CHROMONE DERIVATIVES AS ATTRACTANTS AND REPELLENTS OF BLOOD-SUCKING, BITING INVERTEBRATES

Abstract

Disclosed is the use of a compound with the following formula (I):

##STR00001##

R is a linear or branched alkyl group including from 2 to 20 carbon atoms, the compound being in the form of a racemic mixture, an enantiomer (R) or an enantiomer (S), as an attractant or repellent for blood-sucking, biting invertebrates.

Claims

1. A method for attracting or repelling blood-sucking, biting invertebrates, comprising the use of a compound with formula (I): ##STR00017## R being a linear or branched alkyl group comprising from 2 to 20 carbon atoms, said compound being achiral when R is a linear group or in the form of a racemic mixture, an enantiomer (R) an enantiomer (S) when R is a branched group, as an.

2. The method of claim 1, for attracting blood-sucking, biting invertebrates, comprising the use of a compound with the formula (II): ##STR00018## wherein R represents an alkyl group containing 3 to 18 carbon atoms, as an attractant for blood-sucking, biting invertebrates.

3. The method according to claim 1, for repelling blood-sucking, biting invertebrates, comprising the use of a compound with the formula (II): ##STR00019## wherein R represents an alkyl group containing 2 carbon atoms, as a repellent for blood-sucking, biting invertebrates.

4. The method for repelling blood-sucking, biting invertebrates according to claim 3, wherein the compound with the formula (II) is in the form of the enantiomer (R) or a racemic mixture, or wherein the compound with the formula (II) is in the form of the enantiomer (S), and wherein the compound is used in a composition wherein the content of said compound is greater than or equal to 20% by weight with respect to the total weight of said composition.

5. The method for attracting blood-sucking, biting invertebrates according to claim 2, wherein R represents an alkyl group comprising 2 carbon atoms, said compound being in the form of the enantiomer (S), and wherein the compound is used in a composition wherein the content of said compound is less than or equal to 20% by weight with respect to the total weight of said composition.

6. An attractant or repellent composition for blood-sucking, biting invertebrates comprising at least one compound with the following formula (I): ##STR00020## R being a linear or branched alkyl group comprising from 2 to 20 carbon atoms, said compound being achiral when R is a linear group or in the form of a racemic mixture, an enantiomer (R) an enantiomer (S) when R is a branched group.

7. The attractant composition for blood-sucking, biting invertebrates according to claim 6, comprising: at least one compound with the formula (I), wherein R represents an alkyl group comprising from 2 to 16 carbon atoms, or at least one compound with the formula (I), wherein R represents an alkyl group comprising 4 carbon atoms, said compound being in the form of the enantiomer (S), and wherein the compound in the form of the enantiomer (S) is used in a concentration smaller than or equal to 20% of said composition.

8. The repellent composition for blood-sucking, biting invertebrates according to claim 6, comprising: at least one compound with the formula (I) wherein R represents an alkyl group containing 4 carbon atoms, the compound with the formula (I) being in the form of the enantiomer (R) or of a racemic mixture, or of a mixture of the enantiomers (R) and (S) in mass concentrations different from 50/50%; or at least one compound with the formula (I) wherein R represents an alkyl group comprising 4 carbon atoms, said compound being in the form of the enantiomer (S) and wherein said compound in the form of the enantiomer (S) is used in a concentration greater than or equal to 20% by weight with respect to the weight of said composition.

9. A kit for trapping blood-sucking, biting invertebrate, in particular Aedes albopictus, comprising: at least a composition according to claim 6, and at least one blood-sucking, biting invertebrate trap.

10. A method for trapping blood-sucking, biting invertebrates, comprising of providing the kit according to claim 9, and disposing the trap with the composition in the presence of the blood-sucking, biting invertebrates.

11. A repellent support for blood-sucking, biting invertebrates, said support being impregnated with at least one repellent composition according to claim 8.

12. The attractant or repellent composition of claim 6, further comprising an additional compound that is attractant or repellent for a blood-sucking, biting invertebrate.

13. The attractant composition for blood-sucking, biting invertebrates according to claim 12, comprising: at least one compound with the formula (I), wherein R represents an alkyl group comprising from 2 to 16 carbon atoms, or at least one compound with the formula (I), wherein R represents an alkyl group comprising 4 carbon atoms, said compound being in the form of the enantiomer (S), and wherein the compound in the form of the enantiomer (S) is used in a concentration smaller than or equal to 20% of said composition.

14. The repellent composition for blood-sucking, biting invertebrates according to claim 12, comprising: at least one compound with the formula (I) wherein R represents an alkyl group containing 4 carbon atoms, the compound with the formula (I) being in the form of the enantiomer (R) or of a racemic mixture, or of a mixture of the enantiomers (R) and (S) in mass concentrations different from 50/50%; or at least one compound with the formula (I) wherein R represents an alkyl group comprising 4 carbon atoms, said compound being in the form of the enantiomer (S) and wherein said compound in the form of the enantiomer (S) is used in a concentration greater than or equal to 20% by weight with respect to the weight of said composition.

15. A kit for trapping blood-sucking, biting invertebrate, comprising: at least a composition according to claim 12, and at least one blood-sucking, biting invertebrate trap.

16. A kit for trapping blood-sucking, biting invertebrate, comprising: at least a composition according to claim 7, and at least one blood-sucking, biting invertebrate trap.

