DD248056A5 - MEDICINES AND ITS USE - Google Patents
MEDICINES AND ITS USE Download PDFInfo
- Publication number
- DD248056A5 DD248056A5 DD86292009A DD29200986A DD248056A5 DD 248056 A5 DD248056 A5 DD 248056A5 DD 86292009 A DD86292009 A DD 86292009A DD 29200986 A DD29200986 A DD 29200986A DD 248056 A5 DD248056 A5 DD 248056A5
- Authority
- DD
- German Democratic Republic
- Prior art keywords
- chloro
- amino
- benzoic acid
- compound
- formula
- Prior art date
Links
- 239000003814 drug Substances 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 21
- 239000001257 hydrogen Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 18
- 150000002367 halogens Chemical group 0.000 claims abstract description 16
- -1 CF 3 Inorganic materials 0.000 claims abstract description 15
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 13
- 125000005843 halogen group Chemical group 0.000 claims abstract description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 6
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical class [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 5
- 239000000460 chlorine Substances 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- 239000005711 Benzoic acid Substances 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- OQWDZCCPSBDNLQ-UHFFFAOYSA-N 5-chloro-2-[(3,4-dichlorophenyl)sulfonylamino]benzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1NS(=O)(=O)C1=CC=C(Cl)C(Cl)=C1 OQWDZCCPSBDNLQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- HKGMXNOAQXUHDQ-UHFFFAOYSA-N 5-chloro-2-[(4-chlorophenyl)sulfonylamino]-N-(4-fluorophenyl)benzamide Chemical compound C1=CC(F)=CC=C1NC(=O)C1=CC(Cl)=CC=C1NS(=O)(=O)C1=CC=C(Cl)C=C1 HKGMXNOAQXUHDQ-UHFFFAOYSA-N 0.000 claims description 2
- QDLNCDXRGPFFTQ-UHFFFAOYSA-N 5-chloro-2-[(4-chlorophenyl)sulfonylamino]-n-(3,4-dichlorophenyl)benzamide Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)NC1=CC=C(Cl)C=C1C(=O)NC1=CC=C(Cl)C(Cl)=C1 QDLNCDXRGPFFTQ-UHFFFAOYSA-N 0.000 claims description 2
- WMIMTWDRYBWISW-UHFFFAOYSA-N C1=CC(=CC=C1S(=O)(=O)NC2=C(C=C(C=C2)Cl)C(=O)NC3=C(C=C(C=C3)Cl)Cl)Cl Chemical compound C1=CC(=CC=C1S(=O)(=O)NC2=C(C=C(C=C2)Cl)C(=O)NC3=C(C=C(C=C3)Cl)Cl)Cl WMIMTWDRYBWISW-UHFFFAOYSA-N 0.000 claims description 2
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 2
- ZDAVRJFJUFFQIX-UHFFFAOYSA-N n-(4-bromophenyl)-5-chloro-2-[(4-chlorophenyl)sulfonylamino]benzamide Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)NC1=CC=C(Cl)C=C1C(=O)NC1=CC=C(Br)C=C1 ZDAVRJFJUFFQIX-UHFFFAOYSA-N 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 claims description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 2
- NHYURXHIYONRCY-UHFFFAOYSA-N 5-chloro-2-[(4-chlorophenyl)sulfonylamino]benzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1NS(=O)(=O)C1=CC=C(Cl)C=C1 NHYURXHIYONRCY-UHFFFAOYSA-N 0.000 claims 1
- 239000002552 dosage form Substances 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 13
- 244000000013 helminth Species 0.000 abstract description 10
- 238000002360 preparation method Methods 0.000 abstract description 10
- 238000001228 spectrum Methods 0.000 abstract description 2
- 231100001274 therapeutic index Toxicity 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical class NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 12
- 241000242711 Fasciola hepatica Species 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- 241001494479 Pecora Species 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 208000006275 fascioliasis Diseases 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000000973 chemotherapeutic effect Effects 0.000 description 6
- 244000045947 parasite Species 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 5
- 229960004050 aminobenzoic acid Drugs 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 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 4
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 4
- 235000013601 eggs Nutrition 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 230000000507 anthelmentic effect Effects 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 210000000232 gallbladder Anatomy 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 229920000728 polyester Polymers 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- CUKXRHLWPSBCTI-UHFFFAOYSA-N 2-amino-5-bromobenzoic acid Chemical compound NC1=CC=C(Br)C=C1C(O)=O CUKXRHLWPSBCTI-UHFFFAOYSA-N 0.000 description 2
- VIUDTWATMPPKEL-UHFFFAOYSA-N 3-(trifluoromethyl)aniline Chemical compound NC1=CC=CC(C(F)(F)F)=C1 VIUDTWATMPPKEL-UHFFFAOYSA-N 0.000 description 2
- XUJFOSLZQITUOI-UHFFFAOYSA-N 4-(trifluoromethoxy)aniline Chemical compound NC1=CC=C(OC(F)(F)F)C=C1 XUJFOSLZQITUOI-UHFFFAOYSA-N 0.000 description 2
- KLWDPIXDUVYHMS-UHFFFAOYSA-N 4-chloro-n-ethylaniline Chemical compound CCNC1=CC=C(Cl)C=C1 KLWDPIXDUVYHMS-UHFFFAOYSA-N 0.000 description 2
- ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 4-chlorobenzenesulfonyl chloride Chemical compound ClC1=CC=C(S(Cl)(=O)=O)C=C1 ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 0.000 description 2
- DUIABMMUEIBHGY-UHFFFAOYSA-N 5-chloro-2-[(4-chlorophenyl)sulfonylamino]-N-dodecylbenzamide Chemical compound C(CCCCCCCCCCC)NC(C1=C(C=CC(=C1)Cl)NS(=O)(=O)C1=CC=C(C=C1)Cl)=O DUIABMMUEIBHGY-UHFFFAOYSA-N 0.000 description 2
- SXAQGOKZXZMPPJ-UHFFFAOYSA-N 5-chloro-n-(4-chlorophenyl)-2-[(3,4-dichlorophenyl)sulfonylamino]benzamide Chemical compound C1=CC(Cl)=CC=C1NC(=O)C1=CC(Cl)=CC=C1NS(=O)(=O)C1=CC=C(Cl)C(Cl)=C1 SXAQGOKZXZMPPJ-UHFFFAOYSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 206010061217 Infestation Diseases 0.000 description 2
- 241000244206 Nematoda Species 0.000 description 2
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 241000242541 Trematoda Species 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- ILRSCQWREDREME-UHFFFAOYSA-N dodecanamide Chemical compound CCCCCCCCCCCC(N)=O ILRSCQWREDREME-UHFFFAOYSA-N 0.000 description 2
- JRBPAEWTRLWTQC-UHFFFAOYSA-N dodecylamine Chemical compound CCCCCCCCCCCCN JRBPAEWTRLWTQC-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- 210000003608 fece Anatomy 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 208000015181 infectious disease Diseases 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
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- GBDASNVDZSNODC-UHFFFAOYSA-N n-phenyl-2-(sulfonylamino)benzamide Chemical class C=1C=CC=C(N=S(=O)=O)C=1C(=O)NC1=CC=CC=C1 GBDASNVDZSNODC-UHFFFAOYSA-N 0.000 description 2
- 229920000620 organic polymer Polymers 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- NEMNPWINWMHUMR-UHFFFAOYSA-N rafoxanide Chemical compound OC1=C(I)C=C(I)C=C1C(=O)NC(C=C1Cl)=CC=C1OC1=CC=C(Cl)C=C1 NEMNPWINWMHUMR-UHFFFAOYSA-N 0.000 description 2
- 229950002980 rafoxanide Drugs 0.000 description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical class OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- GUMCAKKKNKYFEB-UHFFFAOYSA-N 2,4,5-trichloroaniline Chemical compound NC1=CC(Cl)=C(Cl)C=C1Cl GUMCAKKKNKYFEB-UHFFFAOYSA-N 0.000 description 1
- LEDKKDPOPIKMSZ-UHFFFAOYSA-N 2,4,5-trichlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC(Cl)=C(Cl)C=C1Cl LEDKKDPOPIKMSZ-UHFFFAOYSA-N 0.000 description 1
- XPCHQESFRULWBG-UHFFFAOYSA-N 2,4-dichloro-n-ethylaniline Chemical compound CCNC1=CC=C(Cl)C=C1Cl XPCHQESFRULWBG-UHFFFAOYSA-N 0.000 description 1
- KQCMTOWTPBNWDB-UHFFFAOYSA-N 2,4-dichloroaniline Chemical compound NC1=CC=C(Cl)C=C1Cl KQCMTOWTPBNWDB-UHFFFAOYSA-N 0.000 description 1
- XCLCLCNSGDHVFE-UHFFFAOYSA-N 2,4-dichlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1Cl XCLCLCNSGDHVFE-UHFFFAOYSA-N 0.000 description 1
- LFXZSGVZSSMCMB-UHFFFAOYSA-N 2,5-dichlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC(Cl)=CC=C1Cl LFXZSGVZSSMCMB-UHFFFAOYSA-N 0.000 description 1
- NNJBQTDFDVLWEQ-UHFFFAOYSA-N 2-(sulfonylamino)benzoic acid Chemical class OC(=O)C1=CC=CC=C1N=S(=O)=O NNJBQTDFDVLWEQ-UHFFFAOYSA-N 0.000 description 1
- PYMUBSQISKHDBE-UHFFFAOYSA-N 2-[(3,4-dichlorophenyl)sulfonylamino]-N-dodecyl-5-fluorobenzamide Chemical compound C(CCCCCCCCCCC)NC(C1=C(C=CC(=C1)F)NS(=O)(=O)C1=CC(=C(C=C1)Cl)Cl)=O PYMUBSQISKHDBE-UHFFFAOYSA-N 0.000 description 1
- WNABMWFLKQEGCP-UHFFFAOYSA-N 2-amino-3,5-dibromobenzoic acid Chemical compound NC1=C(Br)C=C(Br)C=C1C(O)=O WNABMWFLKQEGCP-UHFFFAOYSA-N 0.000 description 1
- KTHTXLUIEAIGCD-UHFFFAOYSA-N 2-amino-3,5-dichlorobenzoic acid Chemical compound NC1=C(Cl)C=C(Cl)C=C1C(O)=O KTHTXLUIEAIGCD-UHFFFAOYSA-N 0.000 description 1
- PWXLBVZWVKCFHR-UHFFFAOYSA-N 2-amino-3-bromo-5-chlorobenzoic acid Chemical compound NC1=C(Br)C=C(Cl)C=C1C(O)=O PWXLBVZWVKCFHR-UHFFFAOYSA-N 0.000 description 1
- MQWFRBVVABTUKS-UHFFFAOYSA-N 2-amino-4,5-dichlorobenzoic acid Chemical compound NC1=CC(Cl)=C(Cl)C=C1C(O)=O MQWFRBVVABTUKS-UHFFFAOYSA-N 0.000 description 1
- SPLPEXZBYCUXLL-UHFFFAOYSA-N 2-amino-4-chloro-5-methylbenzenecarbothioic S-acid Chemical compound NC1=C(C(=S)O)C=C(C(=C1)Cl)C SPLPEXZBYCUXLL-UHFFFAOYSA-N 0.000 description 1
- WYPQWEYJRBPSKL-UHFFFAOYSA-N 2-amino-5-bromo-3-chlorobenzoic acid Chemical compound NC1=C(Cl)C=C(Br)C=C1C(O)=O WYPQWEYJRBPSKL-UHFFFAOYSA-N 0.000 description 1
- TUDNMLBIHIWVJM-UHFFFAOYSA-N 2-amino-5-bromo-4-chlorobenzoic acid Chemical compound NC1=CC(Cl)=C(Br)C=C1C(O)=O TUDNMLBIHIWVJM-UHFFFAOYSA-N 0.000 description 1
- IFXKXCLVKQVVDI-UHFFFAOYSA-N 2-amino-5-chlorobenzoic acid Chemical compound NC1=CC=C(Cl)C=C1C(O)=O IFXKXCLVKQVVDI-UHFFFAOYSA-N 0.000 description 1
- RNPCYAANUCXYCW-UHFFFAOYSA-N 2-amino-5-ethylbenzenecarbothioic s-acid Chemical compound CCC1=CC=C(N)C(C(S)=O)=C1 RNPCYAANUCXYCW-UHFFFAOYSA-N 0.000 description 1
- BAAKKUXKPWHNID-UHFFFAOYSA-N 2-amino-5-ethylsulfonylbenzoic acid Chemical compound C(C)S(=O)(=O)C1=CC=C(C(C(=O)O)=C1)N BAAKKUXKPWHNID-UHFFFAOYSA-N 0.000 description 1
- YLMFXCIATJJKQL-UHFFFAOYSA-N 2-bromo-4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1Br YLMFXCIATJJKQL-UHFFFAOYSA-N 0.000 description 1
- XRAKCYJTJGTSMM-UHFFFAOYSA-N 2-chloro-4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1Cl XRAKCYJTJGTSMM-UHFFFAOYSA-N 0.000 description 1
- NIWKKBFUCZGFMT-UHFFFAOYSA-N 2-chloro-5-[(4-chlorophenyl)sulfonylamino]-N-(4-fluorophenyl)benzamide Chemical compound Fc1ccc(NC(=O)c2cc(NS(=O)(=O)c3ccc(Cl)cc3)ccc2Cl)cc1 NIWKKBFUCZGFMT-UHFFFAOYSA-N 0.000 description 1
