, >ca-prolaktam, a-pyrrolidon eller forbindelser med aktiv metylengruppe. Som eksempler for benzolsulfonylisocyanater skal nevnes: benzolsulfonylisocyanat, 4-, 3- og 2-metyl-benzolsulfonylisocyanat, 4-etyl-benzolsulfonylisocyanat, 4-metoksyben-zolsulfonylisocyanat, 2-, 3- og 4-klorben-zolsulfonylisocyanat, 4-acetylbenzolsulfo-nylisocyanat. Variants of such isocyanates are also the so-called "masked" isocyanates. As known, the reaction products of isocyanates with thermally relatively easily separable components, for example with phenols, bisulphite, malonesters, >ca-prolactam, α-pyrrolidone or compounds with an active methylene group, are considered "masked" isocyanates. Examples of benzenesulfonyl isocyanates are: benzenesulfonyl isocyanate, 4-, 3- and 2-methyl-benzenesulfonyl isocyanate, 4-ethyl-benzenesulfonyl isocyanate, 4-methoxybenzenesulfonyl isocyanate, 2-, 3- and 4-chlorobenzenesulfonyl isocyanate, 4-acetylbenzenesulfonyl isocyanate .
På samme måte kan det istedenfor nortricyklylisocyanat generelt anvendes slike forbindelser som under reaksjons-forløpet reagerer som nortricyklyl-isocyanat, spesielt imidlertid også såkalte «maskerte» isocyanater. En modifisert form for omsetningen av isocyanater med benzolsulfonamider er også den under punkt c spesielt nevnte reaksjon av sulfonsyre-halogen-amider med formamider, hvor det ved omsetning av reaksjonspartnerne intermediært dannes benzolsulfonamid og nortricyklyl-isocyanat. Som benzolsul-fonsyre-halogenamider egner det seg ved denne omsetning spesielt bromidene og kloridene. In the same way, instead of nortricyclyl isocyanate, such compounds can generally be used which react as nortricyclyl isocyanate during the course of the reaction, especially however also so-called "masked" isocyanates. A modified form of the reaction of isocyanates with benzenesulfonamides is also the reaction of sulfonic acid halogen amides with formamides specifically mentioned under point c, where benzenesulfonamide and nortricyclyl isocyanate are intermediately formed by reaction of the reaction partners. The bromides and chlorides are particularly suitable for this reaction as benzolsulphonic acid halogenamides.
De nevnte benzolsulfonyl-karbaminsyreestere respektiv -tiokarbaminsyreestere kan i alkoholkomponenten ha en lavmolekylær alkylrest eller en fenylrest. Det samme gjelder for nortricyklyl-karbaminsyreestere respektiv de tilsvarende mono-tiokarbaminsyreestere. Med en lavmolekylær respektiv lavere alkylrest innen oppfinnelsens ramme skal det forstås en slik med inntil 4 karbonatomer. Eksempler for egnede benzolsulfonyl-karbaminsyreestere respektiv nortricyklylkarba-minsyreestere er 4-metylbenzolsulfonyl-metyluretan, 4-metoksy-benzolsulfonyl-metyluretan, 4-n-propoksy-benzolsulfonyl-metyluretan, N-nortricyklyl-karbaminsy-remetylester, N-nortricyklyl-karbaminsy-re-isobutylester og N-nortricyklyl-karb-aminsyre-fenylester. The mentioned benzenesulfonyl-carbamic acid esters or -thiocarbamic acid esters can have a low molecular weight alkyl residue or a phenyl residue in the alcohol component. The same applies to nortricyclyl-carbamic acid esters or the corresponding mono-thiocarbamic acid esters. A low molecular or lower alkyl residue within the scope of the invention shall be understood to mean one with up to 4 carbon atoms. Examples of suitable benzenesulfonyl-carbamic acid esters or nortricyclylcarbamic acid esters are 4-methylbenzenesulfonyl-methylurethane, 4-methoxy-benzenesulfonyl-methylurethane, 4-n-propoxy-benzenesulfonyl-methylurethane, N-nortricyclyl-carbamic acid methyl ester, N-nortricyclyl-carbamic acid -isobutyl ester and N-nortricyclyl-carbamic acid phenyl ester.