17. A method for trapping blood-sucking, biting invertebrates, comprising providing the kit according to claim 15, and disposing the trap with the composition in the presence of the blood-sucking, biting invertebrates.

18. A method for trapping blood-sucking, biting invertebrates, comprising providing the kit according to claim 16, and disposing the trap with the composition in the presence of the blood-sucking, biting invertebrates.

Description

FIGURES

[0065] FIG. 1 represents the synergistic effect between the compounds 4-hydroxycoumarin and 7-nonyloxychromone with regard to Aedes albopictus. Said figure represents the IK (in %) as a function of the amount deposited (in mg). The curve with diamonds corresponds to 4-hydroxycoumarin, the curve with squares corresponds to 7-nonyloxychromone and the curve with triangles corresponds to the synergy.

[0066] FIG. 2 represents the IK (in %) as a function of the amount deposited (in mg) for 7-n-decyloxychromone with regard to Aedes albopictus.

[0067] FIG. 3 represents the IK (in %) as a function of the amount deposited (in mg) for 7-(2-ethyl)hexyloxychromone with respect to Aedes albopictus.

EXAMPLES

Equipment and Methods

Synthesis of Chromone Derivatives

[0068] 7-hydroxy-4-chromone is used as the starting substance for obtaining the ether derivatives. The synthesis is carried out according to the effect of the structure of the molecule on the behavior of mosquitoes.

1. Synthesis by phase transfer catalysis

[0069] A reaction with a phase transfer catalyst is used for the synthesis of non-chiral substances as shown below:

##STR00008##

Example 1: Synthesis of Racemic 7-sec-butoxychromone (1CPT)

[0070] 100 ml of toluene and 8.4 g of K.sub.2CO.sub.3 (61 mmol), are added to a 250 ml three-neck reflux reactor equipped with a magnetic stirrer and a thermometer, then 2 g of 7-hydroxychromone (12 mmol) and 10.14 g of 2-bromobutane (82 mmol) are added to the mixture. For the phase transfer catalyst, 0.1 g of tetrabutyl ammonium hydrogen sulfate is added. The mixture is stirred under reflux for 6 h at 120? C. and the organic phase is recovered by decanting, washed with distilled water, dried with Na.sub.2SO.sub.4 and then evaporated. The resulting oily mixture is purified by column chromatography with silica gel (eluent: ethyl acetate 2 hexane 8). The pure product is obtained in the form of a yellow oil with a yield equal to 73%.

Example 2: Synthesis of Racemic 7-sec-pentoxychromone (2CPT)

[0071] 100 ml of toluene and 4.2 g of K.sub.2CO.sub.3 (30.6 mmol), are added to a 250 ml three-neck reflux reactor equipped with a magnetic stirrer and a thermometer, then 1 g of 7-hydroxychromone (6.15 mmol) and 5 g of 2-bromopentane (41.2 mmol) are added to the mixture. For the phase transfer catalyst, 0.05 g of tetrabutyl ammonium hydrogen sulfate is added. The mixture is stirred under reflux for 6 h at 120? C. and the organic phase is recovered by decanting, washed with distilled water, dried with Na.sub.2SO.sub.4 and then evaporated. The oily mixture is purified by column chromatography with silica gel (eluent: ethyl acetate 2 hexane 8). The pure product is obtained in the form of a yellow oil with a yield equal to 33.1%.

Example 3: Synthesis of Racemic 7-sec-nonyloxychromone (3CPT)

[0072] 100 ml of toluene and 2.13 g of K.sub.2CO.sub.3 (15.3 mmol), are added to a 250 ml three-neck reflux reactor equipped with a magnetic stirrer and a thermometer, then 0.5 g of 7-hydroxychromone (3.1 mmol) and 3 g of 2-bromononane (20.6 mmol) are added to the mixture. For the phase transfer catalyst, 0.025 g of tetrabutyl ammonium hydrogen sulfate is added. The mixture is stirred under reflux for 6 h at 120? C. and the organic phase is recovered by decanting, washed with distilled water, dried with Na.sub.2SO.sub.4 and then evaporated. The oily mixture is purified by column chromatography with silica gel (eluent: ethyl acetate 2 hexane 8). The pure product is obtained in the form of a yellow oil with a yield equal to 35.2%.

Example 4: Synthesis of 7-isopropyloxychromone (4CPT)

[0073] 7 ml of toluene and 0.8 g of K.sub.2CO.sub.3 (5.8 mmol), 0.25 g of 7-hydroxychromone (1.54 mmol) are added to a 15 ml sealed tube equipped with magnetic stirrer and a thermometer, then 2 g of 2-bromopropane (16.26 mmol) are added to the mixture. As phase transfer catalyst, 0.4 g of tetrabutyl ammonium hydrogen sulfate is added. The mixture is stirred for 24 hours at 90? C. and the organic phase is recovered by decanting, washed with distilled water, dried with Na.sub.2SO.sub.4 and then evaporated. The oily mixture is purified by column chromatography with silica gel (eluent: ethyl acetate 2 hexane 8). The pure product is obtained in the form of white solids with a yield equal to 29.4%.