- MNURPFVONZPVLA-UHFFFAOYSA-N 2-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1Cl MNURPFVONZPVLA-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 150000005341 2-nitrobenzoic acids Chemical class 0.000 description 1
- DUSNCFKVMGTTFK-UHFFFAOYSA-N 3,4-dichloro-n-methylaniline Chemical compound CNC1=CC=C(Cl)C(Cl)=C1 DUSNCFKVMGTTFK-UHFFFAOYSA-N 0.000 description 1
- SDYWXFYBZPNOFX-UHFFFAOYSA-N 3,4-dichloroaniline Chemical compound NC1=CC=C(Cl)C(Cl)=C1 SDYWXFYBZPNOFX-UHFFFAOYSA-N 0.000 description 1
- WIWQDBABYGRKEW-UHFFFAOYSA-N 3,4-dichlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C(Cl)=C1 WIWQDBABYGRKEW-UHFFFAOYSA-N 0.000 description 1
- NYIBPWGZGSXURD-UHFFFAOYSA-N 3,4-dichlorobenzenesulfonyl chloride Chemical compound ClC1=CC=C(S(Cl)(=O)=O)C=C1Cl NYIBPWGZGSXURD-UHFFFAOYSA-N 0.000 description 1
- PMCTVEUSFRTCQX-UHFFFAOYSA-N 3,5-dichloro-2-[(4-chlorophenyl)sulfonylamino]-N-dodecylbenzamide Chemical compound C(CCCCCCCCCCC)NC(C1=C(C(=CC(=C1)Cl)Cl)NS(=O)(=O)C1=CC=C(C=C1)Cl)=O PMCTVEUSFRTCQX-UHFFFAOYSA-N 0.000 description 1
- UPMIEBBZKWZYEZ-UHFFFAOYSA-N 3-chloro-4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1Cl UPMIEBBZKWZYEZ-UHFFFAOYSA-N 0.000 description 1
- 150000005416 4-aminobenzoic acids Chemical class 0.000 description 1
- INMZDDDQLHKGPF-UHFFFAOYSA-N 4-bromo-2-chloroaniline Chemical compound NC1=CC=C(Br)C=C1Cl INMZDDDQLHKGPF-UHFFFAOYSA-N 0.000 description 1
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 1
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 0.000 description 1
- HKCFHDMLRDLQSN-UHFFFAOYSA-N 4-chloro-3-methylbenzenesulfonic acid Chemical compound CC1=CC(S(O)(=O)=O)=CC=C1Cl HKCFHDMLRDLQSN-UHFFFAOYSA-N 0.000 description 1
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- WVSYONICNIDYBE-UHFFFAOYSA-N 4-fluorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(F)C=C1 WVSYONICNIDYBE-UHFFFAOYSA-N 0.000 description 1
- VLVCDUSVTXIWGW-UHFFFAOYSA-N 4-iodoaniline Chemical compound NC1=CC=C(I)C=C1 VLVCDUSVTXIWGW-UHFFFAOYSA-N 0.000 description 1
- ODGIMMLDVSWADK-UHFFFAOYSA-N 4-trifluoromethylaniline Chemical compound NC1=CC=C(C(F)(F)F)C=C1 ODGIMMLDVSWADK-UHFFFAOYSA-N 0.000 description 1
- BLSQHCZLHPYFFO-UHFFFAOYSA-N 5-bromo-2-[(4-chlorophenyl)sulfonylamino]-n-[3-(trifluoromethyl)phenyl]benzamide Chemical compound FC(F)(F)C1=CC=CC(NC(=O)C=2C(=CC=C(Br)C=2)NS(=O)(=O)C=2C=CC(Cl)=CC=2)=C1 BLSQHCZLHPYFFO-UHFFFAOYSA-N 0.000 description 1
- MNPOXVZMRSDIJD-UHFFFAOYSA-N 5-bromo-n-(4-chlorophenyl)-2-[(4-chlorophenyl)sulfonylamino]benzamide Chemical compound C1=CC(Cl)=CC=C1NC(=O)C1=CC(Br)=CC=C1NS(=O)(=O)C1=CC=C(Cl)C=C1 MNPOXVZMRSDIJD-UHFFFAOYSA-N 0.000 description 1
- YMCIVAPEOZDEGH-UHFFFAOYSA-N 5-chloro-2,3-dihydro-1h-indole Chemical compound ClC1=CC=C2NCCC2=C1 YMCIVAPEOZDEGH-UHFFFAOYSA-N 0.000 description 1
- DSSAJVLTBRCVQP-UHFFFAOYSA-N 5-chloro-2-(ethylamino)benzoic acid Chemical compound CCNC1=CC=C(Cl)C=C1C(O)=O DSSAJVLTBRCVQP-UHFFFAOYSA-N 0.000 description 1
- LGSLJYKPSNTHRS-UHFFFAOYSA-N 5-chloro-2-[(3,4-dichlorophenyl)sulfonylamino]-N-dodecyl-N-methylbenzamide Chemical compound CN(C(C1=C(C=CC(=C1)Cl)NS(=O)(=O)C1=CC(=C(C=C1)Cl)Cl)=O)CCCCCCCCCCCC LGSLJYKPSNTHRS-UHFFFAOYSA-N 0.000 description 1
- ONZFSRODGZDADL-UHFFFAOYSA-N 5-chloro-2-[(4-chlorophenyl)sulfonylamino]-N-octadecylbenzamide Chemical compound C(CCCCCCCCCCCCCCCCC)NC(C1=C(C=CC(=C1)Cl)NS(=O)(=O)C1=CC=C(C=C1)Cl)=O ONZFSRODGZDADL-UHFFFAOYSA-N 0.000 description 1
- WJISECLQUDQXEB-UHFFFAOYSA-N 5-chloro-2-[(4-chlorophenyl)sulfonylamino]-n-[3-(trifluoromethyl)phenyl]benzamide Chemical compound FC(F)(F)C1=CC=CC(NC(=O)C=2C(=CC=C(Cl)C=2)NS(=O)(=O)C=2C=CC(Cl)=CC=2)=C1 WJISECLQUDQXEB-UHFFFAOYSA-N 0.000 description 1
- ZYUYCUXFKGUOSP-UHFFFAOYSA-N 5-chloro-2-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(Cl)C=C1C(Cl)=O ZYUYCUXFKGUOSP-UHFFFAOYSA-N 0.000 description 1
- RSYOZOBYFLADPX-UHFFFAOYSA-N 5-chloro-N-cyclododecyl-2-[(3,4-dichlorophenyl)sulfonylamino]benzamide Chemical compound C1(CCCCCCCCCCC1)NC(C1=C(C=CC(=C1)Cl)NS(=O)(=O)C1=CC(=C(C=C1)Cl)Cl)=O RSYOZOBYFLADPX-UHFFFAOYSA-N 0.000 description 1
- FXQDQTQDBSVZDO-UHFFFAOYSA-N 5-chloro-n-(3,5-dichlorophenyl)-2-[(4-fluorophenyl)sulfonylamino]benzamide Chemical compound C1=CC(F)=CC=C1S(=O)(=O)NC1=CC=C(Cl)C=C1C(=O)NC1=CC(Cl)=CC(Cl)=C1 FXQDQTQDBSVZDO-UHFFFAOYSA-N 0.000 description 1
- HGFHUHMLZIJOAS-UHFFFAOYSA-N 5-chloro-n-(4-chlorophenyl)-2-[(4-chlorophenyl)sulfonylamino]benzamide Chemical compound C1=CC(Cl)=CC=C1NC(=O)C1=CC(Cl)=CC=C1NS(=O)(=O)C1=CC=C(Cl)C=C1 HGFHUHMLZIJOAS-UHFFFAOYSA-N 0.000 description 1
- FPQMGQZTBWIHDN-UHFFFAOYSA-N 5-fluoroanthranilic acid Chemical compound NC1=CC=C(F)C=C1C(O)=O FPQMGQZTBWIHDN-UHFFFAOYSA-N 0.000 description 1
- RUCHWTKMOWXHLU-UHFFFAOYSA-N 5-nitroanthranilic acid Chemical compound NC1=CC=C([N+]([O-])=O)C=C1C(O)=O RUCHWTKMOWXHLU-UHFFFAOYSA-N 0.000 description 1
- SRTBBLNAKMLZTN-UHFFFAOYSA-N 6-amino-2,3-dichlorobenzoic acid Chemical compound NC1=CC=C(Cl)C(Cl)=C1C(O)=O SRTBBLNAKMLZTN-UHFFFAOYSA-N 0.000 description 1
- PASUADIMFGAUDB-UHFFFAOYSA-N 6-chloro-1,2,3,4-tetrahydroquinoline Chemical compound N1CCCC2=CC(Cl)=CC=C21 PASUADIMFGAUDB-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-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
- 235000009051 Ambrosia paniculata var. peruviana Nutrition 0.000 description 1
- 235000003097 Artemisia absinthium Nutrition 0.000 description 1
- 240000001851 Artemisia dracunculus Species 0.000 description 1
- 235000017731 Artemisia dracunculus ssp. dracunculus Nutrition 0.000 description 1
- 235000003261 Artemisia vulgaris Nutrition 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- AKVPOSMYTMWRLS-UHFFFAOYSA-N C1=CC(=CC=C1Cl)S(=O)(=O)NC1=C(C=C(Br)C=C1)C(=O)NC1=C(Cl)C=C(Cl)C=C1 Chemical compound C1=CC(=CC=C1Cl)S(=O)(=O)NC1=C(C=C(Br)C=C1)C(=O)NC1=C(Cl)C=C(Cl)C=C1 AKVPOSMYTMWRLS-UHFFFAOYSA-N 0.000 description 1
- RLRYGYVBLLACOL-UHFFFAOYSA-N C1=CC(=CC=C1NC(=O)C2=C(C(=CC(=C2)Cl)Cl)NS(=O)(=O)C3=CC(=C(C=C3)Cl)Cl)Cl Chemical compound C1=CC(=CC=C1NC(=O)C2=C(C(=CC(=C2)Cl)Cl)NS(=O)(=O)C3=CC(=C(C=C3)Cl)Cl)Cl RLRYGYVBLLACOL-UHFFFAOYSA-N 0.000 description 1
- UFSKSQKCZDGPGN-UHFFFAOYSA-N C1=CC(=CC=C1NC(=O)C2=C(C(=CC(=C2)Cl)Cl)NS(=O)(=O)C3=CC(=C(C=C3)Cl)Cl)OC(F)(F)F Chemical compound C1=CC(=CC=C1NC(=O)C2=C(C(=CC(=C2)Cl)Cl)NS(=O)(=O)C3=CC(=C(C=C3)Cl)Cl)OC(F)(F)F UFSKSQKCZDGPGN-UHFFFAOYSA-N 0.000 description 1
- YVDOOSYUEALOHG-UHFFFAOYSA-N C1=CC(=CC=C1NC(=O)C2=C(C(=CC(=C2)Cl)Cl)NS(=O)(=O)C3=CC=C(C=C3)Cl)Cl Chemical compound C1=CC(=CC=C1NC(=O)C2=C(C(=CC(=C2)Cl)Cl)NS(=O)(=O)C3=CC=C(C=C3)Cl)Cl YVDOOSYUEALOHG-UHFFFAOYSA-N 0.000 description 1
- AVEQYIIEPPTALM-UHFFFAOYSA-N C1=CC(=CC=C1NC(=O)C2=C(C(=CC(=C2)Cl)Cl)NS(=O)(=O)C3=CC=C(C=C3)Cl)F Chemical compound C1=CC(=CC=C1NC(=O)C2=C(C(=CC(=C2)Cl)Cl)NS(=O)(=O)C3=CC=C(C=C3)Cl)F AVEQYIIEPPTALM-UHFFFAOYSA-N 0.000 description 1
- XAYDKHOISHYSJO-UHFFFAOYSA-N C1=CC(=CC=C1NC(=O)C2=C(C=C(C=C2)Br)NS(=O)(=O)C3=CC=C(C=C3)Cl)Cl Chemical compound C1=CC(=CC=C1NC(=O)C2=C(C=C(C=C2)Br)NS(=O)(=O)C3=CC=C(C=C3)Cl)Cl XAYDKHOISHYSJO-UHFFFAOYSA-N 0.000 description 1
- BKJLTZPYUQKACT-UHFFFAOYSA-N C1=CC(=CC=C1NC(=O)C2=C(C=C(C=C2)Cl)NS(=O)(=O)C3=CC=C(C=C3)Cl)Cl Chemical compound C1=CC(=CC=C1NC(=O)C2=C(C=C(C=C2)Cl)NS(=O)(=O)C3=CC=C(C=C3)Cl)Cl BKJLTZPYUQKACT-UHFFFAOYSA-N 0.000 description 1
- MDMSMAVQJUZLSY-UHFFFAOYSA-N C1=CC(=CC=C1NC(=O)C2=C(C=CC(=C2)Cl)NS(=O)(=O)C3=C(C=C(C=C3)Cl)Cl)Cl Chemical compound C1=CC(=CC=C1NC(=O)C2=C(C=CC(=C2)Cl)NS(=O)(=O)C3=C(C=C(C=C3)Cl)Cl)Cl MDMSMAVQJUZLSY-UHFFFAOYSA-N 0.000 description 1
- DZOAHWSNYQYKAE-UHFFFAOYSA-N C1=CC(=CC=C1NC(=O)C2=C(C=CC(=C2)Cl)NS(=O)(=O)C3=CC(=C(C=C3)Cl)Cl)OC(F)(F)F Chemical compound C1=CC(=CC=C1NC(=O)C2=C(C=CC(=C2)Cl)NS(=O)(=O)C3=CC(=C(C=C3)Cl)Cl)OC(F)(F)F DZOAHWSNYQYKAE-UHFFFAOYSA-N 0.000 description 1
- JODQQBGLOIKOPI-UHFFFAOYSA-N C1=CC(=CC=C1NC(=O)C2=C(C=CC(=C2)Cl)NS(=O)(=O)C3=CC=C(C=C3)Br)Cl Chemical compound C1=CC(=CC=C1NC(=O)C2=C(C=CC(=C2)Cl)NS(=O)(=O)C3=CC=C(C=C3)Br)Cl JODQQBGLOIKOPI-UHFFFAOYSA-N 0.000 description 1
- GRHIEOKXDZXYBL-UHFFFAOYSA-N C1=CC(=CC=C1NC(=O)C2=C(C=CC(=C2)Cl)NS(=O)(=O)C3=CC=C(C=C3)F)Cl Chemical compound C1=CC(=CC=C1NC(=O)C2=C(C=CC(=C2)Cl)NS(=O)(=O)C3=CC=C(C=C3)F)Cl GRHIEOKXDZXYBL-UHFFFAOYSA-N 0.000 description 1
- OOKWRHUHJPLYTD-UHFFFAOYSA-N C1=CC(=CC=C1NC(=O)C2=C(C=CC(=C2)F)NS(=O)(=O)C3=CC(=C(C=C3)Cl)Cl)F Chemical compound C1=CC(=CC=C1NC(=O)C2=C(C=CC(=C2)F)NS(=O)(=O)C3=CC(=C(C=C3)Cl)Cl)F OOKWRHUHJPLYTD-UHFFFAOYSA-N 0.000 description 1
- ZRIUZWHHEZBGFU-UHFFFAOYSA-N C1=CC(=CC=C1NC(=O)C2=C(C=CC(=C2)[N+](=O)[O-])NS(=O)(=O)C3=CC(=C(C=C3)Cl)Cl)Cl Chemical compound C1=CC(=CC=C1NC(=O)C2=C(C=CC(=C2)[N+](=O)[O-])NS(=O)(=O)C3=CC(=C(C=C3)Cl)Cl)Cl ZRIUZWHHEZBGFU-UHFFFAOYSA-N 0.000 description 1
- URXHBJLPBDRVCC-UHFFFAOYSA-N C1=CC(=CC=C1NC(=O)C2=CC(=C(C=C2)Cl)NS(=O)(=O)C3=CC=C(C=C3)Cl)Cl Chemical compound C1=CC(=CC=C1NC(=O)C2=CC(=C(C=C2)Cl)NS(=O)(=O)C3=CC=C(C=C3)Cl)Cl URXHBJLPBDRVCC-UHFFFAOYSA-N 0.000 description 1
- JFTCNYYODCCDJZ-UHFFFAOYSA-N C1=CC(=CC=C1NC(=O)C2=CC(=C(C=C2NS(=O)(=O)C3=CC=C(C=C3)Cl)Cl)Cl)Cl Chemical compound C1=CC(=CC=C1NC(=O)C2=CC(=C(C=C2NS(=O)(=O)C3=CC=C(C=C3)Cl)Cl)Cl)Cl JFTCNYYODCCDJZ-UHFFFAOYSA-N 0.000 description 1
- QHGAWHJBLKUAJI-UHFFFAOYSA-N C1=CC(C(C=C1)(NS(=O)(=O)C2=CC=C(C=C2)F)Cl)C(=O)NC3=CC=C(C=C3)F Chemical compound C1=CC(C(C=C1)(NS(=O)(=O)C2=CC=C(C=C2)F)Cl)C(=O)NC3=CC=C(C=C3)F QHGAWHJBLKUAJI-UHFFFAOYSA-N 0.000 description 1
- UJVWIRCPWAIDKM-UHFFFAOYSA-N CCC1=CC(=C(C=C1)NS(=O)(=O)C2=CC(=C(C=C2)Cl)Cl)C(=S)NC3=CC=C(C=C3)Cl Chemical compound CCC1=CC(=C(C=C1)NS(=O)(=O)C2=CC(=C(C=C2)Cl)Cl)C(=S)NC3=CC=C(C=C3)Cl UJVWIRCPWAIDKM-UHFFFAOYSA-N 0.000 description 1
- STPWFXLFBHTEEC-UHFFFAOYSA-N CCCCCCCCCCCCNC(=O)C1=C(C=CC(=C1)Cl)NS(=O)(=O)C2=CC(=C(C=C2)Cl)Cl Chemical compound CCCCCCCCCCCCNC(=O)C1=C(C=CC(=C1)Cl)NS(=O)(=O)C2=CC(=C(C=C2)Cl)Cl STPWFXLFBHTEEC-UHFFFAOYSA-N 0.000 description 1
- QEHJXGKTYJAUIV-UHFFFAOYSA-N CCN(C(C(C=C(C=C1)F)=C1NS(C(C=C1)=CC(Cl)=C1Cl)(=O)=O)=O)C(C=C1)=CC=C1Cl Chemical compound CCN(C(C(C=C(C=C1)F)=C1NS(C(C=C1)=CC(Cl)=C1Cl)(=O)=O)=O)C(C=C1)=CC=C1Cl QEHJXGKTYJAUIV-UHFFFAOYSA-N 0.000 description 1
