EP3386961A1 - Stereoisomer of flocoumafen, composition and rodenticide bait comprising same, and method for controlling target rodent pests - Google Patents
Stereoisomer of flocoumafen, composition and rodenticide bait comprising same, and method for controlling target rodent pestsInfo
- Publication number
- EP3386961A1 EP3386961A1 EP16809712.9A EP16809712A EP3386961A1 EP 3386961 A1 EP3386961 A1 EP 3386961A1 EP 16809712 A EP16809712 A EP 16809712A EP 3386961 A1 EP3386961 A1 EP 3386961A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- enantiomer
- flocoumafene
- composition
- configuration
- amount
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- OWUZCVPRFKSBRG-UHFFFAOYSA-N flocoumafen Chemical compound OC=1OC2=CC=CC=C2C(=O)C=1C(C1=CC=CC=C1C1)CC1C(C=C1)=CC=C1OCC1=CC=C(C(F)(F)F)C=C1 OWUZCVPRFKSBRG-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 239000000203 mixture Substances 0.000 title claims description 130
- 239000003128 rodenticide Substances 0.000 title claims description 110
- 241000283984 Rodentia Species 0.000 title claims description 62
- 238000000034 method Methods 0.000 title claims description 33
- 241000607479 Yersinia pestis Species 0.000 title description 3
- 238000004587 chromatography analysis Methods 0.000 claims abstract description 41
- 230000014759 maintenance of location Effects 0.000 claims abstract description 40
- 238000004458 analytical method Methods 0.000 claims abstract description 13
- KKBGNYHHEIAGOH-UHFFFAOYSA-N Flocoumafen Chemical compound O=C1OC=2C=CC=CC=2C(O)=C1C(C1=CC=CC=C1C1)CC1C(C=C1)=CC=C1OCC1=CC=C(C(F)(F)F)C=C1 KKBGNYHHEIAGOH-UHFFFAOYSA-N 0.000 claims description 176
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 66
- KSOVGRCOLZZTPF-QMKUDKLTSA-N (1s,2s,3r,4r)-3-[[5-fluoro-2-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound N([C@H]1[C@H]([C@@]2([H])C[C@@]1(C=C2)[H])C(N)=O)C(C(=CN=1)F)=NC=1NC(C=C1C)=CC=C1N1CCN(C)CC1 KSOVGRCOLZZTPF-QMKUDKLTSA-N 0.000 claims description 43
- 239000007788 liquid Substances 0.000 claims description 35
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 20
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 20
- 235000013339 cereals Nutrition 0.000 claims description 19
- 239000002245 particle Substances 0.000 claims description 19
- 235000013305 food Nutrition 0.000 claims description 13
- 230000005526 G1 to G0 transition Effects 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 10
- 235000019253 formic acid Nutrition 0.000 claims description 10
- VWOVELKWMFTNCE-UHFFFAOYSA-N (4-chloro-3-methylphenyl)carbamic acid Chemical compound CC1=CC(NC(O)=O)=CC=C1Cl VWOVELKWMFTNCE-UHFFFAOYSA-N 0.000 claims description 9
- 239000007983 Tris buffer Substances 0.000 claims description 9
- 239000001913 cellulose Substances 0.000 claims description 9
- 229920002678 cellulose Polymers 0.000 claims description 9
- 239000011148 porous material Substances 0.000 claims description 9
- 238000002347 injection Methods 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 7
- 235000012054 meals Nutrition 0.000 claims description 2
- 239000004464 cereal grain Substances 0.000 claims 1
- 241000700159 Rattus Species 0.000 description 20
- 239000012071 phase Substances 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 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 13
- 239000007787 solid Substances 0.000 description 13
- 210000004185 liver Anatomy 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 239000000546 pharmaceutical excipient Substances 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- -1 4-trifluoromethylbenzyloxy Chemical group 0.000 description 5
- 231100000518 lethal Toxicity 0.000 description 5
- 230000001665 lethal effect Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- 231100001160 nonlethal Toxicity 0.000 description 4
- 230000001119 rodenticidal effect Effects 0.000 description 4
- 235000020374 simple syrup Nutrition 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 229940127219 anticoagulant drug Drugs 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 235000013312 flour Nutrition 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 229910021642 ultra pure water Inorganic materials 0.000 description 3
- 239000012498 ultrapure water Substances 0.000 description 3
- 244000060011 Cocos nucifera Species 0.000 description 2
- 235000013162 Cocos nucifera Nutrition 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- 208000005374 Poisoning Diseases 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 108010009736 Protein Hydrolysates Proteins 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930003448 Vitamin K Natural products 0.000 description 2
- 230000036528 appetite Effects 0.000 description 2
- 235000019789 appetite Nutrition 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 235000013601 eggs Nutrition 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 238000000265 homogenisation Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 231100000566 intoxication Toxicity 0.000 description 2
- 230000035987 intoxication Effects 0.000 description 2
- 229940040511 liver extract Drugs 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- 230000002688 persistence Effects 0.000 description 2
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 2
- 231100000572 poisoning Toxicity 0.000 description 2
- 230000000607 poisoning effect Effects 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003531 protein hydrolysate Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 235000019168 vitamin K Nutrition 0.000 description 2
- 239000011712 vitamin K Substances 0.000 description 2
- 150000003721 vitamin K derivatives Chemical class 0.000 description 2
- 229940046010 vitamin k Drugs 0.000 description 2
- ZOCSXAVNDGMNBV-UHFFFAOYSA-N 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile Chemical compound NC1=C(S(=O)C(F)(F)F)C(C#N)=NN1C1=C(Cl)C=C(C(F)(F)F)C=C1Cl ZOCSXAVNDGMNBV-UHFFFAOYSA-N 0.000 description 1
- 241000208140 Acer Species 0.000 description 1
- 235000010319 Acer grandidentatum Nutrition 0.000 description 1
- 235000010328 Acer nigrum Nutrition 0.000 description 1
- 235000002629 Acer saccharinum Nutrition 0.000 description 1
- 235000010157 Acer saccharum subsp saccharum Nutrition 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
- 235000007319 Avena orientalis Nutrition 0.000 description 1
- 244000075850 Avena orientalis Species 0.000 description 1
- 241000723382 Corylus Species 0.000 description 1
- 235000007466 Corylus avellana Nutrition 0.000 description 1
- 240000003133 Elaeis guineensis Species 0.000 description 1
- 239000005899 Fipronil Substances 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 240000005979 Hordeum vulgare Species 0.000 description 1
- 235000007340 Hordeum vulgare Nutrition 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 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
- 241000124008 Mammalia Species 0.000 description 1
- 240000004658 Medicago sativa Species 0.000 description 1
- 235000017587 Medicago sativa ssp. sativa Nutrition 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 235000019482 Palm oil Nutrition 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 240000001987 Pyrus communis Species 0.000 description 1
- 235000019484 Rapeseed oil Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UHFFFAOYSA-N Rohrzucker Natural products OCC1OC(CO)(OC2OC(CO)C(O)C(O)C2O)C(O)C1O CZMRCDWAGMRECN-UHFFFAOYSA-N 0.000 description 1
- 240000000111 Saccharum officinarum Species 0.000 description 1