Som karbaminsyrehalogenider egner det seg i første rekke kloridene. Det skal eksempelvis nevnes 4-metyl- eller 4-klor-benzolsulfonyl-karbaminsyreklorid. As carbamic acid halides, the chlorides are primarily suitable. For example, 4-methyl- or 4-chloro-benzenesulfonyl-carbamic acid chloride should be mentioned.
De som utgangsstoffer for fremgangsmåten aktuelle benzolsulfonylurinstoffer The benzenesulfonylureas in question as starting materials for the method
kan på den ene side av urinstoffmolekylet som er vendt bort fra sulfonylgruppen, can on one side of the urea molecule facing away from the sulfonyl group,
være usubstituert eller være en eller to ganger substituert med fortrinnsvis lavere alkylrester eller arylrester. Istedenfor på slik måte substituerte benzolsulfonylurinstoffer kan det også anvendes tilsvarende N-benzolsulfonyl-N'-acyl-urinstoffer og også bis-( benzolsulf onyl )-urinstoff er. be unsubstituted or be once or twice substituted with preferably lower alkyl residues or aryl residues. Instead of benzenesulfonylureas substituted in this way, corresponding N-benzenesulfonyl-N'-acyl ureas and also bis-(benzenesulfonyl)ureas can also be used.
Man kan eksempelvis behandle slike bis-(benzolsulf onyl )-urinstof f er eller N-ben-bolsulfonyl-N'-acylurinstoffer med amino-nortricyklen og oppvarme de dannede salter til forhøyede temperaturer, spesielt slike over 100°C. Som eksempler for egnede urinstoffer kan nevnes: 4-metyl-ben-zolsulfonylurinstoff, 3-amino-4-metylben-zolsulfonylurinstoff, N-( 4-metyl-benzolsulfonyl)-N'-acetyl- respektiv -N'-propionyl-urinstoff, N-( 4-metyl-benzolsulfonyl )-N', N'-difenylurinstoff eller N, N'-di-(p-toluolsulfonyl )-urinstoff. One can, for example, treat such bis-(benzenesulfonyl)-ureas or N-benz-bolsulfonyl-N'-acylureas with amino-nortricycle and heat the formed salts to elevated temperatures, especially those above 100°C. Examples of suitable ureas can be mentioned: 4-methyl-benzenesulfonylurea, 3-amino-4-methylbenzenesulfonylurea, N-(4-methyl-benzenesulfonyl)-N'-acetyl- respectively -N'-propionyl-urea, N-(4-methyl-benzenesulfonyl)-N',N'-diphenylurea or N,N'-di-(p-toluenesulfonyl)-urea.
