EP3386971A1 - Configurational stereoisomer of difethialone, composition and rodenticide bait comprising same, and method for controlling target rodent pests - Google Patents
Configurational stereoisomer of difethialone, composition and rodenticide bait comprising same, and method for controlling target rodent pestsInfo
- Publication number
- EP3386971A1 EP3386971A1 EP16809709.5A EP16809709A EP3386971A1 EP 3386971 A1 EP3386971 A1 EP 3386971A1 EP 16809709 A EP16809709 A EP 16809709A EP 3386971 A1 EP3386971 A1 EP 3386971A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- difethialone
- stereoisomer
- hetero
- bait
- dextrorotatory enantiomer
- 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- Withdrawn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
- VSVAQRUUFVBBFS-UHFFFAOYSA-N difethialone Chemical compound OC=1SC2=CC=CC=C2C(=O)C=1C(C1=CC=CC=C1C1)CC1C(C=C1)=CC=C1C1=CC=C(Br)C=C1 VSVAQRUUFVBBFS-UHFFFAOYSA-N 0.000 title claims abstract description 327
- 239000003128 rodenticide Substances 0.000 title claims description 103
- 239000000203 mixture Substances 0.000 title claims description 85
- 241000283984 Rodentia Species 0.000 title claims description 69
- 238000000034 method Methods 0.000 title claims description 34
- 241000607479 Yersinia pestis Species 0.000 title description 2
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims abstract description 18
- NDCHCKSZQISZEJ-UHFFFAOYSA-N BrC1=CC=C(C=C1)C1=CC=C(C=C1)C1CC(C2=CC=CC=C2C1)C=1C(OC2=CC=CC=C2C=1O)=S Chemical compound BrC1=CC=C(C=C1)C1=CC=C(C=C1)C1CC(C2=CC=CC=C2C1)C=1C(OC2=CC=CC=C2C=1O)=S NDCHCKSZQISZEJ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 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 claims description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 235000013339 cereals Nutrition 0.000 claims description 20
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 19
- 230000014759 maintenance of location Effects 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 14
- 235000013305 food Nutrition 0.000 claims description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
- 238000004587 chromatography analysis Methods 0.000 claims description 10
- 239000002245 particle Substances 0.000 claims description 10
- 238000000926 separation method Methods 0.000 claims description 9
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 230000005526 G1 to G0 transition Effects 0.000 claims description 7
- 231100000518 lethal Toxicity 0.000 claims description 7
- 230000001665 lethal effect Effects 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 231100001160 nonlethal Toxicity 0.000 claims description 5
- 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 4
- 239000007983 Tris buffer Substances 0.000 claims description 4
- 239000001913 cellulose Substances 0.000 claims description 4
- 229920002678 cellulose Polymers 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- LPNBBFKOUUSUDB-UHFFFAOYSA-M p-toluate Chemical compound CC1=CC=C(C([O-])=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-M 0.000 claims description 4
- 235000012054 meals Nutrition 0.000 claims description 2
- 239000011148 porous material Substances 0.000 claims description 2
- 239000004464 cereal grain Substances 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 241000700159 Rattus Species 0.000 description 16
- 239000007787 solid Substances 0.000 description 12
- 239000000126 substance Substances 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 210000004185 liver Anatomy 0.000 description 8
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- -1 4'-bromo [1,1'-biphenyl] -4-yl Chemical group 0.000 description 6
- 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
- 230000010287 polarization Effects 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 238000001142 circular dichroism spectrum Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000003146 anticoagulant agent Substances 0.000 description 4
- 229940127219 anticoagulant drug Drugs 0.000 description 4
- 238000002983 circular dichroism Methods 0.000 description 4
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- 231100000566 intoxication Toxicity 0.000 description 4
- 230000035987 intoxication Effects 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
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- 238000002835 absorbance Methods 0.000 description 3
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- 238000000605 extraction Methods 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000007790 solid phase Substances 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
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- 235000013162 Cocos nucifera Nutrition 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- 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 2
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- 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
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- 238000005100 correlation spectroscopy Methods 0.000 description 2
- 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 2
- 235000005911 diet Nutrition 0.000 description 2
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- 235000013601 eggs Nutrition 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
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- 229940040511 liver extract Drugs 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- QCAWEPFNJXQPAN-UHFFFAOYSA-N methoxyfenozide Chemical compound COC1=CC=CC(C(=O)NN(C(=O)C=2C=C(C)C=C(C)C=2)C(C)(C)C)=C1C QCAWEPFNJXQPAN-UHFFFAOYSA-N 0.000 description 2
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- 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
- 239000010453 quartz Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
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- 235000019871 vegetable fat Nutrition 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 241000208140 Acer Species 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
- 235000016068 Berberis vulgaris Nutrition 0.000 description 1
- 241000335053 Beta vulgaris Species 0.000 description 1
- 241000723382 Corylus Species 0.000 description 1
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- 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
- 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
- 238000005481 NMR spectroscopy Methods 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
- 235000019484 Rapeseed oil Nutrition 0.000 description 1
- 240000000111 Saccharum officinarum Species 0.000 description 1
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- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 230000000895 acaricidal effect Effects 0.000 description 1
- 239000000642 acaricide Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
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- 239000003698 antivitamin K Substances 0.000 description 1
- 125000004429 atom Chemical group 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
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- 125000004243 coumarin-3-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C(=O)OC2=C1[H] 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
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- 244000062645 predators Species 0.000 description 1
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- 230000002335 preservative effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011002 quantification Methods 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
- 239000004627 regenerated cellulose Substances 0.000 description 1
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- 230000002000 scavenging effect Effects 0.000 description 1
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- 239000002689 soil Substances 0.000 description 1
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Classifications
-
- 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
- A01N43/18—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 sulfur as the ring hetero atom
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
-
- 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
- DIETHIALONE CONFIGURATION STEREO-ISOMER COMPOSITION AND RODONTICIDE BAIT COMPRISING THE SAME, AND METHOD OF CONTROLLING HARMFUL TARGET RODENTS
- the invention relates to a configuration stereoisomer of difethialone as an isolated compound, a composition and a rodenticide bait comprising such a configuration stereoisomer and a method for controlling deleterious target rodents.
