NO763194L - Fremgangsm}te til fremstilling av antelmintisk virksomme basisk substituerte 2-karbalkoksyamino-benzimidazolyl-5(6)-fenyletere og -ketoner. - Google Patents
Fremgangsm}te til fremstilling av antelmintisk virksomme basisk substituerte 2-karbalkoksyamino-benzimidazolyl-5(6)-fenyletere og -ketoner.Info
- Publication number
- NO763194L NO763194L NO763194A NO763194A NO763194L NO 763194 L NO763194 L NO 763194L NO 763194 A NO763194 A NO 763194A NO 763194 A NO763194 A NO 763194A NO 763194 L NO763194 L NO 763194L
- Authority
- NO
- Norway
- Prior art keywords
- ether
- phenyl
- amino
- benzimidazolyl
- ethoxy
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 9
- 150000002576 ketones Chemical class 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 4
- 230000000694 effects Effects 0.000 title description 3
- JWYUFVNJZUSCSM-UHFFFAOYSA-N 2-aminobenzimidazole Chemical class C1=CC=C2NC(N)=NC2=C1 JWYUFVNJZUSCSM-UHFFFAOYSA-N 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 150000004657 carbamic acid derivatives Chemical class 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 314
- -1 ethylene, propylene, butylene, methylethylene, methylpropylene Chemical group 0.000 description 48
- 238000000354 decomposition reaction Methods 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 241001465677 Ancylostomatoidea Species 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 244000182067 Fraxinus ornus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 125000000872 2-diethylaminoethoxy group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241000242711 Fasciola hepatica Species 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 241000243797 Trichostrongylus Species 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000000507 anthelmentic effect Effects 0.000 description 2
- 229940124339 anthelmintic agent Drugs 0.000 description 2
- 239000000921 anthelmintic agent Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000004651 carbonic acid esters Chemical class 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 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
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WEYSQARHSRZNTC-UHFFFAOYSA-N 1h-benzimidazol-2-ylcarbamic acid Chemical compound C1=CC=C2NC(NC(=O)O)=NC2=C1 WEYSQARHSRZNTC-UHFFFAOYSA-N 0.000 description 1
- BHFLSZOGGDDWQM-UHFFFAOYSA-N 1h-benzimidazole;carbamic acid Chemical compound NC(O)=O.C1=CC=C2NC=NC2=C1 BHFLSZOGGDDWQM-UHFFFAOYSA-N 0.000 description 1
- 125000003635 2-dimethylaminoethoxy group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241001466804 Carnivora Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241001126268 Cooperia Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000243976 Haemonchus Species 0.000 description 1
- 241000545744 Hirudinea Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001547406 Hyostrongylus Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229910018954 NaNH2 Inorganic materials 0.000 description 1
- VNQABZCSYCTZMS-UHFFFAOYSA-N Orthoform Chemical compound COC(=O)C1=CC=C(O)C(N)=C1 VNQABZCSYCTZMS-UHFFFAOYSA-N 0.000 description 1
- 241000243795 Ostertagia Species 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 241000282849 Ruminantia Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241000242541 Trematoda Species 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 244000000013 helminth Species 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000004987 o-phenylenediamines Chemical class 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 229950006098 orthocaine Drugs 0.000 description 1
- 125000005489 p-toluenesulfonic acid group Chemical group 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003826 tablet Substances 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- IAQRGUVFOMOMEM-ONEGZZNKSA-N trans-but-2-ene Chemical group C\C=C\C IAQRGUVFOMOMEM-ONEGZZNKSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
- C07D235/32—Benzimidazole-2-carbamic acids, unsubstituted or substituted; Esters thereof; Thio-analogues thereof
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Fremgangsmåte til fremstilling av antelmintdsk virksomme basisk substituerte 2-karbalkoksyamino-bénzimidazolyl-5(6)-fenyletere og -ketoner.
2-karbalkoksyamino-benzimidazolderivater med alkyl-, acyl-j fenoksy- og fenyltio-rester i 5(6)-stilling' er kjent som antelmintika (P. Actor. og-andre, Nature- 215, 321 (1967)., DOS 2.029.637 og 2.164.690).
Oppfinnelsens gjenstand er en fremgangsmåte til fremstilling av antelmintisk virksomme basisk substituerte 2-karbalkoksyamino-benzimidazolyl-5(6)-fenyletere og -ketoner med formel (1): hvori R betyr alkyl-med 1-4 C-atomer, X betyr oksygen, svovel eller >C = 05 Y betyr en rettlinjet eller forgrenet alkylengruppe med 1-4 C-atomer og R-^og R2betyr 'en alkylrest med 1-4 C-atomer idet de to-rester R-^og R~sammen med n-atomet, som bærer dem også kan bety pyrrolidin-, piperidin-, morfolin- eller tiomorfolin-ringen, idet fremgangsmåten erkarakterisert vedat et 2-aminobenzimidazolderivat med formel (2):
hvori R13R2, X og Y har den for formel (1) angitte betydning,
under utelukkelse av vann, omsettes med en sterk, uorganisk e-ller organisk base, fortrinnsvis et alkalialkoholat, med en karbonsyreester med formel (3):
hvori og R^uavhengig av hverandre betyr en lavere alkylrest med 1-4 C-atomer,-. f enylrestén eller p-nitrof enylrestén, og det dannede karbaminatsalt overføres hvis ønsket ved tilsetning av en base, fortrinnsvis ammoniakk, i den fri 2-benzimidazol-karbaminsyreester med formel (1).
Som alkylrester i substituentene R-^, R^og R^kommer det. spesielt i betraktning metyl, etyl, propyl, isopropyl,
butyl, sekundær-butyl og tert.-butyl. Som alkylengruppe Y kommer det spesielt på tale etylen-, propylen-, butylen-, metyletylen—, metylpropylen og dimetyletylengruppen.
Fra US-patent nr. 3.480.642 er det riktignok kjent
at man kan fremstille.. enklere strukturerte l-alkoksykarbonyl-2-aminobenzimidazoler fra 2-aminobenzimidazol ved omsetning med klormaursyreestere og kan omleire disse deretter ved oppvarming. ,i vannfritt pyridin, dimetylformamid eller acetonitril til 2-alkoksykarbonylamino-benzimidazoler. - Omleiringen lykkes imidlertid bare med meget dårlige utbytter og fører hovedsake-lig til biprodukter. Overraskende forløper omsetningen av de mere komplisert strukturerte 2-aminobenzimidazolderivater med formel (2) med en karbonsyreester med formel (3)med utmerkede utbytter og uten dannelse av den uønskede 1-isomere.
Omsetningen foregår f.eks. etter.følgende reaksjons-. skjema når det som base anvendes Na-metylat:
De som utgangsmateriale anvendte nye 2-aminobenzimidazolderivater med formel (2) fremstilles av 6-fenylendiaminderivatene med formel (5) ved reaksjon med bromcyan. (Formlene angis nedenfor).
o-fenylendiaminderivatene med formel (5) fås ved reduksjon av et tilsvarende aminonitroderivat med formel. (6)
hvori R^, R2, X og Y har samme betydning som i formel (1).
