WO2015189321A1

WO2015189321A1 - Composition comprising difethialone, rodenticide bait and method for controlling target rodent pests

Info

Publication number: WO2015189321A1
Application number: PCT/EP2015/063028
Authority: WO
Inventors: Hervé CARUEL; Bernadette ESPANA; Stéphane Besse; Virginie LATTARD; Etienne Benoit
Original assignee: Liphatech
Priority date: 2014-06-13
Filing date: 2015-06-11
Publication date: 2015-12-17
Also published as: FR3022113B1; FR3022113A1; AR100833A1

Abstract

The invention relates to a composition comprising difethialone mainly in the form of 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 group 1,2,3,4- tetrahydronaphthalene have the same absolute configuration. The invention also relates to a rodenticide bait and to a method for controlling target rodent pests.

Description

COMPOSITION COMPRISING DIFETHIALONE, RODONTICIDAL BAIT AND METHOD FOR FIGHT AGAINST RODENTS

HARMFUL TARGETS

The present invention provides a composition comprising difethialone, a rodenticide bait and a method of controlling harmful target rodents. The invention therefore relates to the technical field of combating the excessive development of target rodent pest populations.

It is known to use harmful target rodent traps to collect a small number of individuals from a harmful target rodent species. Rodenticide baits are also known as poison for harmful target rodents.

In particular, US 2005/181003 discloses a rodenticide bait in gel form comprising between 15 and 1000 ppm of active substance, for example difethialone in a mass proportion of 25 ppm.

Such bait is problematic when it is made available to rodent pests and is likely to be consumed by animals other than harmful target rodents. For example, they can be consumed by pets or pets. They can also be accidentally consumed by humans.

In addition, a large quantity of the difethialone of these rodenticide baits can be ingested secondarily by animals - in particular by bird-predators or scavengers of rodent pests and in particular weak rodents that have consumed such rodenticide bait. This so-called secondary consumption is likely to eventually lead to the death of these predatory or scavenger animals, which may be animals belonging to protected species.

The invention therefore aims to overcome these drawbacks by proposing a composition, a rodenticide bait and a method for controlling harmful target rodents that are effective for controlling rodent nuisance populations and which, however, make it possible to limit the risks of primary poisoning. a human accidentally consuming such rodenticide bait; and the risk of secondary poisoning by non-target animals-especially domestic mammals, such as pets, or wild animals-especially foxes or poisonous bird-poison predators or poisoned rodent corpse scavengers .

The invention also relates to a composition, a rodenticide bait and a method for controlling harmful rodent rodents whose implementation is in accordance with the rules of good practice -especially with respect to the protection of birds, and in particular rapaces-.

The invention also relates to a composition, a rodenticide bait and a method for controlling harmful rodent rodents that do not require, to eradicate a target rodent rodent population, to use massive doses of a rodenticide agent and which is respectful environment, human health and non-target animals - especially birds.

For this purpose, the invention relates to a composition comprising difethialone predominantly in the form of a homo-stereoisomer of formula

3- (4'-bromobiphenyl-4-yl) -1- (4-hydroxythiocoumarin-3-yl) -1,2,3,4-tetrahydronaphthalene, carbons 1 and 3 of the 1,2,3,4-group; tetrahydronaphthalene being of the same absolute configuration.

Throughout the text, the term "difethialone" 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 of formula (I) below:

in which are presented the numbers of carbons 1 and 3 of the group 1, 2,3,4-tetrahydronaphthalene. The expression "ho mo-stereoisomer of difethialone" designates the "trans" configuration stereoisomer of difethialone in which the proton carried by carbon 1 and the proton carried by carbon 3 of group 1,2, 3,4-tetrahydronaphthalene extend on either side of the plane defined by the carbon atoms of the 1,2,3,4-tetrahydronaphthalene group, and in which the carbons 1 and 3 of the 1,2,3-group, 4-Tetrahydronaphthalene are of the same absolute configuration.

Throughout the text:

"Stereoisomers" denote isomers of the same semi-developed formula, but whose relative position of atoms differs in space.