2. Synthesis by the Mitsunobu Reaction

[0074] The Mitsunobu reaction is used for selectively converting an alcohol into different functional groups such as ether, in only one step. Such reaction is also used for a chiral inversion of enantiomers of chiral alcohols, as shown below:

##STR00009##

Example 5: Synthesis of R-(?)-sec-butoxychromone (5M)

[0075] 15 ml of dichloromethane, 1 g of 7-hydroxychromone (6.2 mmol), then 1.2 ml of S-butan-2-ol (12.4 mmol) and 3.2 g of triphenylphosphine (12.4 mmol) are successively added to a 50 ml reactor equipped with a thermometer, a magnetic stirrer and a slight nitrogen overpressure. The mixture is then stirred for a few minutes and then 2.2 ml of DEAD (diethyl azodicarboxylate) solution (24 mmol) are added dropwise. The reaction is carried out at room temperature for 15 to 24 hours. The solution is then evaporated and the mixture is purified by column chromatography with silica gel (eluent: ethyl acetate 2 hexane 8). The pure product is obtained in the form of a pale yellow oil with a yield equal to 52.6%.

Example 6: Synthesis of S-(+)-sec-butoxychromone (6M)

[0076] 30 ml of dichloromethane, 2 g of 7-hydroxychromone (12.4 mmol), then, 2.4 ml R-butan-2-ol (24.6 mmol) and 6.4 g of triphenylphosphine (24.6 mmol) are successively added to a 50 ml reactor equipped with a thermometer, a magnetic stirrer and a slight nitrogen overpressure. The mixture is then stirred for a few minutes and then 4.2 ml of DEAD solution (24 mmol) are added dropwise. The reaction is carried out at room temperature for 15 to 24 hours. The solution is then evaporated and the mixture is purified by column chromatography with silica gel (eluent: ethyl acetate 2 hexane 8). The pure product is obtained in the form of a pale pink oil with a yield equal to 53%.

Example 7: Synthesis of (R) 7-sec-pentoxychromone (7M)

[0077] 30 ml of dichloromethane, 1 g of 7-hydroxychromone (6.2 mmol), then 1.4 ml of S-pentan-2-ol (12.3 mmol) and 3.23 g of triphenylphosphine (12.3 mmol) are successively added to a 50 ml reactor equipped with a thermometer, a magnetic stirrer and a slight nitrogen overpressure. The mixture is then stirred for a few minutes and then 2.1 ml of DEAD solution (12.3 mmol) are added dropwise. The reaction is carried out at room temperature for 15 to 24 hours. The solution is then evaporated and the mixture is purified by column chromatography with silica gel (eluent: ethyl acetate 2 hexane 8). The pure product is obtained in the form of a pale pink oil with a yield equal to 63.3%.

Example 8: Synthesis of (S) 7-sec-pentoxychromone (8M)

[0078] 30 ml of dichloromethane, 1 g of 7-hydroxychromone (6.2 mmol), then 1.4 ml R-pentan-2-ol (12.3 mmol) and 3.23 g of triphenylphosphine (12.3 mmol) are successively added to a 50 ml reactor equipped with a thermometer, a magnetic stirrer and a slight nitrogen overpressure. The mixture is then stirred for a few minutes and then 2.1 ml of DEAD solution (12.3 mmol) are added dropwise. The reaction is carried out at room temperature for 15 to 24 hours. The solution is then evaporated and the mixture is purified by column chromatography with silica gel (eluent: ethyl acetate 2 hexane 8). The pure product is obtained in the form of a pale yellow oil with a yield equal to 42.4%.

Example 4bis: Synthesis of 7-n-decyloxychromone (5CPT)

[0079] ##STR00010##

[0080] 10 ml of toluene and 0.691 g of K.sub.2CO.sub.3 (5 mmol), are added to a 50 ml three-neck reflux reactor equipped with a magnetic stirrer and a thermometer, then 0.2 g of 7-hydroxychromone (1 mmol) and 0.660 g of 1-bromodecane (3 mmol) are added to the mixture. For the phase transfer catalyst, 0.05 g of tetrabutyl ammonium hydrogen sulfate is added. The mixture is stirred under reflux for 3 h at 120? C. and the organic phase is recovered by decanting, washed with distilled water, dried with Na.sub.2SO.sub.4 and then evaporated. The oily mixture is purified by extraction by liquid-liquid partitioning (hexane and distilled water). The pure product is obtained in the form of a white solid (MP=45? C.) with a yield equal to 66%.

Example 4ter: Synthesis of 7-(2-ethyl)hexyloxychromone

[0081] ##STR00011##

[0082] 10 ml of toluene and 0.691 g of K.sub.2CO.sub.3 (5 mmol), are added to a 50 ml three-neck reflux reactor equipped with a magnetic stirrer and a thermometer, then 0.2 g of 7-hydroxychromone (1.2 mmol) and 0.580 g of 1-bromo-2-ethylhexane (3 mmol) are added to the mixture. For the phase transfer catalyst, 0.02 g of tetrabutyl ammonium hydrogen sulfate is added. The mixture is stirred under reflux for 6 h at 120? C. and the organic phase is recovered by decanting, washed with distilled water, dried with Na.sub.2SO.sub.4 and then evaporated. The crude mixture is purified by column chromatography with silica gel (eluent: hexane/ethyl acetate 98/2). The pure product is obtained in the form of a yellow oil with a yield equal to 65%.

CHEMICAL ANALYSIS

[0083] The RMN .sup.1H and .sup.13C spectra of the synthesized products are obtained with a BRUKER spectrometer.