- the invention thus relates to the technical field of the fight against target rodent pest populations.
- rodenticide baits As a poison for harmful target rodents. It is known from EP 2,090,164 that difethialone is a second-generation anticoagulant acting at a single dose. US 2005/181003 discloses a rodenticide bait in gel form comprising difethialone in a mass proportion of 25 ppm.
- 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.
- a fraction of the difethialone of these rodenticide baits may be ingested (secondary consumption) by animals - in particular by weaker rodent-killing predatory birds that have consumed such a rodenticide bait or by dead rodent-killing scavenging animals. have consumed such rodenticide bait.
- This secondary consumption is likely to eventually lead to the death of these predatory animals or scavengers that may be animals - especially birds - belonging to protected species.
- the invention therefore aims to overcome these disadvantages by proposing a configuration stereoisomer of difethialone, a composition comprising and a rodenticide bait comprising such a stereoisomer of and a method of controlling harmful rodent rodents that are effective in controlling target rodent populations.
- the invention also aims at providing a configuration stereoisomer of difethialone, a composition and a rodenticide bait comprising such a configuration stereoisomer 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, especially raptors.
- the invention also aims at providing a configuration stereoisomer of difethialone, a composition and a rodenticide bait comprising such a configurational stereoisomer and a method for controlling harmful target rodents that do not require, to control a population harmful rodent rodents, use massive doses of rodenticide agents and are environmentally friendly, human health and non-target animals.
- the object of the invention is therefore to propose a configuration stereoisomer of difethialone, a composition and a rodenticide bait comprising such a configuration stereoisomer and a method for controlling harmful target rodents that is effective at a reduced dose of agent. rodenticide.
- the invention also aims to propose a configuration stereoisomer of difethialone, 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 control against harmful target rodents resistant to known rodenticide baits.
- the invention therefore aims to propose an alternative to known rodenticide baits.
- the invention relates to a dextrorotatory enantiomer of a configuration stereoisomer of the hetero-stereoisomer difethialone of the formula 3- (4'-bromobiphenyl-4-yl) -1- (4- hydroxy thiocoumarin-3-yl) -1,2,3,4-tetrahydronaphthalene, in which the carbons 1 and 3 of the 1,2,3,4-tetrahydronaphthalene group are of absolute configurations distinct.
- diazolethialone refers to the compound 3- (4'-bromobiphenyl-4-yl) -1- (4-hydroxythiocoumarin-3-yl) -1,2,3,4-tetrahydronaphthalene or 3- [3- [4] - (4-bromophenyl) phenyl] -1-tetralinyl] -2-hydroxy-4-thiochromenone or 3- [3- (4'-bromo [1,1'-biphenyl] -4-yl) -1,2 3,4-tetrahydro-1-naphthalenyl] -4-hydroxy-2H-1-benzothiopyran-2-ene of formula (I) below:
- stereoisomers refers to isomers of the same semi-expanded 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 one to the other of the conformational isomers 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);
- hetero-stereoisomer of difethialone refers to the configuration stereoisomer of the difethialone of formula 3- (4'-bromobiphenyl-4-yl) -1- (4-hydroxythiocoumarin-3-yl) - 1, 2,3,4-tetrahydronaphthalene, wherein carbons 1 and 3 of the 1,2,3,4-tetrahydronaphthalene moiety of said hetero-stereoisomer are of distinct absolute configurations (1R, 3S and 1S, 3R), said absolute configurations being determined according to the sequential priority rules and the nomenclature of Cahn, Ingold and Prelog (CIP);
- homo-stereoisomer of difethialone refers to the configuration stereoisomer of the difethialone of formula 3- (4'-bromobiphenyl-4-yl) -1- (4-hydroxythiocoumarin-3-yl) - 1,2,3,4-tetrahydronaphthalene, wherein carbons 1 and 3 of the 1,2,3,4-tetrahydronaphthalene moiety of said homo-stereoisomer are of the same absolute configuration (1R, 3R and 1S, 3S);
- 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 performance liquid chromatography
- retention time designates the duration, measured at the peak of the chromatogram peak, during which a compound is retained on a chromatography column.
- the invention thus relates to the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone in the isolated state. It relates to this dextrorotatory enantiomer of said hetero-stereoisomer of difethialone separated from the laevorotatory enantiomer of said hetero-stereoisomer of difethialone and separated from the enantiomers of said homo-stereoisomer of difethialone.
- the inventors have succeeded in separating the levorotatory and dextrorotatory enantiomers of said hetero-stereoisomer from difethialone and the levorotatory and dextrorotatory enantiomers of said homo-isomer of difethialone by high-pressure liquid chromatography in isocratic mode and under specific conditions. using a chromatography column comprising a specific chiral stationary phase and isolating the dextrorotatory enantiomer of said hetero-stereoisomer of the difethialone.