Videre er det mulig å gå ut fra N-nortricyklylurinstoffer eller N-nortricyklyl-N'-acyl-urinstoffer, hvor acyl betyr en fortrinnsvis lavmolekylær alifatisk eller en aromatisk syrerest eller nitrogruppen, respektiv fra N-nortricyklyl-N'-fenylurin-stoffer eller fra nortricyklyl-N', N'-dife-nylurinstoffer, hvori fenylresten kan være Furthermore, it is possible to start from N-nortricyclyl ureas or N-nortricyclyl-N'-acyl ureas, where acyl means a preferably low molecular weight aliphatic or an aromatic acid residue or the nitro group, respectively from N-nortricyclyl-N'-phenylureas or from nortricyclyl-N', N'-difenylurines, in which the phenyl residue may be
substituert såvel som kan også være di-rekte eller også over et broledd som substituted as well as can also be direct or also over a bridge link which
-CHr, -NH-, -O- eller -S- forbundet med hverandre eller fra N,N'-di-tricyklylurin- -CHr, -NH-, -O- or -S- connected with each other or from N,N'-di-tricyclylurin-
stoff og å omsette disse med R,R'-substituerte benzolsulfonamider. Som eksempler for slike benzolsulfonamider kan nevnes : benzolsulfonsyreamid, 2-, 3- og 4-metyl-benzolsulfonsyreamid, 2- og 4-klorben-zolsulfonsyreamid, 4-acetyl- og 4-metoksy-benzolsulf onsyreamid, 3-amino-4-metyl-benzolsulf onsyreamid, 4-( «-hydroksyetyl )-benzolsulfonsyreamid. Som eksempler for egnede nortricyklylurinstoffer kan nevnes : N-nortricyklyl-N'-acetyl- respektiv -N'-propionylurinstoff, N-nortricyklyl-N', N'-difenylurinstoff. substance and reacting these with R,R'-substituted benzenesulfonamides. Examples of such benzenesulfonamides include: benzenesulfonic acid amide, 2-, 3- and 4-methyl-benzenesulfonic acid amide, 2- and 4-chlorobenzenesulfonic acid amide, 4-acetyl- and 4-methoxy-benzenesulfonic acid amide, 3-amino-4-methyl -benzenesulfonic acid amide, 4-(«-hydroxyethyl )-benzenesulfonic acid amide. Examples of suitable nortricyclylureas can be mentioned: N-nortricyclyl-N'-acetyl- respectively -N'-propionylurea, N-nortricyclyl-N', N'-diphenylurea.
Som eksempel for den under punkt As an example for the one under point
d) nevnte reaksjon skal det nevnes omsetningen av et nortricyklyl-isourinstoff- d) mentioned reaction, mention must be made of the turnover of a nortricyclyl-isourea-
alkyleter med et benzolsulfonsyreklo-rid. Den dannede benzolsulfonylisourin-stoffeter kan således, f. eks. ved behandling med en halogenhydrogensyre, spal-tes til et alkylhalogenid og det ønskede benzolsulf onylurinstoff. alkyl ether with a benzenesulfonic acid chloride. The formed benzenesulfonylisourin ether can thus, e.g. on treatment with a hydrohalic acid, splits into an alkyl halide and the desired benzenesulfonylurea.
Man kan videre også gå ut fra andre kullsyrederivater og erstatte en heri be-finnende uønsket rest hydrolytisk med oksygen eller overføre i oksygen ved en annen f. eks. oksydativ forholdsregel. I det følgende er det gitt et reaksjonsek-sempel for omdannelsen av et guanidin, f. eks. ved alkalisk hydrolyse til det ønskede sulfonylurinstoff. One can also proceed from other carbonic acid derivatives and replace an unwanted residue contained therein hydrolytically with oxygen or transfer in oxygen by another, e.g. oxidative precaution. In the following, a reaction example is given for the conversion of a guanidine, e.g. by alkaline hydrolysis to the desired sulfonylurea.
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 hyd-rogenperoksyd, natriumperoksyd eller salpetersyrer. The replacement of the sulfur atom with an oxygen atom in the correspondingly substituted benzenesulfonylthioureas can for example be carried out using oxides or salts of heavy metals or also by using oxidizing agents such as hydrogen peroxide, sodium peroxide or nitric acids.
Tiourinstoffene kan også avsvovles ved behandling med fosgen eller fosfor-pentaklorid. Klormaursyreamidiner respektiv -karbodiimider som dannes som mellomtrinn, kan ved egnede forholdsregler som forsåpning eller vanntilleiring overføres i benzolsulfonylurinstoffene. The thioureas can also be desulphurised by treatment with phosgene or phosphorus pentachloride. Chloroformic amidines or carbodiimides which are formed as an intermediate step can be transferred into the benzenesulfonylureas by suitable precautions such as saponification or water addition.
På samme måte som benzolsulfonyl-tiourinstoffene kan også benzolsulfonyl-isourinstoffetere avsvovles, som innen oppfinnelsens ramme er likestilt med ben-zolsulfonyltiourinstoffene. In the same way as the benzenesulfonylthioureas, benzenesulfonyl isourea ethers can also be desulphurised, which within the scope of the invention are equated with the benzenesulfonylthioureas.