- CQJLCQAIZWUBIV-UHFFFAOYSA-N CCN(C(C(C=C(C=C1Cl)Cl)=C1NS(C(C=C1)=CC(Cl)=C1Cl)(=O)=O)=O)C(C=C1)=CC=C1Cl Chemical compound CCN(C(C(C=C(C=C1Cl)Cl)=C1NS(C(C=C1)=CC(Cl)=C1Cl)(=O)=O)=O)C(C=C1)=CC=C1Cl CQJLCQAIZWUBIV-UHFFFAOYSA-N 0.000 description 1
- CZELKJMSKPGKEF-UHFFFAOYSA-N CCN(C(C(C=C(C=C1Cl)Cl)=C1NS(C(C=C1)=CC=C1Cl)(=O)=O)=O)C(C=C1)=CC=C1Cl Chemical compound CCN(C(C(C=C(C=C1Cl)Cl)=C1NS(C(C=C1)=CC=C1Cl)(=O)=O)=O)C(C=C1)=CC=C1Cl CZELKJMSKPGKEF-UHFFFAOYSA-N 0.000 description 1
- NMAXBJXQQKAHOV-UHFFFAOYSA-N CCS(=O)(=O)C1=CC(=C(C=C1)NS(=O)(=O)C2=CC(=C(C=C2)Cl)Cl)C(=O)NC3=CC=C(C=C3)Cl Chemical compound CCS(=O)(=O)C1=CC(=C(C=C1)NS(=O)(=O)C2=CC(=C(C=C2)Cl)Cl)C(=O)NC3=CC=C(C=C3)Cl NMAXBJXQQKAHOV-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000242722 Cestoda Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241001126268 Cooperia Species 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- FVIGODVHAVLZOO-UHFFFAOYSA-N Dixanthogen Chemical compound CCOC(=S)SSC(=S)OCC FVIGODVHAVLZOO-UHFFFAOYSA-N 0.000 description 1
- 241000243974 Haemonchus contortus Species 0.000 description 1
- 108010034145 Helminth Proteins Proteins 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- HGOOMSYBJREBQG-UHFFFAOYSA-N O=C(C(C=C(C=C1)Cl)=C1NS(C(C=C1)=CC=C1Cl)(=O)=O)NC(C=C1)=CC=C1I Chemical compound O=C(C(C=C(C=C1)Cl)=C1NS(C(C=C1)=CC=C1Cl)(=O)=O)NC(C=C1)=CC=C1I HGOOMSYBJREBQG-UHFFFAOYSA-N 0.000 description 1
- DDQRUWFFNFOLQD-UHFFFAOYSA-N O=C(C(C=C(C=C1)NS(C(C=C2)=CC=C2Cl)(=O)=O)=C1Cl)NC(C=C1)=CC=C1Cl Chemical compound O=C(C(C=C(C=C1)NS(C(C=C2)=CC=C2Cl)(=O)=O)=C1Cl)NC(C=C1)=CC=C1Cl DDQRUWFFNFOLQD-UHFFFAOYSA-N 0.000 description 1
- CYOAGZTYIRCZTP-UHFFFAOYSA-N O=C(C(C=C1)=CC(Cl)=C1NS(C(C=C1)=CC=C1Cl)(=O)=O)NC(C=C1)=CC=C1Cl Chemical compound O=C(C(C=C1)=CC(Cl)=C1NS(C(C=C1)=CC=C1Cl)(=O)=O)NC(C=C1)=CC=C1Cl CYOAGZTYIRCZTP-UHFFFAOYSA-N 0.000 description 1
- DKGPHUYZJWKRLJ-UHFFFAOYSA-N O=C(C(C=CC(NS(C(C=C1)=CC=C1Cl)(=O)=O)=C1)=C1Br)NC(C=C1)=CC=C1Cl Chemical compound O=C(C(C=CC(NS(C(C=C1)=CC=C1Cl)(=O)=O)=C1)=C1Br)NC(C=C1)=CC=C1Cl DKGPHUYZJWKRLJ-UHFFFAOYSA-N 0.000 description 1
- 241000243795 Ostertagia Species 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- 241000282849 Ruminantia Species 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 241000869417 Trematodes Species 0.000 description 1
- 241000243797 Trichostrongylus Species 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- CTCKOPRVSJSTDI-UHFFFAOYSA-N [N]=S(=O)=O Chemical group [N]=S(=O)=O CTCKOPRVSJSTDI-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000323 aluminium silicate Inorganic materials 0.000 description 1
- 229940051881 anilide analgesics and antipyretics Drugs 0.000 description 1
- 150000003931 anilides Chemical class 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000001138 artemisia absinthium Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 210000000013 bile duct Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 125000005521 carbonamide group Chemical group 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- HBGGBCVEFUPUNY-UHFFFAOYSA-N cyclododecanamine Chemical compound NC1CCCCCCCCCCC1 HBGGBCVEFUPUNY-UHFFFAOYSA-N 0.000 description 1
- HSOHBWMXECKEKV-UHFFFAOYSA-N cyclooctanamine Chemical compound NC1CCCCCCC1 HSOHBWMXECKEKV-UHFFFAOYSA-N 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- LAWOZCWGWDVVSG-UHFFFAOYSA-N dioctylamine Chemical compound CCCCCCCCNCCCCCCCC LAWOZCWGWDVVSG-UHFFFAOYSA-N 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000002550 fecal effect Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229910021485 fumed silica Inorganic materials 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 244000144980 herd Species 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229920000592 inorganic polymer Polymers 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- USGSGFWEGZVPNF-UHFFFAOYSA-N methyl 2-chloro-6-nitrobenzoate Chemical compound COC(=O)C1=C(Cl)C=CC=C1[N+]([O-])=O USGSGFWEGZVPNF-UHFFFAOYSA-N 0.000 description 1
- BCZDZOCTLAKTMP-UHFFFAOYSA-N methyl 5-bromo-2-[(4-chlorophenyl)sulfonylamino]benzoate Chemical compound COC(=O)C1=CC(Br)=CC=C1NS(=O)(=O)C1=CC=C(Cl)C=C1 BCZDZOCTLAKTMP-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- KUDPGZONDFORKU-UHFFFAOYSA-N n-chloroaniline Chemical compound ClNC1=CC=CC=C1 KUDPGZONDFORKU-UHFFFAOYSA-N 0.000 description 1
- SDQCOADWEMMSGK-UHFFFAOYSA-N n-ethyloctan-1-amine Chemical compound CCCCCCCCNCC SDQCOADWEMMSGK-UHFFFAOYSA-N 0.000 description 1
- PXSXRABJBXYMFT-UHFFFAOYSA-N n-hexylhexan-1-amine Chemical compound CCCCCCNCCCCCC PXSXRABJBXYMFT-UHFFFAOYSA-N 0.000 description 1
- OMEMQVZNTDHENJ-UHFFFAOYSA-N n-methyldodecan-1-amine Chemical compound CCCCCCCCCCCCNC OMEMQVZNTDHENJ-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 238000009304 pastoral farming Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008063 pharmaceutical solvent Substances 0.000 description 1
- 229920000111 poly(butyric acid) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 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
- 239000004540 pour-on Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229950000975 salicylanilide Drugs 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003530 tetrahydroquinolines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- 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
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (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)
Abstract
Die Erfindung betrifft ein Verfahren zur Herstellung eines Arzneimittels zur Bekaempfung von Helminthen. Ziel der Erfindung ist die Bereitstellung eines Mittels mit besserer Wirksamkeit, breiterem Spektrum und groesserem therapeutischem Index. Erfindungsgemaess werden Arzneimittel hergestellt mit einem Gehalt an Verbindungen der allgemeinen Formel I, worin beispielsweise bedeuten:X Halogen, CF3, NO2, SOnR mit RCH3 oder C2H5, n0-2, Y Wasserstoff oder Halogen, R1 einen ggf. substituierten Phenylrest oder einen Alkylrest mit 6-18 Kohlenstoffatomen, R2 Wasserstoff oder einen Alkylrest mit 1 bis 8 Kohlenstoffatomen u. a., R3 und R4 unabhaengig voneinander Wasserstoff, Methyl oder Aethyl und Z mindestens 1 Halogenatom. Formel IThe invention relates to a process for the preparation of a medicament for the control of helminths. The aim of the invention is to provide a composition with better efficacy, broader spectrum and greater therapeutic index. According to the invention, medicaments are prepared containing compounds of the general formula I in which, for example: X is halogen, CF 3, NO 2, SOnR with RCH 3 or C 2 H 5, n o -2, Y is hydrogen or halogen, R 1 is an optionally substituted phenyl radical or an alkyl radical 6-18 carbon atoms, R2 is hydrogen or an alkyl radical having 1 to 8 carbon atoms u. a, R3 and R4 independently of one another are hydrogen, methyl or ethyl and Z is at least 1 halogen atom. Formula I
Description
Die Erfindung bezieht sich auf ein Verfahren zur Herstellung eines Arzneimittels mit einem Gehalt an Anthranilsäurederivaten. Die erfindungsgemäß hergestellten Arzneimittel werden angewandt zur Behandlung von Infektionen durch Helminthen, insbesondere bei Haustieren, vor allem Wiederkäuern wie Schaf und Rind.The invention relates to a process for the preparation of a medicament containing anthranilic acid derivatives. The medicaments produced according to the invention are used for the treatment of infections by helminths, in particular in domestic animals, above all ruminants such as sheep and cattle.
Aus der GB-PS 865735 sind bereits Anthranilsäurederivate bekannt. Hierin werden jedoch lediglich insektizide Wirkungen beschrieben.From GB-PS 865735 anthranilic acid derivatives are already known. However, only insecticidal effects are described herein.
Ziel der Erfindung ist die Bereitstellung neuer Arzneimittel, die zur Bekämpfung von Helminthen angewandt werden können und die gegenüber bekannten Arzneimitteln hierfür eine bessere Wirksamkeit, ein breiteres Spektrum und einen größeren chemotherapeutischen Index aufweisen.The aim of the invention is the provision of new medicaments which can be used for the control of helminths and which have better efficacy, a broader spectrum and a greater chemotherapeutic index than known medicaments for this purpose.
Der Erfindung liegt die Aufgabe zugrunde, neue Verbindungen aufzufinden, die zur Bekämpfung von Helminthen geeignetThe invention has for its object to find new compounds that are suitable for controlling helminths
Es wurde gefunden, daß sich bestimmte Anthranilsäurederivate zur Bekämpfung von Helminthen ausgezeichnet geeignetIt has been found that certain anthranilic acid derivatives are excellently suitable for controlling helminths
Erfindungsgemäß werden Arzneimittel hergestellt, die mindestens eine Verbindung der Formel IAccording to the invention, medicaments are prepared which contain at least one compound of the formula I
(I)(I)
enthalten,contain,
worin X Halogen, CF3, NO2, SOnR mit R=CH3 oder C2H6, η = 0-2 bedeutet, Y Wasserstoff oder Halogen, R1 einen durch mindestens ein Halogenatom oder eine CF3- oder OCF3-Gruppe substituierten Phenylrest oder einen Alkylrest mit 6-18 Kohlenstoffatomen, R2 Wasserstoff oder einen Alkylrest mit 1 bis 8 Kohlenstoffatomen bedeuten, oder R1 und R2 zusammen einen gesättigten oder äthylenisch ungesättigten Kohlenwasserstoff rest, an den ein durch ein oder zwei Halogenatome substituierter Phenylrest ankondensiert ist dergestalt, daß sich mit dem N-Atom ein fünf- oder sechsgliedriger Ring bildet, R3 und R4 unabhängig voneinander Wasserstoff, Methyl oder Äthyl und Z mindestens 1 Halogenatom bedeuten.wherein X is halogen, CF 3 , NO 2 , SO n R where R = CH 3 or C 2 H 6 , η = 0-2, Y is hydrogen or halogen, R 1 is a by at least one halogen atom or a CF 3 - or OCF 3 group substituted phenyl radical or an alkyl radical having 6-18 carbon atoms, R 2 is hydrogen or an alkyl radical having 1 to 8 carbon atoms, or R 1 and R 2 together a saturated or ethylenically unsaturated hydrocarbon radical to which a by one or two halogen atoms fused substituted phenyl is fused such that forms with the N-atom, a five- or six-membered ring, R 3 and R 4 are independently hydrogen, methyl or ethyl and Z is at least 1 halogen atom.
