DE2423679C3 - Substituted phenylguanidines, a process for their preparation and pharmaceuticals containing these compounds - Google Patents
Substituted phenylguanidines, a process for their preparation and pharmaceuticals containing these compoundsInfo
- Publication number
- DE2423679C3 DE2423679C3 DE19742423679 DE2423679A DE2423679C3 DE 2423679 C3 DE2423679 C3 DE 2423679C3 DE 19742423679 DE19742423679 DE 19742423679 DE 2423679 A DE2423679 A DE 2423679A DE 2423679 C3 DE2423679 C3 DE 2423679C3
- Authority
- DE
- Germany
- Prior art keywords
- och
- cooch
- coc
- methoxycarbonyl
- bis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000002360 preparation method Methods 0.000 title claims description 15
- 238000000034 method Methods 0.000 title claims description 12
- QRJZGVVKGFIGLI-UHFFFAOYSA-N 2-phenylguanidine Chemical class NC(=N)NC1=CC=CC=C1 QRJZGVVKGFIGLI-UHFFFAOYSA-N 0.000 title claims description 11
- 150000001875 compounds Chemical class 0.000 title claims description 10
- 239000003814 drug Substances 0.000 title claims description 6
- 230000000507 anthelmentic Effects 0.000 claims description 7
- 229940079593 drugs Drugs 0.000 claims description 3
- 229940036592 ANTHELMINTICS Drugs 0.000 claims description 2
- 239000000921 anthelmintic agent Substances 0.000 claims description 2
- 229920000089 Cyclic olefin copolymer Polymers 0.000 description 74
- 239000004480 active ingredient Substances 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- 238000002844 melting Methods 0.000 description 22
- 241000243976 Haemonchus Species 0.000 description 21
- 229910052757 nitrogen Inorganic materials 0.000 description 21
- -1 1-aminophenyl group Chemical group 0.000 description 18
- 125000000217 alkyl group Chemical group 0.000 description 15
- 241000244188 Ascaris suum Species 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 11
- 125000001309 chloro group Chemical group Cl* 0.000 description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 239000000969 carrier Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 125000004435 hydrogen atoms Chemical class [H]* 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 244000045947 parasites Species 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 239000007900 aqueous suspension Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- 241000283898 Ovis Species 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N Thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 230000000875 corresponding Effects 0.000 description 4
- 235000013601 eggs Nutrition 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 4
- GAYRVKNOXPSDIN-UHFFFAOYSA-N methyl N-(methoxycarbonylcarbamothioyl)carbamate Chemical compound COC(=O)NC(S)=NC(=O)OC GAYRVKNOXPSDIN-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 229960000583 Acetic Acid Drugs 0.000 description 3
- 241001126260 Nippostrongylus Species 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 241000607143 Toxascaris leonina Species 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002224 dissection Methods 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 150000002541 isothioureas Chemical class 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 241001465677 Ancylostomatoidea Species 0.000 description 2
- 241000760148 Aspiculuris tetraptera Species 0.000 description 2
- 241000931178 Bunostomum Species 0.000 description 2
- 241000931177 Bunostomum trigonocephalum Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000243974 Haemonchus contortus Species 0.000 description 2
- 241001464384 Hymenolepis nana Species 0.000 description 2
- 206010061217 Infestation Diseases 0.000 description 2
- 241000244206 Nematoda Species 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 241000243796 Trichostrongylus colubriformis Species 0.000 description 2
- 241000571986 Uncinaria Species 0.000 description 2
- 241000571980 Uncinaria stenocephala Species 0.000 description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000003931 anilides Chemical class 0.000 description 2
- 150000001448 anilines Chemical class 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 125000004432 carbon atoms Chemical group C* 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 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 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 235000013312 flour Nutrition 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 2
- MMZDUHCTUSJDHW-UHFFFAOYSA-N methyl N-[amino-(methoxycarbonylamino)methylidene]carbamate Chemical compound COC(=O)NC(=N)NC(=O)OC MMZDUHCTUSJDHW-UHFFFAOYSA-N 0.000 description 2
- XQLWPOXMLSCQLM-UHFFFAOYSA-N methyl N-[methylsulfanyl-(propanoylamino)methylidene]carbamate Chemical compound CCC(=O)N=C(SC)NC(=O)OC XQLWPOXMLSCQLM-UHFFFAOYSA-N 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 230000003000 nontoxic Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 125000004430 oxygen atoms Chemical group O* 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000011435 rock Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000015424 sodium Nutrition 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atoms Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- YERCHTOSYPJWTE-UHFFFAOYSA-N 2-amino-4-(benzenesulfonyl)-N-phenylbutanamide Chemical compound C=1C=CC=CC=1NC(=O)C(N)CCS(=O)(=O)C1=CC=CC=C1 YERCHTOSYPJWTE-UHFFFAOYSA-N 0.000 description 1
- DYTVCSKPYOHQAE-UHFFFAOYSA-N 2-nitro-5-phenoxyaniline Chemical compound C1=C([N+]([O-])=O)C(N)=CC(OC=2C=CC=CC=2)=C1 DYTVCSKPYOHQAE-UHFFFAOYSA-N 0.000 description 1
- ZCWXYZBQDNFULS-UHFFFAOYSA-N 5-chloro-2-nitroaniline Chemical compound NC1=CC(Cl)=CC=C1[N+]([O-])=O ZCWXYZBQDNFULS-UHFFFAOYSA-N 0.000 description 1
- 229940100198 ALKYLATING AGENTS Drugs 0.000 description 1
- 229940045714 Alkyl sulfonate alkylating agents Drugs 0.000 description 1
- 240000002470 Amphicarpaea bracteata Species 0.000 description 1
- 241001147657 Ancylostoma Species 0.000 description 1
- 241001147672 Ancylostoma caninum Species 0.000 description 1
- 240000007109 Arundinaria gigantea Species 0.000 description 1
- 241000760149 Aspiculuris Species 0.000 description 1
- DVECBJCOGJRVPX-UHFFFAOYSA-N Butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 1
- KCISOGPFZLHQAK-UHFFFAOYSA-N COC(=O)NC(N)=NC(CC)=O Chemical compound COC(=O)NC(N)=NC(CC)=O KCISOGPFZLHQAK-UHFFFAOYSA-N 0.000 description 1
- 241000244203 Caenorhabditis elegans Species 0.000 description 1
- 229960003563 Calcium Carbonate Drugs 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K Dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 241000189163 Dipetalonema Species 0.000 description 1
- 239000004097 EU approved flavor enhancer Substances 0.000 description 1
- 241000244160 Echinococcus Species 0.000 description 1
- 206010014881 Enterobiasis Diseases 0.000 description 1
- 241000498255 Enterobius vermicularis Species 0.000 description 1
- 230000036826 Excretion Effects 0.000 description 1
- 210000003608 Feces Anatomy 0.000 description 1
- 241000239183 Filaria Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000243994 Litomosoides carinii Species 0.000 description 1
- 241001673868 Oesophagostomum columbianum Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000244173 Rhabditis Species 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N Silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 241001480236 Strongyloides ratti Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L Sulphite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 241001672170 Taenia pisiformis Species 0.000 description 1
- 241000244030 Toxocara canis Species 0.000 description 1
- 241001221734 Trichuris muris Species 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000008055 alkyl aryl sulfonates Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000036576 dermal application Effects 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- LVUHKVRTGUIFRB-UHFFFAOYSA-N ethyl (NE)-N-[(2-acetamido-4-phenoxyanilino)-(ethoxycarbonylamino)methylidene]carbamate Chemical compound C1=C(NC(C)=O)C(NC(NC(=O)OCC)=NC(=O)OCC)=CC=C1OC1=CC=CC=C1 LVUHKVRTGUIFRB-UHFFFAOYSA-N 0.000 description 1
- LHMVPJRQOJKPNS-UHFFFAOYSA-N ethyl (NE)-N-[[2-(butanoylamino)-4-phenoxyanilino]-(ethoxycarbonylamino)methylidene]carbamate Chemical compound C1=C(NC(NC(=O)OCC)=NC(=O)OCC)C(NC(=O)CCC)=CC(OC=2C=CC=CC=2)=C1 LHMVPJRQOJKPNS-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 1
- 230000000968 intestinal Effects 0.000 description 1
- 238000009114 investigational therapy Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 238000003475 lamination Methods 0.000 description 1
- 229920005610 lignin Polymers 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- HBMUNBYFEGQSSQ-UHFFFAOYSA-N methyl (NE)-N-[[2-(butanoylamino)-4-(3-chlorophenoxy)anilino]-(propanoylamino)methylidene]carbamate Chemical compound C1=C(NC(NC(=O)CC)=NC(=O)OC)C(NC(=O)CCC)=CC(OC=2C=C(Cl)C=CC=2)=C1 HBMUNBYFEGQSSQ-UHFFFAOYSA-N 0.000 description 1
- HJDHBKAOXIYUQI-UHFFFAOYSA-N methyl (NE)-N-[[2-(butanoylamino)-4-phenoxyanilino]-(propanoylamino)methylidene]carbamate Chemical compound C1=C(NC(NC(=O)CC)=NC(=O)OC)C(NC(=O)CCC)=CC(OC=2C=CC=CC=2)=C1 HJDHBKAOXIYUQI-UHFFFAOYSA-N 0.000 description 1
- NMFKBAYGDYCTSY-UHFFFAOYSA-N methyl (NE)-N-[[4-phenoxy-2-(propanoylamino)anilino]-(propanoylamino)methylidene]carbamate Chemical compound C1=C(NC(=O)CC)C(NC(NC(=O)CC)=NC(=O)OC)=CC=C1OC1=CC=CC=C1 NMFKBAYGDYCTSY-UHFFFAOYSA-N 0.000 description 1
- GCVMBQDGMAWBSM-UHFFFAOYSA-N methyl (NZ)-N-[[2-(butanoylamino)-4-phenoxyanilino]-(cyclohexanecarbonylamino)methylidene]carbamate Chemical compound C=1C=C(NC(NC(=O)C2CCCCC2)=NC(=O)OC)C(NC(=O)CCC)=CC=1OC1=CC=CC=C1 GCVMBQDGMAWBSM-UHFFFAOYSA-N 0.000 description 1
- FFIGCHDTLUTYQR-UHFFFAOYSA-N methyl (NZ)-N-[[2-acetamido-4-(3-chlorophenoxy)anilino]-(propanoylamino)methylidene]carbamate Chemical compound C1=C(NC(C)=O)C(NC(NC(=O)CC)=NC(=O)OC)=CC=C1OC1=CC=CC(Cl)=C1 FFIGCHDTLUTYQR-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
- OAQFTVPOKDOFLY-UHFFFAOYSA-N methyl N-[(cyclohexanecarbonylamino)-methylsulfanylmethylidene]carbamate Chemical compound COC(=O)NC(SC)=NC(=O)C1CCCCC1 OAQFTVPOKDOFLY-UHFFFAOYSA-N 0.000 description 1
- MMBXQPGOPHKATO-UHFFFAOYSA-N methyl N-[(ethoxycarbonylamino)-methylsulfanylmethylidene]carbamate Chemical compound CCOC(=O)NC(SC)=NC(=O)OC MMBXQPGOPHKATO-UHFFFAOYSA-N 0.000 description 1
- DZUBGXXPPAMZOX-UHFFFAOYSA-N methyl N-[(methoxycarbonylamino)-[5-phenoxy-2-(propanoylamino)anilino]methylidene]carbamate Chemical compound C1=C(NC(NC(=O)OC)=NC(=O)OC)C(NC(=O)CC)=CC=C1OC1=CC=CC=C1 DZUBGXXPPAMZOX-UHFFFAOYSA-N 0.000 description 1
- YLIKVHZEGNKQDM-UHFFFAOYSA-N methyl N-[[4-(4-acetamidophenoxy)-2-(butanoylamino)anilino]-(methoxycarbonylamino)methylidene]carbamate Chemical compound C1=C(NC(NC(=O)OC)=NC(=O)OC)C(NC(=O)CCC)=CC(OC=2C=CC(NC(C)=O)=CC=2)=C1 YLIKVHZEGNKQDM-UHFFFAOYSA-N 0.000 description 1
- LVCVYPKHUBZTOO-UHFFFAOYSA-N methyl N-[[4-(benzenesulfonyl)-2-(propanoylamino)anilino]-(methoxycarbonylamino)methylidene]carbamate Chemical compound C1=C(NC(NC(=O)OC)=NC(=O)OC)C(NC(=O)CC)=CC(S(=O)(=O)C=2C=CC=CC=2)=C1 LVCVYPKHUBZTOO-UHFFFAOYSA-N 0.000 description 1
- MKFSHVVOAIQUGS-UHFFFAOYSA-N methyl N-carbamothioylcarbamate Chemical compound COC(=O)NC(N)=S MKFSHVVOAIQUGS-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000010422 painting Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- YYYQBHIPOIHCNT-UHFFFAOYSA-N propan-2-yl (NE)-N-[[2-(butanoylamino)-4-phenoxyanilino]-(propan-2-yloxycarbonylamino)methylidene]carbamate Chemical compound C1=C(NC(NC(=O)OC(C)C)=NC(=O)OC(C)C)C(NC(=O)CCC)=CC(OC=2C=CC=CC=2)=C1 YYYQBHIPOIHCNT-UHFFFAOYSA-N 0.000 description 1
- XKBSKWWBLQEEJJ-UHFFFAOYSA-N propan-2-yl (NE)-N-[[4-phenoxy-2-(propanoylamino)anilino]-(propan-2-yloxycarbonylamino)methylidene]carbamate Chemical compound C1=C(NC(NC(=O)OC(C)C)=NC(=O)OC(C)C)C(NC(=O)CC)=CC(OC=2C=CC=CC=2)=C1 XKBSKWWBLQEEJJ-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000717 retained Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Description
N·COORN COOR
NH·COORNH · COOR
in welcher R und R1 voneinander verschieden sind und wechselseitig für jeweils einen der Reste -COR4 undin which R and R 1 are different from one another and alternately for one of the radicals -COR 4 and
NH · CO · R'NH CO R '
N—COORS N — COOR S
—C—C
2020th
NH-COR6 NH-COR 6
stehen und R2 für Wasserstoff, Alkyl (C1-C4), Halogen, Alkoxy (C1-C4), Trifluormethyl oder Acetylamino, R3 fiir Wasserstoff, Alkyl (C1-C4), Alkoxy (C1-C4), Halogen, R4 für Wasserstoff, Alkyl (C1-C6), Cyclohexyl, Methoxymethyl oder Phenoxymethyl, R5 für Alkyl (Ci-C4), R6 für Alkyl (C1 — C4), Alkoxy (C1 — C4), Cyclohexyl oder Methoxymethyl und X für ein Sauerstoffatom, ein Schwefelatom, die Sulfinylgruppe oder die Sulfonylgruppe steht.and R 2 is hydrogen, alkyl (C 1 -C 4 ), halogen, alkoxy (C 1 -C 4 ), trifluoromethyl or acetylamino, R 3 is hydrogen, alkyl (C 1 -C 4 ), alkoxy (C 1 - C 4 ), halogen, R 4 for hydrogen, alkyl (C 1 -C 6 ), cyclohexyl, methoxymethyl or phenoxymethyl, R 5 for alkyl (Ci-C 4 ), R 6 for alkyl (C 1 -C 4 ), alkoxy (C 1 -C 4 ), cyclohexyl or methoxymethyl and X represents an oxygen atom, a sulfur atom, the sulfinyl group or the sulfonyl group.
