NO792696L - Monokarboksylater av fenylguanidinsyre-estere samt fremgangsmaate til deres fremstilling - Google Patents
Monokarboksylater av fenylguanidinsyre-estere samt fremgangsmaate til deres fremstillingInfo
- Publication number
- NO792696L NO792696L NO792696A NO792696A NO792696L NO 792696 L NO792696 L NO 792696L NO 792696 A NO792696 A NO 792696A NO 792696 A NO792696 A NO 792696A NO 792696 L NO792696 L NO 792696L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- methoxycarbonyl
- phenyl
- guanidine
- alkyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 17
- 239000002253 acid Substances 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title description 6
- -1 phenylguanidine sulfonic acid esters Chemical class 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 125000004432 carbon atom Chemical group C* 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 6
- 150000007524 organic acids Chemical class 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- QRJZGVVKGFIGLI-UHFFFAOYSA-N 2-phenylguanidine Chemical compound NC(=N)NC1=CC=CC=C1 QRJZGVVKGFIGLI-UHFFFAOYSA-N 0.000 claims description 5
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 5
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 244000000013 helminth Species 0.000 claims description 3
- 150000002541 isothioureas Chemical class 0.000 claims description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- RMAHPRNLQIRHIJ-UHFFFAOYSA-N methyl carbamimidate Chemical class COC(N)=N RMAHPRNLQIRHIJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 229940126601 medicinal product Drugs 0.000 claims 1
- 210000000056 organ Anatomy 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 6
- 241000545744 Hirudinea Species 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 241000244206 Nematoda Species 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- 241000283690 Bos taurus Species 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 241000283086 Equidae Species 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 230000000507 anthelmentic effect Effects 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- PEOUQUKUHBWKGO-UHFFFAOYSA-N [3-(trifluoromethyl)phenyl] 4-amino-3-nitrobenzenesulfonate Chemical compound C1=C([N+]([O-])=O)C(N)=CC=C1S(=O)(=O)OC1=CC=CC(C(F)(F)F)=C1 PEOUQUKUHBWKGO-UHFFFAOYSA-N 0.000 description 2
- DOCSUTOJBMLNFH-UHFFFAOYSA-N [3-[(n-methoxycarbonyl-n'-methylcarbamimidoyl)amino]-4-(propanoylamino)phenyl] benzenesulfonate Chemical compound C1=C(NC(NC(=O)OC)=NC)C(NC(=O)CC)=CC=C1OS(=O)(=O)C1=CC=CC=C1 DOCSUTOJBMLNFH-UHFFFAOYSA-N 0.000 description 2
- MNRWLAGBOWNDOE-UHFFFAOYSA-N [3-[2-(2-methoxyacetyl)hydrazinyl]phenyl] benzenesulfonate Chemical compound COCC(=O)NNC1=CC=CC(OS(=O)(=O)C=2C=CC=CC=2)=C1 MNRWLAGBOWNDOE-UHFFFAOYSA-N 0.000 description 2
- QSHNOLMLGJKXGB-UHFFFAOYSA-N [4-formamido-3-[(n-methoxycarbonyl-n'-methylcarbamimidoyl)amino]phenyl] benzenesulfonate Chemical compound C1=C(NC=O)C(NC(NC(=O)OC)=NC)=CC(OS(=O)(=O)C=2C=CC=CC=2)=C1 QSHNOLMLGJKXGB-UHFFFAOYSA-N 0.000 description 2
- RHDZSFLIWVFNOW-UHFFFAOYSA-N [carbamoyl(methyl)amino] methyl carbonate Chemical compound C(=O)(OC)ON(C(O)=N)C RHDZSFLIWVFNOW-UHFFFAOYSA-N 0.000 description 2
- 229960001413 acetanilide Drugs 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 150000001448 anilines Chemical class 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- MMBDAJMDNVQFDV-UHFFFAOYSA-N methyl n-[amino(methylsulfanyl)methylidene]carbamate Chemical compound COC(=O)N=C(N)SC MMBDAJMDNVQFDV-UHFFFAOYSA-N 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000007306 turnover Effects 0.000 description 2
- QGRNOSUTWZYDTP-UHFFFAOYSA-N (2-chlorophenyl) 4-acetamido-3-[(n'-methoxycarbonylcarbamimidoyl)amino]benzenesulfonate Chemical compound C1=C(NC(C)=O)C(NC(=N)NC(=O)OC)=CC(S(=O)(=O)OC=2C(=CC=CC=2)Cl)=C1 QGRNOSUTWZYDTP-UHFFFAOYSA-N 0.000 description 1
- OQLVOYMTVSGURZ-UHFFFAOYSA-N (3-chlorophenyl) 4-acetamido-3-[(n'-methoxycarbonylcarbamimidoyl)amino]benzenesulfonate Chemical compound C1=C(NC(C)=O)C(NC(=N)NC(=O)OC)=CC(S(=O)(=O)OC=2C=C(Cl)C=CC=2)=C1 OQLVOYMTVSGURZ-UHFFFAOYSA-N 0.000 description 1
- ZVYDMTNZGWUXFR-UHFFFAOYSA-N (3-ethoxyphenyl) 3-[[amino-(methoxycarbonylamino)methylidene]amino]-4-[(2-methoxyacetyl)amino]benzenesulfonate Chemical compound CCOC1=CC=CC(OS(=O)(=O)C=2C=C(N\C(N)=N\C(=O)OC)C(NC(=O)COC)=CC=2)=C1 ZVYDMTNZGWUXFR-UHFFFAOYSA-N 0.000 description 1
- BCKMKZCGVQENKO-UHFFFAOYSA-N (4-cyanophenyl) 4-[(2-methoxyacetyl)amino]-3-[[(e)-n'-methoxycarbonylcarbamimidoyl]amino]benzenesulfonate Chemical compound C1=C(N\C(N)=N/C(=O)OC)C(NC(=O)COC)=CC=C1S(=O)(=O)OC1=CC=C(C#N)C=C1 BCKMKZCGVQENKO-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KWCPQPFOPUCWPH-UHFFFAOYSA-N 1-(oxomethylidene)guanidine Chemical compound NC(=N)N=C=O KWCPQPFOPUCWPH-UHFFFAOYSA-N 0.000 description 1
- GEGLCBTXYBXOJA-UHFFFAOYSA-N 1-methoxyethanol Chemical compound COC(C)O GEGLCBTXYBXOJA-UHFFFAOYSA-N 0.000 description 1
- WEYSQARHSRZNTC-UHFFFAOYSA-N 1h-benzimidazol-2-ylcarbamic acid Chemical class C1=CC=C2NC(NC(=O)O)=NC2=C1 WEYSQARHSRZNTC-UHFFFAOYSA-N 0.000 description 1
- BHFLSZOGGDDWQM-UHFFFAOYSA-N 1h-benzimidazole;carbamic acid Chemical class NC(O)=O.C1=CC=C2NC=NC2=C1 BHFLSZOGGDDWQM-UHFFFAOYSA-N 0.000 description 1
- SADHVOSOZBAAGL-UHFFFAOYSA-N 3-(trifluoromethoxy)aniline Chemical compound NC1=CC=CC(OC(F)(F)F)=C1 SADHVOSOZBAAGL-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000893172 Chabertia Species 0.000 description 1
- 241001126268 Cooperia Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000243976 Haemonchus Species 0.000 description 1