Halogen bedeutet stets bevorzugt Fluor, Chlor oder Brom.Halogen is always preferably fluorine, chlorine or bromine.
Bevorzugt sind solche Verbindungen, in denen X Chlor oder Brom, Y Wasserstoff oder Chlor, R1 Phenyl, das durch ein bis drei Halogenatome aus der Gruppe Fluor, Chlor und Brom oder durch eine CF3- oder OCF3-Gruppe, vorzugsweise in 4-Stellung zur Aminofunktion, substituiert ist, R2 Wasserstoff, Methyl oder Äthyl, R3 und R4 Wasserstoff und Zein bis drei Halogenatome aus der Gruppe Fluor, Chlor und Brom bedeuten.Preference is given to those compounds in which X is chlorine or bromine, Y is hydrogen or chlorine, R 1 is phenyl which is substituted by one to three halogen atoms from the group consisting of fluorine, chlorine and bromine or by a CF 3 or OCF 3 group, preferably in 4 Position to the amino function, R 2 is hydrogen, methyl or ethyl, R 3 and R 4 are hydrogen and zein to three halogen atoms from the group fluorine, chlorine and bromine.
Insbesondere auch unter dem Gesichtspunkt der wirtschaftlichen Zugänglichkeit bevorzugt sind die Verbindungen, in denen X Chlor, Y Wasserstoff, R ein durch ein oderzwei Chlor- oder Bromatome substituiertes Phenyl, R2 bis R4 Wasserstoff und Z ein oder 2 Chloratome bedeuten.Particularly preferred from the point of view of economic accessibility are the compounds in which X is chlorine, Y is hydrogen, R is a phenyl substituted by one or two chlorine or bromine atoms, R 2 to R 4 are hydrogen and Z is one or two chlorine atoms.
Für den Fall, daß R1 und R2 zusammen einen Kohlenwasserstoffrest bedeuten, entspricht dieser, wenn man das benachbarte Stickstoffatom mit einbezieht, insbesondere einem halogenierten Tetrahydrochinolin- oder Dihydroindol-Rest.In the event that R 1 and R 2 together denote a hydrocarbon radical, this corresponds, if one includes the adjacent nitrogen atom, in particular a halogenated tetrahydroquinoline or dihydroindole radical.
Die allgemeine Formel I enthält 3 Bauelemente: Eine substituierte Anthranilsäure, ein Amin R1R2NH und eine durch Z jGeneral Formula I contains 3 building blocks: a substituted anthranilic acid, an amine R 1 R 2 NH, and a through Z j
substituierte Benzosulfonsäure.substituted benzosulfonic acid.
Beispiele für die substituierte Anthranilsäure sind:Examples of the substituted anthranilic acid are:
2-Amino-5-chlor-benzoesäure, 2-Amino-3,5,-dichlor-benzoesäure, 2-Amino-4,5-dichlorbenzoesäure, 2-Amino-5,6-dichlorbenzoesäure, 5-Chlor-2-methy!amino-benzoesäure, 5-Chlor-2-äthylamino-benzoesäure, 2-Amino-5-fluor-benzoesäure, 2-Amino-5-brom-benzoesäure, 2-Amino-3,5-dibrombenzoesäure, 2-Amino-5-brom-3-chlor-benzoesäure, 2-Amino-5-brom-4-chlor-benzoesäure, 2-Amino-3-brom-5-chlor-benzoesäure, 2-Amino-5-nitro-benzoesäure, 2-Amino-5-nitro-3-chlorbenzoesäure, 2-Amino-5-nitro-4-chlor-benzoesäure, 2-Amino-5-trifluormethyl-benzoesäure, 2-Amino-5-äthylthiobenzoesäure, j 2-Amino-4-chlor-5-methylthio-benzoesäure, 2-Amino-5-äthylsulfonylbenzoesäure.2-amino-5-chloro-benzoic acid, 2-amino-3,5-dichloro-benzoic acid, 2-amino-4,5-dichlorobenzoic acid, 2-amino-5,6-dichlorobenzoic acid, 5-chloro-2-methyl ! amino-benzoic acid, 5-chloro-2-ethylamino-benzoic acid, 2-amino-5-fluoro-benzoic acid, 2-amino-5-bromo-benzoic acid, 2-amino-3,5-dibromobenzoic acid, 2-amino-5 bromo-3-chloro-benzoic acid, 2-amino-5-bromo-4-chloro-benzoic acid, 2-amino-3-bromo-5-chloro-benzoic acid, 2-amino-5-nitro-benzoic acid, 2-amino 2-amino-5-trifluoromethylbenzoic acid, 2-amino-5-ethylthiobenzoic acid, 2-amino-4-chloro 5-methylthio-benzoic acid, 2-amino-5-ethylsulfonylbenzoic acid.
Als Beispiele für die Aminkomponente seien genannt:As examples of the amine component may be mentioned:
4-Fluoranilin, 4-Chlor-anilin, 4-Brom-anilin, 4-Jod-anilin, 3,4-Dichloranilin, 2,4-Dichloranilin, 2,4,5-Trichloranilin, 2-Brom-4- i4-fluoroaniline, 4-chloroaniline, 4-bromoaniline, 4-iodoaniline, 3,4-dichloroaniline, 2,4-dichloroaniline, 2,4,5-trichloroaniline, 2-bromo-4-i
chloranilin, 4-Brom-2-chloranilin, 4-Fluor-2-chloranilin, 4-Fluor-2-bromanilin, 3-Trifluormethyl-anilin, 4-Trifluormethyl-anilin, 4-Trifluormethoxyanilin, 4-Chlor-N-äthyl-anilin, 2,4-Dichlor-N-äthylanilin, 3,4-Dichlor-N-methyl-anilin, 5-Chlor-indolin, 6-Chlor-1,2,3,4-tetrahydrochinolin, 1-Amino-octan, 1-Amino-dodecan, 1-Amino-octadecan, 1-(Äthylamino-)octan, 1-(Methylamino-)dodecan, Dihexylamin, Dioctylamin, Cyclooctylamin, Cyclododecylamin.chloroaniline, 4-bromo-2-chloroaniline, 4-fluoro-2-chloroaniline, 4-fluoro-2-bromoaniline, 3-trifluoromethyl-aniline, 4-trifluoromethyl-aniline, 4-trifluoromethoxyaniline, 4-chloro-N-ethyl- aniline, 2,4-dichloro-N-ethylaniline, 3,4-dichloro-N-methylaniline, 5-chloro-indoline, 6-chloro-1,2,3,4-tetrahydroquinoline, 1-amino-octane, 1-amino-dodecane, 1-amino-octadecane, 1- (ethylamino) -octane, 1- (methylamino) -dodecane, dihexylamine, dioctylamine, cyclooctylamine, cyclododecylamine.
Beispiele für die Sulfonsäure-Komponente sind:Examples of the sulfonic acid component are:
4-Fluor-benzolsulfonsäure, 4-Chlor-benzolsulfonsäure, 4-Brom-benzolsulfonsäure, 2-Chlor-benzolsulfonsäure, 3,4-Dichlorbenzolsulfonsäure, 2,4-Dichlor-benzolsulfonsäure, 2,5-Dichlorbenzolsulfonsäure, S-ChloM-fluor-benzolsulfonsäure, 4-Chlor-3-methylbenzolsulfonsäure, 3-Chlor-4-methyl-benzolsulfonsäure, 2,4,5-Trichlorbenzolsulfonsäure.4-fluorobenzenesulfonic acid, 4-chlorobenzenesulfonic acid, 4-bromobenzenesulfonic acid, 2-chlorobenzenesulfonic acid, 3,4-dichlorobenzenesulfonic acid, 2,4-dichlorobenzenesulfonic acid, 2,5-dichlorobenzenesulfonic acid, S-chlorofluoro- benzenesulfonic acid, 4-chloro-3-methylbenzenesulfonic acid, 3-chloro-4-methylbenzenesulfonic acid, 2,4,5-trichlorobenzenesulfonic acid.
Wichtige Vertreter der durch die Formel I definierten Verbindungsklasse sind z. B. 5-Chlor-2-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-(4-chloranilid), Schmp. 2160C (1); 5-Chlor-2-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-(2,4-dichlor-anilid), Schmp. 1730C (2); 5-Chlor-2-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-(3,4-dichloranilid), Schmp. 244X (3); 5-Chlor-2-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-(4-fluoranilid), Schmp. 266°C (4); 5-Chlor[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-(4-brom-anilid), Schmp. 2100C (5); 5-Chlor-2-[4-chlorphenylsulfonyl)-amino]-benzoesäure-(4-chlor-N-methylanilid), Schmp. 1830C (6); 5-Chlor-2-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-(3-trifluormethyl-anilid), Schmp.Important representatives of the compound class defined by the formula I are z. B. 5-Chloro-2 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid (4-chloroanilide), mp 216 0 C (1);. 5-chloro-2 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid (2,4-dichloro-anilide), mp 173 0 C (2). 5-Chloro-2 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid (3,4-dichloroanilide), m.p. 244X (3); 5-Chloro-2 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid (4-fluoroanilide), m.p. 266 ° C (4); 5-chloro [(4-chloro-phenylsulfonyl) -amino] -benzoic acid (4-bromo-anilide), mp 210 0 C (5). 5-Chloro-2- [4-chlorophenylsulfonyl) amino] -benzoic acid (4-chloro-N-methylanilide), mp 183 0 C (6). 5-Chloro-2 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid (3-trifluoromethyl-anilide), m.p.
2160C (7); 5-Chlor-2-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-(4-jod-anilid), Schmp. 229°C (8); 5-Brom-2-[(4-chlorphenylsulfonyl)-amino]-benzoesäure-(4-chlor-anilid), Schmp. 21O0C (9); 5-Brom-2-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-(2,4-dichlor-anilid), Schmp. 1730C(IO); 5-Brom-2-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-(3-trifluormethylanilid), Schmp. 22O0C (11); 4,5-Dichlor-2-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-(4-chlor-anilid), Schmp. 2070C (12); 3,5-Dichlor-2-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-(4-chlor-anilid), Schmp. 26O0C (13); 3,5-Dichlor-2-[(4-chlorphenylsulfonyl)-amino]-benzoesäure-(4-fluor-anilid), Schmp. 256°C (14); 3,5-Dichlor-2-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-(4-chlor-N-äthyl-anilid), Schmp. 163°C (15); 3,5-Dichlor-2-[(4-chlor-phenyl-sulfonyl)-amino]-benzoesäuredodecylamid, Schmp. 193°C(16); 5-Chlor-2-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-dodecylamid, Schmp. 117°C(17); 5-Chlor-2-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-octadecylamid, Schmp. 108°C (18); 5-Chlor-2-[(4-chlorphenylsulfonyO-aminol-benzoesäure-fN-methyl-dodecylamid), Schmp. 500C (19); 5-Chlor-2-[(4-brom-phenylsulfonyl)-amino]-benzoesäure-(4-chloranilid), Schmp. 217°C (20); 5-Chlor-2-[(4-brom-phenylsulfonyl)-amino)-benzoesäure-(4-brom-anilid), Schmp. 209°C (21); 5-Chlor-2-[(4-fluor-phenylsulfonyl)-amino]-benzoesäure-(4-chloranilid), Schmp. 207°C (22); 2-Chlor-2-[(4-fluorphenylsulfonyl)-amino]-benzoesäure-(4-fluoranilid), Schmp. 2250C (23); 5-Chlor-2-[(4-fluor-phenylsulfonyl)-amino]-benzoesäure-(3,5-dichloranilid),Schmp.250°C(24);5-Chlor-2-[(2,4-dichlor-phenylsulfonyl)-amino]-benzoesäure-(4-chloranilid), Schmp. 2240C (25); 5-Chlor-2-[(3,4-dichlor-phenylsulfonyl)-amino]-benzoesäure-(4-chloranilid), Schmp. 225°C (26); 5-Chlor-2-[(SAdichlor-phenylsulfonyD-aminoJ-benzoesäure-octylamid, Schmp. 145°C (27); 5-Chlor-2-[(3,4-dichlor-phenyl-sulfonyl)-amino]-benzoesäure-(4-fluor-anilid), Schmp. 2300C (28); ö-Chlor^-IOAdichlor-phenylsulfonyD-aminol-benzoesäure^chlor-216 0 C (7); 5-Chloro-2 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid (4-iodo-anilide), m.p. 229 ° C (8); 5-bromo-2 - [(4-chlorophenylsulfonyl) -amino] -benzoic acid (4-chloroanilide), m.p. 21O 0 C (9); 5-bromo-2 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid (2,4-dichloro-anilide), mp 173 0 C (IO). 5-Bromo-2 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid (3-trifluoromethylanilide), m.p. 22O 0 C (11); 4,5-dichloro-2 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid (4-chloro-anilide), mp 207 0 C (12);. 3,5-dichloro-2 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid (4-chloroanilide), m.p. 26O 0 C (13); 3,5-dichloro-2 - [(4-chlorophenylsulfonyl) amino] benzoic acid (4-fluoroanilide), m.p. 256 ° C (14); 3,5-dichloro-2 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid (4-chloro-N-ethyl-anilide), m.p. 163 ° C (15); 3,5-dichloro-2 - [(4-chloro-phenyl-sulfonyl) -amino] -benzoic acid dodecylamide, m.p. 193 ° C (16); 5-Chloro-2 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid dodecylamide, m.p. 117 ° C (17); 5-Chloro-2 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid octadecylamide, m.p. 108 ° C (18); 5-chloro-2 - [(4-amino-benzoic acid chlorphenylsulfonyO-fN-methyl-dodecylamide), mp 50 0 C (19). 5-Chloro-2 - [(4-bromo-phenylsulfonyl) -amino] -benzoic acid (4-chloroanilide), m.p. 217 ° C (20); 5-Chloro-2 - [(4-bromo-phenylsulfonyl) -amino) -benzoic acid (4-bromo-anilide), m.p. 209 ° C (21); 5-Chloro-2 - [(4-fluoro-phenylsulfonyl) -amino] -benzoic acid (4-chloroanilide), m.p. 207 ° C (22); . 2-chloro-2 - [(4-fluorophenylsulphonyl) amino] -benzoic acid (4-fluoroanilide), mp 225 0 C (23); 5-chloro-2 - [(4-fluoro-phenylsulfonyl) -amino] -benzoic acid (3,5-dichloroanilide), Schmp.250 ° C (24); 5-chloro-2 - [(2,4-dichloro phenylsulfonyl) -amino] -benzoic acid (4-chloroanilide), mp 224 0 C (25). 5-Chloro-2 - [(3,4-dichloro-phenylsulfonyl) -amino] -benzoic acid (4-chloroanilide), m.p. 225 ° C (26); 5-Chloro-2 - [(5-chloro-2 - [(3,4-dichloro-phenyl-sulfonyl) -amino] -benzoic acid, 5-chloro-2 - [(3,4-dichloro-phenyl-sulfonyl) -amino] -benzoic acid, (S-dichloro-phenylsulfonyD-amino-1-benzoic acid octylamide, mp . - (4-fluoro-anilide), mp 230 0 C (28); ö-chloro ^ -IOAdichlor-phenylsulfonyD-amino-benzoic acid ^ chloro-