2. Verfahren zur Herstellung von substituierten Phenylguanidinen nach Anspruch 1, dadurch gekennzeichnet, daß man in an sich bekannter Weise substituierte Anilinderivate der allgemeinen Formel 2. Process for the preparation of substituted phenylguanidines according to claim 1, characterized in that that one in a conventional manner substituted aniline derivatives of the general formula
R2 R 2
NH-CO—R4 (II)NH-CO — R 4 (II)
NH,NH,
in welcher R2, R3, R4 und X die im Anspruch 1 angegebene Bedeutung besitzen und in welcher X mit Stellung 4 oder Stellung 5 der substituierten 1-Aminophenylgruppe der Formel II verknüpft sein kann, mit Isothioharnstoffen der allgemeinen Formelin which R 2 , R 3 , R 4 and X have the meaning given in claim 1 and in which X can be linked to position 4 or position 5 of the substituted 1-aminophenyl group of the formula II, with isothioureas of the general formula
R7 R 7
N-COOR5 N-COOR 5
NH-COR6 NH-COR 6
(III)(III)
in welcher R5 und R6 die im Anspruch 1 angegebene Bedeutung besitzen und R7 Für Alkyl mit 1 bis 4 Kohlenstoffatomen steht, in Gegenwart eines Verdünnungsmittels und gegebenenfalls in Gegenwart einer Säure umsetzt.in which R 5 and R 6 have the meaning given in claim 1 and R 7 represents alkyl having 1 to 4 carbon atoms, is reacted in the presence of a diluent and, if appropriate, in the presence of an acid.
3. Arzneimittel, gekennzeichnet durch einen Gehalt an mindestens einem substituierten Phenylguanidin gemäß Anspruch 1 als Wirkstoff.3. Medicines, characterized by a content of at least one substituted phenylguanidine according to claim 1 as an active ingredient.
in der R niederes Alkyl und R' sowohl niederes Alkyl als auch Wasserstoff bedeuten kann, anthelmintische Wirkungen aufweisen (s. dazu DT-OS 21 17 293).in which R can mean lower alkyl and R 'can mean both lower alkyl and hydrogen, anthelmintic Have effects (see DT-OS 21 17 293).
Sie zeigen jedoch den Nachteil, daß ihre anthelmintische Wirkung wesentlich schwächer ausgeprägt ist als bei den erfindungsgemäßen substituierten Phenylguanidinen.However, they have the disadvantage that their anthelmintic effect is much less pronounced is than with the substituted phenylguanidines according to the invention.
Es wurde nämlich gefunden, daß die neuen substituierten Phenylguanidine der allgemeinen FormelIt has been found that the new substituted phenylguanidines of the general formula
NH-R1 NH-R 1
in welcher R und R1 voneinander verschieden sind und wechselseitig für jeweils einen der Reste — COR4 undin which R and R 1 are different from one another and alternately for one of the radicals - COR 4 and
N-COOR5 N-COOR 5
4040
NH-COR6 NH-COR 6
stehen und R2 für Wasserstoff, Alkyl (C1-C4), Halogen, Alkoxy (C1—C4), Trifluormethyl oder Acetylamino, R3 für Wasserstoff, Alkyl (C1-C4), Alkoxy (C1—C4), Halogen, R4 für Wasserstoff, Alkyl (C1—C6), Cyclohexyl, Methoxymethyl oder Phenoxymethyl, Rs für Alkyl (C1-C4), R6 für Alkyl (C1-C4), Alkoxy (C1—C4), Cyclohexyl oder Methoxymethyl und X für ein Sauerstoffatom, ein Schwefelatom, die Sulfinylgruppe oder die Sulfonylgruppe steht, sehr gute anthelmintische Wirkungen aufweisen.and R 2 is hydrogen, alkyl (C 1 -C 4 ), halogen, alkoxy (C 1 -C 4 ), trifluoromethyl or acetylamino, R 3 is hydrogen, alkyl (C 1 -C 4 ), alkoxy (C 1 - C 4 ), halogen, R 4 for hydrogen, alkyl (C 1 -C 6 ), cyclohexyl, methoxymethyl or phenoxymethyl, R s for alkyl (C 1 -C 4 ), R 6 for alkyl (C 1 -C 4 ), Alkoxy (C 1 -C 4 ), cyclohexyl or methoxymethyl and X represents an oxygen atom, a sulfur atom, the sulfinyl group or the sulfonyl group, have very good anthelmintic effects.
Weiterhin wurde gefunden, daß man die substituierten Phenylguanidine der Formel I erhält, wenn man substituierte Anilinderivate der allgemeinen Formel It has also been found that the substituted phenylguanidines of the formula I are obtained if substituted aniline derivatives of the general formula
6060
NH-CO—R4 (II)NH-CO — R 4 (II)
NH2 NH 2
in welcher R2, R3, R4 und X die vorstehende Bedeutung besitzen und in welcher X mit Stellung 4 oder Stellung 5 der substituierten 1-Amino-phenylgruppe der Formel II verknüpft sein kann, mit Isothioharnstoffen derin which R 2 , R 3 , R 4 and X have the above meaning and in which X can be linked to position 4 or position 5 of the substituted 1-aminophenyl group of the formula II, with isothioureas
!!gemeinen Formel!! mean formula
R7-S — CR 7 -S - C
N—COOR5 N — COOR 5
NH-COR6 NH-COR 6
(IU)(IU)
η welcher R5 und R6 die vorstehende Bedeutung be-η which R 5 and R 6 have the above meaning
NH-R
N-COOR5 NH-R
N-COOR 5
NHCNHC
sitzen und R7 Tür Alkyl mit 1 bis 4 Kohlenstoffatomensit and R 7 door alkyl with 1 to 4 carbon atoms
steht, in Gegenwart eines Verdünnungsmittels undstands, in the presence of a diluent and
gegebenenfalls in Gegenwart einer Säure umsetzt.optionally reacted in the presence of an acid.
Die erfindungsgemäßen Verbindungen der Formel 1The compounds of formula 1 according to the invention
können ir. tautomeren Formen vorliegen, wie ancan be in tautomeric forms, such as an
folgendem Beispiel gezeigt werden soll:should be shown in the following example:
V-NH-RV-NH-R
NH-COOR5 NH-COOR 5
NH-CNH-C
N-CO-R6 N-CO-R 6
Im Anmeldungstext wurden die jeweiligen Strukturformeln aus Gründen der Einheitlichkeit in allen Fällen gleichartig formuliert.In the registration text, the respective structural formulas have been used for reasons of consistency in all Cases formulated in the same way.
Überraschenderweise zeigen die erfindungsgemäßen substituierten Phenylguanidine eine erheblich höhere anthelmintische Wirkung als die in der DT-OS 21 17 293 genannten Phenylguanidine, welche die chemisch nächstliegenden Wirkstoffe gleicher Wir-Surprisingly, the substituted phenylguanidines according to the invention show a considerably higher one anthelmintic effect than the phenylguanidines mentioned in DT-OS 21 17 293, which the chemically closest active ingredients of the same effec-
kungsart sind. Die erfindungsgemäßen Wirkstoffe stellen somit eine wertvolle Bereicherung der Pharmazie dar.kungart are. The active ingredients according to the invention thus represent a valuable addition to pharmacy represent.
Verwendet man N.N'-bis-Methoxycarbonyl-S-methyl-isothioharnstoff und 2-Amino-5-phenoxyn-butyranilid als Ausgangsstoffe, so kann der Reaktionsablauf durch das folgende Formelschema wiedergegeben werden:If you use N.N'-bis-methoxycarbonyl-S-methyl-isothiourea and 2-amino-5-phenoxyn-butyranilide as starting materials, the reaction can proceed can be represented by the following equation:
N-COOCH3 N-COOCH 3
ζ V-NH-CO-C3H71n, + CH3S-C ζ V-NH-CO-C 3 H 71n , + CH 3 SC
NH,NH,
NH-COOCH3 NH-COOCH 3
C3H701, + CH3SH
N-COOCH3 C 3 H 701 , + CH 3 SH
N-COOCH 3
NNH—COOCH3 N NH-COOCH 3
Verwendet man N-Methoxycarbonyl-N'-propionyl-S-methyl-isothioharnstofT und 2-Amino-5-phenylthioacetanilid als Ausgangsstoffe, so kann der Reaktionsverlauf durch das folgende Reaktionsschema wiedergegeben werden:Using N-methoxycarbonyl-N'-propionyl-S-methyl-isothiourea and 2-amino-5-phenylthioacetanilide as starting materials, the course of the reaction can be shown by the following reaction scheme will:
N—COOCH,N — COOCH,
NH-CO-C2H5 NH-CO-C 2 H 5
f V-NH-CO-CH3 + CH3S-C'f V-NH-CO-CH 3 + CH 3 S-C '
NH,NH,
NH-CO-CH3 + CH3SH
N-COOCH3 NH-CO-CH 3 + CH 3 SH
N-COOCH 3
NH-CNH-C
Die als Ausgangsstolfe verwendeten Thioharnstoffe sind durch die Formel III definiert. Sie sind zum Teil bekannt (vgl. Ol in und Dains, J. Amer. ehem. Soc. 52, 3326 (1930) sowie US-PS 29 93 502) und können im übrigen in Analogie zu bekannten Verfahren leicht gewonnen werden. Zu ihrer Herstellung geht man im allgemeinen von bekannten N-Acylthioharnstoffen aus (vgl. zum Beispiel Berichte der deutschen Chemischen Gesellschaft, 6, 755 [1873]; Ann. chim. [5] 11,313 [1877]; J. Amer. Chem. Soc. 62, 3274 [1940]), die man in ebenfalls bekannter Weise mit Alkylierungsmitteln wie Alkylhalogeniden, -sulfaten und -sulfonaten zu den entsprechenden S-Alkyl-N-acyliso-thioharnstoffen umsetzt (vgl. zum Beispiel J. org. Chem. 30, 560 [1965]; Chem. Pharm. Bull. [Tokyo], 9, 245 [1961]). Diese S-Alkyl-N-acyl-iscthioharnstoffe können dann mit Halogenameisensäureestern oder auch mit Pyrokohlensäuredialkylestern (vgl. Ber. dtsch. chem. Ges. 71, 1797 [1938]) zu den S - Alkyl - N - acyl - N' - alkoxycarbonyl - isothioharnstoffen umgesetzt werden.The thioureas used as starting materials are defined by the formula III. They are part known (see Ol in and Dains, J. Amer. Soc. 52, 3326 (1930) and US-PS 29 93 502) and can otherwise in analogy to known processes easily won. Known N-acylthioureas are generally used for their preparation from (cf., for example, reports of the German Chemical Society, 6, 755 [1873]; Ann. chim. [5] 11,313 [1877]; J. Amer. Chem. Soc. 62, 3274 [1940]), which can also be used in a known manner with alkylating agents such as alkyl halides and sulfates and sulfonates to the corresponding S-alkyl-N-acyliso-thioureas converts (cf., for example, J. org. Chem. 30, 560 [1965]; Chem. Pharm. Bull. [Tokyo], 9, 245 [1961]). These S-alkyl-N-acyl-iscthioureas can then with haloformic acid esters or with pyrocarbonic acid dialkyl esters (cf. Ber. dtsch. chem. Ges. 71, 1797 [1938]) on the S-alkyl-N-acyl-N'-alkoxycarbonyl-isothioureas implemented.
Diese letzte Reaktion entspricht dem Prinzip der bekannten Substitution von S-Alkyl-isothioharnstoffen mit Chlorameisensäurealkylestern (vgl. J. Amer. chem. Soc. 52, 3326 [1930]).This last reaction corresponds to the principle of the known substitution of S-alkyl-isothioureas with alkyl chloroformates (cf. J. Amer. chem. Soc. 52, 3326 [1930]).
NH-CO-C2H5 NH-CO-C 2 H 5
Als Beispiele für die erfindungsgemäß einsetzbaren Isothioharnstoffe seien genannt:Examples of the isothioureas which can be used according to the invention are:
Ν,Ν'-bis-Methoxycarbonyl-S-methylisothioharnstoff (Schmp. 99—100° C), fyN'-bis-Äthoxycarbonyl-S-methylisothioharnstoff (Schmp. 50—5 Γ C), N-Äthoxycarbonyl-N'-propionyl-S-methyl-Ν, Ν'-bis-methoxycarbonyl-S-methylisothiourea (M.p. 99-100 ° C), fyN'-bis-ethoxycarbonyl-S-methylisothiourea (Mp. 50-5 Γ C), N-ethoxycarbonyl-N'-propionyl-S-methyl-
isothioharnstoff (Schmp. 92—94° C),isothiourea (m.p. 92-94 ° C),
N-Methoxycarbonyl-N'-propionyl-S-methylisothioharnstoff (Schmp. 97—99° C), N-Methoxycarbonyl-N'-cyclohexylcarbonyl-S-methyl-isothioharnstoff (Schmp. 67—68° C),N-methoxycarbonyl-N'-propionyl-S-methylisothiourea (M.p. 97-99 ° C), N-methoxycarbonyl-N'-cyclohexylcarbonyl-S-methyl-isothiourea (M.p. 67-68 ° C),
N-Äthoxycarbonyl-N '-methoxycarbonyl-S-methyl-isothioharnstoff (Schmp. 690C).N-ethoxycarbonyl-N '-methoxycarbonyl-S-methyl-isothiourea (mp. 69 0 C).
Die als Ausgangsstoffe verwendeten substituierten 2-Aminoanilide sind teilweise noch nicht bekannt. Sie können in Analogie zu literaturbekannten Verfahren leicht hergestellt werden.Some of the substituted 2-aminoanilides used as starting materials are not yet known. she can easily be prepared in analogy to processes known from the literature.