- 241000920462 Heterakis Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- YRWLZFXJFBZBEY-UHFFFAOYSA-N N-(6-butyl-1H-benzimidazol-2-yl)carbamic acid methyl ester Chemical compound CCCCC1=CC=C2N=C(NC(=O)OC)NC2=C1 YRWLZFXJFBZBEY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000510960 Oesophagostomum Species 0.000 description 1
- 241000243795 Ostertagia Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 241000282849 Ruminantia Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000244174 Strongyloides Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 241000242541 Trematoda Species 0.000 description 1
- 241000243797 Trichostrongylus Species 0.000 description 1
- TWELYPUFCLUBML-UHFFFAOYSA-N [3-(2-methylpropoxy)phenyl] 4-[(2-methoxyacetyl)amino]-3-[[(e)-n'-methoxycarbonylcarbamimidoyl]amino]benzenesulfonate Chemical compound C1=C(N\C(N)=N/C(=O)OC)C(NC(=O)COC)=CC=C1S(=O)(=O)OC1=CC=CC(OCC(C)C)=C1 TWELYPUFCLUBML-UHFFFAOYSA-N 0.000 description 1
- AUNRIVCUEICHNU-UHFFFAOYSA-N [3-(trifluoromethyl)phenyl] 4-(butanoylamino)-3-[[(e)-n'-methoxycarbonylcarbamimidoyl]amino]benzenesulfonate Chemical compound C1=C(N\C(N)=N/C(=O)OC)C(NC(=O)CCC)=CC=C1S(=O)(=O)OC1=CC=CC(C(F)(F)F)=C1 AUNRIVCUEICHNU-UHFFFAOYSA-N 0.000 description 1
- QRLSALSSWXAEJB-UHFFFAOYSA-N [3-(trifluoromethyl)phenyl] 4-[(2-methoxyacetyl)amino]-3-[[(e)-n'-methoxycarbonylcarbamimidoyl]amino]benzenesulfonate Chemical compound C1=C(N\C(N)=N/C(=O)OC)C(NC(=O)COC)=CC=C1S(=O)(=O)OC1=CC=CC(C(F)(F)F)=C1 QRLSALSSWXAEJB-UHFFFAOYSA-N 0.000 description 1
- LJNJJEMEHCBZQQ-UHFFFAOYSA-N [3-(trifluoromethyl)phenyl] 4-chloro-3-nitrobenzenesulfonate Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC(S(=O)(=O)OC=2C=C(C=CC=2)C(F)(F)F)=C1 LJNJJEMEHCBZQQ-UHFFFAOYSA-N 0.000 description 1
- GWBSILSTUTUSGM-UHFFFAOYSA-N [3-[(N'-ethyl-N-methoxycarbonylcarbamimidoyl)amino]-4-[(2-methoxyacetyl)amino]phenyl] benzenesulfonate Chemical compound C1=C(NC(=O)COC)C(NC(NC(=O)OC)=NCC)=CC(OS(=O)(=O)C=2C=CC=CC=2)=C1 GWBSILSTUTUSGM-UHFFFAOYSA-N 0.000 description 1
- UPTWTJUIAGWTBP-UHFFFAOYSA-N [3-[(n'-benzyl-n-methoxycarbonylcarbamimidoyl)amino]-4-[(2-methoxyacetyl)amino]phenyl] benzenesulfonate Chemical compound C1=C(NC(NC(=O)OC)=NCC=2C=CC=CC=2)C(NC(=O)COC)=CC=C1OS(=O)(=O)C1=CC=CC=C1 UPTWTJUIAGWTBP-UHFFFAOYSA-N 0.000 description 1
- DYALAEHIWFZFKL-UHFFFAOYSA-N [3-[[(e)-n'-methoxycarbonylcarbamimidoyl]amino]-4-(pentanoylamino)phenyl] benzenesulfonate Chemical compound C1=C(NC(=N)NC(=O)OC)C(NC(=O)CCCC)=CC=C1OS(=O)(=O)C1=CC=CC=C1 DYALAEHIWFZFKL-UHFFFAOYSA-N 0.000 description 1
- QMUPLEHOHBUTHM-UHFFFAOYSA-N [3-[bis(methoxycarbonylamino)methylideneamino]-4-[(2-methoxyacetyl)amino]phenyl] benzenesulfonate Chemical compound C1=C(N\C(NC(=O)OC)=N\C(=O)OC)C(NC(=O)COC)=CC=C1OS(=O)(=O)C1=CC=CC=C1 QMUPLEHOHBUTHM-UHFFFAOYSA-N 0.000 description 1
- FOLKNFXXHSKYJY-UHFFFAOYSA-N [4-(butanoylamino)-3-[(n-methoxycarbonyl-n'-methylcarbamimidoyl)amino]phenyl] benzenesulfonate Chemical compound C1=C(NC(NC(=O)OC)=NC)C(NC(=O)CCC)=CC=C1OS(=O)(=O)C1=CC=CC=C1 FOLKNFXXHSKYJY-UHFFFAOYSA-N 0.000 description 1
- IDFGSVLIZIXOET-UHFFFAOYSA-N [4-(butanoylamino)-3-[[(e)-n'-methoxycarbonylcarbamimidoyl]amino]phenyl] benzenesulfonate Chemical compound C1=C(NC(=N)NC(=O)OC)C(NC(=O)CCC)=CC=C1OS(=O)(=O)C1=CC=CC=C1 IDFGSVLIZIXOET-UHFFFAOYSA-N 0.000 description 1
- ABSAIOOLAAECTK-UHFFFAOYSA-N [4-(hexanoylamino)-3-[[(e)-n'-methoxycarbonylcarbamimidoyl]amino]phenyl] benzenesulfonate Chemical compound C1=C(NC(=N)NC(=O)OC)C(NC(=O)CCCCC)=CC=C1OS(=O)(=O)C1=CC=CC=C1 ABSAIOOLAAECTK-UHFFFAOYSA-N 0.000 description 1
- YUYMYANYNVLLBW-UHFFFAOYSA-N [4-[(2-methoxyacetyl)amino]-3-[(n'-methoxycarbonylcarbamimidoyl)amino]phenyl] benzenesulfonate Chemical compound C1=C(N\C(N)=N/C(=O)OC)C(NC(=O)COC)=CC=C1OS(=O)(=O)C1=CC=CC=C1 YUYMYANYNVLLBW-UHFFFAOYSA-N 0.000 description 1
- LSAQGPKXLWRUGT-UHFFFAOYSA-N [4-[(2-methoxyacetyl)amino]-3-[[(e)-n'-methoxycarbonylcarbamimidoyl]amino]phenyl] 3-(2-methylpropoxy)benzenesulfonate Chemical compound C1=C(N\C(N)=N/C(=O)OC)C(NC(=O)COC)=CC=C1OS(=O)(=O)C1=CC=CC(OCC(C)C)=C1 LSAQGPKXLWRUGT-UHFFFAOYSA-N 0.000 description 1
- SDPFRUQGUODQOX-UHFFFAOYSA-N [4-[(2-methoxyacetyl)amino]-3-[[(e)-n'-methoxycarbonylcarbamimidoyl]amino]phenyl] 3-chloro-4-methylbenzenesulfonate Chemical compound C1=C(N\C(N)=N/C(=O)OC)C(NC(=O)COC)=CC=C1OS(=O)(=O)C1=CC=C(C)C(Cl)=C1 SDPFRUQGUODQOX-UHFFFAOYSA-N 0.000 description 1
- IOARJLPLSGAIGG-UHFFFAOYSA-N [4-[(2-methoxyacetyl)amino]-3-[[(e)-n'-methoxycarbonylcarbamimidoyl]amino]phenyl] 3-methoxybenzenesulfonate Chemical compound C1=C(N\C(N)=N/C(=O)OC)C(NC(=O)COC)=CC=C1OS(=O)(=O)C1=CC=CC(OC)=C1 IOARJLPLSGAIGG-UHFFFAOYSA-N 0.000 description 1
- KLJCYFNEAWWWFY-UHFFFAOYSA-N [4-[(2-methoxyacetyl)amino]-3-[[(e)-n'-methoxycarbonylcarbamimidoyl]amino]phenyl] 3-propan-2-yloxybenzenesulfonate Chemical compound C1=C(N\C(N)=N/C(=O)OC)C(NC(=O)COC)=CC=C1OS(=O)(=O)C1=CC=CC(OC(C)C)=C1 KLJCYFNEAWWWFY-UHFFFAOYSA-N 0.000 description 1
- WRXCMINGXAVONE-UHFFFAOYSA-N [4-[(2-methoxyacetyl)amino]-3-[[(e)-n'-methoxycarbonylcarbamimidoyl]amino]phenyl] 3-propoxybenzenesulfonate Chemical compound CCCOC1=CC=CC(S(=O)(=O)OC=2C=C(N\C(N)=N/C(=O)OC)C(NC(=O)COC)=CC=2)=C1 WRXCMINGXAVONE-UHFFFAOYSA-N 0.000 description 1
- PSEVLPBSVNCJCN-UHFFFAOYSA-N [4-acetamido-3-[(n-methoxycarbonyl-n'-methylcarbamimidoyl)amino]phenyl] benzenesulfonate Chemical compound C1=C(NC(C)=O)C(NC(NC(=O)OC)=NC)=CC(OS(=O)(=O)C=2C=CC=CC=2)=C1 PSEVLPBSVNCJCN-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 229940124339 anthelmintic agent Drugs 0.000 description 1