N-äthyl-anilid), Schmp. 136°C (29); S-Chlor^-KS^-dichlor-phenylsulfonyO-methylaminol-benzoesäure-ti-chlor-anilid), Schmp. 151oC(30);5-Chlor-2-[(3,4-dichlor-phenylsulfonyl)-amino]-benzoesäure-dodecylamid, Schmp. 13O0C (31); 5-Chlor-2-[(3,4-dichlor-phenyl-sulfonyO-aminol-benzoesäure-octadecylamid, Schmp. 1200C (32); 5-Chlor-2-[(3,4-dichlor-phenylsulfonyl)-amino]-benzoesäure-(N-methyl-dodecylamid), Schmp. 52°C (33); S-Chlor^-KS^-dichlor-phenylsulfonyO-aminoJ-benzoesäure-(4-trifluormethyl-anilid), Schmp. 225°C (34); 5-Chlor-2-[(3,4-dichlorphenylsulfonyl)-amino]-benzoesäure-(4-trifluormethoxyanilid), Schmp. 2000C (35); 2-[(4-Chlor-phenylsulfonyl)-amino]-5-nitro-benzoesäure-(4-chlor-anilid), Schmp. 215°C (36); 2-[(4-Chlor-phenylsulfonyO-aminol-S-nitrobenzoesäure-fS-trifluoromethyl-anilid), Schmp. 218°C (37); 2-[(3,4-Dichlorphenylsulfonyl)-amino]-5-nitro-benzoesäure-(4-chlor-anilid), Schmp. 228°C (38); 2-[(3,4-Dichlor-phenyl-sulfonyl)-amino]-5-äthylthio-benzoesäure-(4-chloranilid), Schmp. 169°C (39); 2-[(3,4-Dichlor-phenylsulfonyl)-amino]-5-äthylsulfonyl-benzoesäure-(4-chlor-anilid), Schmp. 1950C (40); 5-Chlor-2-[(3,4-dichlor-phenylsulfonyl)-amino]-benzoesäure-cyclododecylamid, Schmp. 192°C, (41); 5-Chlor-2-[(3,4-dichlor-phenylsulfonylmethylamino]-benzoesäure-(4-chlor-N-äthyl-anilid), Schmp. 1220C (42). 2-(3,4-Dichlor-phenylsulfonyl-amino]-5-fluor-benzoesäure-(4-chlor-anilid), Schmp. 2270C (43) 2-(3,4-Dichlor-phenylsulfonyl-amino)-5-fluor-benzoesäure-(4-chlor-N-äthyl-anilid), Schmp. 1200C (44) 2-(3,4-Dichlor-phenylsulfonyl-amino)-5-fluor-benzoesäure-dodecylamid, Schmp. 134°C (45) 2-(3,4-Dichlor-phenylsulfonyl-amino)-5-fluor-benzoesäure-(4-fluor-anilid), Schmp. 216°C (46) Außerdem:N-ethylanilide), m.p. 136 ° C (29); S-chloro-C 1-8 -dichloro-phenylsulfony-O-methylaminol-benzoic acid-t-chloro-anilide), m.p. 151 o C (30); 5-chloro-2 - [(3,4-dichloro-phenylsulfonyl) -amino ] benzoic acid dodecylamide, m.p. 13O 0 C (31); . 5-chloro-2 - ([(3,4-dichloro-phenyl-sulfonyO-amino-benzoic acid octadecylamid, mp 120 0 C 32); 5-chloro-2 - [(3,4-dichloro-phenylsulphonyl) - amino] -benzoic acid (N-methyl-dodecylamide), mp 52 ° C (33), S-chloro-K, S-dichloro-phenylsulfonyo-amino-J-benzoic acid (4-trifluoromethyl-anilide), m.p. 225 ° C (34); 5-chloro-2 - [(3,4-dichlorophenylsulphonyl) -amino] -benzoic acid (4-trifluormethoxyanilid), mp 200 0 C (35); 2 - [(4-chloro-phenylsulfonyl). -amino] -5-nitro-benzoic acid (4-chloroanilide), m.p. 215 ° C (36); 2 - [(4-chloro-phenylsulfonyo-aminol-S-nitrobenzoic acid-fS-trifluoromethyl-anilide), Mp 218 ° C (37); 2 - [(3,4-dichlorophenylsulfonyl) amino] -5-nitrobenzoic acid (4-chloroanilide), m.p. 228 ° C (38); 2 - [( 3,4-dichloro-phenyl-sulfonyl) -amino] -5-ethylthio-benzoic acid (4-chloroanilide), m.p. 169 ° C (39); 2 - [(3,4-dichloro-phenylsulfonyl) -amino] -5-ethylsulfonyl-benzoic acid (4-chloro-anilide), mp 195 0 C (40); 5-chloro-2 - [(3,4-dichloro-phenylsulfonyl) -amino] -benzoic acid cyclododecylamid, mp.. 19 2 ° C, (41);. 5-chloro-2 - [(3,4-dichloro-phenylsulfonylmethylamino] -benzoic acid (4-chloro-N-ethyl-anilide), mp 122 0 C (42). . 2- (3,4-dichloro-phenylsulfonyl-amino] -5-fluoro-benzoic acid (4-chloro-anilide), mp 227 0 C (43) 2- (3,4-dichloro-phenylsulfonyl-amino) - 5-fluoro-benzoic acid (4-chloro-N-ethyl-anilide), m.p. 120 0 C (44) 2- (3,4-dichloro-phenylsulfonyl-amino) -5-fluoro-benzoic acid dodecylamide, m.p. 134 ° C (45) 2- (3,4-dichloro-phenylsulfonyl-amino) -5-fluoro-benzoic acid (4-fluoroanilide), m.p. 216 ° C (46) Also:
5-Chlor-2-[(3,4-dichlor-phenylsulfonyl)-äthylamino]-benzoesäure-(4-chlor-anilid), Schmp. 1300C (47) 3,5-Dichlor-2-(3,4-dichlor-phenylsulfonyl-amino)-benzoesäure-(4-trifluormethoxy-anilid), Schmp. 26O0C (48) 3,5-Dichlor-2-(3,4-dichlor-phenylsulfonyl-amino)-benzoesäure-(4-chlor-N-äthyl-anilid), Schmp. 173°C(49) Sjö-Dichlor^-O^-dichlor-phenylsulfonyl-aminol-benzoesäure-dodecylamid, Schmp. 197T (50) 3,5-Dichlor-2-(3,4-dichlor-phenylsulfonyl-amino)-benzoesäure-(4-chlor-anilid), Schmp. 2600C (51) Die nachgeordneten Zahlen in dieser Aufstellung beziehen sich auf die Tabellen 1 bis 3 zur Wirksamkeit dieser Verbindungen. Als isomere, nicht unter den Anspruch fallende Vergleichsverbindungen V1-10 wurden die nachfolgend aufgeführten synthetisiert und geprüft:5-chloro-2 -. [(3,4-dichloro-phenylsulfonyl) -äthylamino] -benzoic acid (4-chloro-anilide), mp 130 0 C (47) 3,5-Dichloro-2- (3,4 dichloro-phenylsulfonyl-amino) -benzoic acid (4-trifluoromethoxy-anilide), m.p. 26O 0 C (48) 3,5-dichloro-2- (3,4-dichloro-phenylsulfonyl-amino) -benzoic acid (4 -chloro-N-ethyl-anilide), m.p. 173 ° C (49) Sjö-dichloro-O, -dichloro-phenylsulfonyl-aminol-benzoic acid dodecylamide, mp 197T (50) 3,5-dichloro-2- (3,4-dichloro-phenylsulfonyl-amino) -benzoic acid- (4-chloro-anilide), mp. 260 0 C (51) the downstream numbers in this table refer to the tables 1 to 3 for the activity of these compounds. As isomeric comparison compounds V1-10 not covered by the claim, the following were synthesized and tested:
4-Chlor-2-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-(4-chloranilid), Schmp. 224°C (V 1); 2-Chlor-4-[(4-chlorphenylsulfonyl)-amino]-benzoesäure-(4-chlor-anilid), Schmp. 185°C (V2); 3-Chlor-4-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-(4-chlor-anilid), Schmp. 1540C (V3); 4-Chlor-3-[(4-Chlorphenylsulfonyl)-amino]-benzoesäure-(4-chloranilid), Schmp. 2060C (V4); 2-Chlor-5-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-(4-chlor-anilid), Schmp. 1820C (V5); 4-Chlor-2-[(4-chlor-phenylsulfonyÖ-aminol-benzoesäure-fS^-dichlor-anilid), Schmp. 228°C (V6); 2-Chlor-5-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-(4-fluor-anilid), Schmp. 194°C (V7); 2-Brom-4-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-(4-chlor-anilid), Schmp. 2150C (V8); 4-Brom-2-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-(4-chlor-anilid), Schmp. 214°C (V9); 2-Chlor-4-[(4-chlor-phenylsulfonylJ-aminol-benzoesäure-OAdichlor-anilid), Schmp. 2010C(VIO). ν4-Chloro-2 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid (4-chloroanilide), m.p. 224 ° C (V 1); 2-Chloro-4 - [(4-chlorophenylsulfonyl) amino] benzoic acid (4-chloroanilide), m.p. 185 ° C (V2); 3-chloro-4 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid (4-chloro-anilide), mp 154 0 C (V3);. 4-chloro-3 - [(4-chlorophenylsulfonyl) amino] -benzoic acid (4-chloroanilide), mp 206 0 C (V4);. 2-chloro-5 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid (4-chloro-anilide), mp 182 0 C (V5). 4-Chloro-2 - [(4-chloro-phenylsulfony-amino-benzoic acid-F5-dichloroanilide), m.p. 228 ° C (V6); 2-Chloro-5 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid (4-fluoroanilide), m.p. 194 ° C (V7); 2-bromo-4 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid (4-chloro-anilide), mp 215 0 C (V8). 4-Bromo-2 - [(4-chloro-phenylsulfonyl) -amino] -benzoic acid (4-chloro-anilide), m.p. 214 ° C (V9); 2-chloro-4 -. [(4-chloro-phenylsulfonylJ-amino-benzoic acid OAdichlor-anilide), mp 201 0 C (VIO). ν
Die erfindungsgemäß zu verwendenden Verbindungen sind zum Teil bereits aus der britischen Patentschrift 865,735 bekannt. In dieser fehlt jedoch jeder Hinweis auf eine Wirksamkeit der Verbindungen gegen Helminthen, insbesondere Leberegel. Zudem ist offensichtlich die Wirksamkeit gegen Insekten wenig strukturspezifisch und sehr stark auf den Halogengehalt abgestellt, was daraus hervorgeht, daß der Halogengehalt nur als Summe der Atome bzw. Trifluormethylgruppen ohne Rücksicht auf die Position im Molekül angegeben wird. Demgegenüber sind für die anthelmintische Wirksamkeit wesentlich engere strukturelle Bedingungen gegeben, wie sie durch die allgemeine Formel I beschrieben werden. Isomere Derivate der 3- bzw. 4-Aminobenzoesäuren sind deutlich schwächer als die der Anthranilsäure, wie sich aus der Tabelle 3 ergibt. Weiterhin ist der Substituent X in 5-Position wesentlich und schließlich kommen als Aminkomponente der Carbonamidstruktur nicht nur substituierte Aniline, sondern auch hinreichend langkettige aliphatische Amine in Betracht.Some of the compounds to be used according to the invention are already known from British Pat. No. 865,735. In this, however, lacks any evidence of efficacy of the compounds against helminths, especially liver fluke. In addition, the activity against insects is apparently not structurally specific and is very strongly based on the halogen content, which shows that the halogen content is given only as the sum of the atoms or trifluoromethyl groups regardless of the position in the molecule. In contrast, the anthelmintic efficacy given much narrower structural conditions, as described by the general formula I. Isomeric derivatives of 3- or 4-aminobenzoic acids are significantly weaker than those of anthranilic acid, as shown in Table 3. Furthermore, the substituent X in the 5-position is essential and, finally, not only substituted anilines, but also sufficiently long-chain aliphatic amines are suitable as the amine component of the carbonamide structure.