So kann man z. B. das 2-Amino-5-phenoxy-butyr-So you can z. B. the 2-amino-5-phenoxy-butyr-
anilid aus dem bekannten 2-Nitro-5-phenoxy-anilin durch Acylierung mit Butyrylchlorid zum 2-Nitro-anilide from the well-known 2-nitro-5-phenoxy-aniline by acylation with butyryl chloride to form 2-nitro
5-phenoxy-butyranilid und nachfolgende katalytische Hydrierung gewinnen:5-phenoxy-butyranilid and subsequent catalytic hydrogenation win:
O
</~X_NH CH3-CH2-CH2-COClO
< / ~ X_ NH CH 3 -CH 2 -CH 2 -COCl
NO2 NO 2
— CO -CH2-CH2-CH3 - CO -CH 2 -CH 2 -CH 3
Raney-Ni/H2 Raney Ni / H 2
/"^-NH-CO-CH2-CH2-CH3 / "^ - NH-CO-CH 2 -CH 2 -CH 3
NH2 NH 2
Die Phenylsulfinyl-anilide können nach an sich Durch Oxidation mit H2O2 in Eisessig bei erhöhterThe Phenylsulfinyl-anilide can after per se by oxidation with H 2 O 2 in glacial acetic acid at increased
bekannter Methode durch Oxidation der Phenylthio- 55 Temperatur erhält man die Phenylsulfonyl-anilideknown method by oxidation of the phenylthio- 55 temperature one obtains the phenylsulfonyl-anilide
anilide mit H2O2 in Acetanhydrid oder mit Benzo- z. B. persäure in Dioxan oder Chloroform erhalten werden,anilide with H 2 O 2 in acetic anhydride or with benzo z. B. peracid can be obtained in dioxane or chloroform,
NO2 NO 2
(CH3CO)2O(CH 3 CO) 2 O
CH3COOH x=/
100°CCH 3 COOH x = /
100 ° C
NH-COC2H5 NH-COC 2 H 5
-SO2^VnO2 -SO 2 ^ VnO 2
NH-COC2H5 NH-COC 2 H 5
Einige Phenylsulfonyl-anilidc lassen sich auch durch Umsetzung von benzolsulfonsäuren! Natrium mit 2-Nitro-5-chloranilin gemäß folgender Gleichung gewinnen: Some phenylsulfonyl-anilidc can also be passed through Implementation of benzenesulfonic acids! Sodium with Obtain 2-nitro-5-chloroaniline according to the following equation:
NO,NO,
DMFDMF
NH2 NH 2
Als Verdünnungsmittel kommen bei der Durchführung des erfindungsgemäßen Verfahrens alle polaren organischen Lösungsmittel in Frage. Hierzu gehören vorzugsweise Alkohole, wie Methanol, Äthanol, iso-Propanol sowie deren Gemische mit Wasser, Ketone wie Aceton (auch mit Wasser gemischt), Essigsäure (auch mit Wasser gemischt), aber auch Äther wie Dioxan oder Tetrahydrofuran.All polar diluents can be used as diluents when carrying out the process according to the invention organic solvents in question. These preferably include alcohols such as methanol, ethanol, isopropanol and their mixtures with water, ketones such as acetone (also mixed with water), Acetic acid (also mixed with water), but also ethers such as dioxane or tetrahydrofuran.
Die bei der Durchführung des erfindungsgemäßen Verfahrens als reaktionsfördernde Katalysatoren zugesetzten Säuren können im Prinzip aus der Reihe der bekannten organischen oder anorganischen Säuren beliebig ausgewählt werden. Vorteilhaft verwendet man jedoch die leicht zugänglichen, technisch bedeutenden Vertreter dieser Klassen. Als Beispiele seien genannt: Salzsäure, Schwefelsäure, Salpetersäure, Ameisensäure, Essigsäure, p-Toluolsulfonsäure.The catalysts added as reaction-promoting catalysts when carrying out the process according to the invention Acids can in principle be selected from the series of known organic or inorganic acids can be selected at will. However, it is advantageous to use the easily accessible, technically important ones Representatives of these classes. Examples include: hydrochloric acid, sulfuric acid, nitric acid, Formic acid, acetic acid, p-toluenesulfonic acid.
Die Reaktionstemperaturen können in einem größeren Bereich variiert werden. Im allgemeinen arbeitet man zwischen 0 und 120° C, vorzugsweise zwischen 30 und 100°C, Die Umsetzung wird im allgemeinen bei Normaldruck durchgeführt.The reaction temperatures can be varied over a wide range. Generally works between 0 and 120 ° C, preferably between 30 and 100 ° C, The reaction is generally carried out at normal pressure.
Bei der Durchführung des erfindungsgemäßen Verfahrens setzt man auf 1 Mol des substituierten 2-Amino-anilids 1 Mol Isothioharnstoffäther ein. über- bzw. Unterschreitungen um bis zu 20% sind ohne wesentliche Ausbeuteverminderung möglich. Die Reaktion wird bevorzugt in siedendem Lösungsmittel durchgeführt, wobei Alkylmercaptan als Nebenprodukt entsteht. Die Endprodukte fallen beim Abkühlen des Reaktionsgemisches kristallin an und können durch Absaugen abgetrennt und gegebenenfalls durch Umlösen bzw. Umkristallisieren gereinigt werden.When carrying out the process according to the invention, 1 mol of the substituted 2-amino-anilide is used 1 mole of isothiourea ether. Exceeding or falling below by up to 20% are without significant Reduction in yield possible. The reaction is preferably carried out in a boiling solvent, whereby alkyl mercaptan is formed as a by-product. The end products fall when the The reaction mixture becomes crystalline and can be separated off by suction and, if necessary, by dissolving or recrystallization are purified.
Die erfindungsgemäß dargestellten Verbindungen zeigen eine überraschend gute und breite Wirkung gegen folgende Nematoden und Cestoden:The compounds presented according to the invention show a surprisingly good and broad action against the following nematodes and cestodes:
1. Hakenwürmer (z. B. Uncinaria stenocephala, Ancyclostoma caninum, Bunostomum trigonocephalum), 1. Hookworms (e.g. Uncinaria stenocephala, Ancyclostoma caninum, Bunostomum trigonocephalum),
2. Trichostrongylidcn (z. B. Nippostrongylus muris, Haemonchus contortus, Trichostrongylus colubriformis, Ostcrtagia circumcincta),2. Trichostrongylidcn (e.g. Nippostrongylus muris, Haemonchus contortus, Trichostrongylus colubriformis, Ostcrtagia circumcincta),
3. Strongyliden (z. B. Oesophagostomum columbianum), 3. Strongyles (e.g. Oesophagostomum columbianum),
4. Rhabditiden (z. B. Strongyloides ratti),4. Rhabditis (e.g. Strongyloides ratti),
5. Spulwürmer (z. B. Ascaris suum, Toxocara canis, Toxascaris leonina),5. roundworms (e.g. Ascaris suum, Toxocara canis, Toxascaris leonina),
6. Madenwürmer (z. B. Aspiculuris tetraptcra),6. pinworms (e.g. Aspiculuris tetraptcra),
7. Heterakiden (z. B. Hctcrakis spumosa), (157. Heteracids (e.g. Hctcrakis spumosa), (15
8. Peitschcnwürmer (z. B. Trichuris muris),8. whipworms (e.g. Trichuris muris),
9. Filarien(z. B. Litomosoidescarinii, Dipetalonema witei).9. Filaria (e.g. Litomosoidescarinii, Dipetalonema witei).
10. Cestoden (z. B. Hymenolepis nana, Taenia pisiformis, Echinococcus multiloeularis).10. Cestodes (e.g. Hymenolepis nana, Taenia pisiformis, Echinococcus multiloeularis).
Die Wirkung wurde im Tierversuch nach oraler und parenteraler Applikation bei stark mit Parasiten befallenen Versuchstieren geprüft. Die angewendeten Dosierungen wurden sehr gut von den Versuchstieren vertragen.The effect was demonstrated in animal experiments after oral and parenteral administration with strong parasites infected test animals checked. The dosages used were very good by the test animals tolerate.
Die neuen Wirkstoffe können als Anthelmintika sowohl in der Human- als auch in der Veterinärmedizin verwendet werden.The new active ingredients can be used as anthelmintics in both human and veterinary medicine be used.
Die neuen Wirkstoffe können in bekannter Weise in die üblichen Formulierungen übergeführt werden.The new active ingredients can be converted into the customary formulations in a known manner.
Die neuen Verbindungen können entweder als solche oder aber in Kombination mit pharmazeutisch annehmbaren Trägern zur Anwendung gelangen. Als Darreichungsformen in Kombination mit verschiedenen inerten Trägern kommen Tabletten, Kapseln, Granulate, wäßrige Suspensionen, injizier bare Lösungen, Emulsionen und Suspensionen, Elixiere, Sirup, Pasten und dergleichen in Betracht. Derartige Träger umfassen feste Verdünnungsmittel oder Füllstoffe, ein steriles, wäßriges Medium sowie verschiedene nichttoxische organische Lösungsmittel und dergleichen. Selbstverständlich können die für eine orale Verabreichung in Betracht kommenden Tabletten und dergleichen mit Süßstoffzusatz und ähnlichem versehen werden. Die therapeutisch wirksame Verbindung soll im vorgenannten Fall in einer Konzentration von etwa 0,5 bis 90 Gew.-% der Gesamtmischung vorhanden sein, d. h. in Mengen, die ausreichend sind, um den obengenannten Dosierungsspielraum zu erreichen. The new compounds can be used either as such or in combination with pharmaceutical acceptable carriers are used. As dosage forms in combination with various inert carriers come tablets, capsules, granules, aqueous suspensions, injectable solutions, Emulsions and suspensions, elixirs, syrups, pastes and the like can be considered. Such carriers include solid diluents or fillers, a sterile aqueous medium, as well as various non-toxic organic solvents, and the like. It goes without saying that tablets and the like which are suitable for oral administration can be used be provided with added sweeteners and the like. The therapeutically effective compound is said to be in the aforementioned case present in a concentration of about 0.5 to 90% by weight of the total mixture be, d. H. in amounts sufficient to achieve the above dosage range.
Die Formulierungen werden in bekannter Weise hergestellt, z. B. durch Verstrecken der Wirkstoffe mit Lösungsmitteln und/oder Trägerstoffen, gegebenenfalls unter Verwendung von Emulgiermitteln und/ oder Dispergiermitteln, wobei z. B. im Fall der Benutzung von Wasser als Verdünnungsmittel gegebenenfalls organische Lösungsmittel als Hilfslösungsmittel verwendet werden können.The formulations are prepared in a known manner, e.g. B. by stretching the active ingredients with solvents and / or carriers, if necessary with the use of emulsifiers and / or dispersants, e.g. B. in the case of the use of water as a diluent, if appropriate organic solvents can be used as auxiliary solvents.
Als Hilfsstoffe seien beispielhaft aufgerührt: Wasser, nichttoxische organische Lösungsmittel, wie Paraffine (z. B. Erdölfraktionen), pflanzliche öle (z. B. Erdnuß-/ Sesamöl), Alkohole (z. B. Äthylalkohol, Glycerin), Glykole (z. B. Propylenglykol, Polyäthylenglykol) und Wasser; feste Trägerstoffe, wie natürliche Gesteinsmehle (z. B. Kaoline, Tonerden, Talkum, Kreide), synthetische Gesteinsmehle (z. B. nochdisperse Kieselsäure, Silikate), Zucker (z. B. Rohr-, Milch- und Traubenzucker); Emulgiermittel, wie nichtionogcnc und anionische Emulgatoren (z. B. Polyoxyäthylen-Fett· säure - Ester, Polyoxyäthylen - Fettalkohol - Äther Alkylsulfonate und Arylsulfonate), Dispergicrmittc (z. B. Lignin, Sulfitablaugen, Methylccllulosc, Stärkt und Polyvinylpyrrolidon) und Gleitmittel (z. B. Ma gnesiumstearat, Talkum, Stearinsäure und Natrium laurylsulfat).The following are examples of auxiliary substances: water, non-toxic organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut / Sesame oil), alcohols (e.g. ethyl alcohol, glycerine), glycols (e.g. propylene glycol, polyethylene glycol) and Water; solid carriers, such as natural rock flour (e.g. kaolins, clays, talc, chalk), synthetic rock flour (e.g. still dispersed silicic acid, silicates), sugar (e.g. cane, milk and grape sugar); Emulsifiers such as nonionic and anionic emulsifiers (e.g. polyoxyethylene fat acid esters, polyoxyethylene fatty alcohol ethers, alkyl sulfonates and aryl sulfonates), dispersants (e.g. lignin, sulphite waste liquors, methylccllulosc, starch and polyvinylpyrrolidone) and lubricants (e.g. Ma magnesium stearate, talc, stearic acid and sodium lauryl sulfate).
Im Falle der oralen Anwendung können Tablette! selbstverständlich außer den genannten Trägcrstoffci auch Zusätze, wie Natriumeitrat, Calciumcarbonu und Dicalciumphosphat, zusammen mit verschiedene! Zuschlagstoffen, wie Stärke, vorzugsweise Kartoffel stärke, Gelatine, enthalten. Weiterhin können Gleil mittel, wie Magnesiumstcarat, Natriumlaurylsulfti und Talkum, zum Tablettieren mitverwendet wcrdeiIn the case of oral use, tablet can! of course, except for the carriers mentioned also additives such as sodium citrate, calcium carbonate and dicalcium phosphate, along with various! Contains additives such as starch, preferably potato starch, gelatin. Furthermore, Gleil medium, such as magnesium stcarate, sodium lauryl sulfi and talc, used for tableting
Im Falle wäßriger Suspensionen und/oder Elixierei die für orale Anwendungen gedacht sind, können diIn the case of aqueous suspensions and / or elixir eggs intended for oral use, di
Wirkstoffe außer mit den obengenannten Hilfsstoffen mit verschiedenen Geschmacksaufbesserern oder Farbstoffen versetzt werden.Active ingredients apart from the above-mentioned auxiliaries with various flavor enhancers or colorings be moved.
Für den Fall der parenteralen Anwendung können Lösungen der Wirkstoffe unter Verwendung geeigneter flüssiger Trägermaterialien eingesetzt werden.In the case of parenteral use, solutions of the active ingredients can be made using suitable solutions liquid carrier materials are used.
Die Wirkstoffe können in Kapseln, Tabletten. Pastillen, Dragees, Ampullen usw. auch in Form von Dosierungseinheiten enthalten sein, wobei jede Dosierungseinheit so angepaßt ist, daß sie eine einzelne Dosis des aktiven Bestandteils liefert.The active ingredients can be in capsules, tablets. Pastilles, coated tablets, ampoules etc. also in the form of dosage units be included, each dosage unit being adapted to be a single Dose of the active ingredient delivers.
Die neuen Wirkstoffe können in üblicher Weise angewendet werden. Die Applikation erfolgt vorzugsweise oral, eine parenteral, insbesondere subkutane, aber auch eine dermale Applikation sind jedoch ebenfalls möglich.The new active ingredients can be used in the usual way. The application is preferably carried out Oral, parenteral, especially subcutaneous, but also dermal application are, however also possible.
Im allgemeinen hat es sich als vorteilhaft erwiesen, Mengen von etwa 0,1 bis etwa 50 mg der neuen Verbindungen je kg Körpergewicht pro Tag zur Erzielung wirksamer Ergebnisse zu verabreichen.In general, it has proven advantageous to use amounts of about 0.1 to about 50 mg of the new compounds to be administered per kg of body weight per day for effective results.
Trotzdem kann es gegebenenfalls erforderlich sein, von den genannten Mengen abzuweichen, und zwar in Abhängigkeit vom Körpergewicht des Versuchstieres bzw. der Art des Applikationsweges, aber auch aufgrund der Tierart und deren individuellem Verhalten gegenüber dem Medikament bzw. der Art von dessen Formulierung und dem Zeitpunkt bzw. Intervall, zu welchem die Verabreichung erfolgt. So kann es in einigen Fällen ausreichend sein, mit weniger als der vorgenannten Mindestmenge auszukommen, während in anderen Fällen die genannte obere Grenze überschritten werden muß. Im Fall der Applikation größerer Mengen kann es empfehlenswert sein, diese in mehrere Einzelgaben über den Tag zu verteilen. Für die Applikation in der Human- und Veterinärmedizin ist der gleiche Dosierungsspielraum vorgesehen. Sinngemäß gelten auch die weiteren vorstehenden Ausführungen. Nevertheless, it may be necessary to deviate from the stated amounts, in Depending on the body weight of the test animal or the type of application route, but also due to the animal species and their individual behavior towards the drug or the type of it Formulation and the time or interval at which the administration takes place. So it can be in in some cases it may be sufficient to make do with less than the aforementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. In the case of application larger In amounts, it can be advisable to distribute these in several individual doses over the day. for the same dosage range is provided for application in human and veterinary medicine. Analogous The other statements above also apply.