- This separation is carried out using a LUX ® Cellulose-3 HPLC column (phenomenex, Le Pecq, France) of size 150 ⁇ 2 mm and comprising a chiral stationary phase consisting of porous particles of cellulose tris (4-methylbenzoate), a particle size of 3 ⁇ and a porosity of 1000 A.
- a chiral stationary phase consisting of porous particles of cellulose tris (4-methylbenzoate), a particle size of 3 ⁇ and a porosity of 1000 A.
- mobile phase an eluent obtained by mixing acetonitrile (A) and water comprising formic acid in a volume proportion of 0.1 is used.
- the flow rate of the mobile phase in the column is maintained at a value of 0.25 ml / min and the separation is carried out at a temperature of 23.2 ° C.
- the composition to be analyzed is at a concentration of 1 ⁇ g of difethialone per milliliter in acetonitrile and the volume of composition injected on the column is 1 ⁇ l ⁇ .
- the detection can be carried out by tandem mass spectrometry (MS / MS) at the outlet of the separating column. Detection and quantification can be performed photometrically or spectrophotometrically by adjusting the difethialone concentration and injection volume for optimal detection and by measuring the area under the peak of each stereoisomer configuration.
- the value of the retention time (t 3 ) of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone may vary according to the operating conditions - in particular according to the temperature conditions of the column - and be between 11.3 min and 11.8 min.
- the value of the retention time (t 2 ) of the laevorotatory enantiomer of said hetero-stereoisomer of difethialone may vary according to the operating conditions - in particular according to the temperature conditions of the column - and be between 9.0 min and 9.5 min, so that the dextrorotatory and laevorotatory enantiomers of said hetero-stereoisomer can be separated by high pressure liquid chromatography on a chiral column.
- the value of the retention time () of the laevorotatory enantiomer of said ho-stereo-isomer of difethialone can vary according to the operating conditions - in particular according to the temperature conditions of the column - and be between 7.8 min and 8 min. ,2 min.
- the value of the retention time (t 4 ) of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone may vary according to the operating conditions -particularly according to the temperature conditions of the column-and be between 14.0 min and 14.4 min. so that the dextrorotatory and laevorotatory enantiomers of said homo-stereoisomer of difethialone can be separated by high pressure liquid chromatography on a chiral column.
- the elution order of the configuration stereoisomers of the difethialone is such that ti ⁇ t 2 ⁇ t 3 ⁇ t 4 .
- the values of the retention times t 15 t 2 , t 3 and t are likely to vary, in particular with the temperature of the chromatography column.
- the order of elution of the configuration stereoisomers of the difethialone remains unchanged.
- the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone isolated in the pure state according to the invention, dissolved in chloroform (CHCt 3 ) has a specific rotatory power [a] C 589 nm measured at 25 ° C. and on the sodium D-line (589 nm) of an average value obtained over two series of ten measurements of + 9.1 °.
- the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone isolated in the pure state according to the invention has in magnetic resonance spectroscopy (1H-NMR) of the 500 MHz proton in CDCt 3 a multiplet exhibiting a chemical shift ( ⁇ ) of between 5.2 ppm and 5.4 ppm, in particular of the order of 5.3 ppm, corresponding to the proton carried by carbon 1 of the 1,2,3,4-tetrahydronaphthalene group of said hetero-stereoisomer of difethialone.
- hetero-stereoisomers are distinguished from difethialone and said homo-stereoisomer of difethialone by their proton NMR spectra.
- the chemical shift of the proton carried by carbon 1 of the 1,2,3,4-tetrahydronaphthalene group of said homo-stereoisomer of difethialone is between 4.9 ppm and 5 , 1 ppm.
- the invention also relates to a composition
- a composition comprising the dextrorotatory enantiomer of said hetero-stereoisomer of the difethialone according to the invention, excluding a racemic mixture of dextrorotatory and levorotatory enantiomers of said hetero-stereoisomer of difethialone.
- the invention therefore relates to a composition
- a composition comprising a dextrorotatory enantiomer of a configuration stereoisomer of the hetero-stereoisomer difethialone of formula 3- (4'-bromobiphenyl-4-yl) -1- (4- hydroxythiocoumarin-3-yl) -1,2,3,4-tetrahydronaphthalene, wherein carbons 1 and 3 of the 1,2,3,4-tetrahydronaphthalene group are of distinct absolute configurations, with the exception of a mixture in wherein the dextrorotatory enantiomer and the laevorotatory enantiomer of said hetero-stereoisomer of difethialone are in equal amounts.
- the dextrorotatory enantiomer of said hetero-stereoisomer and the laevorotatory enantiomer of said hetero-stereoisomer of difethialone are in unequal (distinct) amounts.
- said hetero-stereo- isomer is predominantly in the form of dextrorotatory enantiomer in the composition.
- a composition according to the invention comprises the stereoisomer of difethialone predominantly in the form of dextrorotatory enantiomer.
- the expression "said hetero-stereoisomer is predominantly in the form of dextrorotatory enantiomer” means that the quantity (mass, molar or volume) of dextrorotatory enantiomer of said hetero-stereoisomer of difethialone is predominant greater than 50% in the totality of said hetero-stereoisomer of the difethialone present in the composition (in all of its dextrorotatory and levorotatory enantiomeric forms), that is to say the amount (mass, molar or volumic)
- the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone is such that the ratio of this amount to the (total) amount of said hetero-stereoisomer is greater than 50%.
- the composition comprises an amount of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone such as the ratio of this amount to the (total) amount of said hetero-stereoisomer of difethialone 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%, even more preferably greater than 99% or of the order of 100%.