- 235000007201 Saccharum officinarum Nutrition 0.000 description 1
- 244000228451 Stevia rebaudiana Species 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 238000004847 absorption spectroscopy Methods 0.000 description 1
- 230000000895 acaricidal effect Effects 0.000 description 1
- 239000000642 acaricide Substances 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 230000002498 deadly effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- VWTINHYPRWEBQY-UHFFFAOYSA-N denatonium Chemical compound [O-]C(=O)C1=CC=CC=C1.C=1C=CC=CC=1C[N+](CC)(CC)CC(=O)NC1=C(C)C=CC=C1C VWTINHYPRWEBQY-UHFFFAOYSA-N 0.000 description 1
- 229960001610 denatonium benzoate Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012527 feed solution Substances 0.000 description 1
- 229940013764 fipronil Drugs 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 230000003370 grooming effect Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 239000010903 husk Substances 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 235000014571 nuts Nutrition 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- 235000021400 peanut butter Nutrition 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 238000005375 photometry Methods 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 235000008476 powdered milk Nutrition 0.000 description 1
- 244000062645 predators Species 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000012069 sugar maple Nutrition 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 235000021147 sweet food Nutrition 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
- C07D311/56—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 without hydrogen atoms in position 3
-
- 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
- A01N25/002—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 a foodstuff as carrier or diluent, i.e. baits
- A01N25/004—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 a foodstuff as carrier or diluent, i.e. baits rodenticidal
-
- 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
- A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
- A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
- A01N43/14—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings
- A01N43/16—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings with oxygen as the ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
- B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
- B01D15/38—Selective adsorption, e.g. chromatography characterised by the separation mechanism involving specific interaction not covered by one or more of groups B01D15/265 - B01D15/36
- B01D15/3833—Chiral chromatography
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the present invention relates to a configuration stereoisomer of flocoumafene, a composition and a rodenticide bait comprising such a confocal configuration isomer of flocoumafene and a method for controlling harmful target rodents.
- the invention also relates to a process for obtaining such a configuration stereoisomer of flocoumafene.
- the invention thus relates to the technical field of the fight against target rodent pest populations.
- a rodenticide bait comprising a proportion of flocoumafene of 50 ppm in the bait and a proportion of fipronil of 40 ppm is known from WO2005 / 072524.
- Such bait is likely to be consumed by animals other than harmful target rodents when made available to harmful target rodents. It can be consumed directly (primary consumption) by pets or pets. It can also be accidentally consumed by humans. Such consumption may produce poisoning in these pets, pets, or humans that can be lethal.
- the invention therefore aims to overcome these drawbacks by proposing a configurational stereoisomer of flocoumafene, a composition and a rodenticide bait comprising such a configuration stereo-isomer and a method for controlling harmful target rodents which are at the same time effective to control target rodent pest populations and also to limit the risk of poisoning non-target animals - including domestic animals, pets or humans - accidentally consuming such rodenticide bait.
- the invention also aims at providing a configuration stereoisomer of flocoumafene, a composition and a rodenticide bait comprising such a configuration stereo-isomer and a method for controlling harmful target rodents whose implementation is in accordance with the rules of good practice -especially with respect to the protection of birds, and in particular birds of prey-.
- the invention also aims at providing a configurational stereoisomer of flocoumafene, a composition and a rodenticide bait comprising such a configurational stereoisomer and a method for controlling harmful target rodents which are environmentally friendly, safe and effective. human health and non-target animals.
- the invention also aims at providing a configurational stereoisomer of flocoumafene, a composition and a rodenticide bait comprising such a configuration stereo-isomer and a method for controlling harmful target rodents which make it possible to use only reduced doses. of flocoumafene.
- the invention also aims at providing a configuration stereoisomer of flocoumafene, a composition and a rodenticide bait comprising such a configuration stereoisomer and a method for controlling harmful target rodents that are likely to be used to fight against harmful target rodents resistant to known baits for the control of harmful target rodents.
- the invention therefore aims to propose an alternative to known rodenticide baits.
- the invention relates to a configuration stereoisomer, referred to as the enantiomer E 4 , of flocoumafene, said E 4 enantiomer having, by chromatographic analysis of a flocoumafene composition, comprising four stereoisomers of flocoumafene configuration carried out in conditions described below, a retention time t 4 of value such that
- liquid mobile phase a mixture of acetonitrile (A) and water comprising 0.1% by volume of formic acid (B), with a ratio by volume A / B of 92/8; and with a flow rate of the liquid mobile phase in the chromatography column of 0.25 mL / min;
- locoumafene designates the compound of the formula 3- [4- (4-trifluoromethylbenzyloxy) phenyl-4-yl] -1- (4-hydroxycoumarin-3-yl) -1,2,3,4-tetrahydronaphthalene or 4-hydroxy-3- [1,2,3,4-tetrahydro-3- [4- [4-
- stereoisomers denotes isomers of the same semi-developed formula, but whose relative position of atoms differs in space.
- configuration stereo-isomers refers to stereoisomers whose conversion of these configuration stereoisomers into one another requires a break / reformation of an interatomic covalent bond.
- configuration stereo-isomers refers to stereoisomers which are not conformational isomers (or “rotamers”), whose conversion of the conformational isomers into each other is accompanied only by a rotation of a part of the molecule along the axis of a bond ⁇ (sigma) formed by axial overlap of orbitals);
- the term "quantity" means a molar amount, a mass quantity or a volume quantity. The proportions are therefore proportions of a molar amount relative to a molar amount, of a mass quantity relative to a mass quantity, or of a volume quantity referred to a volume quantity;
- HPLC high pressure liquid chromatography
- HPLC high performance liquid chromatography
- retention time designates the duration measured at the top of the chromatogram peak during which a compound is retained on the chromatography column.
