WO2016097496A1

WO2016097496A1 - Use of evodone derivatives as repellent, novel evodone derivatives and synthesis process

Info

Publication number: WO2016097496A1
Application number: PCT/FR2015/000182
Authority: WO
Inventors: Sophie Lavoine-Hanneguelle; Marina Humbert; Jean-Philippe PIERRAT
Original assignee: Charabot
Priority date: 2014-12-16
Filing date: 2015-09-16
Publication date: 2016-06-23
Also published as: FR3029739A1; FR3029739B1

Abstract

The invention relates to the use of an evodone derivative as an active agent intended for repelling insects, in particular mosquitoes and, more particularly, mosquitoes of the species Aedes aegypti, Aedes albopictus and Culex pipiens. The invention is characterized in that the evodone derivative is of general formula (I): in which R1 and R2 are identical or different, and are -H or a linear alkyl group having from 1 to 3 carbon atoms, and X is =O or -OAc, with the exclusion of evodone (with R1 or R2 = -H, R1 or R2 = -CH₃, R1 being different from R2, and X = =O). The invention also relates to novel evodone derivatives of general formula (I) in which R1 and R2 are identical and are -H, and X is -OAc; R1 and R2 are different and R1 or R2 is -H, R1 or R2 is -CH₂CH₃, and X is =O or -OAc; R1 and R2 are different and R1 or R2 is -H, R1 or R2 is -(CH₂)₂CH₃, and X is =O or -OAc; and R1 and R2 are identical and are -CH₃, and X is -OAc, and also to a process for the synthesis of evodyl acetate without methyl (with R1=R2= -H and X = -OAc), to a composition comprising an effective amount of a novel evodone derivative, and to the use of such a composition for repelling insects, in particular mosquitoes and, more particularly, mosquitoes of the species Aedes aegypti, Aedes albopictus and Culex pipiens.

Description

USE OF EVODONE DERIVATIVES AS REPELLENT, NEW EVODONE DERIVATIVES AND SYNTHESIS METHOD

The invention relates to the use of an evodone derivative for repelling insects, in particular mosquitoes and, more particularly, mosquitoes of the species Aedes aegypti, Aedes albopictus and Culex pipiens.

Mosquitoes are attracted by the C0 ₂ released by humans, a substance they can detect more than 6 meters away. Then, to ensure that the C0 ₂ does not come from a car, an industrial chimney or a plant, the mosquito identifies secondary attractants such as heat, lactic acid or water vapor which are produced by humans during sweating and muscle activity and are released into the air by breathing and by the skin. Not only are mosquitoes uncomfortable, but their bites can cause severe itching and even a severe allergic reaction in some people. Some mosquitoes can also transmit serious diseases, such as malaria.

There are two main categories of "anti-mosquito" products: repellents that are intended to keep them away, and insecticides whose mission is to kill them.

However, insecticides use active substances that are harmful to health and should therefore be used very moderately.

Therefore, it is preferred the use of repellents, synthetic or natural chemicals, capable of causing negative chemotropism in pests such as mosquitoes. Repellents are also called insect repellents or "anti-mosquito". They do not usually kill insects, but keep them away. Repellents cause the insect to alter the locating line, diverting it from its potential target.

The family of repellents mainly includes skin repellents that apply to the skin, but also some household repellents to install in the home. If the references of repellents are numerous, the active substances used are less so. DEET (N, -diethyl-3-methylbenzamide), IR 3535 (or ethyl-butyl-acetylaminopropionate), icaridine, plant extracts such as pyrethrum, or an essential oil such as lemongrass.

The most effective products are based on DEET, at 30 or 50%. They are particularly recommended in all areas where mosquitoes may transmit dengue, chikungunya or malaria.

However, DEET has an unpleasant and persistent odor, has a greasy consistency on the skin, is irritating to the eyes and mucous membranes, and also has an aggressive effect on certain plastics (watches, glasses). Also, even if it has been re-registered by the Environmental Protection Agency (EPA), it can be toxic at a concentration greater than 30%, especially in children under 12, the pregnant woman and the nursing woman. In addition, its toxicity is related to its skin permeability, DEET being absorbed at 30% of its dose through the skin, and its storage capacity at the cutaneous level, the urinary excretion being 10 to 15% of its dose. it may not be advisable to use it at a concentration higher than 30%.

However, a concentration of less than 30% in DEET is not very effective against mosquitoes in people over 12, the active concentration being 30 to 50%.

In addition, studies have shown that DEET may increase the concentration of acetylcholine in the synaptic cleft by inhibiting acetylcholinesterase (Vincent Corbel et _al.. "Evidence for inhibition of cholinesterases in insect and mammalian nervous sytem by.the insect repellent DEET "BMC Biology, August 2009). Acetylcholinesterase is a key enzyme in the transmission of nerve impulses. Once the information is transmitted, the chemical mediator 1 acetylcholine is degraded. Inhibition of acetylcholinesterase results in an accumulation of acetylcholine which maintains the permanent transmission of nerve impulses that can cause muscle tétanies.