- 239000000921 anthelmintic agent Substances 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 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
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229960005473 fenbendazole Drugs 0.000 description 1
- IRHZVMHXVHSMKB-UHFFFAOYSA-N fenbendazole Chemical compound [CH]1C2=NC(NC(=O)OC)=NC2=CC=C1SC1=CC=CC=C1 IRHZVMHXVHSMKB-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 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
- 239000008187 granular material Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- BAXLBXFAUKGCDY-UHFFFAOYSA-N mebendazole Chemical compound [CH]1C2=NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CC=C1 BAXLBXFAUKGCDY-UHFFFAOYSA-N 0.000 description 1
- 229960003439 mebendazole Drugs 0.000 description 1
- BPQPMIVFFHJAMW-UHFFFAOYSA-N methyl (ne)-n-[amino-[2-[(2-methoxyacetyl)amino]-5-phenoxyanilino]methylidene]carbamate Chemical compound C1=C(NC(N)=NC(=O)OC)C(NC(=O)COC)=CC=C1OC1=CC=CC=C1 BPQPMIVFFHJAMW-UHFFFAOYSA-N 0.000 description 1
- CTTQZMFVWLLLCK-UHFFFAOYSA-N methyl N-(N'-methylcarbamimidoyl)carbamate Chemical compound COC(=O)NC(N)=NC CTTQZMFVWLLLCK-UHFFFAOYSA-N 0.000 description 1
- PYYOLLJLOKSVNW-UHFFFAOYSA-N methyl N-[C-methylsulfanyl-N-(1-phenylethyl)carbonimidoyl]carbamate Chemical compound COC(=O)NC(SC)=NC(C)C1=CC=CC=C1 PYYOLLJLOKSVNW-UHFFFAOYSA-N 0.000 description 1
- PAVDBWFMFPEZIE-UHFFFAOYSA-N methyl n-(diaminomethylidene)carbamate Chemical compound COC(=O)NC(N)=N PAVDBWFMFPEZIE-UHFFFAOYSA-N 0.000 description 1
- ZVQWOWXQCUFSCA-UHFFFAOYSA-N methyl n-(n-butyl-c-methylsulfanylcarbonimidoyl)carbamate Chemical compound CCCCN=C(SC)NC(=O)OC ZVQWOWXQCUFSCA-UHFFFAOYSA-N 0.000 description 1
- YOHHRGBAXFZGRV-UHFFFAOYSA-N methyl n-(n-ethyl-c-methylsulfanylcarbonimidoyl)carbamate Chemical compound CCN=C(SC)NC(=O)OC YOHHRGBAXFZGRV-UHFFFAOYSA-N 0.000 description 1
- MVLWYBBNGYTKJB-UHFFFAOYSA-N methyl n-[n-(cyclohexylmethyl)-c-methylsulfanylcarbonimidoyl]carbamate Chemical compound COC(=O)NC(SC)=NCC1CCCCC1 MVLWYBBNGYTKJB-UHFFFAOYSA-N 0.000 description 1
- MZGCLZOJWGVQGX-UHFFFAOYSA-N methyl n-carbamimidoyl-n-phenylcarbamate Chemical class COC(=O)N(C(N)=N)C1=CC=CC=C1 MZGCLZOJWGVQGX-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical class C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 229950007337 parbendazole Drugs 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- HIYSRSZBCNBQSY-UHFFFAOYSA-N phenyl 3-[(n'-butyl-n-methoxycarbonylcarbamimidoyl)amino]-4-[(2-methoxyacetyl)amino]benzenesulfonate Chemical compound C1=C(NC(=O)COC)C(NC(NC(=O)OC)=NCCCC)=CC(S(=O)(=O)OC=2C=CC=CC=2)=C1 HIYSRSZBCNBQSY-UHFFFAOYSA-N 0.000 description 1
- LAZBFXGTLDXAJE-UHFFFAOYSA-N phenyl 4-(hexanoylamino)-3-[[(e)-n'-methoxycarbonylcarbamimidoyl]amino]benzenesulfonate Chemical compound C1=C(NC(=N)NC(=O)OC)C(NC(=O)CCCCC)=CC=C1S(=O)(=O)OC1=CC=CC=C1 LAZBFXGTLDXAJE-UHFFFAOYSA-N 0.000 description 1
- HDRHWXNZPUTFLK-UHFFFAOYSA-N phenyl 4-[(2-methoxyacetyl)amino]-3-[(n-methoxycarbonyl-n'-methylcarbamimidoyl)amino]benzenesulfonate Chemical compound C1=C(NC(NC(=O)OC)=NC)C(NC(=O)COC)=CC=C1S(=O)(=O)OC1=CC=CC=C1 HDRHWXNZPUTFLK-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000007017 scission Effects 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
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/75—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Monokarboksylater av fenylguanidinsulfonsyreestere, fremgangsmåte til deres fremstilling og deres anvendelse som legemiddel.
Det er kjent at fenylguanidiner med formel:,
hvori R betyr lavere alkyl, R' betyr lavere-alkyl eller hydrogen og R" betyr -C4Hg, -COCgH5, -OCgH5 eller -SC6H5er antelmintisk virksomme (sml. DOS 21 17 293, 22 50 911, 23 04 764 og 24 23 679).
Disse fenylguanidiner og også antelminthica fra klassen benzimidazol-2-karbaminater, som parbendazol, mebendazol, fenbendazol og andre representater for denne stoffklasse er tungt oppløselig i vann og kan derfor bare appliseres oralt'i human-
og veterinærmedisinen. Med disse stoffer lar det seg ikke uten videre fremstille parenteralt anvendbare,lokalt godt tålbare opp-løsninger, slik de spesielt kreves for behandling av store dyr som storfe, hester og svin.
Videre er det ifølge DOS 26 30 847 kjent metoksy-karbonylfenylguanidiner med formel:
hvori X betyr oksygen, svovel, -SO-, -SO^- eller -CO-gruppen og
hvori X i stilling 4 eller 5 er forbundet med fenylguanidino-resten, R betyr hydrogen, halogen, alkoksy-(C-^-C^) eller trifluormetyl, R^" betyr hydrogen, eventuelt substituert alkyl, eventuelt, substituert alkoksy, eventuelt substituert alkoksyalkyl,
2
eventuelt substituert aralkyl, R betyr hydrogen, alkyl, cykloalkyl, cykloalkylalkyl eller aralkyl, hvis salter med uorganiske eller organiske syrer er oppløselig i vann og dermed anvendbare parenteralt. De virker riktignok mot et bredt spektrum av nematoder, imidlertid ikke tilstrekkelig overfor leverigler, en parasitt som ofte forekommer sammen med nematoden i mave-tarm-kanalen,, og hensiktsmessig bekjempes sammen med nematodene.
Ifølge DOS 24 41 201 og 24 41 202 er det riktignok kjent benzimi-dazolkarbaminater med formel
hvori X betyr gruppen -OSO2- eller -SO2O-, R betyr alkyl med 1 til 4 C-atomer, R<1>og R" betyr hver uavhengig av hverandre hydrogen, hydroksyl, alkyl eller alkoksy med hver gang 1-4 C-atomer, halogen, trifluormetyl eller CN og som er virksomme såvel overfor nematoder som også overfor leverigler, men på grunn av den lille oppl.øselighet i vann bare er appliserbare oralt.