Die Herstellung der erfindungsgemäß zu verwendenden Verbindungen kann nach üblichen Methoden erfolgen, z. B. durch Acylierung der entsprechend substituierten Anthranilsäuren mit den Sulfochloriden, Umwandlung der Carboxylgruppen in die Säurechloride und Umsetzung mit den Aminen, s. jeweils GB-PS 865,735; EP-A 148,725 oder durch Überführung entsprechend substituierter 2-Nitro-benzoesäuren in die entsprechenden Amide, Reduktion der Nitrogruppe und Acylierung mit den Sulfochloriden, s. EP-A 148,725, oder durch Austausch des Halogens in 5-Halogen-2-nitro-benzoesäure-amiden mit Nucleophilen, Reduktion und Acylierung, oder durch Kernchlorierung der im Sulfonsäurerest entsprechend substituierten 2-Sulfonylamino-benzoesäuren bzw. deren Estern und nachfolgende Umwandlung in die Amide, oder Derivatierung von Verbindungen der Formel I wie die Oxidation von Thioethern (X = SR)The preparation of the compounds to be used according to the invention can be carried out by customary methods, for. By acylation of the appropriately substituted anthranilic acids with the sulfochlorides, conversion of the carboxyl groups to the acid chlorides, and reaction with the amines, s. in each case GB-PS 865,735; EP-A 148,725 or by conversion of appropriately substituted 2-nitro-benzoic acids into the corresponding amides, reduction of the nitro group and acylation with the sulfochlorides, s. EP-A 148,725, or by replacement of the halogen in 5-halo-2-nitro-benzoic acid amides with nucleophiles, reduction and acylation, or by nuclear chlorination of the sulfonic in the correspondingly substituted 2-sulfonylamino-benzoic acids or their esters and subsequent conversion into the amides, or derivatization of compounds of the formula I such as the oxidation of thioethers (X = SR)
Insbesondere sind die folgenden Verfahren von Bedeutung: a) Umsetzung der Verbindungen der Formel Il In particular, the following processes are of importance: a) reaction of the compounds of the formula II
HNHN
(II) (III)(II) (III)
mit Verbindungen der Formel (III), wobei A in Formel (M)OH oder eine reaktive Abgangsgruppe wie Halogen, Tosyloxy oder einen aktivierten Esterrest wie Alkoxycarbonyloxy bedeutet. Diese Umsetzung wird in einem geeigneten inerten Lösungsmittel wie Benzol, Toluol, CH2CI2, Dimethylformamid, Tetrahydrofuran, Aceton, Acetonitril, gegebenenfalls in Gegenwart einer Base wie Triethylamin, Pyridin, Picolin zwischen 00C bis 1500C. Wenn A = OH bedeutet kann die Reaktion in Gegenwart eines Kondensationsmittels wie Dicyclohexylcarbodiimid durchgeführt werden, b) Umsetzung der Verbindungen der Formel (IV)with compounds of the formula (III) in which A in formula (M) denotes OH or a reactive leaving group such as halogen, tosyloxy or an activated ester radical such as alkoxycarbonyloxy. This reaction is carried out in a suitable inert solvent such as benzene, toluene, CH 2 Cl 2, dimethylformamide, tetrahydrofuran, acetone, acetonitrile, optionally in the presence of a base such as triethylamine, pyridine, picoline, between 0 ° C. and 150 ° C. If A = OH, then Reaction in the presence of a condensing agent such as dicyclohexylcarbodiimide, b) reaction of the compounds of the formula (IV)
CONR1R2 CONR 1 R 2
- (X1 = Halogen)- (X 1 = halogen)
.. _Jiv) (ν) .. _Jiv) (ν)
mit Verbindungen der Formel V und gegebenenfalls anschließende Alkylierung des Sulfonylstickstoffatoms, vgl. EP-A 148,725. Die Umsetzung wird analog wie unter a) beschrieben durchgeführt, (Temperaturbereich O0C bis 100°C), wobei ebenfalls die obengenannten Basen zugesetzt werden können; es kann auch Pyridin als Lösungsmittel verwendet werden. Die Ausgangsverbindungen der Formeln (II) bis (V) können nach dem Fachmann bekannten Methoden, beispielsweise, wie sie in EP-A 148,725 beschrieben sind, hergestellt werden.with compounds of the formula V and, if appropriate, subsequent alkylation of the sulfonyl nitrogen atom, cf. EP-A 148,725. The reaction is carried out analogously as described under a), (temperature range O 0 C to 100 ° C), wherein also the abovementioned bases can also be added; Pyridine can also be used as solvent. The starting compounds of the formulas (II) to (V) can be prepared by methods known to those skilled in the art, for example as described in EP-A 148,725.
Die Verbindungen der allgemeinen Formel I gemäß der Erfindung sind wertvolle Chemotherapeutika. Sie wirken gegen Helminthen, insbesondere Trematoden,Zestoden und Nematoden. Besonders ausgeprägt ist ihre Wirksamkeit gegen Leberegel, z. B. gegen den großen Leberegel Fasciola hepatica, der als Parasit von Nutztieren wie Schafen und Rindern weit verbreitet ist. Weidetiere sind häufig von Bandwürmern und in besonderem Maße von Nematoden befallen. Die Verseuchung einer Herde mit diesen Helminthen führt zu empfindlichen wirtschaftlichen Schäden. Deshalb kommt einem spezifischen Therapeutikum gegen die genannten drei Helminthen-Gruppen eine erhebliche Bedeutung zu.The compounds of general formula I according to the invention are valuable chemotherapeutic agents. They act against helminths, in particular trematodes, cestodes and nematodes. Particularly pronounced is their effectiveness against liver fluke, z. B. against the large liver fluke Fasciola hepatica, which is widely used as a parasite of farm animals such as sheep and cattle. Grazing animals are often infested with tapeworms and in particular with nematodes. The contamination of a herd with these helminths leads to serious economic damage. Therefore, a specific therapeutic against the mentioned three helminth groups is of considerable importance.
Der anthelminthische Effekt der Verbindungen der Formel I läßt sich sowohl an Laboratoriumstieren als auch an Haustieren zeigen. Die Wirkstoffe werden auf einmal oder in einer Mehrzahl kleiner Dosen ggf. über einen längeren Zeitraum verteilt, zusammen mit einem geeigneten pharmazeutischen Lösungsmittel bzw. Trägerstoff oral oder parenteral, ζ. B. auch mit der „pour-on" Methode, vgl. z.B. EP-A 45424 appliziert. Die Applikationsart ist je nach Lage des Falles zu wählen. Die Anwendungskonzentration liegt bei parenteralerGabe im Bereich von 0,1-5,0 mg/kg Körpergewicht bzw. bei oraler Gabe im Bereich von 0,5-50 mg/kg Körpergewicht.The anthelminthic effect of the compounds of the formula I can be demonstrated both on laboratory animals and on domestic animals. The active ingredients are distributed all at once or in a plurality of small doses over a longer period if necessary, together with a suitable pharmaceutical solvent or carrier orally or parenterally, ζ. Example, with the "pour-on" method, see, for example, EP-A 45424. The application should be selected depending on the situation of the case.The use concentration is in parenteral administration in the range of 0.1-5.0 mg / kg Body weight or oral administration in the range of 0.5-50 mg / kg body weight.
Zur oralen Applikation sind feste oder flüssige Verabreichungsformen,wie Tabletten, Dragees, BoIi, Pulver, Granulate oder Mischungen der Wirkstoffe mit Futter möglich; aucfi Arzneitränke können verwendet werden. Zur parenteralen Applikation verwendet man flüssige oder feste Zubereitungen,wie Emulsionen, Suspensionen, Lösungen oder Implantate der Wirkstoffe. Zur Herstellung dieser Zubereitungen kommen übliche, physiologisch unbedenkliche Hilfs- und Trägerstoffe in Fragefwie Talk, Milchzucker, Magnesiumstearat, anorganische Polymere(wie hochdisperses Siliziumdioxid, Alumosilikate, Polyphosphate, organische Polymere, wie Polyglykolsäure, Polymilch- oder Polybuttersäure oder deren Copolymere, Zellulose und deren Derivate, Polyacrylsäuren, Polyvinylpyrrolidon, Polyfvinyl oder ähnliche) alkohole, Polyäthylenglykol, ferner Paraffinöl, Lösemittel, Wasser, ferner übliche Konservierungsmittel oder Puffersubstanzen.For oral administration, solid or liquid administration forms, such as tablets, dragees, candies, powders, granules or mixtures of the active ingredients with food are possible; aucfi medicine cabinets can be used. For parenteral administration, liquid or solid preparations are used, such as emulsions, suspensions, solutions or implants of the active ingredients. For the preparation of these preparations are conventional, physiologically acceptable excipients and carriers in question f such as talc, lactose, magnesium stearate, inorganic polymers ( such as fumed silica, alumosilicates, polyphosphates, organic polymers such as polyglycolic, polylactic or polybutyric acid or their copolymers, cellulose and their derivatives, polyacrylic acids, polyvinylpyrrolidone, polyvinyl or similar) alcohols, polyethylene glycol, also paraffin oil, solvents, water, furthermore customary preservatives or buffer substances.
Flüssige Zubereitungen enthalten im allgemeinen 1-50Gew.-% Wirkstoff, feste Zubereitungen im allgemeinen 1-80Gew.-% Wirkstoff.Liquid preparations generally contain 1-50% by weight of active ingredient, while solid preparations generally contain 1-80% by weight of active ingredient.
Eine flüssige Zubereitungkwie eine Suspension4wird beispielsweise hergestellt, in dem man zu einer Trägerlösung (enthaltend beispielsweise das lösliche organische Polymer, Konservierungsstoffe, Puffersubstanzen, Lösungsmittel) eine Mischung aus Siliciumdioxid (oder eines Alumosilikats) und dem Wirkstoff hinzugibt und dieses Gemisch auf geeignete Weise (z.B. Schütteln) homogenisiert. Eine solche Zubereitung enthält beispielsweise 6% Wirkstoff, 3% SiO2,3% eines Cellulosederivats, 3% eines Puffers (z. B. eines Zitrats), 1 % Konservierungsmittel und 84% Wasser. (% & Gew.-%).A liquid preparation k, such as a suspension 4 , is prepared, for example, by adding to a carrier solution (containing, for example, the soluble organic polymer, preservatives, buffering agents, solvents) a mixture of silica (or aluminosilicate) and the active ingredient, and mixing this mixture to appropriate Homogenized (eg shaking). Such a preparation contains, for example, 6% active ingredient, 3% SiO 2 , 3% of a cellulose derivative, 3% of a buffer (eg of a citrate), 1% preservative and 84% water. (% & Wt.%).
Zur Feststellung der anthelminthischen Wirkung der Verbindungen der Formel I wurden chemotherapeutische Untersuchungen an ca. 25-30kg schweren Schaflämmern ausgeführt, die entweder mit Metazerkarien von Fasciola hepatica oder mit Larven von Magen-Darm-Strongyliden, vornehmlich Haemonchus contortus und Trichostongylus colubriformis, oral infiziert worden waren. Nach Ablauf der Präpatenzperiode (Zeit zwischen Infektion und Geschlechtsreife der Parasiten mit beginnender Ausscheidung von Eiern oder Larven) wurde der Parasitenbefall durch Kotuntersuchungen gesichert. Im Fall der Leberegel-Infektion erfolgte der qualitativ-quantitative Nachweis von Eiern nach derTelemann-Anreicherung (Deutsche Medizinische Wochenschrift 34 1510, [1908]). Die Eizahl pro Gramm Kot von Magen-Darm-Strongyliden wurde im modifizierten McMaster-Verfahren nach Wetzel (Tierärztliche Umschau 6,209, [1951]) bestimmt. Unmittelbar danach wurde die Behandlung der Schafe (im allgemeinen 3—4 Tage pro Wirkstoff, mindestens aber 2) vorgenommen. Den Tieren wurde oral oder parenteral eine Suspension von unterschiedlicher Wirkstoffmenge in jeweils 10 ml einer 1%igenCarboxymethylcellulose-Suspension appliziert. Jeweils am 7., 14. und 28.Tag nach der Behandlung wurde wiederum nach den vorstehend angegebenen Verfahren die Eizahl pro Gramm Kot ermittelt und ihre prozentuale Abnahme im Vergleich zum Ausgangswert vor der Behandlung errechnet. Mit einigen Verbindungen wurden außerdem beim Fasciola-Befall noch eine zusätzliche Prüftechnik angewandt: Nach Abschluß der Präpatenzperiode wurde bei Fasciola-positiven Schafen ein künstlicher Gallengang geschaffen, der am Ausgang der Gallenblase ein Sieb enthielt, so daß die nach der Behandlung abgetöteten Leberegel in der Gallenblase aufgefangen werden konnten. Vier bis sieben Tage nach der Behandlung wurden die so operierten und dann behandelten Schafe getötet, die abgetöteten Leberegel ! in der Gallenblase sowie noch eventuell in der Leber vorhandene lebende Leberegel gezählt und von der gesamten Wurmbürde jTo determine the anthelmintic effect of the compounds of formula I, chemotherapeutic studies were carried out on sheep weighing about 25-30 kg, orally infected with either metacercariae of Fasciola hepatica or larvae of gastrointestinal strongyles, notably Haemonchus contortus and Trichostongylus colubriformis were. At the end of the prepatent period (time between infection and sexual maturity of the parasites with beginning excretion of eggs or larvae) the parasitic infestation was confirmed by fecal examinations. In the case of liver fluke infection, the qualitative-quantitative detection of eggs after the telemann enrichment was done (German Medical Weekly 34 1510, [1908]). The egg number per gram feces of gastrointestinal strongylids was determined in the modified McMaster method according to Wetzel (Veterinary Survey 6,209, [1951]). Immediately thereafter, the treatment of the sheep (generally 3-4 days per active ingredient, but at least 2) was carried out. The animals were orally or parenterally applied a suspension of different amounts of active ingredient in each 10 ml of a 1% carboxymethylcellulose suspension. On the 7th, 14th and 28th day after the treatment, in each case, the egg count per gram of faeces was determined according to the methods indicated above and their percentage decrease compared to the starting value before the treatment was calculated. An additional test technique was also used with some compounds in Fasciola infestation: After completion of the prepatency period, an artificial bile duct was created in Fasciola-positive sheep which contained a sieve at the exit of the gallbladder, so that the liver flukes in the gallbladder killed after treatment could be caught. Four to seven days after the treatment, the sheep so treated and then treated were killed, the killed liver flukes! counted in the gallbladder as well as possibly in the liver existing liver flukes and of the entire wormwood j
der Prozentsatz der abgetöteten Parasiten berechnet. the percentage of killed parasites is calculated.
Zusätzlich sind auch Wirksamkeitstest bei Helminthen während der Präpatenzperiode möglich. Hierbei werden die Wirkstoffe zu IIn addition, efficacy testing of helminths during the prepatency period is possible. Here, the active ingredients become I.
bestimmten Zeitpunkten innerhalb dieser Periode appliziert, bei denen der Übergang von einen zum nächsten japplied to certain times within this period, in which the transition from one to the next j
Entwicklungsstadium erfolgt. |Development stage takes place. |
Von den Verbindungen der Formel I sind neu diejenigen Stoffe, bei denen R2 einen Alkylrest mit 1 bis 8 C-Atomen oder solche, jOf the compounds of formula I, those are those in which R 2 is an alkyl radical having 1 to 8 C atoms or those, j
bei denen R1 einen durch eine OCF3-Gruppe substituierten Phenylrest und R2 = H bedeutet. Diese Verbindungen sind ebenfalls j Gegenstand der vorliegenden Erfindung.in which R 1 is a phenyl radical substituted by an OCF 3 group and R 2 = H. These compounds are also the subject of the present invention.
In den nachfolgenden Tabellen 1 und 2 sind die Wirkungen von Verbindungen der Formel I und von bekannten handelsüblichen Vergleichsprodukten aufgeführt. Als Vergleichsprodukte dienten S'-ChloM'-ip-chlor-phenoxyl-S.ö-dijodsalicylanilid (Rafoxandine) und 5,5'-Dichlor-2-2'-dihydroxy-3,3'-dinitro-biphenyl (Niclofolan).Tables 1 and 2 below list the effects of compounds of formula I and of known commercial comparative products. S'-ChloM'-ip-chloro-phenoxy-S-diiodo-salicylanilide (rafoxandine) and 5,5'-dichloro-2-2'-dihydroxy-3,3'-dinitro-biphenyl (Nicolofolan) were used as reference products.
