EP3386969A1 - 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
- EP3386969A1 EP3386969A1 EP16809707.9A EP16809707A EP3386969A1 EP 3386969 A1 EP3386969 A1 EP 3386969A1 EP 16809707 A EP16809707 A EP 16809707A EP 3386969 A1 EP3386969 A1 EP 3386969A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- difethialone
- stereoisomer
- homo
- dextrorotatory enantiomer
- bait
- 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- Withdrawn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 371
- 239000003128 rodenticide Substances 0.000 title claims description 100
- 239000000203 mixture Substances 0.000 title claims description 93
- 241000283984 Rodentia Species 0.000 title claims description 90
- 238000000034 method Methods 0.000 title claims description 33
- 241000607479 Yersinia pestis Species 0.000 title description 4
- 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 7
- 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 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- 235000013339 cereals Nutrition 0.000 claims description 20
- 230000014759 maintenance of location Effects 0.000 claims description 18
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 17
- 239000007788 liquid Substances 0.000 claims description 17
- 238000004587 chromatography analysis Methods 0.000 claims description 13
- 235000013305 food Nutrition 0.000 claims description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 12
- 239000002245 particle Substances 0.000 claims description 10
- -1 4'-bromobiphenyl-4-yl Chemical group 0.000 claims description 9
- 238000000926 separation method Methods 0.000 claims description 9
- 231100000518 lethal Toxicity 0.000 claims description 8
- 230000001665 lethal effect Effects 0.000 claims description 8
- 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
- 230000008569 process Effects 0.000 claims description 7
- 231100001160 nonlethal Toxicity 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 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
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- 235000019253 formic acid Nutrition 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
- 125000004243 coumarin-3-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C(=O)OC2=C1[H] 0.000 claims description 2
- 235000012054 meals Nutrition 0.000 claims description 2
- 239000011148 porous material Substances 0.000 claims description 2
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- 125000004432 carbon atom Chemical group C* 0.000 abstract description 2
- 241000700159 Rattus Species 0.000 description 41
- 239000000243 solution Substances 0.000 description 27
- 210000004185 liver Anatomy 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 230000002440 hepatic effect Effects 0.000 description 19
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 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
- 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
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- 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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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
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- 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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- 238000006243 chemical reaction Methods 0.000 description 2
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- 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
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- 238000003304 gavage Methods 0.000 description 2
- 238000000265 homogenisation Methods 0.000 description 2
- 150000002419 homosteroids Chemical class 0.000 description 2
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- 150000002632 lipids Chemical class 0.000 description 2
- 229940040511 liver extract Drugs 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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- 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
- 230000001119 rodenticidal effect Effects 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
- 238000004885 tandem mass spectrometry Methods 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 235000019871 vegetable fat Nutrition 0.000 description 2
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ADOREHXDLCEYIE-UHFFFAOYSA-N 2-sulfanylchromen-4-one Chemical compound C1=CC=C2OC(S)=CC(=O)C2=C1 ADOREHXDLCEYIE-UHFFFAOYSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
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- 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
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000007319 Avena orientalis Nutrition 0.000 description 1
- 244000075850 Avena orientalis Species 0.000 description 1
- 241000282421 Canidae Species 0.000 description 1
- 241000723382 Corylus Species 0.000 description 1
- 235000007466 Corylus avellana Nutrition 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 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
- ABSPRNADVQNDOU-UHFFFAOYSA-N Menaquinone 1 Natural products C1=CC=C2C(=O)C(CC=C(C)C)=C(C)C(=O)C2=C1 ABSPRNADVQNDOU-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
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- 235000019482 Palm oil Nutrition 0.000 description 1
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- 235000019484 Rapeseed oil Nutrition 0.000 description 1
- 241000700157 Rattus norvegicus Species 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
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- MBWXNTAXLNYFJB-NKFFZRIASA-N phylloquinone Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CCC[C@H](C)CCC[C@H](C)CCCC(C)C)=C(C)C(=O)C2=C1 MBWXNTAXLNYFJB-NKFFZRIASA-N 0.000 description 1
- 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 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
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.