Die anthelmintische Wirkung der erfindungsgemäßen Wirkstoffe sei anhand der folgenden Anwendungsbeispiele näher erläutert.The anthelmintic effect of the active ingredients according to the invention is based on the following application examples explained in more detail.
VV
Hakenwurm-Test/Schaf, HundHookworm test / sheep, dog
Experimentell mit Bunostomum trigonocephalum infizierte Schafe wurden nach Ablauf der Praepatenzzeit der Parasiten behandelt. Die Wirkstoffmenge wurde als reiner Wirkstoff in Gelatine-Kapseln oral appliziert.Sheep experimentally infected with Bunostomum trigonocephalum became after the expiration of the prepatent period the parasite treated. The amount of active ingredient was taken orally as the pure active ingredient in gelatin capsules applied.
Experimentell mit Uncinaria stenocephala bzw. Ancylostoma caninum infizierte Hunde wurden nachDogs experimentally infected with Uncinaria stenocephala or Ancylostoma caninum were identified
Ablauf der Praepatenz der Parasiten behandelt. Die Wirkstoffmenge wurde als reiner Wirkstoff in Gelatinekapseln orals appliziert.Expiry of the prepatency of the parasites treated. The amount of active ingredient was given as pure active ingredient in gelatin capsules applied orally.
Der Wirkungsgrad wird dadurch bestimmt, daß man die nach der Behandlung abgetriebenen und dieThe efficiency is determined by the fact that the aborted after the treatment and the
in den Versuchstieren überlebenden Würmer nach Sektion zählt und den Prozentsatz der abgetriebenen Würmer errechnet.in the test animals surviving worms by section counts and the percentage of aborted Worms calculated.
Geprüfte Wirkstoffe, angewandte Dosierungen und Wirkung sind aus der nachfolgenden Tabelle ersieht·Tested active ingredients, applied dosages and effects are shown in the following table
lieh. In der nachfolgenden Tabelle sind die Wirkstoffe und die geringste Dosierung in mg Wirkstoff pro k§ Körpergewicht des Versuchstieres, die den Wurmbefall des Versuchstieres um mehr als 90% reduziert aufgeführt.borrowed. The active ingredients are shown in the table below and the lowest dose in mg of active ingredient per k§ body weight of the test animal that caused the worm infestation of the test animal reduced by more than 90%.
Tabelle 1 (zu Beispiel A)Table 1 (for example A)
Erfindungsgemäßcr WirkstoffActive ingredient according to the invention
Dosis effectiva minima
(Red. > 90%) in mg/kgDose effectiva minima
(Red.> 90%) in mg / kg
N—CO-OCH3
V-NH-C-NH-CO-OCH3
Uncinaria sten. 3 χ 25
Bunostomum trig. 2,5N-CO-OCH 3 V-NH-C-NH-CO-OCH 3 Uncinaria sten. 3 χ 25
Bunostomum trig. 2.5
NH-CO-CH2-CH2-CH3 NH-CO-CH 2 -CH 2 -CH 3
■r■ r
N HN H
NH- C— NH- CO — OCH3 NH-C-NH-CO-OCH 3
N-CO-OCH3 O O C3 H 7 N-CO-OCH 3 OOC 3 H 7
Ancylostoma can. 3 χ 25
Uncinaria sten. 3 χ 1
Bunostomum trig. IAncylostoma can. 3 χ 25
Uncinaria sten. 3 χ 1
Bunostomum trig. I.
Beispiel B
Nippostrongylus muris-RattcExample B.
Nippostrongylus muris-Rattc
Experimentell mit Nippostrongylus muris infizierte Ratten wurden nach Ablauf der Prüputcnzzcit der Parusiten behandelt. Die Wirkstoffmcnge wurde als wäßrige Suspension oral appliziert.Rats experimentally infected with Nippostrongylus muris were tested after the end of the test Parusites treated. The amount of active ingredient was administered orally as an aqueous suspension.
Der Wirkungsgrad des Präparates wird dadurchThe degree of effectiveness of the preparation is thereby
fts bestimmt, daß man nach Sektion die im Versuchst verbleibencn Würmer im Vergleich zu unbehandcltc Kontrolltieren zählt und danach den Prozentsatz d( Wirkung errechnet.It is determined that after dissection the worms remaining in the test are compared with untreated Control animals counts and then the percentage d (effect calculated.
In der nachfolgenden Tabelle sind die Wirkstofi und die geringste Dosierung, die den Wurmbcfall df Versuchstiere um mehr als 90% reduziert, im Vergleic zu verwandten Präparaten aufgeführt.The table below shows the active ingredients and the lowest dose, which reduces worms in test animals by more than 90%, in comparison to related preparations listed.
1111th
Tabelle 2 (zu Beispiel B) 12 Table 2 (for example B) 12
Erfindungsgemiißer WirkstoffActive ingredient according to the invention
/~V-s—/~\-NH-C = N-CO-OCH3 / ~ Vs- / ~ \ -NH-C = N-CO-OCH 3
NH-CO-OCH3 NH-CO-CH3 NH-CO-OCH 3 NH-CO-CH 3
^ V_s-^ >-NH — C = N-CO-OCH3 ^ V_s- ^> -NH - C = N-CO-OCH 3
NH-CO-OCH3 NH — CO — CH2- OCH3 NH-CO-OCH 3 NH - CO - CH 2 - OCH 3
N-CO-OCH3 N-CO-OCH 3
NH-CO-OC2H5 NH-CO-OC 2 H 5
NH-CO-C3H7 NH-CO-C 3 H 7
N-COOCH3 N-COOCH 3
NH-CO-OC2H5 NH-CO-CH2-OCH3 NH-CO-OC 2 H 5 NH-CO-CH 2 -OCH 3
Verwandte Präparate zum Vergleich (bekannt aus DT-OS 21 17 293)Related preparations for comparison (known from DT-OS 21 17 293)
N-CO-OCH3 f ^pNH-C-NH-CO—OCH3 N-CO-OCH 3 f ^ pNH-C-NH-CO-OCH 3
NH-CO-CH3 NH-CO-CH 3
N-CO-OCH3 NH—C— NH — CO — OCH3 N-CO-OCH 3 NH-C-NH-CO-OCH 3
NH-CO-C2H5 NH-CO-C 2 H 5
Beispiel C
Magen- und Darmwurm-Test/SchafExample C
Gastric and intestinal worm test / sheep
Experimentell mit Haemonchus contortus oder Trichostrongylus colubriformis infizierte Schafe wurden nach Ablauf der Präpatcnzzeit der Parasiten behandelt. Die Wirkstoffmenge wurde als reiner Wirkstoff in Gclatinckupseln oral appliziert.Sheep experimentally infected with Haemonchus contortus or Trichostrongylus colubriformis have been made treated after the parasites have been prepared. The amount of active ingredient was administered orally as the pure active ingredient in gclatin capsules.
Der Wirkungsgrad wird dadurch bestimmt, daß Dosis cffectiva minim» (Red. > 90%) in mg/kgThe degree of effectiveness is determined by that dose cffectiva minim »(Red.> 90%) in mg / kg
2525th
Dosis effectiva minima (Red. > 90%) in mg/kgDose effectiva minima (red.> 90%) in mg / kg
>500> 500
500500
man die mit dem Kot ausgeschiedenen Wurmeier vor und nach der Behandlung quantitativ auszählt.the worm eggs excreted with the faeces are counted quantitatively before and after the treatment.
Ein völliges Sistiercn der Eiausscheidung nach der Behandlung bedeutet, daß die Würmer abgetrieben wurden oder so geschädigt sind, daß sie keine Eier mehr produzieren können (Dosis effectiva).A complete suspension of egg excretion after the Treatment means that the worms have been aborted or are so damaged that they do not have eggs can produce more (dose effectiva).
Geprüfte Wirkstoffe und wirksame Dosierungen (Dosis effectiva minima) sind aus der nachfolgenden Tabelle ersichtlich.Tested active ingredients and effective dosages (dose effectiva minima) are from the following Table.
1313th
Tabelle 3 (zu Beispiel C)
Erfindungsgemäßer WirkslolTTable 3 (for example C)
Effectiveness according to the invention
NH-CN-CO-OCH3 NH-CN-CO-OCH 3
NH-CO-OCH3 NH-CO-CH3 NH-CO-OCH 3 NH-CO-CH 3
^-NH-C = N-CO-OCH3 ^ -NH-C = N-CO-OCH 3
NH-CO-OCH3 NH-CO-CH2-CH3 NH-CO-OCH 3 NH-CO-CH 2 -CH 3
N-CO-OCH3 -C-NH-CO-OCH3 N-CO-OCH 3 -C-NH-CO-OCH 3
NH — CO — CH2- CH2-CH3 NH - CO - CH 2 - CH 2 -CH 3
N-CO-OCH3 NH-CO-CH3-CH2 N-CO-OCH 3 NH-CO-CH 3 -CH 2
/~V_0—«^~V-NH—C = N-CO —OCH3 / ~ V_0 - «^ ~ V-NH-C = N-CO -OCH 3
NH-CO-C2H5 NH-CO-C 2 H 5
NH-CO—< HNH-CO- < H
NH-C = N-CO-OCH3 NH-C = N-CO-OCH 3
NH-CO-OCH3 NH-CO-CH3 NH-CO-OCH 3 NH-CO-CH 3
NH-CO-OCH3 NH-CO-OCH 3
NH-CO-C2H5 J' V- NH _.-c — NH — CO — OCH3 NH-CO-C 2 H 5 J ' V- NH _.- c - NH - CO - OCH 3
N-CO-OCH3 N-CO-OCH 3
NH-CO-C3H7 NH-CO-C 3 H 7
NH-CO-C2H5 NH-CO-C 2 H 5
V--ν H-CV - ν H-C
N-CO-OCH3 N-CO-OCH 3
NH-CO-CH3 NH-CO-CH 3
OCH3 OCH 3
Nil — C= N-CO- OCH3 Nil - C = N-CO- OCH 3
NH-CO-OCH3 NH- CO — CH,NH-CO-OCH 3 NH- CO - CH,
Dosis effcctiva minima (Red. > 90%) in mg/kyDose effcctiva minima (Red.> 90%) in mg / ky
Haemonchus cont. 5 Trichostrong. col. 5Haemonchus cont. 5 Trichostrong. col. 5
Haemonchus cont. 2,5 Trichostrong. col. 2,5Haemonchus cont. 2.5 Trichostrong. col. 2.5
Haemonchus cont. 2,5 Trichostrong. col. 2,5Haemonchus cont. 2.5 Trichostrong. col. 2.5
Haemonchus sont. 5 Trichostrong. col. 5Haemonchus sont. 5 Trichostrong. col. 5
Haemonchus cont. 5Haemonchus cont. 5
Haemonchus cont. 2,5 Trichostrong. col. 2,5Haemonchus cont. 2.5 Trichostrong. col. 2.5
Haemonchus cont. 2,5 Trichostrong. col. 2,5Haemonchus cont. 2.5 Trichostrong. col. 2.5
Haemonchus cont. 0,5 Trichostrong. col. IHaemonchus cont. 0.5 trichostrong. col. I.
Haemonchus cont. 2,5 Trichostrong. col. 5Haemonchus cont. 2.5 Trichostrong. col. 5
Haemonchus cont. 5Haemonchus cont. 5
1515th
-"ortsct/ung
irfindungsgcmäBcr Wirkstoff- "ortsct / ung
founding agent
NH-CO-C2H5 NH-CO-C 2 H 5
NH-C = N-CO-OCH3
NH-CO-OCH3 NH-C = N-CO-OCH 3
NH-CO-OCH 3
NH-C = N-CO-OC2H5 NH-C = N-CO-OC 2 H 5
NH-CO-OCH3 NH-CO-CH3 NH-CO-OCH 3 NH-CO-CH 3
NH-CO-CH3 NH-CO-CH 3
NH-C-NH-CO-C2H5 N-CO-OCH3 NH-C-NH-CO-C 2 H 5 N-CO-OCH 3
N-CO-OCH3 N-CO-OCH 3
/"V-S-ZA-NH-C/ "V-S-ZA-NH-C
NH-CO-OCH3 NH — CO — CH2- OCH3 NH-CO-OCH 3 NH - CO - CH 2 - OCH 3
N-COOCH3 N-COOCH 3
NH-CO-C2H5 NH-CO-C2H5 NH-CO-C 2 H 5 NH-CO-C 2 H 5
N-CO-OCH3 N-CO-OCH 3
NH-CO-C2H5 NH-CO-C3H7 NH-CO-C 2 H 5 NH-CO-C 3 H 7
N-CO-OCH3 N-CO-OCH 3
NH-CO-OC2H5 NH — CO — CH2- OCH3 NH-CO-OC 2 H 5 NH - CO - CH 2 - OCH 3
Dosis effectiva minima (Red. > 90%) in mg/kgDose effectiva minima (red.> 90%) in mg / kg
Haemonchus cont. 5 Trichostrong. col. IHaemonchus cont. 5 Trichostrong. col. I.
Haemonchus cont. 2,5 Trichostrong. col. 2,5Haemonchus cont. 2.5 Trichostrong. col. 2.5
Trichostrong. col. 5Trichostrong. col. 5
Haemonchus cont. 0,5 Trichostrong. col. 1Haemonchus cont. 0.5 trichostrong. col. 1
Haemonchus cont. 2,5 Trichostrong. col. 2,5Haemonchus cont. 2.5 Trichostrong. col. 2.5
Haemonchus cont. 2,5 Trichostrong. col. 2,5Haemonchus cont. 2.5 Trichostrong. col. 2.5
Haemonchus cont. 1Haemonchus cont. 1
\-NH—C\ -NH-C
N-CO-OCH3 N-CO-OCH 3
NH-CO—OCH3 NH-CO-C2H5 NH-CO-OCH 3 NH-CO-C 2 H 5
Trichostrong. col. 5Trichostrong. col. 5
Fortsetzungcontinuation
Erfindungsgemäßer WirkstoffActive ingredient according to the invention
Dosis effcctivu minima (Red. > 90%) in mg/kgDose effcctivu minima (Red.> 90%) in mg / kg
N-CO-OCH3 N-CO-OCH 3
QYl Co — HN—<f V-O-V^ V-NH — C Haemonchus cont. 2,5 QYl Co - HN— <f VOV ^ V-NH - C Haemonchus cont. 2.5
NH-CO-OCH3 NH-CO-C2H5 NH-CO-OCH 3 NH-CO-C 2 H 5
N-CO-OCH3 N-CO-OCH 3
NH-CNH-C
NH-CO-OCH3 NH-CO-OCH 3
NH — CO — CH2- OC6H5 NH - CO - CH 2 - OC 6 H 5
Haemonchus 2,5Haemonchus 2.5
HaemonchusHaemonchus
NH-CNH-C
N-COOCH3 N-COOCH 3
NH-CO-C2H5 NH-CO-C 2 H 5
Verwandte Präparate zum Vergleich (bekannt aus DT-OS 21 17 293) Dosis effective minima (Red. > 90%) in mg/kgRelated preparations for comparison (known from DT-OS 21 17 293) Dose effective minima (Red.> 90%) in mg / kg
N-CO-OCH3
NH-C-NH-CO-OCH3 N-CO-OCH 3
NH-C-NH-CO-OCH 3
NH-CO-CH3 NH-CO-CH 3
N-CO-OCH3
NH-C-NH-CO-OCH3 N-CO-OCH 3
NH-C-NH-CO-OCH 3
NH-CO-C2H5 NH-CO-C 2 H 5
Beispiel D
Spulwurmtest/Hund, RatteExample D
Roundworm test / dog, rat
Natürlich oder experimentell mit Toxascaris leonina infizierten Hunden wurde die Wirkstoffmenge als reiner Wirkstoff in Gelatinekapseln oral appliziert.Naturally or experimentally infected dogs with Toxascaris leonina was determined to be the amount of the active substance pure active ingredient in gelatin capsules applied orally.
