NO770649L - Substituerte fenylguanidiner og fremgangsm}te til deres fremstilling. - Google Patents
Substituerte fenylguanidiner og fremgangsm}te til deres fremstilling.Info
- Publication number
- NO770649L NO770649L NO770649A NO770649A NO770649L NO 770649 L NO770649 L NO 770649L NO 770649 A NO770649 A NO 770649A NO 770649 A NO770649 A NO 770649A NO 770649 L NO770649 L NO 770649L
- Authority
- NO
- Norway
- Prior art keywords
- phenoxysulfonyl
- bis
- guanidine
- optionally substituted
- methoxycarbonyl
- Prior art date
Links
- -1 PHENYL GUANIDINES Chemical class 0.000 title claims description 25
- 238000002360 preparation method Methods 0.000 title claims description 20
- 238000000034 method Methods 0.000 title claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- QRJZGVVKGFIGLI-UHFFFAOYSA-N 2-phenylguanidine Chemical class NC(=N)NC1=CC=CC=C1 QRJZGVVKGFIGLI-UHFFFAOYSA-N 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 7
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 5
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 5
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 5
- 125000003107 substituted aryl group Chemical group 0.000 claims description 5
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 3
- 150000002541 isothioureas Chemical class 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 2
- 229940124339 anthelmintic agent Drugs 0.000 claims description 2
- 239000000921 anthelmintic agent Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 229940126601 medicinal product Drugs 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 101150054552 bet3 gene Proteins 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 231100000252 nontoxic Toxicity 0.000 claims 1
- 230000003000 nontoxic effect Effects 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
- 229960001413 acetanilide Drugs 0.000 description 54
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- FGUJEHLUNQOXRC-UHFFFAOYSA-N (4-amino-3-nitrophenyl) benzenesulfonate Chemical compound C1=C([N+]([O-])=O)C(N)=CC=C1OS(=O)(=O)C1=CC=CC=C1 FGUJEHLUNQOXRC-UHFFFAOYSA-N 0.000 description 5
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000007868 Raney catalyst Substances 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 239000004202 carbamide Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- JHPZZIVXMGPZIL-UHFFFAOYSA-N phenyl 3-amino-4-anilino-4-oxobutane-1-sulfonate Chemical compound C=1C=CC=CC=1NC(=O)C(N)CCS(=O)(=O)OC1=CC=CC=C1 JHPZZIVXMGPZIL-UHFFFAOYSA-N 0.000 description 4
- VBZVAWRTBMVSLW-UHFFFAOYSA-N phenyl 3-amino-4-nitrobenzenesulfonate Chemical compound C1=C([N+]([O-])=O)C(N)=CC(S(=O)(=O)OC=2C=CC=CC=2)=C1 VBZVAWRTBMVSLW-UHFFFAOYSA-N 0.000 description 4
- NEZIKMJTIOLUGU-UHFFFAOYSA-N phenyl 4-amino-3-nitrobenzenesulfonate Chemical compound C1=C([N+]([O-])=O)C(N)=CC=C1S(=O)(=O)OC1=CC=CC=C1 NEZIKMJTIOLUGU-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000052 vinegar Substances 0.000 description 4
- 235000021419 vinegar Nutrition 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000545744 Hirudinea Species 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 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 3
- 230000000694 effects Effects 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- USMJZRPMPIERSK-UHFFFAOYSA-N (3-amino-4-nitrophenyl) benzenesulfonate Chemical compound C1=C([N+]([O-])=O)C(N)=CC(OS(=O)(=O)C=2C=CC=CC=2)=C1 USMJZRPMPIERSK-UHFFFAOYSA-N 0.000 description 2
- CYFAIHXFTARDJC-UHFFFAOYSA-N (4-anilino-3-nitro-4-oxobutyl) benzenesulfonate Chemical compound C=1C=CC=CC=1NC(=O)C([N+](=O)[O-])CCOS(=O)(=O)C1=CC=CC=C1 CYFAIHXFTARDJC-UHFFFAOYSA-N 0.000 description 2
- KWCPQPFOPUCWPH-UHFFFAOYSA-N 1-(oxomethylidene)guanidine Chemical compound NC(=N)N=C=O KWCPQPFOPUCWPH-UHFFFAOYSA-N 0.000 description 2
- LUBJCRLGQSPQNN-UHFFFAOYSA-N 1-Phenylurea Chemical compound NC(=O)NC1=CC=CC=C1 LUBJCRLGQSPQNN-UHFFFAOYSA-N 0.000 description 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- XGEGHDBEHXKFPX-UHFFFAOYSA-N N-methylthiourea Natural products CNC(N)=O XGEGHDBEHXKFPX-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 229940051881 anilide analgesics and antipyretics Drugs 0.000 description 2
- 150000003931 anilides Chemical class 0.000 description 2
- 230000000507 anthelmentic effect Effects 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000005290 ethynyloxy group Chemical group C(#C)O* 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 244000000013 helminth Species 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- UCFFGYASXIPWPD-UHFFFAOYSA-N methyl hypochlorite Chemical compound COCl UCFFGYASXIPWPD-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
- XGEGHDBEHXKFPX-NJFSPNSNSA-N methylurea Chemical compound [14CH3]NC(N)=O XGEGHDBEHXKFPX-NJFSPNSNSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- HWPPQQIZUZFEJV-UHFFFAOYSA-N phenyl 3-chloro-4-nitrobenzenesulfonate Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC=C1S(=O)(=O)OC1=CC=CC=C1 HWPPQQIZUZFEJV-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 2
- ZQKBAUMILMJZGK-UHFFFAOYSA-N (3-amino-4-anilino-4-oxobutyl) benzenesulfonate Chemical compound C=1C=CC=CC=1NC(=O)C(N)CCOS(=O)(=O)C1=CC=CC=C1 ZQKBAUMILMJZGK-UHFFFAOYSA-N 0.000 description 1
- BXZKGFCRNIHISS-UHFFFAOYSA-N (4-acetamidophenyl) benzenesulfonate Chemical compound C1=CC(NC(=O)C)=CC=C1OS(=O)(=O)C1=CC=CC=C1 BXZKGFCRNIHISS-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- SXAMGRAIZSSWIH-UHFFFAOYSA-N 2-[3-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,2,4-oxadiazol-5-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NOC(=N1)CC(=O)N1CC2=C(CC1)NN=N2 SXAMGRAIZSSWIH-UHFFFAOYSA-N 0.000 description 1
- VDLGLFVMQUNFST-UHFFFAOYSA-N 2-phenoxy-n-phenylacetamide Chemical compound C=1C=CC=CC=1NC(=O)COC1=CC=CC=C1 VDLGLFVMQUNFST-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 229940018563 3-aminophenol Drugs 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- IQXUIDYRTHQTET-UHFFFAOYSA-N 4-amino-3-nitrophenol Chemical compound NC1=CC=C(O)C=C1[N+]([O-])=O IQXUIDYRTHQTET-UHFFFAOYSA-N 0.000 description 1
- SEWNAJIUKSTYOP-UHFFFAOYSA-N 4-chloro-3-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC(S(Cl)(=O)=O)=CC=C1Cl SEWNAJIUKSTYOP-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
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- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 241000244206 Nematoda Species 0.000 description 1
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- NKRCJLKENZARMP-UHFFFAOYSA-N [3-amino-4-(methylcarbamoylamino)phenyl] benzenesulfonate Chemical compound C1=C(N)C(NC(=O)NC)=CC=C1OS(=O)(=O)C1=CC=CC=C1 NKRCJLKENZARMP-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
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- 150000001298 alcohols Chemical class 0.000 description 1
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- ZVSKZLHKADLHSD-UHFFFAOYSA-N benzanilide Chemical compound C=1C=CC=CC=1C(=O)NC1=CC=CC=C1 ZVSKZLHKADLHSD-UHFFFAOYSA-N 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
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- QTCANKDTWWSCMR-UHFFFAOYSA-N costic aldehyde Natural products C1CCC(=C)C2CC(C(=C)C=O)CCC21C QTCANKDTWWSCMR-UHFFFAOYSA-N 0.000 description 1
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- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- SHTHWCQBJTUESB-UHFFFAOYSA-N ethyl hypofluorite Chemical compound CCOF SHTHWCQBJTUESB-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- ISTFUJWTQAMRGA-UHFFFAOYSA-N iso-beta-costal Natural products C1C(C(=C)C=O)CCC2(C)CCCC(C)=C21 ISTFUJWTQAMRGA-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- SDDKIZNHOCEXTF-UHFFFAOYSA-N methyl carbamimidothioate Chemical compound CSC(N)=N SDDKIZNHOCEXTF-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
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002004 n-butylamino group Chemical group [H]N(*)C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- UHANVDZCDNSILX-UHFFFAOYSA-N n-phenylbutanamide Chemical compound CCCC(=O)NC1=CC=CC=C1 UHANVDZCDNSILX-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- HOFJSWRLSVFLOK-UHFFFAOYSA-N phenyl 3-amino-4-(2-anilino-2-oxoethyl)benzenesulfonate Chemical compound NC1=CC(S(=O)(=O)OC=2C=CC=CC=2)=CC=C1CC(=O)NC1=CC=CC=C1 HOFJSWRLSVFLOK-UHFFFAOYSA-N 0.000 description 1
- RURAGVGCJIBJEK-UHFFFAOYSA-N phenyl 4-anilino-3-nitro-4-oxobutane-1-sulfonate Chemical compound C=1C=CC=CC=1NC(=O)C([N+](=O)[O-])CCS(=O)(=O)OC1=CC=CC=C1 RURAGVGCJIBJEK-UHFFFAOYSA-N 0.000 description 1
- DXNLDBASBALMSX-UHFFFAOYSA-N phenyl 4-chloro-3-nitrobenzenesulfonate Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC(S(=O)(=O)OC=2C=CC=CC=2)=C1 DXNLDBASBALMSX-UHFFFAOYSA-N 0.000 description 1
- BSGJMEBYWCAVOS-UHFFFAOYSA-N phenyl 5-amino-6-anilino-6-oxohexane-3-sulfonate Chemical compound NC(C(=O)NC1=CC=CC=C1)CC(CC)S(=O)(=O)OC1=CC=CC=C1 BSGJMEBYWCAVOS-UHFFFAOYSA-N 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/76—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Substituert©fenylguanidiner og fremgangsmåta
til deres fremstilling.
Oppfinnelsen vedrører nye substituerte fenylguanidiner, fremgangsmåte til deres fremstilling og anvendelse som legemiddel, spesielt som anthelmintika.
Penylguanidiner med antelmintiske virkninger er kjent-fra DOS 2.11?.293»2.304.764 og 2.423.679.
Det er nå funnet nye substituerte fenylguanidiner med den generelle formel I:
hvor R og R1 er forskjellig fra hverandre og vekselvis betyr en av restene
hvori R^ betyr hydrogen, eventuelt substituert alkyl, eventuelt substituert cykloalkyl, eventuelt substituert aryl, eventuelt substituert aiaino, eventuelt substituert alkoksy eller eventuelt
substituert aralkyl, betyr eventuelt substituert alkyl, eventuelt substituert alkenyl eller eventuelt substituert alkinyl,
R^ betyr hydrogen, eventuelt substituert.alkyl, eventuelt substituert cykloalkyl, eventuelt substituert alkoksy, eventuelt substituert alkenyloksy, eventuelt substituert alkinyloksy, eventuelt substituert aryl, eventuelt substituert aralkyl, eventuelt substituert alkenyl eller eventuelt substituert alkinyl, og hvor R<2>og R^ hver uavhengig av hverandre betyr hydrogen, alkoksy med 1 til 4 C-atomer, halogen, trifluonaetyl, alkyl med 1 til 4 C-atomer, eller CH og
X betyr grupperingen -0-S02- eller -SOg-O-.