Oppfinnelsens gjenstand er monokarboksylater av fenylguanidinsulfonsyreestere med formel:
hvori
X betyr-OS02- eller -S020-
R betyr hydrogen, halogen, alkyl med 1-4 C-atomer,
alkoksy med 1-4 C-atomer, -CN eller -CF.,,
R betyr hydrogen,
eventuelt substituert alkyl,
eventuelt substituert alkoksy,
eventuelt substituert alkoksyalkyl eller
eventuelt substituert aralkyl og
2
R betyr hydrogen, alkyl, cykloalkyl, cykloalkyl-alkyl
eller aralkyl, og deres fysiologisk tålbare salter med organiske eller uorganiske syrer.
Forbindelsene ifølge oppfinnelsen med formel I har basisk karakter. De kan anvendes som antelmintiske virksomme stoffer,som frie baser eller i form av deres salter med fysiologisk tålbare uorganiske eller organiske syrer, eksempelvis hydro-halogenider, fortrinnsvis hydroklorider, sulfater, fosfater, nitrater, maleinater, fumarater, acetater, propionater, lactater, metansulfonater eller naftalindisulfonater.
Oppfinnelsens gjenstand er også en fremgangsmåte til fremstilling av monokarboksylater av fenylguanidinsulfonsyreestere med formel I, idet fremgangsmåten erkarakterisert vedat
a) et substituert anilinderivat med formel II
hvori X, R og R har den for formel I angitte betydning, omsettes
enten
a-^) med et isotiourinstof f derivat med formel III
2 3
hvori R har den til formel I angitte betydning og R betyr alkyl med 1-4 C-atomer, eller
a2^ med et O-metylisourinstoffderivat med formel Illa
3
hvori R betyr alkyl med 1-4 Oatomer,
i nærvær av et .oppløsningsmiddel og eventuelt i nærvær av en syre, eller
b) et fenylguanidin-bis-karboksylat med formel IV
. hvori X, R og R 1 har den ovenfor angitte betydning og R 4 betyr
alkyl eller alkoksy,
hydrolyseres,
og eventuelt en således dannet forbindelse med formel I, hvori R 2 betyr hydrogen alkyleres.
I formlene I til IV har substituentene følgende fore-trukne betydninger: R som halogen betyr fluor, klor eller brom, spesielt klor og fluor.
Alkoksy-(C^-C^) betyr metoksy, etoksy, n-propoksy, i-propoksy, n-butoksy, i-butoksy og t-butoksy, fortrinnsvis metoksy og etoksy.'
Som eventuelt substituert alkyl R står rettlinjet^ eller forgrenet alkyl med fortrinnsvis 1-6, spesielt 1-4 C-atomer. Eksempelvis skal det nevnes eventuelt substituert metyl, etyl,
n- og i-propyl, n-,1- og t-butyl.
Som eventuelt substituert alkoksy R"<*>" står rettlinjet eller forgrenet alkoksy med fortrinnsvis 1 til 6, spesielt 1-4 C-atomer. Eksempelvis skal det hevnes eventuelt substituert metoksy,. etoksy, n- og i-propoksy og n-, i- og t-butoksy.
som eventuelt substituert alkoksyalkyl betyr rettlinjet eller forgrenet alkoksyalkyl med fortrinnsvis 1-6, spesielt 1-4 C-atomer i alkoksydelen og fortrinnsvis 1-6, spesielt 1-4 C-atomer i alkyldelen. Eksempelvis skal det nevnes eventuelt substituert
metoksymetyl, metoksyetyl, etoksymetyl, etoksyetyl.
R som eventuelt substituert aralkyl betyr eventuelt
i aryldelen og/eller alkyldélen substituert aralkyl med fortrinnsvis 6-10 karbonatomer i aryldelen og fortrinnsvis 1-4, spesielt 1 eller 2 karbonatomer i alkyldélen, idet alkyldélen kan være
rettlinjet eller forgrenet. Eksempelvis skål det nevnes eventuelt substituert benzyl og fenyletyl.
De forskjellige rester R kan ha en eller flere, fortrinnsvis 1-3, spesielt 1 eller 2 like eller forskjellige substituenter. Som substituenter skal det eksempelvis anføres: Alkoksy med fortrinnsvis 1-4, spesielt 1 eller 2 karbonatomer som metoksy, etoksyd, n- og i-propyloksy og n-, i- og t-butyloksy; alkyltio med fortrinnsvis 1-4, spesielt 1 eller 2 karbonatomer, som metyltio, etyltio, n- og i-propyltio og n-, i-og t-butyltio; halogenalkyl med fortrinnsvis 1-4, spesielt 1 eller 2 karbonatomer og fortrinnsvis 1-5, spesielt 1-3 halogenatomer, idet halogenatomene er like eller forskjellige, og som halogenatomer står fortrinnsvis fluor, klor eller brom, spesielt fluor som trifluormetyl; hydroksy; halogen, fortrinnsvis fluor, klor, brom og jod, spesielt fluor og klor; cyano; nitro; amino; mono-alkyl- og dialkylamino med fortrinnsvis 1-4, spesielt 1 eller 2 karbonatomer pr.alkylgruppe som metylamino, metyl-etyl-amino,
n- og i-propylamino og metyl-n-butylamino; karbalkoksy med fortrinnsvis 2-4, spesielt 2 eller karbonatomer, som karbometoksy og karboetoksy; sulfo (-SO^H); alkylsulfonyl med fortrinnsvis 1-4, spesielt.1 eller 2 karbonatomer, som metylsulfonyl og etyl-sulfohyl; arylsulfonyl med fortrinnsvis 6 eller 10 arylkarbonatomer som fenylsulfonyl.
R 2som alkyl betyr rettlinjet eller forgrenet alkyl med fortrinnsvis 1-6, spesielt 1-4 karbonatomer. Eksempelvis skal det nevnes metyl, etyl, n- og i-propyl, n-, i- og t-butyl.
R 2 som cykloalkyl betyr mono-, bi- og tricyklisk cykloalkyl med fortrinnsvis 3-10, spesielt 3, 5 eller 6 karbonatomer. Eksempelvis skal det nevnes cyklopropyl, cyklobutyl, cyklopentyl, oyklohexyl, cykloheptyl, bicyklo[2.2.1]heptyl, bicyklo[2.2.2]octyl og adamantyl.
Som cykloalkylalkyl R 2 står cykloalkylalkyl med fortrinnsvis 3-10, spesielt 3/5 eller 6 karbonatomer i cykloalkyl- v delen og fortrinnsvis 1-6, spesielt 1-4 karbonatomer i alkyldélen.
Eksempelvis skal det nevnes cyklopropylmetyl, cyklo-pentylmetyl, cyklohexylmetyl, cyklopropyletyl, cyklopentyletyl og cyklohexyletyl.
Som aralkyl R står aralkyl med fortrinnsvis 6Qlier 10, spesielt 6 karbonatomer i aryldelen og fortrinnsvis 1-4, spesielt 1 eller 2 karbonatomer i alkyldélen, idet alkyldélen kan være rettkyedet eller forgrenet. Eksempelvis skal det nevnes benzyl og fenyletyl.
Som R3-alkyl-(C^-C^) i formel III står metyl, etyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, spesielt metyl og etyl..
R 4 som alkyl betyr rettlinjet eller forgrenet alkyl med fortrinnsvis 1-6, spesielt 1-4 karbonatomer.. Eksempelvis skal det nevnes metyl, etyl, n- og i-propyl, n-, i- og t-butyl.
R som alkoksy betyr rettlinjet eller forgrenet alkoksy med . fortrinnsvis 1-6, spesielt 1-4 karbonatomer. Eksempelvis skal det nevnes metyl, etoksy, n- og i-propoksy og n-, i- og t-butoksy.
i Blant monokarboksylatene av fenylguanidinsulfonsyre-estere med formel I har det som antelminthica vist seg egnet de i spesiell grad hvori substituentene R betyr hydrogen, klor, trifluormetyl eller -CN, R"*" betyr hydrogen,metyl, etyl, propyl, isopropyl eller metoksymetyl og R<2>betyr hydrogen.
De som utgangsmaterialer anvendte substituerte anilin-derivater med formel II og fenylguanidinderivatene med formel IV, samt fremgangsmåten til deres fremstilling er kjent fra DOS 2608 238.