Experimentell mit Ascaris suum infizierte Ratten wurden 2 bis 4 Tage p. inf. behandelt. Die Wirkstoffmenge wurde als wäßrige Suspension oral appliziert.Rats experimentally infected with Ascaris suum were given 2 to 4 days p. inf. treated. The amount of active ingredient was administered orally as an aqueous suspension.
Tabelle 4 (zu Beispiel D)Table 4 (for example D)
Haemonchus cont.> Trichostrong. col.Haemonchus cont.> Trichostrong. col.
Haemonchus cont. Trichostrong. col.Haemonchus cont. Trichostrong. col.
Der Wirkungsgrad des Präparates wird dadurchThe degree of effectiveness of the preparation is thereby
bestimmt, daß man nach Sektion die im Versuchstierdetermined that after the dissection, the one in the test animal
verbliebenen Würmer im Vergleich zu unbehandeltenremaining worms compared to untreated
Kontrolltieren zählt und danach den Prozentsatz der Wirkung errechnet.Control animals counts and then the percentage of effect is calculated.
In der nachfolgenden Tabelle sind die Wirkstoffe und die geringste Dosierung, die den Wurmbefall der Versuchstiere um mehr als 90% reduziert, im Vergleich zu verwandten Präparaten aufgeführt.The table below shows the active ingredients and the lowest dosage that can prevent worm infestation Test animals reduced by more than 90% compared to related preparations listed.
llrfindungsgemUlter WirkstoffActive ingredient according to the invention
Dosis effectiva minima (Red. > 90%) in mg/kgDose effectiva minima (red.> 90%) in mg / kg
N-CO-OCH3
O~/ V-NH-C —NH-CO—OCH,N-CO-OCH 3
O ~ / V-NH-C -NH-CO-OCH,
Toxascaris
leoninaToxascaris
leonina
2525th
NH-CO-CH2-CH2-CH3 NH-CO-CH 2 -CH 2 -CH 3
1919th
Λ ΛΛ Λ
irtscizung
limiungsgemaßer Wirkstoffirtscizung
limited active ingredient
V-S-< >-NH— C = N-CO-OCH3 VS- <> -NH- C = N-CO-OCH 3
NH-CO-OCH3 NH-CO-CH3 NH-CO-OCH 3 NH-CO-CH 3
Dosis effectiva minima (Red. > 90%) in mg/kg)Dose effectiva minima (red.> 90%) in mg / kg)
Ascaris suum-Larv. Ascaris suum larva.
—C = N-CO--OC2 - C = N-CO - OC 2
NH-CO-OCH3 NH-CO-CH3 NH-CO-OCH 3 NH-CO-CH 3
Ascaris suum-Larv. Ascaris suum larva.
'''^1X-S-/ Vnh—c '''^ 1 XS- / Vnh-c
N-CO-OCH3 N-CO-OCH 3
NH-CO-OC2H5 NH-CO-CH2-OCH3 NH-CO-OC 2 H 5 NH-CO-CH 2 -OCH 3
Ascaris suum-Larv. Ascaris suum larva.
N-CO-OCH3 N-CO-OCH 3
/Λ-0-// Λ-0- /
NH-CNH-C
NH-CO-OCH3 NH-CO-C3H7 NH-CO-OCH 3 NH-CO-C 3 H 7
Ascaris suum-Larv. Ascaris suum larva.
N-CO-OCH3 N-CO-OCH 3
NH-CNH-C
j NH-CO-OCH3 j NH-CO-OCH 3
NH-CO-CH2-OCH3 NH-CO-CH 2 -OCH 3
A-S-/A-S- /
N-CO-OCH3 N-CO-OCH 3
NH-CO-C2H5 NH-CO-CH3 NH-CO-C 2 H 5 NH-CO-CH 3
N-CO-OCH3 N-CO-OCH 3
AV-S-/AV-S- /
NH-CO-C2H5 NH-CO-C2H5 NH-CO-C 2 H 5 NH-CO-C 2 H 5
Ascaris suum Larv.Ascaris suum larv.
Ascaris suum Larv.Ascaris suum larv.
Ascaris suum Larv.Ascaris suum larv.
N-CO-OCH3 N-CO-OCH 3
— C- C
NH-CO-OC2H5 NH-CO-C3H7 NH-CO-OC 2 H 5 NH-CO-C 3 H 7
Ascaris suum Larv.Ascaris suum larv.
2121
Fortsetzungcontinuation
Erfindungsgemäßer WirkstoffActive ingredient according to the invention
Dosis effect iva minima (Red. > 90%) in mg/kg)Dose effect iva minima (Red.> 90%) in mg / kg)
N-CO-OCH3 N-CO-OCH 3
j NH-CO-OC2H5 j NH-CO-OC 2 H 5
NH-CO-CH3 NH-CO-CH 3
N-CO-OCH3 N-CO-OCH 3
NH-CNH-C
NH-CO-OC2H5 NH-CO— C3H-NH-CO-OC 2 H 5 NH-CO— C 3 H-
Vcrwandtc Präparate zum Vergleich (bekannt aus DT-OS 21 17 293)Comparative preparations for comparison (known from DT-OS 21 17 293)
Ascaris suum 50 Larv.Ascaris suum 50 larva.
Ascaris suum 100 Larv.Ascaris suum 100 larva.
Dosis cffecüva minima (Red. > 90%) in mg/kgDose of cffecüva minima (Red.> 90%) in mg / kg
N-CO-OCH3 NH-C-NH-CO-OCH3 N-CO-OCH 3 NH-C-NH-CO-OCH 3
NH-CO-CH3 NH-CO-CH 3
N-CO-OCH3 N-CO-OCH 3
NH-C-NH-CO-OCH3 NH-C-NH-CO-OCH 3
NH-CO-C2H5 NH-CO-C 2 H 5
Beispiel E Aspiculuris tetraptera/MausExample E. Aspiculuris tetraptera / mouse
unwirksamineffective
unwirksamineffective
Die Wirkstoffmenge wurde als wäßrige Suspension 40 oral appliziert.The amount of active ingredient was administered orally as an aqueous suspension 40.
Der Wirkungsgrad des Präparates wird dadurch bestimmt, daß man nach Sektion die im Versuchstier Natürlich mit Aspiculuris tetraptera infizierte Mäuse verbliebenen Würmer im Vergleich zu unbehandelten wurden nach Ablauf der Präpatenzzeit der Parasiten Kontrolltieren zählt und danach den Prozentsatz der behandelt. 45 Wirkung errechnet.The degree of effectiveness of the preparation is determined by the fact that after sectioning the test animal Mice naturally infected with Aspiculuris tetraptera retained worms compared to untreated ones control animals were counted after the prepatency period of the parasites and then the percentage of treated. 45 effect calculated.
Tabelle 5 (zu Beispiel E)Table 5 (for example E)
Erfindungsgemäßer WirkstoffActive ingredient according to the invention
Dosis
effectiva
minima
(Red.
> 90%)
in mg/kgdose
effectiva
minimum
(Red.
> 90%)
in mg / kg
V-NH-C = N-CO-OCH3 V-NH-C = N-CO-OCH 3
NH-CO-OCH3
NH-CO-CH3 NH-CO-OCH 3
NH-CO-CH 3
Ν —CO—OCH,Ν —CO — OCH,
NH-CO-C2H5
NH-CO-C2H5 NH-CO-C 2 H 5
NH-CO-C 2 H 5
Fortsetzungcontinuation
lirfindungsgcmüßcr WirkstoffIrfindungsgcmüßcr active ingredient
N-CO-OCH3 N-CO-OCH 3
2424
Dosis cffectiva minima (Red. > 90%) in mg/kgDose cffectiva minima (Red.> 90%) in mg / kg
2525th
NH-CO-C2H5 NH-CO-C3H7 NH-CO-C 2 H 5 NH-CO-C 3 H 7
NH-CO-C2H5 NH-CO-C 2 H 5
N-CO-OCH3 N-CO-OCH 3
5050
NH-CNH-C
NH-CO-OCH3 NH-CO-OCH 3
Bekanntes Präparat zum Vergleich (bekannt aus DT-OS 21 17 293)Known preparation for comparison (known from DT-OS 21 17 293)
Dosis ctTcctiva minima (Red. > 90%) in mg/kgDose ctTcctiva minima (Red.> 90%) in mg / kg
N-CO-OCH3 N-CO-OCH 3
C-NH-CO-OCH3 unwirksamC-NH-CO-OCH 3 ineffective
NH-CO-CH3 NH-CO-CH 3
Beispiel F Hymcnolcpis nana/MausExample F Hymcnolcpis nana / mouse
Experimentell mit H.nana infizierte Versuchstiere bestimmt, daß man nach Sektion die im VcrsuchstieiTest animals experimentally infected with H.nana determined that after dissection, the animals in the investigation
werden nach Ablauf der Praepatcnz der Parasiten verbliebenen Würmer im Vergleich zu unbehandelterworms that remain after the parasite has expired compared to untreated worms
behandelt. Die Wirkstoffmenge wird als wäßrige Sus- 45 Kontrolltieren zählt und danaeh den Prozentsatz dcitreated. The amount of active ingredient is counted as aqueous sus- 45 control animals and then the percentage dci
pension oral appliziert. Wirkung errechnet.pension administered orally. Effect calculated.
Der Wirkungsgrad des Präparates wird dadurchThe degree of effectiveness of the preparation is thereby
Hrlindungsgemäller WirkstoffActive ingredient according to the invention
Dosis effccliva (Red. > 90%) in mg/kgEffccliva dose (ed.> 90%) in mg / kg
■< V-NIl C N CO OCH,■ <V-NIl C N CO OCH,
Nil CO OCH3 NH CO CH3 Nile CO OCH 3 NH CO CH 3
NH CO C2II5 -/"Y-NH" C·"" NH CO C 2 II 5 - / "Y-NH" C · ""
N COOCH, Nil CO CiI,N COOCH, Nile CO CiI,
K)OK) O
Fortsetzung
Erfindungsgemäßer Wirkstoff IW continuation
Active ingredient IW according to the invention
Dosis
effectiva
(Red.
> 90%)
in mg/kgdose
effectiva
(Red.
> 90%)
in mg / kg
NH-CO-OCH3 NH-CO-CH2-OCH3 NH-CO-OCH 3 NH-CO-CH 2 -OCH 3
Herstellungsbeispiele Beispiel 1Preparation examples Example 1
NH-CNH-C
- CO-CH3 N-COOCH3 - CO-CH 3 N-COOCH 3
NH-COOCH3 NH-COOCH 3
24,2g (0,1 Mol) 2-Amino-5-phenoxy-acetanilid vom Fp. 120° C werden zusammen mit 20,6 g (0,1 Mol) N,N' - bis - Methoxycarbonyl - isothioharnstoff - S-methyläther und 2,6 g (0,015 Mol) p-Toluolsulfonsäure in 200 ml absol. Methanol 3 Stunden unter Rühren und Rückfluß erhitzt. Danach wird heiß filtriert und nach dem Erkalten das auskristallisierte N - (2 - Acetamido - 4 - phenoxy - phenyl) - Ν',Ν " - bismethoxycarbonyl - guanidin abgesaugt, mit Äther nachgewaschen und im Hochvakuum getrocknet, Fp. 168° C, Ausbeute 27 g = 67,5% der Theorie.24.2 g (0.1 mole) 2-amino-5-phenoxy-acetanilide of melting point 120 ° C. together with 20.6 g (0.1 mol) of N, N '- bis - methoxycarbonyl - isothiourea - S-methyl ether and 2.6 g (0.015 moles) of p-toluenesulfonic acid in 200 ml absolute Methanol heated for 3 hours with stirring and reflux. After that it gets hot filtered and after cooling the crystallized N - (2 - acetamido - 4 - phenoxyphenyl) - Ν ', Ν "- bismethoxycarbonyl - Guanidine suctioned off, washed with ether and dried in a high vacuum, mp. 168 ° C., yield 27 g = 67.5% of theory.
Durch Aufarbeitung der Mutterlauge läßt sich die Ausbeute erhöhen.The yield can be increased by working up the mother liquor.
Analog Beispiel 1 wurden erhalten aus:As in Example 1, the following were obtained:
2-Amino-5-phenoxy-acelanilid und N,N'-Bis-Älhoxycarbonyl-isolhiohurnstoff-S-methylüther tlas N-(2-Acetamido-4-phenoxy-phenyl)-N',N"-bis-äthoxycarbonyl-guanidin vom Fp, 159"C; 2-Amino-5-phenoxy-acetunilid und N,N'-Bisiso-Propoxycarbonyl-isothioharnstoff-S-nielhyliither das N-(2-Acctamido-4-phenoxy-phenyl)-N',N"-bis-iso-propoxycarbonyl-guanidin vom Fp. 165" C;2-Amino-5-phenoxy-acelanilide and N, N'-bis-Älhoxycarbonyl-isolhiorstoff-S-methylether tlas N- (2-acetamido-4-phenoxyphenyl) -N ', N "-bis-ethoxycarbonyl-guanidine of m.p. 159 "C; 2-amino-5-phenoxy-acetunilide and N, N'-bisiso-propoxycarbonyl-isothiourea-S-nielhyliither the N- (2-Acctamido-4-phenoxyphenyl) -N ', N "-bis-iso-propoxycarbonyl-guanidine of m.p. 165 "C;
rp. loj i^,rp. loj i ^,
2-Amino- 5-phenoxy- propionanilid vom Fp.2-Amino-5-phenoxypropionanilide of m.p.