Oppfinnelsen vedreører en fremgangsmåte til fremstilling av de substituerte fenylguanidiner med formel I,
idet fremgangsmåten erkarakterisert vedat substituerte anilinderivater med den generelle formel II
hvori R2, R^, R^ og X har den ovenfor angitte betydning og X er sammenknyttet med stilling 4 eller stilling 5 av den substituerte 1-amino-fenylgruppe med formel (II) omsettes med isotiourinstoffer med den generelle formel III
hvori R^ og R^ har den ovenfor angitte betydning og R^ betyr alkyl med 1,-4 C-atomer, i nærvær av et fortynningsmiddel og eventuelt i nervær av en syre.
I formelen II og III betyr som eventuelt substituert alkyl R<2>, R^, ffi, R^ og R^ rettlinjet eller forgrenet alkyl med fortrinnsvis 1 til 6, spesielt 1 til 4 karbonatomer. Eksempelvis skal det nevnes eventuelt substituert metyl, etyl, n- og 1- propyl, n-, i- og t-butyl..
Som eventuelt substituert alkenyl betyr R^ og R
i formel III rettlinjet eller forgrenet alkenyl med fortrinnsvis
2- 6, spesielt 2-4 karbonatomer. Eksempelvis skal det nevnes eventuelt substituert etenyl, propenyl-(l), propenyl-(2) og butenyl-O). ' Som eventuelt substituert alkinyl betyr R-' og R i formel III rettlinjet eller forgrenet alkinyl med fortrinnsvis 2-6, spesielt 2-4 karbonatomer. Eksempelvis skal det nevnes
eventuelt-substituert etinyl, propinyl-(l), propinyl-(2) og butinyl-(3).
Som eveituelt substituert alkoksy betyr R2, R^, R^ og R^ i formlene II og III rettlinjet eller forgrenet alkoksy med 1-4 karbonatomer. Eksempelvis skal nevnes eventuelt substituert metoksy, etoksy, n- og i-propoksy og n-, i- og t-butoksy.
Som halogen betyr R p og R- o* i formel II fortrinnsvis
fluor, klor*brom og jod, spesielt fluor, klor og brom.
Som evsituelt substituert aryl betyr R^" og R^ i formlene II og III aryl med fortrinnsvis 6 eller fortrinnsvis 6-10 karbonatomer i aryldelen. Eksempelvis skal nevnes eventuelt substituert fenyl eller naftyl.
Som eventuelt substituert aralkyl betyr R^- og R^ i formel III eventuelt i aryldelen og/eller alkyldelen substituert aralkyl aied fortrinnsvis 6 eller 10, spesielt 6 karbonatomer
i aryldelen og fortrinnsvis 1-4, spesielt 1 eller 2 karbonatomer i alkyldelen, idet alkyldelen kan være rettlinjet eller forgrenet. Eksempelvis skal nevnes eventuelt substituert bensyl og fenyl-etyl.
å6 Som eventuelt substituert cykloalkyl betyr R^" og R iformelen II og III mono- bi- og tricyklisk cykloalkyl med fortrinnsvis 3-10, spesielt 3,5 eller 6 karbonatomer. Eksempelvis skal nevnes eventuelt substituert cyklopropyl, cyklobutyl, cyklopentyl, cyklohexyl, cykloheptyl, bieyklo-/2,2,l7-heptyl, bicyklo-/2,2,27-oktyl og adamantyl.
Som eventuelt substituert alkinyloksy,R^ betyr i formel III rettlinjet eller forgrenet alkinyloksy med fortrinnsvis 2*6, spesielt 2-4 karbonatomer. Eksempelvis skal nevnes eventuelt substituert etinyloksy, propényl-(1)-oksy, propényl-(2)-oksy og butényl-(3)-oksy.
Som eventuelt substituert alkinyloksy betyr R^ i formel III rettlinjet eller forgrenet alkinyl med fortrinnsvis 2-6, spesielt 2-4 karbonatomer. Eksempelvis skal nevnes eventuelt substituert etinyloksy, propinyl-(l)-oksy, propinyl-(2)-oksy og butinyl-(3)-oksy.
Som alkyl betyr R^ i formel III fortrinnsvis metyl eller etyl;
Spesielt foretrukket er forbindelser med formel I, hvor: R<2>og R^ betyr hydrogen, metyl, etyl, n-butyl, metoksy,
etoksy, fluor, klor, brom, cyan eller trifluormetyl»idet R^ spesielt med fordel substituerer 3~stUlingen av fenylringen, mens R p er hydrogen,
R^ betyr metyl, etyl, propyl, n-butyl, i-butyl, n-pen-tyl, n-hexyl, cyklopentyl, cyklohexyl, f enyl, benzyl, metoksymetyl, metoksy, etoksy, fenoksymetyl, metyl-amino, etylamirio, n-butylamino, co -cyanpentylamino, p-metoksyetylamino,
R^ betyr metyl, etyl, i-propyl, sek.-butyl, propenyl-
( (2), propinyl,
R betyr metyl, etyl, propyl, isopropyl, n-amyl, iso-amyl, n-butyl, cyklohexyl, fenyl, benzyl, metoksymetyl, fenoksymetyl, allyl, krotyl, metallyl, metoksy, etoksy-i-propoksy, sek.-butyloksy, propenyl-(2)-oksy, propinyl-(2)-oksy, 2-metylpropenyl-(2)-okny.
I gruppene R^, R^ og R^ av forbindelsene med formel I kommer det som eventuelt tilstedeværende substituenter i betraktning følgende: r<4>for alkylsubstituentene til Cg-alkoksy, halogen,
cyano, Cg til Cg aryloksy, fortrinnsvis metoksy, klor eller fenoksy,
for cykloalkyirsubstituentene metyl og etyl;
for aryltsubstituentene C^til C^alkyl, halogen, C^til C^alkoksy, fortifeinsvis metyl, klor, metoksy,
for amino 1 eller 2 C^til C^alkyl, fortrinnsvis dimetyl og dietyl,
for alkoksy substituentene C^til Cg alkyl, halogen, for aralkyl substituentene C^til Cg alkyl, halogen, C^til C^alkoksy, fortrinnsvis metyl, klor, metoksy.
R^: for alkyl substituentene G^ til Cg alkoksy, halogen,
cyano, fortrinnsvis metoksy eller klor,
for alkenyl og alkinyl hver gang substituentene etyl og metyl.
R^: for alkyl C^til Cg alkoksy, halogen, cyan, Cg til Cg aryloksy, fortrinnsvis metoksy, klor, fenoksy, for cykloalkyl substituentene metyl eller etyl,
for alkoksy substituentene metoksy eller klor;
for alkenyloksy og alkinyloksy hver gang metyl eller etyl}
for aryl og aralkyl hver gang substituentene C-^til
alkyl, halogen, til C^alkoksy, fortrinnsvis metyl, klor, metoksy;
for alkenyl og alkinyl hver gang substituentene metyl og etyl.
De som anvendte utgangsstoffer tiourinstoffer er definert med formel III. De er delvis kjent (Jfr. Olin og Dains, J.Amer.chem.Soc. 52, 3326(1930), samt DS-patent 2.993.502) og
kan forøvrig lett fremstilles analogt de kjente fremgangsmåter.
Por deres fremstilling går man vanligvis ut fra kjente H-acyl-tiourinstoffer [" jfr. fjåcs. Berichte der deutschen Chemischen Gesellschaft, 6, 755(1873)»Ann.chim. (5)11, 313(1877), J.Amer. Chem.Soc. 62 , 3274 (1940)7 som man på eventuelt kjent måte om-r
setter med ålkyleringsmidler som alkylhalogenider, - sulfater og -sulfohater til de tilsvarende S-alkyl-K~aeyl-iso-tiourinstoffer /^fr. f.eks. J.org.Chem. 30, 560 (1965), Chem.Pharm. Bull. (Tokyo), $,245 (I96I)/. Disse S-alkyl-H-acyl-iso-tiourinstoffer kan deretter omsettes med halogenmaursyreestere eller også med pyrokarbonsyredialkylester /3fr. Ber.deutschen chem.
Ges. 71»1797»(1938)/ til.S-alkyl-N-acyl-N<*->alkoksykarbonyl-isotiourinstoff.
Denne siste reaksjon tilsvarer prinsippet med den, kjente substitusjon med S-alkyl-isotiourinstoff med klormaursyre-alkylestere /3fr. (I93O)/.
Som eksempler for de ifølge oppfinnelsen anvendbare isotiourinstoffer skal nevnes:
NjU^bis-metoksykarbonyl-S-metyl-isotiourinstoff
(smp. 99~100°C)
!l ,<N>'^bis-etoksykarbonyl-S-metyl-isotiourinstoff
(smp. 50-51°C)
N-etoksykarbonyl-Nr<->propionyl-S-metyl-isotiourin3toff
(smp. 92-94°C;)
N-metoksykarbonyl-N' -prd>pionyl-S-metyl-isotiourinstof f
(smp. 97-99°<c>)
N-metoksykarbonyl-N *-etoks<y>acet<y>l-S-met<y>l-isotiourinstoff
(smp. 69-70°C)
M~metoksykarbonyl-H'-cykloheksylkarbonyl-S-raetyl-isotiourin*toff
(smp. 67-68°C)
H-metoksykarbonyl-K^fenylacetyl-S-metyl-isotiourinstoff
(smp. 55-56°C)
N-etoksykarbonylTN*-benzoyl-S-metyl-isotiourinstoff
(smp. 79-80°C) N-etoksykarbonyl-IP-metoksykarbonyl-S-metyl-isot iourinstoff
(smp. 69°C)
N-allyloksykarbonyl-N'-metoksykarbonyl~S-metyl-isotiourinstoff, K-propinyloksykarbonyl-N'-metoksykarbonyl-S-metyl-isotiourinstoff, N ,H f -bis-allyloksykarbonyl-Sj<metyl-isotiourinstof f, K.N^bis-propinyloksykarbonyl-S-metyl-isotiourinstoff.
De som utgangsstoffer anvendte substituerte 2-amino-anilider kan lett fremstilles analogt til litteraturkjente fremgangsmåter.
Således kan man eksempelvis fremstille 2-amino-4-fenoksysulfonyl-butyranilid ved omsetning av 3-«itro-4-klor-benzensulfonsyre-klorid med fenol til 2~nitro-4~fenoksysulfonyl-klorbenzen, omsetning av dette produkt med ammoniakk til 2-nitro-4-fenoksy-sulfonyl-anilin, acylering med butyrylklorid til 2-nitro-4-fenoksy-sulfonyl-butyranilid og etterfølgende kataly-tiske hydrering.
På den annendide kan man eksempelvis fremstille 2-amino-4-fenylsulfonyloksy-propionanilid ved omsetning av benzensulfonsyreklorid med 2-nitro-4-bydroksyanilin til 2-nitro-4-fenylsQlfonyloksyanilin, acylering med propionylklorid til 2-nitro-4-fenyisulfonyloksy-propionanilid og etterfølgende kata-lytisk hydrering.