- the composition comprises an amount of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone such that the ratio of this amount to the amount of said hetero-stereoisomer of difethialone in the composition is greater than 75%, of preferably between 85% and 100%, more preferably between 90% and 98%.
- the composition comprises an amount of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone such that the ratio of this amount to the amount of said hetero-stereoisomer of difethialone in the composition is between 98% and 100%. %.
- the invention therefore relates to a composition wherein said hetero-stereoisomer of difethialone is predominantly in the form of a dextrorotatory enantiomer.
- composition according to the invention In a composition according to the invention:
- the ratio of the quantity of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone to the sum of the amounts of each of the enantiomers (levorotatory and dextrorotatory) of said hetero-stereoisomer of difethialone is greater than 0.5 ( greater than 50%);
- the ratio of the concentration of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone to the sum of the concentrations of each of the enantiomers (levorotatory and dextrorotatory) of said hetero-stereoisomer of difethialone is greater than 0.5 ( greater than 50), and;
- the proportion of dextrorotatory enantiomer of said hetero-stereoisomer of difethialone in the composition is greater than the proportion of the other enantiomer (levorotatory) of said hetero-stereoisomer of difethialone.
- the composition may also comprise an amount of the levorotatory enantiomer of said hetero-stereoisomer of difethialone such that the ratio of this amount to the amount of said hetero-stereoisomer of difethialone is less than 50, especially less than 25, preferably between 0% and 25, in particular less than 10%.
- the difethialone is mainly in the form of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone.
- the composition therefore comprises an amount of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone such that the ratio of this amount to the (total) amount of difethialone is greater than the ratios of the amount of each enantiomer of the difethialone distinct from the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone over the (total) amount of difethialone.
- the ratio of the amount of dextrorotatory enantiomer of said hetero-stereoisomer of difethialone to the sum of the amounts of each of the enantiomers of said hetero-stereoisomer of difethialone and of each of the enantiomers of said homo-stereo-isomer of difethialone is greater than 0.25 (greater than 25%);
- the ratio of the dextrorotatory enantiomer concentration of said hetero-stereoisomer of difethialone to the sum of the concentrations of each of the enantiomers of said hetero-stereoisomer of the difethialone and of each of the enantiomers of said homo-stereoisomer of the difethialone is greater than 0.25 (greater than 25%), and;
- the proportion of dextrorotatory enantiomer of said hetero-stereoisomer of the difethialone in the composition is greater than the proportion of each of the enantiomers of said homo-stereoisomer of the difethialone and of the other enantiomer (levorotatory) of said hetero-stereo; isomer of difethialone.
- the proportion of dextrorotatory enantiomer of said hetero-stereoisomer of difethialone in the composition is more than 25% relative to the total difethialone.
- the composition comprises an amount of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone such that the ratio of this amount to the amount of difethialone in the composition is greater than 25%, especially greater than 50%, in particular greater than 70%, more preferably 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 100%.
- the composition comprises an amount of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone such that the ratio of this amount to the amount of difethialone in the composition is greater than 70%, preferably between 80% and 100%. %, more preferably between 90% and 100%.
- the composition comprises an amount of the dextrorotatory enantiomer of said hetero stereoisomer of difethialone such that the ratio of this amount to the amount of difethialone in the composition is between 95% and 99%.
- the composition comprises an amount of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone such that the ratio of this amount to the amount of difethialone in the composition is between 98% and 100%.
- the composition comprises an amount of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone such that the ratio of this amount to the amount of difethialone in the composition is substantially of the order of 100%.
- the composition comprises an amount of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone such that the ratio of this amount to the amount of difethialone in the composition is greater than 95%.
- a composition according to the invention may be substantially free of the levorotatory enantiomer of said hetero-stereoisomer of difethialone, that is to say that the levorotatory enantiomer of said hetero-stereoisomer of difethialone may be present in the composition but only in the form of traces. It may also be substantially free of said homo-stereoisomer of difethialone, that is to say that said homo-stereoisomer of difethialone may be present in the composition but only in the form of traces.
- the composition is in the liquid state and comprises a liquid solvent of difethialone.
- a liquid solvent of difethialone may be a solution of difethialone in a solvent of difethialone, excluding a racemic mixture of said levogyre and dextrorotatory enantiomers of said hetero-stereoisomer of difethialone.
- It may also be a solution comprising difethialone in a solvent of difethialone and wherein said hetero-stereoisomer of difethialone is predominantly in the form of a dextrorotatory enantiomer.
- composition may also be a solution comprising difethialone in a solvent of difethialone and in which the difethialone is predominantly in the dextrorotatory enantiomer form of said hetero-stereoisomer of difethialone.
- the composition is in the solid state. It may also be a solid comprising difethialone, excluding a racemic mixture of dextrorotatory and levorotatory enantiomers of said hetero-stereoisomer of difethialone.
- It may also be a solid comprising difethialone and wherein said hetero-stereoisomer of difethialone is predominantly in the form of a dextrorotatory enantiomer. It may also be a solid comprising difethialone and in which the difethialone is predominantly in the dextrorotatory enantiomer form of said hetero-stereoisomer of difethialone.
- the invention therefore also relates to a composition
- a composition comprising the dextrorotatory enantiomer of said hetero-stereoisomer according to the invention, excluding a racemic mixture of the levorotatory and dextrorotatory enantiomers of said hetero-stereoisomer of difethialone, the difethialone of said composition being optically active and dextrorotatory.