- 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 and a rodenticide bait comprising such a configuration stereo-isomer and a a method of controlling harmful rodent rodents which are at the same time effective in controlling target rodent pest populations and which also limit the risk of poisoning non-target animals - particularly domestic or farmed animals; pets or humans - accidentally consuming such rodenticide bait.
- the invention therefore aims to overcome these drawbacks by proposing a configuration stereoisomer of difethialone, a composition and a rodenticide bait comprising such a configuration stereo-isomer and a method of combating harmful target rodents which are at the same time effective control of target rodent pest populations and also to minimize the risk of secondary poisoning by animals - for example, foxes or wild birds that are predators of weakened target rodents that have consumed rodenticide bait or 'wild animal rodent scavengers target harmful poisoned dead.
- 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 rodenticide, use a high-dose rodenticide and are environmentally friendly, human health and non-target animals - especially birds-.
- 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 target rodents that are 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 dextrorotatory enantiomer of a difethialone configuration stereoisomer, said homo-isomer, of formula 3- (4'-bromobiphenyl-4-yl) -1- (4- hydroxythio coumarin-3-yl) -1,2,3,4-tetrahydronaphthalene, wherein the carbons 1 and 3 of the 1,2,3,4-tetrahydronaphthalene group of said homo-stereoisomer are of the same absolute configuration.
- diazolethialone designates 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-one, Formula (I) below:
- 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 designates stereoisomers that are not conformational isomers (or “rotamers”, whose conversion from 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 (i.e., 1S-3R and 1R-3S), the absolute configurations being determined according to the sequential priority rules and the nomenclature of Cahn, Ingold and Prelog (CIP);
- homo-stereo-isomer 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 (i.e., 1S-3S and 1R-3R);
- 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;
- high pressure liquid chromatography or “high performance liquid chromatography”("HPLC) refer to “HPLC” or “High Performance Liquid Chromatography” chromatography, and; the expression “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 relates to the dextrorotatory enantiomer of said ho mo-stereoisomer of difethialone. It relates to the dextrorotatory enantiomer of said ho mo-stereoisomer of difethialone in the isolated state and in particular separated from the levorotatory enantiomer of said homo-isomer of difethialone and of the levorotatory and dextrorotatory enantiomers of a stereo- isomer of configuration of the difethialone, said hetero-stereoisomer, in which the carbons 1 and 3 of the 1,2,3,4-tetrahydronaphthalene group are of distinct absolute configurations.
- the inventors have discovered that it is possible to separate the levorotatory and dextrorotatory enantiomers of said homo-isomer of difethialone and the levogyre and dextrorotatory enantiomers of said hetero-stereoisomer of difethialone by high pressure liquid chromatography in isocratic and under particular conditions using a chromatography column comprising a chiral stationary phase. It was in fact not known at the time of the invention to be able to separate the configuration stereoisomers of the difethialone and especially the laevorotatory enantiomer and the dextrorotatory enantiomer of said homo-isomer of the difethialone.
- the inventors have succeeded in achieving this separation by selecting a column LUX ® HPLC particular chromatography Cellulose-3 (Phenomenex, Le Pecq, France) of dimension 150 x 2 mm and comprising a chiral stationary phase consisting of cellulose porous particles tris (4 -methylbenzoate), of a particle size of 3 ⁇ and a porosity of 1000 A. They used, as mobile phase, an eluent formed of a mixture of acetonitrile (A) and water comprising formic acid in a volume proportion of 0.1% in water (B) with an A / B volume ratio of 80/20.
- 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 injected on the column is 1 ⁇ L ⁇ .
- Detection can be performed by tandem mass spectrometry (MS / MS). Detection can also be performed photometrically or spectrophotometrically by adjusting the difethialone concentration and injection volume to obtain optimal detection and by measuring the area under the peak of each configuration stereoisomer .
- the value of the retention time (t 4 ) of the dextrorotatory enantiomer of said homo-stereoisomer according to the invention may vary according to the operating conditions - in particular according to the temperature conditions of the column - and be understood between 14.0 min and 14.4 min.
- the value of the retention time (ti) of the laevorotatory enantiomer of said homo-stereoisomer may vary according to the operating conditions - in particular according to the temperature conditions of the column - and be between 7.8 min and 8.2 min. , so that the dextrorotatory and laevorotatory enantiomers of said homo-stereoisomer can be separated by high pressure liquid chromatography on a chiral column.