Som. eksempler for de som utgangsstoffer anvendte 2-amino-anilider skal nevnes: a)
2-amino-4-fenoksysulfonyl-metoksyacetanilid
2-amino-4-fenoksysulfonyl-acetanilid
2-amino-4-fenoksysulfonyl-pripionanilid
2-amino-4-fenoksysulfonyl-butyranilid
2-amino-4-fenoksysulfonyl-iso-butyranilid
2-amlno-4-fenoksysulfonyl-valeranilid
2-amino-4-fenoksysulfonyl-iso-valeranilid
2-amino-4-fenoksysulfonyl-capron-anilid
2-amino-4-fenoksysulfonyl-iso-capron-anilid
2-amino-4-fenoksysulfonyl~cyklopentankarbonanilid 2-amino-4-fenoksysulfonyl-cyklohexankarbonanilid 2-amino-4-fenoksysulfonyl-fenylacetanilid
2-amino-4-fenoksysulfonyl~fénoksyacetanilid
2-amino-4-fenoksyaulfonyl-benzanilid
b) 2-amino-4-(4-klor-fenoksyfiulfonyl)-acetanilid
2-araino-4-(3-klor-fenoksysulfonyl)-acetanilid 2-amino-4-(2-klor-f enok'!ysulf onyl)-acetanilid ogdSPBiB til avsnitt a) tilsvarende homologer
c)
2-amino-4-(4-brom-fenoksysulfonyl)acetanilid
2-amino-4-(4-n»etyl-f enoksysulf onyl)-acetanilid 2-amino-4-(4-t.butyl-fenoksysulfonyl)-acetanilid 2-amino-4-(4-metoksy-fenoksysulfonyl)-acetanilid 2-amino-4-(4-etoksy-fenoksysulfonyl)-acetanilid; 2-amino-4-(4-propoksy-fenoksysulfony1)-acetani1id 2-amino-4~(4~isopropoksy-fenoksysulfonyl)-acetanilid 2-amino-4-(4-butoksy-fenoksysulfonyl)-acetanilid 2-amino-4-(4-isobutoksy-fenoksysulfonyl)-acetanilid 2-amino-4-(4-cyano-fenoksysulfonyl)-acetan ilid og deres til b) tilsvarende stillingsisomere og homologe
d)
2-amino-4-(3~trifluormetyl-fenoksysulfonyl)acetanilid
2-amin0-4-(3T5-Dis-trifluormetyl-fenoksysulfonyl)-acetanilid og deres til avsnitt a) tilsvarende homologe
2-amino-4-(2-klor-3-metyl-fenoksysulfonyl)-acetanilid 2-amino-4-(2-klor-4-metyl-fenoksysulfonyl)-acetanilid 2-amino-4-(2-klor-5-metyl-fenoksysulfonyl)-acetanilid 2-amino-4-(2-klor-6-metyl-feonoksysulfonyl)-acetanilid
2-amino-4-(3-klor.-2~iaetyl.-f enoksysulf onyl) -acetanilid 2-aralno~4-(3~klor-4-metyl-fenoksysulfonyl)-acetanilid 2-ataino-4- (3~klor-5-metyl-f enoksysulf onyl) -acetanilid 2-aroino-4- (3-klor-6-iaetyl-f enoksysulf onyl)-acetanilid 2-amino-4-(4^klor-2-m©tyl-fenoksysulfonyl)-acetanilid 2-amino-4- (4-klor-3-metyl-f enoksysulf onyl) -acetanilid og deres til avsnitt a) tilsvarende homologe
f)
2-aminO-4»(2,3-diklor-fenoksysulfonyl)-acetanilid
2-amino~4~(2,4-dlklor-fenoksysulfonyl)-acetanilid 2-amino-4-(2,5-diklor-f enoksysulf onyl )-ace'ianilid 2-amino-4-(2,6-diklor-fenoksysulfonyl)-acetanilid 2-araino-4-(3»4-diklor-fenoksysulfonyl)-acetanilid 2-åmino-4-(3»5~diklor-fenoksysulfonyl)-acetanilid og deres til avsnitt a) tilsvarende homologe
<g>) 2-amino-4-(2,3-diraetyl-fenoksysulfonyl)-acetanilid
og dens til avsnitt f) tilsvarende stillingéisoaere og homologe
h)
2-amin6-5-fenoksysulfonyl-acetanilid
og dens til avsnitt a)-g) tilsvarende analoge
i)
2-amino-4-£enylsulfonyloksy-acetanilid
og dens til avsnittene å) til h) tilsvarende analoge
k)
2-amino-5-fenylsulfonyloksy-acetanilid
og dens til avsnittene a) til h) tilsvarende analoge
M-(2-amino-4-fenoksysulfonyl-fenyl)-M<*->metyl-urinstoff K-(2-amino-4-fenoksysulfonyl-fenyl)'-etyl-urinstoff K-(2-amino-4-fenoksysulfonyl-fenyl)-U*-butyl-urinstoff H-(2-aminoT4-fenoksysulfonyl-fenyl)-N+- <jj -cyan£entyl-urinstoff N-(2-araino-4-fenoksysulfonyl~fenyl)-N'-p-metoksyetyl-urinstoff N- (2-aiaino-4-f enoksysulf onyl-f enyl )-N' -benayl-urinstof f N-(2-amino-4-fenoksysulfonyl-fenyl)-N<*->fenyl-urinstoff
N- (2-aiaino-4~ (4-klor-f enoksysulf onyl-f enyl) -H * -metyl-urinstoff og dens til avsnitt b) tilsvarende stillingsisomere og avsnitt 1) tilsvarende homolog
n)
W-(2-amino-4~(4-brom-fenoksysulfonyl-fenyl)-W *-metyl-urinstoff og dens til avsnitt c) tilsvarende analoge og
avsnitt 1) tilsvarende homologe
P)
K- (2-amino-4- (3-trifluormetyl-f enoksysulf onyl-) fenyl) -K' -metyl-urinst off
B-(2-amino-4-(3»5-bis~trifluormetyi-fenoksysulfonyl-fenyl)-H'-metyl-urinstoff . • •-og deres til avsnitt 1) tilsvarende homologe
<q>) H- (2-amino-4- (2-klor-3-metyl-f enoksysulf onyl-f enyl) -W'f -metyl-urinst off
og dens til avsnitt e) tilsvarende stillingsisomere og avsnitt 1) tilsvarende homologe
r) N-(2-amino-4-(2,3-diklor-fenoksysulfonyl-fenyl)-H<*->metyl-urin-st of f
og dens til avsnitt f) tilsvarende stillingsisomere og avsnitt 1). tilsvarende homologe
s)
S-(2-araih0-4-(2,3-dimetyl-fenoksysulfonyl-fenyl)-H♦-metyl-" urinstoff
og dens til avsnitt g) tilsvarende stillingsisomere og avsnitt 1) tilsvarende homologe
t)
N-(2-amino~5-fenoksysulfonyl-fenyl)-N<1->metyl-urinstoff
og dens til avsnitt 1) til s) tilsvarende analoge u)
N- (2-ainino-4-f enyl sulf onyloksy-f enyl) -N' -metyl-urinstof f
og dens til avsnitt 1) til t) tilsvarende analoge
v)
R-(2-amino~5-fenylsul£onyloksy-fenyl)~N'-metyl-urinstoff
og dens til avsnittene 1) til t) tilsvarende analoge.
Ved gjennomføring av fremgangsmåten ifølge oppfinnelsen anvender man hensiktsmessig på 1 mol av det substituerte 2-amino-anilid 1 mol isotiourinstoffeter. Reaksjonen gjennomføres fortrinnsvis i kokende oppløsningsmiddel idet det oppstår alkyl-merkaptan som biprodukt. Sluttproduktene .fremkommer ved av-kjøling av reaksjonoblandingens krystallinske og kan adskilles
ved frasuging og eventuelt renses ved gjenoppløsning respå om-krystallisering.
Som oppløsningsmiddel kommer det ved gjennomføring av fremgangsmåten ifølge oppfinnelsen på tale alle polare organiske oppløsningsmidler. Her tilhører fortrinnsvis alkoholer som metanoler, etanol, iso-propanol og-deres blandinger med. vann, ketoner som aceton (også blandet med vann), eddiksyre (også blandet med vann)., men også etere som dioksan eller tetra-hydrofuran.
' De ved gjennomføringen av fremgangsmåten ifølge oppfinnelsen som reaksjonsbefordrende katalysatorer tilsatte syrer kan prinsippielt velges fra rekken av kjente organiske eller uorganiske.syrer. Fortrinnsvis anvender man imidlertid.Tett tilgjengelige, teknisk betydelige representanter av disse klas-ser. Som eksempler skal nevnes: saltsyre, svovelsyre, salpeter-syre, maursyre, eddiksyre, p-toluensulfonsyre.
Reaksjonstemperaturene kan varieres innen et stort område. Vanligvis arbeider man mellom 0°C og 120°C, fortrinnsvis, mellom JO og 100°C. Omsetningen gjennomføres vanligvis ved normalt trykk.