[0084] An ATAGO POLAX-D polarimeter is used for determining the optical rotations of chiral products with a 2 dm observer tube. The products are diluted in 0.2% ethanol.

EVALUATION OF THE REPELLENT AND/OR ATTENUATING EFFECT OF CHROMONE ETHERS IN A TUNNEL OLFACTOMETER

[0085] The tunnel olfactometer is a 1 m long glass parallelepiped with a 5?5 cm side. The tube is equipped with 3 openings: two on each side, one for feeding in the paper impregnated with the product to be tested, and the other for the paper containing a control. The opening in the middle is for feeding in mosquitoes. Both ends of the tube are closed by covers.

[0086] The olfactometer is divided into three compartments or zones: [0087] a neutral zone in the middle; [0088] a test or treated area which is on the side of depositing the product; and [0089] a control area which is located on the side of depositing the control.

[0090] For each test, 15 Aedes albopictus females (aged 5 to 12 days) are fed into the neutral zone of the tunnel olfactometer. Mosquitoes are kept for 10 minutes for a time of adaptation. Papers impregnated and dried with a solution of product in ethanol and pure ethanol as a reference are fed in, then the barriers are opened to allow mosquitoes to circulate freely inside the tube. Three test repetitions were carried out for each product. A repetition lasts 20 minutes and the results observed were recorded every 5 minutes.

[0091] The values measured are the activity index and the repulsion index. The activity index (Al) describes the percentage of mosquitoes in the control zone (T) and in the treated zone (P) with respect to the total number of mosquitoes tested. Said value should be greater than 30% for the test to be considered significant.

[0092] The repulsion index (RI) represents the percentage of the difference in the number of mosquitoes in the control part and in the treated part divided by the sum of the two values. A negative value of the parameter (RI) indicates an attractant activity (kairomone index. KI) of the product tested.

[00001]$\begin{array}{cc}\mathrm{AI}=\left(\frac{T+P}{15}\right)?100& \mathrm{RI}=\left(\frac{T-P}{T+P}\right)\end{array}?100$ [0093] Al: Activity index [0094] RI: Repulsion index [0095] T: Number of mosquitoes in the control area [0096] P: Number of mosquitoes in the treated area

RESULTS

Synthesis of Chromone Derivatives

1. Synthesis by Phase Transfer Catalysis

[0097] Five products were synthesized as a function of the length of the alkyl chain: 7-sec-butoxychromone, 7-sec-pentoxychromone, 7-sec-nonyloxychromone, 7-isopropyloxychromone and 7-decyloxychromone. The results obtained are presented in Table 1.

TABLE-US-00001 TABLE 1 Results obtained from the synthesis of non-chiral chromone ethers by the phase transfer catalysis reaction Input Halogenoalkane Product obtained Pure yield Appearance 1 CPT 2-bromobutane 7-sec-butoxychromone .sup.73% Yellow oil 2 CPT 2-bromopentane 7-sec-pentoxychromone 33.1% Yellow oil 3 CPT 2-bromononane 7-sec-nonyloxychromone 35.2% Yellow oil 4 CPT 2-bromopropane 7-isopropyloxychromone 29.4% White solid 5 CPT 1-bromodecane 7-n-decyloxychromone .sup.66% Yellow solid

2. Synthesis by the Mitsunobu Reaction

[0098] Four enantiomers were synthesized: R-(?)-sec-butoxychromone, S-(+)-sec-butoxychromone, R-(?)-sec-pentoxychromone and S-(+)-sec-pentoxychromone. Table 2 shows the results obtained during the synthesis reactions.

TABLE-US-00002 TABLE 2 Results obtained from the synthesis of chiral products by the Mitsunobu reaction Optical rotation Chiral (0.2% in Pure Input alcohol Product obtained EtOH) yield Appearance 5 M (S) R-(?)-sec- ?35 52.6% Pale yellow butan- butoxychromone oil 2-ol 6 M (R) S-(+)-sec- +35 .sup.53% Pale pink oil butan- butoxychromone 2-ol 7 M (R) R-(?)-sec- ?22.5 63.3% Pale pink oil pentan- pentoxychromone 2-ol 8 M (S) S-(+)-sec- +22.5 42.4% Pale pink oil pentan- pentoxychromone 2-ol

CHEMICAL ANALYSIS OF PRODUCTS BY NUCLEAR MAGNETIC SPECTROMETRY (NMR)

Racemic 7-sec-butoxychromone (1CPT)

[0099] RMN .sup.1H (300 MHZ) in CDCl.sub.3: 8.11 (1H, d, H.sub.5), 7.77 (1H, d, H.sub.2), 6.96 (1H, dd, H.sub.6), 6.82 (1H, s, H.sub.8), 6.26 (1H, d, H.sub.3), 4.41 (1H, m, H.sub.11), 1.77 (2H, m, H.sub.13), 1.36 (3H, d, H.sub.12), 1 (3H, t, H.sub.14)

RMN.sup.13C in CDCl.sub.3: 177.05, 162.90, 158.31, 154.83, 127.18, 118.40, 115.49, 112.83, 101.82, 75.82, 28.99, 9.68