- 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 understood 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 -particularly according to the temperature conditions of the column-and be between 9.0 min and 9.5 min.
- the order of elution of the configuration stereoisomers of the difethialone is such that t ⁇ t 2 ⁇ t 3 ⁇ t.
- 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.
- the order of elution of the configuration stereoisomers of the difethialone remains unchanged.
- the invention therefore relates to the dextrorotatory enantiomer of said homo-isomer of difethialone in the isolated state and having the property of being elutable, under the chromatography conditions described above, the last of the four stereoisomers. configuration of difethialone.
- the dextrorotatory enantiomer of said homo-stereoisomer of difethialone isolated in the pure state according to the invention, in solution in chloroform (CHCt 3 ) has a specific rotational power [a] C 589 nm measured at 25 ° C. and on the sodium D line (589 nm) with a value of + 19.9 °.
- the dextrorotatory enantiomer of said homo-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 ( ⁇ ) between 4.9 ppm and 5.1 ppm corresponding to the proton carried by carbon 1 of the 1,2,3,4-tetrahydronaphthalene group of said homo-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 hetero-stereoisomer of difethialone is of the order of 5.3 ppm.
- the invention also relates to a composition
- a composition comprising the dextrorotatory enantiomer of said homo-stereoisomer of the difethialone according to the invention, excluding a racemic mixture of dextrorotatory and levorotatory enantiomers of said homo-stereo-isomer of difethialone, that is to say an optically inactive mixture of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone and of the laevorotatory enantiomer of said homo-stereo-isomer of the difethialone.
- the invention therefore also relates to a composition
- a composition comprising a dextrorotatory enantiomer of the difethialone configuration stereoisomer, said homo-stereoisomer, 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, excluding a mixture in which the dextrorotatory enantiomer and the laevorotatory enantiomer of said homo-stereoisomer of difethialone are in the same amount.
- said homo-stereoisomer is predominantly in the form of a dextrorotatory enantiomer.
- homo-stereoisomer is predominantly in the form of a dextrorotatory enantiomer
- quantity (mass, molar or volume) of dextrorotatory enantiomer of said homo-stereoisomer of difethialone is predominant.
- the dextrorotatory enantiomer of said homo-stereoisomer of the difethialone in the composition is such that the ratio of this amount to the (total) amount of said homo-isomer in the composition is greater than 50%.
- composition according to the invention in particular, in a composition according to the invention:
- the ratio of the amount of dextrorotatory enantiomer of said homo-stereoisomer of difethialone to the sum of the amounts of each of the enantiomers (dextrorotatory and levorotatory) of said homo-stereoisomer of difethialone is greater than 0.5 (greater than at 50%);
- the ratio of the dextrorotatory enantiomer concentration of said homo-stereoisomer of difethialone to the sum of the concentrations of each of the enantiomers (dextrorotatory and levorotatory) of said homo-stereoisomer of difethialone is greater than 0.5 (greater than at 50%), and; the proportion of dextrorotatory enantiomer of said ho-stereo-isomer of difethialone in the composition is greater than the proportion of the levorotatory enantiomer of said homo-isomer of difethialone.
- the composition comprises an amount of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone in the composition such as the ratio of this amount to the total amount of said homo-stereoisomer of difethialone in the composition is greater than 50%, in particular 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%; more preferably greater than 99% or of the order of 100%.
- it comprises an amount of the dextrorotatory enantiomer of said homo-stereoisomer of the difethialone in the composition such that the ratio of this amount to the total amount of said homo-stereoisomer of the difethialone in the composition is between 85.degree. % and 100%, more preferably between 90% and 98%.
- it comprises an amount of the dextrorotatory enantiomer of said homo-stereoisomer of the difethialone in the composition such that the ratio of this amount to the total amount of said homo-stereoisomer of the difethialone in the composition is between 98. % and 100%.
- the composition may also comprise the levorotatory enantiomer of said homo-stereoisomer of difethialone, but with a proportion in the composition which is less than 50%, especially less than 25%, preferably between 0% and 25%. , in particular less than 10% - with respect to the homo-stereoisomer of difethialone.
