TW201607919A - 新穎磺醯胺基苯甲醯胺化合物 - Google Patents
新穎磺醯胺基苯甲醯胺化合物 Download PDFInfo
- Publication number
- TW201607919A TW201607919A TW104118201A TW104118201A TW201607919A TW 201607919 A TW201607919 A TW 201607919A TW 104118201 A TW104118201 A TW 104118201A TW 104118201 A TW104118201 A TW 104118201A TW 201607919 A TW201607919 A TW 201607919A
- Authority
- TW
- Taiwan
- Prior art keywords
- group
- formula
- alkyl
- compound
- alkoxy
- Prior art date
Links
- CAWFFBLMSQUZPF-UHFFFAOYSA-N 2-(sulfonylamino)benzamide Chemical class NC(=O)C1=CC=CC=C1N=S(=O)=O CAWFFBLMSQUZPF-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 104
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 244000045947 parasite Species 0.000 claims abstract description 14
- 244000079386 endoparasite Species 0.000 claims abstract description 6
- -1 alkyl sulphide Chemical compound 0.000 claims description 40
- 229910052736 halogen Inorganic materials 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 35
- 150000002367 halogens Chemical group 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 22
- 241001465754 Metazoa Species 0.000 claims description 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 13
- 125000001188 haloalkyl group Chemical group 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 8
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 7
- 125000004995 haloalkylthio group Chemical group 0.000 claims description 7
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims description 5
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 5
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 5
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 5
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 5
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000004749 (C1-C6) haloalkylsulfinyl group Chemical group 0.000 claims description 4
- 125000006771 (C1-C6) haloalkylthio group Chemical group 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- 125000004741 (C1-C6) haloalkylsulfonyl group Chemical group 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000005554 pyridyloxy group Chemical group 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 239000002270 dispersing agent Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 abstract 1
- 238000000034 method Methods 0.000 description 34
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 16
- 241000002163 Mesapamea fractilinea Species 0.000 description 15
- 241000244206 Nematoda Species 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 14
- 125000000623 heterocyclic group Chemical group 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 125000001424 substituent group Chemical group 0.000 description 13
- 230000000694 effects Effects 0.000 description 11
- 241000242722 Cestoda Species 0.000 description 10
- 125000001309 chloro group Chemical group Cl* 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 241000282472 Canis lupus familiaris Species 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 239000012267 brine Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000004094 surface-active agent Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 230000003071 parasitic effect Effects 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 241000282326 Felis catus Species 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 241000244174 Strongyloides Species 0.000 description 5
- 241000607479 Yersinia pestis Species 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 244000000013 helminth Species 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 241001124076 Aphididae Species 0.000 description 4
- 241000244186 Ascaris Species 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- 241000243774 Trichinella Species 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 235000013601 eggs Nutrition 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 238000005342 ion exchange Methods 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 3
- 241001147657 Ancylostoma Species 0.000 description 3
- 241000271566 Aves Species 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 241000242711 Fasciola hepatica Species 0.000 description 3
- 241000699694 Gerbillinae Species 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 241001494479 Pecora Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 241000242541 Trematoda Species 0.000 description 3
- 241000869417 Trematodes Species 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 3
- 244000144972 livestock Species 0.000 description 3
- 230000033001 locomotion Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002062 proliferating effect Effects 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 235000001508 sulfur Nutrition 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 2
- JHPDYTWKYXLERH-UHFFFAOYSA-N 5-bromo-2-(methanesulfonamido)benzoic acid Chemical compound CS(=O)(=O)NC1=CC=C(Br)C=C1C(O)=O JHPDYTWKYXLERH-UHFFFAOYSA-N 0.000 description 2
- XCVCVXQXUHWWMN-UHFFFAOYSA-N 5-chloro-2-nitro-N-(3,4,5-trichlorophenyl)benzamide Chemical compound [O-][N+](=O)C1=C(C=C(Cl)C=C1)C(=O)NC1=CC(Cl)=C(Cl)C(Cl)=C1 XCVCVXQXUHWWMN-UHFFFAOYSA-N 0.000 description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 241000238876 Acari Species 0.000 description 2
- 241000272517 Anseriformes Species 0.000 description 2