Although the serious side effects remain exceptional and are often related to overdose or overuse, this finding raises the problem of the safe use of DEET and raises the hypothesis that DEET poses a risk of nerve toxicity to the patient. 'human race.

IR3535 has an active concentration between 20 and 35%. His acute and chronic toxicities are low. According to the EPA, with regard to its use for 20 years in Europe without significant adverse effects, the risk is considered minimal to zero.

However, the effectiveness of IR 3535 depends on the composition of the finished product: a repellent that contains 20% IR 3535 can be very effective, another that contains 25% may not be.

Icaridine is also known which is of average efficiency.

Finally, in general, it is known that natural herbal products, whether extracts, or essential oils such as lemongrass, have a lower repellency than synthetic products. In addition, such natural products may have a strong odor, annoying or even unpleasant, for example for pyrethrum.

Among domestic repellents, there are often long-lasting platelets whose effectiveness is however very low.

Electrical diffusers that plug into an outlet are sometimes effective, sometimes less, depending on their composition, even though most appear to use pyrethroids as an insecticide.

The spirals to be burned which also contain a molecule of the pyrethroid family are quite effective but they must be used exclusively outside and for a good protection, it is necessary to be in the immediate vicinity. The effectiveness of a repellent therefore depends on its concentration, the target insect, the excipient (volatility, prolonged release ...) but also many other environmental factors.

Manufacturers are optimistic, and often announce a repulsive efficacy of 8 hours, sometimes more. In reality, it is always less and it varies depending on the individual and the context (rain, wind, skin type, sweat ...). When a product is good, the average duration of protection measured during laboratory tests is rather of the order of 4 hours.

In general, it is of interest to find a natural or synthetic repellent, non-irritating and non-toxic so that it can advantageously be administered topically to the skin, as effective for example as DEET, and not presenting therefore not the undesirable effects of the repellents according to the prior art.

For this purpose, the Applicant has already developed and describes (FR2942938) extracts derived from Euodia suaveolens Scheff, containing no linalool, alpha-pinene, evodiamine and / or rutaecarpine or, at least, not in an effective amount, having a remarkable repellent activity against insects, in particular mosquitoes and, more particularly, European / Mediterranean mosquitoes of the Aedes aegypti species. The Applicant has also more particularly identified the active agent, namely evodone, responsible for such repellent activity. Evodone and such extracts including evodone thus provide a new response for insect protection, while respecting the environment and human health.

However, it is harder to grow the plant

Euodia suaveolens Scheff for extracting an extract comprising evodone for use as a repellent. In addition, such a process is subject to environmental constraints due to the cultivation of this plant.

Evodone can alternatively be synthesized chemically. Nevertheless, it is relatively expensive to use industrially known synthesis processes of evodone due in particular to the constraints related to at the choice of the raw materials and at each stage to obtain 99% pure evodone (racemic mixture) (A. Srikrisma and G. Veera Raghava Sharma, "A simple synthesis (+/-) evodone", Indian Journal of Chemistry 1989, p.852).

Considering the above, a problem to be solved by the invention is to obtain a new natural or synthetic repellent agent, non-toxic and non-irritating, easy to implement, able to repel insects as effectively as insect repellent natural or chemical known, economically interesting by providing an optimized cost / efficiency ratio and which does not have the adverse effects observed in the prior art.

Thus, in order to satisfy this need, the Applicant has discovered, unexpectedly, that evodone derivatives, which are easier and less costly to use, exhibit good repellency against insects, in particular mosquitoes and, more particularly, mosquitoes of the species Aedes aegypti, Aedes albopictus and Culex pipiens. Such compounds thus provide a new response for protection against insects, respecting the environment and human health, while significantly reducing the cost.

The invention therefore firstly relates to the use of an evodone derivative of general formula (I):

in which,

R1 and R2 are the same or different, and represent -H or a linear alkyl group of 1 to 3 carbon atoms, and X represents = 0 or -OAc, excluding evodone (with R1 or R2 = -H , RI or R2 = CH _3, RI is different from R2, and X = = 0) as an active agent to repel insects, especially mosquitoes and more particularly mosquitoes of the species Aedes aegypti, Aedes albopictus and Culex pipiens. In addition, the second object of the solution of the invention is an evodone derivative of general formula (I):

in which,

R1 and R2 are the same and represent -H, and X represents -OAc; RI and R2 are different and R2 is RI or -H, RI or R2 is -CH ₂ CH _3, and X is = 0 or -OAc; RI and R2 are different and RI or R2 is -H, RI or R2 represents - (CH ₂₎ ₂ CH _3, and X is = 0 or -OAc; and R1 and R2 are the same and represent -CH ₃ , and X is -OAc.