- the difethialone of the composition according to the invention comprising the dextrorotatory enantiomer according to the invention, to the exclusion of a racemic mixture of the levorotatory and dextrorotatory enantiomers of said hetero-stereoisomer of the difethialone, itself optically active and levorotatory, or 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:
- hetero-stereoisomer of formula 3- (4'-bromobiphenyl-4-yl) -1- (4-hydroxythiocoumarin-3-yl) ) -l, 2,3,4-tetrahydronaphthalene, wherein carbons 1 and 3 of the 1,2,3,4-tetrahydronaphthalene group are of distinct absolute configurations, with the exception of a racemic mixture of dextrorotatory and laevorotatory enantiomers of said hetero-stereoisomer of difethialone.
- the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone and the laevorotatory enantiomer of said hetero-stereoisomer of difethialone are in unequal (distinct) amounts.
- a bait according to the invention comprises an edible excipient for harmful target rodents and said hetero-stereoisomer of difethialone mainly in the form of a dextrorotatory enantiomer of said hetero-stereoisomer of difethialone.
- a bait according to the invention comprises an edible excipient for harmful target rodents and difethialone mainly in the form of dextrorotatory enantiomer of said hetero-stereoisomer of difethialone.
- the rodenticide of the laevorotatory enantiomer of said hetero-stereoisomer of difethialone and also higher than the rodenticide remanences and efficiencies of the two levogyre and dextrorotatory enantiomers of said homo-stereoisomer of difethialone.
- the dextrorotatory enantiomer of said hetero-stereoisomer of the difethialone according to the invention makes it possible to produce rodenticide baits with a maintained efficacy compared with the baits of the state of the art but with a proportion of reduced rodenticidal active substance. .
- Such rodenticide baits are therefore less toxic to the environment.
- Such rodenticide baits can also be used to combat Target rodent populations that are resistant to known rodenticide treatments.
- the bait comprises a mass quantity of difethialone such that the ratio (mass proportion) of this mass quantity of difethialone to the mass quantity of rodenticide bait is less than 50 ppm-that is, say less than 50 mg of difethialone per kilogram of rodenticide bait.
- the mass proportion of the difethialone relative to the bait is greater than 1 ppm.
- the mass proportion of the difethialone relative to the amount of bait is between 1 ppm and 50 ppm (1 mg to 50 mg of difethialone per kilogram of bait), especially between 1 ppm and 40 ppm (1 mg 40 mg of difethialone per kilogram of bait), preferably between 1 ppm and 25 ppm (1 mg to 25 mg of difethialone per kilogram of bait), more preferably between 2 ppm and 15 ppm (2 mg to 15 ppm). mg of difethialone per kilogram of bait), more preferably between 5 ppm and 10 ppm (5 mg to 10 mg of difethialone per kilogram of bait).
- the bait comprises difethialone with a mass proportion of the order of 3 ppm.
- the rodenticide bait comprises an amount of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone such that the ratio of this amount to the amount of difethialone 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 difethialone in a mass proportion of less than 50%. ppm in relation to the bait.
- the bait comprises an amount of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone such that the ratio of this amount to the amount of difethialone is between 95% and 100% (limits included). ), and difethialone in a mass proportion of between 2 ppm and 10 ppm with respect to the bait.
- the edible excipient for harmful rodent targets is chosen to allow consumption of the 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 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 be foods comprising at least one 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 'a sugar syrup beet, 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 difethialone and a solid 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 in the form of a powder, in the form of a foam or in the form of a gel is adapted to be able to soil the fur of the target rodent (s) harmful (s) ) and to be ingested by him (them) during his (their) grooming.
- This may be a solid rodenticide bait containing difethialone, with the exception of a racemic mixture of dextrorotatory and levorotatory enantiomers of said hetero-stereoisomer of difethialone. It may also be a solid rodenticide bait comprising difethialone and wherein said hetero-stereoisomer of difethialone is predominantly in the form of a dextrorotatory enantiomer.
- It may also be a solid rodenticide bait comprising difethialone wherein the difethialone is predominantly in the dextrorotatory enantiomer form of said hetero-stereoisomer of difethialone.
- the rodenticide bait is chosen from the group consisting of liquid baits comprising difethialone and a liquid edible excipient.
- the rodenticide bait is then a drink for harmful target rodents. It may be a solution of difethialone in a solvent of difethialone, excluding a racemic mixture of dextrorotatory and levorotatory enantiomers of said hetero-stereoisomer of difethialone.
- the invention thus also relates to a rodenticide bait in which the difethialone is optically active.
- the difethialone of the rodenticide bait according to the invention is 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 comprises at least one bittering compound denatonium benzoate, also known as "Bitrex" to reduce the risk of accidental consumption by non-target organisms.
- the composition and the rodenticide bait according to the invention comprise exclusively difethialone-in which the hetero-stereoisomer is not a racemic mixture-as a rodenticide substance.
- the composition and the rodenticide bait according to the invention are free of any other anticoagulant substance for rodenticide use.
- the composition and rodenticide bait may include any harmful substance other than a rodenticide, such as an insecticide and / or acaricide.
- composition and the rodenticide bait according to the invention comprise difethialone, excluding a racemic mixture of levogyre and dextrorotatory enantiomers of said heterois stereoisomer and at least one other substance. distinct from difethialone as a rodenticide.
- This other rodenticide substance, distinct from difethialone may be another anticoagulant, particularly anti-vitamin K or non-anticonagulant, or another 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
- 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.
- a quantity of rodenticide bait is thus disseminated in which the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone and the laevorotatory enantiomer of said hetero-stereoisomer of difethialone are in unequal amounts.