"Stereoisomers of configuration" refers to stereoisomers whose conversion from one to the other requires a rupture / reformation of an interatomic covalent bond. Thus, the term "configuration stereoisomers" refers to stereoisomers which are not conformational isomers (or "rotamers", whose conversion of conformational isomers to each other is accompanied only by a rotation of a part of the molecule along the axis of a bond σ formed by axial overlap of orbitals). A same configuration stereoisomer may be formed of one or the other of the possible different enantiomers of this configuration stereoisomer or of a mixture, racemic or not, of these possible enantiomers;

the absolute configurations of carbons 1 and 3 of the 1,2,3,4-tetrahydronaphthalene group of the difethialone configuration stereoisomers are determined according to the nomenclature of Cahn, Ingold and Prelog;

the expressions "the homo-stereoisomer is predominant in the difethialone" and "the difethialone is predominantly in the form of a homo-stereoisomer", mean that the quantity (mass, molar or volume) of homo-stereo is The difethialone isomer is predominant - greater than 50% - in all of the difethialone present in the composition (in all its stereoisomeric forms of configuration).

The invention therefore relates to any composition comprising a major amount of homo-stereoisomer of difethialone relative to the total amount of difethialone. The invention therefore relates to any composition comprising a major proportion of homo-stereoisomer of difethialone relative to the set of stereoisomers of configuration -ho mo-stereo-isomer and hetero-stereoisomer of difethialone . The invention therefore relates to a composition in which the difethialone is predominantly Γ ho mo-stereoisomer of difethialone.

The invention therefore relates to a composition comprising a major amount of homo-stereoisomer of difethialone in total difethialone.

In a composition and a bait according to the invention:

the amount of homo-stereoisomer of the difethialone relative to the sum of the amounts of each of the stereoisomers (i) of configuration of the difethialone is greater than 0.5 (50%):

Amount of homo-stereoisomer of difethialone. _^ . «, ^

0.5 (50%);

Σi [Amount of stereoisomer (i) of difethialone]

the concentration of homo-stereoisomer of the difethialone relative to the sum of the concentrations of each of the stereoisomers (i) of configuration of the difethialone is greater than 0.5 (50%):

[homo-stereoisomer of difethialone] Q g S ^ Q O / Λ Σi [stereoisomer (i) of difethialone]

the proportion (pHomo-si) of homo-stereoisomer (Homo-SI) of the difethialone in the composition is greater than the proportion of the other stereoisomer (hetero-stereoisomer (Hetero-SI)) of the difethialone. In a composition according to the invention, the proportion of homo-stereoisomer of the difethialone in the composition is more than 50% relative to the total difethialone.

The inventors have observed that the configuration stereoisomers of difethialone do not exhibit the same hepatic persistence in harmful target rodents and that the homo-stereoisomer of difethialone is in fact the configuration stereoisomer of the difethialone which is of lower hepatic persistence in target rodents, especially in rodents harmful target. They observed that Γ homo-stereo-isomer of the difethialone, when ingested by a harmful target rodent, disappears from the target harmful rodent's liver having consumed a composition according to the invention more rapidly than the hetero-stereoisomer. The harmful or dead target rodent having ingested said composition is less dangerous with regard to non-rodent mammals and birds consuming the target harmful rodent and in particular with respect to predators (of non-rodent mammals and of birds) which preferentially consume the viscera of their preys and in particular their liver.

The inventors have further observed that such a composition according to the invention comprising predominantly homo-stereoisomer of the difethialone of lesser hepatic persistence in harmful target rodents in fact makes it possible to effectively fight against harmful target rodents.

Advantageously, the composition may also comprise another hetero-stereoisomeric configuration stereoisomer of the difethialone, in which the carbons 1 and 3 of the 1,2,3,4-tetrahydronaphthalene group of the difethialone are of absolute configurations. distinct. Advantageously, said hetero-stereoisomer of difethialone has in the composition a proportion of less than 50% -in particular less than 25, preferably between 0% and 25, in particular less than 10% - relative to the difethialone.

Advantageously and according to the invention, the homo-stereoisomer is in the composition in an amount of greater than 50%, in particular greater than 70, preferably of between 80% and 100%, more preferably of between 90% and 99% by weight. compared to difethialone. Advantageously, the homo-stereoisomer is in the composition in an amount of between 92% and 97% relative to the difethialone. Advantageously and according to the invention, the homo-stereoisomer is in the composition in an amount substantially of the order of 100% relative to the difethialone.