- 241000255789 Bombyx mori Species 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- DRAPCFCYPRVFRY-UHFFFAOYSA-N C1C=C(C(=CC1=CC2=CC=C(C=C2)Cl)C(=O)O)[N+](=O)[O-] Chemical compound C1C=C(C(=CC1=CC2=CC=C(C=C2)Cl)C(=O)O)[N+](=O)[O-] DRAPCFCYPRVFRY-UHFFFAOYSA-N 0.000 description 2
- 241000244203 Caenorhabditis elegans Species 0.000 description 2
- 241000282465 Canis Species 0.000 description 2
- 241000253350 Capillaria Species 0.000 description 2
- 241000244160 Echinococcus Species 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 241001626440 Joyeuxiella Species 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 241000244155 Taenia Species 0.000 description 2
- 241001489151 Trichuris Species 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- DOZZESQBLWOEBQ-UHFFFAOYSA-N chlorohydrazine Chemical compound NNCl DOZZESQBLWOEBQ-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Chemical compound CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 235000013373 food additive Nutrition 0.000 description 2
- 239000002778 food additive Substances 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 230000012447 hatching Effects 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000002917 insecticide Substances 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- HJOVHMDZYOCNQW-UHFFFAOYSA-N isophorone Chemical compound CC1=CC(=O)CC(C)(C)C1 HJOVHMDZYOCNQW-UHFFFAOYSA-N 0.000 description 2
- 230000007653 larval development Effects 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 description 2
- 229940041033 macrolides Drugs 0.000 description 2
- AWLNSBUBLUCQJD-UHFFFAOYSA-N methyl 2-amino-5-[(4-chlorophenyl)-cyanomethyl]benzoate Chemical compound COC(=O)C1=C(N)C=CC(=C1)C(C#N)C1=CC=C(Cl)C=C1 AWLNSBUBLUCQJD-UHFFFAOYSA-N 0.000 description 2
- QDPZOIXFPCHMLR-UHFFFAOYSA-N methyl 5-bromo-2-(methanesulfonamido)benzoate Chemical compound COC(=O)C1=CC(Br)=CC=C1NS(C)(=O)=O QDPZOIXFPCHMLR-UHFFFAOYSA-N 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical compound CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 description 1
- FUWVMBCPMRAWPG-UHFFFAOYSA-N 2,3-dihydroxypropyl 2-hydroxyoctadecanoate Chemical compound CCCCCCCCCCCCCCCCC(O)C(=O)OCC(O)CO FUWVMBCPMRAWPG-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- MLZOTIHLJQSLIN-UHFFFAOYSA-N 2-amino-5-(4-chlorophenoxy)-N-(3,4,5-trichlorophenyl)benzamide Chemical compound NC1=C(C=C(OC2=CC=C(Cl)C=C2)C=C1)C(=O)NC1=CC(Cl)=C(Cl)C(Cl)=C1 MLZOTIHLJQSLIN-UHFFFAOYSA-N 0.000 description 1
- XRXMNWGCKISMOH-UHFFFAOYSA-M 2-bromobenzoate Chemical compound [O-]C(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-M 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- AZSNMRSAGSSBNP-UHFFFAOYSA-N 22,23-dihydroavermectin B1a Natural products C1CC(C)C(C(C)CC)OC21OC(CC=C(C)C(OC1OC(C)C(OC3OC(C)C(O)C(OC)C3)C(OC)C1)C(C)C=CC=C1C3(C(C(=O)O4)C=C(C)C(O)C3OC1)O)CC4C2 AZSNMRSAGSSBNP-UHFFFAOYSA-N 0.000 description 1
- ZKUYSJHXBFFGPU-UHFFFAOYSA-N 2516-95-2 Chemical compound OC(=O)C1=CC(Cl)=CC=C1[N+]([O-])=O ZKUYSJHXBFFGPU-UHFFFAOYSA-N 0.000 description 1
- XOGYQVITULCUGU-UHFFFAOYSA-N 3,4,5-trichloroaniline Chemical compound NC1=CC(Cl)=C(Cl)C(Cl)=C1 XOGYQVITULCUGU-UHFFFAOYSA-N 0.000 description 1
- CDIDGWDGQGVCIB-UHFFFAOYSA-N 3,5-bis(trifluoromethyl)aniline Chemical compound NC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 CDIDGWDGQGVCIB-UHFFFAOYSA-N 0.000 description 1
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 1
- IVYMIRMKXZAHRV-UHFFFAOYSA-N 4-chlorophenylacetonitrile Chemical compound ClC1=CC=C(CC#N)C=C1 IVYMIRMKXZAHRV-UHFFFAOYSA-N 0.000 description 1
- BMFMOTVRIVPSGS-UHFFFAOYSA-N 5-(4-chlorophenoxy)-2-(methanesulfonamido)-N-(3,4,5-trichlorophenyl)benzamide Chemical compound CS(=O)(=O)NC1=C(C=C(OC2=CC=C(Cl)C=C2)C=C1)C(=O)NC1=CC(Cl)=C(Cl)C(Cl)=C1 BMFMOTVRIVPSGS-UHFFFAOYSA-N 0.000 description 1
- IYVZZSMKXCNKGD-UHFFFAOYSA-N 5-(4-chlorophenoxy)-2-nitro-N-(3,4,5-trichlorophenyl)benzamide Chemical compound [O-][N+](=O)C1=C(C=C(OC2=CC=C(Cl)C=C2)C=C1)C(=O)NC1=CC(Cl)=C(Cl)C(Cl)=C1 IYVZZSMKXCNKGD-UHFFFAOYSA-N 0.000 description 1
- AFSKOMLWCFUJIG-UHFFFAOYSA-N 5-[(4-chlorophenyl)-cyanomethyl]-2-(methanesulfonamido)-N-(3,4,5-trichlorophenyl)benzamide Chemical compound CS(=O)(=O)NC1=C(C=C(C=C1)C(C#N)C1=CC=C(Cl)C=C1)C(=O)NC1=CC(Cl)=C(Cl)C(Cl)=C1 AFSKOMLWCFUJIG-UHFFFAOYSA-N 0.000 description 1
- UUBWDEJASHPUBR-UHFFFAOYSA-N 5-[(4-chlorophenyl)-cyanomethyl]-2-nitrobenzoic acid Chemical compound OC(=O)c1cc(ccc1[N+]([O-])=O)C(C#N)c1ccc(Cl)cc1 UUBWDEJASHPUBR-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- SPBDXSGPUHCETR-JFUDTMANSA-N 8883yp2r6d Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)CC4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 SPBDXSGPUHCETR-JFUDTMANSA-N 0.000 description 1
- 241000244037 Acanthocheilonema viteae Species 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 206010003399 Arthropod bite Diseases 0.000 description 1
- 241000204727 Ascaridia Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000244036 Brugia Species 0.000 description 1
- JHMPREHBWONKGF-UHFFFAOYSA-N C1C=C(C(=CC1=CC2=CC=C(C=C2)Cl)C(=O)NC3=CC(=C(C(=C3)Cl)Cl)Cl)[N+](=O)[O-] Chemical compound C1C=C(C(=CC1=CC2=CC=C(C=C2)Cl)C(=O)NC3=CC(=C(C(=C3)Cl)Cl)Cl)[N+](=O)[O-] JHMPREHBWONKGF-UHFFFAOYSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- SSUFDOMYCBCHML-UHFFFAOYSA-N CCCCC[S](=O)=O Chemical class CCCCC[S](=O)=O SSUFDOMYCBCHML-UHFFFAOYSA-N 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241001126268 Cooperia Species 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 241000218691 Cupressaceae Species 0.000 description 1
