CH650243A5 - ACID DERIVATIVES (1R, CIS) 2,2-Dimethyl-3- (2,2-DIFLUOROETHENYL) CYCLOPROPANE CARBOXYLIC, METHOD OF PREPARATION AND USE THE FIGHT AGAINST MITES. - Google Patents

Description

650 243

2

1. Compounds of formula (I): CH.

\

./

c »cy

(m, Cls)

° ~ 0

X)

JLJj-0

(ÎR> eis) * <5 ^

R, can represent in particular the methyl, ethyl, iso-propyl, n-propyl, isobutyl, n-butyl or n-pentyl radical.

A very particular subject of the invention is the compounds whose preparation is given below in the experimental part and in particular (1R, cis) -2,2-dimethyl-3- (2,2-difluoroethenyl) cyclo-propanecarboxylate from ( 1R) -1- (3-phenoxyphenyl) ethyl.

The products of formula I are covered by the general formulas of various patents, in particular French patent N ° 2340925, which describes and claims the compounds of formula A:

of configuration 1 R, eis for the cyclopropanic cycle and R for the benzyl carbon, in which R represents an alkyl radical containing from 1 to 5 carbon atoms.

2. (1R, cis) -2,2-dimethyl-3- (2,2-difluoroethenyl) cyclo-propanecarboxylate from (1R) -1- (3-phenoxyphenyl) ethyl according to the specification 1.

3. Compounds of formula (I) according to claim I as medicaments.

4. Compounds according to claim 2 as medicaments.

5. Process for the preparation of the compounds defined in one of claims 1 or 2, characterized in that the acid (1R, cis) -2,2-dimethyl-3- (2, 2-difluoroethenyl) cyclopropane-1-carboxyli-que, or one of its functional derivatives, with an alcohol of formula:

\

C = CH— CH - CH-

V /

H3C

VS

/ \

"- ° -CHtjTc

(AT)

(II)

in which X and Y can each represent a fluorine atom, R2 can represent a methyl radical and R! represents an alkyl radical containing from 1 to 5 carbon atoms.

However, this French patent No. 2340925 gives no indication of the stereochemistry of the compounds obtained.

We have just discovered that certain products corresponding to formula A, of very specific stereochemistry, namely the compounds of formula I:

I

in which R! represents an alkyl radical containing from 1 to 30 carbon atoms, the benzyl carbon having the R configuration, to obtain the corresponding compound of formula (I).

6. Use of the compounds of formula (I) according to one of claims 1 or 2 in the fight against mites pests of plants and ectoparasites of animals. 35

7. Compositions intended for the fight against plant pest mites, containing as active principle at least one of the compounds of formula (I) defined in one of claims 1 or 2.

8. Compositions intended for the fight against parasitic mites of animals, containing as active principle at least one of the 40 compounds of formula (I) defined in one of claims I or 2.

9. Compositions intended for animal feed, containing as active principle at least one of the compounds of formula (I)

defined in either of claims 1 or 2.

10. Pharmaceutical compositions containing as active principle 45 at least one compound defined in one of claims 1 or 2.

in which the cyclopropanic cycle has the 1R configuration, eis and the benzyl carbon the R configuration have remarkable anti-acacia properties which make it possible to use them in the fight against parasitic mites of animals and plants.

Nothing in the prior art suggested that the products of formula I would exhibit such a degree of activity.

The subject of the invention is also a process for preparing the compounds of formula I, characterized in that the acid (1R, cis) -2,2-dimethyl-3- (2,2-difluoroethenyl) is reacted cyclo-propane-1-carboxylic acid, or one of its functional derivatives, with an alcohol of formula: R

I1

HO-CH

(R) \ =,

° X)

(II)

The present invention relates to new derivatives of (1 R, cis) -2,2-dimethyl-3- (2,2-difluoroethenyl) cyclopropane-carboxylic acid, their preparation process and their use in the fight against mites plant pests and ectoparasites of 55 animals.

The subject of the invention is the compounds of formula:

60

(I)

of configuration 1R, eis for the cyclopropane ring and R for benzyl carbon, in which R represents an alkyl radical containing from 1 to 5 carbon atoms.

in which Rj represents an alkyl radical containing from 1 to 5 carbon atoms, the benzyl carbon having the R configuration, to obtain the corresponding compound of formula I.