The third subject of the invention is also a process for the synthesis of evodyl acetate, without methyl (with R1 = R2 = -H and X = -OAc), characterized in that it comprises the following stages: cyclocondensation reaction of 1,3-cyclohexanedione in the presence of HOCH ₂ CO e and ZnCl ₂ to 3-methyl-β, 7-dihydro-1-benzofuran-4 (5H) -one at room temperature; - reduction of 3-methyl-6,7-dihydro-1-benzofuran-4 (5H) -one by addition of NaBH ₄ or by catalytic hydrogenation, then acetylation with acetic anhydride to obtain evodyl acetate without methyl; and - isolating evodyl acetate without methylation by vacuum distillation.

Finally, the solution of the ^'fourth invention provides a composition, characterized in that it comprises, as active agent repellent against insects, particularly against mosquitos and, more particularly, mosquitoes Aedes species aegypti, Aedes albopictus and Culex pipiens, an effective amount of a new derivative of évodone according to the invention, and fifth object the use of a composition according to the invention for repelling insects, in particular, mosquitoes and, more particularly, the mosquitoes of the species Aedes aegypti, Aedes albopictus and Culex pipiens. The invention and the advantages thereof will be better understood on reading the description and the non-limiting embodiments which follow.

In this description, unless otherwise specified, it is understood that, when a concentration range is given, it includes the upper and lower limits of said range, and the concentration is given by weight of the total weight of the composition.

The present invention relates to the use of an evodone derivative as an active agent for repelling insects, in particular mosquitoes and, more particularly, mosquitoes of the species Aedes aegypti, Aedes albopictus and Culex pipiens.

According to the invention, the evodone derivative used as an active agent for repelling insects, in particular mosquitoes and, more particularly, the mosquitoes of the species Aedes aegypti, Aedes albopictus and Culex pipiens has the general formula (I):

in which,

R1 and R2 are the same or different, and represent -H or. a linear alkyl group of 1 to 3 carbon atoms, and X is = 0 or -OAc, excluding the evodone (with RI or R2 = -H, RI or R2 = CH _3, RI is different from R2, and X = = 0).

Ac denotes the acetyl group of chemical formula COCH ₃ .

A linear alkyl group of 1 to 3 carbon atoms according to the invention denotes a methyl, ethyl or propyl group, preferably a methyl.

An evodone derivative according to the invention denotes a compound which has a chemical structure comparable to that of evodone and which differs, by replacement, addition and / or deletion, from one or more atoms or functional groups, more particularly by replacement. a atom or functional group at the groups R 1, R 2 and / or X. The evodone derivative according to the invention can be obtained by transformation of evodone, but is advantageously obtained by another synthetic route, easier and less expensive to implement.

The evodone derivative preferentially used according to the invention is 4-benzofuranol-4,5,6,7-tetrahydro-3, 6-dimethyl-4-acetate or evodyl acetate (with RI or R2 = -H, RI or R2 = CH _3, RI is different from R2, and X = -OAc), methyl 3--6, 7-dihydro-l-benzofuran-4 (5H) -one or demethylated evodone (evodone or without methyl) (with R1 = R2 = -H, and X = = 0), or evodyl acetate without methyl (with R1 = R2 = -H, and X = -OAc), even more preferentially evodone demethyl .

The derivatives can be used as repellents as such, advantageously at a concentration of between 0.1 and 25%, preferably 3% or 5%, even more preferentially 3%, in the presence of any cosmetically acceptable carrier such as solvent selected from, for example, ethanol, glycerine, triglycerides such as capric and / or caprylic acid triglycerides (Miglyol®). They can also be used in the formulation of more complex repellent compositions comprising more than 2 ingredients.

Among the evodone derivatives used according to the invention and falling within the scope of the general formula (I), some are known as such, as is evodone.

In particular, demethyl evodone or evodone without the methyl (with R1 = R2 = -H, and X = = 0) is registered with the Chemical Abstracts Service (CAS) database under the number 6906-61-2 and identified for example in the publication M. Aso et al. ("Furannulation strategy for synthesis of the naturally occuring fused 3-methylfurans: efficient synthesis of evodone and menthofuran and regioselective synthesis of maturone via a Lewis acid catalyzed Diels-Alder reactions." Some comments for its mechanistic aspects "J. Org. 1993); the évodyle acetate (with RI or R2 = -H, RI or R2 = CH _3, RI is different from R2, and X = -OAc) is registered under the CAS number 1241388-85-1 and identified in the publication Brophy et al. (Flavor and Fragrance, vol. 1, p.17-20, 1985); or else 3,6,6-trimethyl-6,7-dihydro-1-benzofuran-4 (5H) -one or dimethyl evodone (with R 1 = R 2 = -CH ₃ and X = = O) recorded under the number CAS 67808-95-1.