- the invention therefore relates to said enantiomer E 4 in the isolated state and which has the property of being elutable, under the chromatography conditions described above, the last with respect to the four configurational stereoisomers of flocoumafene.
- the inventors have observed that the analysis of flocoumafene by high pressure liquid chromatography under the conditions described above reveals four signals or peaks corresponding to four compounds of the same chemical formula developed and corresponding to the formula (I) flocoumafene. They determined, by the analysis of flocoumafene preparations comprising variable proportions of the two diastereomers of flocoumafene that:
- the compound corresponding to the retention time signal ti of a value of the order of 4.5 min is an enantiomer, referred to as the enantiomer E 1 , of one of the two diastereoisomers, called diastereoisomer D 1; 4 , of flocoumafene; ;
- the compound corresponding to the retention time signal t 4 with a value of the order of 9.3 min is the other enantiomer, referred to as the enantiomer E 4 , of said diastereoisomer D 1; 4 , distinct from said enantiomer E 1 ;
- the compound corresponding to the retention time signal t 2 having a value of the order of 6.2 min is an enantiomer, referred to as the enantiomer E 2 , of the other diastereoisomer, called diastereoisomer D 2 3 , of the flocoumafene, distinct said diastereoisomer D 1; 4 , and;
- the compound corresponding to the retention time signal t 3 with a value of the order of 6.8 min is the other enantiomer, referred to as the enantiomer E 3 , of said diastereoisomer D 2 3 distinct from said enantiomer E 2 .
- the values of the retention times t 15 t 2 , t 3 and t 4 are likely to vary, in particular with the temperature of the chromatography column. However, in these chromatographic conditions, the order of elution of the enantiomers of flocoumafene remains unchanged.
- One of the two diastereoisomers of flocoumafene is a configuration stereoisomer of flocoumafene in which carbons 1 and 3 of the 1,2,3,4-tetrahydronaphthalene group of flocoumafene are of the same absolute configuration and the other of the two diastereoisomers of flocoumafen is a configurational stereoisomer of flocoumafen in which carbons 1 and 3 of the 1,2,4,4-tetrahydronaphthalene group of flocoumafene are of distinct absolute configurations, the absolute configurations being determined according to the sequential rules of priority and the nomenclature from Cahn, Ingold and Prelog.
- the inventors have achieved such a separation of configuration stereoisomers, that is to say enantiomers of the two diastereoisomers, of flocoumafene by high pressure liquid chromatography. on a LUX ® Cellulose-4 chiral column (00F-4490-B0, phenomenex, Le Pecq, France). If necessary, it is possible to successively carry out several stages of high-pressure liquid chromatography on a chiral column in order to obtain the quantity of said desired enantiomer E 4 at the desired purity.
- the inventors obtained said enantiomer E 4 purified and separated from the enantiomer Ei of said diastereoisomer D 1; 4 of flocoumafene and enantiomers E 2 and E 3 of said diastereoisomer D 2 3 of flocoumafene by elimination of the mobile phase of the fraction collected and containing said enantiomer ⁇ ⁇ It is possible to carry out such a separation by high-pressure liquid chromatography on a larger chiral preparative column -in particular with an internal diameter greater than 2 mm- and in which the stationary phase has a particle size greater than 3 ⁇ .
- the invention therefore relates to said enantiomer E 4 of said diastereoisomer D 1 4 which is the most selected (of the highest retention time) of the four enantiomers of the diastereoisomers of flocoumafene separated by chromatography under the above conditions.
- the invention therefore relates to said enantiomer E 4 separated from the enantiomer E 1 of said diastereoisomer D 1 4 and separated from the enantiomer E 2 and the enantiomer E 3 of said diastereoisomer D 2 3 .
- the invention also relates to a chromatographic process for the separation of configuration stereoisomers -in particular said enantiomers E 1 and E 4 of said diastereoisomer D 1; 4 and said enantiomers E 2 and E 3 of said diastereoisomer D 2 3 .
- the invention also relates to a chromatographic process for obtaining said enantiomer E 4 according to the invention.
- the invention thus relates to such a chromatographic process for obtaining said enantiomer E 4 according to the invention, in which:
- a column for high pressure liquid chromatography of dimensions 150 ⁇ 2 mm, and comprising a chiral stationary phase consisting of tris (4-chloro-3-methylphenylcarbamate) cellulose particles, said particles being of an average size of 3 ⁇ and having an average pore size of 1000 A;
- the liquid composition is entrained with the mobile phase in the chromatography column under conditions suitable for separating the configuration stereoisomers from the flocoumafene, and a fraction of the mobile phase comprising said E 4 enantiomer is collected with a retention time t 4 of value such that ⁇ t 2 ⁇ t 3 ⁇ t; l5 t t 2 and t 3 is the retention time of each separate flocoumafen configuration of the stereoisomers of said enantiomer S 4, separately from said Ei enantiomer retention time t and l5;
- the invention also relates to said enantiomer E 4 obtained by a process according to the invention.
- the invention also relates to a composition comprising said enantiomer E 4 according to the invention, excluding a racemic mixture of said enantiomer E 4 and said enantiomer E 1 .
- the invention therefore relates to a composition comprising a configuration stereoisomer, referred to as the enantiomer E 4 , of flocoumafene, excluding a racemic mixture of said enantiomer E 4 and a configuration stereoisomer, referred to as the enantiomer E 1. flocoumafene;
- said enantiomer E 4 having, by chromatographic analysis of a flocoumafene composition comprising four stereoisomers of flocoumafene configuration carried out under the conditions described below, a retention time t 4 ;
- said enantiomer Ei having, by chromatographic analysis of a flocoumafene composition comprising four stereoisomers of flocoumafene configuration carried out under these same conditions, a retention time ti;
- ti and t 4 being of values such that ⁇ ⁇ t 2 ⁇ t 3 ⁇ t 4 ; t 2 and t 3 representing the retention times of each of the configuration stereoisomers of the flocoumafene distinct from said enantiomer E 4 and said enantiomer E 1 , said analysis being carried out at the temperature of 23.5 ° C and under the following conditions:
- a column for high-pressure liquid chromatography of dimensions 150 ⁇ 2 mm, and comprising a chiral stationary phase consisting of cellulose particles tris (4-chloro-3-methylphenylcarbamate), said particles being of average size of 3 ⁇ and having an average pore size of 1000 A;
- liquid mobile phase a mixture of acetonitrile (A) and water comprising 0.1% by volume of formic acid (B), with a ratio by volume A / B of 92/8; and with a flow rate of the liquid mobile phase in the chromatography column of 0.25 mL / min;
- the invention thus relates to such a composition
- a composition comprising said enantiomer E 4 , excluding a racemic mixture of said enantiomer E 1 and said enantiomer E 4 , that is to say excluding a wherein said enantiomer E 1 and said enantiomer E 4 are in an equimolar and non-optically active mixture.