Advantageously and according to the invention, the homo-stereoisomer of difethialone has liver remanence in rodents targets lower than the hepatic persistence of the hetero-stereoisomer configuration of difethialone. Advantageously, the ho-stereo-isomer of difethialone has a hepatic persistence in target rodents less than the hepatic persistence of the hetero-stereoisomer of difethialone.

Advantageously and according to the invention, the homo-stereoisomer of the difethialone has a proton NMR in CDCt ₃ a multiplet having a chemical shift (δ) between 4.9 ppm and 5.0 ppm and corresponding to the proton carried by carbon 1 of the 1,2,3,4-tetrahydronaphthalene group of difethialone. Advantageously and according to the invention, the coupling constant of this proton is 5.5 Hz. The hetero-isomer of the Γ ho mo-stereoisomer difethialone is distinguished by their proton NMR spectra. . On the proton NMR spectrum carried out in CDCt ₃ , the chemical shift of the proton carried by carbon 1 of the 1,2,3,4-tetrahydronaphthalene group of the hetero-stereoisomer of difethialone is between 5.0 ppm and 5.4 ppm, and its coupling constant is between 6 Hz and 10 Hz.

Advantageously and according to the invention, the proportion (mass, molar or volume) of difethialone is between 1 ppm to 10 ⁶ ppm, that is to say between 1 and 10 mg ⁶ mg difethialone per kilogram of composition. It can therefore be a pure composition consisting exclusively of difethialone, or a dilute liquid solution comprising difethialone and a solvent, or a solid pre-mix.

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. The invention also relates to a rodenticide bait comprising a composition according to the invention and an edible excipient for harmful target rodents and chosen to allow consumption of the composition by harmful target rodents. The invention therefore relates to such a rodenticide bait which comprises a composition comprising a proportion majority of homo-stereoisomer of difethialone and an edible excipient.

In particular, advantageously and according to the invention, a rodenticide bait also comprises an edible excipient-in particular an edible non-lethal excipient for harmful target rodents. In particular, the edible carrier is not a rodenticide in itself and is free from rodenticide compounds.

Advantageously and according to the invention, the edible excipient for harmful target rodents comprises at least one food selected from the group consisting of cereal seeds - in particular dehulled cereal seeds -, cereal seed mills, seed flours cereal flakes, cereal grain flakes, cereal bran and non-cereal seeds, eg alfalfa seeds. The edible carrier may include any carrier that may be consumed by the target harmful rodent.

Advantageously, the edible carrier comprises at least one food selected from the group consisting of plant foods and foods of animal origin. Advantageously, the excipient comprises at least one food chosen to stimulate the appetite of harmful target rodents. In particular, 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. For example, cereals are selected from the group consisting of oats, wheat, barley, corn, soybeans and rice.

Advantageously, the food is selected from the group consisting of sweet foods. For example, 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.

Advantageously, the food is chosen from the group consisting of flakes and coconut albumen flour (copra). Advantageously, the food is selected from the group consisting of nuts, hazelnuts and almonds-shredded and / or powdered.

Advantageously, 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).

Advantageously, the food is selected from the group consisting of animal proteins. By way of example, mention may be made, for example, of powdered milk, particularly skimmed milk powder, eggs, especially powdered eggs, and hydrolysates of animal proteins.

Advantageously and according to the invention, the difethialone is present in the bait with a mass proportion of less than 200 ppm, that is to say 200 mg of difethialone per kilogram of bait. Advantageously, the mass proportion of difethialone is between 10 ppm and 100 ppm (10 mg to 100 mg of difethialone per kilogram of bait), especially between 10 ppm and 50 ppm (10 mg to 50 mg of difethialone per kilogram of difethialone). bait), preferably between 5 ppm and 25 ppm (5 mg to 25 mg of difethialone per kilogram of bait), more preferably of the order of 15 ppm (15 mg of difethialone per kilogram of bait).

The use of a bait according to the invention comprising a majority proportion of homo-stereoisomer of difethialone is less dangerous for the species exposed to the risk of primary intoxication (ingestion of the bait according to the invention by a child or by a non-target animal - for example by a dog - since the mass proportion of difethialone in the bait is moderate and for the species exposed to the risk of secondary intoxication as soon as the phenomenon of accelerated elimination homo-stereo- isomer in the rodent's liver decreases the amount of residual difethialone in the body of a poisoned rodent - dead or alive - likely to be consumed by said species.