On the other hand, according to another object of the invention, new evodone derivatives, not described in the literature, have been discovered and synthesized by the Applicant. The new evodone derivatives according to the invention are of general formula (I):

in which,

R1 and R2 are the same and represent -H, and X represents -OAc;

RI and R2 are different and Rl or R2 is -H, RI or R2 is -CH ₂ CH _3, and X is = 0 or -OAc;

Rl and R2 are different and Rl or R2 is -H, Rl or R2 represents - (CH ₂₎ ₂ CH _3, and X is = 0 or -OAc; and

R 1 and R 2 are identical and represent -CH ₃ , and X represents -OAc.

Preferably, the evodone derivative according to the invention is evodyl acetate without methyl (with R1 = R2 = -H and X = -OAc).

Moreover, the evodone derivatives used according to the invention, and in particular the new evodone derivatives according to the invention, can be obtained at low cost, in particular for evodyl acetate without methyl. The cost / efficiency ratio is thus advantageous compared with evodone.

Another subject of the invention thus relates to the synthesis of evodyl acetate without methyl by a process advantageously implemented by the Applicant comprising the following steps:

- Cyclocondensation reaction of 1,3-cyclohexanedione in the presence of HOCH ₂ COMe and ZnCl ₂ to 3-methyl-6,7-dihydro-1-benzofuran-4 (5H) -one at room temperature;

reduction of 3-methyl-6,7-dihydro-1-benzofuran-4 (5H) -one by addition of NaBH ₄ or by catalytic hydrogenation, followed by acetylation with acetic anhydride to obtain evodyl acetate without methyl; and

- Isolation of evodyl acetate without methyl by vacuum distillation.

By using, for example, commercially available 1,3-cyclohexanedione as starting material, it is much more economically advantageous to synthesize evodone without methyl than evodone, the production costs being reduced by at least 50%. The cost / effectiveness ratio is thus substantially optimized compared to the evodone. In addition, evodone without methyl can be used as such especially as a repellent, or as a pivot for other syntheses and more particularly for the preparation of evodyl acetate without methyl.

For this purpose, Examples 1-3 below illustrate, in a nonlimiting manner, less expensive and easy-to-use procedures for the synthesis of evodone without methyl (Example 1, in which R 1 and R 2 are identical and represent -H, and X represents = 0) and evodyl acetate without methyl (Example 3, wherein R1 and R2 are the same and represent -H, and X represents -OAc) from 1,3-cyclohexanedione.

Example 1: Evodone (3-methyl-6,7-dihydro-1-benzofuran-4 (5H) -one) demethyl synthesis protocol from 1,3-cyclohexanedione In a 1 liter reactor, under nitrogen, are 59.56 g of anhydrous zinc chloride, 500 ml of toluene, and 78.63 g of hydroxy acetone were slowly added with vigorous stirring, keeping the temperature between 25 ° C and 30 ° C. 50g of 1-3- cyclQhexanedione are introduced into the reaction medium, then the medium is maintained 48h at 25 ° C. After stirring for 48 hours, two liquid phases are observed which decant perfectly; in the toluene phase resulting from the reaction medium, the toluene extractions are added to the aqueous phase. The toluene extracts are concentrated under vacuum and then hydrodistilled, then recrystallized from an ethanol / water mixture. 28.14 g of demethyl evodone (3-methyl-6,7-dihydro-1-benzofuran-4 (5H) -one) are thus obtained in the form of a white crystalline powder. The yield is 42%.

EXAMPLE 2 Protocol for Synthesis of Evodol (3-methyl-6,7-dihydro-1-benzofuran-4 (5H) -ol) from Demethyl Evodone (3-methyl-6,7-dihydro-1) benzofuran-4 (5H) -one) obtained according to Example 1

10 g of demethyl evodone (3-methyl-6,7-dihydro-1-benzofuran-4 (5H) -one) are dissolved in 40 ml of ethanol, the medium is heated to 50 ° C. On the medium are introduced 1.5 g of sodium borohydride in aqueous alkaline solution. The medium is neutralized with 2.8 g of glacial acetic acid and then concentrated under vacuum. The concentrate is taken up in 50 ml of toluene and 50 ml of water. The toluene phase is washed again with 50 ml of bicarbonate water. The toluene phase is concentrated under vacuum: 9 g of evodol (3-methyl-6,7-dihydro-1-benzofuran-4 (5H) -ol) in solid form are obtained. The yield is 88%. Example 3: Synthesis of acetate Protocol of évodyle without methyl (3- -methyl-6, 7-dihydro-1- -benzofurane- ^• 4 (5H) -acetate) from the évodol (3- methyl- -6, 7-dihydro-1-benzofuran ^■

4 (5H) -ol) obtained according to Example 2

10 g of evodol (3-methyl-6,7-dihydro-1-benzofuran-4 (5H) -ol) are dissolved in 50 ml of toluene and 7 g of triethylamine. On the medium is heated, under reflux, are introduced dropwise 7.1 g of acetic anhydride. The medium is maintained 2h at reflux. After verifying the disappearance of the raw material, the reaction medium is poured onto 200 ml of tap water; after decantation and neutralization with a solution of sodium bicarbonate, the toluene phase is concentrated and then distilled on a Vigreux assembly (vacuum 1 mb); 10.26 g of evodyl acetate are thus obtained without the methyl (3-methyl-6,7-dihydro-1-benzofuran-4 (5H) -acetate) being in the form of a viscous oil. The yield is 82%.