- 201000003808 Cystic echinococcosis Diseases 0.000 description 1
- 238000010485 C−C bond formation reaction Methods 0.000 description 1
- 241001147667 Dictyocaulus Species 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 241001626447 Diplopylidium Species 0.000 description 1
- 241001559132 Dipylidiidae Species 0.000 description 1
- 241000935792 Dipylidium caninum Species 0.000 description 1
- 241000243988 Dirofilaria immitis Species 0.000 description 1
- 235000003550 Dracunculus Nutrition 0.000 description 1
- 241000316827 Dracunculus <angiosperm> Species 0.000 description 1
- 241000244170 Echinococcus granulosus Species 0.000 description 1
- 241000244163 Echinococcus multilocularis Species 0.000 description 1
- 241000498256 Enterobius Species 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- 229920000896 Ethulose Polymers 0.000 description 1
- 239000001859 Ethyl hydroxyethyl cellulose Substances 0.000 description 1
- 241000567920 Filariidae Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000243976 Haemonchus Species 0.000 description 1
- 241000255990 Helicoverpa Species 0.000 description 1
- 241000920462 Heterakis Species 0.000 description 1
- 241000244156 Hydatigera taeniaeformis Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010093096 Immobilized Enzymes Proteins 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
- 241000520690 Mesocestoides Species 0.000 description 1
- 241000322137 Mesocestoides lineatus Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- SWTNRGGUOSJMBO-UHFFFAOYSA-N N-(3,4,5-trichlorophenyl)benzamide Chemical compound C(C1=CC=CC=C1)(=O)NC1=CC(=C(C(=C1)Cl)Cl)Cl SWTNRGGUOSJMBO-UHFFFAOYSA-N 0.000 description 1
- UMAMCCVQWMKGLF-UHFFFAOYSA-N N-[3,5-bis(trifluoromethyl)phenyl]-5-bromo-2-(methanesulfonamido)benzamide Chemical compound FC(C=1C=C(C=C(C=1)C(F)(F)F)NC(C1=C(C=CC(=C1)Br)NS(=O)(=O)C)=O)(F)F UMAMCCVQWMKGLF-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 241000498271 Necator Species 0.000 description 1
- 241001137882 Nematodirus Species 0.000 description 1
- IGFHQQFPSIBGKE-UHFFFAOYSA-N Nonylphenol Natural products CCCCCCCCCC1=CC=C(O)C=C1 IGFHQQFPSIBGKE-UHFFFAOYSA-N 0.000 description 1
- 241000510960 Oesophagostomum Species 0.000 description 1
- 241000243981 Onchocerca Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000283868 Oryx Species 0.000 description 1
- 241000243795 Ostertagia Species 0.000 description 1
- 241000904715 Oxyuris Species 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 241000244187 Parascaris Species 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 241000243820 Polychaeta Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002675 Polyoxyl Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 208000035415 Reinfection Diseases 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 241000232199 Setariidae Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229910021607 Silver chloride Inorganic materials 0.000 description 1
- 241000122932 Strongylus Species 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 241000356560 Taenia multiceps Species 0.000 description 1
- 241000244154 Taenia ovis Species 0.000 description 1
- 241001672170 Taenia pisiformis Species 0.000 description 1
- 241000356557 Taenia serialis Species 0.000 description 1
- 241000244161 Taeniidae Species 0.000 description 1
- 241000607216 Toxascaris Species 0.000 description 1
- 241000244031 Toxocara Species 0.000 description 1
- 241000243797 Trichostrongylus Species 0.000 description 1
- 241000571986 Uncinaria Species 0.000 description 1
- 241000244002 Wuchereria Species 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- 108010055615 Zein Proteins 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 1
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 description 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 1
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 1
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000001195 anabolic effect Effects 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 229940125687 antiparasitic agent Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229910052785 arsenic Inorganic materials 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000003139 biocide Substances 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000006630 butoxycarbonylamino group Chemical group 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000003224 coccidiostatic agent Substances 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 description 1
- 229940099686 dirofilaria immitis Drugs 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000004495 emulsifiable concentrate Substances 0.000 description 1
- 239000008393 encapsulating agent Substances 0.000 description 1
- 125000006437 ethyl cyclopropyl group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000019326 ethyl hydroxyethyl cellulose Nutrition 0.000 description 1
- 208000006275 fascioliasis Diseases 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000004209 hair Anatomy 0.000 description 1
- 125000004440 haloalkylsulfinyl group Chemical group 0.000 description 1
- 125000004441 haloalkylsulfonyl group Chemical group 0.000 description 1