Reduksjonen kan eksempelvis foregå ved hydrering i nærvær av Raney-nikkel i et oppløsningsmiddel som metanol eller dimetylformamid ved temperaturer mellom 2Q og 60°C eller ved behandling med reduserende stoffer som natriumditionitt.
Aminonitroderivatene med formel (6) blir på sin side ved reaksjon av den tilsvarende hydroksy-nitramino-difenyleter med formel (8), hvori X. har samme betydning som for formel (1),
hensiktsmessig i form av dets alkalisalt, fortrinnsvis av natriumsaltet, oppvarmet med en basisk forbindelse med formel'(7) hvori R-^, R2og Y har samme betydning som for formel (1) og
W betyr en avspaltbar gruppe som halogen, eksempelvis klor, brom eller jod, eller som resten av en uorganisk eller organisk oksygenholdig syre som et sulfat- eller p-toluensulfonsyre-gruppe i et hensiktsmessig åprotisk dipolart oppløsningsmiddel som
-aceton, dimetylformamid eller dimetylsulfoksyd eller i. en
alkohol som metanol , eller etanol ved høyere temperatur, fortrinnsvis det anvendte oppløsniirgsmiddels kokepunkt. Etter avsluttet reaksjon fjernes oppløsningsmidlet ved destillering og residuet isoleres etter behandling med én base som'' fortrinnsvis ammoniakk eller et alkalihydroksyd som natronlut eller anvendelse av et med'vann ikke-blandbart oppløsningsmiddel som eddikester, metylendiklorid eller kloroform.
Hydroksy-nitramino-difenyleter med formel (8) behand-les på sin side ved behandling av tilsvarende metoksyderivater av formel. C9)jhvori. X har s.amme betydning som for' formel (1) med sterke mineralsyrer som fortrinnsvis bromhydrogensyre''eller organiske forbindelser som kan avspalte slike syrer, som pyri-dinhydroklorid, ved forhøyet temperatur, fortrinnsvis kokepunk-tet åv den vandige oppløsning a<y>denne syre eller oppløsningen
av den saitaktige organiske forbindelse i den dertil til grunn liggende base som f;eks. pyridin i tilfelle av pyridinhydro-kloridet og isolerer reaksjonsproduktet ved fortynning med vann.
Réaksjonsforløpet kan gjengis- ved følgende skjema:
Som utgangsstoffer med formel (2) kommer det■ eksempelvis i betraktning: 4 -(2-dimetylaminoétoksy)-fenyl-2-aminobenzimidazolyl-5(6 ) - eter, 4-(3-dimetylaminopropoksy)-fen<y>1-2-aminobenzimidazol<y>1-5(6) - eter,' 4-(4-dimetylaminobutoksy)-fenyl-2-aminobenzimidazolyl-5(6)-eter, 4-(2-dimetylamino-l-metyletoksy)-fenyl-2-aminobenzimidazoly1-5(6)-eter, 4- (2-dimetylamino-2-metyletoksy )'-fenyl-2-aminobenzimidazolyl-:5(.6)-eter, 4-(2-dimetylamino-l,2-dimetyletoksy)-fenyl-2-aminobenzimidazolyl-5(6)-eter, 4-(2-dietylaminoétoksy)-fenyl-2-aminobenzimidazolyl-5(6)-eter, 4 -(3-dietylaminopropoksy)-fenyl-2-aminobenzimidazolyl-5(6)-eter, 4 - ( 4 -diety laminobutoksy) - f en'yl-2-amino-benzimidazolyl-5 ( 6 ) - et er 4-(2-dietylamino-l-metyletoksy)-fenyl-2-aminobenzimidazolyl-5(6)-eter, 4-(2-dietylamino-2-metyletoksy)-fenyl-2-aminobenzimidazolyl-5(6)-eter, 4-(2-dietylamino-l,2-metyletoksy)-fenyl-2-aminobenzimidazolyl-5(6)-eter, 4 -(2-dipropylaminoétoksy)-fenyl-2-aminobenzimidazolyl-5(6)-eter, 4-(3-dipropylaminopropoksy)-fenyl-2-aminobenzimidazolyl-5(6)-eter.,
4-(4-dipropylaminobutoksy)-fenyl-2-aminobenzimidazolyl-5(6)-eter, 4 -(2-dipropylamino-l-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
4-(2-dipropylamino-2-metyletoksy)-fenyl-2-aminobenzimidazolyl-5.(6)-eter,
4-(2-dipropylamino-1,2-dimetyletoksy)-fenyl-2-aminobenzimidazo-lyl-5(6)-eter,
4-(2-diisopropylaminoétoksy)-fenyl-2-aminobenzimidazolyl-5(6)-eter,
■ 4 - (3-diisopropylaminopropoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 4 -(4-diisopropylaminobutoksy)-fenyl-2-amino-benzimidazolyl-5(6) - eter,
4-(2-diisopropylamino-l-metyl-etoksy)-feny1-2-aminobenzimida-zolyl-,5( 6)-eter,
4-(2-diisopropylamino-2-metyletoksy)-fenyl-2-amino-benzimida-zolyl-5(6)-eter,
4 -(2-diisopropylamino-l,2-dimetyletoksy)-fenyl-2-amino-benzimidazoly.1-5 ( 6 )-eter , 4-(2-dibutylaminoétoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 4 - ( 3-dibutylaminopropoksy) -f enyl-2-amino.-benzimidazolyl-5 ( 6) - eter,
■ 4-(4-dibutylaminobutoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 4 -(2-dibutylamino-1-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6) -eter, 4-(2 *-dibutylamino-2-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6) -eter, 4-(2-dibutylamino-1,2-dimetyletoksy)-fenyl-2-amino-benzimidazo-lyl-5(6)-eter, 4-(2-pyrrolidyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 4-(3-pyrrolidylpropoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 4-(4-pyrrolidylbutoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 4-(2-pyrrolidyl-l-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 4 - ( 2-pyrrolidyl-2-metyletoksy ) - f enyl-2-amino-benzimidazolyl-5(6)-eter, 4-(2-pyrrolidyl-l,2-dimetyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 4-(2-piperidyletoksy) - f.enyl-2-amino-benzimidazolyl-5 ( 6 ) - eter , ^"(3,-piperidylprdpoksy) - f enyl-2-amino-benzimidazolyl-5 ( 6 ) - eter , 4 -(4-piperidylbutoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 4-(2-piperidyl-l-metyletoksy)-fenyi-2-amino-benzimidazolyl-5(6)-eter, 4-(2-piperidyl-2-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 4-(2-piperidyl-l,2-dimetyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, • 4 - (2-morfolyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, .4 -(3-morfolylpropoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 4 -(4-morfolylbutoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 4 -(2-morfolyl-l-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
4-(2-morfolyl-2-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6) - eter,
4 -(2-morfolyl-1,2-dimetyletoksy)-fenyl-2-amino-benzimidazolyl-'5(6)-eter,'
3- ( 2-dimetylaminoétoksy) - f enyl-2-amino-benzimidazolyl-5.( 6) -eter , 3-(3-dimetylaminopropoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(4-dimetylaminobutoksy)-fenyl-2-amino-benzimidazolyl-5(6)-et er,
3~ (-2-dimety lamino -1-mety let oksy ) - f enyl-2-amino-benzimidazolyl-5(6)-eter,
3-(2-dimetylamino-2-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(2-dimetylamino-1,2-dimetyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(2-dietylaminoetoksy)-fenyl-2-amino-benzimidazolyl-5(6)eter, 3-(3-dietylaminopropoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(4-dietylaminobutoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 3-(2-dietylamino-l-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(2-dietylamino-2-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6 ) -eter,.