Likewise, Examples 4-6 below illustrate in a nonlimiting manner procedures that are less expensive and easy to implement from products commercially available for the synthesis of other evodone derivatives used according to the invention, and in particular new evodone derivatives according to the invention, in which R 1 and R 2 are identical and represent -CH ₃ , and X represents = O (example 4) or -OAc (example 6).

EXAMPLE 4 Synthesis Protocol of Dimethyl Evodone (3,6,6-Trimethyl-6,7-Dihydro-1-benzofuran-5H) -one from Dimedone (5,5-Dimethyl-1,3) -cyclohexanedione)

In a 1-liter reactor, under nitrogen, are introduced 66.32 g of anhydrous zinc chloride, 440 ml of toluene, then with vigorous stirring 87.85 g of hydroxyacetone, maintaining the temperature between 25 ° C and 30 ° C . On the reaction medium are introduced, maintaining the temperature between 25 ° C and 30 ° C, 70 g of dimedone. The medium is stirred for 48 hours. After 48 hours of stirring, the medium is decanted; the aqueous phase is extracted with 3 times 100 ml of toluene. The toluene phases are concentrated and hydrodistilled to obtain 27.93 g of dimethyl evodone (3,6,6-trimethyl-6,7-dihydro-1-benzofuran-4 (5H) -one) which is in the form of an oil. The yield is 31.4%.

EXAMPLE 5 Synthesis Protocol of Dimethyl Evodol (3,6,6-trimethyl-6,7-dihydro-1-benzofuran-4 (5H) -ol) from the dimethyl evodone (3,6,6-trimethyl-6,7-dihydro-1-benzofuran-4 (5H) -one) obtained according to Example 4

In a 250-ml reactor under nitrogen, 19.71 g of dimethyl-evodone (3,6,6-trimethyl-6,7-dihydro-1-benzofuran-4 (5H) -one) are introduced, which are dissolved in 50 ml of ethanol. The ethanolic solution of dimethyl evodone (3,6,6-trimethyl-6,7-dihydro-1-benzofuran-4 (5H) -one) is introduced into an alkaline solution of sodium borohydride (4 g of sodium hydrobromide; 0.1 g of 30% sodium hydroxide, 20 ml of tap water), at around 50 ° C. The medium is stirred for the night, in slow cooling. The medium is acidified with acetic acid, taken up after concentration, in 50 ml of toluene. The toluene solution is washed with water and then neutralized with a saturated solution of sodium bicarbonate and then concentrated in vacuo to obtain 18.23 g of dimethyl evodol (3,6,6-trimethyl-6,7-dihydro-1). benzofuran-4 (5H) -ol), which is in the form of a viscous oil. The yield is 91.5%.

EXAMPLE 6 Synthesis Protocol of Dimethyl Evodol Acetate (3,6,6'-Trimethyl-6,7-dihydro-1-benzofuran-4 (5H) -acetate) from Dimethyl Evodol (3, 6) 6-trimethyl-6,7-dihydro-1-benzofuran-4 (5H) -ol) obtained according to Example 5

13.23 g of dimethyl evodol (3,6,6-trimethyl-6,7-dihydro-1-benzofuran-4 (5H) -ol) are dissolved in a mixture of 100 ml of toluene and 8.92 g of triethylamine. . 9 g of acetic anhydride are refluxed on the previously prepared solution. Then the medium is poured on 200 ml of tap water. The toluene solution containing the acetate formed is neutralized with a saturated solution of sodium bicarbonate, concentrated and distilled on a Vigreux column to obtain 14.05 g of dimethyl acetate evodol (3,6,6-trimethyl-6). 7-dihydro-1-benzofuran-4 (5H) -acetate) which is in the form of an oil. The yield is 86%. With regard to the procedure advantageously carried out for the synthesis of the other novel evodone derivatives used as repellent according to the invention, in which R 1 and R 2 are different and R 1 or R 2 represents -H, R 1 or R 2 represents -CH ₂ CH ₃ and X is = 0 or -OAc, or Rl and R2 are different and Rl or R2 is -H, Rl or R2 represents - (CH ₂₎ ₂ CH _3, and X is = 0 or -OAc, it may be similar to that described in Examples 4 to 6, with the only difference that 5-ethyl-1,3-cyclohexanedione and 5-propyl-1,3-cyclohexanedione are used as starting material instead of dimedone (5). 5-dimethyl-1,3-cyclohexanedione).