- the enantiomer E 4 and said enantiomer E 1 are dosed with any composition comprising flocoumafene by analysis and separation by chromatography using a chiral stationary phase and a liquid mobile phase as described above for the analysis of configuration stereoisomers flocoumafene, by performing a quantitative detection of stereoisomers of flocoumafene configuration at the outlet of the separating column, for example by photometry or absorption spectrometry, by adjusting the flocoumafene concentration and the injection volume in order to obtain optimal detection and by measuring the value of the area under the peak of each enantiomer E 4 and Ei. It is also possible to assay said enantiomer E 4 and said enantiomer E 1 of any composition comprising flocoumafene by performing a mass spectrometric detection at the outlet of the separating column.
- said enantiomer E 4 has in the composition an amount greater than the amount of said enantiomer E 1 in the composition.
- said diastereoisomer D 1; 4 is predominantly in the form of said enantiomer E 4 .
- the composition according to the invention comprises said diastereoisomer D 1 4 mainly in the form of said enantiomer E 4 .
- the ratio of the amount of said enantiomer S 4 of the sum of the amount of said enantiomer E 4 and the amount of said enantiomer Ei is greater than 0.5 (greater than 50%); the ratio of the concentration of said enantiomer E 4 to the sum of the concentration of said enantiomer E 4 and the concentration of said enantiomer E 1 is greater than 0.5 (greater than 50%), and;
- the proportion of said enantiomer E 4 in the composition is greater than the proportion of said enantiomer Ei in the composition.
- the composition comprises an amount of said enantiomer E 4 such that the ratio of this amount to the sum of the amount of said enantiomer E 4 and the amount of said enantiomer Ei present in the composition is greater than 50%, especially greater than 60%, in particular greater than 70%, more particularly greater than 80%, preferably greater than 90%, more preferably greater than 95%, particularly preferably greater than 98%, still more preferably greater than 99%, or the order of 100%.
- the composition comprises an amount of said enantiomer E 4 such that the ratio of this amount to the sum of the amount of said enantiomer E 4 and the amount of said enantiomer E 1 present in the composition is greater than 75%, preferably between 85% and 100%, more preferably between 90% and 98%.
- the composition comprises an amount of said enantiomer E 4 such that the ratio of this amount to the sum of the amount of said enantiomer E 4 and the amount of said enantiomer Ei present in the composition is between 98% and 100%.
- composition may also comprise an amount of said enantiomer Ei such that the ratio of this amount to the sum of the amount of said enantiomer E 4 and the amount of said enantiomer E 1 is less than 50%, especially less than 25%, preferably between 0% and 25%, especially less than 10%.
- the flocoumafene is predominantly in the form of said enantiomer E 4 in the composition.
- the composition therefore comprises an amount of said enantiomer E 4 such that the ratio of this amount to the amount of flocoumafene in the composition is greater than the ratio of the amount of said enantiomer E 1 to the amount of flocoumafene in the composition and greater than the ratio of the amount of each enantiomer of said diastereoisomer D 2 , 3 on the amount of flocoumafene in the composition.
- the ratio of the amount of said enantiomer E 4 to the amount of flocoumafene is greater than 0.25 (greater than 25%);
- the ratio of the amount of said enantiomer E 4 to the sum of the amounts of each enantiomer of said diastereoisomer D 1; 4 and the quantities of each enantiomer of said diastereoisomer D 2 3 is greater than 0.25 (greater than 25%);
- the ratio of the concentration of said enantiomer E 4 in the composition to the concentration of flocoumafene in the composition is greater than 0.25 (greater than 25%);
- the proportion of said enantiomer E 4 in the composition is greater than the proportion of each enantiomer of said diastereoisomer D 2 3 in the composition and to the proportion of said enantiomer E 1 in the composition.
- the composition comprises an amount of said enantiomer E 4 such that the ratio of this amount to the amount of flocoumafene in the composition is greater than 25%, especially greater than 50%, in particular greater than 70%, more particularly greater than 80%, preferably greater than 90%, particularly preferably greater than 95%, more preferably greater than 98%, still more preferably greater than 99% or of the order of 100%.
- the composition comprises an amount of said enantiomer E 4 such that the ratio of this amount to the amount of flocoumafene in the composition is greater than 70, preferably between 80% and 100, more preferably between 90% and 100.
- the composition comprises an amount of said enantiomer E 4 such that the ratio of this amount to the amount of flocoumafene in the composition is between 95% and 99.
- the composition comprises an amount of said enantiomer E 4 such that the ratio of this amount to the amount of flocoumafene in the composition is greater than 95%.
- the composition comprises an amount of said enantiomer E 4 such that the ratio of this amount to the amount of flocoumafene in the composition is between 98% and 100% -bornes consist- .
- the composition comprises an amount of said enantiomer E 4 such that the ratio of this amount to the amount of flocoumafene in the composition is substantially of the order of 100%.
- a composition according to the invention may be substantially free of said enantiomer E 1 , that is to say that said enantiomer E 1 may optionally be present in the composition but only in the form of traces.
- a composition according to the invention may also be substantially free of said diastereoisomer D 2 , 3, that is to say that said diastereoisomer D 2 3 may optionally be present in the composition but only in the form of traces.
- the composition may be in the liquid state and comprise a liquid solvent of flocoumafene.
- It can be a flocoumafen solution in a solvent of flocoumafen, excluding a racemic mixture of said enantiomer and E 4 of said enantiomer Ei.
- It may also be a solution comprising flocoumafene in a flocoumafene solvent and in which the amount of said E 4 enantiomer is greater than the amount of said enantiomer E 1 .
- It may also be a solution comprising flocoumafene in a flocoumafene solvent and in which the flocoumafene is predominantly in the form of said E 4 enantiomer.
- the composition is in the solid state. It may also be a solid comprising flocoumafene, excluding a racemic mixture of said enantiomer E 4 and said enantiomer E 1 . It can also be a solid comprising flocoumafene and in which the amount of said enantiomer E 4 is greater than the amount of said enantiomer E 1 . It may also be a solid comprising flocoumafene and in which the flocoumafene is predominantly in the form of said enantiomer E 4 .