Utførelsesformene av fremgangsmå-tene ifølge oppfinnelsen kan generelt va-riere sterkt med hensyn til reaksjonsbe-tingelser og tilpasses de eventuelle for-hold. Eksempelvis kan omsetningene gjennomføres under anvendelse av opp-løsningsmidler ved værelsetemperatur eller ved forhøyet temperatur. Som opp-løsningsmidler er det f. eks. egnet indif-ferente aromatiske hydrokarboner som toluol, xylol, klorbenzol, diklorbenzol, videre visse polare oppløsningsmidler som dimetylformamid, dimetylsulfoksyd, dioksan, aceton, videre glykolmonometyl-eter eller deres blandinger. For å få de ved fremgangsmåten ifølge oppfinnelsen fremstilte forbindelser i renest mulig form, foretar man hensiktsmessig en om-f eining fra ammoniakk/saltsyre, idet man oppløser fremgangsmåteproduktene i fortynnet ammoniakk, frafiltrerer eventuelt under reaksjonsforløpet dannede benzolsulfonamider og surgjør filtratet. The embodiments of the methods according to the invention can generally vary greatly with regard to reaction conditions and can be adapted to any circumstances. For example, the reactions can be carried out using solvents at room temperature or at an elevated temperature. As solvents there are e.g. suitable indifferent aromatic hydrocarbons such as toluene, xylol, chlorobenzene, dichlorobenzene, further certain polar solvents such as dimethylformamide, dimethylsulfoxide, dioxane, acetone, further glycol monomethyl ether or their mixtures. In order to obtain the compounds produced by the process according to the invention in the purest possible form, a conversion from ammonia/hydrochloric acid is expediently carried out, dissolving the process products in dilute ammonia, filtering out any benzenesulfonamides formed during the course of the reaction and acidifying the filtrate.
Fremgangsmåteproduktene kan omkrystalliseres fra egnede oppløsningsmid-ler som fortynnede alkoholer. The process products can be recrystallized from suitable solvents such as dilute alcohols.
De etter fremgangsmåten ifølge oppfinnelsen dannede forbindelser utmerker seg ved en sterk blodsukkersenkende virkning. For å undersøke den blodsukkersenkende virkning ble et fremgangs-måteprodukt, nemlig N-( 4-metyl-benzolsulfonyl )-N'-nortricyklylurinstoff admini-strert til nøkterne, svovelvekselnormale hunder i den angitte dosering som tra-gantoppslemming ved hjelp av svelgson-de. Den første blodprøve foregikk kort før applikasjonen for å bestemme nøk-ternblodsukkeret, de ytterligere blodprø-ver ble uttatt pr. time fra hundens ben-vene. Blodsukkerbestemmelsen ble gjen-nomført etter Hagedorn-Jensen-metoden. The compounds formed according to the method according to the invention are distinguished by a strong blood sugar-lowering effect. In order to investigate the blood sugar-lowering effect, a process product, namely N-(4-methyl-benzenesulfonyl)-N'-nortricyclylurea, was administered to sober, sulfur metabolism-normal dogs in the indicated dosage as a tragacanth suspension by means of a throat probe. The first blood sample took place shortly before the application to determine the fasting blood sugar, the further blood samples were taken per hour from the dog's leg vein. The blood sugar determination was repeated according to the Hagedorn-Jensen method.
I den følgende tabell er det angitt blodsukkersenkningen i prosent av ut-gangsverdien og til sammenlikning den senkning som oppnås under samme for-søksbetingelser med N-(4-metyl-benzolsulf onyl )-N'-n-butylurinstoff. In the following table, the lowering of blood sugar is indicated as a percentage of the initial value and, for comparison, the lowering achieved under the same test conditions with N-(4-methyl-benzenesulfonyl)-N'-n-butylurea.