Isotiourinstoffer med formel III er delvis kjent.
De kan fåes ved omsetning av eventuelt substituerte S-alkyliso-tiourinstoffer med klormaursyremetylester.
I detalj skal det eksempelvis nevnes følgende isotiourinstof f er med formel III: N-metoksykarbonyl-S-metyl-isotiourinstoff
N-metoksykarbonyl-N<1->metyl-S-metyl-isotiourinstoff
N-metoksykarbonyl-N'-etyl-S-metyl-isotiourinstoff
N-metoksykarbonyl-N1-propyl-S-metyl-isotiourinstoff N-metoksykarbonyl-N'-isopropyl-S-metyl-isotiourinstoff.
N-metoksykarbonyl-N'-butyl-S-metyl-isotiourinstoff
N-metoksykarbonyl-N'-isobutyl-S-metyl-isotiourinstoff N-metbksykarbonyl-N'-tert.butyl-S-metyl-isotiourinstoff N-metoksykarbonyl-N'-cyklohexyl-S-metyl-isotiourinstoff
N-metoksykarbonyl-N'-cyklohexylmetyl-S-metyl-isotiourinstoff N-metoksykarbonyl-N<1->benzyl-S-metyl-isotiourinstoff
N-metoksykarbonyl-N'-a-fenetyl-S-mety1-isotiourinstoff N-metoksykarbonyl-N'-3-fenetyl-S-metyl-isotiourinstoff.
O-metylisourinstoffer med formel Illa kan fåes ved omsetning, av. tilsvarende O-alkylisourinstof f er med klormaursyremetylester.
Som oppløsningsmidler kommer det ved omsetning av forbindelser med formel II'" med> stoffer med formel III resp.
Illa på tale alle polare organiske oppløsningsmidler, fortrinns-
vis alkoholer, som metanol, isopropanol, samt deres blandinger
med vann, ketoner, som aceton, samt deres blanding med vånn, men også etere som dioksan eller tetrahydrofuran.
Ved fremstillingen av forbindelsene med formel il fra forbindelser med formel II med stoffer av formel III resp. Illa kan det som katalysatorer anvendes ønskelige organiske eller uorganiske syrer. Fortrinnsvis anvendér man lett tilgjengelige
syre som saltsyre, svovelsyre, salpetersyre,maursyre, eddiksyre, p-toluensulfonsyre.
Reaksjonstemperaturene ved fremstillingen kan vari-
eres innen et område. Vanligvis arbeider man mellom 0°C og 120°C, fortrinnsvis mellom 10 og 30°C. Omsetningen gjennomføres vanligvis ved normaltrykk.
Omsetningen av forbindelsene med formel II med slike
med formel III resp. Illa foregår hensiktsmessig i ekvimolare mengder.
Hydrolysene av forbindelser med formel IV gjennom-
føres hensiktsmessig ved oppvarming i en alkohol som metanol, etanol, isopropanol samt deres blandinger med vann i nærvær av en base,f.eks. et alifatisk amin som metylamin, butylamin, piperidin eller N-metyl-piperazin, et alkoholat som natriummetylat, eller i nærvær av en uorganisk base som KOH eller NaOH. Som spesielt egnet har det vist seg oppløsninger av butylamin i metanol eller etanol. Hydrolysen lykkes også ved lengere oppvarming med vann i nærvær av et oppløsningsmiddel som aceton.
Hydrolysereaksjonens reaksjonstemperaturer kan varieres innenfor et stort område, vanligvis arbeider man mellom 0°C og 120°C, fortrinnsvis mellom 40 og 100°C. Omsetningen gjennomføres vanligvis ved normaltrykk. Den er vanligvis i basisk område av-
sluttet allerede etter få minutter.
Monokarboksylatene av fenylguanidinsulfonsyreestrene med formel I omfatter eksempelvis følgende forbindelser: N-(2-acetamido-5-fenylsulfonyloksy-fenyl)-N<1->metoksykarbonyl-guanidin
N-(2-formamido-5-fenylsulfonyloksy-fenyl)-N<1->metoksykarbonyl-guanidin
N-(2-propionamido-5-fenylsulfonyloksy-fenyl)-N-metoksykarbonyl-guanidin
N-(2-butyramido-5-fenylsulfonyloksy-fenyl)-N'-metoksykarbonyl-guanidin N-(2-iso-butyramido-5-fenylsulfonyloksy-fenyl)-N<1->metoksykarbonyl-guanidin
N-(2-valeramido-5-fenylsulfonyloksy-fenyl)-N'-metoksykarbonyl-guanidin
.N-(2-iso-valeramido-5-fenylsulfonyloksy-fenyl)-N'-metoksykarbony1-guanidin
N-(2-capronamido-5-fenylsulfonyloksy-fenyl)-N'-metoksykarbonyl-guanidin
N-(2-iso-capronamido-5-fenylsulfonyloksy-fenyl)-N'-metoksykarbony1-guanidin-N-(2-metoksyacetamido-5-fenylsulfonyloksy-fenyl)-N'-metoksykarbonyl-guanidin
N- (2-acetamido-5- (4-klor-f enylsulfonyloksy) -f enyl) -N/.-metoksykarbonyl-guanidin
N- (-2-acetamido-5- (3-klor-f enylsulf onyloksy) -f enyl) -N' -metoksy-karbony 1-guanid in
N-(2-acetamido-5-(2-klor-fenylsulfonyloksy)-fenyl)-N'-metoksykar-bony 1-guanidin
N-(2-metoksyacetamido-5-(3-klor-fenylsulfonyloksy)-fenyl)-N'-metoksykarbony1-guanidin
N-(2-metoksyacetamido-5-(3-brom-fenylsulfonyloksy)-fenyl)-N1 - metoksykarbony1-guanidin
N-(2-metoksyåcetamido-5-(3-metyl-fenylsulfonyloksy)-fenyl)-N* - metoksykarbony1-guanidin
N-(2-metoksyacetamido-5-(3-metyl-fenulsylfonyloksy)-fenyl)-N'-metoksykarbony1-guanidin
N-(2-metoksyacetamido-5-(3-tert.-butyl-fenylsulfonyloksy)-fenyl)-N<1->metoksykarbonyl-guanidin
N-(2-metoksyacetamido-5-(3-metoksy-fenylsulfonyloksy)-fenyl)-N'-metoksykarbonyl-guanidin
N-(2-metoksyacetamido-5-(3-etoksy-fenylsulfonyloksy)-fenyl)-N'-metoksyakrbony1-guanidin
N-(2-metoksyacetamido-5-(3-propoksy-fenylsulfonyloksy)-fenyl)-N'-metoksykarbonyl-guanidin
N-(2-metoksyacetamido-5-(3-isopropoksy-fenylsulfonyloksy)-fenyl)-N'-metoksykarbonyl-guanidin
N-(2-metoksyacetamido-5-(3-butoksy-fenylsulfonyloksy)-fenyl)-N1 - metoksykarbonyl-guanidin
N-(2-metoksyacetamido-5-(3-isobutoksy-fenylsulfonyloksy)-fenyl)-N'-metoksykarbonyl-guanidin
N-(2-metoksyacetamido-5-(4-cyano-fenylsulfonyloksy)-fenyl)-N'-metoksykarbonyl-guanidin
N-(2-metoksyacetamido-5-(3-trifluormetyl-fenylsulfonyloksy)-fenyl)-N<1->metoksykarbony1-guanidin
N-(2-metoksyacetamido-5-(3-klor-4-metyl-fenylsulfonyloksy)-fenyl)-N'-metoksykarbonyl-guanidin
N-(2-propionamido-5-(3-trifluormetyl-fenylsulfonyloksy)-feny1-N'-metoksykarbonyl-guanidin
N-(2-butyramido-5-(3-trifluormetyl-fenylsulfonyloksy)-fenyl-N'-metoksykarbonyl-guanidin