- the difethialone is predominantly in the form of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone.
- the composition comprises an amount of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone in the composition such as the ratio of that amount to the amount of each of the enantiomers (said hetero-isomer and said homo-stereoisomer ) of the difethialone is greater than 25%.
- the ratio of the amount of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone to the sum of the amounts of each of the enantiomers of said homo-stereoisomer of difethialone and of each of the enantiomers of said hetero-stereoisomer of difethialone is greater than 0.25 (greater than 25%);
- the ratio of the concentration of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone relative to the sum of the concentrations of each of the enantiomers of said homo-stereoisomer of difethialone and of each of the enantiomers of said heterois stereoisomer difethialone is greater than 0.25 (greater than 25%), and;
- the proportion of dextrorotatory enantiomer of said homo-stereoisomer of difethialone in the composition is greater than the proportion of each of the enantiomers of said homo-stereoisomer of difethialone and of said hetero-stereoisomer of difethialone.
- the proportion of dextrorotatory enantiomer of said homo-stereoisomer of difethialone is more than 25% relative to difethialone (total).
- the composition comprises an amount of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone in the composition such that the ratio of this amount to the amount of total difethialone in the composition is greater than 25. % -particularly 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 in the order of 100% -.
- a composition according to the invention therefore comprises difethialone predominantly in the form of a dextrorotatory enantiomer of said homo-stereoisomer of difethialone.
- the composition comprises an amount of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone such as that the ratio of this amount to the amount of the total difethialone 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 homo-stereoisomer of difethialone such that the ratio of this amount to the amount of total difethialone is between 95% and 99%.
- the composition comprises an amount of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone such that the ratio of this amount to the amount of total difethialone is between 98% and 100%.
- the composition comprises an amount of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone such that the ratio of this amount to the amount of the total difethialone is substantially of the order of 100%.
- the composition comprises an amount of the dextrorotatory enantiomer of said homo-isomer of difethialone in the composition such that the ratio of this amount to the amount of total difethialone in the composition is greater than 97. %.
- a composition according to the invention may be substantially free of the levorotatory enantiomer of said homo-stereoisomer of difethialone, that is to say that the levorotatory enantiomer of said homo-stereoisomer of difethialone may be present in the composition but only in the form of traces. It may also be substantially free of said hetero-stereoisomer of difethialone, that is to say that said hetero-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 homo-stereoisomer of difethialone.
- It may also be a solution comprising difethialone in a solvent of difethialone and wherein said homo-stereoisomer of difethialone is predominantly in the form of of dextrorotatory enantiomer.
- 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 ho-stereoisomer of difethialone. It may also be a solid comprising difethialone and wherein said ho-stereo-isomer of difethialone is predominantly in the form of dextrorotatory enantiomer. It may also be a solid comprising difethialone and in which the difethialone is predominantly in the dextrorotatory enantiomer form of said homo-stereoisomer of difethialone.
- the invention therefore also relates to a composition
- a composition comprising the dextrorotatory enantiomer according to the invention, with the exclusion of a racemic mixture of the levorotatory and dextrorotatory enantiomers of said homo-isomer of difethialone, the difethialone of the composition being optically active and dextrorotary.
- composition according to the invention comprising dextrorotatory enantiomer according to the invention, to the exclusion of a racemic mixture of the levorotatory and dextrorotatory enantiomers of said homo-stereoisomer of difethialone, is 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:
- the dextrorotatory enantiomer of said homo-stereoisomer of difethialone and the laevorotatory enantiomer of said homo-isomer of difethialone are in distinct amounts.
- a bait according to the invention comprises an edible excipient for harmful target rodents and said homo-stereoisomer of difethialone mainly in the form of a dextrorotatory enantiomer.
- the dextrorotatory enantiomer of said homo-stereoisomer of the residual difethialone in the body of a poisoned rodent disappears more rapidly than the other enantiomer (laevorotatory) of said homo-stereoisomer of the difethialone.