3-(2-dietylamino-1,2-dimetyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(2-dipropylamino-etoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(3-dipropylaminopropoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(4-dipropylaminobutoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(2-dipropylamino-l-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(2-dipropylamino-2-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(2-dipropyiamino-l,2-dimetyletoksy)-fenyl-2-amino-benzimidazo-lyl-5(6)-eter, 3-(2-diisopropylamino.etoksy)-feny 1-2-amin o-benz imidazolyl-5(6)-eter,
3-(3-diisopropylaminopropoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(4-diisopropylaminobutoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
.3-(2-diisopropylamino-1-metyletoksy)-fenyl-2-amino-benzimidazo-lyl-5(6)-eter, 3-(2-diisopropylamino-2-metyletoksy)-fenyl-2-amind-benzimidazo-lyl-5(6)-eter, 3-(2-diisopropyiamino-l,2-dimetyletoksy)-fenyl-2-amino-benzimi-dazolyl-5(6)-eter, 3 - ( 2-dib.utylaminoétoksy ) -f enyl-2-amino-benzimidazolyl-5 ( 6) - eter , 3-(3-dibutylaminopropoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 3-(4-dibutylaminobutoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(2-dibutylamino-1-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(2-dibutylamino-2-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(2-dibutylamino-1,2-dimetyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(2-pyrrolidyl-etoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 3- ( 3-pyrro.lidyl-propoksy) -f enyl-2-amino-benzimidazolyl-5 ( 6) -eter , 3-(4-pyrrolidyl-butoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 3-(2-pyrrolidyl-l-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(2-pyrrolidyl-2-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(2-pyrrolidyl-l,2-dimetyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(2-piperidyl-etoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 3-(3-piperidylpropoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 3-(4-piperidylbutoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 3-(2-piperidyl-1-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(2-pipéridyl-2-metyletoksy)-fenyl-2-aminobenzimidazoly1-5(6) - eter, 3- ( 2-piperidyl-l2-dimetyletoksy) -fenyl-2-aminobenzimidazolyl-5(6)-eter, 3-(2-morfolyl-etoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 3-(3-morfolylpropoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3-(4-morfoly1-butoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 3-(2-morfolyl-l-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
3- ( 2-mor f.o ly 1-2-me ty let oksy ) - f eny1-2-amino-benzimidazoly1-5 ( 6 ) - eter, 3-(2-morfoly1-1,2-dimetyletoksy)-fenyl-2-amino-benzimidazoly1-5(6)-eter,
2-(2-dimetylamino-etoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 2-(3-dimetylamino-propoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter,
2-(4-dimetylamino-butoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
2-(2-dimetylamino-1-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
2-(2-dimetylamino-2-metyletoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 2-(2-dimetylamino-1,2-dimetyletoksy)-fenyl-2-amino-benzimidazo-lyl-5(6)-eter,
2-(2-dietylamino-etoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 2-(3-dietylamino-propoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 2-(4-dietylamino-butoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 2-(2-dietylamino-1-metyletoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 2-(2-dietylamino-2-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter,
2-(2-dietylamino-1,2-dimetyletoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter,
2-(2-dipropylamino-etoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter,
2-(3-dipropylamino-propoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter,
2-(4-dipropylamino-butoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter,
2- (2-dipropylamino-1-metyletoksy)-feny1-2-amino-benzimidåzolyl-5(6)-eter,
2-(2-dipropylamino-2-metyletoksy)-feny1-2-amino-benzimidazoly1-■5(6)-eter,
2-(2-dipropylamino-1, 2-dimetyletoksy)-feny1-2-amino-benzimidazo-lyl-5 ( 6.)-eter,
2-(2-diisopropylamino-etoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter,
• 2-(3-diisopropylamino-propoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 2-(4-diisopropylamino-butoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 2-(2-diisopropylamino-1-metyletoksy)-feny1-2-amino-benzimida-■zolyl-5(6)-eter, 2- ( 2-diisopropy lamino-2-metyletoksy.) - f eny 1-2-amino-benz imidazo-'lyl-5(6)-eter, 2-(2-diisopropylamino-1,2-dimetyletoksy)-feny1-2-amino-benzimida-zolyl-5(6)-eter,
2-(2-dibutylamino-etoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 2-(3-dibutylaminopropoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 2- ( 4-dibuty laminobutoksy ) - f eny 1-2-amino-benz imidazo ly 1-5 ( 6 ) - eter-, 2-(2-dibutylamino-l-metyletoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter,
2-(2-dibutylamino-2-metylétoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 2-(2-dibutylamino-l,2-dimetyletoksy)-feny1-2-amino-benzimidazo-lyl-5(6)-eter, 2-(2-pyrrolidy1-etoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 2-(3-pyrrolidyl-propoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 2-(4-pyrrolidyl-butoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 2-(2-pyrrolidyl-l-metyletoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter, 2-(2-pyrrolidy1-2-metyletoksy)-feny1-2-amino-benzimidazolyl-5(6)-eter, 2 -(2-pyrrolidy1-1,2-dimetyletoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter,
2- ( 2-piperidyl-etoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter,
2-(3-piperidyl-propoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, .2-(4-piperidyl-butoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 2-(2-piperidyl-l-metyletoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 2-(2-piperidyl-2-metyletoksy)-feny1—2-amino-benzimidazoly1-5(6)-eter, 2-(2—piperidyl-1,2-dimetyletoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, • 2-(2-morfdly1-etoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 2-(3-morfoly1-propoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 2-(4-morfolyl-butoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter, 2-(2-morfoly1-1-metyl-etoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter,
' 2-(2-morfoly1-2-metyl-etoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter,
2-(2-morfoly1-1, 2-dimetyletoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter,
samt av samtlige nevnte forbindelser de analoge tioetere og ketoner som eksempelvis
4-(2-dimetylamino-etoksy)-feny1-2-amino-benzimidazoly1-5(6)-tioeter eller
4-(2-dimetylamino-etoksy)-feny1-2-amino-benzimidazoly1-5(6)-keton.
De for fremgangsmåten ifølge oppfinnelsen nødvendige karbonsyreestere er kjent. Det skal nevnes karbonsyredimetyl-ester, karbonsyredibutylester, karbonsyremetyl-fenylester, karbonsyredifenylester og karbonsyremetyl-(p-nitrofeny1)-ester.