##STR00012##

[0100] Yield=73% (pale yellow oil) 7-sec-pentoxychromone (2CPT) RMN .sup.1H (300 MHZ) in CDCl.sub.3: 8.13 (1H, d, H.sub.5), 7.75 (1H, d, H.sub.2), 6.9 (1H, DD, H.sub.6), 6.8 (1H, S, H.sub.8), 6.28 (1H, d, H.sub.3), 4.5 (1H, m, H.sub.11), 1.75 (2H, m, H 13), 1.6 (3H, D, H.sub.12), 1.38 (2H, M, H.sub.14), 0.90 (3H, t, H.sub.15)

[0101] RMN .sup.13C in CDCl.sub.3: 177.03, 162.90, 158.31, 154.79, 127.19, 118.40, 115.45, 112.84, 101.75, 74.42, 38.31, 19.44, 18.64, 13.95

##STR00013##

Yield=33.1% (pale yellow oil)
7-sec-nonyloxychromone (3CPT)

[0102] RMN .sup.1H (300 MHZ) in CDCl.sub.3: : 8.09 (1H, d, H.sub.5), 7.75 (1H, d, H.sub.2), 6.93 (1H, dd, H.sub.6), 6.8 (1H, s, H.sub.8), 6.28 (1H, d, H.sub.3), 4.46 (1H, m, H.sub.11), 1.76 (2H, m, H.sub.13), 1.62 (3H, d, H.sub.12), 1.41 (2H, m, H.sub.18), 1.34 (2H, t, H.sub.17), 1.34 (2H, t, H.sub.16), 1.28 (2H, t, H.sub.15), 1.28 (2H, t, H.sub.14), 0.87 (3H, t, H.sub.19) RMN.sup.13C in CDCl.sub.3: 177, 162.88, 158.30, 154.77, 127.18, 118.40, 115.44, 112.84, 101.77, 74.69, 36.18, 31.75, 29.46, 29.18, 25.40, 22.61, 19.45, 14.05

##STR00014##

Yield=35.2% (pale yellow oil)
7-isopropyloxychromone (4CPT)

[0103] RMN .sup.1H (300 MHZ) in CDCl.sub.3:8.09 (1H, d, H.sub.5), 7.76 (1H, d, H.sub.2), 6.93 (1H, dd, H.sub.6), 6.8 (1H, s, H.sub.8), 6.26 (1H, d, H.sub.3), 4.64 (1H, m, H.sub.11), 1.35 (3H, d, H.sub.12), 1.35 (3H, d, H.sub.13),

[0104] RMN.sup.13C in CDCl.sub.3: 176.98, 162.52, 158.27, 154.77, 127.15, 118.43, 115.43, 112.84, 101.81, 70.73, 21.77

##STR00015##

Yield=29.4% (White solid)
7-decyloxychromone

[0105] RMN .sup.1H (300 MHZ) in CDCl.sub.3: 8.02 (1H, d, H.sub.5), 7.68 (1H, d, H.sub.2), 6.89 (1H, dd, H.sub.6), 6.75 (1H, d, H.sub.8), 6.20 (1H, d, H 3), 3.87-3.85 (2H, d, H.sub.1), 1.72 (1H, m, H.sub.12), 1.49 (2H, m, H.sub.13), 1.39(2H, m, H.sub.17), 1.26 (2H, m, H.sub.16), 1.19 (2H, m, H.sub.15), 0.90(3H, m, H.sub.14), 0.85 (3H, m, H.sub.18),

[0106] RMN .sup.13C in CDCl.sub.3: 177.98 (C.sub.4), 164.24 (C.sub.7), 158.49 (C.sub.10), 155.60 (C.sub.2), 126.79 (C.sub.5), 118.08 (C.sub.9), 115.32 (C.sub.3), 112.34 (C.sub.6), 100.78 (C.sub.8), 71.21 (C.sub.11), 39.15 (C.sub.12), 30.36 (C.sub.15), 28.95 (C.sub.16), 23.72 (C.sub.13), 22.88 (C.sub.17), 13.83 (C.sub.18), 10.88 (C.sub.14)

7-(2-ethyl)hexyloxychromone

[0107] RMN .sup.1H (300 MHZ) in CDCl.sub.3: 8.03 (1H, d, H.sub.5), 7.68 (1H, d, H.sub.2), 6.84 (1H, dd, H.sub.6), 6.75 (1H, d, Ha), 6.20 (1H, d, H.sub.3), 3.87-3.85 (2H, d, H.sub.11), 1.72 (1H, m, H.sub.12), 1.49 (2H, m, H.sub.13), 1.39(2H, m, H.sub.17), 1.26 (2H, m, H.sub.16), 1.19 (2H, m, H.sub.15), 0.90(3H, m, H.sub.14), 0.85 (3H, m, H.sub.18),

[0108] RMN .sup.13C in CDCl.sub.3: 177.98 (C.sub.4), 164.24 (C.sub.7), 158.49 (C.sub.10), 155.60 (C.sub.2), 126.79 (C.sub.5), 118.08 (C.sub.9), 115.32 (C.sub.3), 112.34 (C.sub.6), 100.78 (C.sub.8), 71.21 (C.sub.11), 39.15 (C.sub.12), 30.36 (C.sub.15), 28.95 (C.sub.16), 23.72 (C.sub.13), 22.88 (C.sub.17), 13.83 (C.sub.18), 10.88 (C.sub.14)

##STR00016##

EVALUATION OF THE REPELLENT AND/OR ATTENUATING EFFECT OF CHROMONE ETHERS IN A TUNNEL OLFACTOMETER

Chromone Derivatives Having Repellent Properties Against Aedes albopictus

Example 9: Evaluation of Racemic 7-sec-butoxychromone (1CPT)

[0109] The results obtained for the evaluation of the repellent or attractant activity against Aedes albopictus with the 7-sec-butoxychromone compound racemate are described in Table 3 for doses of products corresponding to 5, 10, 30 and 60 mg/ml.