Fremgangsmåteproduktene skal fortrinnsvis anvendes som oralt administrer-bare preparater med blodsukkersenkende virkning til behandling av diabetes mel-litus og kan såvel appliseres som sådan-ne som også i form av deres salter, re- spektiv i nærvær av stoffer som fører til en saltdannelse. Til saltdannelse kan det eksempelvis anvendes: alkaliske midler som alkali- eller jordalkalihydroksyder, -karbonater eller -bikarbonater, ammoniakk, videre fysiologisk tålbare organiske baser. Som tilberedninger kommer det fortrinnsvis i betraktning tabletter, som ved siden av fremgangsmåteproduktene inneholder de vanlige hjelpe- og bærestof-fer som talkum, stivelse, melkesukker, tragant, magnesiumstearat. The method products should preferably be used as orally administrable preparations with a blood sugar-lowering effect for the treatment of diabetes mellitus and can be applied both as such and also in the form of their salts, respectively 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, ammonia, and other physiologically tolerable organic bases can be used. Tablets are preferably taken into consideration as preparations, which, in addition to the process products, contain the usual auxiliary and carrier substances such as talc, starch, milk sugar, tragacanth, magnesium stearate.
Eksempel 1. Example 1.
Til en oppløsning av 67 vektdeler p-toluolsulfonsyreamid og 15,5 vektdeler natriumhydroksyd i 150 vektdeler vann og 120 vektdeler aceton ble det under av-kjøling til +10°C tildryppet 55 vektdeler nortricyklylisocyanat. Man lar reaksjons-blandingen reagere i 3 timer ved værelsetemperatur, filtrerer og surgjør filtratet med eddiksyre. Derved utfelles et krystallinsk produkt som suges fra, ettervaskes med vann og tørkes i vakuum. Man får N-( 4-metyl-benzolsulf onyl )-N'-nortricyklyl-urinstoff i en mengde på 101 g med smeltepunkt 200°C. To a solution of 67 parts by weight of p-toluenesulfonic acid amide and 15.5 parts by weight of sodium hydroxide in 150 parts by weight of water and 120 parts by weight of acetone, 55 parts by weight of nortricyclisocyanate were added dropwise while cooling to +10°C. The reaction mixture is allowed to react for 3 hours at room temperature, filtered and the filtrate acidified with acetic acid. This precipitates a crystalline product which is sucked off, washed with water and dried in a vacuum. N-(4-methyl-benzenesulfonyl)-N'-nortricyclylurea is obtained in an amount of 101 g with a melting point of 200°C.
Eksempel 2. Example 2.
Til en oppløsning av 30,5 vektdeler benzolsulfonsyreamid og 8 vektdeler natriumhydroksyd i 75 vektdeler vann og 60 vektdeler aceton tildryppes under av-kjøling til +10°C 27,5 vektdeler nortricyklylisocyanat. Man lar det etterreagere i 3 timer ved værelsetemperatur, opparbeider som beskrevet i eksempel 1 og får etter omkrystallisering fra n-propanol N-benzolsulfonyl-N'-nortricyklylurinstoff To a solution of 30.5 parts by weight of benzenesulphonic acid amide and 8 parts by weight of sodium hydroxide in 75 parts by weight of water and 60 parts by weight of acetone, 27.5 parts by weight of nortricyclisocyanate are added dropwise while cooling to +10°C. It is left to react for 3 hours at room temperature, worked up as described in example 1 and, after recrystallization from n-propanol, N-benzenesulfonyl-N'-nortricyclylurea is obtained
med smeltepunkt 228°C. with melting point 228°C.
Eksempel 3. Example 3.