- the invention therefore also relates to a composition according to the invention comprising flocoumafene, the flocoumafene of the composition being optically active.
- the flocoumafene of the composition according to the invention is optically inactive.
- the invention also relates to the use of a composition according to the invention for the preparation of a rodenticide bait for harmful target rodents.
- the invention also relates to a rodenticide bait comprising a composition according to the invention, and at least one edible excipient for harmful target rodents.
- a rodenticide bait according to the invention comprises:
- At least one edible carrier for harmful target rodents at least one edible carrier for harmful target rodents
- enantiomer E 4 a configuration stereoisomer, referred to as the enantiomer E 4 , of flocoumafene, excluding a racemic mixture of said enantiomer E 4 and a configuration stereoisomer, referred to as the enantiomer E 15 of flocoumafene;
- said enantiomer E 4 having, by chromatographic analysis of a flocoumafene composition comprising four stereoisomers of flocoumafene configuration carried out under the conditions described below, a retention time t; said enantiomer E 1 having, by chromatographic analysis of a flocoumafene composition comprising four stereoisomers of flocoumafene configuration carried out under these same conditions, a retention time ti;
- ti and t 4 being of values such that ti ⁇ t 2 ⁇ t 3 ⁇ t 4 ; t 2 and t 3 representing the retention times of each of the flocoumafene configuration stereoisomers distinct from said enantiomer E 4 and said enantiomer E 15, said analysis being carried out at a temperature of 23.5 ° C and under the following conditions:
- a column for high pressure liquid chromatography of dimensions 150 x 2 mm, and comprising a chiral stationary phase consisting of tris (4-chloro-3-methylphenylcarbamate) cellulose particles, said particles being of an average size of 3 ⁇ and having an average pore size of 1000 A;
- liquid mobile phase a mixture of acetonitrile (A) and water comprising 0.1% by volume of formic acid (B), with a ratio by volume A / B of 92/8; and with a flow rate of the liquid mobile phase in the chromatography column of 0.25 mL / min;
- a rodenticide bait according to the invention comprises an edible excipient for harmful target rodents and flocoumafen in which the amount of said enantiomer E 4 is greater than the amount of said enantiomer E 1 . It may also be a rodenticide bait comprising flocoumafene and wherein flocoumafene is predominantly in the form of said enantiomer E 4 .
- Said enantiomer E 4 according to the invention makes it possible to produce rodenticide baits of rodenticidal efficacy maintained with respect to the baits of the state of the art but with a reduced proportion of flocoumafene. Such rodenticidal baits according to the present invention are therefore less toxic to the environment.
- a rodenticide bait according to the invention is likely to be used to control populations of rodent harmful targets resistant to known rodenticide treatments.
- a rodenticide bait according to the invention comprises a mass quantity of flocoumafen such that the ratio (mass proportion) of this mass quantity of flocoumafene to the amount of rodenticide bait is less than 50 ppm-that is to say less than 50 mg flocoumafene per kilogram of rodenticide bait.
- it comprises a mass quantity of flocoumafen such that the ratio of this mass quantity to the mass quantity of rodenticide bait is greater than 1 ppm.
- a rodenticide bait according to the invention comprises a mass quantity of flocoumafene such that the ratio of this mass quantity to the mass quantity of rodenticide bait is between 1 ppm and 50 ppm (1 mg to 50 mg of flocoumafene per kilogram of rodenticide bait).
- the ratio of this mass quantity to the mass quantity of rodenticide bait is between 1 ppm and 25 ppm (1 mg to 25 mg of flocoumafene per kilogram of rodenticide bait), especially between 1 ppm and 20 ppm (1 mg to 20 mg of flocoumafene per kilogram of rodenticide bait), particularly from 5 ppm to 15 ppm (5 mg to 15 mg of flocoumafene per kilogram of rodenticide bait).
- a rodenticide bait according to the invention comprises an amount of said enantiomer E 4 such that the ratio of this amount to the amount of flocoumafene in the rodenticide bait is greater than 70%, more particularly greater than 80%, preferably greater than 90%, particularly preferably greater than 95%, more preferably greater than 98%, still more preferably greater than 99% or of the order of 100%, and flocoumafene in a mass proportion of less than 25 ppm relative to the bait.
- the edible excipient for harmful target rodents is chosen to allow consumption of the rodenticide bait by harmful target rodents.
- each edible excipient is non-lethal for harmful target rodents.
- the edible carrier is not a rodenticide in itself.
- the edible excipient comprises at least one food selected from the group consisting of cereal seeds-notably dehulled cereal seeds-cereal seed mills, cereal seed flours, flakes cereal seeds, cereal bran and non-cereal seeds, eg alfalfa seeds - in particular in the form of husks, in the form of milling, in the form of flour, in the form of flakes or of ses-.
- the edible carrier may include any carrier that may be consumed by harmful target rodents.
- the edible carrier comprises at least one food selected from the group consisting of plant foods and foods of animal origin.
- the edible carrier comprises at least one food chosen to be able to stimulate the appetite of harmful target rodents.
- this food is selected from the group consisting of seeds of one or more cereals, seeds of one or more grains, seeds of one or more grains, seed flakes of one or more cereals, the sound of one or more cereals, and the grain meal of one or more cereals.
- cereals are selected from the group consisting of oats, wheat, barley, corn, soybeans and rice.
- the food is selected from the group consisting of sweet foods.
- these may include foods that include less a sugar selected from the group consisting of sucrose, lactose, fructose and glucose.
- It may be a sugar syrup-for example, a sugar syrup obtained by hydrolysis of the starch-or a sugar syrup obtained by hydrolysis of sucrose (invert sugar syrup), or beet sugar syrup, or maple syrup or sugar cane syrup, or syrup obtained from a plant of the genus stevia.
- the food is chosen from the group consisting of flakes and coconut albumen flour (copra).
- the food is selected from the group consisting of nuts, hazelnuts and almonds-shredded and / or powdered.
- the food is selected from the group consisting of vegetable fats, vegetable oils (for example rapeseed oil, soy fat, sunflower oil, cocoa butter, peanut oil, peanut butter, corn oil palm oil), animal fats and animal oils (butter, lard, fish oil).
- vegetable oils for example rapeseed oil, soy fat, sunflower oil, cocoa butter, peanut oil, peanut butter, corn oil palm oil
- animal fats and animal oils (butter, lard, fish oil).