TABLE-US-00003 TABLE 3 Comparison by t-test of the means of the number of mosquitoes in the two zones: control and treated. Activity index and repulsion index for 7-sec-butoxychromone. Dose Product Control (mg/ml) (?SD) (?SD) t p-value AI (%) RI (%) 5 3.3 ? 0.1 7.3 ? 0.4 ?12.8 0.0002 71.1 37.6 10 3.6 ? 0.4 7.2 ? 0.9 ?4.52 0.01 71.8 37.9 30 3.4 ? 0.9 8.3 ? 0.5 ?5.43 0.006 78 56.1 60 1.8 ? 0.2 11.8 ? 0.7 ?16.5 <0.0001 90.6 72.9

Example 10: Evaluation of R-(?)-sec-butoxychromone (5M)

[0110] The results obtained for the evaluation of the repellent or attractant activity against Aedes albopictus with the racemic compound 7-sec-butoxychromone are described in Table 4 for doses of products corresponding to 5, 10, 30 and 60 mg/ml.

TABLE-US-00004 TABLE 4 Comparison by t-test of the means of the number of mosquitoes in the two zones: control and treated. Activity index and repulsion index for R-(?)-sec-butoxychromone. Dose Treated Control (mg/ml) (?SD) (?SD) t p-value AI (%) RI (%) 5 3.1 ? 0.1 9.5 ? 0.3 ?25.12 <0.0001 84 51.3 10 2.3 ? 0.7 .sup.11 ? 0.3 ?16.4 <0.0001 88.9 65.6 30 1.4 ? 0.1 12.4 ? 0.1 ?93.3 <0.0001 92.2 79.5 60 1.6 ? 0.2 12.2 ? 0.1 ?66.7 <0.0001 92 76.6

Example 11: Evaluation of S-(+)-sec-butoxychromone (6M)

[0111] The results obtained for the evaluation of the repellent or attractant activity against Aedes albopictus with the racemic compound 7-sec-butoxychromone are described in Table 5 for doses of products corresponding to 5, 10, 30 and 60 mg/ml.

TABLE-US-00005 TABLE 5 Comparison by t-test of the means of the number of mosquitoes in the two zones: control and treated. Activity index and repulsion index for S-(+)-sec-butoxychromone. Dose Treated Control (mg/ml) (?SD) (?SD) t p-value AI (%) RI (%) 5 9.0 ? 0.2 4.8 ? 0.5 10.4 0.0004 91.7 ?31.2 10 8.9 ? 1.1 4.2 ? 0.9 4.03 0.016 87.2 ?35.8 30 3.3 ? 0.2 9.3 ? 0.8 ?8.8 0.001 83.3 47.9 60 2.0 ? 0.0 11.4 ? 0.8 ?15.6 <0.0001 89.4 70.5

[0112] Activity indices are very high >70% indicating that the results are reliable. The racemic compound and the compound (R) are repellent at any dose. The compound (S) is attractant at low doses and repellent at high doses. Such phenomenon of inversion of the effect has already been observed on some coumarins.

[0113] It is noted that the racemic compound has an effect corresponding substantially to the mean of the effects of the two enantiomers.

Example 12: Comparison of (R) 7-sec-butoxychromone with Picaridin and DEET

[0114] The repellent properties of the (R) 7-sec-butoxychromone are now compared with same of known repellents at equivalent doses of 10 and 30 mg/ml; it is observed that the new repellent is as effective and more effective than Picaridin and DEET, which are considered to be the most effective products on the market.

TABLE-US-00006 TABLE 6 Comparison of the effects of (R) 7-sec- butoxychromone with DEET and picaridin. Repulsion Repulsion Repulsion index 5 mg index 10 mg index 30 mg deposition deposition deposition (R) 7-sec- .sup.51% 65.6% 79.5% butoxychromone DEET 55.5% 60.4% 59.1% Picaridin 42.6% 49.6% 59.7%
Chromone Derivatives Having Attractant Properties Towards Aedes albopictus

[0115] It is equally interesting to obtain attractant products for harmful insects because same can be used for the manufacture of selective and effective traps for dangerous insects. Some substituted chromones have shown attractant activities.

[0116] The syntheses of such compounds are carried out according to the same methods as for the 7-sec-butoxychromones: by phase transfer catalysis for the racemic compound and by Mitsunobu reaction for the enantiomers R and S.

Example 13: Evaluation of racemic 7-sec-pentoxychromone or (+/?) (2CPT)

[0117] The results obtained for the evaluation of the attractant activity towards Aedes albopictus with the racemic compound 7-sec-pentoxychromone are described in Table 7 for doses of products corresponding to 1, 5, 10 and 30 mg/ml.