The compounds synthesized and used according to the invention are in solid form (powder) or advantageously in liquid form, as shown in Table 1 below summarizing some properties of certain derivatives of 1 evodone.

Table 1:

Improvement of

Appearance process

Compound Chemical Name CAS Odor

physical report to

1 evodone

3,6-dimethyl-6,7-dihydro-anis-powder,

Evodone 529-63-5 - 1- white tarragon

benzofuran-4 (5H) -one

4- benzofuranol-

102275- 4,5,6,7-

Acetate 309 / liquid

tetrahydro-Aniseed, fresh liquid · evodyl 1241388-orange

3, 6-85-1

dimethyl-4-acetate

Evodone 3-methyl- without 6,7-dihydro-

6906-61- Menthol powder

methyl 1- cheaper

2 fresh white ethereal

(demethyl benzofuran-evodone) 4 (5H) -one

3-methyl-

Acetate

6, 7-dihydro-Menthol,

cheaper liquid evodyl,

1- carvone,

without the liquid jnne

benzofuran terpene

methyl

4 (5H) -acetate 3, 6, 6-

minty,

trimethyl-anisated,

Dimethyl 6,7-dihydro-67808- rising liquid with evodone liquid 1- 95-1

a side

benzofuran - floral fat

4 (5H) -one

3, 6, 6-trimethyl-

Phenolic Acetate,

6, 7-dihydro-liquid

mentholated dimethyl, liquid

1- day

evodyl aniseed

benzofuran-4 (5H) -acetate

The compounds obtained in liquid form can be advantageously used as such or are easily used in the composition of a finished product, with respect to a compound obtained in powder form such as evodone.

The compounds used according to the invention advantageously have a neutral odor or even more preferably mentholée and / or aniseed, which can be pleasant for the individual when they are applied directly to the skin, clothing or the environment.

The invention also relates to a composition comprising, as an insect repellent active agent, in particular against mosquitoes, and more particularly, the mosquitoes of the species Aedes aegypti, Aedes albopictus and Culex pipiens, an effective amount of a new evodone derivative according to the invention as described above.

Of course, according to another aspect of the invention, the compositions according to the invention may comprise an evodone derivative used as a repellent according to the invention, known as such, such as for example evodone without methyl (with R1 = R2 = -H and X = = 0), the acetate évodyle (with RI or R2 = -H, RI or R2 = CH _3, RI is different from R2, and X = -OAc) or still dimethyl evodone (with R1 = R2 = -CH ₃ , and X = = 0).

The composition preferably comprises the evodone derivative at a concentration of between 0.1 and 25% by weight relative to the total weight of the composition, for example 3% or 5%, even more preferably at a concentration of 3%, and a medium cosmetically acceptable.

The term "cosmetically acceptable medium" in the composition according to the invention means a non-toxic medium and can be applied to human keratin materials including skin, lips, nails, hair, scalp, eyelashes, eyebrows.

Those skilled in the art will take care to choose the cosmetically acceptable medium so that it does not harm the interesting properties of the evodone derivatives and repellent compositions according to the invention, in particular in that there is no of chemical interaction.

Examples of a cosmetically acceptable medium in the composition according to the invention include, for example, ethanol, glycerine, triglycerides such as capric and / or caprylic acid triglycerides (miglyol®).

The compositions according to the invention may be more or less fluid and may be in any galenical form suitable for use for topical application to the skin, for example in the form of milk, gel, cream, lotion, emulsion, soap washing base, spray, and preferably in the form of a spray.

According to another embodiment, the compositions according to

^'The invention comprising an effective amount of the derivative of evodone, preferably at a concentration between 0.1 and 25% by weight of the total weight of the composition may also be formulated as candle, spiral anti-mosquitoes, aerosol or spray to spray on an individual's clothing, or micro-capsules embedded in supports such as bracelet, collar, garment.

The composition according to the invention is optionally capable of optionally comprising another active element chosen from agents for which a repellent effect on insects is recognized, preferably a repellent agent of natural origin, such as for example menthoglycol (paramenthanum). -3, 8-diol) or citriodiol, derived from the essential oil of Eucalyptus citriodora.

By way of illustration, reference is made hereinafter to examples of composition formulation according to the invention, advantageously containing a new evodone derivative according to the invention: _^ Formulation 1: mosquito spray for topical application

Alcohol 72-74%

Water 20%

Glycerin 3%

Evodyl acetate without Methyl 3-5%

Formulation 2: mosquito spray for topical application

Alcohol 72-74%

Water 20%

Glycerin 3%

Evodone without the methyl 3-5%

Formulation 3: repellent cream for topical application

Fluid paraffin oil 24%

Paraffin 54-56 12%

Lanolin 1.2%

Nacol® C16 10%

Demethyl evodone 3-5%

Lanette © E 0.8%

Purified water 39, 45% -41, 45%

Glycerin 6, 3%

EDTA 0, 05%

Germaben® E II 1%

dL-α-Tocopherol acetate 0.2%

According to a final subject of the invention, compositions comprising an effective amount of a new evodone derivative are used to repel insects, in particular mosquitoes and, more particularly, mosquitoes of the species Aedes aegypti, Aedes albopictus and Culex pipiens.