In der Tabelle 3 werden die Wirksamkeiten von erfindungsgemäßen 5-Halogen-benzoesäureaniliden mit denen entsprechender Derivate isomerer nicht beanspruchter Halogen-aminobenzoesäuren verglichen.Table 3 compares the efficacies of 5-halo-benzoic acid anilides according to the invention with those of corresponding derivatives of isomeric unclaimed haloaminobenzoic acids.
Aus den Tabellen ist eine Überlegenheit der erfindungsgemäßen Sulfonylanthranilsäureanilide, meistens in mehreren, mindestens aber in einem der folgenden Punkte ersichtlich:From the tables, a superiority of the sulfonylanthranilic acid anilides according to the invention, usually in several, but at least one of the following points:
1. geringere Dosierung (Dosis curativa minima/D.c.m.)1. lower dosage (dose curativa minima / D.c.m.)
2. bessere Wirksamkeit (Effekt)2. better effectiveness (effect)
3. breiteres Spektrum3. wider range
4. größerer chemotherapeutischer Index4. larger chemotherapeutic index
Der chemotherapeutische Index gibt den Quotienten aus Dosis tolerata maxima und Dosis curativa minima an.The chemotherapeutic index gives the quotient of dose tolerata maxima and dose curativa minima.
Die typischen Verfahrensweisen für die Herstellung der erfindungsgemäß verwendeten Produkte der allgemeinen Formel I werden durch die folgenden Beispiele erläutert.The typical procedures for the preparation of the products of the general formula I used according to the invention are illustrated by the following examples.
1: B-Brom^-t^-chlor-phenylsulfonyll-arninoJ-benzoesäure-fS-tnfluorrnethyl-anilid) Zu einer Lösung von 69g 2-Amino-5-brom-benzoesäure-methylester in 150ml Pyridin gab man unter Eiskühlung und gutem Rühren portionsweise 63g gepulvertes 4-Chlor-benzolsulfochlorid, rührte anschließend noch 12 Stunden bei Raumtemperatur nach, goß auf Wasser und Eis, dekantierte ab, behandelte das organische Produkt mit verdünnter Salzsäure, zerkleinerte, saugte ab, wusch in Wasser nach und trocknete. Ausbeute 115g an praktisch sauberen 5-Brom-2-[(4-chlorphenylsulfonyl)-amino]-benzoesäure-methylestervom Schmp. 104°C. 45g dieses Esters erhitzte man in der Lösung 9,8g NaOH in einer Mischung aus 20 ml Wasser und 30 ml Methanol 4 Stunden unter Rückfluß, löste das ausgefallene Natriumsalz durch Zugabe von 11 Wasser auf, stellte mit konzentrierter Salzsäure sauer, saugte die Ausfällung ab, wusch mit Wasser und trocknete. Ausbeute 39,9 g, Schmp. 225X. Die rohe Säure erhitzte man in 100 ml Thionylchlorid 1 Stunde unter Rückfluß und entfernte anschließend den Überschuß im Vakuum der Wasserstahlpumpe. Das rohe Säurechlorid wog 42,6g und schmolz bei ca. 125g. Zu einer Lösung von 20 g dieses Säurechlorids und 8,9 g 3-Trifluormethyl-anilin in 200 ml Methylenchlorid tropfte man unter Eiskühlung 6,1 g Triäthylamin, rührte noch 24 Sunden bei Raumtemperatur nach, saugte die Ausfällung, wusch mit verdünnter Salzsäure mit Wasser und trocknete. Die Ausbeute des bei 2200C schmelzenden Anilids betrug 19,1 g. Das Produkt war fast sauber, konnte jedoch auch noch mit geringem Verlust aus Acetonitril umkristallisiert werden1: B-bromo ^ -t ^ -chloro-phenylsulfonyl-arninoJ-benzoic acid-fS-t-n-fluoro-anilide) To a solution of methyl 69g of 2-amino-5-bromo-benzoic acid in 150 ml of pyridine was added under ice-cooling with good stirring 63 g of powdered 4-chloro-benzenesulfonyl chloride, then stirred for a further 12 hours at room temperature, poured onto water and ice, decanted, treated the organic product with dilute hydrochloric acid, crushed, sucked off, washed in water and dried. Yield 115g of virtually clean 5-bromo-2 - [(4-chlorophenylsulfonyl) -amino] -benzoic acid methyl ester of mp 104 ° C. 45 g of this ester were heated in the solution 9.8 g of NaOH in a mixture of 20 ml of water and 30 ml of methanol for 4 hours under reflux, dissolved the precipitated sodium salt by addition of 11 water, acidified with concentrated hydrochloric acid, sucked the precipitate, washed with water and dried. Yield 39.9 g, mp 225X. The crude acid was refluxed in 100 ml of thionyl chloride for 1 hour and then the excess was removed in vacuo of the water jet pump. The crude acid chloride weighed 42.6g and melted at about 125g. To a solution of 20 g of this acid chloride and 8.9 g of 3-trifluoromethyl-aniline in 200 ml of methylene chloride was added dropwise with ice cooling 6.1 g of triethylamine, stirred for a further 24 hours at room temperature, the precipitate sucked, washed with dilute hydrochloric acid with water and dried. The yield of the melting at 220 0 C anilide was 19.1 g. The product was almost clean but could be recrystallized from acetonitrile with little loss
2: 5-Chlor-2-[(4-chlor-phenylsulfonyl)-amino]-benzoesäure-dodecylamid2: 5-Chloro-2 - [(4-chloro-phenylsulfonyl) amino] benzoic acid dodecylamide
Zu einer Lösung von 28,2 g 5-Chlor-2-nitro-benzoylchlorid in 120ml Methylenchlorid tropfte man unter Eiskühlung eine Lösung von 27,8g Dodecylamin und 17,7 g Triäthylamin in 120 ml Methylenchlorid, rührte noch 24 Stunden bei Raumtemperatur, wusch mit verdünnter Salzsäure und mit Wasser und destillierte das Lösungsmittel unter vermindertem Druck ab. Man erhielt 43,6 g praktisch sauberes Produkt von Schmp. 1100C. 37,4 g dieser Verbindung wurden in 400 ml Methanol gelöst und mit Raney-Nickel bei Raumtemperatur unter Normaldruck hydriert. Innerhalb von 3 Stunden wurde die berechnete Menge Wasserstoff aufgenommen. Man filtrierte heiß vom Katalysator ab, dampfte das Filtrat unter vermindertem Druck ein und kristallisierte den Rückstand aus Methanol um. Ausbeute 28g, Schmp. 113°C.To a solution of 28.2 g of 5-chloro-2-nitro-benzoyl chloride in 120 ml of methylene chloride was added dropwise with ice cooling, a solution of 27.8 g of dodecylamine and 17.7 g of triethylamine in 120 ml of methylene chloride, stirred for 24 hours at room temperature, washed with dilute hydrochloric acid and with water and the solvent was distilled off under reduced pressure. 43.6 g was obtained practically pure product of mp. 110 0 C. 37.4 g of this compound were dissolved in 400 ml of methanol and hydrogenated with Raney nickel at room temperature under normal pressure. Within 3 hours, the calculated amount of hydrogen was taken up. It was filtered hot from the catalyst, the filtrate was evaporated under reduced pressure and the residue was recrystallized from methanol. Yield 28g, mp 113 ° C.
Man löste 17g dieser Aminoverbindung in 50ml Pyridin, gab unter Rühren und Eiskühlung portionsweise 11 g gepulvertes 4-Chlor-benzolsulfochlorid zu, rührte noch 24 Stunden bei Raumtemperatur nach, gab das Gemisch dann auf 11 Eiswasser, dekantierte die wäßrige Phase ab, behandelte das organische Material mit verdünnter Salzsäure, saugte ab, wusch mit Wasser, trocknete und kristallisierte aus Methanol um. Die Ausbeute an reinem Produkt betrug 20,2g, der Schmp. 117°C. 3: 2-[(3,4-Dichlor-phenyisuifonyl)-amino]-5-äthylthiobenzoesäure-(4-chlor-anilid) Zu einer Lösung von 108g ö-Chlor^-nitrobenzoesäuremethylester und 35g Äthylmercaptan in 170ml Dimethylsulfoxid gab man unter guter Kühlung bei OX portionsweise 57 g K-tert.-Butanolat. Dabei erfolgte jeweils eine heftige Reaktion. Nach 24 Stunden versetzte man mit Wasser, saugte die Ausfällung ab, wusch mit Wasser, trocknete, verrührte mit 400 ml Methanol, kühlte auf -78°C, saugte ab, wusch mit tiefgekühltem Methanol und trocknete. Die Ausbeute an dem sauberen Thioäther vom Schmp. 71 °C betrug 91,8g. 40 g dieser Verbindung löste man in 350 ml Methanol und fügte eine Lösung von 16,6 g NaOH in 40 ml Wasser hinzu. Nach 24 Stunden bei Raumtemperatur destillierte man das Lösungsmittel unter vermindertem Druck ab, nahm den Rückstand in Wasser auf, säuerte mit Salzsäure an, saugte ab, wusch mit Wasser und trocknete. Ausbeute 34,1 g, Schmp. 1420C. Man erhitzte die rohe Säure mit 100ml Thionylchlorid 31/2 Stunden unter Rückfluß, destillierte den Überschuß unter vermindertem Druck ab, versetzte den Rückstand zweimal mit je 100 ml Toluol und destillierte jeweils unter vermindertem Druck ab. Der Rückstand betrug 37,8g. Die gesamte Menge des Säurechlorids löste man in 100ml Methylenchlorid und tropfte unter Eiskühlung eine Lösung von 22,3g 4-Chlor-anilin und 20,2g Triäthylamin in 75ml Methylenchlorid zu. Nach 24 Stunden Rühren bei Raumtemperatur wusch man mit verdünnter Salzsäure und mit Wasser, trocknete, destillierte das Lösungsmittel ab und kristallisierte den Rückstand aus 300ml Toluol um. Ausbeute 38,3g, Schmp. 1610C.17 g of this amino compound was dissolved in 50 ml of pyridine, 11 g of powdered 4-chloro-benzenesulfonyl chloride were added in portions with stirring and ice cooling, the mixture was stirred for a further 24 hours at room temperature, then the mixture was added to ice-water, the aqueous phase was decanted, and the organic phase was treated Material with dilute hydrochloric acid, filtered off with suction, washed with water, dried and recrystallized from methanol. The yield of pure product was 20.2 g, the mp. 117 ° C. 3: 2 - [(3,4-Dichloro-phenylisulfonyl) -amino] -5-ethylthiobenzoic acid (4-chloro-anilide) To a solution of 108 g of 6-chloro-nitrobenzoic acid methyl ester and 35 g of ethylmercaptan in 170 ml of dimethylsulfoxide was added good Cooling with OX in portions 57 g K-tert-butoxide. In each case, a violent reaction took place. After 24 hours, water was added, the precipitate was filtered off with suction, washed with water, dried, stirred with 400 ml of methanol, cooled to -78 ° C., filtered off with suction, washed with deeply cooled methanol and dried. The yield of the clean thioether of mp. 71 ° C was 91.8 g. 40 g of this compound were dissolved in 350 ml of methanol and added to a solution of 16.6 g of NaOH in 40 ml of water. After 24 hours at room temperature, the solvent was distilled off under reduced pressure, the residue was taken up in water, acidified with hydrochloric acid, filtered off with suction, washed with water and dried. Yield 34.1 g, mp. 142 0 C. The mixture was heated with 100 ml of thionyl chloride, the crude acid 3 1/2 hours at reflux, the excess distilled off under reduced pressure, the residue is shifted twice with 100 ml of toluene and distilled under reduced respectively Pressure off. The residue was 37.8 g. The entire amount of the acid chloride was dissolved in 100 ml of methylene chloride and added dropwise under ice-cooling, a solution of 22.3 g of 4-chloroaniline and 20.2 g of triethylamine in 75 ml of methylene chloride. After stirring at room temperature for 24 hours, the mixture was washed with dilute hydrochloric acid and with water, dried, the solvent was distilled off and the residue was recrystallized from 300 ml of toluene. 38,3g yield, mp. 161 0 C.
Man löste 30g desAnilidsin einer Mischung von 250 ml Methanol und 50ml Dimethylformamid und hydrierte mit Raney-Nickel bei etwa 4O0C unter Normaldruck. Innerhalb von 2 Stunden wurde die berechnete Menge Wasserstoff aufgenommen. Man filtrierte heiß vom Katalysator ab, entfernte das Lösungsmittel unter vermindertem Druck, behandelte den Rückstand mit Wasser, saugte ab, wusch mit Wasser und trocknete. Das Produkt war fast sauber, die Ausbeute betrug 25,2 g, Schmp. ca. 130°C. Man löste 24,5 g dieses Amins in 70 ml Pyridin und tropfte unter Eiskühlung 20,9 g S^-Dichlorbenzolsulfochlorid zu. Nach 2 Tagen Rühren bei Raumtemperatur gab man auf Eis und Wasser, dekantierte, behandelte mit verdünnter Salzsäure, saugte ab, wusch mit Wasser, trocknete und kristallisierte aus Acetonitril um. Man erhielt 30,2 g reines Produkt vom Schmp. 1690C. 4: 2-[{3,4-Dichlorphenylsulfonyl)-amino]-5-äthylsulfonylbenzoesäure-(4-chlor-anilid) Man löste 8g der nach Beispiel 3 gewonnenen Verbindung in 110 ml Eisessig, erhitzte auf 6O0C und gab 5,8g und nach 17 Stunden weitere 2,5g 35%iges Wasserstoffperoxid zu. Nach insgesamt 21 Stunden Reaktionszeit destillierte man das Lösungsmittel unter vermindertem Druck ab und kristallisierte den Rückstand aus Toluol um. Ausbeute 7,0g, Schmp. 1950C. 5: 5-Chlor-2-[(3,4-dichlor-phenylsulfonyl)-amino]-benzoesäure-(4-chloranilid) Zur Lösung von 390 g Natriumcarbonat in 2,251 Wasser gab man bei 6O0C portionsweise 205,5g Anthranilsäure. Nach Auflösung tropfte man innerhalb von 30 Minuten bei der gleichen Temperatur 442g 3,4-Dichlor-benzolsulfochlorid zu, rührte 2 Stunden nach, filtrierte heiß und versetzte das Filtrat unter Rühren vorsichtig mit Salzsäure, bis ein pH-Wert von 3 erreicht wurde. DieWas dissolved 30g desAnilidsin a mixture of 250 ml methanol and 50 ml of dimethylformamide and hydrogenated with Raney nickel at about 4O 0 C under atmospheric pressure. Within 2 hours, the calculated amount of hydrogen was recorded. It was filtered hot from the catalyst, the solvent was removed under reduced pressure, the residue treated with water, filtered off with suction, washed with water and dried. The product was almost clean, the yield was 25.2 g, mp. 130 ° C. Dissolved 24.5 g of this amine in 70 ml of pyridine and added dropwise with ice cooling 20.9 g S ^ -Dichlorbenzolsulfochlorid. After stirring for 2 days at room temperature, the mixture was poured onto ice and water, decanted, treated with dilute hydrochloric acid, filtered off with suction, washed with water, dried and recrystallized from acetonitrile. 30.2 g of pure product of mp 169 0C. 4: 2 - [{3,4-Dichlorophenylsulphonyl) amino] -5-äthylsulfonylbenzoesäure- (4-chloro-anilide) was dissolved 8g of the obtained according to Example 3 Compound in 110 ml of glacial acetic acid, heated to 6O 0 C and added 5.8 g and after 17 hours, another 2.5 g of 35% hydrogen peroxide. After a total of 21 hours of reaction time, the solvent was distilled off under reduced pressure and the residue was recrystallized from toluene. Yield 7.0 g, mp 195 0 C.. 5: 5-Chloro-2 - [(3,4-dichloro-phenylsulfonyl) -amino] -benzoic acid (4-chloroanilide) were to a solution of 390 g of sodium carbonate in water 2.251 at 6O 0 C in portions 205.5 g of anthranilic acid. After dissolution was added dropwise within 30 minutes at the same temperature 442g 3,4-dichloro-benzenesulfonyl chloride, stirred for 2 hours, filtered hot and added the filtrate with stirring carefully with hydrochloric acid until a pH of 3 was reached. The
Ausfällung war erst harzig, wurde aber nach einiger Zeit kristallin. Man verrieb mit Wasser, saugte ab, wusch mit Wasser und trocknete. Die Ausbeute betrug 426 g, der Schmp. 174°C. Das Produkt war fast rein und konnte direkt weiterverarbeitet werden.Precipitation was only resinous, but became crystalline after some time. It was rubbed with water, sucked off, washed with water and dried. The yield was 426 g, the mp. 174 ° C. The product was almost pure and could be processed directly.