Advantageously, the rodenticide bait is in solid form. Advantageously, the rodenticide bait according to the invention may be in the form of pellets, granules, block or paste that can be consumed by the target harmful rodents or a solid material that may be eaten by the target rodents. harmful. Advantageously, the solid rodenticide bait according to the invention can be in the form of a rigid block, a semi-rigid block or a gel.

Advantageously, the rodenticide bait is in the form of a powder. In particular, such a rodenticide bait is adapted to be able to soil the fur rodent (s) target (s) injurious (s) and to be ingested by it (them) during his (their) grooming.

Advantageously, the rodenticide bait can be in liquid form. The rodenticide bait is then a drink.

Advantageously, the rodenticide bait comprises at least one dye. In particular, such a dye makes it possible to give said bait a color that is easily detectable and identifiable by a person handling the rodenticide bait.

Advantageously, the rodenticide bait comprises at least one preservative able to ensure its conservation during storage.

Advantageously, in a particular variant according to the invention, the composition and the rodenticide bait exclusively comprise difethialone as a rodenticide substance. In particular, the composition and the rodenticide bait according to the invention are free of any other anticoagulant substance for rodenticide use.

However, in another variant according to the invention, the composition and the rodenticide bait may comprise another rodenticide substance other than difethialone and / or any other harmful substance such as an insecticide and / or acaricide. The invention also relates to a method for controlling harmful target rodents in which a quantity of bait is dispersed comprising:

o difethialone in the form of a stereoisomer of the difethialone, said ho-mono-isomer, of formula 3- (4'bromobiphenyl-4-yl) -1- (4-hydroxythiocoumarin-3-yl) - 1,2,3,4-tetrahydronaphthalene, carbons 1 and 3 of the 1,2,3,4-tetrahydronaphthalene group of said homo-isomer being of the same absolute configuration, and

an edible carrier for harmful target rodents; wherein the bait is selected so that the homo-stereoisomer is predominant in the difethialone.

The invention therefore relates to a method for controlling harmful target rodents in which a quantity of bait is dispersed comprising:

o difethialone predominantly in the form of homo-stereoisomer, of formula 3- (4'bromobiphenyl-4-yl) -1- (4-hydroxythiocoumarin-3-yl) -1,2,3,4-tetrahydronaphthalene the carbons 1 and 3 of the 1,2,3,4-tetrahydronaphthalene group being of the same absolute configuration, and

an edible carrier for harmful target rodents.

The invention therefore relates to a method for controlling harmful target rodents in which a quantity of rodenticide bait according to the invention is dispersed, that is to say a bait comprising a majority proportion of homo-steroids. isomer of difethialone in difethialone, said amount of bait being sufficient to be rodenticide. A quantity of bait comprising mainly the homo-stereoisomer of difethialone in difethialone is therefore disseminated in the difethialone, said difethialone having decreased hepatic persistence in the target harmful rodent but maintained rodenticidal efficacy. The method according to the invention therefore makes it possible to limit the secondary poisoning of non-rodent mammals and birds that can feed on dead or poisoned rodents, 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 poisoned rodents.

Advantageously and according to the invention, the homo-stereoisomer is in the bait in an amount greater than 50% -in particular greater than 70, preferably between 80% and 100, more preferably between 90% and 99% - in the difethialone. Advantageously, the homo-stereoisomer is in the bait in an amount of between 92% and 97% relative to the difethialone. Advantageously and according to the invention, the homo-stereoisomer is in the bait in an amount substantially of the order of 100% relative to the difethialone.

Advantageously and according to the invention, the bait is chosen so that the difethialone is present in the bait with a mass proportion of less than 200 ppm, that is to say 200 mg of difethialone per kilogram of bait. Advantageously, the mass proportion of difethialone is between 10 ppm and 100 ppm (10 mg to 100 mg of difethialone per kilogram of bait), especially between 10 ppm and 50 ppm (10 mg to 50 mg of difethialone per kilogram of difethialone). bait), preferably between 5 ppm and 25 ppm (5 mg to 25 mg of difethialone per kilogram of bait), more preferably of the order of 15 ppm (15 mg of difethialone per kilogram of bait).