Til en oppløsning av 41,5 vektdeler p-acetylamino-benzolsulfonsyreamid og 8 vektdeler natriumhydroksyd i 75 vektdeler vann og 60 vektdeler aceton tildryppes under avkjøling til +10°C 27,5 vektdeler nortricyklylisocyanat. Man lar det etterreagere ytterligere i 3 timer ved værelsetemperatur, opparbeider som beskrevet i eksempel 1 og får det dannede N-(p-acetylamino-benzolsulf onyl )-N'-nortricyklyl-urinstoff i en mengde på 56 vektdeler med smeltepunkt 228°C. To a solution of 41.5 parts by weight of p-acetylamino-benzenesulphonic acid amide and 8 parts by weight of sodium hydroxide in 75 parts by weight of water and 60 parts by weight of acetone, 27.5 parts by weight of nortricyclisocyanate are added dropwise while cooling to +10°C. It is left to react for a further 3 hours at room temperature, worked up as described in example 1 and the formed N-(p-acetylamino-benzenesulfonyl)-N'-nortricyclylurea is obtained in an amount of 56 parts by weight with a melting point of 228°C.
Reaksjonsproduktet oppløser seg klart i fortynnet ammoniakk. The reaction product dissolves clearly in dilute ammonia.
34 vektdeler av N-(p-acetylamino-ben- 34 parts by weight of N-(p-acetylamino-ben-
zolsulf onyl )-N'-nortricyklyl-urinstoff oppvarmes med 60 vektdeler 5 n-KOH i 70 minutter i vannbad av 92°C under om-røring. Det oppstår en stiv krystallkake som oppløses med 150 vektdeler vann under oppvarmning. Oppløsningen rystes med aktivkull og filtreres deretter. Filtratet bringes ved 50°C med 10%ig saltsyre til pH 5,2. Det oppstår en krystallinsk utfelling av N-(p-aminobenzolsulfonyl)-N'-nortricyklyl-urinstoff. Utbytte 24 vektdeler, smeltepunkt 204—206°C. zolsulfonyl)-N'-nortricyclylurea is heated with 60 parts by weight of 5 n-KOH for 70 minutes in a water bath of 92°C with stirring. A stiff crystal cake is formed which dissolves with 150 parts by weight of water during heating. The solution is shaken with activated charcoal and then filtered. The filtrate is brought to pH 5.2 with 10% hydrochloric acid at 50°C. A crystalline precipitate of N-(p-aminobenzenesulfonyl)-N'-nortricyclylurea occurs. Yield 24 parts by weight, melting point 204-206°C.
Eksempel 4. Example 4.
Til en oppløsning av 39 vektdeler p-acetyl-benzolsulfonsyreamid og 8 vektdeler natriumhydroksyd i 125 vektdeler vann og 100 vektdeler aceton tildryppes under avkjøling til +10°C 27,5 vektdeler nortricyklylisocyanat. Man lar det etterreagere ytterligere i 3 timer ved værelsetemperatur, opparbeider som beskrevet i eksempel 1 og får 20 vektdeler N-(p-acetyl-benzolsulf onyl )-N'-nortricyklyl-urinstoff med smeltepunkt 168°C som er klart oppløselig i fortynnet ammoniakk. To a solution of 39 parts by weight of p-acetyl-benzenesulphonic acid amide and 8 parts by weight of sodium hydroxide in 125 parts by weight of water and 100 parts by weight of acetone, 27.5 parts by weight of nortricyclisocyanate are added dropwise while cooling to +10°C. It is left to react for a further 3 hours at room temperature, worked up as described in example 1 and obtains 20 parts by weight of N-(p-acetyl-benzenesulfonyl)-N'-nortricyclyl urea with a melting point of 168°C which is readily soluble in dilute ammonia .
Eksempel 5. Example 5.
N-[ 4- klor- bemolsulfonyl]- N'- nortricyklyl-urinstoff. N-[ 4- chlorobemolsulfonyl]- N'- nortricyclylurea.
12,5 g N-(4-klor-benzolsulfonyl)-karb-aminsyremetylester, 250 ml dioksan og 5,6 nortricyklylamin oppvarmes i 45 minutter under tilbakeløpskokning. Man fjerner oppløsningsmidlet under nedsatt 12.5 g of N-(4-chloro-benzenesulfonyl)-carbamic acid methyl ester, 250 ml of dioxane and 5.6 nortricyclylamine are heated for 45 minutes under reflux. The solvent is removed under reduced pressure
trykk og behandler residuet med 1%-ig press and treat the residue with 1% ig
vandig ammoniakk. Den ammoniakalske aqueous ammonia. The ammoniacal
oppløsning filtreres under anvendelse av kull og filtratet surgjøres med fortynnet saltsyre. Det i godt utbytte dannede produkt suges fra og omkrystalliseres fra metanol. Smeltepunkt 213—215°C. solution is filtered using charcoal and the filtrate is acidified with dilute hydrochloric acid. The product formed in good yield is suctioned off and recrystallized from methanol. Melting point 213-215°C.