- the harmful or dead target rodent having ingested the dextrorotatory enantiomer of said homo-stereoisomer of difethialone is therefore of low toxicity to non-rodent mammals and to birds consuming the harmful target rodent - dead or alive. and in particular vis-à-vis predators (including non-rodent mammals and birds) who preferentially consume the viscera of their prey and in particular their liver.
- the inventors have also observed that the dextrorotatory enantiomer of said homo-stereoisomer of difethialone, although having low hepatic persistence in harmful target rodents, makes it possible, and in a completely surprising manner to date, to effectively fight against harmful target rodents.
- the rodenticide 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 200 ppm-that is less than 200 mg of difethialone per kilogram of bait.
- the mass proportion of the difethialone in the rodenticide bait is between 1 ppm and 100 ppm (1 mg to 100 mg of difethialone per kilogram of rodenticide bait), in particular between 5 ppm and 100 ppm (5 mg to 100 ppm).
- mg of difethialone per kilogram of rodenticide bait preferably of between 5 ppm and 50 ppm (5 mg to 50 mg of difethialone per kilogram of rodenticide bait), more preferably between 10 ppm and 50 ppm (10 mg to 50 ppm).
- mg of difethialone per kilogram of rodenticide bait more preferably between 15 ppm and 50 ppm (15 mg to 50 mg of difethialone per kilogram of rodenticide bait), for example of the order of 15 ppm (15 mg of difethialone per kilogram of bait).
- 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, for Alfalfa seeds - in particular in shell form, in the form of flour, in the form of flour, in the form of flakes or bran.
- 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 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 chosen from the group consisting of vegetable fats, vegetable oils (for example rapeseed oil, soy fat, sunflower oil, cocoa butter, peanut oil, butter peanuts, 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, butter peanuts, 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 edible carrier for harmful target rodents is selected to allow bait consumption by harmful target rodents.
- each edible excipient is non-lethal for harmful target rodents.
- the edible carrier is not a rodenticide in itself.
- 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.
- 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.
- 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 enantiomers and levorotatory of said homo-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 includes at least one compound bittering agent denatonium benzoate type, also known under the name of "Bitrex ®" for 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 homo-stereoisomer is not a racemic mixture-as 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 rodenticidal bait according to the invention comprise difethialone excluding a racemic mixture of levogyre and dextrorotatory enantiomers of said homo-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 comprising said homo-isomer of difethialone predominantly in the form of a dextrorotatory enantiomer, having decreased hepatic persistence in the target rodent and, surprisingly, at least one rodenticide efficacy.
- the method according to the invention therefore makes it possible to limit the secondary poisoning of non-rodent mammals and of birds capable of feeding with poisoned rodents, dead or alive, but comprising a reduced amount, and especially a non-lethal amount, of difethialone.
- the method according to the invention also makes it possible to limit such secondary poisoning of non-rodent mammals and birds likely to preferentially consume the viscera, in particular the liver, of said dead or alive poisoned rodents.
- said homo-stereoisomer of difethialone is predominantly in the form of a dextrorotatory enantiomer.
- the difethialone is predominantly in the form of dextrorotatory enantiomer of said homo-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 between 2 ppm and 200 ppm, in particular between 5 ppm and 100 ppm, preferably between 10 ppm and 50 ppm, more preferably between 15 ppm and 50 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;
- the 24-hour 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 rodents consuming this rodenticide and non-lethal rodent bait for a long time. or non-target animals 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 days will result in the death of the target rodent.
- the invention therefore relates to a method for controlling a target rodent nuisance population in which rodenticide rodent bait capable of being ingested by the target harmful rodent is made available to harmful target rodents, said quantity of rodenticide bait being sufficient to kill harmful target rodents consuming the rodenticide bait for several days.
- a quantity of rodenticide bait is dispersed so that harmful target rodents consume a quantity of difethialone sufficient to be lethal to said harmful target rodents consuming said bait for several periods of 24 hours. said periods being consecutive.
- the mass proportion of difethialone is between 5 ppm and 50 ppm, in particular between 5 ppm and 30 ppm - in particular of the order of 15 ppm - relative to the rodenticide bait.