De nye substituerte fenylguanidiner med den generelle formel I ifølge oppfinnelsen omfatter eksempelvis følgende forbindelser: a) N-(2-acetamido-5-fenoksysulfonyl)-N<f>,N"-bis-metoksykarbonyl-g-uanidin
N-(2-acetamido-5-fenoksysulfonyl)-K',N°-bis-etoksykarbonyl-guanidin
N-{2-acetamido-5-fenoksysulfonyl)~N' jH^-bis-propoksykarbonyl-guanidin N- (2-acetamido-5-fenoksysulfonyl)-K' ,NH-bis-isopropoksykarbonyl-guanidin
■N- (2-a cetamido-5~f enoksysulf onyl) -K*, l\Tn-bis-butoksykarbonyl-guanidin N-(2-acetamido-5~^eo^°ksysulfOnyl )-K?,<N>"-bis--is<o>butoksykarbonyl-guanidin
b)
N-(2-propionaraido-5-fenoksysulfonyl)-tø',$n-bis-metoksykarbonyl-guanidin
W-(2~butyramido-5~ f enoksysulf onyl)-JJ* ,NM-bis-met oksykarbonyl-guanidin W-(2-iso-butyraarido~5-fenoksysulfonyl)-N*,K0-bis-metoksykarbonyl-guanidin<;>
fJ- (2-valeranaido-5-fenoksysulf onyl)-T?JT ,Kn-bis-metoksykarbonyl-guanidin
H-(2-iso-valeramido-5-fenoksysulfonyl).-N<?>,N<M->bis-metoksykarbonyl-guanidin
W-( 2-capronamido--5-fenoksysulfonyl )-M' ,H"-bis-metoksykarbonyl-guanidin H- (2-iso-kapronamido-5-f enoksysulf onyl )-N', IP-bis-metoksykarbonyl-guanidin
W-(2-metoksyacetamido-5-fenoksysulfonyl)-W',N"-bis~metoksykarbonyl-guanidin N-(2-cyklopentankarbonamid-5-fenoksysulfonyl)-M',Nn-bis-metoksy-karbonyl-guanidin N- (2-cyklohexankarbonamido-5-f enoksysulf onyl )-N * ,N"-bis-sietoksy-karbonyl-guanidin
n-(2-fenylacetamido-5-£enoksysulfonyl)- lV ,N"-bis-metoksykarbonyl-guanidin M - (2 - fen oksyac et am ido - 5 -f en oksys ulf onyl) -N', N" - b i s-met oksykarbonyl-guanidin K-(2-bensamido-5-f enoksysulf onyl) -fl' ,K,'-bis-metpksykarbonyl-guanidin
og deres til avsnitt a) tilsvarende homologe
c)
N-(2-acetamido-5-{4-klor-fenoksysulfonyl)-M'.N^-bis-metoksy- karbonyl-guanidin
fJ- (2-acetamido~5- (3-klor-fenoksysulfonyl) -fl' .N^-bis-metoksy-karbonyl-guanidin N- (2-acetamido-5- (2-klor-f enoksysulf onyl )-N' ,tJ"-bis-met oksykarbonyl-guanidin H-(2-butyrafflido-5-{ 3-klor-fenoksysulfonyl)- lV ,N°-bis-métoksy-karbonyl-guanidin
og deres til avsnittene a) og b) tilsvarende homologe,
d)
W-(2-acetamido-5-(4-brom-fenoksysulfonyl)-N',Nn-bis-metoksy-karbonyl -guanidin
N-(2-aeetamido-5-(4-metyl-fenoksysulfonyl,N<M->bis-metoksy-karbonyl-guanidin H-(2-acetamido-5-(4^t-butyl-fenoksysulfonyl)-NT,H"-bis-metoksy-karbonyl-guanidin H-(2-acetaraido-5-(4-metoksy-fenoksysulfonyl)-N',N"-bis-metoksy-karbonyl-guanidin M-(2~aeetamido-5~(4-Qtoksy-fenoksysulfonyl)-M',Kw-bis-metoksy-karbonyl-guanidin K-{ 2-acetamido-5- (4-propoksy-f enoksysulf onyl )-Ef' ,N"-bis-metoksy-karbonyl-guanidin
U-(2-acetamido-5-(4-isopropoksy-fenoksysulfonyl)-N',K<n->bis-metoksy-karbonyl-guanidin
H-(2-acetamido-5-(4-butoksy-fenoksysulfonylJ-N*^fP-bis-met oksykarbonyl-guanidin
K-(2-ac etamido-5-(4-isobutoksy-fenoksysulfonyl)-N',Nn-bis-metoksy-karbonyl-guanidin N-(2-acetamido-5-(4-cyano-fenoksysulfonyl)-N',N<tt->bis-metoksy-karbonyl-guanidin fI-(2-aeetamido-5-(3~métyl-fenoksysulfonyl)-^3, ,H"-bis-metoksy-karbonyl-guanidin M-(2-metoksyacetamido-5-(3-metyl-fenoksysulfonyl)-N',K"-bis-metoksy-karbonyl-guanidin TJ-(2-butyramido-5-(3-metyl-fenoksysulfonyl}-K* jM^-bis-metoksy-karbonyl-guanidin og deres til avsnitt c) tilsvarende stillingcisoaere og avsnittene a) og b) tilovarende homologe.
e)
N-(2-acetaKldo-5-(3-trif luoriaetyl-fenoksysulfonyl)-M1^"-bis-laet oksy-karbonyl -guanidin M-{2-acetataido-5-( 3,5-bis-trifluormetyl-f enoksysulf onyl)-If ,Hn-bis-metoksy-karbonyl-guanidin R- (2-metoks<y>acetamido~5~( 3~trifluørmetyl-rf eno<k>s<y>sulf onyl)-N f bis-metoksy-karbonyl-guariidin N- (2-butyramido-5- (3-trifluormetyl-f enoksysulf onyl) -8' ,Wn-bis-metoksy-karbonyl-guanidin og deres til avsnittene a) og b) tilsvarende homologe,
<f>) N-(2-acetamido-5-(2-klor-3-metyl-f enoksysulf onyl) )-&' -ftn-bis-raetoksykarbonyl-guanidin R-(2-acetamido-5-(2-klor-4-metyl~fenoksysulfonyl))-W',M"-bis-metoksykarbonyl-guanidin W-(2-aeetamido-5-(2-klor-5-metyl-fenoksysulfonyl)) -N',N"-bis-metokaykarbonyl-guanidin K-(2-acetamido-5-(2-klor-6-metyl-fenoksysulfonyl))-W<f>,M"-bis-metoksykarbonyl-guanidin K-(2-acetamido-5-(3-klor-2-metyl-fenoksysulfonyl))-N<T>,N"-bis-metoksykarbonyl-guanidin
R- (2-acetamido-5-(3-klor-4-metyl-fenoksysulf onyl) )-H* ,K"-bis-metoksykarbonyl-guanidin H-(2-acetamido-5-(3-"-klor-5-metyl~f enoksysulf onyl) )-NT ,W"-bis-metoksykarbonyl-guanidin t<J-(2-acetaaido-5-(3~klor-6-metyl-f enoksysulf onyl) )-IIf ,N"-bis-metoksykarbonyl-guanidin
H-(2-acetamido-5-(4-klor-2-aetyl-fenoksysulfonyl))-H<T>,M"-bis-metoksykarbonyl-guanidin .J?-( 2-acetamido-*5-(4-klor-3-metyl-f enoksysulf onyl) )-$* ,Mn;-bis-metoksykarbonyl-guanidin og deres til avsnittene a) og b) tilsvarende homologe,
<g>) N-(2-acetamido-5-(2,3-diklor-fenoksysulfonyl))-H<*>,N<»->bis-metoksykarbonyl-guanidin H-{2-acetamido-5-(2,4-diklor-fenoksysulfonyl) )-M' ,Mn-bis-metoksykarbonyl-guanidin
N- (2~acetamido-5-{ 2,5-diklor-f enoksysulf onyl ))-??':,N»-bis-metoksykarbonyl-guanidin.
N-(2^acetamido-5~(2,6-diklor-fenoksysulfonyl))-H?. ,Hw-bis-raetoksykarbonyl-guanidin
K-(2-acetamido-5-(3,4-diklor-renoksysulfonyl))-»♦,Nn-bis-metoksykarbonyl-guanidin N- (2~acetaraido~5~(.5,5-diklor- f enoksysulf onyl)) -Nf, NR-bis-metoksykarbonyl-guanidin
og deres til avsnittene a) og b) tilsvarende homologe,
h) M-(2-acetamido-5-(2,3-dimetyl-fenoksysulfonyl))-B<f>,N<tt->bie~
metoksykarbonyl^guanidin
og dens til avsnitt g) tilsvarende stillingsisomere og avsnittene a) og b) tilsvarende homologe.
Dessuten til avsnitt:
c) M-/2-raetoksyacetåmido-5~(3-klor-fenoksysulfonyl 17~N'»N"-bis-raetoksykarbonyl-guanidin H-/2-propionamido-5-(3-klor-fenoksysulfonyl *,N"-bis-metoksykarbonyl-guanidin
H-/2-butyramido-5r(3~klor-fenoksysulfonyl)/-N',N"-bis-metoksy-karbonyl-guanidin
og deres til avsnittene a) og b) tilsvarende homologe,
d) R-Z2-metoksyacetamido-5"^3-^etyl-fenoksysulfonyl1/-H',N"-bis-metoksykarbonyl-guanidin
R-.Z2-metoksyacetaEiido-5- (3-cyan-f enoksysulf onyl )/-H JK"-bis-métoksykarbonyl-guanidin
M-/2-propionamido-5-(3-metyl-fenoksysulfonyl1/-N',N"-bis-metoksykarbonyl-guanidin
K-/2-propionamido-5-{3-cyan-fenoksysulfonyl )/-H',NM-bis-metoksykarbonyl-guanidin
S-/2-butyramido-5-(3-metyl-fenoksysulfonyl )/-N',W"-bis-metoksy-karbonyl-guanidin
U-^2-butyramido-5-(3-cyan-fenoksysulfonyl)7-N *,N"-bis-metokey-karbonyl-guanidin
og deres til avsnitt c) tilsvarende stillingsisomere
e)
N-/2-metoksyacetamido-5-(3-trif1uornetyl-fenoksysulfonyl ) J -
IV ,Wn-bis-metoksykarbonyl-guanidin
^T-^2-propionamido-5-( 3-trifluormetyl-fenoksysulfonyl)7-K, ,Nn-bis-metoksykarbonyl-guanidinW n-/2-bufcyranido-5-( 3-trif luormetyl-f enoksysulf onyl ' ,N"-bio-metoksykarbonyl-guanidin
og deres til avsnittene a) og b) tilsvarende homologe,
i)
N-(2-acetamido-4-(4-metyl-fenoksysulfonyl))-N<f>,N<H->bis-metoksy-karbonyl-guanidin
N-(2-acetamido-4-(3-metyl-fenoksysulfonyl))-W,M"-bis-metoksy-karbonyl-guanidin
N-(2-acetamido-4-(3-klor-fenoksysulfonyl) )-N',NM-bis-metoksy-karbonyl-guanidin
K-(2-acetamido-4-(3-trifluormetyl-fenoksysulfonyl))-W,M"-bis-netoksykarbonyl-guanidin
N-(2-acetamido-4-( 3-c3a no-fenoksysulfonyl))-NT,Nn-bis-metoksy-karbonyl-guanidin
N-(2-metoksyaoetaroido-4-fenoksysulfonyl))-N',N<n->bis-metoksy-karbonyl-guanidin
tJ-(2-raetoksyacetanido-4-(4-metyl-f enoksysulf onyl) )-N* ,N"-bis-metoksykarbonyl-guanidin
N-(2-metoksyacetamido-4-(3-metyl-fenoksysulfonyl))-N•^"-bis-net oksykarbonyl-guanidin
N-(2-metoksyacetamido-4*(3-klor-fenoksysulfonyl))-N',K"-bis-metoksykarbonylvguanidin
N-(2-metoksyacetamido-4-(3-trifluormetyl-fenoksysulfonyl))-N',N"-bis-metoksykarbonyl-guanidin
H-(2-metoksyacetamido-4-(3-cyano-fenoksysulfonyl))-N',N°-bis-metoksykarbonyl-guanidin H-(2-propionamido-4-fenoksysulfonyl)-N<f>,H"-bis-metoksykarbonyl-guanidin
W- (2~propionamido~4-(4-metyl~f enoksysulf onyl) , ^-bis-laet oksykarbonyl-guanidin
PT( 2-propionamido-4- (3-metyl-f enoksysulf onyl)) -H',Nlf-bis- . raetoksykarbony1-guanidin fl-{2-pripionamido-4-(3-klor-f enoksysulf onyl))-HHM-bis«