Fremgangsmåten gjennomføres hensiktsmessig i et indifferent organisk'oppløsningsmiddel som alkoholer med 1-4 C-atomer, tetrahydrofuran, dioksan, acetonitril, dimetylformamid, aceton, metyletylketon,. dietylenglykol-dimetyleter eller i et overskudd av den anvendte karbonsyreester med formel (3) som oppløsningsmiddel. Man kan i første rekke overføre 2-aminobenzimidazolet eller et tilsvarende substituert derivat ved hjelp av en sterk uorganisk eller organisk base i et salt og anvende dette for reaksjonen. Til denne saltdannelse egner det seg fremfor alt alkali- og jordalkali-alkoholater og -hydroksy-der, dessuten baser som NaNH2og NaH, samt metallorganiske forbindelser som f.eks. trifenylnatrium. Man kan imidlertid også danne saltet in situ og videre forarbeide det en gang i oppløsning eller . suspensjon og da imidlertid anvende vannfrie baser.
Vanligvis setter man til oppløsningen eller.suspensjonen av 2-aminobenzimidazolet i et organisk oppløsningsmiddel baaen og karbonsyreesteren, idet tilse.tningsrekkefølgen av reaksjonsdeltageren og mengde av oppløsningsmidlet ikke er avgjørende. Av økonomiske grunner er det fordelaktig å holde .reaksjonsvolumene små. Det er ikke nødvendig å anvende reak-sjonsdeltagerne av 2-aminobenzimidazol i ekvivalente mengde-forhold.'Man kan absolutt anvende karbonsyreesteren i overskudd resp. som oppløsningsmiddel og arbeide i et overskudd av base.
Reaksjonstiden utgjør noen minutter til noen timer
.mens. reaksjonstemperaturen ligger mellom 10 og 150°C, fortrinnsvis mellom 25 og 100°C. Omsetningen fører til et benzimidazol-karbamatsalt som vanligvis er uoppløselig i reaksjonsmediet. Man kan isolere dette salt ved frafiltrering. Fordelaktig
suspenderer man det'i vandig metanol eller et annet med vann blandbart oppløsningsmiddel og bringer det i oppløsning ved tilsetning av en mineralsyre som saltsyre. Etter fjerning av uoppløselige biprodukter ved filtrering eller sentrifugering kan man utskille frie baser med formel (1) .i fast form og ren tilstand ved tilsetning av en base som ammoniakk.
Man får med de ovennevnte 2-aminobenzimidazolderivater med formel (2) ved reaksjon med karbonsyreestere med formel (3) på denne måte følgende produkter med formel (1): 4-(2-dimetylamino-etoksy)-feny1-2-karbometoksyamino-benzimidazo-lyl-5(6)-eter, 4-(3-dimetylamino-propoksy)-feny1-2-karbometoksyamino-benzimida-zolyl-5(6)-eter, 4-(4-dimetylamino-butoksy)-feny1-2-karbornetoksyamino-benzimida-zolyl-5(6)-eter, 4-(2-dimet<y>lamino-1-met<y>letoks<y>)-fen<y>1-2-karbometoksyamino-benzimidazolyl-5(6)-eter, 4-(2-dimetylamino-2-metyletoksy)-feny1-2-karbornetoksyamino-benzimidazolyl-5(6)-eter, 4-(2-dimetylamino-1,2-dimetyl-etoksy)-feny1-2-karbometoksyamino-benz imidazoly1-5(6)-eter, 4-(2-dimetylamino-etoksy)-feny1-2-karbometoksyamino-benzimida-zolyl-5(6)-eter, 4 - (3-dimetylamino-propoksy)-feny1-2-karbornetoksyamino-benzimidazoly 1- 5 ( 6 ) -eter , 4-( 4-dimetylamino-butoksy )-f enyl-2-karbo.metoksyamino-benzimida-zolyl-5(6)-eter, 4- ( 2-dimetylamino-l-metylet'oksy') -f enyl-2-karbometoksyamino-benzimidazolyl-5(6)-eterj4-(2-dietylamino-2-metyletoksy)-feny1-2-karbometoksyamino-benzimidazoly1-5(6)-eter, ■ 4-(2-diet<y>lamino<->1,2-dimet<y>letoks<y>)-fen<y>1-2-karbornetoksyamino-benzimidazolyl-5(6)-eter, 4-(2-dipropylamino-etoksy)-feny1-2-karbornetoksyamino-benzimidazoly.1-5 ( 6 )-eter, 4-(3-dipropylamino-propoksy)-feny1-2-karbometoksyamino-benzimida-zolyl-5(6)-eter, 4-(4-dipropylamino-butoksy)-fenyl-2-karbometoksyamino-benz-' imidazolyl-5(6)-eterj4-(2-dipropylamino-1-metyletoksy)-feny1-2-karbometoksyamino-benz imidazo lyl-5 ( 6 ) -eter 3 4-(2-dipropylamino-2-metyletoksy)-fenyl-2-karbometoksyamino-benzimidazolyl-5(6)-eter, 4-(2-dipropylamino-1,2-dimetyl-etoksy)-feny1-2-karbornetoksyamino-benz imidazoly 1-5 ( 6 ) -eter , 4-(2-diisopropylamino-etoksy)-feny1-2-karbornetoks<y>amino-benzimidazoly 1-5(6)-eter, 4-(3-diisopropylamino-propoksy)-feny1-2-karbornetoksyamino-benz-imidazolyl-5(6)-eter, 4- ( 4-diisopropylamino-butoksy )-f enyl-2-karbometo'ksyamino-benz-imidazolyl-5(6)-eter, 4-(2-diisopropylamino-1-metyletoksy)-feny1-2-karbornetoksyamino-benzimidazoly1-5(6)-eter, 4-(2-diisopropylamino-2-metyletoksy)-feny1-2-karbometoksyamino-benz imidazoly1-5(6)-eter, 4-(2-diisopropylamino-1,2-dimetyletoksy)-fenyl-2-karbometoksy-amino-benzimidazolyl-5(6)-eter, 4-(2-dibutylamino-etoksy)-feny1-2-karbornetoksyamino-benzimida-zolyl-5(6)-eter, 4-(3-dibutylamino-propoksy)-feny1-2-karbornetoksyamino-benzimidazoly 1-5(6)-eter} 4-(4-dibutylamino-butoksy)-feny1-2-karbometoksyamino-benzimidazoly1-5(6)-eter, 4 - (2-dibutylamino-1-metyletoksy)-feny1-2-karbornetoksyamirio-benzimidazolyl-5(6)-eter, 4-(2-dibutylamino-2-metyletoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5 ( 6 ) -eter , 4- ( 2-dibutylamino-1, 2 - dimety l-e toks.y )-feny1-2-karbornetoksyamino-benzimidazolyl-5 ( 6 )-eter, 4-(2-pyrrolidyl-etoksy)-fenyl-2-karbometoksyamino-benzimidazo-lyl-5(6)-eter,
4-(3-pyrrolidyl-propoksy)-fenyl-2-karbornetoksyamino-benzimidazo-lyl-5(6)-eter, 4~ ( 4-pyrrolidyl-b.utoksy )-f enyl-2-karbometoksyamino-benzimidazo-lyl-5(6)-eter,