In a preferred embodiment of the process of the invention, the functional acid derivative used is acid chloride.

The esterification reaction can be carried out by other methods. It is possible, for example, to react the (1R, cis) -2,2-dimethyl-3- (2,2-difiuoroethényI) cyclopropane-1-carboxylic acid with an alcohol of formula II in the presence of dicyclohexylcarbodiimide or diisopropylcarbodiimide.

The subject of the invention is also the use of the compounds of formula I as defined above in the fight against plant mites and plant ectoparasites.

Thus, the subject of the invention is the compositions intended for the fight against plant pest mites, containing as active principle at least one of the compounds of formula I, as well as the compositions intended for the fight against mites animal parasites, containing as active principle at least one of the compounds of formula I.

The compounds of formula I can be used to control plant mites, such as red and yellow spiders from fruit and vine trees and ec- mites.

3

650 243

animal toparasites, such as ticks in particular of the Boophilus species, of the Hyalomtiia species, of the Amblyomnia species and of the Rhipicephalus species, or to fight against all kinds of scabies and in particular the sarcoptic scab, the psoroptic scab and cho-rioptic mange.

When it comes to combating parasitic mites of animals, the products of the invention can be incorporated into food compositions, in combination with a nutritive mixture suitable for animal feed. The nutritive mixture can vary according to the animal species; it may contain cereals, sugars and grains, soybean, peanut and sunflower meal, meal of animal origin, for example fish meal, synthetic amino acids, mineral salts, vitamins and antioxidants.

A subject of the invention is therefore also compositions intended for animal feed, containing as active principle at least one of the compounds of formula I.

The compositions of the invention are prepared according to the usual methods of the agrochemical industry, the veterinary industry or the industry of products intended for animal nutrition.

In the compositions intended for agrochemical use, the active ingredient (s) may be optionally added with one or more other pesticidal agents. These compositions can be in the form of powders, granules, suspensions, emulsions, solutions, solutions for aerosols, combustible strips, baits or other preparations conventionally used for the use of this type of compound.

To enhance the biological activity of the products of the invention, they can be added to conventional synergists used in such cases, such as l- (2,5,8-ttrioxadodecyl) -2-propyl-4,5-methylenedioxy -benzene (or piperonyl butoxide), N- (2-ethylheptyl) -bicyclo [2,2-l] 5-heptene-2,3-dicarboximide or piperonyl-bis-2- (2'-n-butoxyethoxy ) ethylacetal (or tropital).

In addition to the active principle, these compositions generally contain a vehicle and / or a nonionic surfactant ensuring, in addition, a uniform dispersion of the constituent substances of the mixture. The vehicle used can be a liquid, such as water, alcohol, hydrocarbons or other organic solvents, a mineral, animal or vegetable oil, a powder such as talc, clays, silicates, kieselguhr or a combustible solid, such as tabu powder or pyrethrum marc.

To fight against plant pest mites, wettable powders are preferably used for foliar spraying, containing from 1 to 80% of active ingredient, or liquids for foliar spraying, containing from 1 to 500 g / l of active ingredient. It is also possible to use powders for leaf dusting, containing from 0.05 to 3% of active material.

The acaricide compositions according to the invention are preferably used in doses of between 1 and 100 g of active material per hectare.

The products of the invention can be used to eliminate mites in all animals affected by these parasites, in particular in cattle, sheep, poultry and household animals such as dogs and cats.

The products of the invention not only exhibit excellent anti-mite activity, but also excellent tolerance.

The subject of the invention is therefore, as medicaments, the products of formula I. The invention more particularly relates, as medicaments, to the product of Example 1.

A subject of the invention is also pharmaceutical compositions intended for the fight against mites, containing as active principle the drugs defined above.

The compositions according to the invention can be used externally, parenterally or digestively. They can advantageously be added with a pyrethroid synergizing agent.

The compositions intended for the fight against parasitic mites of animals, as defined above, can be prepared according to the usual techniques.