- a quantity of rodenticidal bait comprising said hetero-stereoisomer of difethialone is disseminated, mainly in the form of a dextrorotatory enantiomer.
- an amount of rodenticide bait comprising difethialone is dispersed, mainly in the form of a dextrorotatory enantiomer, the amount of dextrorotatory enantiomer of said hetero-stereoisomer of the disseminated difethialone being reduced (bait slightly dosed to the substance of the rodenticide). bait, however, with sufficient rodenticidal efficacy.
- said hetero-stereoisomer of difethialone is predominantly in the form of a dextrorotatory enantiomer.
- the difethialone is predominantly in the form of dextrorotatory enantiomer of said hetero-stereoisomer of difethialone.
- a rodenticide bait according to this variant of the invention is a deadly bait in a single catch or "one-shot" in English.
- the mass proportion of difethialone in the rodenticide bait is less than 50 ppm, between 1 and 40 ppm, especially between 1 ppm and 25 ppm, preferably between 5 ppm and 25 ppm. ppm, more preferably between 10 ppm and 25 ppm.
- the mass proportion of difethialone in the rodenticide bait may be between 10 ppm and 15 ppm.
- non-lethal for harmful target rodents i.e., generally non-lethal to harmful target rodents, consuming said bait for a period of 24 consecutive hours, and; o sufficient to be lethal to harmful target rodents consuming said bait for several 24-hour periods.
- said periods are consecutive.
- 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 the rodent harmful rodent consuming this rodenticide and non-lethal rodent bait for rodents or non-rodent animals durably. 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 generally insufficient to cause the death of said rodent, while a repeated consumption of rodenticide bait for at least two consecutive days can lead to the death of the rodent harmful target.
- 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 amount of disseminated rodenticide bait, the mass proportion of difethialone relative to the rodenticide bait and the proportion of dextrorotatory enantiomer of said heterois stereoisomer are adjusted.
- difethialone compared to difethialone so that rodenticide bait consumption is lethal to target rodents that consume daily bait for at least 2 24-hour periods, including 3 to 7 periods; consecutive.
- the proportion of dextrorotatory enantiomer of said hetero-stereoisomer of difethialone being greater than 95% -particularly of the order of 100% - compared to the difethialone, the mass proportion of difethialone compared to the rodenticide bait is between 2 ppm and 15 ppm - in particular of the order of 10 ppm-.
- harmful target rodents are provided with a quantity of rodenticide bait sufficient to satisfy daily the appetite of the target harmful rodents, said rodenticide bait comprising a major proportion of dextrorotatory enantiomer of said hetero-steroid isomer of difethialone.
- the amount of disseminated rodenticide bait, the proportion of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone relative to difethialone and the mass proportion of difethialone relative to the rodenticide bait to allow rodenticide bait consumption for several days by harmful target rodents, while limiting:
- the amount of disseminated bait, the mass proportion of difethialone relative to the bait and the proportion of dextrorotatory enantiomer of said hetero-stereoisomer of difethialone are adjusted to limit the amount of hetero -stereoisomer of difethialone in the liver of rodents killed by consumption of said bait.
- the invention also relates to a chromatographic process for obtaining a dextrorotatory enantiomer of a configuration stereoisomer of the hetero-stereoisomer difethialone of formula 3- (4'-bromobiphenyl-4-yl) 1- (4-hydroxythio coumarin-3-yl) -1,2,3,4-tetrahydronaphthalene, wherein carbons 1 and 3 of the 1,2,3,4-tetrahydronaphthalene moiety of said hetero-stereoisomer are of distinct absolutes, a process in which: a column for high pressure liquid chromatography of dimensions 150 ⁇ 2 mm, and comprising a chiral stationary phase consisting of tris (4-methylbenzoate) cellulose particles, said particles having an average size of 3 ⁇ and presenting a average pore size of 1000 ⁇ ;
- a mixture of acetonitrile (A) and water comprising 0.1% by volume of formic acid (B) is chosen as liquid mobile phase, with an A / B volume ratio of 80/20; and with a flow rate of the liquid mobile phase in the chromatography column of 0.25 mL / min;
- a liquid composition comprising said dextrorotatory enantiomer of said hetero-stereoisomer of difethialone is introduced at the top of the chromatography column, and then;
- the liquid composition is entrained with the mobile phase in the column for chromatography under conditions suitable for separating the configuration stereoisomers from the difethialone, and;
- the invention also relates to said dextrorotatory enantiomer of said hetero-stereoisomer of difethialone obtained by a process according to the invention.
- the invention also relates to a configuration stereoisomer of difethialone, a process for obtaining such a configuration stereoisomer of difethialone, a composition and a rodenticide bait comprising such a configuration stereoisomer, and a method of controlling harmful target rodents characterized in combination by all or some of the characteristics mentioned above or hereafter.
- FIG. 1 is a chromatogram of separation and a chromatogram of analysis by high pressure liquid chromatography on a chiral column of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone;
- FIG. 2 is a 300 MHz proton NMR spectrum of said hetero-stereoisomer of difethialone
- FIG. 3 is a 300 MHz proton NMR spectrum of said homo-isomer of difethialone
- FIG. 4 is a 500 MHz proton NMR spectrum of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone;
- FIG. 5 is a 13 C-carbon NMR spectrum at 500 MHz of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone;
- FIG. 6 is a 500 MHz proton NMR correlation spectroscopy analysis (1H-NMR) of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone, and
- FIG. 7 is a circular dichroism spectrum of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone.