- 125000005347 halocycloalkyl group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical class [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000000077 insect repellent Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960002418 ivermectin Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000001365 lymphatic vessel Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- SDYDKJHWMWDIKC-UHFFFAOYSA-N methyl 5-[(4-chlorophenyl)-cyanomethyl]-2-(methanesulfonamido)benzoate Chemical compound COC(=O)C1=C(NS(C)(=O)=O)C=CC(=C1)C(C#N)C1=CC=C(Cl)C=C1 SDYDKJHWMWDIKC-UHFFFAOYSA-N 0.000 description 1
- QPMSONXPAOSXJT-UHFFFAOYSA-N methyl 5-[(4-chlorophenyl)-cyanomethyl]-2-nitrobenzoate Chemical compound ClC1=CC=C(C=C1)C(C=1C=CC(=C(C(=O)OC)C=1)[N+](=O)[O-])C#N QPMSONXPAOSXJT-UHFFFAOYSA-N 0.000 description 1
- JGBJHRKCUKTQOE-UHFFFAOYSA-N methyl 5-chloro-2-nitrobenzoate Chemical compound COC(=O)C1=CC(Cl)=CC=C1[N+]([O-])=O JGBJHRKCUKTQOE-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- CKVMAPHTVCTEMM-ALPQRHTBSA-N milbemycin oxime Chemical compound O1[C@H](C)[C@@H](C)CC[C@@]11O[C@H](C\C=C(C)\C[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)C(=N/O)/[C@H]3OC\2)O)C[C@H]4C1.C1C[C@H](C)[C@@H](CC)O[C@@]21O[C@H](C\C=C(C)\C[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)C(=N/O)/[C@H]3OC\1)O)C[C@H]4C2 CKVMAPHTVCTEMM-ALPQRHTBSA-N 0.000 description 1
- 229940099245 milbemycin oxime Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- YZBLFMPOMVTDJY-CBYMMZEQSA-N moxidectin Chemical compound O1[C@H](C(\C)=C\C(C)C)[C@@H](C)C(=N/OC)\C[C@@]11O[C@H](C\C=C(C)\C[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 YZBLFMPOMVTDJY-CBYMMZEQSA-N 0.000 description 1
- 229960004816 moxidectin Drugs 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 230000001069 nematicidal effect Effects 0.000 description 1
- ZNPKAOCQMDJBIK-UHFFFAOYSA-N nitrocyanamide Chemical compound [O-][N+](=O)NC#N ZNPKAOCQMDJBIK-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- SNQQPOLDUKLAAF-UHFFFAOYSA-N nonylphenol Chemical compound CCCCCCCCCC1=CC=CC=C1O SNQQPOLDUKLAAF-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical class C(CCCC)* 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 235000013594 poultry meat Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000005871 repellent Substances 0.000 description 1
- 230000002940 repellent Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000003378 silver Chemical class 0.000 description 1
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 description 1
- 229940071536 silver acetate Drugs 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- 239000012748 slip agent Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical class [H]S* 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
- A01N25/04—Dispersions, emulsions, suspoemulsions, suspension concentrates or gels
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N41/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom
- A01N41/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a sulfur atom bound to a hetero atom containing a sulfur-to-oxygen double bond
- A01N41/04—Sulfonic acids; Derivatives thereof
- A01N41/06—Sulfonic acid amides
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
- A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/84—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N55/00—Biocides, pest repellants or attractants, or plant growth regulators, containing organic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen and sulfur
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
- C07D213/643—2-Phenoxypyridines; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Environmental Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Dentistry (AREA)
- Engineering & Computer Science (AREA)
- Plant Pathology (AREA)
- Pest Control & Pesticides (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Dispersion Chemistry (AREA)
- Toxicology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
本發明係關於一種新式(I)之化合物
□其中該等變數具有如申請專利範圍中所指示之含義,或其對映異構體或鹽。該等式(I)化合物係用於在脊椎動物中及在脊椎動物上防治寄生蟲,尤其是體內寄生蟲。
Description
本發明係關於新穎磺醯胺基苯甲醯胺化合物及其在溫血動物中防治體內寄生蟲(例如心絲蟲)之用途。
心絲蟲(犬心絲蟲(Dirofilaria immitis))為經由蚊子叮咬在宿主之間傳播的寄生蛔蟲。確定的宿主為狗,但其亦可感染貓及其他溫血動物。儘管通常稱為「心絲蟲」,但成年蠕蟲實際上大部分存在於肺部動脈系統(肺動脈)中,且對動物健康之第一影響為對肺血管及組織之損害。間或,成年心絲蟲在重感染中遷移至右心及甚至大靜脈中。心絲蟲感染可導致宿主嚴重的疾病。
心絲蟲感染可以用以砷為主之化合物抗擊;該治療耗時、繁瑣且通常僅部分成功。因此,主要集中於預防心絲蟲感染。當前心絲蟲預防藉由將巨環內酯(諸如伊維菌素、莫昔克丁或米爾倍黴素肟)全年定期投藥至狗、貓或其他溫血動物中而專門進行。不利的是,即將來臨之犬心絲蟲對抗巨環內酯的抗性已在美國之某些部分中觀測到。因此,強烈需要尋找以防治之方式或藉由直接殺滅不同階段之心絲蟲而有效地防治心絲蟲感染的新穎類別化合物。現已出人意料地發現,一組新穎之磺醯胺基苯甲醯胺化合物對溫血動物有效地防治包括心絲蟲之體內寄生蟲。
因此,根據一項實施例,本發明係關於式(I)化合物:
或其鹽或對映異構體,其中X為O、S、NR2C(O)、C(CN)或CH=CH,R0為H、C1-C4烷基或羥基;n為0或1,各R獨立地為鹵素;C1-C6烷基;C1-C6鹵烷基;C3-C6環烷基;C3-C6鹵環烷基;胺基;N-單-或N,N-二-C1-C4烷基胺基;羥基;C1-C6烷氧基;C1-C6鹵基烷氧基;C1-C6烷基硫基;C1-C6鹵烷硫基;C1-C6烷基-亞磺醯基;C1-C6鹵烷基亞磺醯基;C1-C6烷基磺醯基;C1-C6鹵烷基磺醯基;SF5;三-C1-C4烷基矽烷基;C1-C6烷氧基羰基;胺基羰基;N-單-或N,N-二-C1-C6烷胺基羰基;胺基磺醯基;N-單-或N,N-二-C1-C6烷基胺基磺醯基;N-C1-C6烷基磺醯基胺基;C1-C6烷氧基羰基胺基;N-C1-C4烷基-N-C1-C6烷氧基羰基胺基;氰基;硝基;或C3-C6雜環基,該C3-C6雜環基未經取代或經鹵素、C1-C4烷基、C1-C4鹵烷基、C3-C6環烷基、C1-C4烷氧基、C1-C4鹵基烷氧基、胺基、氰基或硝基取代;m為0至4之整數;各R1獨立地為鹵素;C1-C6烷基;C1-C6鹵烷基;C3-C6環烷基;C3-C6鹵環烷基;C1-C6烷氧基;C1-C6鹵基烷氧基;C1-C6烷基硫基;C1-C6鹵烷硫基;C1-C6烷基-亞磺醯基;C1-C6鹵烷基亞磺醯基;C1-C6烷基磺醯基;C1-C6鹵烷基磺醯基;SF5;胺基;N-單-或N,N-二-C1-C6烷基胺基;三-C1-C4烷基矽烷基;C1-C6烷氧基羰基;胺基羰基;N-單-或N,N-二-C1-C6烷基胺基羰基;N,N-二-C1-C4烷基胺基-C1-C4烷基胺基羰基;胺基磺醯基;N-單-或N,N-二-
C1-C6烷基胺基磺醯基;N-C1-C6烷基磺醯基胺基;C1-C6烷氧基羰基胺基;N-C1-C4烷基-N-C1-C6烷氧基羰基胺基;氰基;硝基;羥基;B(OH)2;或苯基、苯甲醯基、C3-C6雜環基、C3-C6雜環基氧基或C6-C8苯并雜環基,其各自未經取代或經鹵素、C1-C4烷基、C1-C4鹵烷基、C3-C6環烷基、C1-C4烷氧基、C1-C4鹵基烷氧基、胺基、氰基或硝基取代;且r為1至4之整數。
本發明亦提供一種組合物,其包含式(I)化合物或其鹽或對映異構體,及至少一種載劑,例如界面活性劑、固態稀釋劑及/或液態稀釋劑。
在一項實施例中,本發明亦提供用於防治寄生蟲(尤其是體內寄生蟲)之組合物,該組合物包含生物有效量之式(I)化合物或其鹽,及選自由界面活性劑、固態稀釋劑及液態稀釋劑組成之群之至少一種額外組份,該組合物視情況進一步包含生物有效量之至少一種額外之醫藥或獸醫活性化合物或藥劑。