N-(2-formamido-5-(3-trifluormetyl-fenylsulfonyloksy)-fenyl-N'-metoksykarbonyl-guanidin
N-(2-metoksyacetamido-5-fenylsulfonyloksy-fenyl)-N'-metoksykarbo-ny 1-N "-me ty 1-guanidin
N-(2-metoksyacetamido-5-fenylsulfonyloksy-fenyl)-N<1->metoksykarbo-ny 1-N "-bu ty 1-guanid in
N-(2-metoksyacetamido-5-fenylsulfonyloksy-feny1)-N<1->metoksykarbo-ny 1-N" -cyklohexy 1-guanid in
N-(2-formamido-5-fenylsulfonyloksy-fenyl)-N'-metoksykarbonyl-N"-metylguanidin
N-(2-propionamido-5-fenylsulfonyloksy-feny1)-N'-metoksykarbony1-N"-metylguanidin
N-(2-butyramido-5-fenylsulfonyloksy-fenyl)-N'-metoksykarbony1-N"-metylguanidin
N-(2-acetamido-5-fenoksysulfonyl-fenyl)-N'-metoksykarbonyl-metylguanidin
N-(2-butyramido-5-fenoksysulfonyl-fenyl)-N<1->metoksyakrbonyl-guanidin
N-(2-iso-butyramido-5-fenoksysulfonyl-fenyl)-N'-metoksykarbonyl-guanidin
N-(2-valeramido-5-fenoksysulfonyl-fenyl)-N<1->metoksykarbonyl-guanidin
N-(2-iso-valeramido-5-fenoksysulfonyl-fenyl)-N'-metoksykarbonyl-guanidin
N-(2-capronamido-5-fenoksysulfonyl-fenyl)-N'-metoksykarbonyl-guanidin
N-(2-iso-capronamido-5-fenoksysulfonyl-fenyl)-N'-metoksykarbonyl-guanidin
N-(2-metoksyacetamido-5-fenoksysulfonyl)-fenyl)-N'-metoksykarbonyl-guanidin N- (2-acetamido-5- (4-klor-f enoksysulf onyl) -fenyl.) -N' -metoksykarbonyl-guanidin
N-(2-acetamido-5-(3-klor-fenoksysulfonyl)-fenyl)-N'-metoksykarbonyl-guanidin
N-(2-acetamido-5-(2-klor-fenoksysulfonyl)-fenyl)-N'-metoksykarbonyl-guanidin
N-(2-metoksyacetamido-5-(3-klor-fenoksysulfonyl)-fenyl)-N'-metoksykarbonyl-guanidin
N-(2-metoksyacetamido-5-(3-brom-fenoksysulfonyl)-fenyl)-N1-metoksy- .
karbony1-guanidin
N-(2-metoksyacetamido-5-(3-metyl-fenoksysulfonyl)-fenyl)-N'-metoksykarbonyl-guanidin
N, (2-metoksyacetamido-5- (3-.tert.-butyl-f enoksysulf onyl) -fenyl) -N1-me toksykarbony1-guanidin
N-(2-metoksyacetamido-5-(3-metoksy-fenoksysulfonyl)-fenyl) -N1 - metoksykarbonyl-guanidin
N-(2-metoksyacetamido-5-(3-etbksy-fenoksysulfonyl)-fenyl)-N'-metoksykarbonyl-guanidin
N-(2-metoksyacetamido-5-(3-propoksy-fenoksysulfonyl)-fenyl)-N1 - metoksykarbonyl-guanidin
N-(2-métoksyacetamido-5-(3-isopropoksy-fenoksysulf onyl)-fenyl)-N'-metoksykarbony1-guanidin
N-(2-metoksyacetamido-5-(3-butoksy-fenoksysulfonyl)-fenyl)-N<1->metoksykarbonyl-guanidin
N-(2-metoklsyacetamido-5-(3-isobutoksy-fenoksysulfonyl)-fenyl)-N'-metoksykarbonyl-guanidin
N-(2-metoksyacetamido-5-(4-cyano-fenoksysulfonyl)-fenyl)-N'-metoksykarbonyl-guanidin
N-(2-metoksyacetamido-5-(3-trifluormetyl-fenoksysulfonyl)-fenyl)-N'-metoksykarbonyl-guanidin N-(2-metpksyacetamido-5-(3-klor-4-metyl-fenoksysulfonyl)-fenyl)-N<1->metoksykarbonyl-guanidin
N-(2-propionamido-5-(3-trifluormetyl-fenoksysulfonyl)-fenyl)-N<1->metoksykarbonyl-guanidin
N-(2-butyramido-5-(3-trifluormetyl-fenoksysulfonyl)-fenyl)-N' - metoksykarbonyl-guanidin
N-(2-formamido-5-(3-trifluormetyl-fenoksysulfonyl)-fenyl)-N<1->metoksykarbonyl-guanidin
N-(2-metoksyacetamido-5-fenoksysulfonyl-fenyl)-N'-metoksykarbonyl-N"-mety1-guanidin
N-(2-metoksyacetamido-5-fenoksysulfonyl-fenyl)-N'-metoksykarbonyl-N"-butyl-guanidin N-(2-metoksyacetamido-5-fenoksysulfonyl-fenyl)-N<1->metoksykarbonyl-N"-butyl-guanidiri
N-(2-metoksyacetamido-5-fenoksysulfonyl-fenyl)-N'-metoksykarbonyl-N"-dyklohexyl-guanidin
N-(2-formamido-5-fenoksysulfonyl-fenyl)-N<1->metoksykarbonyl-N"-mety1-guanidin
N-(2-propionamido-5-fenoksysulfonyl-fenyl)-Nr<->metoksykarbony1-N"-mety1-guanidin
N-(2-butyramido-5-fenoksysulfonyl-fenyl)-N<1->metoksykarbony1-N"-metyl-guanidin.
Monokarboksylatene av fenylguanidinsulfonsyreestere med formel I i henhold til oppfinnelsen er verdifulle kjemotera-peutika og egner seg til bekjempelse av parasitære sykdommer hos mennesker og dyr, spesielt av helminter og leverigler.
De er spesielt virksomme overfor et stort antall helminter, f.eks. Haemonchus, Trichostrongylus, Ostertagia, Strongy-loides, Cooperia, Chabertia, Oesophagostomum, Hyostrongulus, Ankylostoma, Askaris og Heterakis og Fasciola. Spesielt utpreget er virkningen overfor mave-tarm-strongylider og leverigler, hvorav fremfor alt drøvtyggere angripes. Derfor anvendes forbindelsen i henhold til oppfinnelsen spesielt i veterinærmidler.
Forbindelsen ifølge, oppfinnelsen med formel I kan i motsetning til de ifølge DOS 21 17 293, 22 50 911, 23 04 764 og 24 23 679 kjente forbindelser, fortrinnsvis appliseres.parenteralt og virker, i motsetning til de ifølge DOS 26 30 84 7 kjente forbihdel- ser overraskende såvel overfor nematoder som også overfor leverigler.
Forbindelsen med formel I administreres alt etter til-fellets tilstand i doseringer mellom 0,5 og.50 mg/kg legemsvekt i 1 til 14 dager.
Til oral applikasjon kommer det på tale tabletter,, dragéer, kapsler, pulvere, granulater eller pastaer som inneholder de virksomme stoffer sammen med vanlige hjelpe- eller bærestoffer som stivelse, cellulosepulvere, talkum, magnesiumstearat, sukker, gelatin, kalsiumkarbonat, finfordelt kiselsyre, karboksymetylcellu-lose eller lignende stoffer.
Fremgangsmåteproduktene er ikke bare utmerket virksomme applisert oralt, men virker også parenteralt.
Til parenteral applikasjon oppløser man enten en forbindelse med formel I i en ekvivalent av en organisk eller uorganisk syre, eller man oppløser et salt av disse forbindelser i vann.
Muligheten for parenteral applikasjon av forbindelser med formel I er et betraktelig fremskritt i den antelmintiske behandling av dyr, som storfe, hester, svin, sauer, hunder, katter osv. Det er spesielt egnet for massebehandling av store dyr som storfe og hester, spesielt, når disse dyr samtidig er infisert med leverigler.