122" C! und N1N' - Bis - methoxycarbonyl - iso-122 "C! And N 1 N '- bis - methoxycarbonyl - iso-
(hiohumstoff-S-methylüthcr das N-(2-Propion-(Hiohumstoff-S-methylüthcr the N- (2-propion-
amiil('i-4-phenoxy-phenyl)-N',N"-bis-metlH)xy-amiil ('i-4-phenoxyphenyl) -N', N "-bis-metlH) xy-
tnrbonyl-guaniclin, Fp. 143"C;carbonyl guanicline, m.p. 143 "C;
2-Amino-5-phenoxy-propionanilid und N1N'-2-amino-5-phenoxy-propionanilide and N 1 N'-
bis -Älhoxycarbony I - isothioharnstoff- S - melhyl-bis -älhoxycarbony I - isothiourea- S - melhyl-
iilher das N - (2 - Propionamido - 4 - phonoxy-iilher the N - (2 - propionamido - 4 - phonoxy-
phenyl) - Ν',Ν" - bis - äthoxycarbonyl - guanidinphenyl) - Ν ', Ν "- bis - ethoxycarbonyl - guanidine
vom Fp. I67"C;of m.p. 166 "C;
2-Amino-5-phenoxy-propionanilid und N,N'-2-amino-5-phenoxy-propionanilide and N, N'-
(10 Bis - iso - Propoxycarbonyl - isothioharnstoff- S-mcthylather
das N-(2- Propionamido-4-phenoxy
- phenyl) - N ',N " - bis - iso - propoxycarbonylguanidin vom Fp. 161" C;
2 - Amino - 5 - phenoxy - butyranilid vom Fp. 118° C und N,N' - Bis - methoxycarbonyl - isothioharnstoff
- S - methyläther das N - (2 - Butyramido-4-phenoxy-phenyl)-N',N'-bis-methoxy- carbonyl-guanidin vom Fp. 136° C;
2-Amino-5-phcnoxy-butyranilid und N,N'-Bis-Äthoxycarbony 1 - isothioharnstoff- S - methyläther
das N-(2-Butyramido-4-phenoxy-phenyl)-N ',N "-bis-äthoxycarbonyl-guanidin
vom Fp. 142° C; 2-Amino-5-phenoxy-butyranilid und N,N'-Bisiso-Propoxycarbonyl-isothioharnstoff-S-methyläther
das N-(2-Butyramido-4-phenoxy-phenyl)-N ',N " - bis - iso - propoxycarbonyl - guanidin vom
Fp. 163° C; (10 bis-iso-propoxycarbonyl-isothiourea-S-methyl ether the N- (2-propionamido-4-phenoxy-phenyl) -N ', N "-bis-iso-propoxycarbonylguanidine of melting point 161"C;
2 - amino - 5 - phenoxy - butyranilide of melting point 118 ° C and N, N '- bis - methoxycarbonyl - isothiourea - S - methyl ether the N - (2 - butyramido-4-phenoxyphenyl) -N', N ' bis-methoxycarbonyl-guanidine, melting point 136 ° C; 2-Amino-5-phenoxy-butyranilid and N, N'-bis-ethoxycarbony 1 - isothiourea- S - methyl ether the N- (2-butyramido-4-phenoxyphenyl) -N ', N "- bis-ethoxycarbonyl- guanidine of melting point 142 ° C; 2-amino-5-phenoxy-butyranilide and N, N'-bisiso-propoxycarbonyl-isothiourea-S-methyl ether, the N- (2-butyramido-4-phenoxyphenyl) -N ', N "- bis - iso - propoxycarbonyl - guanidine melting at 163 ° C .;
2 - Amino - 5 - phenoxy - cyclohexancarbonanilid2 - amino - 5 - phenoxy - cyclohexanecarbonanilide
vom Fp. 142° C und Ν,Ν'-Bis-Methoxycarbonyl-of melting point 142 ° C and Ν, Ν'-bis-methoxycarbonyl-
isothioharnstoff-S-methyläther das N-(2-Cyclohexancarbonamido - 4 - phenoxy - phenyl) - N ',N "-isothiourea-S-methyl ether the N- (2-cyclohexanecarbonamido - 4 - phenoxy - phenyl) - N ', N "-
bis-methoxycarbonyl-guanidin vom Fp. 155° C;bis-methoxycarbonyl-guanidine, mp 155 ° C;
2 - Amino - 5 - phenoxy - cyclohexancarbonanilid2 - amino - 5 - phenoxy - cyclohexanecarbonanilide
und Ν,Ν'-Bis-Äthoxycarbonyl-isothioharnstoff-S - methyläther das N - (2 - Cyclohexancarbonamido - 4 - phenoxy - phenyl) - N ',N " - bis - äthoxycarbonyl-guanidin vom Fp. 132° C;and Ν, Ν'-bis-ethoxycarbonyl-isothiourea-S - methyl ether the N - (2 - cyclohexanecarbonamido - 4 - phenoxy - phenyl) - N ', N "- bis - ethoxycarbonyl-guanidine of m.p. 132 ° C;
2 - Amino - 5 - (3 - chlor - phenoxy) - acetanilid und2 - amino - 5 - (3 - chloro - phenoxy) - acetanilide and
N,N' - Bis - Methoxycarbonyl - isothioharnstoff-S-mcthyläther das N-[2-Acetamido-4-(3-chlorphcnoxy)-phenyl] - N ',N " - bis- methoxycarbonyl· guanidin vom Fp. 160— 161" C; 2-Amino-5-(3-chlor-phcnoxy)-butyranilid umN, N '- bis - methoxycarbonyl - isothiourea-S-methyl ether the N- [2-acetamido-4- (3-chlorophynoxy) -phenyl] - N ', N "- bis-methoxycarbonyl · guanidine of m.p. 160-161" C; 2-Amino-5- (3-chlorophynoxy) -butyranilide
N1N' - Bis - Methoxycarbonyl - isothioharnstoff S-mcthyläthcr das N-[2-Butyramido-4-(3-chlorN 1 N '- bis - methoxycarbonyl - isothiourea S-methylethylether N- [2-butyramido-4- (3-chloro
phcnoxy)-phenyl]-N',N"-bis-methoxycarbonyl guanidin vom Fp. 163"C;phcnoxy) -phenyl] -N ', N "-bis-methoxycarbonyl guanidine, m.p. 163 "C;
2 - Amino - 5 - (4- chlor - phenoxy) - acetanilid von Fp. 150 ■ 151'1C und N1N' - Bis - Methoxy carbonyl - isothioharnstoff - S - methyläther da:2 - Amino - 5 - (4-chloro - phenoxy) - acetanilide of melting point 150 ■ 151 ' 1 C and N 1 N' - bis - methoxy carbonyl - isothiourea - S - methyl ether because:
N-[2-Acctamido-4-(4-chlor-phcnoxy)-phenyl] Ν',Ν" - bis - methoxycarbonyl - guanidin von Fp. 170" C;N- [2-Acctamido-4- (4-chlorophynoxy) -phenyl] Ν ', Ν "- bis - methoxycarbonyl - guanidine of M.p. 170 "C;
2-Amino-5-(4-chlor-phenoxy)-butyranilid von Fp. 10111C und N,N'- Bis- Methoxycarbonyl isothioharnstoff - S - methyläther das N - [2 Butyramido - 4 - (4 - chlor - phenoxy) - phenyl] Ν',Ν" - bis - melhoxycarbonyl - guanidin von Fp. 201 "C;2-Amino-5- (4-chloro-phenoxy) -butyranilide of m.p. 101 11 C and N, N'-bis-methoxycarbonyl isothiourea - S - methyl ether the N - [2 butyramido - 4 - (4 - chloro - phenoxy ) - phenyl] Ν ', Ν "- bis - melhoxycarbonyl - guanidine of melting point 201"C;
titi
2 - Amino - 5 - (3 - methoxy - phenoxy) - acetanilid vom Fp. 107- 1080C und Ν,Ν'-Bis-Mcthoxycarbonyl - isothioharnstoff - S - methyläther das N - [2 - Acetamido - 4 - (3 - methoxy - phcnoxy)-phenyl] - N ',N " - bis - methoxycarbonyl - guanidin vom Fp. 164" C;2 - amino - 5 - (3 - methoxy - phenoxy) - acetanilide, mp 107- 108 0 C and Ν, Ν'-bis-Mcthoxycarbonyl -. Isothiourea - S - methyl ether N - [2 - acetamido - 4 - (3 - methoxy - phenoxy) - phenyl] - N ', N "- bis - methoxycarbonyl - guanidine of melting point 164"C;
2-Amino-5-(3-methoxy-phenoxy)-propionanilid vom Fp. 57°C und Ν,Ν'-Bis-Methoxycarbonylisothiohamstoff-S-methyläther das. N-[2-Propionamido - 4 - (3 - methoxy - phenoxy) - phenyl]-Ν',Ν" - bis - methoxycarbonyl - guanidin vom Fp. 133—134° C;2-Amino-5- (3-methoxyphenoxy) propionanilide of melting point 57 ° C. and Ν, Ν'-bis-methoxycarbonylisothiourea-S-methyl ether das. N- [2-Propionamido - 4 - (3 - methoxy - phenoxy) - phenyl] -Ν ', Ν "- bis - methoxycarbonyl - guanidine vom Mp 133-134 ° C;
2-Amino-5-(4-methyl-phenoxy)-propionanilid vom Fp. 125UC und Ν,Ν'-Bis-Methoxycarbonylisothioharnstoff-S-methyläther das N-[2-Pro- ,5 pionamido - 4 - (4 - methyl - phenoxy) - phenyl]-Ν',Ν" - bis - methoxycarbonyl - guanidin vom Fp. 165—166° C;2-Amino-5- (4-methyl-phenoxy) -propionanilide of melting point 125 U C and Ν, Ν'-bis-methoxycarbonylisothiourea-S-methyl ether, the N- [2- prop, 5- pionamido - 4 - (4 - methyl - phenoxy) - phenyl] -Ν ', Ν "- bis - methoxycarbonyl - guanidine of melting point 165-166 ° C;
2 - Amino - 5 - (4 - methyl - phenoxy) - butyranilid vom Fp. 1220C und Ν,Ν'-Bis-Methoxycarbonylisothioharnstoff-S-methyläther das N-[2-Butyramido - 4 - (4 - methyl - phenoxy) - phenyl] - N ',N "-bis-methoxycarbonyl-guanidin vom Fp. 161— 162° C;2 - amino - 5 - (4 - methyl - phenoxy) - butyranilid mp 122 0 C and Ν, methyl ether Ν'-bis-Methoxycarbonylisothioharnstoff-S-N- [2-butyramido -. 4 - (4 - methyl - phenoxy ) - phenyl] - N ', N "-bis-methoxycarbonyl-guanidine of m.p. 161-162 ° C;
2 - Amino - 5 - (4 - acetamino - phenoxy) - propionanilid vom Fp. 2000C und Ν,Ν'-Bis-Methoxycarbonyl - isothioharnstoff - S - methyläther das N-[2-Propionamido-4-(4-acetamido-phenoxy)-phenyl] - Ν',Ν " - bis - methoxycarbonyl - guanidin vom Fp. 197—199° C; 2-Amino-5-(4-acetamino-phenoxy)-butyranilid vom Fp. 1500C und Ν,Ν'-Bis-Methoxycarbonylisothioharnstoff-S-methyläther das N-[2-Butyramido - 4 - (4 - acetamido - phenoxy) - phenyl]-N',N" - bis - methoxycarbonyl - guanidin vom Fp. 190° C;2 - amino - 5 - (4 - acetamino - phenoxy) - propionanilide of melting point 200 0 C and Ν, Ν'-bis-methoxycarbonyl -. Isothiourea - S - methyl ether, the N- [2-propionamido-4- (4-acetamido phenoxy) -phenyl] - Ν ', Ν' - bis - methoxycarbonyl - guanidine, mp 197-199 ° C; 2-amino-5- (4-acetamino-phenoxy) -butyranilid mp 150 0 C and Ν.. , Ν'-bis-methoxycarbonylisothiourea-S-methyl ether, N- [2-butyramido - 4 - (4 - acetamido - phenoxy) - phenyl] - N ', N "- bis - methoxycarbonyl - guanidine, melting at 190 ° C;
2 - Amino - 5 - (3 - trifluormethyl - phenoxy) - butyranilid und Ν,Ν'-bis-Methoxycarbonyl-isothioharnstoff-S-methyläther das N-[2-Butyramido-4 - (3 - trifluormethyl - phenoxy) - phenyl] - N ',N "-bis-methoxycarbonyl-guanidin. 2 - amino - 5 - (3 - trifluoromethyl - phenoxy) - butyranilide and Ν, Ν'-bis-methoxycarbonyl-isothiourea-S-methyl ether the N- [2-butyramido-4 - (3-trifluoromethyl-phenoxy) -phenyl] -N ', N "-bis-methoxycarbonyl-guanidine.
4545
/ X-NH-CO-CH.,/ X-NH-CO-CH.,
j ^NH-CO-C2II5 j ^ NH-CO-C 2 II 5
NH-C S5 NH-C S5
NCOOCH,NCOOCH,
24,2g (0,1 Mol) 2-Amino-5-phenoxy-aectanilkl (,0
werden zusammen mit 22g (0,1 Mol) N-Methoxycarbonyl
- N' - propionyl - isothioharnstoff- S - melhylälhcr
und 2,6 g (0,015 Mol) p-Toluolsulfonsäure in
ml absol. Methanol 3 Stunden unter Rühren und Rückfluß erhitzt. Danach wird heiß filtriert und nach
<>s dem Erkalten das auskristallisiertc N-(2-Acetamido-
- phenoxy - phenyl) - N' - methoxycarbonyl - N " - propionyl-guanidin
abgesaugt, mit Äther gut nachgewaschen und im Hochvakuum getrocknet, Fp. 134°C,
Ausbeute 2Og= 50% der Theorie. Die Ausbeute
kann durch Aufarbeiten der Mutterlauge gesteigert werden.
Analog Beispiel 2 wurden erhalten aus:24.2g (0.1 mol) of 2-amino-5-phenoxy-aectanilk (, 0 together with 22g (0.1 mol) of N-methoxycarbonyl-N'-propionyl-isothiourea-S-methylhyl ether and 2.6 g (0.015 mol) p-toluenesulfonic acid in ml of absolute methanol heated for 3 hours with stirring and reflux, followed by hot filtration and, after cooling, the crystallized N- (2-acetamido- - phenoxyphenyl) - N'-methoxycarbonyl - N "- propionylguanidine suctioned off, washed thoroughly with ether and dried in a high vacuum, melting point 134 ° C., yield 20 g = 50% of theory. The yield can be increased by working up the mother liquor.
Analogously to Example 2, the following were obtained:
2-Amino-5-phenoxy-propionanilid und N-Methoxycarbonyl - N' - propionyl - isothioharnstoff-S
- methyläther das N - (2 - Propionamido - 4-phenoxy - phenyl)- N'- methoxycarbonyl - N "- propionyl-guanidin
vom Fp. 132° C;
2-Amino-5-phenoxy-butyranilid und N-Methoxycarbonyl - N' - propionyl - isothioharnstoff-S-methyläther
das N - (2 - Butyramido - 4 - phenoxy-phenyl)-N'-methoxycarbonyl-N"-propionyl- guanidin vom Fp. 125" C;2-Amino-5-phenoxy-propionanilide and N-methoxycarbonyl-N '-propionyl-isothiourea-S-methyl ether the N - (2-propionamido-4-phenoxy-phenyl) -N'-methoxycarbonyl-N "-propionyl-guanidine of m.p. 132 ° C;
2-Amino-5-phenoxy-butyranilide and N-methoxycarbonyl-N '-propionyl-isothiourea-S-methyl ether N - (2 - butyramido - 4 - phenoxyphenyl) -N'-methoxycarbonyl-N "-propionyl-guanidine of m.p. 125 "C;
2 - Amino - 5 - phenoxy - cyclohexancarbonanilid und N - Methoxycarbonyl - N' - propionyl - isothioharnstoff-S-methyläther das N-(2-Cyclohexancarbonamido - 4 - phenoxy - phenyl) - N'-methoxycarbony 1 - N " - propionyl - guanidin vom Fp. 139°C;2 - amino - 5 - phenoxy - cyclohexanecarbonanilide and N - methoxycarbonyl - N '- propionyl - isothiourea-S-methyl ether the N- (2-cyclohexanecarbonamido - 4 - phenoxy - phenyl) - N'-methoxycarbony 1 - N "- propionyl - guanidine, mp 139 ° C;
2-Amino-5-phenoxy-butyranilid und N-Methoxycarbonyl - N' - cyclohexylcarbonyl - isothioharnstoff-S-methyläther
das N-(2-Butyramido-4 - phenoxy - phenyl) - N' - methoxycarbonyl - N"-cyclohexylcarbonyl-guanidin
vom Fp. 146° C;
2 - Amino - 5 - (3 - chlor - phenoxy) - acetanilid und N - Methoxycarbonyl - N' - propionyl - isothioharnstoff-S-methyläther
das N-[2-Acetamido-4 - (3 - chlor - phenoxy) - phenyl] - N' - methoxycarbonyl - N" - propionyl - guanidin vom Fp.