本發明亦提供用於防治寄生蟲之方法,該方法包含將寄生蟲或其環境與醫藥或獸醫有效量之式(I)化合物、對映異構體或其鹽((例如,如本文中所述之組合物)接觸。本發明亦係關於其中將寄生蟲或其環境與組合物接觸之此方法,該組合物包含醫藥或獸醫有效量之式(I)化合物、對映異構體或其鹽,及選自由界面活性劑、固態稀釋劑及液態稀釋劑組成之群的至少一種額外組份,該組合物視情況進一步包含醫藥或獸醫有效量之至少一種額外醫藥或獸醫活性化合物或藥劑。
本發明亦提供用於保護動物免遭寄生害蟲之方法,該方法包含向動物投與殺寄生蟲有效量之式(I)化合物、其對映異構體或鹽。
在上述敍述中,單獨使用或用於諸如「烷基硫基」、「鹵烷硫基」、「鹵烷基」、「N-烷基胺基」、「N,N-二-烷基胺基」及其類似者之組合詞彙的術語「烷基」包括直鏈或分支鏈烷基(諸如甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基或第三丁基或不同的戊基或己基異構體)。
單獨使用或用於諸如「鹵烷氧基」、「烷氧基羰基」之組合詞彙的術語「烷氧基」包括(例如)甲氧基、乙氧基、正丙氧基、異丙氧基及不同的丁氧基、戊氧基及己氧基異構體。「烷基硫基」包含分支鏈或直鏈烷基硫基部分,諸如甲基硫基、乙基硫基及不同的丙基硫基、丁基硫基、戊基硫基及己基硫基異構體。
「烷基亞磺醯基」包括烷基亞磺醯基之兩種對映異構體。「烷基亞磺醯基」之實例包括CH3S(O)-、CH3CH2S(O)-、CH3CH2CH2S(O)-、(CH3)2CHS(O)-及不同的丁基亞磺醯基、戊基亞磺醯基及己基亞磺醯基異構體。
「烷基羰基」指代與C(=O)部分鍵結之直鏈或分支鏈烷基部分。「烷基羰基」之實例包括CH3C(=O)-、CH3CH2CH2C(=O)-及(CH3)2CHC(=O)-。「烷氧基羰基」之實例包括CH3OC(=O)-、CH3CH2OC(=O)-、CH3CH2CH2OC(=O)-、(CH3)2CHOC(=O)-及不同的丁氧基或戊氧基羰基異構體(例如第三丁氧基羰基(Boc))。「烷氧基羰基胺基」或N-烷氧基羰基,N-烷基胺基之實例包括第三丁氧基羰基胺基及N-第三丁氧基羰基,N-甲基胺基。「N-單-或N,N-二烷基胺基羰基」之實例包括「N-甲基胺基羰基」、「N-乙基胺基羰基」、「N-甲基-N-乙基胺基羰基」、「N,N-二甲基胺基羰基」或「N,N-二乙基胺基羰基」。「烷基羰基胺基」之實例包括「甲基羰基胺基」或「乙基羰基胺基」。
「烷基磺醯基」之實例包括CH3S(O)2-、CH3CH2S(O)2-、CH3CH2CH2S(O)2-、(CH3)2CHS(O)2-及不同之丁基磺醯基、戊基磺醯基及己基磺醯基異構體。「N-單-或N,N-二烷基胺基磺醯基」之實例包括「N-甲基胺基磺醯基」、「N-乙基胺基磺醯基」、「N-甲基-N-乙基胺基磺醯基」、「N,N-二甲基胺基磺醯基」或「N,N-二乙基胺基磺醯基」。「烷基磺醯基胺基」之實例包括「甲基磺醯基胺基」或「乙基磺醯基胺基」。
「環烷基」包括(例如)環丙基、環丁基、環戊基及環己基。術語「烷基環烷基」指代在環烷基部分上之烷基取代基,且包括(例如)乙基環丙基、異丙基環丁基、3-甲基環戊基及4-甲基環己基。
單獨或在諸如「鹵烷基」之組合詞彙中之術語「鹵素」包括氟、氯、溴或碘。此外,當用於諸如「鹵烷基」之組合詞彙中時,該烷基可經相同或不同之鹵素原子部分或完全取代。「鹵烷基」實例包括F3C-、ClCH2-、CF3CH2-及CF3CCl2-。術語「鹵環烷基」、「鹵烷氧基」、「鹵烷硫基」及類似者類似於術語「鹵烷基」加以定義。「鹵烷氧基」之實例包括CF3O-、CF3CF2-O-、CF3CH2O-、CCl3CH2O-、CF3CHFCF2O-及HCF2CH2CH2O-;且「鹵烷硫基」之實例包括CCl3S-、CF3S-、CCl3CH2S-及ClCH2CH2CH2S-。「鹵烷基亞磺醯基」之實例包括CF3S(O)-、CCl3S(O)-、CF3CH2S(O)-及CF3CF2S(O)-。「鹵烷基磺醯基」之實例包括CF3S(O)2-、CCl3S(O)2-、CF3CH2S(O)2-及CF3CF2S(O)2-。
在取代基基團中之碳原子之總數由其中i及j係整數之「Ci-Cj」字首指示。舉例而言,C1-C4烷基磺醯基標明甲基磺醯基至丁基磺醯基。
當化合物經由取代基(帶有指示該等取代基之數目可超出1之下標)取代時,該等取代基(當其超出1時)係獨立地選自由經定義之取代
基之群(例如,(R2)n,n為1或2)。「芳族」指示環原子中之每一者基本上在同一平面上,且具有垂直於環平面之ap-軌道,且其中(4n+2)π電子(其中n為正整數)遵守休克爾規則(Hckel's rule)與環相關聯。
術語「雜環基」、「雜環」或「雜環」指代其中形成環骨架之至少一個原子(例如,氮、氧、硫、或基團S(O)或S(O2))並非碳之環。通常雜環含有不多於4個氮、不多於2個氧及不多於2個硫。此外,雜環可含有基團-C(O)-、-S(O)-或-S(O2)-。除非另有指示,否則雜環可為飽和環、部分不飽和環或完全不飽和環。當完全不飽和雜環滿足休克爾規則時,則該環亦稱為「雜芳族環」或「雜芳基」取代基。除非另有指示,否則雜環及環系統可藉由替代該碳或氮上之氫經由任何可用的碳或氮連接。
單獨或在諸如雜環基氧基之組合詞彙中之術語雜環基可為(例如)具有1至4(較佳為1至3)個相同或不同雜原子(選自由N、O及S之組成之群)的5員或6員雜環基,該5員或6員雜環基進一步不經取代或經取代。
術語雜環基可指代(例如)具有1至4(較佳為1至3)個相同或不同雜原子(選自由N、O及S之組成之群)的5員或6員雜芳基,該5員或6員雜芳基進一步不經取代或經如以下所提及之一或多個取代基取代。雜芳基較佳經來自如下文所定義之群的0至3(尤其是0、1或2)個取代基取代。
雜芳基之適合取代基之實例為鹵素、羥基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6環烷基、C1-C6鹵烷基、C1-C6烷氧基、C1-C6鹵烷氧基、C1-C6烷基硫基、C1-C6烷基亞磺醯基、C1-C6烷基磺醯基、氰基、硝基、胺基、N-單-或N,N-二-C1-C6烷基胺基、C3-C6環烷基胺基、COOH、C1-C6烷氧基-羰基、C2-C6烷基羰基、C1-C6烷基羰基胺基、胺基羰基、N-單-或N,N-二-C1-C6烷基胺基羰基、胺基磺醯基或N-單-或N,N,二-C1-C4烷基胺基磺醯基。
5員或6員雜芳基之實例包括噻吩基、吡咯基、呋喃基、噁唑基、噻唑基、吡啶基或嘧啶基,其各自(例如)未經取代或經鹵素、C1-C2烷基、C1-C2鹵烷基、C3-C6環烷基或C1-C4烷氧基羰基取代。
術語雜環基可進一步指代具有1至3個相同或不同雜原子(選自由N、O及S之組成之群)的3員至6員雜環烷基,該3員至6員雜環烷基進一步不經取代或經用於雜環基之如上文所定義之一或多個取代基取代。伸雜環烷基較佳經來自如上文所定義之群的0至3(詳言之0、1或2)個取代基取代。實例為四氫呋喃基、吡咯啶基、嗎啉基、哌啶基或哌嗪基,其各自未經取代或經鹵素、C1-C2烷基、C1-C2鹵烷基或C1-C2烷氧基取代。
雜環基氧基之實例為2-吡啶氧基、3-吡啶氧基或4-吡啶氧基或嘧啶-4-基氧基,其各自未經取代或經鹵素、C1-C2烷基、C3-C6環烷基、C1-C2鹵烷基或C1-C2烷氧基取代。
C6-C8苯并雜環基之實例為苯并噁唑基、苯并噻唑基或吲哚基,其各自(例如)未經取代或經鹵素、C1-C2烷基、C1-C2鹵烷基或C1-C2烷氧基取代。
關於式(I)化合物中所含有的變數,以下含義及優先選擇適用。
變數m較佳為自1至4之整數,更佳為整數1、2或3,甚至更佳為整數1或2且尤其是1。
各R獨立地較佳為鹵素;C1-C4烷基;C1-C4鹵烷基;胺基;C1-C4烷氧基;C1-C4鹵基烷氧基;C1-C4鹵烷硫基;C1-C4烷基磺醯基;C1-C4鹵烷基磺醯基;三C1-C2烷基矽烷基;C1-C4烷氧基羰基;N-單-或N,N-二-C1-C4烷基胺基-羰基;胺基磺醯基;N-單-或N,N-二-C1-C4烷基胺基磺醯基;N-C1-C2烷基-N-C1-C4烷氧羰基胺基;氰基;硝基;或包含1或2個相同或不同雜原子(選自O、S及N)的5員或6員雜環烷基,該5員或6員雜環烷基未經取代或經鹵素、C1-C2烷基、C1-C2鹵烷基或
C1-C2烷氧基取代。
各R獨立地更佳為鹵素;C1-C2烷基;C1-C4鹵烷基;胺基;C1-C4烷氧基;C1-C4鹵基烷氧基;C1-C4烷基磺醯基;C1-C4鹵烷基磺醯基;三甲基矽烷基;C1-C4烷氧基羰基;N,N-二-C1-C2烷基胺基羰基;胺基磺醯基;N,N-二-C1-C2烷基胺基磺醯基;N-C1-C2烷基-N-C1-C4烷氧基羰基胺基;氰基;硝基或選自由四氫呋喃基、吡咯啶基、嗎啉基及哌啶基組成之群的雜環烷基。
各R獨立地特別較佳為鹵素、C1-C2烷基、C1-C2鹵烷基、C1-C2烷氧基、C1-C2鹵基烷氧基或氰基,且尤其為氯、氟或CF3。特定較佳的取代基(R)m為2-Cl、3-Cl或4-Cl、4-CF3、3,5-二-Cl、3,5-二-CF3、2,4,6-三-Cl、3,4,5-三-Cl、2-Cl-4-CF3、2-CF3-4-Cl、2,6-二-Cl-4-CF3,尤其是4-Cl。
變數r較佳為整數1、2或3,且更佳為2或3。
各R1獨立地較佳為鹵素;C1-C4烷基;C1-C4鹵烷基;C3-C6環烷基;C1-C4烷氧基;C1-C4鹵烷氧基;C1-C4鹵烷硫基;SF5;N,N-二-C1-C4烷基胺基-C1-C4烷基胺基羰基;N-C1-C4烷基磺醯基胺基;氰基;硝基;羥基;B(OH)2、嗎啉基或苯基、苯甲醯基、吡啶氧基、嘧啶氧基、或苯并噻唑基,其各自未經取代或經鹵素、C1-C4烷基、C1-C4鹵烷基、C3-C6環烷基或C1-C4烷氧基取代。
各R1獨立地更佳為鹵素;C1-C2烷基;C1-C3鹵烷基;C1-C2烷氧基;C1-C3鹵烷氧基;C1-C2鹵烷硫基;SF5;硝基或羥基。
每一R1獨立地尤其較佳為鹵素、甲基、C1-C3鹵烷基、甲氧基、C1-C3鹵烷氧基、SCF3、SF5、硝基或羥基,且尤其為鹵素或CF3。特定較佳的取代基(R)m為3,4,5-三-Cl、3,5-二-CF3-4-Cl、3,5-二-CF3。
根據本發明之一項較佳實施例,r為整數1、2或3,且各R1獨立地為鹵素;C1-C2烷基;C1-C3鹵烷基;C1-C2烷氧基;C1-C3鹵烷氧基;
C1-C2鹵烷硫基;SF5;硝基或羥基。根據本發明之一項尤其特別較佳之實施例,r為整數2或3,且各R1獨立地為鹵素;或C1-C3鹵烷基。
變數×較佳指代O。
R0較佳為H或甲基,尤其是H。
本發明之一項實施例關於式(Ia)化合物
其中R、R0、R1、m、及r各自具有包括優先選擇之以上給出之含義。較佳實施例係關於式(Ia)化合物,其中R0為H,m為1、2或3,尤其為1或2,r為2或3,尤其為2,且對於R及R1,每一上文給出之含義及優先選擇適用。特定較佳之實施例係關於式(Ia)化合物,其中R0為H,m為1、2,r為2或3,各R獨立地為鹵素、C1-C2烷基、C1-C4鹵烷基、C1-C4烷氧基、C1-C4鹵烷氧基、C1-C4烷基磺醯基、三甲基-矽烷基、N,N-二-C1-C2烷基胺基磺醯基、N-C1-C2烷基-N-C1-C4烷氧基羰基胺基、氰基、硝基或吡咯啶基,且各R1獨立地為C1-C4鹵烷基。尤其較佳之實施例係關於式(Ia)化合物,其中R0為H,m為1或2,r為2,各R獨立地為鹵素或CF3,且R1為CF3。
本發明之一項較佳實施例關於式(Ia')化合物
其中對於R及m,每一上文給出之含義及優先選擇適用。
本發明之另一實施例關於式(Ib)化合物
其中對於R、R1、m及r,每一上文給出之含義及優先選擇適用。
較佳實施例係關於式(Ib)化合物,其中m為1或2,尤其為1,r為2或3,且對於R及R1,每一上文給出之含義及優先選擇適用。特定較佳實施例係關於式(Ia)化合物,其中m為1,r為2或3,各R為鹵素、C1-C3鹵烷基、C1-C2烷氧基或氰基,且各R1獨立地為鹵素、C1-C2烷基、C1-C3鹵烷基、C1-C2烷氧基、C1-C3鹵烷氧基、C1-C2鹵烷硫基、SF5、硝基或羥基。尤其較佳之實施例係關於式(Ib)化合物,其中m為1,r為2或3,R為鹵素或CF3,尤其是氯,且各R1為鹵素或CF3。
本發明之另一較佳實施例關於式(Ib')化合物
其中變數a及b各自獨立地為0或1,(Hal)為鹵素,且R為鹵素或CF3,尤其是鹵素。在上述式(Ib')中,變數a及b中之一者較佳為1,且另一者為0或1。
可以已知之方式生成式(I)化合物之鹽。酸加成鹽(例如)可藉由用適合之酸或適合之離子交換反應劑處理獲得,且具有鹼基之鹽可藉由用適合之鹼或適合之離子交換反應劑處理獲得。
式(I)化合物之鹽可藉由常用手段轉化成游離化合物,對於酸加成鹽(例如)藉由用適合之鹼性組合物或用適合之離子交換反應劑處理,且對於具有鹼基之鹽(例如)藉由用適合之酸或適合之離子交換反應劑處理。