Fremstillingseksempler
Fremgangsmåte
Eksempel 1. 1
Man oppvarmer en blanding av 3,4 g 2-metoksyacetamido-5-fenylsulfonyloksy-anilin (formel II), 25 ml metanol, 3 ,ml is-eddik og 2 g N-metoksykarbonyl-S-metyl-isotiourinstoff (formel III) en dag under tilbakeløp. Etter henstand natten over ved værelsetemperatur frafiltrerer man det utskilte N-(2-metoksyacetamido-5-fenylsulfonyloksy-fenyl)-N'-metoksykarbonyl-guanidin (formel I). Utbytte 0,4 g, smp. 19 0°C.
På analog måte vil man av substituerte 2-acylamino-anilinderivater (formel II) og N-substituerte N-metoksykarbonyl-S-metyl-isotiourinstoffer (formel III) få: 1.2 N-(2-formamido-5-fenylsulfonyloksy-fenyl)-N'-metyl-N"-metoksykarbonyl-guanidin
1.3. N-(2-acetamido-5-fenylsulfonyloksy-fenyl)-N'-mety1-N"-metoksykarbonyl-guanidin
1.4 N-(2-metoksyacetamido-5-fenylsulfonyloksy-fenyl)-N<1->
mety1-N"-metoksykarbony1-guanidin
1.5 N-(2-propionamido-5-fenylsulfonyloksy-fenyl)-N'-mety1-N"-metoksykarbonyl-guanidin
1.6 N-(2-metoksyacetamido-5-fenylsulfonyloksy-fenyl)-N'-etyl-N"-metoksykarbonyl-guanidin
1.7. N-(2-metoksyacetamido-5-fenylsulfonyloksy-fenyl)-N\-propyl-N"-metoksykarbonyl-guanidin
1.8 N-(2-metoksyacetamido-5-fenylsulfonyloksy-fenyl)-N'-buty1-N"-metoksykarbonyl-guanidin
1.9<;>N-(2-metoksyacetamido-5-fenylsulfonyloksy-fenyl)-N'-isobuty1-N"-metoksykarbony1-guanidin
1.10 N-(2-metoksyacetamido-5-fenylsulfonyloksy-fenyl)-N<1->
cyklohexyl-N"-metoksykarbonyl-guanidin
1.11 N-(2-metoksyacetamido-5-fenylsulfonyloksy-fenyl)-N'-cyklohexyImety1-N"-metoksykarbony1-guanidin 1.12 N-(2-metoksyacetamido-5-fenylsulfonyloksy-fenyl)-N'-benzy1-N"-metoksykarbony1-guanidin
Fremgangsmåte a2)
Eksempel 2
Man oppvarmer en blanding av 3,4 g 2-metoksyacetamido-5-fenylsulfonyloksy-anilin (formel II),, 2,5 ml metanol, 3 ml is-éddik og 2 g.N-metoksykarbonyl-O-metyl-isourinstoff (formel Illa) en dag under tilbakeløp. Etter henstand natten over ved værelsetemperatur frafiltrerer man væsken fra de utskilte forurensninger, inndamper filtratet til tørrhet, opptar residuet i eddikester, vasker flere ganger med vann og inndamper oppløsningsmidlet etter tørking med MgSO^under nedsatt trykk. Etter utrøring av residuet med 0,5 n HCl ved værelsetemperatur og utfelling av filtratet med ammoniakk fåes det dannede N-(2-metoksyacetamido-5-fenyloksy-fenyl)-N'-metoksykarbonyl-guanidin (formel I) i ren form. Det er etter tynnsjiktskromatografien identsik med det ifølge Eks. 1 dannede fremgangsmåte-produkt.
Fremstilling av utgangsmaterialet med formel Illa:
Man oppløser 246 g O-metyl-isourinstoffsulfat i 300 ml vann og tildrypper ved 10°C 163 ml klormaursyremetylester og deretter 170 g NaOH, oppløst i 510 ml vann. Man omrører ytterligere 3 timer ved værelsetemperatur. Deretter ekstraherer man reaksjons-, oppløsningen med eddikester og tørker dette ekstrakt med vannfritt natriumsulfat. Etter inndampning under nedsatt trykk ved en
maksimal badtemperatur på 40°C får man N-metoksykarbonyl-O-metyl-isourinstoff som olje, som etterhvert stivner til krystaller med et smeltepunkt på 4 0°C. Utbytte 150 g.
Fremgangsmåte b) (Hydrolyse)
Eksempel 3
Man omrører en blanding av 2 g N-(2-metoksyacetamido-5-fenylsulfonyloksyfenyl)-N<1>,N"-bis-metoksykarbonylguanidin (formel IV), 20 ml metanol og 2ml butylamin i 10 minutter ved 50°C. Allerede etter to minutter er det dannet en klar oppløsning, hvorav det-kort deretter faller ut N-(2-metoksyacetamido-5-fenylsulfonyl-oksy-f enyl)-N1-metoksykarbonyl-guanidin (formel I).. Man lar reaksjonsb landingen stå noen timer ved 10°C, frafiltrerer ut-fellingen og vasker den med metanol. Utbytte 1,7 g, smp. 190°C under spaltning. Fremgangsmåteproduktet er identisk med det som fåes ifølge Eks. 1.
Det for gjennomføring av reaksjonen nødvendige N-(2-metoksyacetamido-5-fenylsulfonyloksy-fenyl)-N'-N"-bis-metoksykarbonyl-guanidin (formel IV) fåes ifølge. DOS 26 08 .238
Eks. 5.2.
I stedet for butylamin kan man ved samme arbeidsteknikk også anvende en 40%-ig vandig metylaminoppløsning, piperidin eller N-metyl-piperazin. Tilsvarende resultater fåes også med natrpn-lut, ammoniakk eller natriummetylat i alkoholisk oppløsning.
Eksempel 4 (dessuten fremgangsmåte b) )
Analogt Eks. 3 fremstilles de i følgende tabell opp-førte forbindelser med formel I fra de tilsvarende utgangsmaterialer
4
med formel IV, hvori X hver gang betyr -SO2O- og R -OCH^:
Eksempel 5 (dessuten fremgangsmåte b))
Analogt Eks. 3 fremstilles de i følgende tabell opp-stilte forbindelser med formel I fra de tilsvarende utgangsmaterialer med formel IV, hvori X hver gang betyr -0-S09- og 4 z
R betyr -0CH3:
Det for fremstilling av fremgangsmåteproduktet ifølge Eks. 3.36 nødvendige N-(2-acetamido-5-(3-trifluormetyl-fenylsulfonyloksy)-fenyl-N',N"-bis-metoksykarbonylguanidin (formel IV) med smp. 152°C fåes tilsvarende Eks.■3-i DOS 26 08 238 av 2-nitro-4-(3-trifluormetyl-fenoksysulfonyl)-klorbenzol med smp. 65°C over 2-nitro-4-(3-trifluormetyl-fenoksysulfonyl)-anilin med smp. 130°C, 2-nitro-4-(3-trifluormetyl-fenoksysulfonyl)-anilin med smp. 130°C og 2-nitro-4-(3-trifluormetyl-fenoksysulfonyl)-acetanilid med smp. 114°C, samt 2-amino-4-(3-trifluormetyl-fenoksy-sulf onyl) -acetanilid med smp. 141°C.
Eksempel 6 (fremgangsmåte b))
Man oppvarmer 2,5 g N-(2-metoksyacetamido-5-fenyl-sulf onyloksy-f enyl) -N ' ,N"-bis-metoksykarbonyl.guanidin (formel IV)
i 25. ml aceton og 25 ml vann i 24 timer i autoklav ved 90°C.
Etter avkjøling frafiltrerer man råproduktet. Det utrøres for rensing flere ganger i 25 ml 0/5 n HC1 ved værelsetemperatur, frafiltreres hver.gang fra uoppløst og filtratet blandes med ammoniakk. Etter filtrering og tørking av residuet får man 0,5 g rent N-(2-metoks<y>acetamido-5-fen<y>lsulfon<y>loksy-fen<y>l)rN<1->metoksykarbonyl-guanidin med smp. 190°C (under spaltning),
hvilket er identisk med fremgangsmåteproduktet fra Eks. 1.