metoksykarbonyl-guanidin N-(2-propionamido-4-( 3-trif luormetyl-f enoksysulf onyl )')-STf ,Nn-bis-metoksykarbonyl-guanidin N-(2-p.ropionamido-4-(3-cyano-f enoksysulf onyl) J-N* ,K"-bis-metoksykarbonyl-guanidin
W-(2-butyramido-4-fenoksysulfonyl)-N',N"-bis-metoksykarbonyl-guanidin H-(2-butyramidO-4-(4-metyl-fenoksysulfonyl))-N<*>,W"-bis-metoksy-karbonyl -guanidin N-{2-butyramido-4-(3-metyl-fenoksysulfonyl))-N<*>,N"-bis-metoksy-karbonyl-guanidin H-(2-butyramido-4-(3-klor-fenoksysulfonyl))-M',H"-bis-metoksy-karbonyl -guanidin W-(2-butyramidd-4-(3-trifluormetyl-fenoksysulfonyl))-N',H"-bis-metoksykarbonyl-guanidin N-{2-butyramido-4-(3-cyano-fenoksysulfonyl))-N7,N"-bis-metoksykarbonyl-guanidin N-(2-acetaraido-4-fenoksysulfonyl)-N *,H"-bis-metoksykarbonyl-guanidin
og deres til avsnittene a) til H) tilsvarende analoge,
k)
H-(2-acetamido-5-(4-metyl-fenylsulfonyloksy))-K',N"-bis-metoksykarbonyl-guanidin
H-(2-åcetamido-5-(3-metyl-fenylsulfonyloksy))-N<r>,W"-bis-metoksykarbonyl-guanidin M-(2-acetamido-5-(3-klor-fenylsulfonyloksy))-BP ,N"~bis-metoksy-karbonyl-guanidin N-(2-acetamido-5-(3-trifluormetyl-fenylsulfonyloksy))-NV,N"-bis-metoksykarbonyl-guanidin n-(2-acetamido-5^(3-cyano-fenylsulfonyloksy))-K'^"-bis-met oksykarbony 1 -guanidin
K-(2-metoksyaeetamido-5-fenylsulfonyloksy)-BT' ,H"-bis-metoksy-karbonyl-guanidin
N-{2-metoksyacetamido-5-H-metyl-fenylsulfonyloksy) )-5T ,Nn-bis-metoksykarbonyl-guanidin K-(2-metoksyacetataido-5-(3-m©tyl-fenylsulfonyloksy),H"-bis-metoksykarbonyl-guanidin K-(2-metoksyacetamido-5-{3-klorr-f enylsulf onyloksy) )-IT ,H"-bis-metoksykarbonyl-guanidin
K-(2-raetoksyacetatnido-5-( 3-trif luormetyl-fenylsulfonyloksy))-NJ W-bis-metoksykarbonylguanidin H-(2-iaetoksyacetamido-5-(3-cyano-fenylsulfonyloksy),N"-bis-metoksykarbonyl-guanidin
N-(2-propionamido-5-fenylsulfonyloksy)-N<*->tø^-bis-metoksykarbonyl-guanidin
N- {2-propionamido-5- (4-metyl-fenylsulfonyloksy)) -N* ,Kn-bis-metoksykarbonyl-guanidin N-(2-propionasido-5-( 3-metyl-f enylsulf onyloksy)) - IV ,fJ"~bis-metoksykarbonyl-guanidin N-(2-propionamido-5-(3-klor-fenylsulfonyloksy))-N<T>,N"-bis-metoksykarbdnyl-guanidin H-{ 2-|;>ropionamido-5-( 3-trif luoraetyl-f enylsulf onyl oksy) )-N' bis-metoksykarbonyl-guanidin N-(2-propionamido-5-(3-cyano-fenylsulfonyloksy))-H<t>,M"-bis-metoksykarbonyl-guanidin U_(2-butyramido-5-fenylsulfonyloksy)-K *^"-bis-metoksykarbonyl-guanidin N-(2-butyramido-5-(4-metyl-fenylsulfonyloksy))-N',M"-bis-metoksykarbonyl-guanidin M-(2-butyramido-5-(3-metyl-fenylsulfonyloksy))-W,K"-bis-metoksykarbonyl-guanidin M-(2-butyramido-5-(3-klor-fenylsulfonyloksy))-l<T>,M"-bis-metoksykarbonyl-guanidin
W- (2-butyra.mido-5- (3-trif luormetyl-f enylsulf onyloksy)) -H * bis-metoksykarbohyl-guanidin
R-(2-butyramido-5-(3-cyano-fenylsulfonyloksy))-N'$"-bis-metoksy~karbonyl-guanidin N-(2-acetamido~5-fenylsulfonyloksy)-N*,N"-bis-metoksykarbonyl-guanidin
og deres til avsnittene a) til i) tilsvarende analoge.
N-(2-acetamido-4-(4-metyl-f enylsulf onyloksy) )-Nr ,N"-bis-metoksy-karbonyl-guanidin
N-(2-acetamido-4-(3-metyl-fenylsulfonyloksy))-N<r>,K"-bis-metoksykarbonyl-guanidin
N-(2-acetamido-4-(3-klor-fenylsulfonyloksy))-N',N"-bis-metoksy-karbonyl-guanidin
N-(2-acetamido-4-(3-trifluormetyl-fenylsulfonyloksy))-N',N<n->bis-metoksykarbonyl-guanidin
M-(2-acetamido-4-(3-cyanp-fenylsulfonyloksy))-N',N"-bis-metoksy-karbonyl-guanidin
M~( 2-metokr.yacetamido-4-f enylsulf onyloksy )-M' ,N"-bis-metoksy-karbonyl-guanidin
B- (2-metoksyacetamido-4- (4-metyl-f enylsulf onyloksy)) - 11T ,N"-bis-metoksykarbonyl-guanidin
N-(2-metoksyacetamido-4-(3-^etyl-fenylsulfonyloksy))-H<f>,M"-bis-metoksykarbonyl-guanidin K-(2-raetoksyacetamido-4-(3-klor-fenylsulfonyloksy))-N',N<n->bis-met oksykarbonyl-guanidin
N-(2-metoksyacetamido-4-(3-trifluormetyl-fenylsulfonyloksy))-N<*>,N<M->bis-metoksykarbonyl-guanidin
K-(2-metoksyacetamido-4-(3~cyano-fenylsulfonyloksy))-N',W<n->b is-met oksykarbonyl-guarid in
N-(2-propionamido-4-fenylsulfonyloksy)-N',N"-bis-metoksykarbonyl-guanidin r.T-(2-propionamido-4-( 4-metyl-f enylsulf onylotfsy) )-M' ,M"-bis-metoksykarbonyl-guanidin
W-(2-propionamido-4-(3"metyl-fenylsulfonyloksy))-\ V ,N"-bis-metoksykarbonyl-guanidin
N-(2-pripionamido-4-(3-klor-fenylsulfonyloksy))-K',N"-bis-metoksykarbonyl-guanidin M-(2-propionamido-4-(3-trifluormetyl-fenylsulfonyloksy))-N',N"-bis-metoksykarbonyl-guanidin
N-(2-propionaraido-4-(3~cyano-fenylsulfonyloksy))-W',W"-bis-metoksykarbonyl-guanidin
N-(2-butyramido-4-fenylsulfonyloksy)-N<*>,N"-bis-metoksykarbonyl-guanidin
M-(2-butyramido-4-(4-metyl-fenylsulfonyloksyB-N;R"-bis-metoksy-karbonyl-guanidin
W-(2-butyramido-4-(3-metyl-fenylsulfonyloksy))-M<r>,N<tt>rbis-metoksykarbonyl-guanidin N~ (2-butyramido-4-(3-klor-f enylsulf onyloksy)) -53', SJ"-bis-metoksykarbonyl-guanidin Fl- (2-butyramido-4- (3-trif luormetyl-f enylsulf onyloksy) )-fJ' . bis-metoksykarbonyl-guanidin !?-(2-butyramido-4-( 3-cyano-f enylsulf onyl oksy) J-N* ^«-bis-metoksykarbonyl -guanidin
H- (2-acetamido-4-f enylsulf onyloksy )-H' ,fJ"-bis-metoksykarbonyl-guanidin
og deres til avsnittene a) til i) tilsvarende analoge
m) H-(2-(N<2->metylureido)-5-fenoksyåulfonyl)-M<r>,Kf<n->bis-metoksy-karbonyl-guanidin
KM2-(N -étylureido)-5-f enoksysulf onjil J-M* ,K°-bis-metoksy-karbonyl-guanidin
K-(2-(K<2->butylureido)-5-fenoksysulfonyl)-H<f>,H<n->bic-metoksy-karbonyl-guanidin
K-(2-(M2-co -cyanpentylureido)-5-fenoksysulfonyl)-N',K"-bis-metoksykarbonyl-guanidin M-(.2-(N2-p-métoksyetylureido)-5-fenoksysulf onyl)^'-bis-metoksykarbonyl-guanidin N-(2-(N<2->bensylureido)-5-fenyloksysulfonyl)-W',N<n->bis-metoksy-karbonyl-guanidin
K-(2-(H<2->fenylureido)-5-fenoksysulfonyl)-M<T>,M"-bis-metoksy-karbonyl-guanidin
og deres til avsnitt a) til 1) tilsvarende analoge,
n)
N-(2-acetaraino-5-fenoksysulfonyl)-ET-metoksykarbonyi-Nn-acetyl-guanidin
N- (2-acetaraitio-5-f enoksysulf onyl) -H * -metoksykarbonyl-lP-propionyl-guanidin N-(2-acetamirio-5-fenoksysulfonyl)- IV-metoksykarbonyl-Bn-butyry1-guanidin
N-(2-acetamino-5-fenoksysulfonyl)-K'-metoksykarbonyl-K"-cyklohexankarbonyl-guanidin
M- (2-acetamino~5-f enoksysulf onyl) -M' -métoksykarbonyl-H^-benzoyl-guanidin
.13-{2-acetamino-5-f enoksysulf onyl) -N' -metoksykarbonyl-N"-fenacetyl-guanidin
K~ (2-acetamino-5-f enoksysulf onyl) -W' -metoksykarbonyl-tj"-fenoksya.cetyl. -guanidin
og deres til avsnittene a) til rn) tilsvarende analoge.
o)
H-{2-acetamino-5-fenoksysulfonyl)-Hr<->etoksykarbonyl-K"-acetyl-guanidin
K-{2-acetamino-5-fenoksysulfonyl)-M'-propoksykarbonyl-KB-acetyl-guanidin
} l-( 2- acetamino-^- f enoksysulf onyl) - IsopropokBykarbonyl^"-acetyl-guanidin
K-{2-acetamino-5-fenoksysulfonyl)-W1-butoksykarbonyl-K"-acetyl-guanidin
K-(2-acetaraino-5-fenoksysulfonyl)-W'-isobutoksykarbonyl-H"-acetyl-guanidin
og deres til avsnittene a) til n) tilsvarende analoge.
De nye substituerte fenylguanidiner ifølge oppfinnelsen er verdifulle kjeraoterpeutika og egner seg til bekjempelse av parasitære sykdommer hos mennesker og dyr, som av helminter og leverigler.
De er spesielt virksomme mot et stort antall helminter, f.eks.haemonchus, trichostrongylus, ostertagia, strongyloides, cooperia, chabertia, oesophagostomum, hyostron-gulus,. ankylostoma, askaris og heterakis og fasciola. Spesielt utpreget er virkningen overfor mave-tarm-strongulider og leverigler, hvorav fremfor alt drøvtyggere angripes. Derfor anvendes forbindelsene ifølge oppfinnelsen spesielt i veterinær medisin. Forbindelsene med formel I administreres alt etter . tilfellets art i doseringer mellom 0,5 og 50 mg/kg legemsvekt i 1 til 14 dager.
Til oral applikasjon kommer det i betraktning tab-letter, jåragéer, kapsler, pulvere, granulater eller pastaer som inneholder de virksomme stoffer sammen med vanlige hjelpe-eller bærestoffer som stivelse, cellulosepulver, talkum, magnesiumstearat, sukker, gelatin, kalsiumkarbonat, finfordelt kiselsyre, karboksymetylcellulose eller lignende stoffer.
Fremgangsaåteproduktene er ikke bare utmerket virksomme oralt applisert, men virker også parenteralt.