- the quantity of disseminated rodenticide bait, the mass proportion of difethialone relative to the rodenticide bait and the proportion of dextrorotatory enantiomer of said homo-stereoisomer of difethialone relative to the difethialone are adapted so that the consumption of the rodenticide bait is lethal to harmful target rodents consuming bait daily for at least 2 24-hour periods, especially 3 to 7 periods, at least two-especially every period-being consecutive.
- the proportion of dextrorotatory enantiomer of said homo-stereoisomer of difethialone being greater than 95%, in particular of the order of 100%, relative to the difethialone , the mass proportion of difethialone relative to the rodenticide bait is between 5 ppm and 50 ppm -in particular of the order of 15 ppm-.
- harmful target rodents are provided with a quantity of rodenticide bait sufficient to satisfy daily the appetite of harmful target rodents, said rodenticidal bait comprising a major proportion of dextrorotatory enantiomer of said homo-steroid. isomer of difethialone.
- the amount of disseminated rodenticide bait, the proportion of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone relative to the 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 homo-stereoisomer of difethialone are adapted to limit the amount of difethialone ( total) 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 homo-stereo-isomer 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 homo-stereoisomer are of the same absolute configuration, wherein
- 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 homo-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 homo-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 stereo-isomer, a composition comprising such a configuration stereo-isomer, a rodenticide bait 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 analysis by high pressure liquid chromatography on a chiral column of difethialone (top) and of the dextrorotatory enantiomer of said homo-stereoisomer of purified difethialone (bottom);
- FIG. 2 is a 300 MHz proton NMR spectrum of said homo-stereoisomer of difethialone
- FIG. 3 is a 300 MHz proton NMR spectrum of said hetero-stereoisomer of difethialone
- FIG. 4 is a 500 MHz proton NMR spectrum of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone according to the invention.
- FIG. 5 is a 13 C-carbon NMR spectrum at 500 MHz of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone;
- FIG. 6 is a 500 MHz proton NMR correlation spectroscopy analysis (1H-NMR) of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone
- FIG. 7 is a circular dichroism spectrum of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone
- FIG. 8 is a graphical representation of the temporal evolution of the hepatic concentration in rats (males and females) of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone ( ⁇ ) and of the levorotatory enantiomer of said homo-stereoisomer of -steroisomer of difethialone (O);
- FIG. 9 is a graphical representation of the temporal evolution of the hepatic concentration in rats (males and females) of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone ( ⁇ ), said homo-stereo-isomer of difethialone ( ⁇ ) and said hetero-stereoisomer of difethialone ( ⁇ ), and;
- FIG. 10 is a graphical representation of the temporal evolution of the mean hepatic concentration in rats of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone ( ⁇ ) and of total difethialone ( ⁇ ).
- the homo-stereoisomer of the difethialone is identified by proton magnetic resonance spectroscopy (1H NMR).
- the homo-stereoisomer difethialone dissolved in CPDC 3 shows a multiplet at a chemical shift ( ⁇ ) of between 4.9 ppm and 5.1 ppm corresponding to the proton borne by the carbon of group 1 1.2 3,4-tetrahydronaphthalene of difethialone as illustrated in FIG.
- 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 homo-stereoisomer of the difethialone.
- 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 ⁇ .
- the value of the retention time (t 4 ) of said dextrorotatory enantiomer of said homo-stereoisomer according to the invention is of the order of 14.4 min as described in FIG. 1.
- the value the retention time 3 ⁇ 4) of the levorotatory enantiomer of said homo-stereoisomer is of the order of 8.1 min as described in FIG. 1, so that the dextrorotatory and laevorotatory enantiomers of said homo-stereoisomer can be effectively separated by high pressure liquid chromatography on a chiral column.
- 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 and the value of the retention time (t 2 ) of the levorotatory enantiomer of said hetero-stereoisomer of difethialone is of the order of 9.4 min.
- the elution order of the configuration stereoisomers of the difethialone is such that ⁇ t 2 ⁇ t 3 ⁇ t 4 .
- the UV spectrum of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone in chloroform solution (CHCt 3 ) has absorbance peaks centered at 238.2 nm and 259.5 nm.
- the inventors have characterized the dextrorotatory enantiomer of said homo-isomer of difethialone in the isolated state by its power.