TABLE-US-00007 TABLE 7 Comparison by t-test of the means of the number of mosquitoes in the two zones: control and treated. Activity index and repulsion index for 7-sec-pentoxychromone. Dose Treated Control (mg/ml) (?SD) (?SD) t p-value AI (%) KI (%) 1 9.3 ? 0.7 3.5 ? 0.5 8.49 0.001 85 ?45.6 5 9.5 ? 0.2 2.5 ? 0.3 23.5 <0.0001 80.1 ?59.2 10 9.8 ? 1.1 3.4 ? 0.4 6.8 0.002 88.3 ?47.9 30 8.7 ? 0.4 4.8 ? 0.4 8.5 0.001 90 ?28.6

Example 14: Evaluation of (R) 7-sec-pentoxychromone (6M)

[0118] The results obtained for the evaluation of the attractant activity towards Aedes albopictus with the racemic compound (R) 7-sec-pentoxychromone are described in Table 8 for doses of products corresponding to 1, 5, 10 and 30 mg/ml.

TABLE-US-00008 TABLE 8 Comparison by t-test of the means of the number of mosquitoes in the two zones: control and treated. Activity index and repulsion index for R-(?)-sec-pentoxychromone Dose Treated Control (mg/ml) (?SD) (?SD) t p-value AI (%) KI (%) 1 8.6 ? 0.2 5.3 ? 0.3 10 0.001 92.2 ?24.3 5 10.8 ? 0.6 2.2 ? 0.4 14.7 0.001 86.7 ?66.6 10 8.6 ? 0.1 3.6 ? 0.4 16 <0.0001 81.1 ?47.1 30 6.9 ? 0.3 6.6 ? 0.4 0.89 0.42 90 ?2.8

Example 15: Evaluation of (S) 7-sec-pentoxychromone (7M)

[0119] The results obtained for the evaluation of the attractant activity towards Aedes albopictus with the racemic compound (S) 7-sec-pentoxychromone are described in Table 9 for doses of products corresponding to 1, 5, 10 and 30 mg/ml.

TABLE-US-00009 TABLE 9 Comparison by t-test of the means of the number of mosquitoes in the two zones: control and treated. Activity index and repulsion index for S-(+)-sec-pentoxychromone. Dose Treated Control (mg/ml) (?SD) (?SD) t p-value AI (%) KI (%) 1 10.3 ? 0.7 3.8 ? 0.3 10.3 0.0004 93.3 ?46.3 5 9.5 ? 0.7 3.1 ? 1.2 5.9 0.004 83.9 ?52.4 10 8.4 ? 0.1 5.8 ? 0.2 13.8 0.0001 95 ?18.2 30 6.5 ? 0.7 5.2 ? 0.3 2.15 0.09 77.8 ?10.7

[0120] The two enantiomers R, S and the racemate of 7-pentoxychromone are attractant for Aedes albopictus. The racemic effect appears to cumulate the effects of the 2 pure enantiomers.

[0121] A bell curve is obtained like the curve obtained with known kairomones (isovaleric acid, 1-octen-3-ol) (Andrianjafy et al. 2017).

Example 16: Evaluation of 7-sec-nonyloxychromone (3CPT)

[0122] The 7-sec-nonyloxychromone is evaluated in a tunnel olfactometer for doses of 2 to 30 mg/ml. The results are shown in Table 10.

TABLE-US-00010 TABLE 10 Comparison by t-test of the means of the number of mosquitoes in the two zones: control and treated. Activity index and repulsion index for 7-sec-nonyloxychromone. Dose Treated Control (mg/ml) (?SD) (?SD) t p-value AI (%) KI (%) 0.1 11.2 ? 0.6 2.5 ? 0.2 19.6 <0.0001 91.1 ?63.5 2 12.3 ? 0.0 1.4 ? 0.4 29.8 <0.0001 91.1 ?79.8 5 10.4 ? 0.1 2.2 ? 0.3 35 <0.0001 83.9 ?65.8 10 11.3 ? 0.0 2.5 ? 0.5 15.1 0.0001 91.7 ?63.6 30 8.4 ? 0.2 4.8 ? 0.4 10.4 0.0004 88.3 ?27.1

[0123] As for the 7-sec-pentoxychromone, a bell-shaped curve is obtained with a maximum value of KI close to 80% for a dose of 2 mg/ml. The attractant activity stays above 65% up to 10 mg/ml. Even at high doses (30 mg/ml), 7-nonyloxychromone stays attractant. And taking into account that the vapor pressure of the product should be low due to the high molecular mass thereof, the effectiveness will be long-lasting.

Example 17: Evaluation of the Attractant Properties of 7-n-Decyloxychromone for Aedes albopictus

[0124] The results obtained for the evaluation of the attractant activity with regard to Aedes albopictus with the 7-n-decyloxychromone compound racemate are presented in Table 11 for the product dose corresponding to 10 mg/ml.

TABLE-US-00011 Dose Treated Control AI KI (?SD) (mg/ml) (?SD) (?SD) (%) (%) 10 8.8 ? 0.9 3.9 ? 0.3 85 ?37.8 ? 5.2

[0125] 7-n-decyloxychromone has an attractant effect equivalent to that of 7-sec-nonyloxychromone but has the advantage of being much less expensive (inexpensive and bio-sourced primary halide).

Example 18: Comparison of 7-sec-pentoxychromone and 7-sec-nonyloxychromone with octen-3-ol

[0126] The attractant properties of the racemic 7-sec-pentoxychromone and 7-sec-nonyloxychromone are now compared with octen-3-ol.