Til parenteral applikasjon kommer det i betraktning oppløsninger, f.eks. oljeaktige oppløsninger som fremstilles under anvendelse av sesamolje, ricinusolje eller synte-tiske triglyserider, eventuelt med tilsetning.av tokoferol nom antioksydans og/eller under anvendelse av grenseflateaktive stoffer som sorbltanfettsyreestere. Dessuten kommer det i betraktning vandige suspensjoner som fremstilles under anvendelse av etoksylerte sorbitanfettsyreestere, eventuelt under tilset-ning av fortykningsmldler som polyetylenglykol eller karboksymetylcellulose.
Konsentrasjon av de virksomme stoffer ifølge oppfinnelsen i de dermed fremstilte preparater ligger fortrinnsvis for bruk som veterinærlegemiddel mellom 2 og 20 for bruk som huraanlegemiddel ligger konsentrasjonen av de virksomme stoffer fortrinnsvis mellom 20 og 80 vekt-$.
Fremgangsmåteproduktene er spesielt virksomme mot leverigler. Således virker fremgangsmåteproduktené ifølge eksemplene 5*2, 5*3°S 6.30 allerede med 10 mg/kg ved oralt applikasjon mer enn Virkningen mot mave-tarm-nematoder
er likeledes meget god, eksempelvis oppnåe med fremgangsmåteproduktené ifølga eksemplene 4*1 en 90 $ virkning allerede med 2,5 mg/kg ved subcutan applikasjon.
Fremstillingseksempler♦
Ekpempel 1. 1
3762-amino-4-fenoksysulfonyl-acetanilid oppvarmes i 250 ml metanol med 25 g K,N<T->bic-metoksykarbonyl-isotiourinstoff-?-metyleter og 0,01 g p-toluensulfonsyre 5 timer under tilbakeløp. Deretter avdestilleres oppløsningsmidlet under nedsatt ferykk og residuet utrøres med eddikester. Det utkrystalliserte N-(2-acetamino-5-fenoksy-sulfonyl)-W',N<M->bis-metoksy-karbonyl-guanidin f raf Utreres"og vaskes med eddikester og meta-
noi. Utbytte 3.3S*SmP* under spaltning.
For fremstilling av 2-amino-4-fenoksysulfonyl- . acetanilid hydreres 4$ g 2-nitro-4-fenoksy6ulfonyl-acetanilid 1 500 ml metanol med Raney-nikkel under normalt trykk. Man frafUtrerer oppløsningen fra katalysatoren og inndamper filtratet under nedsatt trykk. Residuet kan videre forarbeides uten ytterligere rensing direkte som ovenfor. Utbytte.av 2-.amino-4-fenoksysulfonyl-acetanilid 32 g. Fra metanol smp. 130°C.
For fremstilling av 2-nitro-4-fenoksysulfonyl-acetanilid blandes 5° g 2-nitro-4-fenoksysulfonyl-anilin i 25$ ml acetanbydrid under omrøring med 1 ml konsentrert H^SO^, idet reaks jone. blandingen oppvarmer seg. Man etteromrøren enda i 2 timer og inndamper deretter under nedsatt trykk. Til det faste residu setter man diisopropyleter og filtrerer fra det utkrystalliserte 2-nitro-4-fenoksysulfonyl-acetanilid. Utbytte 40 g. Fra metanol smp. 124°C.
For fremstilling av 2-nitro~4-fenoksysulfonyl-anilin holdes 54 g 2-nitro-4-fenoks?yPulfonyl-klorben?.en i 500 ral dioksan i en autoklav med gassformet ammoniakk ved 5°°C og 5 atmosfærers overtrykk i 5 timer og derpå avdestilleres oppløs-ningsmidlene under nedsatt tryftk. Residuet blandes med 200 ml av en blanding av like deler metanol og vann. Etter kort tid ut kostal lis er er 2-nitro-4- f enoksysulf onyl-anilin. Råproduktet renses fra metanol og deretter benaen. Utbytte 28 g. Smp. 104°C.
For fremstilling av 2-nitro-4-fenoksysulfonyl-klorbenzen blandes 5* g 3~ni'tro-4-klor-bensensuif pnsyreklorid i 120 ml aceton med 18,8 g fenol og under avkjøling ved én indre temperatur som ikke overstiger 10°C tildryppes 28 ml trietylamin. Etter flere timers etteromrøring ved vssrelsestemperatur blander man med vann, hvorpå det utskiller seg en:olje somropparbeides over eter. Utbytte av 2-nitro-4-^fenoksysulfonyl-kldr-benzen 54 g* Fra metanol smp. 71°C
Analogt vil man av 2-amino-4-£enoksysulfonyl~acet-ani2'4-d og 1.2 H,N<*->bis-etoksykarbonyl-isotiourinstoff-S-metyleter få
N-(2-acetamido-5-fenoksjisulfonyl )-W ,H"-bis-etoksykarbonyl-guanidin 1.3 N,K'-bis-prppoksykarbonyl-i^otiourin?.toff-?-raetyleter få
N-(2-acetamido-5-fenoksysulfonyl)~MJ N^-bis-propoksy-karbonyl-guanidin
1.4 H, N'-bis-isopropoksykarbonyl-isot iourinst off-S-metyleter få H- (2-acetamido-5"fenoksysulf onyl)-N' ,Mn-bis-iso-propoksykarbonyl-guanidin 1.5 H,N'-bis-butoksykarbonyl-isotiourinstoff-S-metyleter få
H-(2-acetamido-5-fenoksysulfonyl)-N; fJn-bis-butoksy-karbonyl-guanidin
1.6 U,K'-bis-isobutoksykarbonyl-isotiourinstoff-S-metyleter få M-(2-acetamido-5-fen oksysulfonyl)-H',N"-bis-iso-butoksykarbonyl-guanidin;
1.7 M-metoksykarbonyl~tP-propioriyl-isqtiourinstoff-S-inetyleter få K-(2-aeetarsido-5-fenoksy<p>ulfonyl -metoksykarbonyl-J3<n->propionyl-guanidin 1.8 K-etoksykarbonyl-K'-bensoyl-isotiourinstoff-S-aetyl-eter få H-(2-acetamido-5-fenoksysulfonyl)-K'-etoksykarbonyl-Jjn-benzoyl -guan idin
1.9 W-metoksykarbonyl-IP-cyklohexylkarbonyl-isotiourinstoff-S-metyleter få Mr (2-acetamido-5-fenoksy3ulf onyl )-fl' -metoksykarbonyl-K"-cyklohexylkarbonyl-guanidin
1.10 N-metoksykarbonyl-Nf<->etoksymetylkarbonyl-isotiourin-stof f-S-metyleter få
fJ-(2-acetamido-5-f enoksysulf onyl) -K.'-metoksykrbonyl-N"-etoksymetylkarbonyl-guanidin
Eksempel 2. 1
27 g 2-amino-4-fenoksysulfonyl-butyranilid omsettes
analogt eksempel 1 med 20 g N,N'-bis-metoksykarbonyl-isotiourinstoff-Sfeietyleter og det fåes 9 g K-(2-butyramido-5-fenoksy
sulfonyl)-MJ N°-bis-metoksykarbonyl-guanidin.
For fremstilling av 2-amino-4-fenoks<y>sulfon<y>l-* butyranilid blandes 29,6 g 2-nitro-4-fenoksysulfonyl-anilin av smp. 104°C i 300 ml toluen under omrøring ved 100°C med 14 ml butyrylklorid dråpeyis og holdes 2 timer under tilbakeløp.
Med en gang inndampes oppløsningen under nedsatt trykk og residuet blandes meddiisopropyleter. Det utfelte 2-nitro-4* f enoksysulf onyl-butyranilid frafiltreres, vaskes med diisopropyleter og hydreres tilsvarende eksempel 1 til 2-amino-4-fenoksy-sulfonyl-butyranilid.
Eksempel 4«1
34 g 2-amino-4-fenyisulfonyloksy-acetanilid oppvarmes i 2QQml metanol med $ Q g H,K'-bis-metoksykarbonyl-isotiourinstoff-S-metyleter og 0,01 g p-toluensulfosyre 5 timer under tilbakeløp. Deretter avdestilleres oppløsningsmidlet under
, nedsatt trykk og residuet utrøres med eddikester. Det utkrystalliserte H-(2-acetamido-5-f enylsulf onyloksy )-F5' ,Nn~bis-metoksy-karbonyl-guanidin frafiltreres og vaskes med eddikester og metanol. Utbytte 35 g. SMp. l8l°C under spaltning.
For fremstilling av 2-amino4-fenylsulfonyloksy-acetanilid hydreres 50 g 2-nitro-4-fenylsulfonyloksy-acetanilid i 25O ml metanol i nærvær av Raney-nikkel under normalt trykk ved værelsestemperatur.. Man frafUtrerer katalysatoren, vasker denne med dimetylformamid og inndamper filtratet under nedsatt trykk.
Den gjenblivendé 2-amino~4-fenylsulfonyloksy-acetanilid er rent nok for den videre forarbeidelse. Utbytte 44,g» Fra metanol Smp. 154°C.
For fremstilling av 2-nitro-4-fenylsulfonyloksy-acetanilid blandes 48 g 2~nitro-4-fenylsulfonyloksy-anilin i 2$ 0 ml acetanhydrid under omrøring med 1 ml konsentrert H2^4*idet reaksjonsblandingen oppvarmer seg. Man oarører enda i to timer og inndamper deretter under nedsatt trykk. Det oljeaktige residu opparbeides oger eddikester og derved fåes fast residu av 2-nitro-4-fenylsulfonyloksy-acetanilid. Til rensing opp-løses det i 100 ml varm metanol og fortynnes med 100 ml vann.
Etter avkjøling frafiltreres det dannede 2-nitro-4-fenylsulfonyloksy-acetanilid og vaskes med vann. Utbytte 52 g. Fra metanol smp. yB°C,
For fremstilling av 2-nitro-4-fenylsulfonyloksy-anilin blandes 15,4 g 3~nitro-4-amino-fenol i 100 ml aceton med 14 ml trietylamin og under omrøring ved maksimalt 20°C i isbad tildryppes en oppløsning av 17»6 g benzensulfonsyreklorid i 3^ mX aceton. Etter tre timers etteromrøring frafiltrerer man reak-sjonsoppløsningen fra- trietylaminhydroklorid og damper filtratet til tørrhet. Man utfører derpå med 50 ml metanol og filtrerer det utfelte 2-nitro-4-fenylsulfonyloksy-anilin og utvasker med metanol. Utbytte 18 g. Fra metanol smp. 140°C.