式(I)化合物之鹽可以已知之方式轉化成式(I)化合物之其他鹽,酸加成鹽可例如藉由用適合之金屬鹽(諸如酸之鈉鹽、鋇鹽或銀鹽,例如用乙酸銀)在適合之溶劑中處理無機酸之鹽(諸如氫氯化物)而轉化(例如)成其他酸加成鹽,其中所得無機鹽(例如氯化銀)不溶且因此自反應混合物沈澱出來。
取決於方法及/或反應條件,具有成鹽特徵之式(I)化合物可以游離形式或以鹽形式獲得。式(I)化合物亦可以其水合物形式獲得及/或亦可包括例如必要的話用於以固體形式存在之化合物結晶的其他溶劑。
如之前所提及,式(I)的化合物可視情況以光學及/或幾何異構體或以其混合物存在。本發明係關於純異構體及所有可能之異構混合物兩者,且在上文中及在下文中按此理解,即使在每一情況下未特定地提及立體化學細節亦如此。
可藉由該方法或以另一方式獲得之式(I)化合物之非對映異構混合物可以基於其成份中之物理化學差異的已知方式分離成純非對映異構體,例如藉由分步結晶、蒸餾作用及/或層析。
可因此獲得之對映異構體之混合物分離成純異構體可藉由已知方法達成,例如藉由自光學活性溶劑再結晶,藉由在對掌性吸附劑上層析(例如在乙醯基纖維素上之高壓液相層析(HPLC)),藉助適合之微生物,藉由用特定之固定化酶類裂解,經由包合物之形成(例如使用對掌性冠醚),藉此僅錯合一種對映異構體。
其中n為0之式(I)化合物可(例如)藉由使(II)式化合物
其中R0、R1及r各自如上文所定義且LG為脫離基(例如諸如溴之鹵素),與式(III)化合物
在鈀催化劑存在下反應而製備,其中R及m各自如上文所定義。此鈀催化之碳-碳鍵形成反應(稱為鈴木反應)之細節自有機化學教科書而已知。
式(II)化合物已知或可根據已知方法製備,例如藉由使式(IV)化合物
與式(V)化合物反應
其中LG'為脫離基團,例如鹵素、C1-C2烷氧基或羥基,且更多變數各自具有上文所提及之含義。自羧酸或其衍生物與胺形成醯胺自有機化學教科書已知。式(IV)化合物已知或可根據已知方法(例如藉由使相對應的胺與甲烷磺醯氯以已知方式反應)製備。式(III)及(V)化合物為可市售之已知化合物。
可製備其中n為1且X為O之式(I)化合物,例如藉由使(VI)化合物
與式(VII)化合物反應
其中變數如上文所定義,接著還原硝基,且進一步使所得胺與甲烷磺醯氯反應。此等反應之細節自有機化學教科書已知。式(VI)化合物可類似於式(II)化合物製備。式(VII)化合物本身已知且可市售。
亦可製備其中n為1之式(I)化合物,藉由使式(VIII)化合物
與式(V)化合物反應
其中變數各自具有上文給出之含義,隨後還原硝基且進一步使所得胺與甲烷磺醯氯反應達成。在替代方式中,式(VIII)化合物之硝基可首先還原,且所得胺基與甲烷磺醯氯反應,然後進行與式(V)化合物之反應。
式(VIII)化合物可以本身已知之方式製備,例如藉由使式(IX)化合物
與式(X)化合物反應
產生式(VIIIa)化合物,該式(VIIIa)化合物可(例如)進一步藉由在含水介質中與諸如氫氧
化鋰之強鹼作用轉化成式(VIIIb)化合物
實例進一步說明不同的合成方法。
根據本發明之式(I)化合物因其寬的活性範圍而引人注目,且對於用於害蟲防治(尤其包括在溫血動物(尤其多產之家畜及寵物)中及在溫血動物上防治體內寄生蟲(尤其蠕蟲))而言為有價值的活性成分,同時被溫血動物及魚良好耐受。
多產家畜包括哺乳動物,諸如(例如)牛、馬、綿羊、豬、山羊、驢、家兔、鹿,以及鳥類,例如雞、鵝、火雞、鴨、及外來鳥類。
寵物包括(例如)狗、貓及倉鼠,尤其是狗及貓。
本發明之式(I)化合物對抗蠕蟲有效,其中體內寄生線蟲及吸蟲可能為哺乳動物及家禽發生嚴重疾病之病因。此適應症之典型線蟲為:絲蟲科(Filariidae)、絲狀科(Setariidae)、血茅線蟲屬(Haemonchus)、毛圓線蟲屬(Trichostrongylus)、毛圓科奧斯特屬(Ostertagia)、細頸線蟲屬(Nematodirus)、古柏線蟲屬(Cooperia)、蛔蟲屬(Ascaris)、仰口線蟲屬(Bunostonum)、結節線蟲屬(Oesophagostonum)、夏伯特線蟲屬(Charbertia)、鞭蟲屬(Trichuris)、圓線蟲屬(Strongylus)、毛樣線蟲屬(Trichonema)、網尾線蟲屬(Dictyocaulus)、毛細線蟲屬(Capillaria)、異刺線蟲屬(Heterakis)、弓蛔蟲屬(Toxocara)、禽蛔蟲屬(Ascaridia)、尖尾線蟲屬(Oxyuris)、鉤口線蟲屬(Ancylostoma)、鉤線蟲屬(Uncinaria)、弓蛔線蟲(Toxascaris)及蛔副蛔屬(Parascaris)。吸蟲尤其包括擬片吸蟲科(Fasciolideae)(尤其是肝片吸蟲(Fasciola hepatica))。
亦出人意料地及意外地展示,本發明之組合物具有對抗線蟲(對
多種活性物質具有抵抗性)之格外較高功效。此可(例如)藉由LDA測試在活體外證明。
某些細頸線蟲屬、古柏線蟲屬及結節線蟲屬害蟲感染寄主動物之腸道,而血茅線蟲屬及毛圓科奧斯特屬中之其他者寄生在胃中,且網尾線蟲屬之彼等者寄生在肺組織中。這些科之寄生蟲可能在內部細胞組織中及器官(例如心臟、血管、淋巴血管及皮下組織)中發現。特別顯著的寄生蟲為狗之心絲蟲,犬心絲蟲。
根據本發明式(I)化合物對抗此等寄生蟲高度有效。
可藉由本發明之式(I)化合物防治之害蟲亦包括來自絛蟲綱(Cestoda)(絛蟲(tapeworms))之彼等者,例如中帶絛蟲科(Mesocestoidae),尤其中殖孔屬(Mesocestoides)(尤其是線中殖孔絛蟲(M.lineatus));複孔科(Dipylidiidae),尤其犬複孔絛蟲(Dipylidium caninum)、約優克斯絛蟲屬(Joyeuxiella spp.)(尤其是帕斯誇約優克斯絛蟲屬(Joyeuxiella pasquali)),及複孔絛蟲屬(Diplopylidium spp.),及帶絛蟲科(Taeniidae),尤其豆狀帶絛蟲(Taenia pisiformis)、獐絛蟲(Taenia cervi)、羊絛蟲(Taenia ovis)、水泡絛蟲(Taeneia hydatigena)、多頭絛蟲(Taenia multiceps)、巨頸絛蟲(Taenia taeniaeformis)、鋸齒狀絛蟲(Taenia serialis),及細粒棘球絛蟲屬(Echinococcus spp.),最佳為水泡絛蟲、羊絛蟲、多頭絛蟲、巨頸絛蟲、細粒棘球絛蟲(Echinococcus granulosus)及多房棘球絛蟲(Echinococcus multilocularis)。
此外,式(I)化合物適合於防治人病原性寄生蟲。其中出現於消化道中之典型代表為鉤口線蟲屬、板口線蟲屬(Necator)、蛔蟲屬、類圓線蟲屬(Strongyloides)、旋毛蟲屬(Trichinella)、毛細線蟲屬、鞭蟲屬及住腸線蟲屬(Enterobius)的這些。本發明化合物亦對來自龍線蟲(Dracunculus)科之吳策線蟲屬(Wuchereria)、布魯格氏絲蟲屬
(Brugia)、盤尾屬(Onchocerca)及羅阿絲蟲屬(Loa)之寄生蟲,以及尤其感染胃腸道之類圓線蟲屬及旋毛蟲屬寄生蟲有效。
式(I)化合物之良好的殺體內寄生蟲活性對應於所述體內寄生蟲的死亡率為至少50-60%,詳言之至少80%,且尤其至少90%。
根據本發明之式(I)化合物之投藥可在治療上或較佳預防上實現。
根據本發明之式(I)化合物施用至待處理之動物可(例如)以局部、經口、非經腸或皮下方式進行。本發明之較佳實施例係關於用於腸胃外使用或詳言之用於經口使用之式(I)化合物。
用於在防治線蟲/蠕蟲時在溫血動物上之使用之較佳施用形式包含溶液;包括經典乳液、微乳液及自乳化組合物之乳液(在添加至動物體之後即刻連同體液形成乳液之無水有機(較佳為含油的)組合物);懸浮液(浸液);傾倒調配物;食品添加劑;散劑;包括發泡錠劑在內之錠劑;食團;包括微膠囊之膠囊;及可咀嚼物;由此必須考慮調配物賦形劑之生理相容性。尤其較佳之施用形式為錠劑、膠囊、食品添加劑或可咀嚼物。
本發明之式(I)化合物以未改質形式使用,或較佳地與習知用於調配物技術之佐劑一起使用,且可因此以已知方式加工以得到(例如)可乳化濃縮物、可直接稀釋溶液、稀乳液、可溶性粉末、粉末混合物、顆粒或在聚合物質中之微囊封裝劑。如同組合物,施用之方法根據意欲之目標及當前環境選擇。
調配物,亦即含有一或多種活性成分及視情況存在之固態或液態佐劑之試劑、製劑或組合物以本身已知之方式生產,例如藉由將活性成分與佐劑(例如溶劑、固態載劑及/或表面活性化合物(界面活性劑))精細混合及/或研磨達成。
所討論之溶劑可為:醇類(諸如乙醇、丙醇或丁醇),及二醇及其
醚及酯(諸如丙二醇、二丙二醇醚、乙二醇、乙二醇單甲醚或乙二醇單乙醚)、酮類(諸如環己酮、異佛爾酮或雙丙酮醇)、強極性溶劑(諸如N-甲基-2-吡咯啶酮、二甲亞碸或二甲基甲醯胺)、或水,植物油(諸如菜油、蓖麻油、椰子油或大豆油),以及若適宜聚矽氧油。
適合之界面活性劑為(例如)非離子界面活性劑,諸如(例如)壬基苯酚聚乙氧基乙醇;蓖麻油聚二醇醚,例如聚乙二醇甘油羥基硬脂酸酯40;聚乙二醇;聚氧化丙烯/聚氧化乙烯加合物;或聚氧化乙烯脫水山梨糖醇之脂肪酸酯類(例如聚氧化乙烯脫水山梨糖醇單油酸酯)。
例如用於錠劑及食團之固態載劑可為可溶於水或酒精之經化學改質之聚合天然物質,諸如澱粉、纖維素或蛋白質衍生物(例如甲基纖維素、羧甲基纖維素、乙基羥乙基纖維素、諸如玉米蛋白、明膠及其類似物之蛋白質),以及合成聚合物(諸如聚乙烯醇、聚乙烯基吡咯啶酮等)。錠劑亦含有填充劑(例如澱粉、微晶纖維素、糖、乳糖等)、滑動劑及崩解劑。
若驅蟲藥以飼料濃縮物之形式存在,則使用之載劑為(例如)效能飼料、穀類飼料或蛋白質濃縮物。除活性成分之外,該等飼料濃縮物或組合物亦可含有添加劑、維生素、抗生素、化學治療劑或其他殺蟲劑,主要為抑菌劑、抑真菌劑、球蟲預防劑,或甚至激素製劑,具有合成代謝作用之物質或促進生長、影響屠宰動物之肉品質或以另一方式對該有機體有益的物質。
式(I)化合物之適合組合物亦可進一步含有添加劑,諸如穩定劑、抗氧化劑(例如類似α-生育酚之生育酚)、消泡劑、黏度調節劑、黏合劑、著色劑或增黏劑,以及其他活性成分,以便達成特定效果。較佳地,組合物包含0.001至1% w/v之一或多種抗氧化劑。若須要,本發明之調配物可包含著色劑,例如呈0.001至1% w/v之量。
按一般規則,根據本發明之驅蟲組合物含有0.1至99重量%(尤其
0.1至95重量%)之式(I)化合物,99.9至1重量%(尤其99.8至5重量%)之固態或液態混雜物,包括0至25重量%(尤其0.1至25重量%)之界面活性劑。
在根據本發明之用於害蟲防治之方法中之每一者中,或在根據本發明之害蟲防治組合物中之每一者中,式(I)化合物可以其所有空間構型或其混合物使用。
本發明亦包括預防保護溫血動物(尤其多產家畜及寵物,尤其是狗或貓)以對抗寄生蠕蟲之方法,其特徵在於將式(I)化合物或自其製備之活性成份調配物作為飼料或飲用水添加劑或亦以固態或液態形式經口或藉由注射或非經腸投與溫血動物。本發明亦包括用於該等方法中之一者的根據本發明之式(I)化合物。
根據本發明之式(I)化合物可單獨使用或與其他殺生物劑組合使用。其可與具有相同活性範圍之殺蟲劑組合,以例如增加活性,或與具有另一活性範圍之物質組合,例如以拓寬活性範圍。添加所謂的拒避劑亦可合理。
以下實例進一步說明本發明。
在各情況下對純樣品之分析使用Waters Autopurification(HPLC/MS)系統進行,其中逆相柱使用如下所描述之方法B。樣品之特徵在於m/z及滯留時間。上文給出之滯留時間在所有情況下與溶劑系統之使用有關,該溶劑系統包含兩種不同的溶劑,溶劑A:H2O+0.01% HCOOH,及溶劑B:CH3CN+0.01% HCOOH。
- 方法B:柱Waters XTerra MS C18 5μm,50×4.6mm(Waters),流動速率3.00ml/min,如表中所給出之時間相依梯度:
步驟A:5-溴-2-(甲基磺醯胺基)苯甲酸甲酯。
將10mL 1吡啶中之2-胺基-5-溴苯甲酸甲酯(2.8g)之N2脫氣溶液冷卻至0℃,然後逐滴添加甲烷磺醯氯(0.9mL)。反應混合物在室溫下攪拌隔夜,接著用50mL乙酸乙酯稀釋。有機層用Na2CO3飽和溶液、鹽水洗滌,接著經MgSO4乾燥且蒸發至乾燥(產率:82%)。LCMS(方法B):在1.55min時305.6(M-H)-。
步驟B:5-溴-2-(甲基磺醯胺基)苯甲酸
5-溴-2-(甲基磺醯胺基)苯甲酸甲酯(3.15g)懸浮於THF中(20mL,1/1)。添加4N NaOH(6.9mL),且在回流下攪拌反應混合物4h。在完成後,反應混合物即刻用2N HCl(1mL)處理且用乙酸乙酯萃取兩次。經合併之有機層用H2O、鹽水洗滌,經Na2SO4乾燥,過濾且蒸發至乾燥。標題產物藉由LCMS可知純度足以不經進一步純化即參與至下一步驟。(產率:66%)