- rotary also called optical activity or circular birefringence
- 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
- 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 homo-stereoisomer of difethialone in chloroform (CHCt 3 ) is measured at a concentration of 11.6 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 10 measurements is 2.308 °.
- the specific rotation power at 25 ° C [ ⁇ ] 25 C 589 nm of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone in solution in chloroform, measured on the sodium D-line (589 nm) is +19 , 9 °.
- FIGS. 2 and 3 respectively represent a nuclear magnetic resonance spectrum of the proton (1 H NMR) at 300 MHz of the homo-stereoisomer of difethialone in CDCC 3 (FIG. 2) and a nuclear magnetic resonance spectrum of the proton at 300 MHz in CDCC 3 of the hetero-stereoisomer of difethialone in CDCC 3 ( Figure 3).
- Said homo-stereoisomer of difethialone has (FIG. 2) a multiplet whose chemical shift ( ⁇ ) is between 4.9 ppm and 5.1 ppm corresponding to carbon 1 of the 1,2,3,4-tetrahydronaphthalene group.
- said homo-stereoisomer of difethialone has (Figure 3) a multiplet whose chemical shift ( ⁇ ) is between 5.2 ppm and 5.4 ppm.
- Figure 4 shows a 500 MHz proton NMR spectrum of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone in CDCC 3 .
- the proton NMR spectra of the dextrorotatory and levorotatory enantiomers of said homo-stereoisomer of difethialone are indistinguishable from each other.
- FIG. 6 is a two-dimensional (1H-NMR) two-dimensional proton NMR spectrum obtained by correlation spectroscopy of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone in solution in CDCt 3 at a concentration of 40 mg / mL performed on a Brucker AVANCE III HD (500 MHz) spectrometer equipped with a PRODIGY motorized multi-core direct cryoprobe.
- FIG. 5 is a 13 C NMR spectrum of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone in solution in CDCt 3 at a concentration of 40 mg / ml produced on a Brucker AVANCE III HD (500 MHz) spectrometer equipped a motorized multi-core direct cryoprobe PRODIGY. It allows an identification of the 31 carbon atoms of the difethialone.
- the 13 C-NMR spectrum of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone is indistinguishable from the 13 C-NMR spectrum of the levorotatory enantiomer of said ho-stereoisomer of difethialone.
- said homo-isomer of difethialone has a signal between 34 ppm and 38 ppm characteristic and distinctive of said hetero-stereoisomer of difethialone.
- 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 and methanol 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 eluate solvent is evaporated under a stream of nitrogen (N 2 ) at a temperature of 40 ° C.
- the sample is taken up in 0.5 ml of acetonitrile and the acetonitrile solution containing the difethialone is filtered on a 0.2 ⁇ filter.
- rats were administered gavage solution so that the amount of difethialone ingested by each rat was in the order of 3.4 mg per kilogram of rat.
- fed rats are treated daily by subcutaneous administration of a dose of vitamin K1 (as an antidote to bleeding) at the rate of 0.1U per 200g of rat's weight.
- the content of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone in the liver (average of the contents measured in 6 rats expressed in nanogram of said enantiomer per gram of liver (ng / g)) is represented by solid circles ( ⁇ ) and the content of the laevorotatory enantiomer of said homo-stereoisomer of difethialone in the liver (average of the contents measured on 6 rats expressed in nanograms of said enantiomer per gram of liver (ng / g)) is represented by open circles (O).
- the hepatic content of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone decreases more rapidly than the hepatic content of the laevorotatory enantiomer of said homo-stereoisomer of difethialone, whereas the initial proportion of the two enantiomers ingested by the rats is identical (20%).
- the relative content of the dextrorotatory enantiomer of said homo-stereoisomer of difethialone in the liver (average of the contents measured in 6 rats) expressed in arbitrary units for comparison is represented by solid circles ( ⁇ )
- the relative content of said homo-stereo isomer is represented by open squares ( ⁇ )
- the relative content of said hetero-stereoisomer is represented by solid squares ( ⁇ ).
- the hepatic content of the dextrorotatory enantiomer of the homo-isomer of the difethialone according to the invention decreases more rapidly than the hepatic content of said ho-stereoisomer of difethialone and the hepatic content of said hetero-stereoisone. isomer of difethialone.