- the food is selected from the group consisting of proteins of plant origin and proteins of animal origin.
- proteins of plant origin and proteins of animal origin.
- the rodenticide bait is chosen from the group consisting of solid baits comprising flocoumafene and a liquid edible excipient.
- the rodenticide bait is a solid in the divided state, for example in the form of pellets or granules.
- the rodenticide bait can be a solid in the form of a block or paste that can be consumed by the target harmful rodents or a solid material that can be eaten by the target harmful rodents.
- the solid rodenticide bait according to the invention can be in the form of a rigid block, a semi-rigid block, a foam, a powder or a gel.
- the rodenticide bait presented under form of a powder, in the form of a foam or in the form of a gel is adapted to be able to contaminate the fur of the target rodent (s) harmful (s) and to be able to be ingested by that ( those during his (their) grooming.
- the rodenticide bait is chosen from the group consisting of liquid baits comprising flocoumafene and a liquid edible excipient.
- the rodenticide bait is then a drink for harmful target rodents.
- the rodenticide bait is chosen from the group consisting of liquid baits comprising flocoumafene and a liquid edible excipient.
- the rodenticide bait is then a drink for harmful target rodents.
- It may be a solution of flocoumafene in a flocoumafene solvent, excluding a racemic mixture of said enantiomer E 4 and said enantiomer E 1 .
- It may also be a solution of flocoumafene in a flocoumafene solvent and in which the amount of said enantiomer E 4 is greater than the amount of said enantiomer E 1 .
- It can also be a flocoumafen solution in a solvent and flocoumafen wherein flocoumafen is largely in the form of said enantiomer E 4.
- It may also be a suspension of flocoumafene in the solid state in a liquid medium. It may also be an emulsion of flocoumafene in a liquid medium.
- the invention therefore also relates to a rodenticide bait comprising said E 4 enantiomer, excluding a racemic mixture of said E 4 enantiomer and said E 15 enantiomer, the flocoumafen of the rodenticide bait being optically active.
- a rodenticide bait comprising said E 4 enantiomer, excluding a racemic mixture of said E 4 enantiomer and said E 15 enantiomer, the flocoumafen of the rodenticide bait being optically active.
- flocoumafene the rodenticide bait according to the invention comprising said enantiomer E 4 , excluding a racemic mixture of said enantiomer E 4 and said enantiomer E 1 , which is itself optically inactive.
- the rodenticide bait comprises at least one dye.
- a dye makes it possible in particular to give said rodenticide bait a color easily detectable and identifiable by a person handling the rodenticide bait.
- the rodenticide bait comprises at least one preservative able to ensure its conservation during storage.
- the rodenticide bait includes at least one bittering type compound denatonium benzoate, also known as the "Bitrex ®" designed to reduce the risk of accidental consumption by non-target organisms.
- the composition and the rodenticide bait according to the invention comprise exclusively flocoumafene, excluding a racemic mixture of said enantiomer E 4 and said enantiomer E 15 as a rodenticide substance.
- the composition and the rodenticide bait according to the invention are free of any other anticoagulant substance for rodenticide use distinct from flocoumafene.
- the composition and rodenticide bait may include any harmful substance other than a rodenticide, such as an insecticide and / or acaricide.
- the composition and the rodenticide bait according to the invention comprise flocoumafene excluding a racemic mixture of said enantiomer E 4 and said enantiomer E 1 and at least one other substance distinct from flocoumafene as of rodenticide substance.
- This other rodenticide substance, distinct from flocoumafene may be another anticoagulant, particularly vitamin K or non-vitamin K, or any other non-anticoagulant rodenticide.
- the invention also relates to a method for controlling harmful target rodents in which a quantity of rodenticide bait comprising is dispersed comprising:
- At least one edible carrier for harmful target rodents at least one edible carrier for harmful target rodents
- enantiomer E 4 a configuration stereo-isomer, referred to as the enantiomer E 4 , of flocoumafene, excluding a racemic mixture of said enantiomer E 4 and a configuration stereoisomer, referred to as the enantiomer E 1 , of flocoumafene;
- said enantiomer E 4 having, by chromatographic analysis of a flocoumafene composition comprising four stereoisomers of flocoumafene configuration carried out under the conditions described below, a retention time t;
- said enantiomer E 1 having, by chromatographic analysis of a flocoumafene composition comprising four stereoisomers of flocoumafene configuration carried out under these same conditions, a retention time ti;
- ti and t 4 being of values such that ti ⁇ t 2 ⁇ t 3 ⁇ t 4 ; t 2 and t 3 representing the retention times of each of the flocoumafene configuration stereoisomers distinct from said enantiomer E 4 and said enantiomer E 15, said analysis being carried out at a temperature of 23.5 ° C and under the following conditions:
- a column for high pressure liquid chromatography of dimensions 150 x 2 mm, and comprising a chiral stationary phase consisting of tris (4-chloro-3-methylphenylcarbamate) cellulose particles, said particles being of an average size of 3 ⁇ and having an average pore size of 1000 A;
- liquid mobile phase a mixture of acetonitrile (A) and water comprising 0.1% by volume of formic acid (B), with a ratio by volume A / B of 92/8; and with a flow rate of the liquid mobile phase in the chromatography column of 0.25 mL / min; ⁇ by injection into the chromatography column with a volume of 1 .mu.l ⁇ flocoumafen composition at a concentration of 1 mcg flocoumafen per milliliter of acetonitrile.
- the invention also relates to a method for controlling harmful target rodents in which a quantity of rodenticide bait according to the invention is dispersed, said quantity of bait being sufficient to be rodenticide.
- the amount of said enantiomer E 4 in the rodenticide bait is greater than the amount of said enantiomer E 1 in the rodenticide bait.
- Said diastereoisomer D 1; 4 is predominantly in the form of said enantiomer E 4 .
- the flocoumafene is predominantly in the form of said enantiomer E 4 .
- a rodenticide bait according to this variant of the invention is a deadly rodenticide bait in a single dose or "one-shot" in English.
- the mass proportion of flocoumafene in the rodenticide bait is between 10 ppm and 25 ppm.
- This other variant of the invention therefore also relates to a method for controlling harmful target rodents in which a quantity of lethal rodenticide bait is dispersed for harmful target rodents consuming this rodenticide bait and generally non-lethal for rodents or animals. non-targets accidentally consuming this rodenticide bait.
- This is called a "multi-dose” or "multi-feeding" control method.