LCMS(方法B):在1.2min時291.64(M-H)-。
步驟C:N-(3,5-雙(三氟甲基)苯基)-5-溴-2-(甲基磺醯胺基)苯甲醯胺。
在回流下將5-溴-2-(甲基磺醯胺基)苯甲酸(2.4g)用亞硫醯氯(23mL)處理4h。在真空下移除過量SOCl2。將CH2Cl2(20mL)添加至醯基氯化物中。在0℃,在10mL CH2Cl2中緩慢添加3,5-雙(三氟甲基)苯胺(1.4mL)及NEt3(5.68mL)。允許反應混合物升溫,且將其在室溫下攪
拌隔夜。用30mL CH2Cl2稀釋反應混合物。添加20mL 2N HCl及20mL H2O,且攪拌混合物直至形成黃色沈澱。將沈澱濾出且在高真空下乾燥,然後分析(產率:67%)。
LCMS(方法B):在1.99min時502.93(M-H)-
步驟D:N-(3,5-雙(三氟甲基)苯基)-2'-氯-4-(甲基-磺醯胺基)-4'-(三氟甲基)-[1,1'-聯苯]-3-甲醯胺之合成。
在N2下於二噁烷/H2O(4mL,1/1)中將Na2CO3(636mg)及(1,1'-雙-二苯膦基-二茂鐵)鈀-II-二氯化物(Pd(dppf)Cl2.CH2Cl2,366mg)添加至N-(3,5-雙(三氟甲基)苯基)-5-溴-2-(甲基磺醯胺基)苯甲醯胺(0.5g)及2-氯-4(三氟甲基)苯硼酸(286mg)之溶液中。在85℃下攪拌反應混合物維持1h。該反應混合物用乙酸乙酯稀釋,經由矽藻土過濾。用H2O、鹽水洗滌濾液,經Na2SO4乾燥,過濾且蒸發至乾燥。
粗製混合物藉由在100%庚烷至60%庚烷/40%乙酸乙酯之梯度條件下溶離之急驟層析純化,以提供37%產率之標題化合物。
LCMS(方法C):在2.32min時604.7(M+H)+。
類似於上述方法製備以下表1中所舉出之物質。化合物為下式化合物,
其中(R)m之含義在表1中給出。
根據上述HPLC/MS表徵方法得到以下物理資料。
步驟A:5-氯-2-硝基-N-(3,4,5-三氯苯基)苯甲醯胺。在回流下用亞硫醯氯(7.2mL)處理5-氯-2-硝基苯甲酸(10g)維持4h。在真空下移除過量SOCl2。將CH2Cl2(100mL)添加至醯基氯化物中。在0℃,在100mL CH2Cl2中緩慢添加3,4,5-三氯苯胺(9.7g)及NEt3(13.8mL)。允許反應混合物升溫,且將其在室溫(RT)下攪拌隔夜。
用200ml乙醚稀釋反應混合物。添加10mL 2N HCl及200mL
H2O,且攪拌混合物直至形成黃色沈澱。將沈澱濾出且在高真空下乾燥,然後分析(產率:66%)。
LCMS(方法B):在1.97min下380.59(M+H)+。
步驟B:5-(4-氯苯氧基)-2-硝基-N-(3,4,5-三氯苯基)苯甲醯胺。
在140℃下將DMA中之5-氯-2-硝基-N-(3,4,5-三氯苯基)苯甲醯胺(8.77g)、K2CO3(6.7g)及4-氯苯酚(3.26g)加熱14h。將反應混合物倒入H2O(100mL)中,濾出沈澱,在高真空下乾燥以獲得棕色固體(產率:55%)。
LCMS(方法B):在2.25min時(M-H)-。
步驟C:2-胺基-5-(4-氯苯氧基)-N-(3,4,5-三氯苯基)苯甲醯胺。
在N2下,用Fe(10.9g)及25% HCl(0.6mL)處理在80mL EtOH/H2O(3/1)中之5-(4-氯苯氧基)-2-硝基-N-(3,4,5-三氯苯基)苯甲醯胺(13.2g),且在室溫下攪拌反應混合物維持4h。當完成還原時,在矽藻土墊上過濾反應混合物,且用乙酸乙酯洗滌。在真空下蒸發濾液。添加乙酸乙酯,且有機層用鹽水洗滌,經MgSO4乾燥,且蒸發至乾燥(產率:89%)。
LCMS(方法B):在2.41min時442.54(M+H)+。
步驟D:5-(4-氯苯氧基)-2-(甲基磺醯胺基)-N-(3,4,5-三氯苯基)苯甲醯胺
將吡啶(8.2mL)添加至50mLCH2Cl2中之2-胺基-5-(4-氯苯氧基)-N-(3,4,5-三氯苯基)苯甲醯胺(9g)之N2脫氣溶液中。將混合物冷卻至0℃,然後逐滴添加甲烷磺醯氯(1.6mL)。在室溫下攪拌反應混合物隔夜,接著用額外50mL CH2Cl2稀釋。用Na2CO3飽和溶液、鹽水洗滌有機層,接著經MgSO4乾燥且蒸發至乾燥(產率:81%)。
LCMS(方法B):在2.27min時518.5(M+H)+。
步驟A:5-((4-氯苯基)(氰基)甲基)-2-硝基苯甲酸甲酯。
NaH(140mg)懸浮於10mL DMF中。在0℃下在2mL DMF中逐滴添加2-(4-氯苯基)乙腈(600mg),接著允許其在室溫下攪拌2h。將混合物冷卻至0℃,然後逐滴添加溶解於1.5mL DMF中之5-氯-2-硝基苯甲酸甲酯(1.024g)。在0℃下攪拌反應物2h,接著在室溫下隔夜。添加二異丙基醚,且混合物用H2O、鹽水洗滌,經Na2SO4乾燥,過濾且蒸發至乾燥。在半製備型HPLC上純化粗產物,以12%產率提供標題化合物。
LCMS(方法B):在1.75min時328.84(M-H)-。
步驟B:2-胺基-5-((4-氯苯基)(氰基)甲基)苯甲酸甲酯
以與實例2之步驟C類似之方式還原5-((4-氯苯基)(氰基))甲基)-2-硝基苯甲酸甲酯(產率:96%)。
LCMS(方法B):在1.72min時300.88(M+H)+。
步驟C:5-((4-氯苯基)(氰基)甲基)-2-(甲基磺醯胺基)苯甲酸甲酯
以與實例2之步驟D類似之方式磺醯基化2-胺基-5-((4-氯苯基)(氰基)甲基)苯甲酸甲酯(產率:55%)。
LCMS(方法B):在1.71min時376.76(M-H)-。
步驟D:5-((4-氯苯基)(氰基)甲基)-2-(甲基磺醯胺基)苯甲酸
5-((4-氯苯基)(氰基)甲基)-2-(甲基磺醯胺基)苯甲酸甲酯(50mg)懸浮於MeOH/H2O(1mL,1/1)中。添加NaOH(6mg)且在室溫下攪拌反應混合物隔夜。完成後,反應混合物即刻用2N HCl(1mL)處理,且用乙酸乙酯萃取兩次。將經合併之有機層用H2O、鹽水洗滌,經Na2SO4乾燥,過濾且蒸發至乾燥。標題產物藉由LCMS可知純度足以不經進一步純化即參與至下一步驟中。
LCMS(方法B):在1.52min時362.71(M-H)-。
步驟E:5-((4-氯苯基)(氰基)甲基)-2-(甲基磺醯胺基)-N-(3,4,5-三氯-苯基)苯甲醯胺
將5-((4-氯苯基)(氰基)甲基)-2-(甲基磺醯胺基)苯甲酸(48mg)溶解於CH2Cl2(1.5mL)中。添加3,4,5三氯苯胺(31mg)、六氟磷酸苯并三唑-1-基-氧基三吡咯啶基鏻(Pybop,75mg)及二異丙基乙胺(DIPEA,69μL)。在室溫下攪拌反應混合物隔夜。添加H2O且用CH2Cl2萃取混合物。經合併之有機層用Na2CO3飽和溶液、鹽水洗滌,過濾且蒸發至乾燥。在半製備型HPLC上純化粗產物,提供46%產率之標題化合物。
LCMS(方法B):在2.15min時539.58(M-H)-。
步驟A:5-(4-氯苯甲醯基)-2-硝基苯甲酸。
在室溫下在THF/H2O(4/1,5mL)中用LiOH(6eq.)處理5-((4-氯苯基)(氰基)甲基)-2-硝基苯甲酸甲酯(150mg,參見實例3之步驟A)隔夜。添加額外之6eq.LiOH。在72h之後完成反應。添加2N HCl直至pH達到1-2,且接著將反應混合物用乙酸乙酯萃取兩次。經合併之有機層用H2O、鹽水洗滌,經Na2SO4乾燥,過濾且蒸發至乾燥。標題化合物純度足以用於步驟B。
LCMS(方法B):在1.54min時303.85(M-H)-。
步驟B:5-(4-氯苯甲醯基)-2-硝基-N-(3,4,5-三氯苯基)苯甲醯胺。
以與實例3之步驟E所述類似之方式處理5-(4-氯苯甲醯基)-2-硝基苯甲酸(產率:71%)。
LCMS(方法B):在2.20min時480.57(M-H)-。
步驟C:2-胺基-5-(4-氯苯甲醯基)-N-(3,4,5-三氯苯基)苯甲醯胺。
以與實例3之步驟B中所述類似之方式處理5-(4-氯苯甲醯基)-2-硝
基-N-(3,4,5-三氯苯基)苯甲醯胺(產率:93%)。
LCMS(方法B):在2.31min時450.61(M-H)-。
步驟D:5-(4-氯苯甲醯基)-2-(甲基磺醯胺基)-N-(3,4,5-三氯苯基)苯甲醯胺。
以與實例2之步驟D中所述類似之方式處理2-胺基-5-(4-氯苯甲醯基)-N-(3,4,5-三氯苯基)苯甲醯胺(產率:18%)。
LCMS(方法B):在2.23min時530.5(M+H)+。
類似於上述方法製備以下表2中舉出之物質。化合物為下式化合物
其中(R1)r、(R)m及X之含義在表2中給出。
根據上述HPLC/MS表徵方法得到以下物理資料。
類似於上述方法製備以下表3中舉出之物質。化合物為下式化合物
其中Y之含義在表3中給出。根據上述HPLC/MS表徵方法得到以下物理資料。
新近捕獲且清潔之線蟲蟲卵用以接種適合格式化孔之培養盤,該格式化孔之培養盤含有待評價抗寄生蟲劑活性之測試物質及用於允許蟲卵充分發育至第3齡幼蟲之培養基。將培養盤在25℃及60%相對濕度下培育6天。記錄卵孵化及隨後之幼蟲發育以識別可能的殺線蟲活性。以降低之卵孵化、L3之減少發育或在任何階段下幼蟲之麻痹及死亡的百分比表示功效。化合物第1.9-1.13、1.21-1.23、1.25、1.26、2.13、2.50、2.51及2.54號在10ppm下達成60%功效,且因此視為有活性的。
新近捕獲且清潔之犬心絲蟲幼絲蟲自來自供體動物狗之血製備。接著將幼絲蟲分佈於格式化微量培養盤(含有待評價抗寄生蟲劑活性之測試物質)中。將培養盤在25℃及60%相對濕度(RH)下培育48小時。接著記錄幼絲蟲之活動力以判定功效。以與對照組及標準品相比減弱之活動力百分比表示功效。化合物第1.1-1.25、2.1-2.58及3.1-3.10號在10ppm下顯示高於50%之功效,且因此視為有活性的。
藉由皮下注射用寄生蠕蟲之80 L3幼蟲人工感染沙鼠。在感染之後的第5天至9天藉由管飼法用調配之測試化合物連續處理。在感染後的84天,對沙鼠抽血以使用富克斯-羅森塔爾計數室(Fuchs-Rosenthal
counting chamber)及顯微鏡來計數循環幼絲蟲。僅循環幼絲蟲之平均值至少50%小於安慰劑處理組中的測試組經充分解剖以回收成年蠕蟲。使用阿博特公式(Abbot's formula),功效表示為與安慰劑處理組相比之蠕蟲數目之降低%。化合物第1.5、1.10、1.13、1.17、2.1、2.21、2.26及2.51號在10mg/kg下顯示高於80%之功效。
來自牛肝臟或綿羊肝臟之新近捕獲之成年肝片吸蟲分佈於具有4mL RPMI完全培養基之12孔培養盤(每孔1個吸蟲)中,且在37℃下在培育箱中保存大致12小時。更新培養基後,吸蟲之成活力藉由個別吸蟲(預置值)之運動的視訊對位判定。在100μg/mL濃度下添加測試化合物,且在6小時及24小時後量測吸蟲之運動。功效基於預置值及未經處理之對照組表示為減弱之運動百分比。在此測試中顯示在6h後超過>90%功效及在24h後>95%之以下實例被視為陽性的:1.5、1.10、1.13、2.19、2.21、2.26及2.48。
Claims (14)
- 一種式(I)化合物,
- 如請求項1之式(I)化合物,其中各R獨立地為鹵素;C1-C4烷基;C1-C4鹵烷基;胺基;C1-C4烷氧基;C1-C4鹵烷氧基;C1-C4鹵烷硫基;C1-C4烷基磺醯基;C1-C4鹵烷基磺醯基;三C1-C2烷基矽烷基;C1-C4烷氧基羰基;N-單-或N,N-二-C1-C4烷基胺基羰基;胺基磺醯基;N-單--或N,N-二-C1-C4烷基胺基磺醯基;N-C1-C2烷基-N-C1-C4烷氧基羰基胺基;氰基;硝基;或包含1或2個相同或不同選自O、S及N之雜原子的5員或6員雜環烷基,該5員或6員雜環烷基未經取代或經鹵素、C1-C2烷基、C1-C2鹵烷基或C1-C2烷氧基取代。
- 如請求項1之式(I)化合物,其中各R為鹵素、C1-C2烷基、C1-C2鹵烷基、C1-C2烷氧基、C1-C2鹵基烷氧基或氰基,詳言之氯、氟或CF3。
- 如請求項1至3中任一項之式(I)化合物,其中m為整數1、2或3,較佳地1或2,且尤其是1。
- 如請求項1至3中任一項之式(I)化合物,其中各R1獨立地為鹵素;C1-C4烷基;C1-C4鹵烷基;C3-C6環烷基;C1-C4烷氧基;C1- C4鹵烷氧基;C1-C4鹵烷硫基;SF5;N,N-二-C1-C4烷基胺基-C1-C4烷基胺基羰基;N-C1-C4烷基磺醯基胺基;氰基;硝基;羥基;B(OH)2、嗎啉基;或苯基、苯甲醯基、吡啶氧基、嘧啶氧基、或苯并噻唑基,其各自未經取代或經鹵素、C1-C4烷基、C1-C4鹵烷基、C3-C6環烷基或C1-C4烷氧基取代。