4-(2-pyrrolidyl-1-metyletoksy)-feny1-2-karbornetoksyamino-benz--imidazoly1-5(6)-eter, . 4-(2-pyrrolidy1-2-metyletoksy)-feny1-2-karbornetoksyamino-benzimidazoly1-5(6)-eter,
4- ( 2,-pyrrolidyl-l, 2-dimety 1-etoksy) -f enyl-2-karbometoksyamino-benzimidazolyl-5(6)-eter,
4-(2-piperidyl-etoksy)-feny1-2-karbometoksyamino-benzimidazoly1-5(6)-eter,
4-(3-piperidyl-propoksy)-feny1-2-karbometoksyamino-benzimidazo-' lyl-5(6)-eter, 4-(4-piperidyl-butoksy)-feny1-2-karbometoksyamino-benzimidazoly1-5(6)-eter,
4-(2-piperidyl-1-metyletoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter,
4- ( 2-piper idyl-2-me ty le toksy) - f eny .1-2-karb orne toksy amino-benz-imidazolyl-5(6)-eter,
4-(2-piperidyl-1,2-dimetyletoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter,
4- ( 2-morf oly.l-et oksy ) - f eny 1-2 -karb omet oksy amino-b enz imidazo ly 1-5(6)-eter,
4-(3-morfolyl-propoksy)-feny1-2-karbometoksyamino-benzimidazo-lyl-5(6)-eter,
4-(4-morfolyl-butoksy)-feny1-2-karbométoksyamino-benzimidazoly1-5(6)-eter,
4-(2-morfoly1-1-metyletoksy)-feny1-2-karbometoksyamino-benzimi-daz oly1-5(6)-eter,
4-(2-morfoly1-2-metyl-etoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5 (6)-eter,
4- ( 2-morfoly1-1, 2-dimety l-e toksy ).-f eny 1-2-kar borne toksy amino-benzimidazolyl-5(6)-eter, 3-(2-dimetylamino-etoksy)-feny1-2-karbometoksyamino-benzimidazo-lyl-5(6)-eter,
3-(3-dimetylamino-propoksy)-feny1-2-karbornetoksyamino-benzimida-zolyl-5(6)^eter,
3-(4-dimetylamino-butoksy)-fenyl-2-karbometoksyamino-benzimida-zolyl-5(6)-eter,
3-(2-dimetylamino-1-metyletoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter,
3-( 2-dimetylamino-2-metyletoksy )-f eny 1^-2-karbometoksyamino-benzimidazolyl-5(6)-eterj
3-(2-dimetylamino-1,2-dimetyletoksy)-feny1-2-karbometoksy-amino-benzimidazolyl-5(6)-eterj
3-(2-dietylamino-etoksy)-feny1-2-karbometoksyamino-benzimidazo-lyl-5(6)-eter,
3_(3-dietylamino-propoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter,
3-(4-dietylamino-butoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter, .3-(2-dietylamino-1-metyletoksy)-feny1-2-karbometoksyamino-benzimidazoly1-5(6)-eter, 3-(2-dietylamino-2-metyletoksy)-feny1-2-karbornetoksyamino-benz-3-(2-dietylamino-1,2-dimetyletoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter,
3- ( 2-dipropy lamino-et oksy ) - f eny 1-2-karbomet oksy a.mino-benzimida-zolyl-5 ( 6)-eter,
3"(3~dipropylamino-propoksy)-feny1-2-karbometoksyamino-benzimida-zolyl-5(6)-eter, 3-(4-dipropylamino-butoksy)-feny1-2-karbometoksyamino-benzimida-zolyl-5(6)-eter,
3-(2-dipropylamino-1-metyl-etoksy)-feny1-2-karbornetoksyamino-benz imidaz oly 1-5 ( 6 ) -eter ,
3-(2-dipropylamino-2-metyletoksy)-fenyl-2-karbornetoksyamino-benz imidaz oly 1-5 (6) - eter',
3~(2-dipropylamino-1,2-dimetyletoksy)-feny1-2-karbometoksyamino-benz imidazoly1-5(6)-eter,
3-(2-diisopropylamino-etoksy)-fenyl-2-karbometoksyamino-benz-imida.zolyl-5 ( 6 )-eter,
3-(3-diisopropylamino-propoksy)-feny1-2-karbometoksyamino-benz-vimidazolyl-5(6)-eter3
3_(4-diisopropylamino-butoksy)-fenyl-2-karbometoksyamino-benz-imidazolyl-5(6)-eterj
3-(2-diisopropylamino-1-metyl-etoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter,
3~.( 2-diisopropy lamino -2-me ty l-e toksy ) - f eny 1-2- karb orne toks yamino-benzimidazoly1-5(6)-eter5
3_(2-diisopropylamino-1,2-dimetyl-etoksy)-feny1-2-karbometoksy-amino-benzimidazoly 1-5(6j-eter, 3-(2-dibutylamino-etoksy)-feny1-2-karbometoksyamino-benzimida-zolyl-5 ( 6 ) -eter ,
3~(3-dibutylamino-propoksy)-feny1-karbornetoksyamino-benzimidazoly 1-5(6)-eter,
3- ( 4-di is opropy lamino-butoksy ) -f enyl-2-kar borne toksy amino-benz-imidazolyl-5(6)-eter, .
3~(2-dibutylamino-1-metyletoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter,
3-(2-dibutylamino-2-metyletoksy)-feny1-2-karbometoksyamino-benz-imidazolyl-5(6)-eter,
3-(2-dibutylamino-1,2-dimetyletoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter,
3-(2-pyrrolidyl-etoksy)-feny1-2-karbometoksyamino-benzimidazo-lyl-5 (6)-eter,
3-(3-pyrrolidyl-propoksy)-feny1-2-karbornetoksyamino-benzimidazo-lyl-5 (6)-eter,
3-(4-pyrrolidyl-butoksy)-feny1-2-karbometoksyamino-benzimidazo-lyl-5 (6)-eter,
2- (2-pyrrolidy1-1-metyletoksy) - f enyl^-karbometoksyamino-benz-imidazolyl-S ( 6 )-eter}
3~(2-pyrrolidy1-2-metyl-etoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter,
3- (2-pyrrolidy1-1,2-dimetyl-etoksy)-feny1-2-karbornetoksyamino-benz imidazo ly 1-5 ( 6)-eter,
3~(2-piperidyl-etoksy)-feny1-2-karbometoksyamino-benzimidazoly1-5(6)-eter,
3-(3-piperidyl-propoksy)-feny1-2-karbometoksyamino-benzimidazo-lyl-5 (6)-eter,
3- ( 4-piperidyl-butoksy) - f eny 1-2-karbomet oksy amino-b enz.imidaz oly 1-5(6)-eter,
3-(2-piperidyl-1-metyletoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter,
3-(2-piperidyl-2-metyletoksy)-fenyl-2-karbometoksyamino-benz-
imidazolyl-5(6)-eterj3_(2-piperidyl-lj 2-dimetyl-etoksy)-feny1-2-karbometoksyamino-benz imidaz oly 1-5 ( 6 )-eter,
3-(2-morfolyl-etoksy)-feny1-2-karbometoksyamino-benzimidazoly1-5(6)-eter,
3~(3-morfolyl-propoksy)-fenyl—2-karbometoksyamino-benzimidazoly1-5(6)-eter, 3-(4-morfolyl-butoksy)-fenyl-2-karbometoksyamino-benzimidazolyl-5(6)-eter,