Advantageously and alternatively according to the invention, the mass proportion of difethialone in the bait is chosen in combination with the quantity of disseminated bait so that harmful target rodents consume a quantity of difethialone sufficient to be lethal to said harmful target rodents. consuming said bait during a single period of 24 consecutive hours. A bait according to this variant of the invention is a deadly bait in a single catch or "one-shot" in English. Advantageously and according to this variant of the invention, the mass proportion of difethialone in the bait is of the order of 50 ppm.

Advantageously and in another variant according to the invention, the mass proportion of difethialone in the bait is chosen in combination with the quantity of bait disseminated so that harmful target rodents consume a quantity of difethialone;

- non-lethal for harmful target rodents consuming said bait for a period of 24 consecutive hours, and;

- sufficient to be lethal to harmful target rodents consuming said bait for several 24-hour periods, said periods being consecutive.

This other variant of the invention therefore also relates to a method for controlling harmful target rodents in which a quantity of lethal bait is dispersed for harmful target rodents consuming this bait permanently and not lethal to rodents or non-target animals consuming accidentally this bait. This is called a "multi-dose" or "multi-feeding" control method. In such a method according to the invention, the consumption of bait by a target rodent harmful for a period of 24 hours is insufficient to cause the death of said rodent, while repeated consumption of bait for at least two consecutive days allows to cause the death of the rodent harmful target.

The invention therefore relates to a method of controlling a population of rodent harmful rodent in which the rodenticide rodent bait is put at the disposal of the target rodent that can be ingested by the target harmful rodent, said quantity of bait being sufficient. to kill harmful target rodents consuming said bait for several days.

In a method according to the invention, harmful target rodents are provided with a quantity of bait sufficient to satisfy the appetite of harmful target rodents, said bait comprising a major proportion of homo-stereoisomer of difethialone. Advantageously and according to the invention, the quantity of disseminated bait and the mass proportion of difethialone in the bait are chosen so as to allow daily ingestion of difethialone by a harmful target rodent of between 0.20 and 10 mg per kilogram of target rodent. harmful, preferentially between 0.20 and 2 mg per kilogram of harmful target rodent.

In a method according to the invention, the amount of disseminated bait and the mass proportion of difethialone in the bait are adapted so as to allow bait consumption for several days by harmful target rodents, while limiting:

- the risks of primary intoxication of mammals and non-target birds likely to consume only occasionally and accidentally such bait

the risks of secondary intoxication, for example predators of target rodents, likely to consume rodents-dead or alive-targets having ingested a quantity of said bait.

Advantageously and according to the invention, 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 example alfalfa seeds - in particular in husked form, in the form of milling, in the form of flour, in the form of flakes or bran. The edible carrier may include any carrier that may be consumed by the target harmful rodent. Advantageously and according to the invention, the amount of disseminated bait, the mass proportion of difethialone in the bait and the proportion of homo-stereoisomer of the difethialone are adapted so that the consumption of the bait is lethal for harmful target rodents consuming bait daily for at least 2 24-hour periods, particularly 3 to 7 periods, said periods being consecutive.

Advantageously and according to the invention, the amount of disseminated bait, the mass proportion of difethialone in the bait and the proportion of homo-stereoisomer of difethialone in order to be able to reach harmful target rodents in the liver after the third day of a period of three consecutive days, said period comprising at least one ingestion of bait per day, one quantity of difethialone less than or equal to 10 μg of difethialone per gram of harmful target rodent liver.

The period of three consecutive days in which a harmful target rodent ingests bait may begin from a first ingestion of bait by a rodent harmful target. It can also begin as soon as the bait is released.

Advantageously and according to the invention, the amount of disseminated bait, the mass proportion of difethialone in the bait and the proportion of hetero-stereoisomer of difethialone are adjusted to reach a quantity of hetero-stereoisomer of difethialone in the liver of rodents killed by consumption of said bait less than or equal to 30 μg per dead rodent liver.

The invention also relates to a composition, a rodenticide bait and a method for controlling harmful target rodents characterized in combination by all or some of the characteristics mentioned above or below.

Other objects, features and advantages of the invention will appear on reading the following description and examples given solely by way of non-limiting example and which refer to the appended figures, in which:

FIG. 1 is a proton NMR spectrum of a mixture of homo-stereoisomer and hetero-stereoisomer of difethialone;

FIG. 2 is a detail of a proton NMR spectrum of a homo-stereo-isomer and hetero-stereoisomer mixture of difethialone;

FIG. 3 is a graphical representation of the evolution of the hepatic concentration of the difethialone configuration stereoisomers.