163° C;2-Amino-5-phenoxy-butyranilide and N-methoxycarbonyl-N'-cyclohexylcarbonyl-isothiourea-S-methyl ether N- (2-butyramido-4-phenoxy-phenyl) -N'-methoxycarbonyl-N "-cyclohexylcarbonyl-guanidine of m.p. 146 ° C;
2 - Amino - 5 - (3 - chloro - phenoxy) - acetanilide and N - methoxycarbonyl - N '- propionyl - isothiourea S-methyl ether the N- [2-acetamido-4 - (3 - chloro - phenoxy) - phenyl] - N '- methoxycarbonyl - N "- propionyl - guanidine, mp 163 ° C;
2-Amino-5-(3-chlor-phenoxy)-butyranilid und N - Methoxycarbonyl - N' - propionyl - isothioharnstoff-S-methyläther das N-[2-Butyramido-4 - (3 - chlor - phenoxy) - phenyl] - N' - methoxycarbonyl-N"-propionyl-guanidin vom Fp. 163"C; 2 - Amino - 5 - (4 - acetamido - phenoxy) - propionanilid und N-Methoxycarbonyl-N'-propiony 1-isothioharnstoff-S-methyläther das N-[2-propionamido - 4 - (4 - acetamido - phenoxy) - phenyl]-N' - methoxycarbonyl - N" - propionylguanidin vom Fp. 190" C;2-Amino-5- (3-chlorophenoxy) -butyranilide and N - methoxycarbonyl - N '- propionyl - isothiourea-S-methyl ether the N- [2-butyramido-4 - (3 - chloro - phenoxy) - phenyl] - N '- methoxycarbonyl-N "-propionyl-guanidine of m.p. 163 "C; 2 - amino - 5 - (4 - acetamido - phenoxy) - propionanilide and N-methoxycarbonyl-N'-propiony 1-isothiourea-S-methyl ether the N- [2-propionamido - 4 - (4 - acetamido - phenoxy) - phenyl] -N ' methoxycarbonyl-N "-propionylguanidine of m.p. 190" C;
2-Amino-5-(4-acetamido-phenoxy)-butyranilid und N - Methoxycarbonyl - N' - propionyl - isothioharnstoff-S-methyläther das N-[2-Butyramido - 4 - (4 - acetamido - phenoxy) - phenyl]-N' - methoxycarbonyl - N" - propionylguanidin vom Fp. 178 180" C;2-Amino-5- (4-acetamido-phenoxy) -butyranilide and N-methoxycarbonyl-N'-propionyl-isothiourea-S-methyl ether the N- [2-butyramido - 4 - (4 - acetamido - phenoxy) - phenyl] -N ' methoxycarbonyl-N "-propionylguanidine of m.p. 178-180" C;
2 - Amino - 5 - (4 - methyl - phenoxy) - butyranilid und N - Methoxycarbonyl - N' - propionyl - isothioharnstoff-S-methyläther das N-[2-Butyramido - 4 - (4 - methyl - phenoxy) - phenyl] - Ν'· methoxycarbonyl-N"-propionyl-guanidin voir Fp. 135" C.2 - Amino - 5 - (4 - methyl - phenoxy) - butyranilide and N - methoxycarbonyl - N '- propionyl - isothiourea S-methyl ether the N- [2-butyramido - 4 - (4 - methyl - phenoxy) - phenyl] - Ν '· methoxycarbonyl-N "-propionyl-guanidine voir M.p. 135 "C.
Nach der im Beispiel 2 beschriebenen Method wurden noch die folgenden Verbindungen hergestelltAccording to the method described in Example 2, the following compounds were also prepared
NH CONH CO
N COOCH,N COOCH,
Nil COOCH,Nile COOCH,
F. 13«"F. 13 «"
\ /~V-O--/~V-NH —C \ / ~ VO - / ~ V-NH -C
Ί NH-COOCH.,Ί NH-COOCH.,
NH-CO-CH2-OCH.,NH-CO-CH 2 -OCH.,
P 144'(_■P 144 '(_ ■
— NH- C- NH- C
N-COOCH.,N-COOCH.,
NH-COOCH3 NH-CO-CH3 NH-COOCH 3 NH-CO-CH 3
F. 173 C (Zersetzung)F. 173 C (decomposition)
NH-CO-C2H5
N-COOCH.,NH-CO-C 2 H 5
N-COOCH.,
NH-CNH-C
12,8 g (0,05 Mol) 2-Amino-4-phenoxy-propionanilid (Fp. 110—HTC) werden in 100 ml Methanol mit 10,3 g (0,05 MoI) Ν,Ν'-Bis-Methoxycarbonyl-isothioharnstoff-S-methyiäther unter Zusatz von 1 g p-Toluolsulfonsäure 3 Stunden unter Rückfluß erhitzt. Nach dem Erkalten saugt man den Niederschlag ab, wäscht mit Äther und erhält nach dem Trocknen NH-COOCH3 12.8 g (0.05 mol) of 2-amino-4-phenoxy-propionanilide (melting point 110-HTC) are dissolved in 100 ml of methanol with 10.3 g (0.05 mol) of Ν, Ν'-bis-methoxycarbonyl -isothiourea-S-methyl ether with the addition of 1 g of p-toluenesulfonic acid heated under reflux for 3 hours. After cooling, the precipitate is filtered off with suction, washed with ether and, after drying, NH-COOCH 3 is obtained
11,1g N - (2 - Propionamido - 5 - phenoxy - phenyl)-N ',N "- bis - methoxycarbonyl - guanidin vom Fp 148—149° C.11.1 g of N - (2 - propionamido - 5 - phenoxy - phenyl) -N ', N "- bis - methoxycarbonyl - guanidine of m.p. 148-149 ° C.
In entsprechender Arbeitsweise erhält man au; N,N' - disubstituierten Isothioharnstoff - S - methyl äthern und 2-Amino-4-phenoxy-aniliden folgende Verbindungen;In a corresponding procedure one obtains au; N, N '- disubstituted isothiourea - S - methyl ethers and 2-amino-4-phenoxy-aniliden the following compounds;
AusgangsmatcrialSource material
<C% O -<^ V NUR' <C% O - <^ V ONLY '
Rr ~ "TR r ~ "T
NH2 NH 2
R R'R R '
122—123122-123
108108
Hrlinclungsgcrmiß hergestellte StoffeMisappropriated substances
£>-°O-NHR'£> - ° O- NHR '
NlI - CNlI - C
14 3)· (005 MoI) 2-Amino-5-phcnylthio-butyr-•inilid (Fp 'l52"C) werden in 100 ml Methanol mit lOu (0 05MoI) N N'-Bis-Methoxycarbonyl-isolhio- <,s harnstoff"- S - methyläther unter Zusatz von Ig n-Toluolsulfonsäure 3 Stunden erhitzt. Man erhält nach Aufarbeitung analog Beispiel 3 13.« gN-(2-Bulyramido-4-phenylthio-phenyl)-Ν',Ν"-bis-methox carbonyl-guunidin vom Fp. 155"C.14 3). s urea "- S - methyl ether with the addition of Ig n-toluenesulfonic acid heated for 3 hours. After working up analogously to Example 3, 13. "gN- (2-butyramido-4-phenylthiophenyl) -Ν ', Ν" -bis-methoxycarbonyl-guunidine of melting point 155 "C are obtained.
In entsprechender Arbeitsweise erhält man a N,N'- disul.slituierlcn Isothioharnstoff-S-mclh; äthern und 2-Amino-5-pheiiylthio-aniliden folgen Verbindungen:Corresponding procedure gives a N, N'-disul.slituierlcn isothiourea-S-mclh; ethers and 2-amino-5-pheiiylthio-aniliden follow Links:
3232
Ausgangsmalerial i£-y'~ s Initial painting i £ -y '~ s
R "~R "~
FrfindungsgemiilA hergestellte StoffeSubstances manufactured in accordance with the invention
NHjNHj
-NHR'-NHR '
NR"NO"
\Nile C
\
In Analogie zu der im Beispiel 4 beschriebenen Methodik erhält man die folgenden erfindungsgemäßen Wirkstoffe: In analogy to the methodology described in Example 4, the following active ingredients according to the invention are obtained:
Ausgangsmatcrial -SStarting material -S
Erfindungsgcmäß hergcslclltc StoffeSubstances manufactured according to the invention
("C)F.
("C)
NR"NO"
NH-CNH-C
NUR'"ONLY'"
( C)Fp.
(C)
137136-
137
f.f.
Fortsetzungcontinuation
Ausgangs imtlcriulStarting imtlcriul
>■- NHK'> ■ - NHK '
NH,NH,
l-irlimlungsecniäB hergestellte StoffeSubstances produced by oil-lamination technology
K. RK. R
( C)(C)
NlIK'NlIK '
NR"NO"
NH CNH C
NUR"ONLY"
R' 34 R '34
R"R "
p ( C)p (C)
— C- C
/■·/ ■ ·
2,6-(CH3)2 2,6- (CH 3 ) 2
4-Cl, 5-CF3 4-Cl, 5-CF 3
4-Cl, 5-CF3 4-Cl, 5-CF 3
2-CH3,4-OCH3 2-CH 3 , 4-OCH 3
2-CH3,4-OCH3 2-CH 3 , 4-OCH 3
2-OCH,,5-OCHj2-OCH ,, 5-OCHj
2,5-(Cl)2 2,5- (Cl) 2
2,5-(OCH,)2 2,5- (OCH,) 2
3-CH3,4-Br3-CH 3 , 4-Br
3-CH3,4-Br3-CH 3 , 4-Br
4-C2H5 4-C 2 H 5
4-C2H5 4-C 2 H 5
4-OCH3 4-OCH 3
2-OC2H5 2-OC 2 H 5
2-OC2H5 2-OC 2 H 5
—C—C
\
H\
H
-CO-CH2OCH,-CO-CH 2 OCH,
-CO-C3H7 COC1H9 CO-CH(CHj)2 CO-C3H7 COCH2OCH3 CO-C3H7 CO-C3H7 COC3H7 COCH2OCH COC2H5 COC3H7 COCH2OCH3 -CO-C 3 H 7 COC 1 H 9 CO-CH (CHj) 2 CO-C 3 H 7 COCH 2 OCH 3 CO-C 3 H 7 CO-C 3 H 7 COC 3 H 7 COCH 2 OCH COC 2 H 5 COC 3 H 7 COCH 2 OCH 3
COC2H5 COC 2 H 5
COCH2OCH3 COCH 2 OCH 3
COCH2OCH3 COCH 2 OCH 3
COCH2OCH3 COCH 2 OCH 3
COC3H7 COC 3 H 7
COCH2OCH3 COCH 2 OCH 3
118 H118 H.
2,6-(CHj)2 2,6- (CHj) 2
118 H118 H.
-CO-CH2OCH3 -CO-CH 2 OCH 3
-COC3H7 -COC 3 H 7
-CO-CH2OCH3 -CO-CH 2 OCH 3
-COC3H7 -CO-CH2OCH3 -COC 3 H 7 -CO-CH 2 OCH 3
-CO-CH2OCH3 -CO-CH 2 OCH 3
4-C4H, 4-Cl, 5-CF3 4-Cl, 5-CF3 2-CH3,4-OCH3 2-CH3>4-OCH3 2-OCH3,5-OCH3 4-C 4 H, 4-Cl, 5-CF 3 4-Cl, 5-CF 3 2-CH 3 , 4-OCH 3 2-CH 3> 4-OCH 3 2-OCH 3 , 5-OCH 3
2,5-(Cl)2 2,5- (Cl) 2
155 H155 H.
146 2,5-(OCHj)2 89 4-F 126 4-Cl 126 4-Cl 155 2-Cl 166 2-Cl 154 4-Br 143 3-CH3,4-Br146 2,5- (OCHj) 2 89 4-F 126 4-Cl 126 4-Cl 155 2-Cl 166 2-Cl 154 4-Br 143 3-CH 3 , 4-Br
119- 3-CH3,4-Br 120119- 3-CH3, 4-Br 120
97 4-C2H5 94 4-C2H5 64 3-CF3 63 4-OCH3 2-OC2H5 133 2-OC2H5 97 4-C 2 H 5 94 4-C 2 H 5 64 3-CF 3 63 4-OCH 3 2-OC 2 H 5 133 2-OC 2 H 5
COOCHj COOCHjCOOCHj COOCHj
/O
/
— C
\
H/
- C
\
H
ΧΧ
HH
—C—C
-COCH2OCHj
O-COCH 2 OCHj
O
Γ*Γ *
-COCH2OCH3 -COC3H7 -COCH2OCH3 -COC3H7 -COCH2OCH3 -COCH2OCH3 -COCH 2 OCH 3 -COC 3 H 7 -COCH 2 OCH 3 -COC 3 H 7 -COCH 2 OCH 3 -COCH 2 OCH 3
-COC3H7 -COC 3 H 7
COC4H9 COC 4 H 9
CO-CH(CHj)2 CO-CH (CHj) 2
CO-C3H7 CO-C 3 H 7
CO-CH2OCH3 CO-CH 2 OCH 3
CO-C1H7 CO-C 1 H 7
CO-C3H7 CO-C 3 H 7
COC3H7 COC 3 H 7
COCH2OCHjCOCH 2 OCHj
COC2H5 COC 2 H 5
COC3H7 COC 3 H 7
COCH2OCH,COCH 2 OCH,
COC2H5 COC 2 H 5
COCH2OCH3 COCH 2 OCH 3
COCH2OCHjCOCH 2 OCHj
COCH2OCH3 COCH 2 OCH 3
COC3H,COC 3 H,
COCH2OCHjCOCH 2 OCHj
COOCHj COOCHj 105COOCHj COOCHj 105
COOCH, CO-CH2OCHj 151COOCH, CO-CH 2 OCHj 151
COOCH3 COOC2H5 COOCH 3 COOC 2 H 5
COOCHj COOC2H5 COOCHj COOC 2 H 5
COOCHj COOCHjCOOCHj COOCHj
COOCHj COOCHjCOOCHj COOCHj
COOCHj
COOCHj
COOCH3
COOCHj
COOCHj
COOCHjCOOCHj
COOCHj
COOCH 3
COOCHj
COOCHj
COOCHj
COOCHj
COOCH3
COOCH,
COOCH3
COOCH3
COOCH3
COOCH3
COOCHj
COOCHj
COOCH3
COOCH3
COOCH3 COOCHj
COOCH 3
COOCH,
COOCH 3
COOCH 3
COOCH 3
COOCH 3
COOCHj
COOCHj
COOCH 3
COOCH 3
COOCH 3
COOCH3
COOCH3
COOCHj
COOCHj
COOCH3
COOCH3 COOCH 3
COOCH 3
COOCHj
COOCHj
COOCH 3
COOCH 3
COOCH3 COOCH3 COOCH3 COOCH3 COOCH3 COOCH3 COOCH 3 COOCH 3 COOCH 3 COOCH 3 COOCH 3 COOCH 3
COOCH,COOCH,
COC2H5 COC 2 H 5
COOCH1 COOCH 1
COOCIl.,COOCIl.,
COOCHjCOOCHj
COOCH,COOCH,
COC2H5 COC 2 H 5
COOCH3 COOCH 3
COOCH,COOCH,
COOCH,COOCH,
COOCH,COOCH,
COOCH,COOCH,
COOCH, COOCH, COOCH3 COOCH3 COOCH3 COOCH3 COOCH, COOCH, COOCH 3 COOCH 3 COOCH 3 COOCH 3
169 160 165 142 127 176 155 154 138 158 170 141169 160 165 142 127 176 155 154 138 158 170 141
155 126 120 131 128 110155 126 120 131 128 110
NH-COC3H7 NH-COC 3 H 7
N-COOCH3 N-COOCH 3
NH-CNH-C
NH-COOCH3 NH-COOCH 3
Nach der im Beispiel 3 beschriebenen Methode 14,5 g N - (2 - Butyramido - 5 - phenylthio - phenyl)-According to the method described in Example 3, 14.5 g of N - (2 - butyramido - 5 - phenylthio - phenyl) -
erhält man aus 14,3 g (0,05 Mol) 2-Amino-4-phenyl- N ',N"- bis - methoxycarbonyl- guanidin vom Fp.obtained from 14.3 g (0.05 mol) of 2-amino-4-phenyl-N ', N "- bis - methoxycarbonylguanidine of melting point.