Irreine Lösung von 50g dieser Säure in 130ml Eisessig leitete man bei Rückflußtemperatur innerhalb von drei Stunden 22g Chlor ein, kühlte dann auf Raumtemperatur, saugte die Kristalle ab, wusch mit Eisessig und kaltem Methanol und trocknete. Die Ausbeute an der bei 226°C schmelzenden Chlorverbindung betrug 32,1 g; sie kann durch Aufarbeiten der Mutterlauge erhöhtA pure solution of 50 g of this acid in 130 ml of glacial acetic acid was introduced at reflux temperature within three hours 22g of chlorine, then cooled to room temperature, the crystals were filtered off with suction, washed with glacial acetic acid and cold methanol and dried. The yield of the chlorine compound melting at 226 ° C was 32.1 g; it can be increased by working up the mother liquor
werden. ^become. ^
Man erhitzte 49g dieser Säure mit 150ml Thionylchlorid 3 Stunden zum Rückfluß, destillierte den Überschuß ab, schüttelte den Rückstand zweimal mit je 100 ml Oktan und destillierte jeweils unter vermindertem Druck ab. Man erhielt das Säurechlorid in einer Ausbeute von 51,3g. Zu einer Lösung von 17,6g dieser Verbindung und 6,8g 4-Chlor-anilin in 150 ml Methylenchlorid tropfte man unter Eiskühlung eine Mischung aus 6,1 g Triäthylamin und 30 ml Methylenchlorid. Nach 24 Stunden Nachrühren bei Raumtemperatur wusch man mit verdünnter Salzsäure und Wasser, trocknete, destillierte das Lösungsmittel ab und kristallisierte den Rückstand aus Acetonitril um.49 g of this acid were heated with 150 ml of thionyl chloride for 3 hours to reflux, the excess was distilled off, the residue was shaken twice with 100 ml of octane and each distilled under reduced pressure. The acid chloride was obtained in a yield of 51.3 g. To a solution of 17.6 g of this compound and 6.8 g of 4-chloroaniline in 150 ml of methylene chloride was added dropwise, with ice cooling, a mixture of 6.1 g of triethylamine and 30 ml of methylene chloride. After stirring at room temperature for 24 hours, the mixture was washed with dilute hydrochloric acid and water, dried, the solvent was distilled off and the residue was recrystallized from acetonitrile.
Die Ausbeute an der reinen Verbindung vom Schmp. 225°C betrug 11,6g.The yield of the pure compound of mp. 225 ° C was 11.6 g.
Ersetzte man unter sonst gleichen Reaktionsbedingungen in der letzten Verfahrensstufe von Beispiel 5 4-Chloranilin durch 4-Trifluormethoxy-anilin, so erhielt man die Verbindung 35, mit 4-Chlor-N-äthyl-anilin die Verbindung 29.If, under otherwise identical reaction conditions, 4-chloroaniline was replaced by 4-trifluoromethoxy-aniline in the last process stage of Example 5, compound 35 was obtained, compound 4 using 4-chloro-N-ethylaniline.
Tabelle 1: Chemotherapeutische Untersuchungen (> 90% Reduktion der Wurmbürde) Wirtstier: SchafTable 1: Chemotherapeutic examinations (> 90% reduction of the worm burden) Host animal: sheep
Parasit: Leberegel (Fasciola hepatica) Dosis: mg/kg Körpergewicht, p. o.Parasite: liver fluke (Fasciola hepatica) Dose: mg / kg body weight, p. O.
Verbindung Nr.Connection no.
Dosisdose
Chemotherapeut. IndexChemo therapist. index
9 12 13 14 17 19 . 20 25 26 27 29 30 32 34 35 40 42 Rafoxanide Niclofolan9 12 13 14 17 19. 20 25 26 27 29 30 32 34 35 40 42 Rafoxanide Nicolofolan
Tabelle 2: Chemotherapeutische Untersuchungen (>90% Reduktion der Wurmbürde) Wirtstier: Schaf,Table 2: Chemotherapeutic studies (> 90% reduction in worm burden) Host animal: sheep,
Parasit: Magen-Darm-Würmer (Ostertagia, Haemonchur, Trichostrongylus, Cooperia, jeweils verschiedene Spezies) Dosis: mg/kg Körpergewicht, oral bzw. subkutanParasite: Gastrointestinal worms (Ostertagia, Haemonchur, Trichostrongylus, Cooperia, different species) Dose: mg / kg body weight, oral or subcutaneous
Verbindung Nr.Connection no.
Dosisdose
Chemotherapeut. IndexChemo therapist. index
13 16 20 21 22 33 35 38 42 Rafoxanide Niclofolan13 16 20 21 22 33 35 38 42 Rafoxanide Nicolofolane
Tabelle 3: Vergleichende Untersuchung isomerer Sulfonylamino-benzoesäureanilide (90% Reduktion der Wurmbürde) Wirtstier: SchafTable 3: Comparative study of isomeric sulfonylaminobenzoic acid anilides (90% reduction in worm burden) Host animal: sheep
Parasit: Leberegel (Fasciola hepatica) Dosis: mg/kg Körpergewicht, p.o.Parasite: liver fluke (Fasciola hepatica) Dose: mg / kg body weight, p.o.
Verbindung Nr.Connection no.
Dosisdose
Chemotherapeut. IndexChemo therapist. index
VIVI
V2V2
V3V3
V4V4
V5V5
26 V1026 V10
1,5 30 20 30 15 301.5 30 20 30 15 30
1 101 10
über 25 2 3 2 4 2over 25 2 3 2 4 2
über 25 5over 25 5
Claims (8)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19853523705 DE3523705A1 (en) | 1985-07-03 | 1985-07-03 | MEDICINAL PRODUCTS AND THE USE THEREOF |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DD248056A5 true DD248056A5 (en) | 1987-07-29 |
Family
ID=6274794
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DD86292009A DD248056A5 (en) | 1985-07-03 | 1986-07-01 | MEDICINES AND ITS USE |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0216028A2 (en) |
| JP (1) | JPS6210057A (en) |
| AU (1) | AU5948286A (en) |
| DD (1) | DD248056A5 (en) |
| DE (1) | DE3523705A1 (en) |
| DK (1) | DK314686A (en) |
| GR (1) | GR861712B (en) |
| HU (1) | HUT44483A (en) |
| PT (1) | PT82901B (en) |
| ZA (1) | ZA864915B (en) |
| ZM (1) | ZM4886A1 (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0420805A3 (en) * | 1989-09-26 | 1991-10-16 | Ciba-Geigy Ag | Anthelmintic compounds |
| EP0420804A3 (en) * | 1989-09-26 | 1991-11-27 | Ciba-Geigy Ag | Anthelmintic compounds |
| CA2057324A1 (en) * | 1990-12-18 | 1992-06-19 | Lora Louise Fitch | Benzamide and sulfonamide hypoglycemic agents |
| GB9511694D0 (en) * | 1995-06-09 | 1995-08-02 | Fujisawa Pharmaceutical Co | Benzamide derivatives |
| DE19830431A1 (en) | 1998-07-08 | 2000-01-13 | Hoechst Marion Roussel De Gmbh | Sulfonylamino-carboxylic acid N-arylamides as guanylate cyclase activators |
| US6716879B2 (en) | 2000-08-30 | 2004-04-06 | Compass Pharmaceuticals, Llc | Methods for anti-tumor therapy |
| US7119112B2 (en) * | 2002-02-28 | 2006-10-10 | Icagen, Inc. | Sulfonamides as potassium channel blockers |
| WO2005085188A2 (en) * | 2004-03-02 | 2005-09-15 | Compass Pharmaceuticals Llc | Compounds and methods for anti-tumor therapy |
| US7312248B2 (en) * | 2004-09-23 | 2007-12-25 | Schering-Plough Animal Health Corporation | Control of parasites in animals by the use of novel trifluoromethanesulfonanilide oxime ether derivatives |
| WO2006077901A1 (en) * | 2005-01-20 | 2006-07-27 | Shionogi & Co., Ltd. | Ctgf expression inhibitor |
| WO2006137376A1 (en) | 2005-06-21 | 2006-12-28 | Mitsui Chemicals, Inc. | Amide derivative and pesticide containing such compound |
| EP2990403A1 (en) * | 2014-08-29 | 2016-03-02 | Novartis Tiergesundheit AG | Anthranilamides, sulfonamides and nitro analogues derived therefrom as anthelmintics |
| WO2019232384A1 (en) * | 2018-06-01 | 2019-12-05 | Promega Corporation | Inhibitors of oplophorus luciferase-derived bioluminescent complexes |
-
1985
- 1985-07-03 DE DE19853523705 patent/DE3523705A1/en not_active Withdrawn
-
1986
- 1986-06-26 EP EP86108696A patent/EP0216028A2/en not_active Withdrawn
- 1986-06-27 ZM ZM48/86A patent/ZM4886A1/en unknown
- 1986-07-01 DD DD86292009A patent/DD248056A5/en unknown
- 1986-07-01 HU HU862743A patent/HUT44483A/en unknown
- 1986-07-01 GR GR861712A patent/GR861712B/en unknown
- 1986-07-02 AU AU59482/86A patent/AU5948286A/en not_active Abandoned
- 1986-07-02 ZA ZA864915A patent/ZA864915B/en unknown
- 1986-07-02 JP JP61154281A patent/JPS6210057A/en active Pending
- 1986-07-02 DK DK314686A patent/DK314686A/en not_active Application Discontinuation
- 1986-07-02 PT PT82901A patent/PT82901B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK314686D0 (en) | 1986-07-02 |
| JPS6210057A (en) | 1987-01-19 |
| HUT44483A (en) | 1988-03-28 |
| PT82901A (en) | 1986-08-01 |
| ZM4886A1 (en) | 1987-03-27 |
| GR861712B (en) | 1986-10-31 |
| AU5948286A (en) | 1987-01-08 |
| PT82901B (en) | 1989-01-30 |
| DE3523705A1 (en) | 1987-01-08 |
| ZA864915B (en) | 1987-02-25 |
| DK314686A (en) | 1987-01-04 |
| EP0216028A2 (en) | 1987-04-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE2815621C2 (en) | ||
| DE1668843A1 (en) | Biologically active substituted amidines | |
| DD248056A5 (en) | MEDICINES AND ITS USE | |
| DE2413722B2 (en) | New H4-phenoxyphenyl) -133triazine derivatives, a process for their preparation and their use as pharmaceuticals | |
| DE3005580A1 (en) | GUANIDINOBENZOESAE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE DERIVATIVES | |
| CH678621A5 (en) | ||
| DE2108975A1 (en) | Herbicidal N-acyl biscarbamates | |
| CH628887A5 (en) | METHOD FOR PRODUCING BENZOLSULFONYL UREA. | |
| DE2355262C3 (en) | 1-piperidinesulfonylureas, processes for their production and pharmaceutical preparations containing them | |
| DE2800740A1 (en) | ANTHELMINTICA | |
| EP0073507B1 (en) | Sulfonyl ureas, process for their preparation, pharmaceutical compositions containing them and their use | |
| DE2339993A1 (en) | CONDENSATION PRODUCTS AND THEIR APPLICATION | |
| DE2720926C2 (en) | Benzenesulfonylureas and process for their preparation | |
| DE2509037A1 (en) | 1-(4-(arylthio-or aryloxy) phenyl) uracils - coccidiocides for use in mammals as well as poultry, and for treatment of ioxoplasmosis | |
| DE2300447C2 (en) | Substituted 3-cyanobenzenesulfonamides, processes for their preparation and pharmaceuticals containing these compounds | |
| DE2413514B2 (en) | N-Acylaminoathylbenzenesulfonyl-N'-methylureas, process for their preparation and their use | |
| DE2238870B2 (en) | Benzenesulphonylurea | |
| EP0089597A2 (en) | Sulphonyl ureas, process for their preparation, pharmaceutical compositions containing them and their use | |
| DE2836385A1 (en) | MONOCARBOXYLATES OF PHENYLGUANIDINE SULPHONIC ACID ESTERS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS | |
| EP0007616B1 (en) | Isothiocyanobenzothiazole compound, process for its preparation and its use in anthelmintic compositions | |
| DE2157607C3 (en) | Sulphonylureas, processes for their production and pharmaceutical preparations containing them | |
| EP0031088A1 (en) | Benzene-sulfonyl ureas, processes for their preparation, pharmaceutical compositions based on these compounds and their use | |
| CH374984A (en) | Process for the preparation of benzenesulfonylureas | |
| DE2304764A1 (en) | BENZOYLPHENYLGUANIDINE, A METHOD FOR MANUFACTURING IT AND THEIR USE AS A MEDICINAL PRODUCT | |
| DE1937759A1 (en) | Benzenesul phenyl semicarbazides for diabetes - mellitus |