A composition according to the invention comprises a majority proportion of homo-stereoisomer of difethialone. The inventors have discovered that it is possible to obtain such a homo-isomer of the difethialone by separation of the configuration stereoisomers of the difethialone.

For example, thin layer chromatography of a mixture of difethialone stereoisomers on silica gel with a mobile phase formed of petroleum ether (80), ethyl acetate (4%) and dichloro methane (16%) - the results of which are directly usable on a flash column (50μπι) - makes it possible to separate a configuration stereo-isomer from the difethialone whose reference front (front of the compound / solvent front) is 0.27 and another configuration stereoisomer of the difethialone whose reference face is 0.31.

Can also fractionate such a mixture of two stereoisomers difethialone configuration isomers by HPLC chromatography on reverse phase column INERTSIL ^® ODS2 a length of 150 mm and 4.6 mm internal diameter in which this reverse stationary phase a particle size of 5 μπι, a porosity of 80A and a specific surface area of 500 m ² / g. The mobile phase consists of a mixture of acetonitrile (62), isopropanol (3%) and ammonium acetate (35%) adjusted to pH 4 with acetic acid. The flow rate of the mobile phase is 1.5 ml / min and the detection is carried out by spectrophotometry at 260 nm. A configuration stereoisomer is detected and collected whose retention time is of the order of 10.4 min and another configuration stereo-isomer whose retention time is of the order of 11.8 min.

The purity of the configuration stereoisomers of difethialone is confirmed by high pressure liquid chromatography (UPLC, waters) on an Acquity column UPLC BEH Cl 8 with a particle size of 1.7 μπι and a size of 2.1 x 50 mm at 35. ° C. The mobile phase is formed of a gradient obtained by adding a solution of acetonitrile comprising 0.1% trifluoroacetic acid (TFA) in water supplemented with 0.1% TFA. The flow rate of the mobile phase is 0.6 mL / min. The retention time of the most retained configuration stereoisomer is 4.1 min and that of the least retained configuration stereoisomer is of the order of 3.9 min. The proton NMR (1H-NMR) study of a mixture of the two configuration stereoisomers of difethialone in CDCt ₃ shows that the most conserved configuration stereoisomer has a multiplet (Figure 2) of chemical shift. (δ) between 4.9 ppm and 5.0 ppm and coupling constant of 5 Hz and corresponds to the "trans" or homo-stereoisomeric steroisomer.

In the rest of the text, homo-SI will denote the homo-stereoisomer of difethialone (of "trans" configuration) and of hetero-Si hetero-stereoisomer of difethialone (of "cis" configuration). .

Hepatic remanence of the homo-stereoisomer (homo-

SI) and the hetero-stereoisomer (hetero-SI) of difethialone in rats

Gavage ("peros") was administered to laboratory rats (Sprague Dawley (SD) rats, Charles River, Saint Germain on the Arbresle, France) males, aged 8 weeks and weighing about 200 g, a solution of a mixture of the two configuration stereoisomers of difethialone (Homo-SI 54% and Hetero-SI 46) in a mixture of vegetable oil and 5% DMSO. The solution comprising Homo-SI and Hetero-SI is administered (on day 0) to 20 rats so that the amount of difethialone ingested by each rat is of the order of 3 mg per kilogram of rat.

To avoid hemorrhage, the 40 gavaged rats are treated daily by subcutaneous administration of a dose of vitamin K at a rate of 0.1 U per 200 g of weight of live rat.

At 1 day (D + 1), 3 days (D + 3), 7 days (D + 7), 14 days (D + 14) and 21 days (D + 21) after force-feeding, 4 previously anesthetized rats are sacrificed to isoflurane, the liver is removed from the sacrificed rats and then extracted from the liver and the amount of each of the configuration stereoisomers of the difethialone present in the liver of the gaved rats is assayed. The results are given in Table 1 below, in which the liver levels of difethialone are the average of the contents measured on 4 rats and expressed in μg of difethialone per g of liver (g / g) and represented in FIG. of Homo-SI in the liver is represented by open circles (O) and the content of the Hetero-SI in the liver is represented by solid squares (■).