- the consumption of rodenticide bait by a target rodent harmful for a period of 24 hours is insufficient to cause the death of said rodent, while repeated consumption of rodenticide bait for at least two days resulting in the death of the target rodent.
- This other variant of the invention therefore relates to a method for controlling a population of harmful target rodents in which harmful rodent rodents are provided with a quantity of rodenticide bait capable of being ingested by the target harmful rodents, said quantity of rodenticide.
- rodenticide bait being sufficient to kill harmful target rodents consuming said rodenticide bait for several days.
- the quantity of disseminated rodenticide bait, the mass proportion of flocoumafene in the rodenticide bait and the proportion of said enantiomer E 4 relative to said diastereoisomer D 1 4 are adapted to the consumption of the rodenticide bait is lethal to harmful target rodents consuming daily rodenticide bait for at least 2 periods of 24 hours, particularly 3 to 7 periods, the said periods being consecutive.
- the proportion of said enantiomer E 4 being greater than 95% -particularly of the order of 100% -of flocoumafene in the bait, the mass proportion of flocoumafene relative to the rodenticide bait is between 1 ppm and 20 ppm -in particular between 2 ppm and 10 ppm, preferably of the order of 5 ppm-.
- harmful target rodents are provided with a quantity of rodenticide bait sufficient to daily satisfy the appetite of the target harmful rodents.
- the amount of disseminated rodenticide bait, the proportion of said enantiomer E 4 relative to said diastereoisomer D 1 4 and the mass proportion of flocoumafene relative to the rodenticide bait are adapted so as to allow consumption rodenticide bait for several days by harmful target rodents, while limiting:
- the invention also relates to a configuration stereoisomer of flocoumafene, a process for obtaining this stereoisomer of configuration, a composition and a rodenticide bait comprising this configuration stereoisomer and a method for controlling harmful target rodents characterized in combination by all or some of the characteristics mentioned above or below.
- FIG. 1 is a chromatogram representative of the separation of configuration stereoisomers from flocoumafen on a chiral column
- FIG. 2 is a histogram representation of the persistence of confocal stereoisomers of flocoumafene in the liver of rats.
- 0.525 g ( ⁇ 0.025 g) of rat liver are weighed accurately and placed in a 50 ml polypropylene tube. 10 mL of acetone was added and the suspension is subjected to homogenization using a homogenizer / disperser ® Ultra-Turrax for a period of about 30 sec. The rod of the homogenizer / disperser is rinsed with hot water and then twice with 20 ml of acetone in a polypropylene tube. The homogenate is centrifuged for 5 minutes at a centrifugation rate of 3000 rpm (rotation per minute). The supernatant is collected and decanted into a test tube. The sample is evaporated under a stream of nitrogen (N 2 ) at a temperature of 40 ° C to form a dry extract.
- N 2 nitrogen
- Detection is carried out by tandem mass spectrometry (MS / MS) in Electrospray Negative Ionisation (ESI) mode.
- MS / MS tandem mass spectrometry
- ESI Electrospray Negative Ionisation
- the nebulizer gas temperature is 350 ° C and its flow rate is 8 L / min.
- the nebulizer gas pressure is raised to 2700 hPa. In particular, one detects the MRM transitions m / z 541.1 ⁇ 382.1 and m / z 541.1 ⁇ 161 corresponding to the flocoumafene signal.
- the values of the retention times t 15 t 2 , t 3 and t 4 are likely to vary, in particular with the temperature of the chromatography column. However, under these chromatographic conditions, the order of elution of the enantiomers of flocoumafene remains unchanged.
- the value of the retention time O) of the enantiomer E 1 of said diastereoisomer D 1; 4 may vary between 4.4 min and 4.6 min.
- the value of the retention time (t 2 ) of the enantiomer E 2 of said diastereoisomer D 2 3 can vary between 5.9 min and 6.4 min.
- the value of the retention time (t 3 ) of the enantiomer E 3 of said diastereoisomer D 2 3 may vary between 6.4 min and 6.9 min.
- the value of the retention time (t 4 ) of said enantiomer E 4 according to the invention may vary between 8.9 min and 9.4 min.
- Oral (“peros") rats were administered to laboratory rats (Sprague Dawley rats, Charles River, Saint germain on Arbresle, France), male and female, aged 8 weeks and weighing between 180 and 200 g. comprising flocoumafen in a vegetable oil and 5% DMSO mixture so that the amount of flocoumafen ingested by each rat is in the range of 2.3 mg per kilogram of rat.
- the gaved rats are treated daily by subcutaneous administration of a dose of vitamin Kl at 1U per rat so as to keep the rats alive throughout the experiment.
- the ratio of the sum of the amounts of said enantiomer E 2 and said enantiomer E 3 (diastereoisomer D 2 3 ) to the amount of flocoumafen in the gavage solution is 59% and the ratio of the sum of the amounts of said enantiomer E 1 and said E 4 enantiomer (diastereoisomer D 1 4 ) on the amount of flocoumafene in the feed solution is 41%.
- FIG. 2 represents the evolution of the percentage of the mass quantity of each enantiomer (E 1 and E 4 ) of the diastereoisomer D 1; 4 and of each enantiomer (E 2 and E 3 ) of the diastereoisomer D 2 3 relative to the amount of flocoumafen retained in the liver of rats (male and female) fed and sacrificed on D + 1, D + 3 and D + 7.
- the percentage of said enantiomer E 1 is represented by oblique hatched columns
- the percentage of said enantiomer E 4 is represented by horizontal hatched columns
- the percentage of said enantiomer E 2 is represented by black columns
- the percentage of said enantiomer E 3 is represented. by white columns.
- each of the enantiomers (E 1 and E 4 ) of the diastereoisomer D 1; 4 and of the enantiomers (E 2 and E 3 ) of the diastereoisomer D 2 3 in the flocoumafen of the booster composition are represented in column "X" 2 and are 20.5% for the enantiomer E 1 of said diastereoisomer D 1 4 and 20.5% for the enantiomer E 4 of said diastereoisomer D 1; 4 and 29.5% for said enantiomer E 2 and 29.5% for said enantiomer E 3 .
- the E 4 enantiomer of flocoumafene is more persistent in the liver of harmful target rodents, has an increased rodenticidal efficacy compared to other stereoisomers of configuration and can therefore be used at lower dose in rodenticide baits.
- a rodenticide bait and a method of controlling a population of rodents harmful target according to the invention reduce the amount of flocoumafene in baits for maintained rodenticide effectiveness.