- the hetero-stereoisomer of difethialone is identified by proton magnetic resonance spectroscopy (1H NMR). Said hetero-stereoisomer of the difethialone in solution in CDCl 3 has a signal with a chemical shift ( ⁇ ) of between 5.2 ppm and 5.4 ppm (of the order of 5.3 ppm) and corresponding to the proton carried by carbon 1 of the 1,2,3,4-tetrahydronaphthalene group of difethialone as illustrated in FIG.
- Said hetero-stereoisomer is distinguished from said homo-isomer of the difethialone in solution in CDCt 3 which has (FIG. 3) a multiplet with a chemical shift ( ⁇ ) of between 4.9 ppm and 5.1 ppm and corresponding to the proton carried by carbon 1 of the 1,2,3,4-tetrahydronaphthalene group of difethialone.
- the inventors have solved the complex and unresolved problem to date of the separation of the configuration stereoisomers of the difethialone and in particular of the levorotatory and dextrorotatory enantiomers of said hetero-stereoisomer of the difethialone.
- an eluent consisting of a mixture of acetonitrile (A) and water comprising formic acid in a volume proportion of 0.1%. in water (B) with a volume ratio A / B of 80/20.
- the flow rate of the mobile phase in the column is 0.25 mL / min and the separation is carried out at a temperature of 23.2 ° C.
- the solution containing the sample to be analyzed is at a concentration of 1 ⁇ g of difethialone per milliliter in acetonitrile and is filtered on a regenerated cellulose membrane with a cut-off of 0.2 ⁇ .
- the volume of solution containing the sample to be analyzed injected on the column is 1 ⁇ L ⁇ .
- a process for separating the enantiomers of said hetero-stereoisomer from difethialone it is possible to detect said enantiomers at the outlet of the high-pressure liquid chromatography column by tandem mass spectrometry (MS / MS) in negative ionization mode. by electrospray (ESI, "ElectroSpray Ionization”).
- MS / MS tandem mass spectrometry
- ESI electrospray
- the nebulizer gas temperature is 350 ° C and its flow rate is 8 L / min.
- the nebulizer gas pressure is raised to 2700 hPa.
- FIG. 1 shows the chromatograms of the difethialone (top) and the dextrorotatory enantiomer of the hetero-stereoisomer of the isolated (bottom) difethialone.
- the value of the retention time (t 3 ) of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone is of the order of 11.7 min as described in FIG. 1 and the value of the retention time (t 2 ) of the laevorotatory enantiomer of said hetero-stereoisomer of difethialone is of the order of 9.4 min, so that the dextrorotatory and laevorotatory enantiomers of said heterois stereoisomer can be separated by liquid chromatography. high pressure on a chiral column.
- the value of the retention time (t 4 ) of said dextrorotatory enantiomer of said ho-stereo-isomer according to the invention is of the order of 14.4 min and the value of the retention time (ti) the laevorotatory enantiomer of said ho-stereo-isomer is of the order of 8.1 min so that the dextrorotatory and laevorotatory enantiomers of said homo-isomer can also be separated by high pressure liquid chromatography on a chiral column. and separated from the dextrorotatory and laevorotatory enantiomers of said hetero-stereoisomer of difethialone.
- the UV spectrum of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone in solution in chloroform (CHCt 3 ) has two absorbance peaks centered at 238.2 nm and 259.5 nm.
- the inventors have characterized the dextrorotatory enantiomer of said hetero-stereoisomer of the difethialone in the isolated state by its rotatory power (also called optical activity or circular birefringence), that is to say by its property to deflect the plane.
- rotatory power also called optical activity or circular birefringence
- polarization of a polarized light A deflection of the plane of polarization of the polarized light in the clockwise direction of rotation by facing the polarized light beam characterizes a dextrorotatory solution, and a deflection of the plane of polarization of the polarized light in the anticlockwise direction of rotation facing the Polarized light beam characterizes a solution and a levorotatory compound.
- the rotatory power of a dextrorotatory enantiomer solution of said hetero-stereoisomer of difethialone in chloroform (CHCl 3 ) is measured at a concentration of 6.3 g / L.
- the rotary power of this solution is measured by means of a P 2000 digital polarimeter (JASCO, Bouguenais, France) operating with excitation light with a wavelength of 589 nm.
- the mean rotary power obtained over two series of ten measurements is + 0.573 °.
- FIG. 4 is a 500 MHz proton NMR spectrum of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone in solution at a concentration of 40 mg / ml in CDCt 3 exhibiting a chemical shift signal ( ⁇ ) of in the order of 5.3 ppm and corresponding to the proton carried by carbon 1 of the 1,2,3,4-tetrahydronaphthalene group of difethialone.
- FIG. 5 is a 13 C NMR spectrum of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone in solution at a concentration of 40 mg / ml in CDCt 3 produced on a Bruker AVANCE III HD (500 MHz) spectrometer equipped of a PRODIGY motorized multi-core direct cryoprobe. It allows an identification of the 31 carbon atoms of the difethialone.
- the 13 C-NMR spectrum of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone is not distinguishable from the 13 C-NMR spectrum of the laevorotatory enantiomer of said hetero-stereoisomer of difethialone.
- said hetero-stereoisomer of difethialone has signals of between 40 ppm and 40.5 ppm and between 38.0 ppm and 38.5 ppm characteristic of said hetero-stereoisomer of difethialone and distinctive of said homo-stereo. isomer of difethialone.
- FIG. 6 is a 2D (1H-NMR) two-dimensional proton NMR spectrum obtained by correlation spectroscopy of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone in solution in CDCt 3 at a concentration of 40 mg / mL performed on a Bruker AVANCE III HD (500 MHz) spectrometer equipped with a PRODIGY motorized multi-core direct cryoprobe.