Eksempel 7 (Saltdannelse)
Man utrører 24 g av det ifølge Eks. 1 dannede frie N-(2-metoksyacetamino-5-fenylsulfonyloksy-fenyl)-N<1->metoksykarbonyl-guanidin i 250 ml metanol og gjør det kongosurt med alkoholisk klorhydrogenoppløsning. Derpå inndampes oppløsningen til tørr-
het under nedsatt trykk, residuet blandes med eter og hydroklori-
det av N-(2-metoksyacetamido-5-fenylsulfonyloksy-fenyl)-N1-metoksykarbonyl-guanidin frafiltreres. Etter vasking med eter og tørking under nedsatt trykk over etsnatron utgjør utbyttet 25 g.
Analogt fåes hydrokloridéne av de øvrige fremgangs-måteprodukter slik de omtales i Eks. 2-6.
Claims (5)
1. Monokarboksylater av fenylguanidinsulfonsyre-estere med formel I
hvori
X betyr -OS02- eller -S02 0-R betyr hydrogen, halogen, alkyl med 1-4 C-atomer,
alkoksy med 1-4 C-atomer, -CN eller -CF.,,
1 R betyr hydrogen,
►
eventuelt substituert alkyl, eventuelt substituert alkoksy,
eventuelt substituert alkoksyalkyl. eller
eventuelt, substituert aralkyl ogR 2 betyr hydrogen, alkyl, cykloalkyl, cykloalkyl-alkyl
eller aralkyl,
og deres fysiologisk tålbare salter med organiske eller uorganiske syrer.
2. Fremgangsmåte til fremstilling av monokarboksylater av fenylguanidinsulfonsyreestere med formel I, ifølge krav 1, karakterisert ved ata) et substituert anilinderivat med formel II
hvori X, R og R"<*>" har den under formel I angitte betydning, omsettes entena^) med et isotiourinstoffderivat med formel III
hvori R 2 har den under formel I angitte betydning og R 3 betyr alkyl med 1-4 C-atomer,
eller
a2 ) med et O-metylisourinstoffderivat med formel Illa
hvori R betyr alkyl med 1^ 4 C-atomer, i nærvær av et oppløsnings-middel og eventuelt i nærvær av en syre,ellerb) et fenylguanidin-bis-karboksylat med formel IV
hvori X,R og R1 har ovennevnte betydning og R^ betyr alkyl eller alkoksy,i hydrolyseres,
og eventuelt en således dannet forbindelse med formel I, hvori R 2 betyr hydrogen, alkyleres.
3. Legemiddel karakterisert ved et innhold av en forbindelse med formel I ifølge krav 1, i blanding mediet farmasøytisk vanlig bærestoff og/eller konstituens.
4. i Anvendelse av en forbindelse med formel I ifølge krav 1 til bekjempelse av helminter i derav angrepne organer.
5. Monokarboksylater av fenylguanidinsulfonsyreestere med formel I i krav 1, hvori
X betyr -S02 0-
R betyr meta-trifluormetyl
R''" betyr metyl, etyl, propyl eller metoksymetyl og
R^ betyr hydrogen.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19782836385 DE2836385A1 (de) | 1978-08-19 | 1978-08-19 | Monocarboxylate von phenylguanidinsulfonsaeureestern, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO792696L true NO792696L (no) | 1979-02-20 |
Family
ID=6047464
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO792696A NO792696L (no) | 1978-08-19 | 1979-08-17 | Monokarboksylater av fenylguanidinsyre-estere samt fremgangsmaate til deres fremstilling |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4254143A (no) |
| EP (1) | EP0008438A1 (no) |
| JP (1) | JPS5531083A (no) |
| AU (1) | AU5003679A (no) |
| DE (1) | DE2836385A1 (no) |
| DK (1) | DK344379A (no) |
| ES (2) | ES483349A1 (no) |
| FI (1) | FI792548A (no) |
| IL (1) | IL58066A0 (no) |
| NO (1) | NO792696L (no) |
| NZ (1) | NZ191336A (no) |
| PT (1) | PT70076A (no) |
| ZA (1) | ZA794355B (no) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4348406A (en) | 1980-10-20 | 1982-09-07 | Schering Corporation | Novel guanidine derivatives |
| DE3232959A1 (de) * | 1982-09-04 | 1984-03-08 | Hoechst Ag, 6230 Frankfurt | Substituierte benzolsulfonsaeureester, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
| DE3412939A1 (de) * | 1984-04-06 | 1985-10-17 | Behringwerke Ag, 3550 Marburg | Substrate fuer hydrolasen, verfahren zu ihrer herstellung und ihre verwendung |
| JPH0825731B2 (ja) * | 1990-09-20 | 1996-03-13 | 信越化学工業株式会社 | 希土類リン酸塩の製造方法 |
| CN103848761B (zh) * | 2014-03-19 | 2016-03-23 | 连云港市亚晖医药化工有限公司 | O-甲基异脲甲酸甲酯的制备 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4024176A (en) * | 1974-05-15 | 1977-05-17 | Bayer Aktiengesellschaft | Substituted phenylguanidines and processes for their preparation and use |
| US4088780A (en) * | 1974-05-15 | 1978-05-09 | Bayer Aktiengesellschaft | Substituted phenylguanidines and processes for their preparation and use |
| DE2441201C2 (de) * | 1974-08-28 | 1986-08-07 | Hoechst Ag, 6230 Frankfurt | Anthelminthisch wirksame 2-Carbalkoxyamino-5(6)-phenyl-sulfonyloxy-benzimidazole und Verfahren zu ihrer Herstellung |
| DE2441202C2 (de) * | 1974-08-28 | 1986-05-28 | Hoechst Ag, 6230 Frankfurt | 2-Carbalkoxyamino-benzimidazolyl-5(6)-sulfonsäure-phenylester, Verfahren zu ihrer Herstellung und diese enthaltende anthelmintische Mittel |
| DE2608238A1 (de) * | 1976-02-28 | 1977-09-08 | Hoechst Ag | Substituierte phenylguanidine und verfahren zu ihrer herstellung |
| DE2609994A1 (de) * | 1976-03-10 | 1977-09-15 | Bayer Ag | 2-formylamino-phenylguanidine, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
-
1978
- 1978-08-19 DE DE19782836385 patent/DE2836385A1/de not_active Withdrawn
-
1979
- 1979-08-13 ES ES483349A patent/ES483349A1/es not_active Expired
- 1979-08-13 ES ES483350A patent/ES483350A1/es not_active Expired
- 1979-08-16 US US06/068,532 patent/US4254143A/en not_active Expired - Lifetime
- 1979-08-16 FI FI792548A patent/FI792548A/fi not_active Application Discontinuation
- 1979-08-16 EP EP79102980A patent/EP0008438A1/de not_active Withdrawn
- 1979-08-17 PT PT70076A patent/PT70076A/pt unknown
- 1979-08-17 AU AU50036/79A patent/AU5003679A/en not_active Abandoned
- 1979-08-17 IL IL58066A patent/IL58066A0/xx unknown
- 1979-08-17 DK DK344379A patent/DK344379A/da unknown
- 1979-08-17 ZA ZA00794355A patent/ZA794355B/xx unknown
- 1979-08-17 NO NO792696A patent/NO792696L/no unknown
- 1979-08-17 NZ NZ191336A patent/NZ191336A/xx unknown
- 1979-08-18 JP JP10453679A patent/JPS5531083A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| FI792548A (fi) | 1980-02-20 |
| IL58066A0 (en) | 1979-12-30 |
| DK344379A (da) | 1980-02-20 |
| ZA794355B (en) | 1980-08-27 |
| EP0008438A1 (de) | 1980-03-05 |
| JPS5531083A (en) | 1980-03-05 |
| AU5003679A (en) | 1980-02-28 |
| DE2836385A1 (de) | 1980-03-06 |
| ES483350A1 (es) | 1980-04-16 |
| ES483349A1 (es) | 1980-04-16 |
| NZ191336A (en) | 1981-01-23 |
| US4254143A (en) | 1981-03-03 |
| PT70076A (de) | 1979-09-01 |
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