Analogt vil man av 2-amino-4-f,enylsulfonyloksy- acetanilid og
i
4.2 N,N<r>-bis-etoksykarbonyl-isotiourinstoff-S-metyleter få H-(2-acetamido-5-f enylsulf onyloksy )-NT ,IfM-bis-etoksykarbonyl-guanidin
4.3 N,fJT-bis-propoksykarbonyl-isotiourinstoff-S-metyleter få N-(2-acetamido-5-fenylsulf onyl oks$-N \ M"-bis-propoksy-karbonyl-guanidin
4.4 K >K'-bls-isopropoksykarbonyl-isotiourinstoff-S-nietyleter få M-( 2-acetaraido-5-fenylsulf onyloksy)-fJ ♦ ,N"-bis-iso-propoksykarbonyl-guanidin 4.5 K,N'-bis-butoksykarbonyl-isotiourinstoff-S-metyleter få
W-(2-acetaarido-5-fenylsulfonyloksy)-W',W^-bis-butoksykarbonyl-guanidin
4» 6 H.N^bis-.isobutoksykarbonyl-isotiourinstoff-S-metyl-.eter få W-(2-acetaraido-5-fenylsulfonyloksy)-K'.N^-bis-iso-butoksykarbonyl-guanidin
4.7 K-metoksykarbcnyl-N'-propionyl-isotiourinstoff-S-metyleter få
N-(2-a cetamido-5-fenylsulfonyloksy)-K *-metoksykarbonyl-N"-propionyl-guanidin
4»8 N-etoksykarbonyl-R'-benEoyl-isotiourinstoff-S-metyleter få
N-(2-acetamido-5-fenylsulfonyloksy)-K'-etoksykarbonyl-N"-bensoyl-guanidin
4*9K-metoksykarbonyl-N'-cyklohexylkarbonyl-isotiourinstoff-S-metyleter få
FT-(2-acetamido-5-f enylsulf onyl oksy)-!?.' -metoksykarbonyl-R^-cyklohexylkarbonyl^guanidin,
4*10 M-metoksykarbonyl-IP-etoksymetylkarbonyl-isotiourinstoff-S-metyleter få M-( 2-a cetamido-5-f enylsulf onyloksy )-H"' -metoksykarbonyl-K"-etoksymetylkarbonyl-guanidin
Eksempel 5. 1
27 g 2~ainino~4-fenylsulfonyloksy-butyranilid omsettes analogt Eksempel 4 sed 20 g R,ft<T->bis-metoksykarbonyl-isotiourinstoff-S-metyleter og det fåes 9 g M-(2-butyramido-5-feny.lsulfonyloksy)~Hf .^"-biG-metoksykarbonyl-guanidin.,
smp. 158°C.
For fremstilling av 2-amino-4-fenylsulfonyloksy-buryanilid blandes 29»6 g 2-nitro-4-fenylsulfonyloksy-anilin av smp. 148°C i ^ QO ml toluen under omrøring ved 100°C med 14 ml butyrylklorid dråpevis og holdes 2 timer under tilbaké-løp. Like deretter inndampes oppløsningen under nedsatt trykk og residuet blandes med diisopropyleter. Det utfelte 2-nitro-4-fenylsulfonyloksy-butyranilid av smp. 5^°C frafiltreres, vaskes med diisopropyleter og hydreres tilsvarende Eksempel 4 til 2-amino-4-fenylsulfonyloksy-butyranilid, smp. 89°C.
E ksempel 7-1
37 g 2-amino-5-i-fenoksy5ulfonyl-aeetanilid oppvarmes
i 25O ml metanol med 25 g W,B'-bis-metoksykarbonyl-isotiourinstoff-S-metyleter og 0,01 g p-toluensulfonsyre i 5 timer under tilbakeløp. Deretter avdestilleres oppløsningsmidlet under nedsatt trykk, og residuet utrøres med eddikester. Det utkrystalliserte N-(2-acetaffiino«4~fenoksysulfonyl)-NT,N"-bis-metoksy-karbonyl-guanidin frafUtreres og vaskes med eddikester og metanol.
For fremstilling av 2-amino-5-fenoksysulfonyl-acetanilid hydreres 40 g 2-nitro-5~fenoksysulfonyl-acetanilid i 5°0 Ql metanol med.Raney-nikkel under normalt trykk. Man frafiltrerer katalysatoren og inndamper filtratet under.nedsatt trykk. Residuet kan uten videre rensing forarbeides videre som ovenfor.
For fremstilling av 2-nitro-5-£enoksysulfonyl-acet~anilid blandes 5$62-n.itro-5-f enoksysulf onyl -anilin i 25O ml acetanhydrid under omrøring med 1 ml konsentrert HgSO^, idet reaksjonsblandjngen oppvarmer seg. Man etterorarører enda 2 timer og inndamper deretter under nedsatt trykk. Til det faste residu har man diisopropyleter og frafiltrerte utkrystalliserte 2-nitro-5-fenoksysulfonyl-acetanilid...
For fremstilling av 2-nitro-5-fenoksjisulfonyl-anilin holdes 54 g 2-nitro~5-fénoksysulfonyl~klorbenzen i 500 ml dioksan i en autoklav med gassfornet ammoniakk ved 50°C og 5 atmosfærers overtrykk i 5 timer og derpå avdestilleres oppløsningsmidlet under nedsatt trykk. Residuet blandes med 200 ml av en blanding : av like deler metanol og vann. Etter kort tid utkrystalliserer 2-nitro-5-fenoksysulfonyl-anilin.
For fremstilling av 2-nitro-5-fenoksysulfonyl-klor-bensen blandes 51g 4-hitro-3-klor-benzensulfonsyréklorid i 120 ml aceton med 18,8 g fenol og under avkjøling ved en temperatur som ikke overstiger 10°C tildryppes 28 ml trietylamin. Etter flere timers etteromrøring ved værelsestemperatur blander man med vann, hvorpå det utskiller seg en olje som opparbeides over eter. Ut-byttet av 2-nitro-5-fenoksysulfonjilklorbenzen sr 54 g.
7- 2. Analogt vil man av 2-amino-5-fenoksysulfonyl~
acetanilid og
7-3 H »H'-bis-etoksykarbonyl-isotiourinstoff-S-metyleter få M-(2-acetataido-4-f enoksysulf onyl )-BP ,Nn-bie-etoksykarbonyl-guanidin
7*4 f^i<r->bisrpro<p>oksykarbc-n<y>l-isot iourinstof f-S-set yl-et er få
N- (2-acetaiaido-4- f enoksysulf onyl )-N' ,K"-bis-propoksy-karbonyl-guanidin
7*5 M,K'-bis-isopropoksykarbonyl-isotiourinstoff-S-metyleter få N-(2-aeetaraido-4- f enoksysulf onyl) -N *, fttf-bis-isoprbpok-sykarbonyl-guanidin
7«6 K ,ftP-bis-butQksykarbonyl-isotiouranstoff-S-metyleter få 1- (2-acetai»ldo-4- f enoks<y>sulf onyl)-<N>',<NM>-bis-but oks<y->
karbonyl-guan id in 7«7« N^P-bis-isobutoksykarbonyl-isotiourinstoff-S-metyleter få
ff-{2-a c et aaidp-4-f en oksyculf onyl)-NKtt-bis - isob&t oksykarbonyl-guanidin
7.8 N-Bietbksykarbonyl-K^propionyl-isotiourinstoff-Ji-metyleter få .
N-{ 2-acetamido-4-f enoksysulf onyl )'-H' -©etoksykarbonyl-R°-propiony1-guanidin
7*9N-etoksykarbonyl-IP<->bensoyl-isotiouri<n>stoff-S-raetyl-eter få N-(2-acetamido-4-fenoksysulfonyl)-N'-etoksykarbonyl-M<w>^bensoyl-guanidin .
7 *1Q TJ-taetoksykarbonyl-H' -cyklohexylkarbonyl-isotiourinstoff-S-metyleter.få
W-( 2-acetaraido-4-f enoksysulf onyl)~Hf-metoksykarbonyl-K<CT->cyklohexylkarbonyl-guanidin
7*11 M-metoksykarbonyl-W-etoksyaretylkarbonyl-isotiourinstoff-S-aretyleter få W-(2-acotamido-4-fenoksysulfonyl)-R'-raetoksykarbonyl-K"-etoksymetylkarbonyl-guanidin
Eksempel 8 . 1 .
27 g 2-amino-5-fQnoksysulfonyl-butyranilid omsettes analogt Eksempel 7 med 20 g N,ff'-bis-raetbksykarbonyl-isotiourin-stof f-S-metyleter og det fåes 9 g H-(2-butyraraido-4-fenoksysulfonyl)-N* ,W"-bis~raetoksykarbonyl-guanidin.
For fremstilling av 2-amino-5~fenoksysulfonyl-butyranilid blandes 29,6 g 2-nitro-5-fenoksysulfonyl-anilin i 300 ml toluen under omrøring ved 100°C med 14 ml butyrylklorid dråpevis, under tilbakeløpskoking holdes det i to timer. Derpå inndampes oppløsningen under nedsatt trykk og residuet blandes med diisopropyleter i Det utfelte 2-nitro-5-fenoksysulfonyl-butyranilid frafUtreres, vaskes med diisopropyleter og hydreres tilsvarende Eksempel 7 til 2-amino-5-fenoksysulfonyl-butyranilid.
Analogt fremstilles under anvendelse av tilsvarende modifiserte utgangsmaterialer av R-C0C1.
Eksempel 10. 1
34 g 2-amino-5-fenylsulfOnyloksy~acetanilid oppvarmes i 200 ml metanol med 40 g ft,N'-bis-metoksykarbonyl-isotiourinstoff-S-métyleter og 0,01 g p-toluensulfonsyre 5 timor under tilbakeløpskoking. Deretter avdestilleres oppløs-ningsmidlet under nedsatt trykk.og residuet utrøres med eddikester. Det utkrystalliserte M-(2-acetamid-4-fenylsulfonyloksy )- lV ,Mn-bis-metoksykarbonyl-guanidin f raf Utreres og vaskes med eddikester og metanol.
For fremstilling av 2-^amino-5-f enylsulf onyloksy-acetanilid hydreres 50 g 2-nitro-5-fenylsulfonyloksy-acetanilid i 250 ml metanol i nærvær av Raney-nikkel under normalt trykk ved vsrelsestemperatur. Man frafiltrerer oppløsningen fra katalysatoren, vasker den med dimetylformamid og inndamper filtratet under nedsatt trykk. Det gjenblivende 2-amino-4-fenylsulfonyloksy-acetanilid er rent nok for den videre forarbeidelse.
For fremstilling av 2-nitro-5-fenylsulfonyloksy-acetanilid blandes 48 g 2-nitro-5-fenylsulfonyloksy-anilin i 250 ml acetanhydrid under omrøring med 1 ml konsentrert HgSO^idet re<p>ksjonsblåndingen oppvarmer seg. Man etteromrører enda i to timer og inndamper deretter under nedsatt trykk. Det oljeaktige residu opparbeides oger eddikester og derved fåes et fast residu av 2-nitro-5-fenylsulfonyloksy-acetanilid. Til rensing oppløses det i 100 mi varm metanol og fortynnes med 100 ml, vann. Etter avkjøling frafiltreres det dannede 2-nitro-4-fenyløulfonyloksy-acetanilid og vaskes med vann.
For fremstilling av 2-nitro-5-fenylsulfonyloksy-• anilin blandes 15 > 4 g 4~nitro-3-amino-fenol i 100 ml aceton med 14 ml trietylamin og under omrøring tildryppes ved maksimalt 20°C i isbad en oppløsning av 17,6. g benzensulfonsyreklorid i
30 ml aceton. Etter tre timers etteromrøring frafiltrerer man
trietylaminhydroklorid og inndamper filtratet til tørrhet. Man utrører derpå med 5° m^ metanol og frafiltrerer det utfelt 2-nitro-5-fenylsulfonyloksy-anilin og vasker med metanol.