- 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
- the cartridge is dried by vacuum suction connected at the bottom of the cartridge.
- 1 mL of elution solution consisting of dichloromethane (CH 2 Cl 2 ) and of methanol (CH 3 OH) in a volume proportion of 90/10 is then deposited at the top of the cartridge and an eluate comprising difethialone is collected at the bottom of the cartridge.
- the solvent of the eluate is evaporated under a stream of nitrogen (N 2 ) at a temperature of 40 ° C.
- the solution containing difethialone is analyzed by high pressure liquid chromatography on a chiral column (150 ⁇ 2 mm, 3 ⁇ particle size) LUX® Cellulose-3 (phenomenex, Le Pecq, France) as described in point A2) above. .
- a pasty rodenticide bait according to the invention is produced by dispersing a quantity of dextrorotatory enantiomer of said hetero-stereoisomer of difethialone in an edible excipent comprising vegetable fat and cereal flour.
- the measured proportion of difethialone relative to the rodenticide bait is 3.7 ppm (3.57 mg of dextrorotatory enantiomer of said hetero-stereoisomer per kilogram of bait), and the proportion of dextrorotatory enantiomer of said hetero-stereoisomer is 96.5% relative to the difethialone.
- the hepatic content of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone is measured in each of the rats that died between D9 and D13 by high pressure liquid chromatography on a chiral column.
- the measured values, expressed in microgram of dextrorotatory enantiomer of said hetero-stereoisomer ("DFN-hetero-dextro") per gram of liver are given in Table 2 below.
- Bait assayed at 3.7 ppm dextrorotatory enantiomer of said hetero-stereoisomer difethialone provides a 100% mortality rate by minimizing the risk of primary and secondary intoxication.
- a pasty rodenticide bait according to the invention is made as described for the bait at 3.7 ppm above.
- the measured proportion of difethialone in the bait is 10.6 ppm (10.2 mg of dextrorotatory enantiomer of said heterois stereoisomer per kilogram of bait), and the proportion of dextrorotatory enantiomer of said heterois stereoisomer compared to difethialone difethialone is 96.5%.
- a bait distribution as described above with the 3.7 ppm bait is carried out.
- the liver content of the dextrorotatory enantiomer of said hetero-stereoisomer of difethialone is measured in each of the rats killed between D5 and J8 by analysis in high pressure liquid chromatography on a chiral column.
- the values, expressed in micrograms of dextrorotatory enantiomer of said hetero-stereoisomer ("DFN-hetero-dextro") per gram of liver are given in Table 4 below.
- the bait dosed at 10.6 ppm difethialone allows to obtain a 100% mortality rate by minimizing the risk of primary and secondary intoxication.
- a composition, a rodenticide bait and a method for controlling harmful target rodents are subject to infinity of variants both in the formulation of the bait and in the methods of implementation of the method.
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Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR1562226A FR3045050B1 (en) | 2015-12-11 | 2015-12-11 | DIFETHIALONE CONFIGURATION STEREO-ISOMER, COMPOSITION AND RODONTICIDE APPAT COMPRISING THE SAME AND METHOD OF CONTROLLING HARMFUL TARGET RODENTS |
PCT/EP2016/079857 WO2017097746A1 (en) | 2015-12-11 | 2016-12-06 | Configurational stereoisomer of difethialone, composition and rodenticide bait comprising same, and method for controlling target rodent pests |
Publications (1)
Publication Number | Publication Date |
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EP3386971A1 true EP3386971A1 (en) | 2018-10-17 |
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ID=55236761
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Application Number | Title | Priority Date | Filing Date |
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EP16809709.5A Withdrawn EP3386971A1 (en) | 2015-12-11 | 2016-12-06 | Configurational stereoisomer of difethialone, composition and rodenticide bait comprising same, and method for controlling target rodent pests |
Country Status (5)
Country | Link |
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US (1) | US20190150438A1 (en) |
EP (1) | EP3386971A1 (en) |
BR (1) | BR112018011655A2 (en) |
FR (1) | FR3045050B1 (en) |
WO (1) | WO2017097746A1 (en) |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8333334D0 (en) * | 1983-12-14 | 1984-01-18 | Ici Plc | Rodenticides |
FR2562893B1 (en) * | 1984-04-12 | 1986-06-27 | Lipha | DERIVATIVES OF HYDROXY-4-2H-1-BENZOTHIOPYRAN-2-ONE, THEIR PREPARATIONS AND APPLICATIONS IN THE RODENTICIDE FIELD |
FR3022113B1 (en) * | 2014-06-13 | 2016-07-01 | Liphatech Inc | COMPOSITION COMPRISING DIFETHIALONE, RODONTICIDE APPAT AND METHOD OF CONTROLLING HARMFUL TARGET RODENTS |
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 FR1562226A patent/FR3045050B1/en active Active
-
2016
- 2016-12-06 BR BR112018011655-6A patent/BR112018011655A2/en not_active Application Discontinuation
- 2016-12-06 US US16/061,062 patent/US20190150438A1/en not_active Abandoned
- 2016-12-06 WO PCT/EP2016/079857 patent/WO2017097746A1/en active Application Filing
- 2016-12-06 EP EP16809709.5A patent/EP3386971A1/en not_active Withdrawn
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US20190150438A1 (en) | 2019-05-23 |
FR3045050A1 (en) | 2017-06-16 |
BR112018011655A2 (en) | 2018-12-04 |
WO2017097746A1 (en) | 2017-06-15 |
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