According to another aspect of the invention, compositions comprising the other known evodone derivatives are also used according to the invention for repelling insects, in particular mosquitoes and, more particularly, mosquitoes of the species Aedes aegypti, Aedes albopictus and Culex pipiens.

As such, the invention is illustrated by the following efficacy tests performed in the laboratory. These tests aim at highlighting the repulsive effect of various formulas including evodone derivatives, vis-à-vis mosquitoes of the species Aedes aegypti.

The tests are carried out with female mosquitoes

Aedes aegypti aged 6 to 10 days having undergone fasting before 24 hours (no blood meal) to increase their aggressiveness.

The target of the blood meal is a "hairless" type mouse held in a restraining cage (protected eyes) and coated with the product to be tested (0.1 g / 60 cm ² ) applied with a pipette.

30 minutes after application of the product, the mouse is introduced into a cage containing about 200 +/- 5 female mosquitoes (prior elimination of males by food gradient).

The test lasts 5 minutes and during this period, we record the number of mosquitoes that landed on the mouse ("landing" effect: number of mosquitoes that land on the treated area and leave without stinging) and the number of actual stings.

The test is stopped from 5 effective punctures ("stop" in the table below).

The test is repeated with new batches of mosquitoes, at intervals of one hour up to 8 hours depending on the limit of persistence of the product (the mouse is released in the meantime). According to the first repetition, repetitions are performed with time intervals of 30 minutes to give a more precise limit of the time. duration of protection.

During and between maturities, the mice are maintained in a "tropical" atmosphere under controlled conditions at 27 +/- 1 ° C and 70 +/- 5% relative humidity. The cages are changed at each unit test and spaced 3 meters apart.

3 repetitions are conducted by formula to be tested and this on 3 different mice, or 9 unit tests per formula.

4 formulas are comparatively tested, the solvent serving as a reference (it is verified that there are at least 10 landings in 30 seconds to validate the test):

MEP4 / 13 = 3% evodyl acetate in a 50/50 ethanol / monopropylene glycol mixture;

MEP4 / 14 = 3% evodyl acetate without methyl in a 50/50 ethanol / monopropylene glycol mixture;

MEP4 / 15 = 3% demethyl evodone (evodone without methyl) in a 50/50 ethanol / monopropylene glycol mixture;

MEP4 / 103-2 = 3% dimethyl evodone in monopropylene glycol; and

Test without product (reference): solvent.

The results are collated in the following Tables

AEDES mouse rep. T0 + 2H T0 + 4H T0 + 5H T0 + 6H AEGYPTi P L P L P L L

MEP4 / 13 1 1 0 0 0 0 stop stop stop sto

2 0 0 0 2 stop stop stop stop

3 0 0 0 0 stop sto stop stop

2 1 0 0 0 0 stop stop stop stop

2 0 0 0 1 stop stop stop stop

3 0 0 0 1 stop stop stop stop

1 0 0 0 1 stop stop stop stop

2: 0 0 0 1 stop stop stop

3 0 0 0 1 stop stop stop sto

EP4 14 1 1 0 0 0 0 stop stop stop sto

2 0 0 0 2 stop stop stop stop

3 0 0 0 0 stop stop stop stop

2 1 0 0 0 0 stop stop stop stop

2 0 0 0 2 stop stop stop stop

3 0 0 0 0 stop stop stop stop

3 1 0 0 0 0 stop sto stop stop

2 0 0 0 1 stop stop stop sto

3 0 0 G 1 stop sto stop stop

P: number of bites rep. : repetition

L: "landing" = number of mosquitoes landing without stinging on the treated area stop = the test is stopped when more than 5 stings are observed

Under the conditions of this test, with the formulas provided, the insect strains and the methods under consideration, the compositions comprising respectively 3% of evodyl acetate, of evodyl acetate without methyl and of dimethyl evodone showed a repellent effect against the mosquito with a persistence of 4 hours after application. The composition comprising 3% of evodone demethyl showed a repellent effect vis-à-vis the mosquito having a persistence of 5 hours after application.

Considering that it is generally accepted that a good repellent product is a product with an average duration of protection measured in laboratory tests of the order of 4 hours, the evodone derivatives tested and used according to US Pat. the invention exhibit effective repellent activity.

By comparison (test results not shown), a composition comprising a racemic mixture of synthetic evodone formulated at 3% in an ethanol / monopropylene glycol 50/50 mixture shows a repellent effect vis-à-vis the mosquito with persistence 5-6 hours after application.