- a composition, a rodenticide bait and a method for controlling harmful target rodents are subject to infinite variations both in the formulation of the rodenticide bait and in the methods of implementing the method.
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Dentistry (AREA)
- Engineering & Computer Science (AREA)
- Plant Pathology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Food Science & Technology (AREA)
- Toxicology (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Epoxy Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR1562165A FR3045041B1 (en) | 2015-12-11 | 2015-12-11 | STEREO-ISOMER FOR CONFIGURING FLOCOUMAFENE, COMPOSITION AND RODONTICIDE APPAT COMPRISING SAME, METHOD FOR CONTROLLING HARMFUL TARGET RODENTS |
PCT/EP2016/079861 WO2017097750A1 (en) | 2015-12-11 | 2016-12-06 | Stereoisomer of flocoumafen, composition and rodenticide bait comprising same, and method for controlling target rodent pests |
Publications (1)
Publication Number | Publication Date |
---|---|
EP3386961A1 true EP3386961A1 (en) | 2018-10-17 |
Family
ID=55346044
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP16809712.9A Withdrawn EP3386961A1 (en) | 2015-12-11 | 2016-12-06 | Stereoisomer of flocoumafen, composition and rodenticide bait comprising same, and method for controlling target rodent pests |
Country Status (4)
Country | Link |
---|---|
US (1) | US20190002427A1 (en) |
EP (1) | EP3386961A1 (en) |
FR (1) | FR3045041B1 (en) |
WO (1) | WO2017097750A1 (en) |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3373184D1 (en) * | 1982-06-14 | 1987-10-01 | Shell Int Research | Anti-coagulants of the 4-hydroxycoumarin type, the preparation thereof, and rodenticidal compositions (baits) comprising such anti-coagulants |
US4601712A (en) * | 1983-11-16 | 1986-07-22 | Gould Inc. | Drip chamber |
GB8423782D0 (en) * | 1984-09-20 | 1984-10-24 | Ici Plc | Separation of isomers |
GB2410436A (en) | 2004-01-30 | 2005-08-03 | Reckitt Benckiser | Rodenticidal bait composition |
FR3022110B1 (en) * | 2014-06-13 | 2016-07-01 | Liphatech Inc | RODONTICIDE APPAT AND METHOD FOR CONTROLLING HARMFUL TARGET RODENTS USING SUCH APPAT |
-
2015
- 2015-12-11 FR FR1562165A patent/FR3045041B1/en active Active
-
2016
- 2016-12-06 WO PCT/EP2016/079861 patent/WO2017097750A1/en active Application Filing
- 2016-12-06 EP EP16809712.9A patent/EP3386961A1/en not_active Withdrawn
- 2016-12-06 US US16/060,864 patent/US20190002427A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
US20190002427A1 (en) | 2019-01-03 |
WO2017097750A1 (en) | 2017-06-15 |
FR3045041A1 (en) | 2017-06-16 |
FR3045041B1 (en) | 2019-05-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2015189321A1 (en) | Composition comprising difethialone, rodenticide bait and method for controlling target rodent pests | |
FR3045046B1 (en) | STEREO-ISOMER FOR CONFIGURING BROMADIOLONE, COMPOSITION AND RODONTICIDE APPAT COMPRISING SAME AND METHOD FOR CONTROLLING HARMFUL TARGET RODENTS | |
WO2017097750A1 (en) | Stereoisomer of flocoumafen, composition and rodenticide bait comprising same, and method for controlling target rodent pests | |
FR3045047B1 (en) | STEREO-ISOMER FOR CONFIGURING BROMADIOLONE, COMPOSITION AND RODONTICIDE APPAT COMPRISING SAME AND METHOD FOR CONTROLLING HARMFUL TARGET RODENTS | |
WO2017097752A1 (en) | Stereoisomer of flocoumafen, composition and rodenticide bait comprising same, and method for controlling target rodent pests | |
WO2017097751A1 (en) | Stereoisomer of flocoumafen, composition and rodenticide bait comprising same, and method for controlling target rodent pests | |
WO2017097749A1 (en) | Stereoisomer of flocoumafen, composition and rodenticide bait comprising same, and method for controlling target rodent pests | |
WO2017097753A1 (en) | Composition and rodenticide bait comprising flocoumafen and method for controlling target rodent pests | |
EP3386305B1 (en) | Composition and rodenticide bait comprising difethialone and method for controlling target rodent pests | |
FR3044872A1 (en) | RODONTICIDE APPAT COMPRISING BRODIFACOUM AND METHOD FOR CONTROLLING HARMFUL TARGET RODENTS | |
FR3044873A1 (en) | RODONTICIDE APPAT COMPRISING BRODIFACOUM AND METHOD FOR CONTROLLING HARMFUL TARGET RODENTS | |
FR3044871A1 (en) | RODONTICIDE APPAT COMPRISING BRODIFACOUM AND METHOD FOR CONTROLLING HARMFUL TARGET RODENTS | |
EP3386964A1 (en) | Stereoisomer of bromadiolone, composition and rodenticide bait comprising same, and method for controlling target rodent pests | |
FR3044875A1 (en) | RODONTICIDE APPAT COMPRISING BRODIFACOUM AND METHOD FOR CONTROLLING HARMFUL TARGET RODENTS | |
FR3044874A1 (en) | RODONTICIDE APPAT COMPRISING BRODIFACOUM AND METHOD FOR CONTROLLING HARMFUL TARGET RODENTS | |
FR3045050B1 (en) | DIFETHIALONE CONFIGURATION STEREO-ISOMER, COMPOSITION AND RODONTICIDE APPAT COMPRISING THE SAME AND METHOD OF CONTROLLING HARMFUL TARGET RODENTS | |
FR3044870A1 (en) | RODONTICIDE APPAT COMPRISING DIFENACOUM, METHOD FOR CONTROLLING HARMFUL TARGET RODENTS AND METHOD OF OBTAINING THE SAME | |
WO2017097745A1 (en) | Configurational stereoisomer of difethialone, composition and rodenticide bait comprising same, and method for controlling target rodent pests | |
WO2017097747A1 (en) | Configurational stereoisomer of difethialone, composition and rodenticide bait comprising same, and method for controlling target rodent pests | |
WO2017097744A1 (en) | Configurational stereoisomer of difethialone, composition and rodenticide bait comprising same, and method for controlling target rodent pests |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: UNKNOWN |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20180626 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
AX | Request for extension of the european patent |
Extension state: BA ME |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) | ||
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
17Q | First examination report despatched |
Effective date: 20210521 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20211001 |