TABLE-US-00012 TABLE 12 Comparison of 7-sec-pentoxychromone and 7-sec-nonyloxychromone with octen-3-ol Repulsion Repulsion Repulsion index 5 mg index 10 mg index 30 mg deposition deposition deposition 7-sec- ?59.2% ?47.8% ?28.7% pentoxychromone 7-sec- ?65.8% ?63.7% ?27.1% nonyloxychromone Octen-3-ol ?41.7% ?54.7% ?61.6%

[0127] The analysis of the results on alkoxy chromones shows an attractant activity equivalent to same of octenol. However, it is known that octenol has a high vapor pressure unlike alkoxy chromones which could thus have a longer lasting effect.

[0128] The results hereinabove show that the compounds of the invention have significant attractant or repellent properties on Aedes albopictus depending on the structure of the substituent (chain length, stereochemistry, etc.).

[0129] Unlike the hydroxy or methoxy groups, the 2-butoxy groups lead to significant repellent effects depending on the stereochemistry at the 2-butoxy chain. The repellent effect of the enantiomer R is as significant as DEET and picaridin at identical doses.

[0130] Secondary alkoxy groups higher than butyl (pentyl and nonyl) lead to products of high molecular masses and having attractant properties. The attractant effect also depends on the stereochemistry of the 2 alkoxy group. Similarly, chromones with long-chain primary alkoxy substituents (e.g. decyl) have a very high attractant effect. And comparing with the most used attractant (octenol) with the same doses, alkoxychromones have a higher attractant effect.

[0131] With 7-butoxychromones, it is possible to formulate protective sprays, creams and textiles containing the products alone or mixed with other repellents.

[0132] With attractant products, traps (mechanical, glue-impregnated materials, etc.) baited with the products alone or mixed with other attractants are used for mass trapping of mosquitoes and other blood-sucking insects.

[0133] Such products derived from 7-hydroxychromone have the advantage of having high molecular masses allowing them to have a significant long-lasting effectiveness in terms of repulsion and attraction with regard to Aedes albopictus.

Example 19: Evaluation of Repellent Properties in a Cage Olfactometer

[0134] The long-term evaluation (24 hours) is carried out in a cage system (1 m?1 m?2 m) equipped with two traps, one baited and the other is the control. The tests are carried out in parallel in two experimental rooms (35 m?2 m?2 m) which are maintained at 25+/?5? C., relative humidity 60%, for a photoperiod of 12 h (Andrianjafy et al. 2017). In the large cage is placed a small cage (35 cm?35 cm?35 cm) where the mosquitoes are placed before dropping, as well as the two traps (with the test product and the control). The traps are separated by 1.45 m. For the tests, 100 ?l of the solutions are deposited on filter papers using ethanol as solvent. The ethanol is evaporated before feeding into the trap. A source of CO.sub.2 is placed outside the cage, so as to increase the activity of mosquitoes. 25 females of Aedes albopictus are used for each test which lasts 24 hours and starts at 9 am. Six replications are carried out for each dose of a product. [0135] Test over 24 h in a cage for the repellent properties of (R) 7-sec-butoxychromone. [0136] Test over a period of 24 h in a cage for the attractant properties of (RS) 7-sec-nonyloxychromone. [0137] > In natura test with a sentinel trap of the racemic (RS) 7-sec-nonyloxychromone. [0138] Test of synergistic effects for the attractant properties of (RS) 7-sec-nonyloxychromone and 4-hydroxycoumarin

Example 20: Tests with Traps

[0139] In natura tests of a compound or mixture according to the invention are carried out with the sentinel trap BG (Biogent?) and the light trap CDC, for catching Aedes sp. And Anopheles sp., respectively. The results obtained are conclusive.

Example 21: Evaluation of the Combination of a Compound of the Invention with a Chromone Compound

[0140] It is possible to combine a chromone compound with other compounds of different structure. For example, 4-hydroxy-coumarin is a selective attractant of Aedes albopictus, the use of a 50/50 mixture of 4-hydroxy-coumarin and 7-(2nonyloxy)-chromone has a higher attractant power than the two compounds used separately.

[0141] 7-nonyloxychromone has an attractant effect at low dose (or quantity) with a kairomone index KI-57%. A significant decrease in said effect is observed from the 10 mg dose onwards. Similarly, at low doses, 4-hydroxycoumarin also has an attractant effect with a KI on the order of 40%. A 10% increase in attraction was recorded at higher doses (10 and 30 mg).

[0142] A synergistic effect is observed between 4-hydroxycoumarin and 7-nonyloxychromone (cf. FIG. 1). Such effect is generally little dependent on concentration, unlike pure products, with a KI>55% for all doses tested, which is an important practical advantage. We assume that 4-hydroxycoumarin (appearance: solid) stabilizes 7-nonyloxychromone (appearance: liquid) in order to generate a greater attractant effect.

Example 22: Evaluation of 7-n-decyloxychromone and 7-(2-ethyl)hexyloxychromone

[0143] The evaluation of the attractant properties of 7-n-decyloxychromone and 7-(2-ethyl)hexyloxychromone was carried out in a tunnel olfactometer by varying the quantity of product to be tested, according to the protocol described hereinabove.

[0144] FIGS. 2 and 3 represent the results thereby obtained.