thio-butyranilid und 10,3 g (0,05 Mol) N,N'-bis- 15 164—166°C. Methoxycarbonyl - isothioharnstoff - S - methylätherthio-butyranilide and 10.3 g (0.05 moles) of N, N'-to-15 164-166 ° C. Methoxycarbonyl - isothiourea - S - methyl ether
NH-COC2H5 NH-COC 2 H 5
N—COOCH3 N-COOCH 3
NH-CNH-C
NH-COOCH3 NH-COOCH 3
Nach der im Beispiel 3 beschriebenen Methode 35 N',N" - bis - methoxycarbonyl - guanidin vom Fp.According to the method described in Example 3, 35 N ', N "- bis - methoxycarbonyl - guanidine of melting point.
erhält man aus 14,2 g (0,05 Mol) 2-Amino-5-phenyl- 133—1350C.is obtained from 14.2 g (0.05 mol) of 2-amino-5-phenyl- 133-135 0 C.
sulfinyl-propionanilid und 10,3 g (0,05 Mol) N,N'- In analoger Weise wurden noch die folgenden Ver-sulfinyl propionanilide and 10.3 g (0.05 mol) N, N'- In an analogous manner, the following methods were also
bis-Methoxycarbonyl-isothioharnstoff-S-methyläther bindungen hergestellt: 12,7 g N-(2-Propionamido-4-phenylsulfinyl-phenyl)-bis-methoxycarbonyl-isothiourea-S-methyl ether bonds made: 12.7 g of N- (2-propionamido-4-phenylsulfinyl-phenyl) -
\/— NHR'
NH2 ^ SO
\ / - NHR '
NH 2
\4 -C
\
R- X) _j
R-
R° £
R °
/~V-NHR'
^\ NR"
NH-C
\
NHR'"> -so
/ ~ V-NHR '
^ \ NR "
NH-C
\
NHR '"
NH-CNH-C
NH-COC2H5 NH-COC 2 H 5
N-COOCH3 N-COOCH 3
NH-CNH-C
NH-COOCH,NH-COOCH,
1010
Nach der im Beispiel 3 beschriebenen Methode erhält man aus 14,2 g (0,05 Mol) 2-Amino-4-phenylsulfinyl-propionanilid und 10,3 g (0,05 Mol) N1N'-Bis - Methoxycarbonyl - isothioharnstoff - S - methyläther 12,7 g N-(2-Propionamido-5-phenylsulnnylphenyl) - N ',N " - bis - methoxycarbonyl - guanidin.According to the method described in Example 3, 14.2 g (0.05 mol) of 2-amino-4-phenylsulfinyl-propionanilide and 10.3 g (0.05 mol) of N 1 N'-bis-methoxycarbonyl-isothiourea are obtained - S - methyl ether 12.7 g of N- (2-propionamido-5-phenylsulnnylphenyl) - N ', N "- bis - methoxycarbonyl - guanidine.
Nach der im Beispiel 3 beschriebenen Methode erhält man aus 14,4 g (0,05 Mol) 2-Amino-5-phenylsulfonyl-propionanilid vom Fp. 137°C und 10,3 g (0,05 Mol) N,N'-Bis-Methoxycarbonyl-isothioharnstoff - S - methyläther 12,7 g N - (2 - Propionamido-4 - phenylsulfonyl - phenyl) - N',N" - bis - methoxycarbonyl - guanidin vom Fp. 147° C.According to the method described in Example 3, 14.4 g (0.05 mol) of 2-amino-5-phenylsulfonyl-propionanilide are obtained of melting point 137 ° C. and 10.3 g (0.05 mol) of N, N'-bis-methoxycarbonyl-isothiourea - S - methyl ether 12.7 g of N - (2 - propionamido-4 - phenylsulfonyl - phenyl) - N ', N "- bis - methoxycarbonyl - guanidine with a melting point of 147 ° C.
In entsprechender Arbeitsweise erhält man aus N,N' - disubstituierten Isothioharnstoff - S - methyläthern und 2 - Amino - 5 - phenylsulfonyl - aniliden folgende Verbindungen:In a corresponding procedure, N, N'-disubstituted isothiourea-S-methyl ethers are obtained and 2 - amino - 5 - phenylsulfonyl - aniliden the following compounds:
SO2 SO 2
? ^-NH-CO-C3H7
N-COOCH3 ? ^ -NH-CO-C 3 H 7
N-COOCH 3
NH-CNH-C
NH-COOCH3
Fp. 1800CNH-COOCH 3
M.p. 180 ° C
3535
4040
3838
V-NH-CO-CH2OCH,V-NH-CO-CH 2 OCH,
N — COOCH,N - COOCH,
NH-CNH-C
SO2 SO 2
NH-NH-
NH-COOCH3 Fp. 142° CNH-COOCH 3 m.p. 142 ° C
H
NH-C=--OH
NH-C = - O
N-COOCH3 N-COOCH 3
NH-COOCH3 NH-COOCH 3
Fp. 175°C (Zers.)Mp. 175 ° C (dec.)
SO3 SO 3
NHCO-C3H7 NHCO-C 3 H 7
N-COOCH3 N-COOCH 3
NH-CNH-C
NH-COOCH3 NH-COOCH 3
14,4 g (0,05 Mol) 2 - Amino - 4 - phenylsulfonylbutyranilid (F. 143—145) werden in 100 ml Methanol14.4 g (0.05 mol) of 2 - amino - 4 - phenylsulfonylbutyranilide (F. 143-145) are dissolved in 100 ml of methanol
mit 10,3 g (0,05 Mol) Ν,Ν'-Bis-Methoxycarbonylisothioharnstoff-S-methyläther unter Zusatz von g p-Toluolsulfonsäure 3 Stunden erhitzt. Man erhält nach Aufarbeitung analog Beispiel 3 15,8 g N-(2-Butyramido - 5 - phenylsulfonyl - phenyl) - N',N" - bis-with 10.3 g (0.05 mol) of Ν, Ν'-bis-methoxycarbonylisothiourea-S-methyl ether heated with the addition of g p-toluenesulfonic acid for 3 hours. You get after working up as in Example 3, 15.8 g of N- (2-butyramido - 5 - phenylsulfonyl - phenyl) - N ', N "- bis-
methoxycarbonyl-guanidin vorn Fp. 173° C.methoxycarbonyl-guanidine, mp 173 ° C.
Claims (1)
Priority Applications (42)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19742423679 DE2423679C3 (en) | 1974-05-15 | Substituted phenylguanidines, a process for their preparation and pharmaceuticals containing these compounds | |
| IN765/CAL/75A IN142490B (en) | 1974-05-15 | 1975-04-16 | |
| US05/572,224 US3993682A (en) | 1974-05-15 | 1975-04-28 | Substituted phenylguanidines and processes for their preparation and use |
| NO75751618A NO751618L (en) | 1974-05-15 | 1975-05-06 | |
| PH17141A PH17307A (en) | 1974-05-15 | 1975-05-06 | Substituted phenyl n,n-bis-alkoxycarbonyl-guanidine compositions containing them and their use as anthelmentics |
| CA226,458A CA1071649A (en) | 1974-05-15 | 1975-05-07 | Substituted phenylguanidines and processes for their preparation and use |
| EG279/75A EG11983A (en) | 1974-05-15 | 1975-05-10 | Substituted phenylguanides,a process for their preparation and their use as medicaments |
| SU752132095A SU662006A3 (en) | 1974-05-15 | 1975-05-11 | Method of obtaining substituted phenylguanidines |
| IL7547269A IL47269A (en) | 1974-05-15 | 1975-05-12 | Amido phenylguanidine derivatives, their preparation and pharmaceutical compositions containing them |
| FI751399A FI63020C (en) | 1974-05-15 | 1975-05-13 | FOERFARANDE FOER FRAMSTAELLNING AV SUBSTITUERADE FENYLGUANIDINER ANVAENDBARA SOM MASKMEDEL |
| LU72462A LU72462A1 (en) | 1974-05-15 | 1975-05-13 | |
| JP50055545A JPS5833842B2 (en) | 1974-05-15 | 1975-05-13 | Yakuzai Soseibutsu |
| JP50055544A JPS5915904B2 (en) | 1974-05-15 | 1975-05-13 | Method for producing substituted phenylguanidine |
| AT365475A AT348540B (en) | 1974-05-15 | 1975-05-13 | METHOD FOR PRODUCING NEW SUBSTITUTED PHENYLGUANIDINES |
| NLAANVRAGE7505603,A NL186811C (en) | 1974-05-15 | 1975-05-13 | METHOD FOR PREPARING ANTHELMINTICALLY ACTIVE PHENYLGUANIDINE DERIVATIVES AND METHOD FOR PREPARING AN ANTHELMINTICALLY ACTIVE PREPARATION. |
| DD185999A DD119224A5 (en) | 1974-05-15 | 1975-05-13 | |
| CH615375A CH612925A5 (en) | 1974-05-15 | 1975-05-13 | |
| IT49558/75A IT1047751B (en) | 1974-05-15 | 1975-05-13 | PHENYLGUANIDINS SUBSTITUTED FOR THE PRODUCTION AND VETERINARY PREPARATIONS, IN PARTICULAR ANTIELMINTICICHE CONTAIN THEM |
| PL1975193602A PL98595B1 (en) | 1974-05-15 | 1975-05-13 | METHOD OF MAKING PHENYLGUANIDINE DERIVATIVES |
| PL1975180339A PL99857B1 (en) | 1974-05-15 | 1975-05-13 | METHOD OF MAKING PHENYLGUANIDINE DERIVATIVES |
| ES437692A ES437692A1 (en) | 1974-05-15 | 1975-05-14 | Substituted phenylguanidines and processes for their preparation and use |
| AU81159/75A AU486374B2 (en) | 1975-05-14 | Substituted phenylguanidines, a process for their preparation and their use as medicaments | |
| ZA00753122A ZA753122B (en) | 1974-05-15 | 1975-05-14 | Substituted phenylguanidines, a process for their preparation and their use as medicaments |
| IE1078/75A IE41058B1 (en) | 1974-05-15 | 1975-05-14 | Substituted phenylguanidines, a process for their preparation and their use as medicaments |
| SE7505527A SE430887B (en) | 1974-05-15 | 1975-05-14 | SET TO MAKE SOME SUBSTITUTED PHENYLGUANIDINES |
| BE156330A BE829052A (en) | 1974-05-15 | 1975-05-14 | NEW SUBSTITUTES PHENYLGUANIDINES, THEIR PREPARATION PROCESS AND THE MEDICINAL PRODUCT CONTAINING THEM |
| DK211775A DK134282C (en) | 1974-05-15 | 1975-05-14 | ANALOGICAL PROCEDURE FOR THE PREPARATION OF SUBSTITUTED PHENYLGUANIDINES |
| GB2036275A GB1466839A (en) | 1974-05-15 | 1975-05-14 | Substituted phenylguanidines a process for their preparation and their use as medicaments |
| AR258791A AR208696A1 (en) | 1974-05-15 | 1975-05-15 | PROCEDURE FOR THE PRODUCTION OF NEW N- (2-AMINOCARBONYL-4-O-5-PHENOXYPHENYL-PHENYL-THIOPHENYL PHENYLSULFINYL-PHENYL, RESPECTIVELY PHENYLSULFONYL-PHENYL) -N'CARBONYLOXY-N -TIAN-GUIDED SUSPENSIONS |
| FR7515272A FR2270861B1 (en) | 1974-05-15 | 1975-05-15 | |
| BR3831/75A BR7503008A (en) | 1974-05-15 | 1975-05-15 | PROCESS FOR THE PREPARATION OF REPLACED PHENYLGUANIDINS |
| HUBA003268 HU174257B (en) | 1974-05-15 | 1975-05-15 | Process for producing phenylguanidine derivatives |
| AR262796A AR210116A1 (en) | 1974-05-15 | 1976-04-06 | PROCEDURE FOR THE PRODUCTION OF NEW SUBSTITUTED 4-PHENYLSULFINYL-PHENYLGUANIDINES, SUBSTITUTE 4-PHENYLSULFONYLPHENYLGUANIDINES, SUBSTITUTE 5-PHENYLSULFINYLPHENYLGUANIDINES, AND SUBSTITUTE 5-PHENYLGUIDINESULTIFONPHYLENES |
| US05/690,073 US4088780A (en) | 1974-05-15 | 1976-05-26 | Substituted phenylguanidines and processes for their preparation and use |
| US05/690,075 US4024176A (en) | 1974-05-15 | 1976-05-26 | Substituted phenylguanidines and processes for their preparation and use |
| US05/693,414 US4032655A (en) | 1974-05-15 | 1976-06-07 | Phenylguanidines useful as anthelmintic agents |
| AT0462777A AT365475B (en) | 1974-05-15 | 1977-06-29 | METHOD AND DEVICE FOR PURIFYING A GAS |
| KE2773A KE2773A (en) | 1974-05-15 | 1977-09-08 | Substituted phenylguanidenes, a process for their preparation and their use as medicaments |
| CH86479A CH615157A5 (en) | 1974-05-15 | 1979-01-29 | Process for the preparation of novel substituted phenylguanidines |
| HK16/80A HK1680A (en) | 1974-05-15 | 1980-01-10 | Substituted phenylguanidines, a process for their preparation and their use as medicaments |
| MY1980187A MY8000187A (en) | 1974-05-15 | 1980-12-31 | Substituted phenylguanidines, a process for their preparation and their use as medicaments |
| JP58000561A JPS5945672B2 (en) | 1974-05-15 | 1983-01-07 | Method for producing substituted phenylguanidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19742423679 DE2423679C3 (en) | 1974-05-15 | Substituted phenylguanidines, a process for their preparation and pharmaceuticals containing these compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE2423679A1 DE2423679A1 (en) | 1975-11-20 |
| DE2423679B2 DE2423679B2 (en) | 1977-02-03 |
| DE2423679C3 true DE2423679C3 (en) | 1977-09-22 |
Family
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