3_ ( 2-morf oly 1-1^-me ty l-e toksy)-feny1-2-karbometoksyamino-benz-imidazolyl-5(6)-eter, 3-(2-morfoiyl-2-metyl-etoksy)-feny1-2-karbometoksyamino-benz-imidazolyl-5(6)-eter, 3~(2-morfoly1-1,2-dimetyl-etoksy)-feny1-2-karbometoksyamino-benz-imidazolyl-5(6)-eter,
2-(2-dimetylamino-etoksy)-feny1-2-karbometoksyamino-benzimidazo-lyl-5(6)-eter,
2-(3-dimetylamino-propoksy)-feny1-2-karbornetoksyamino-benz-'imidazolyl-5(6)-eter, 2-(4-dimetylamino-butoksy)-feny1-2-karbometoksyamino-benzimida-zolyl-5(6)-eter,
2-(2-dimetylamino-1-metyl-etoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter,
2-(2-dimetylamino-2-metyl-etoksy)-feny1-2-karbornetoksyamino-benz imidazolyl-5(6)-eter3
2-(2-dimetylamino-1,2-dimetyl-etoksy)-feny1-2-karbometoksy-amino-benzimidazoly 1-5(6)-eter,
2-(2-dietylamino-etoksy)-feny1-2-karbornetoksyamino-benzimidazo-lyl-5(6)-eter,
2-(3-dietylamino-propoksy)-feny1-2-karbornetoksyamino-benzimida-zolyl-5 (6)-eter,
2-(4-dietylamino-butoksy)-feny1-2-karbornetoksyamino-benzimidazoly 1-5(6)-eter,
2-(2-dietylamino-1-metyl-etoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter,
2-(2-dietylamino-2-metyletoksy)-feny1-2-karbometoksyamino-benz-imidazolyl-5(6)-eter,
2 - (2-dietylamino-1,2-dimetyletoksy)-feny1-2-karbometoksyamino-b'enzimidazolyl-5 (6 )-eter3
2-(2-dipropylamino-etoksy)-feny1-2-karbometoksyamino-benzimidazo-lyl-5(6)-eter,
2-(3-dipropylamino-propoksy)-fenyl-2-karbometoksyamino-benzimida-zol'yl-5 ( 6 )-eter, 2-,( 4- dipropy lamino-butoksy ) - f enyl- 2 -karb orne toksy amino-b enz imida-zolyl-5 (6)-eter, 2 - (2-dipropylamino-1-metyletoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter, 2-(2-dipropylamino-2-metyletoksy)-feny1-2-karbornetoksyamino-. benzimidazolyl-5(6)-eter,
2-(2-dietylamino-1,2-dimetyletoksy)-feny1-2-karbornetoksyamino-benzimidazolyl-5(6)-eter,
2-(2-diisopropylamino-etoksy)-feny1-karbornetoksyamino-benzimidazoly 1-5(6)-eter,
2-(3-diisopropylamino-propoksy)-feny1-2-karbometoksyamino-benzimidazoly l-5(6)-eter, 2-(4-diisopropy1-butoksy)-feny1-2-karbornetoksyamino-benzimida-zolyl-5 ( 6 ) -eter ,
2-(2-diisopropylamino-1-metyl-etoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter,
2-(2-diisopropylamino-2-metyl-etoksy)-feny1-2-karbornetoksyamino-benzimidazolyl-5(6)-eterj
2-,( 2-di is opropy lamino-1, 2-dime tyl-et oksy ) -f eny 1-2-karbomet oksy-amino-benzimidazoly 1-5(6)-eter,
2-(2-dibutylamino-etoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5 ( 6 )-e.ter 5
2-(3-dibutylamino-propoksy)-fenyl-2-karbometoksyamino-benzimida-zolyl-5(6)-eter,
2-(4-dibutylamino-butoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter,
2-(2-dibutylamino-1-metyletoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter,
2-(2-dibutylamino-2-metyletoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter,
2-(2-dibutylamino-1,2-dimetyletoksy)-feny1-2-karbometoksyamino-benz imidazo ly 1-5 ( 6 ) -eter ,
2-(2-pyrrolidyl-etoksy)-feny1-2-karbornetoksyamino-benzimidazoly1-5(6)-eter,
2-(3-pyrrolidyl-propoksy)-feny1-2-karbornetoksyamino-benzimidazo-lyl-5(6)-eter, 2-(4-pyrrolidyl-butoksy)-feny1-2-karbometoksyamino-benzimidazo-Tyl-5(6)-eter3
2-(2-pyrrolidyl-l-metyletoksy)-feny1-karbornetoksyamino-benz-imidazolyl-5(6)-eter, 2-.( 2-pyrrolidy 1-2-metyletoksy ) -f eny 1-2-karbomet oksy amino-benz-imidazolyl-5(6)-eter,
" 2- ( 2-pyrrdlidyl-l j 2-dime ty l-e toksy ) -f enyl-2-karb orne toksy amino-benzimidazolyl-5(6)-eterj2-(2-piperidyl-etoksy)-feny1-2-karbometoksyamino-benzimidazoly1-5(6)-eter,
2-(3-piperidyl-propoksy)-feny1-2-karbometoksyamino-benzimidazo-lyl-5 (60-eter, 2-(4-piperidyl-butoksy)-feny1-2-karbornetoksyamino-benzimidazoly 1-5 ( 6 ) -eter 3
2-(2-piperidyl-1-metyletoksy)-feny1-2-karbornetoksyamino-benz-imidazolyl-5(6)-eter3
2-(2-piperidyl-2-metyletoksy)-feny1-2-karbornetoksyamino-benz-imidazolyl-5(6)-eter,
2-(2-piperidyl-l,2-dimetyletoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter, 2-(2-morfolyl-etoksy)-feny1-2-karbornetoksyamino-benzimidazoly1-5(6)-eter,
2-(3-morfolyl-propoksy)-fenyl-2-karbometoksyamino-benzimidazoly1-5(6)-eter,
2-(4-morfolyl-butoksy)-feny1-2-karbornetoksyamino-benzimidazoly1-5(6)-eter,
2-(2-morfoly1-1-metyletoksy)-feny1-2-karbornetoksyamino-benzimidazoly1-5(6)-eter,
2-(2-morfoly1-2-metyletoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter,
2-(2-morfoly1-1j 2-dimetyletoksy)-feny1-2-karbometoksyamino-benzimidazoly 1-5(6)-eter.
Videre får man ved reaksjon ifølge oppfinnelsen de til ovennevnte forbindelse med formel (1) svarende 2-karbetoksy-amino-, 2-karbopropoksyamino-, 2-karboisopropoksyamino-, 2-karbobutoksyamino-, 2-karbo-sekundær-butoksyamino- og 2-karbo-tert.-butoksyamino-analoger samt av samtlige nevnte forbindelser de analoge tioetere og ketoner, eksempelvis 4- ( 2-dimetylamino-etoksy) -f enyl-2-karbetoksyamino-benzimidazo-lyl-5(6)-eter, ■
4-(2-dimetylamino-etoksy)-feny1-2-karbopropoksyamino-bénzimida-zolyl-5(6)-eter,
4-(2-dimetylamino-etoksy)-feny1-2-karbisopropoksyamino-benz-imidazolyl-5(6)-eter,
4-(2-dimetylamino-etoksy)-feny1-2-karbobutoksyamino-benzimidazoly 1-5 ( 6 )'-eter,
4-(2-dimetylamino-etoksy)-feny1-2-karbometoksyamino-benzimida-zolyl-5 (6 )-tioeter, .