- 如請求項1至3中任一項之式(I)化合物,其中各R1獨立地為鹵素;C1-C2烷基;C1-C3鹵烷基;C1-C2烷氧基;C1-C3鹵烷氧基;C1-C2鹵烷硫基;SF5;硝基或羥基;且尤其是鹵素或CF3。
- 如請求項1至3中任一項之式(I)化合物,其中r為1、2或3之整數,尤其是2或3。
- 如請求項1至3中任一項之式(I)化合物,其中R0為H,m為0或1,且X為O。
- 如請求項1之式(Ia')化合物,
- 如請求項1之式(Ib)化合物,
- 如請求項10之式(Ib)化合物,其中m為整數1或2,r為整數2或3,各R獨立地為鹵素或CF3,且各R1獨立地為鹵素或CF3。
- 一種用於防治寄生蟲之組合物,除載劑及/或分散劑之外,其還 含有如請求項1至11中任一項之至少一種式(I)化合物作為活性成份。
- 如請求項1至3及9至11中任一項之式(I)化合物,其用於在溫血動物中或在溫血動物上防治體內寄生蟲。
- 一種如請求項1至11中任一項之式(I)化合物的用途,其用於製備在溫血動物中或在溫血動物上對抗體內寄生蟲之獸醫或醫藥組合物。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14172659.6A EP2957557A1 (en) | 2014-06-17 | 2014-06-17 | New compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201607919A true TW201607919A (zh) | 2016-03-01 |
TWI551580B TWI551580B (zh) | 2016-10-01 |
Family
ID=50980936
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW104118201A TWI551580B (zh) | 2014-06-17 | 2015-06-04 | 新穎磺醯胺基苯甲醯胺化合物 |
Country Status (24)
Country | Link |
---|---|
US (1) | US9714219B2 (zh) |
EP (2) | EP2957557A1 (zh) |
JP (1) | JP6113924B2 (zh) |
KR (1) | KR101926281B1 (zh) |
CN (1) | CN106470972B (zh) |
AR (1) | AR100723A1 (zh) |
AU (1) | AU2015277529B2 (zh) |
BR (1) | BR112016026306B1 (zh) |
CA (1) | CA2958032C (zh) |
CY (1) | CY1120763T1 (zh) |
DK (1) | DK3157902T3 (zh) |
EA (1) | EA030490B1 (zh) |
ES (1) | ES2692849T3 (zh) |
HR (1) | HRP20181530T1 (zh) |
HU (1) | HUE039805T2 (zh) |
LT (1) | LT3157902T (zh) |
MX (1) | MX2016016732A (zh) |
NZ (1) | NZ725417A (zh) |
PL (1) | PL3157902T3 (zh) |
PT (1) | PT3157902T (zh) |
RS (1) | RS57923B1 (zh) |
SI (1) | SI3157902T1 (zh) |
TW (1) | TWI551580B (zh) |
WO (1) | WO2015195423A1 (zh) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2990403A1 (en) * | 2014-08-29 | 2016-03-02 | Novartis Tiergesundheit AG | Anthranilamides, sulfonamides and nitro analogues derived therefrom as anthelmintics |
WO2017213137A1 (ja) * | 2016-06-09 | 2017-12-14 | アグロカネショウ株式会社 | 新規化合物およびこれを有効成分とする農園芸用薬剤 |
EP3508475A4 (en) | 2016-08-30 | 2020-04-15 | Nippon Soda Co., Ltd. | SULFONYLAMINOBENZAMIDE COMPOUND AND PEST CONTROL |
US11517568B2 (en) | 2018-09-12 | 2022-12-06 | The Governing Council Of The University Of Toronto | Compounds and methods for treating nematode infections |
CA3112443A1 (en) | 2018-09-12 | 2020-03-19 | The Governing Council Of The University Of Toronto | Compounds and methods for treating nematode infections |
CN112156087B (zh) * | 2020-11-06 | 2021-10-26 | 牡丹江医学院 | 一种治疗胰腺炎的药物及其制备方法 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19858253A1 (de) * | 1998-12-17 | 2000-06-21 | Aventis Pharma Gmbh | Verwendung von Inhibitoren des KQt1-Kanals zur Herstellung eines Medikaments zur Behandlung von Krankheiten, die durch Helminthen und Ektoparasiten hervorgerufen werden |
CN1865258A (zh) * | 2001-08-15 | 2006-11-22 | 纳幕尔杜邦公司 | 用于控制无脊椎害虫的邻位取代的芳基酰胺化合物 |
GB0214117D0 (en) * | 2002-06-19 | 2002-07-31 | Syngenta Participations Ag | N-sulphonylaminoacetonitriles having pesticidal properties |
WO2005085188A2 (en) | 2004-03-02 | 2005-09-15 | Compass Pharmaceuticals Llc | Compounds and methods for anti-tumor therapy |
ES2314724T3 (es) * | 2004-09-23 | 2009-03-16 | Schering-Plough Ltd. | Control de parasitos en animales mediante el uso de nuevos derivados de eter de trifluorometanosulfonanilida oxima. |
JP5583661B2 (ja) * | 2008-06-13 | 2014-09-03 | バイエル・クロップサイエンス・アーゲー | 殺有害生物剤としての新規ヘテロ芳香族アミド及びチオアミド |
EP2814321B1 (en) * | 2012-02-14 | 2018-09-26 | Syngenta Participations AG | Nematicidal cis (hetero)arylcyclopropylcarboxamide derivatives |
-
2014
- 2014-06-17 EP EP14172659.6A patent/EP2957557A1/en not_active Ceased
-
2015
- 2015-06-04 TW TW104118201A patent/TWI551580B/zh active
- 2015-06-04 AR ARP150101760A patent/AR100723A1/es active IP Right Grant
- 2015-06-10 MX MX2016016732A patent/MX2016016732A/es active IP Right Grant
- 2015-06-10 PL PL15731190T patent/PL3157902T3/pl unknown
- 2015-06-10 HU HUE15731190A patent/HUE039805T2/hu unknown
- 2015-06-10 NZ NZ725417A patent/NZ725417A/en unknown
- 2015-06-10 CA CA2958032A patent/CA2958032C/en active Active
- 2015-06-10 PT PT15731190T patent/PT3157902T/pt unknown
- 2015-06-10 CN CN201580032901.1A patent/CN106470972B/zh active Active
- 2015-06-10 KR KR1020177000971A patent/KR101926281B1/ko active IP Right Grant
- 2015-06-10 ES ES15731190.3T patent/ES2692849T3/es active Active
- 2015-06-10 DK DK15731190.3T patent/DK3157902T3/en active
- 2015-06-10 JP JP2016529446A patent/JP6113924B2/ja active Active
- 2015-06-10 SI SI201530365T patent/SI3157902T1/sl unknown
- 2015-06-10 LT LTEP15731190.3T patent/LT3157902T/lt unknown
- 2015-06-10 EA EA201691999A patent/EA030490B1/ru not_active IP Right Cessation
- 2015-06-10 WO PCT/US2015/035026 patent/WO2015195423A1/en active Application Filing
- 2015-06-10 US US14/917,589 patent/US9714219B2/en active Active
- 2015-06-10 RS RS20181279A patent/RS57923B1/sr unknown
- 2015-06-10 AU AU2015277529A patent/AU2015277529B2/en active Active
- 2015-06-10 EP EP15731190.3A patent/EP3157902B1/en active Active
- 2015-06-10 BR BR112016026306-5A patent/BR112016026306B1/pt active IP Right Grant
-
2018
- 2018-09-26 HR HRP20181530TT patent/HRP20181530T1/hr unknown
- 2018-10-10 CY CY181101041T patent/CY1120763T1/el unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI551580B (zh) | 新穎磺醯胺基苯甲醯胺化合物 | |
AU2018204015B2 (en) | Novel sulfonylaminobenzamide compounds as anthelmintics | |
JP6140373B2 (ja) | 新規化合物 | |
NZ744117B2 (en) | Novel sulfonylaminobenzamide compounds as anthelmintics |