Analogt vil man av 2-amino-5*fenylsulfonyloksy- ,' acetanilid og
10.2 N,N<T->bis-etoksykarbonyl-isotiourinstoff-S-metyleter
få fJ-'(2-acetaiaido-4-f enylsulf onyloksy) -W ^"-bis-et oksyka rbonyl-guan id in
10.3 H,HV-bi3-propoksykarbonyl-isotiourinstoff-9-raetyl-eter få N-(2-acetamido-4-fenylsulfonyloksy)-N',N"-bis-pro-poksykarbonyl-guanidin 10.4 M>M'-bis-isopropoksykarbonyl-isotiourinstoff-S-raetyleter få K- (2-acetaiaido-4~f enylsulf onyloksy )-N' ,fJ"-bis-iso-propoksykarbonyl-guanidin 10.5 N,N'-bis-butoksykarbonyl-isotiourinstoff-S-metyleter få N- (2-acetataido-4- f enylsulf onyloksy) -K* ,fJ'r-bis-but oksykarbonyl -guanidin
10.6 K.M—bis-isobutoksykarbonyl-isotiourinstoff-S-metyleter få HT(2-acetamidor4-fenylsulfonyloksy)-N<f>fi"-bis-isobutoksykarbonyl-guanidin
10.7 N-metoksykarbonyl-K<1->propionyl-isotiourinstoff-S-taetyleter få H-( 2-acetamido-4- £ enylsulf onyloksy) -fl' -metoksykarbonyl-W"-propionyl-guanidin
10.8. N-etoksykarbonyl-K^bonzoyl-isotiourinstoff-S-metyleter få
N-(2-acetamido-4-fenylsulfonyloksy-)-K*-etoksykarbonyl-M"-benzoyl-guanidin
10.9 JT-metoks<y>karbon<y>l-f<T->cyklohexylkarbonyl-isotiourinstoff-S-metyleter få N-(2-acetaraido-4-fenylsulfonyloksy)-N*-metoksykarbonyl~N"-cyklohexylkarbonyl~guanidin
10.10 U-øietoksykarbonyl-N^etoksyiaétylkarbonyl-isotiourinstoff-S-metyleter få M-(2-acetamido-4-fenylsulfonyloksy-K'-metoksykarbonyl-H"-etoksymstylkarbonyl-guanidin
Eksempel 3. 1. 1
27. g 2-amino-5-fenylsulfonyloksy-butyranilid omsettes analogt Eksempel 10 med 20 g R,M'-bis-metoksykarbonyl-isotiourinstoff-S-metyleter og 9 g N-(2~butyramido-4-fenyl-sulf onyl oksy) -NR" -bis-met ok sjrkarbonyl -guanidin fåes.
For fremstilling av 2-araino-5~f<e>nylsulfonyloksy-butyranilid blandes 29,6 g 2-nitro-5-fenoksysulfonyl-anilin i 300 ml toluen under omrøring ved 100°C dråpevis med 14 ml butyrylklorid og holdes 2 timer under tilbakelØpskoking. Deretter inndanpes oppløsningsmidlet under nedsatt trykk og residuet blandes med diisopropyleter; • Det utfelte 2-nitro-4-fenylsulfonyloksy-butyranilid frafiltreres og vaskes, med diisopropyleter og hydreres tilsvarende Eksempel 10 til 2-amino-5-fenylsulfonyloksy-butyranilid.
Claims (1)
1. Substituerte fenyl guan idin er med den generelle formel
hvor
R og R 1er forskjellig fra hverandre og vékselsidig betyr hver
gang en av restene
hvor
R ^ betyr hydrogen
eventuelt substituert alkyl, eventuelt substituert cykloalkyl, eventuelt substituert aryl, eventuelt substituertamino, eventuelt substituert alkoksy eller eventuelt substituert aralkyl R-' bet3 T eventuelt substituert alkyl, eventuelt substituert alkenyl, eller eventuelt substituert alkinyl,R ^ betyr hydrogen
eventuelt substituert alkyl, eventuelt substituert cykloalkyl,
eventuelt substituert alkoksy, eventuelt substituert alkenyloksy, eventuelt substituert alkinyloksy, eventuelt substituert aryl, eventuelt substituert aralkyl, eventuelt substituert alkenyl eller
eventuelt substituert alkinyl.
og hvor R 2 og RJ "3 hver gang uavhengig av hverandre betyr hydrogen,
alkoksy med 1 til 4 C-atoraer, halogen, trifluormetyl, alkyl med 1 til 4-C-atomer eller CM og X betyr grupperingen -O-SOg- eller -SOg-O-,
2» Fremgangsmåte for fremstilling, av substituerte fenylguanidiner med formel
hvori R og R^" er forskjellig fra hverandre og vekselsidig betyr hver
gang en av restene
idet R •i og R C,og X haf ovenevnte betydning, karakterisert ved at substituerte anilinderivater mod formel
hvori R <2> . R^, R^ og X har ovennevnte betydning og hvori X kan være forknyttet med stilling 4 eller stilling 5 av den substituerte 1-amino-fsnylgruppe med formel (II) omsettes i nærvær av et fortynningsK iiddel og eventuelt i nærvær av en syre med isotiourinstoffer med formel
hvori
R-^ og R har ovennevnte betydning og
R^ betyr alkyl med 1-4 karbonatomer.
3. Legemiddel, karakterisert ved et innhold av minst et substituert fenylguanidin med formel I iflg. krav 1, i forbindelse med farmasøytisk vanlig bærer.
4. Fremgangsmåte til fremstilling av antelmintiske midler, karakterisert ved at man bringer et substituert fenylguanidin med formel I ifølge krav 1, i forbindelse med en inert, ikke-tokcisk, farmasøytisk egnet bærer.
5. Anvendelse av en forbindelse med formel I ifølge krav 1 til bekjempelse av helrainthiaser hos mennesker og dyr.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762608238 DE2608238A1 (de) | 1976-02-28 | 1976-02-28 | Substituierte phenylguanidine und verfahren zu ihrer herstellung |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO770649L true NO770649L (no) | 1977-08-30 |
Family
ID=5971154
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO770649A NO770649L (no) | 1976-02-28 | 1977-02-25 | Substituerte fenylguanidiner og fremgangsm}te til deres fremstilling. |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US4176192A (no) |
| JP (1) | JPS52105149A (no) |
| AT (1) | AT360037B (no) |
| AU (1) | AU512953B2 (no) |
| BE (1) | BE851920A (no) |
| CA (1) | CA1092141A (no) |
| DE (1) | DE2608238A1 (no) |
| DK (1) | DK84377A (no) |
| ES (1) | ES456144A1 (no) |
| FI (1) | FI770616A (no) |
| FR (1) | FR2342280A1 (no) |
| GB (1) | GB1570828A (no) |
| HU (1) | HU176254B (no) |
| IL (1) | IL51552A0 (no) |
| LU (1) | LU76855A1 (no) |
| NL (1) | NL7701933A (no) |
| NO (1) | NO770649L (no) |
| NZ (1) | NZ183436A (no) |
| PT (1) | PT66241B (no) |
| SE (1) | SE7702204L (no) |
| ZA (1) | ZA771131B (no) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2653766A1 (de) * | 1976-11-26 | 1978-06-01 | Bayer Ag | Substituierte benzolsulfonsaeureester, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
| DE2836385A1 (de) * | 1978-08-19 | 1980-03-06 | Hoechst Ag | Monocarboxylate von phenylguanidinsulfonsaeureestern, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
| US4217358A (en) | 1979-04-18 | 1980-08-12 | E. R. Squibb & Sons, Inc. | Substituted phenylguanidines and method |
| DE3232959A1 (de) * | 1982-09-04 | 1984-03-08 | Hoechst Ag, 6230 Frankfurt | Substituierte benzolsulfonsaeureester, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2993502A (en) | 1956-09-28 | 1961-07-25 | Gerardus Mathias Johannes Aken | High pressure stop valve |
| NL7104389A (no) | 1970-04-09 | 1971-10-12 | ||
| DE2304764A1 (de) | 1973-02-01 | 1974-08-08 | Bayer Ag | Benzoylphenylguanidine, ein verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
| DE2434183C2 (de) * | 1974-07-16 | 1982-07-01 | Bayer Ag, 5090 Leverkusen | Substituierte Phenylisothioharnstoffe, ein Verfahren zu ihrer Herstellung sowie ihre Verwendung als Arzneimittel |
| DE2441201C2 (de) * | 1974-08-28 | 1986-08-07 | Hoechst Ag, 6230 Frankfurt | Anthelminthisch wirksame 2-Carbalkoxyamino-5(6)-phenyl-sulfonyloxy-benzimidazole und Verfahren zu ihrer Herstellung |
| DE2441202C2 (de) * | 1974-08-28 | 1986-05-28 | Hoechst Ag, 6230 Frankfurt | 2-Carbalkoxyamino-benzimidazolyl-5(6)-sulfonsäure-phenylester, Verfahren zu ihrer Herstellung und diese enthaltende anthelmintische Mittel |
-
1976
- 1976-02-28 DE DE19762608238 patent/DE2608238A1/de not_active Withdrawn
-
1977
- 1977-02-22 ES ES456144A patent/ES456144A1/es not_active Expired
- 1977-02-23 NL NL7701933A patent/NL7701933A/xx not_active Application Discontinuation
- 1977-02-24 CA CA272,554A patent/CA1092141A/en not_active Expired
- 1977-02-25 NO NO770649A patent/NO770649L/no unknown
- 1977-02-25 AT AT128877A patent/AT360037B/de not_active IP Right Cessation
- 1977-02-25 NZ NZ183436A patent/NZ183436A/xx unknown
- 1977-02-25 AU AU22687/77A patent/AU512953B2/en not_active Expired
- 1977-02-25 US US05/772,234 patent/US4176192A/en not_active Expired - Lifetime
- 1977-02-25 FI FI770616A patent/FI770616A/fi not_active Application Discontinuation
- 1977-02-25 PT PT66241A patent/PT66241B/pt unknown
- 1977-02-25 HU HU77HO1962A patent/HU176254B/hu unknown
- 1977-02-25 DK DK84377A patent/DK84377A/da unknown
- 1977-02-25 ZA ZA00771131A patent/ZA771131B/xx unknown
- 1977-02-25 LU LU76855A patent/LU76855A1/xx unknown
- 1977-02-25 IL IL51552A patent/IL51552A0/xx unknown
- 1977-02-28 SE SE7702204A patent/SE7702204L/xx unknown
- 1977-02-28 FR FR7705825A patent/FR2342280A1/fr active Granted
- 1977-02-28 GB GB8393/77A patent/GB1570828A/en not_active Expired
- 1977-02-28 JP JP2210277A patent/JPS52105149A/ja active Pending
- 1977-02-28 BE BE175343A patent/BE851920A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU512953B2 (en) | 1980-11-06 |
| US4176192A (en) | 1979-11-27 |
| PT66241B (de) | 1978-10-13 |
| ATA128877A (de) | 1980-05-15 |
| GB1570828A (en) | 1980-07-09 |
| FR2342280A1 (fr) | 1977-09-23 |
| FR2342280B1 (no) | 1980-02-01 |
| AU2268777A (en) | 1978-08-31 |
| LU76855A1 (no) | 1977-09-12 |
| JPS52105149A (en) | 1977-09-03 |
| PT66241A (de) | 1977-03-01 |
| HU176254B (en) | 1981-01-28 |
| SE7702204L (sv) | 1977-08-29 |
| ES456144A1 (es) | 1978-05-16 |
| ZA771131B (en) | 1978-01-25 |
| NL7701933A (nl) | 1977-08-30 |
| CA1092141A (en) | 1980-12-23 |
| NZ183436A (en) | 1979-07-11 |
| FI770616A (no) | 1977-08-29 |
| IL51552A0 (en) | 1977-04-29 |
| DK84377A (da) | 1977-08-29 |
| DE2608238A1 (de) | 1977-09-08 |
| BE851920A (fr) | 1977-08-29 |
| AT360037B (de) | 1980-12-10 |
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