4-(2-dimetylamino-etoksy)-feny1-2-karbornetoksyamino-benzimida-zolyl-5(6)-keton.
Dé ifølge oppfinnelsen fremstilte stoffer er verdi-fulle kjemoterapeutika og egner seg til bekjempelse av parasi-tære sykdommer hos mennesker og dyr. Disse produkter utfolder en spesiell virkning overfor ankylostomer, er imidlertid også godt virksomme mot andre, helminter.som f.eks. Haemonchus, Ostertagia, Hyostrongylus, Trichostrongylus, Cooperia samt Fasciola hepatica. Spesielt utpreget er virkningen overfor hakeorm som fremfor alt angriper mennesker, karnivorer men også drøvtyggere og frembringer betraktelige sunnhetsmessige og økonomiske skader.
Forbindelsene med formel (1) kan anvendes som antelmintika i human- og veterinærmedisin. De administreres alt etter tilfellets tilstand i doseringer mellom 0,5 og 50 mg/kg legemsvekt 1-14 dager.
Til oral applikasjon kommer det i betraktning
■tabletter, drageer, kapsler, pulvere, granulater eller pastaer som inneholder de virksomme stoffer sammen med vanlige hjelpe-og bærestoffer som stivelse, cellulosepulver, talkum, magnesium-stearat, sukker, gelatin, kalsiumkarbonat, finfordelt kisel-syre, karboksymetylcellulose eller lignende stoffer.
Til parenteral applikasjon kommer det i betraktning oppløsninger, f. eks. olj.eaktige oppløsninger som fremstilles under anvendelse av sesamolje, ricinusolje eller syntetiske triglycerider, eventuelt med en tilsetning av tokoferol som antioksydanS'og/eller under anvendelse av grenseflateaktive stoffer som sorbitanf ettsyreestere. Dertil kommer det. i betraktning vandige suspensjoner som fremstilles under anvendelse av etoksylerte sorbitanfettsyreestere eventuelt under tilsetning av fortyknihgsmidler. som polyetylenglykol eller karboksymetylcellulose.
Konsentrasjonen av de virksomme stoffer ifølge oppfinnelsen i de dermed fremstilte■preparater ligger fortrinnsvis for bruk som veterinærlegemiddel mellom 2 og 20 vekt-%, for bruk som humanlegemiddel ligger konsentrasjonen av de virksomme
■stoffer fortrinnsvis mellom 20 og 80 vekt-%.
Premgangsmåteproduktene virker såvel mot hakeorm.som også mot gruppen av magetarm-strongylider ned til doseringer på mindre enn 10 mg/kg. De er spesielt ved den kombinerte virkning ved relativt liten dosering til behandling av merinfeksjoner overlegen overfor de kjente 5(6)-substituerte 2-benzimidazol-karbaminater.
Også mot, den store leverigle (Fasciola hepatica)
ble det fastslått spesielt gunstige virkninger.
Således bevirker eksempelvis forbindelsen ifølge eksempel 6 med 2,5 mg/kg peroralt en 100 $ig reduksjon av orme-egg av Trichostrongylus i ekskrementer fra sauer. Forbindelsen ifølge eksemplene 10, 11 og l4'med 10 mg/kg peroralt bevirket en 100 % ±g reduksjon av ankylostoma hos hunder, og forbindelsen ifølge eksempel 18 med 5 mg/kg peroralt bevirket en 100. % ±g reduksjon av Fasciola hos sau.
Eksempel .
1. Man oppløser 0,4 g natrium i 10 ml absolutt etanol, tilsetter 4,0 g 4-( 2-dietylamino-e'toksy )-f enyl-2-aminobenz-imidazolyl-5(6)-eter og 1,5 g dimetylkarbonat og oppvarmer blan-
dingen 2 timer under tilbakeløp. Fra den til å begynne med klare oppløsning utskiller det seg etterhvert en utfelling som frafiltreres etter avkjøling. Man vasker residuumet med iso-propanol og suspenderer derpå produktet i 50 %ig vandig metanol. Man blander suspensjonen med fortynnet saltsyre, frafiltrerer uoppløst og feller fra filtratet ved tilsetning av ammoniakk ut 4-(2-dietylamino-etoksy)-feny1-2-karbornetoksyamino-benzimida-zolyl-5 (6)-eter. Det frafiltreres, vaskes med vann og tørkes på dampbad. Utbytte: 1,5 g av smp. 198°C (under spaltning).
Under anvendelse av tilsvarende modifiserte utgangs-materialer vil man analogt
2. av 4-(2-dietylamino-etoksy)-fenyl-2-aminobenzimidazoiyl-5(6)-eter få: 4- ( 2-die ty lamino-et oksy ) - f eny 1-.2-karb et oksy amino-b enz imidazo ly 1-5(6)-eter med smp. 158°C (under spaltning), 3. av 4-(2-dietylamino-etoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter få: 4- (2-dietylamino-etoksy)-feny1-2-karbobutoksyamino-benzimidazo-lyl-5(6)-eter med smp. 131°C (under spaltning), 4. av 3-(2-dietylamino-etoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter få: 3~(2-dietylamino-etoksy)-feny1-2-karbometoksyamino-benzimidazo-lyl-5(6)-eter med smp. l68°C (under spaltning), 5- av 2-(2-dietylamino-etoksy)-fenyl-2-amino-benzimidazoly1-■5(6)-et.er få: 2- (2-dietylamino-etoksy)-feny1-2-karbornetoksyamino-benzimidazo-lyl-5 (6)-eter med smp. 197°C (under spaltning), 6. av 4-(2-dimetylamino-etoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter få: 4-(2-dimetylamino-etoksy)-feny1-2-karbometoksyamino-benzimidazo-lyl-5(6)-eter med smp. 210°C (under spaltning), .7. av 4-(2-dimetylamino-l-metyletoksy)-fenyl-2-amino-benz-imidazolyl-5(6)-eter få: 4-(2-dimetylamino-l-metyletoksy)-f eny 1-2-karb orne toksy amino-benzimidazolyl-5(6)-eter med smp. 200°C (under spaltning), 8. av 4-(3-dimetylamino-propoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter få: 4-(3-dimetylamino-propoksy)-feny1-2-karbometoksyamino-benzimida-zolyl-5(6)-eter med smp. l82°C (under spaltning), 9. av 4-(2-diisopropylamino-etoksy)-feny1-2-amino-benzimidazo-lyl-5(6)-eter få: 4-(2-diisopropylamino-etoksy)-feny1-2-karbometoksyamino-benz-imidazolyl-5(6)-eter med smp. 197°C (under spaltning), 