Table 1

The average level of Γ Homo-SI in the liver of rats is lower than the average content of hetero-S1 in the liver of rats after gavage of said rats with substantially the same amount of each of the Homo configuration stereoisomers. SI and Hetero-SI of difethialone. Homo-SI has a significantly lower hepatic persistence compared to the hepatic persistence of hetero-SI.

Rat fighting bait with difethialone

A pasty rodenticide bait according to the invention is produced by dispersing a quantity of difethialone, predominantly in its homo-stereoisomeric form, in an edible excipent comprising vegetable fat and cereal flour.

Two types of baits are prepared, each comprising a mass proportion of difethialone of 15 ppm (ie 15 mg of difethialone per kilogram of bait):

a bait, called Homo-SI bait, according to the invention comprising, as active substance, 94% of Homo-SI and 6% of Hetero-SI, and

a bait, called bait Hétéro-SI, comprising as active substance 1% of Homo-SI and 99% of Hétéro-SI by way of comparison.

In individual cages, 10 rats (5 male and 5 female rats) from the laboratory (Sprague Dawley rats, Charles River, Saint germain on the Arbresle, France), aged 8 weeks and 200 g of body weight, were made available. bodily, continuously for 4 days a quantity of the first type of bait (Homo-SI) sufficient to satisfy the nutrition of each of these 10 rats. Another 10 rats are also provided with a quantity of the second type of bait (Hetero-SI) sufficient to satisfy the nutrition of each of these animals. 10 other rats At the end of these 4 days, the rats are given a diet free of rodenticide.

The amount of bait consumed by each of the 10 live rats is measured daily. At the death of each animal, the liver of each animal is collected and the difethialone content in each liver is measured. The mean hepatic amount of difethialone is expressed as μg difethialone per gram of rat liver. The hepatic proportion (%) represents the average proportion of difethialone retained in the liver of rats relative to the total amount of difethialone ingested. The results are given in Table 2 below.

Table 2

In the group of rats treated with Homo-SI (second column), two rats died on D + 3 (1 male, 1 female), one rat died on D + 4 (1 male), two rats died at day 5 (2 males), two rats died on D + 7 (2 females), two rats died on D + 8 (2 females) and one rat died on D + 9 (1 male). In the group of rats treated with Hetero-SI, four rats died on D + 4 (2 males, 2 females), two rats died on D + 5 (1 male, 1 female) and four rats died on D + 6 (2 males, 2 females). The amount of residual difethialone in the liver of rat cadavers is twice as low when the rats ingest the Homo-SI bait (8.8 μg / g) rather than the bait hetero-SI (16.5 μg / g ). The amount of residual difethialone in the cadaver of rats is twice as low when the rats ingest the Homo-SI bait (6.7 μg) rather than the Hetero-SI bait (13.8 μg).

The bait according to the invention is as effective as the bait comprising a majority of Γ Hetero-SI and is less dangerous for non-target animals likely to consume poisoned rodents or dead poisoned rodents.

Bait fighting rats "Norwegian Rattus" based on difethialone

Norwegian Rattus rats susceptible to warfarin are available:

A) a solid bait based on wheat according to the invention comprising 100% of homo-SI of difethialone at the rate of 10 ppm or 5 ppm of difethialone in the bait, or

B) a solid bait based on wheat according to the invention comprising 100% of Homo-SI at the rate of 25 ppm or 10 ppm of difethialone in the bait, or

- C) a wheat-based solid bait for comparison and comprising 100% of 25 ppm Hetero-SI or 10 ppm of difethialone in the bait.

The mortality rates of the rats obtained with each of these baits (A to C) according to the modalities described are given in Table 3 below according to the proportion (in ppm or mg / kg) of difethialone in the bait and the number of successive days of baiting by the rats. Bait Proportion Number of days Mortality

A) 100% Homo-SI 10 ppm 3 days 80%

A) 100% Homo-SI 5 ppm 3 days 50%

B) 100% Homo-SI 25 ppm 1 day 90%

B) 100% Homo-SI 10 ppm 1 day 30%

C) 100% Hetero-SI 25 ppm 1 day 90%

C) 100% Hetero-SI 10 ppm 1 day 100%

Table 3

A rodenticide bait according to the invention comprising predominantly Homo-SI (baits A) and B) of difethialone and low hepatic persistence has a high rodenticidal efficacy when it is provided rodents so as to allow consumption in a single dose or repeated over several days. Due to the low hepatic persistence of Homo-SI, such a bait according to the invention limits the risk of poisoning of non-target mammals accidentally consuming such bait and the risk of poisoning of predatory birds or rodent scavengers. dead or alive having consumed such a bait.