- the hepatic content of said homo-stereoisomer of difethialone decreases more rapidly than the hepatic content of said hetero-stereoisomer of difethialone.
- the evolution over time of the dextrorotatory enantiomer content of said homo-stereoisomer of difethialone in the liver is represented (left scale) by solid circles ( ⁇ ) and the evolution over time of the content of the total difethialone is represented (right scale) by open triangles ( ⁇ ).
- the hepatic content of the dextrorotatory enantiomer of said homo-stereoisomer of the difethialone according to the invention decreases more rapidly than the hepatic content of the total difethialone.
- a pasty rodenticide bait according to the invention is produced by dispersing a quantity of difethialone in an edible excipent comprising vegetable fat and cereal flour.
- the measured proportion of difethialone relative to the bait is 14.7 ppm (14.65 mg of dextrorotatory enantiomer of said homo-stereoisomer of difethialone per kilogram of bait) and the proportion of dextrorotatory enantiomer of said homo - stereoisomer to difethialone is 99.7%.
- the bait further comprises a mass proportion of 0.3% levorotatory enantiomer of said hetero-stereoisomer of difethialone relative to difethialone.
- the hepatic content of the dextrorotatory enantiomer of the ⁇ ho mo-stereoisomer of difethialone (“DFN-Homo-dextro") according to the invention is measured for each of the rats that died between D9 and D10 by analysis by high-performance liquid chromatography. pressure on a chiral column.
- the values, expressed in micro-gram of "DFN-Homo-dextro" and difethialone per gram of liver are given in Table 3 below.
- the average amount of "DFN-Homo-dextro" enantiomer retained in the liver of each rodent (males and females) at their death corresponds to 4.7% of the amount of difethialone ingested by each rodent.
- the difethialone content retained in the liver of rats having consumed a bait comprising 15 ppm of difethialone of the state of the art is of the order of 110 ⁇ g / gram.
- Bait dosed at 14.7 ppm difethialone achieves a 100% mortality rate by minimizing the risk of secondary intoxication of animals - in particular, predatory birds or scavengers of weakened target rodents having consumed a rodenticide bait.
- 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
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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FR1562221A FR3045048B1 (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/EP2016/079854 WO2017097744A1 (en) | 2015-12-11 | 2016-12-06 | Configurational stereoisomer of difethialone, composition and rodenticide bait comprising same, and method for controlling target rodent pests |
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Publication Number | Publication Date |
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EP3386969A1 true EP3386969A1 (en) | 2018-10-17 |
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ID=55236759
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EP16809707.9A Withdrawn EP3386969A1 (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) | US10791736B2 (en) |
EP (1) | EP3386969A1 (en) |
BR (1) | BR112018011642A2 (en) |
FR (1) | FR3045048B1 (en) |
WO (1) | WO2017097744A1 (en) |
Family Cites Families (6)
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 |
PL373245A1 (en) | 2002-05-07 | 2005-08-22 | Bayer Cropscience Aktiengesellschaft | Rodenticidal bait system |
AU2008309681A1 (en) * | 2007-10-01 | 2009-04-16 | Basf Se | Rodenticide mixture |
ITMI20080238A1 (en) | 2008-02-15 | 2009-08-16 | Zapi Industrie Chimiche Spa | RHYDENTICIDE LURE BASED ON A SYNERGIC ASSOCIATION OF ANTICOAGULANT ACTIVE PRINCIPLES |
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 FR1562221A patent/FR3045048B1/en active Active
-
2016
- 2016-12-06 EP EP16809707.9A patent/EP3386969A1/en not_active Withdrawn
- 2016-12-06 WO PCT/EP2016/079854 patent/WO2017097744A1/en active Application Filing
- 2016-12-06 BR BR112018011642-4A patent/BR112018011642A2/en not_active Application Discontinuation
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2017
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FR3045048B1 (en) | 2019-04-05 |
US10791736B2 (en) | 2020-10-06 |
WO2017097744A1 (en) | 2017-06-15 |
US20180098538A1 (en) | 2018-04-12 |
BR112018011642A2 (en) | 2018-12-04 |
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