10. av 3_(2-dimetylamino-etoksy)-fenyl-2-amino-benzimidazoly1-5(6)-eter få:' 3- (2-dimetylamino-etoksy)-feny1-2-karbornetoksyamino-benzimidazo-lyl-5 (6)-eter med smp. 190°C (under spaltning), 11. av 3_(3-dimetylamino-propoksy)-fenyl-2-amino-benzimidazo-lyl-5(6)-eter få: 3-(3-dimetylamino-propoksy)-feny1-2-karbornetoksyamino-benzimida-zolyl-5 (6)-eter med smp. 173°C (under spaltning), 12. av 4-(2-morfolyl-etoksy)-fenyl-2-amino-benzimidazolyl-5(6)-e'ter f å :' 4-(2-morfolyl-etoksy)-fenyl-2-karbornetoksyamino-benzimidazoly1-5(6)-eter med smp. 200°C (under spaltning), 13. av 4-(2-piperidyl-etoksy)-fenyl-2-amino-benzimidazolyl-5(6)-eter få: .4 - ( 2-piperidyl-etoksy ) -feny1-2-karbometoksyamino-benzimidazoly1-5(6)-eter med smp. 195°C (under spaltning), 14. av 3-'( 2-piperidyl-etoksy )-f enyl-2-amino-benzimidazolyl-5(6)-eter få: 3- (2-piperidyl-etoksy)-feny1-2-karbometoksyamino-benzimidazoly1-5(6)-eter med smp. 200°C (under spaltning), 15. av 4-(2-diétylamino-etoksy)-fenyl-2-amino-benzimidazolyl-5 ( 6 )-tioeter. få : 4 - (.2-dietylamino-etoksy )-feny1-2-karbometoksyamino-benzimidazo-lyl-5(6)-tioeter med smp. l63°C (under spaltning), 16. av 4-(2-dietylamino-etoksy)-feny1-2-amino-benzimidazolyl-5(6)-eter få: 4- (2-dietylamino-etoksy)-feny1-2-karbometoksyamino-benzimidazo-lyl-5(6)-keton med smp. 2l8°C (under spaltning), 17. av 3-(2-piperidyl-etoksy)-fenyl-2-amino-benzimidazolyl-5(6)-tioeter få: 3-(2-piperidyl-etoksy)-feny1-2-karbometoksyamino-benzimidazoly1-5(6)-tioeter med smp. 198°C (under spaltning), 18. av 3-(2-morfolyl-etoksy)-feny1-2-amino-benzimidazolyl~5(6)-eter få: 3-(2-morfolyl-etoksy)-feny1-2-karbometoksyamino-benzimidazoly1-5(6)-eter med smp. 190°C (under spaltning), 19• av 3-(2-piperidyl-etoksy)-feny1-2-amino-benzimidazoly1-5(6)-eter få: 3-(2-piperidyl-etoksy)-feny1-2-karbetoksyamino-benzimidazoly1-5(6)-eter med smp. l69°C (under spaltning), 20. få: 3-(2-piperidyl-etoksy)-fenyl-2-carbisopropoksyamino-benzimidazolyl-5(6)-eter (som hydroklorid) med smp. 205°C (under spaltning), 21. få: 3-(2-piperidyl-etoksy)-fenyl-2-karbisobutoksyamino-benzimidazolyl-5(6)-eter med smp. 195°C (under spaltning).
Claims (1)
- Fremgangsmåte til fremstilling av basisk substituerte 2-karbalkoksyamino-benzimidazolyl-5(6)-fenyletere og-ketoner med formel (1)hvori betyr alkyl med 1-4 C-atomer, X betyr oksygen, svovel eller >C=0, Y betyr en rettlinjet eller forgrenet alkylengruppe med 1-4 C-atomer og R-, og. R2 betyr en alkylrest med 1-4 C-.atomer, idet de to rester og R2 sammen med N-atomet som bærer dem også kan bety pyrrolidin , piperidin , morfolin eller tiomorfolin, karakterisert ved at 2-amino-benzimidazolderivatet med formel (2)hvori R^ , R2 , X og Y har den for formel (1) angitte betydning under utelukkelse av vann, omsettes med en sterk base med en karbonsyreester med formel:hvori R-^ og R^ uavhengig av hverandre betyr en lavere alkylrest av 1-4 C-atomer, fenylrest eller-p-nitrofenylrestén, og hvis ønsket, overføres det dannede karbaminatsalt ved tilsetning av en base i den fri forbindelse med formel (1).
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19752541741 DE2541741A1 (de) | 1975-09-19 | 1975-09-19 | Anthelminthisch wirksame basisch substituierte 2-carbalkoxyamino-benzimidazolyl-5(6)-phenylaether und -ketone sowie verfahren zu ihrer herstellung |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO763194L true NO763194L (no) | 1977-03-22 |
Family
ID=5956857
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO763194A NO763194L (no) | 1975-09-19 | 1976-09-17 | Fremgangsm}te til fremstilling av antelmintisk virksomme basisk substituerte 2-karbalkoksyamino-benzimidazolyl-5(6)-fenyletere og -ketoner. |
Country Status (12)
| Country | Link |
|---|---|
| DE (1) | DE2541741A1 (no) |
| DK (1) | DK420076A (no) |
| EG (1) | EG12307A (no) |
| ES (1) | ES451513A2 (no) |
| FI (1) | FI762655A (no) |
| GR (1) | GR61184B (no) |
| IT (1) | IT1068314B (no) |
| LU (1) | LU75814A1 (no) |
| NL (1) | NL7610189A (no) |
| NO (1) | NO763194L (no) |
| PT (1) | PT65610B (no) |
| SE (1) | SE7610312L (no) |
-
1975
- 1975-09-19 DE DE19752541741 patent/DE2541741A1/de active Pending
-
1976
- 1976-09-11 EG EG553/76A patent/EG12307A/xx active
- 1976-09-14 NL NL7610189A patent/NL7610189A/xx unknown
- 1976-09-14 ES ES451513A patent/ES451513A2/es not_active Expired
- 1976-09-16 FI FI762655A patent/FI762655A/fi not_active Application Discontinuation
- 1976-09-16 LU LU75814A patent/LU75814A1/xx unknown
- 1976-09-16 SE SE7610312A patent/SE7610312L/xx unknown
- 1976-09-17 PT PT65610A patent/PT65610B/pt unknown
- 1976-09-17 IT IT27368/76A patent/IT1068314B/it active
- 1976-09-17 NO NO763194A patent/NO763194L/no unknown
- 1976-09-17 DK DK420076A patent/DK420076A/da unknown
- 1976-09-18 GR GR51721A patent/GR61184B/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI762655A (no) | 1977-03-20 |
| PT65610A (de) | 1976-10-01 |
| DK420076A (da) | 1977-03-20 |
| IT1068314B (it) | 1985-03-21 |
| PT65610B (de) | 1978-05-10 |
| SE7610312L (sv) | 1977-03-20 |
| ES451513A2 (es) | 1977-11-01 |
| DE2541741A1 (de) | 1977-03-31 |
| NL7610189A (nl) | 1977-03-22 |
| EG12307A (en) | 1982-09-30 |
| GR61184B (en) | 1978-10-05 |
| LU75814A1 (no) | 1977-05-13 |
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