It goes without saying that the invention can be the subject of many variants and applications. In particular, 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.

Claims

1 / - Composition comprising difethialone predominantly in the form of a homo-stereoisomer of formula 3- (4'-bromobiphenyl-4-yl) -1- (4-hydroxythiocoumarin-3-yl) -1,2,3 , 4-Tetrahydronaphthalene, carbons 1 and 3 of the 1,2,3,4-tetrahydronaphthalene group being of the same absolute configuration.

21 - Composition according to claim 1, characterized in that the homo-stereoisomer of the difethialone present by NMR analysis of the proton in CDCt ₃ a multiplet having a chemical shift (δ) between 4.9 ppm and 5, 0 ppm.

3 / - Composition according to one of claims 1 or 2, characterized in that the proportion of diféthialone is between 1 ppm and 10 ⁶ ppm in the composition.

41 - A rodenticide bait comprising a composition according to one of claims 1 to 3, characterized in that it comprises an edible excipient for harmful rodent targets.

5 / - Bait according to claim 4, characterized in that the edible excipient for harmful target rodents is selected from the group consisting of cereal seeds, cereal grain mills, cereal seed meal, flakes of cereal seeds, cereal bran and non-cereal seeds.

6 / - Bait according to one of claims 4 or 5, characterized in that the difethialone is present in the bait with a mass proportion of less than 200 ppm.

II - A method of controlling harmful target rodents in which a quantity of bait is dispersed comprising:

o difethialone predominantly in the form of homo-stereoisomer, of formula 3- (4'bromobiphenyl-4-yl) -1- (4-hydroxythiocoumarin-3-yl) -1,2,3,4-tetrahydronaphthalene , carbons 1 and 3 of 1,2,3,4-tetrahydronaphthalene group being of the same absolute configuration, and

an edible carrier for harmful target rodents.

8 / - Method according to claim 7, characterized in that the bait is chosen so that the difethialone is present in the bait with a mass proportion of less than 200 ppm.

91 - A method according to claim 8, characterized in that the mass proportion of difethialone in the bait is chosen in combination with the amount of disseminated bait so that target harmful rodents consume a quantity of diféthialone sufficient to be lethal to said harmful target rodents consuming said bait during a single 24-hour period.

10 / - A method according to claim 8, characterized in that the mass proportion of difethialone in the bait is chosen in combination with the amount of bait disseminated so that harmful target rodents consume a quantity of difethialone;

11 / - A method according to claim 10, characterized in that the amount of disseminated bait and the mass proportion of difethialone in the bait is chosen to allow daily ingestion of difethialone by a rodent harmful target between 0.20 and 10 mg per kilogram of harmful target rodent.

12 / - Method according to one of claims 7 to 11, characterized in that the edible carrier comprises at least one food selected from the group consisting of cereal seeds, grain cereal millet, cereal seed meal , cereal seed flakes, cereal bran and non-cereal seeds. 13 / - Method according to one of claims 10 to 12, characterized in that the amount of disseminated bait, the mass proportion of difethialone in the bait and the proportion of homo-isomer of the difethialone is adjusted. so that the consumption of the bait is lethal to harmful target rodents consuming daily bait for at least 2 periods of 24 hours, said periods being consecutive.

14 / - Method according to one of claims 10 to 13, characterized in that the amount of disseminated bait, the mass proportion of difethialone in the bait and the proportion of homo-isomer of the difethialone is adjusted. to be able to reach harmful target rodents in the liver after the third day of a period of three consecutive days, said period comprising at least one ingestion of bait per day, a quantity of difethialone less than or equal to 10 μg of difethialone per gram of harmful target rodent liver.

15 / - Method according to one of claims 8 to 14, characterized in that the amount of bait disseminated, the mass proportion of difethialone in the bait and the proportion of hetero-isomer of the difethialone is adjusted. to reach a quantity of hetero-stereoisomer of difethialone in the liver of rodents killed by consumption of said bait less than or equal to 30 μg per dead rodent liver.