Eksempel 6. Example 6.
12,1 g N-(3,4-dimetyl-benzolsulfonyl)-karbaminsyremetylester, 250 ml dioksan og 5,6 g nortricyklylamin oppvarmes i 45 minutter under tilbakeløpskokning. Den klare oppløsning inndampes i vakuum og residuet opptas i 1%-ig vandig ammoniakk. Man filtrerer under anvendelse av kull. Det vannklare filtrat surgjøres med fortynnet saltsyre og den krystallinske utfelling suges fra. Det således dannede N-[3,4-dimetyl-benzolsulfonyl]-N'-nor-tri-cyklyl-urinstoff smelter etter omkrystallisering fra metanol ved 158—160°C. 12.1 g of N-(3,4-dimethyl-benzenesulfonyl)-carbamic acid methyl ester, 250 ml of dioxane and 5.6 g of nortricyclylamine are heated for 45 minutes under reflux. The clear solution is evaporated in vacuo and the residue is taken up in 1% aqueous ammonia. One filters using charcoal. The clear filtrate is acidified with dilute hydrochloric acid and the crystalline precipitate is sucked off. The N-[3,4-dimethyl-benzenesulfonyl]-N'-nor-tricyclylurea thus formed melts after recrystallization from methanol at 158-160°C.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/404,896 US4449596A (en) | 1982-08-03 | 1982-08-03 | Drilling of wells with top drive unit |
| NO832774A NO157630C (en) | 1982-08-03 | 1983-08-01 | DRILLING DEVICE WITH A DRIVING DEVICE LOCATED UPPER IN A DRILLING STREET. |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO854343L NO854343L (en) | 1984-02-06 |
| NO158637B true NO158637B (en) | 1988-07-04 |
| NO158637C NO158637C (en) | 1988-10-12 |
Family
ID=40174223
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO85854202A NO157710C (en) | 1982-08-03 | 1985-10-22 | DRIVING UNIT VERTICALLY MOVABLE IN A DRILL. |
| NO85854343A NO158637C (en) | 1982-08-03 | 1985-10-31 | DRIVE UNIT. |
| NO85854358A NO157709C (en) | 1982-08-03 | 1985-11-01 | DRIVING UNIT VERTICALLY MOVABLE IN A DRILL. |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO85854202A NO157710C (en) | 1982-08-03 | 1985-10-22 | DRIVING UNIT VERTICALLY MOVABLE IN A DRILL. |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO85854358A NO157709C (en) | 1982-08-03 | 1985-11-01 | DRIVING UNIT VERTICALLY MOVABLE IN A DRILL. |
Country Status (1)
| Country | Link |
|---|---|
| NO (3) | NO157710C (en) |
-
1985
- 1985-10-22 NO NO85854202A patent/NO157710C/en not_active IP Right Cessation
- 1985-10-31 NO NO85854343A patent/NO158637C/en not_active IP Right Cessation
- 1985-11-01 NO NO85854358A patent/NO157709C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| NO157709C (en) | 1988-05-04 |
| NO854202L (en) | 1984-02-06 |
| NO157709B (en) | 1988-01-25 |
| NO854343L (en) | 1984-02-06 |
| NO157710C (en) | 1988-05-04 |
| NO158637C (en) | 1988-10-12 |
| NO157710B (en) | 1988-01-25 |
| NO854358L (en) | 1984-02-06 |
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Legal Events
| Date | Code | Title | Description |
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| MK1K | Patent expired |
Free format text: EXPIRED IN AUGUST 2003 |