The repulsive efficacy for each test compound is summarized in the following Table 2:

Table 2:

Efficiency

Compound Chemical Name CAS Various 3%

3,6-dimethyl-6,7-

Evodone dihydro-1- (5H) -5- (5-6H) racemic benzofuran- (5H) -one

4-benzofuranol-

102275-309

4,5,6,7-tetrahydro- / 124,1388-4H Racemic Acetate of Evodyl 3,6-Dimethyl-4-85-1

acetate

Evodone without

3-methyl-6,7- methyl not

Dihydro-1-6906-61-2 5H

(Racemic Demethyl Benzofuran-4 (5H) -one

evodone)

3-methyl-6,7-acetate

evodyl dihydro-1-

4H

without benzofuran-4 (5H) - racemic methyl acetate

3,6,6-trimethyl-6,7-

Dimethyl no

dihydro- 1-67808-95-1 4H

Racemic Evodone Benzofuran-4 (5H) -one , Derivatives of evodone used according to the invention, the new derivatives of the invention evodone and ^• have a good repellent effectiveness against mosquitoes, comparable to the evodone, and can be obtained at costs reduced, in particular compared with evodone and / or formulated more easily. The cost / effectiveness ratio is therefore substantially optimized and very advantageous compared to the evodone.

Of course, the invention is not limited to the embodiments and to the examples presented above, and the person skilled in the art, by virtue of routine operations, may be led to make other embodiments that are not explicitly described. which fall within the broad scope of the invention.

Claims

Use of an evodone derivative of the general formula

in which,

R1 and R2 are the same or different and represent -H or a linear alkyl group of 1 to 3 carbon atoms, and

X represents = 0 or -OAc,

excluding the evodone (with RI or R2 = -H, RI or R2 = CH _3, RI is different from R2, and X = = 0),

as an active agent for repelling insects, in particular mosquitoes and, more particularly, mosquitoes of the species Aedes aegypti, Aedes albopictus and Culex pipiens.

2. Use according to claim 1, characterized in that the evodone derivative is chosen from 4-benzofuranol-4,5,6,7-tetrahydro-3,6-dimethyl-4-acetate or evodyl acetate ( with RI or R2 = -H, RI or R2 = CH _3, RI is different from R2, and X = -OAc), 3-methyl-6, 7-dihydro-l- benzofuran-4 (5H) -one or demethyl evodone (or evodone without methyl) (with R1 = R2 = -H, and X = = 0), or evodyl acetate without methyl (with R1 = R2 = -H, and X = -OAc ).

Evodone derivative of the general formula

D,

in which,

R1 and R2 are the same and represent -H, and X is -OAc;

RI and R2 are different and R2 is RI or -H, Rl or R2 is -CH ₂ CH _3, and X is = 0 or -OAc;

R1 and R2 are different and R1 or R2 represents -H, R1 or ^"

R2 represents - (CH ₂ ) ₂ CH ₃ , and X represents = O or -OAc; and

R 1 and R 2 are identical and represent -CH ₃ , and X represents -OAc. 4. Evodone derivative according to claim 3, characterized in that the derivative is evodyl acetate without methyl (with R1 = R2 = -H and X = -OAc).

5. Process for synthesizing the evodone derivative according to claim 4, characterized in that it comprises the following steps:

- reduction of 3-methyl-6,7-dihydro-1-benzofuran

4 (5H) -one by addition of NaBH ₄ or by catalytic hydrogenation followed by acetylation with acetic anhydride to obtain evodyl acetate without methyl; and

- Isolation of evodyl acetate without methyl by vacuum distillation.

6. Composition, characterized in that it comprises, as active repellent agent against insects, in particular against mosquitoes and, more particularly, the mosquitoes of the species Aedes aegypti, Aedes albopictus and Culex pipiens, an effective amount of an evodone derivative as defined in claim 3.

7. Composition according to claim 6, characterized in that it comprises the evodone derivative at a concentration of between 0.1 and 25% by weight of the total weight of the composition, preferably at a concentration of 3% by weight. weight of the total weight of the composition, and a cosmetically acceptable medium.

8. Composition according to claim 7, characterized in that it is formulated to be applied topically to the skin in the form of milk, gel, cream, lotion, emulsion, soap, washing base, spray, preferably spray.

9. Composition according to claim 6, characterized in that it comprises the evodone derivative at a concentration between 0.1 and 25% by weight of the total weight of the composition and that it is formulated in the form of a candle, anti-mosquito spiral, aerosol or spray spray on an individual's clothing, or micro-capsules embedded in supports such as bracelet, collar, garment.

10. Use of a composition according to. one of claims 6 to 9, for repelling insects, in particular mosquitoes and, more particularly, mosquitoes of the species Aedes aegypti, Aed.es albopictus and Culex pipiens.