For local application, for example, solutions emulsifiable in water are used, to be diluted themselves in water at the time of use; they contain, in general from Vsaa to Vs by weight of active principle and, preferably, from Vioo to Vio, for example from 3/10 to 10%. These solutions generally contain a large amount of pyrethroid synergizing agents , as indicated above; they can contain, for example, an amount by weight of piperonyl butoxide of between 2 and 20 times that of the active principle and, preferably, between 5 and 12 times.

These solutions generally also contain emulsifiers such as those known under the trade names Tween and Span; preferably, non-ionic emulsifying agents are used, such as Polysorbate 80 or Triton X 100 (trademarks). These emulsifying agents have the role of promoting wetting and penetration of the active principle in skin lesions. Preferably, an amount by weight of emulsifying agents of between 2 and 20 times that of the active principle is used, preferably between 5 and 10 times.

These solutions may also contain an antioxidant agent soluble in organic solvents, such as tocopherol acetate.

The active principle and the various agents, for example the synergizing agents, emulsifiers and antioxidants, are generally in solution in an alcohol such as ethyl alcohol or else in a mixture of ethyl and isopropyl alcohol or else in a mixture of alcohol ethyl, isopropyl alcohol or ethyl acetate.

The dosage varies with the animals to be treated, the parasites they harbor and the route of administration.

For parenteral use, solutions are preferably used, and doses of 0.5 to 10 mg of product are administered per kilo of animal weight to be treated. In most cases, excellent results are obtained with doses of 0.5 to 4 mg of product per kilogram of animal weight to be treated.

For use by the subcutaneous or intramuscular route, use is made, for example, of the product in solution in an excipient suitable for this use, such as a mixture of benzyl benzoate and peanut oil. Solutions for injections may also contain α-tocopherol acetate and piperonyl butoxide.

For oral use, capsules can be used, and doses of 0.5 mg to 25 mg of product are administered per kilogram of animal weight to be treated. As indicated above, it may be convenient, for veterinary use, to use the compounds according to the invention in admixture with balanced compound feeds. One could, for example, use compound feed which contains from 100 to 500 mg of active ingredient per kilo of food. These foods may also, according to the invention, contain a synergizing agent.

The following examples illustrate the invention without, however, limiting it.

Example 1:

1 R, Cis-2,2-dimethyl-3- (2,2-difluoroethylenyl) cyclo-propane-1-carboxylate of 1 R-1- (3-phenoxyphenyl) ethyl

In a mixture of 1.8 g of 1R acid chloride, cis-2,2-di-methyl-3- (2,2-difiuoroethenyl) cyclopropane-1-carboxylic, 30 cm3 of benzene and 1.94 g a (R) -methyl-3-phenoxybenzyl alcohol (prepared according to the process indicated in French patent application No. 2423488), a mixture of 3 cm3 of pyridine and 6 cm3 of benzene, stirred for 2 h at 20 ° C., poured the reaction mixture onto an aqueous N solution of hydrochloric acid, extracted with ether, combined the organic extracts, washed them with water, dried them and concentrated them to dryness under reduced pressure, chromatograph the residue on silica eluting with a cyclohexane / petroleum ether mixture (Eb. 30-75 ° C) (1/1) and obtained 2.3 g of 1R, cis-2,2-di- (1R) -1 - (3-Phenoxyphenyl) ethyl methyl-3- (2,2-difiuoroethenyl) cyclopropane-1 -carboxylate.

[a] D = +108 ± 5 (c = 0.1%, benzene)

s

10

15

20

25

30

35

40

45

50

55

60

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IR spectrum (chloroform)

y F

Absorption at 1741 cm "1 attributed to f

F

Absorption at 1720 cm-1 attributed to> C = 0 Absorption at 1585 cm-1, 1489 cm-1 attributed to C

NMR spectrum (deuterochloroform)

Peaks at 1.12-1.17 ppm attributed to the hydrogens of the twin methyls.

Peaks at 1.45-1.56 ppm attributed to methyl hydrogens and metaphenoxybenzyl.

Peaks at 1.58-1.8 ppm attributed to the hydrogens in positions 1 and 3 of cyclopropyl.

Peaks at 4.3-4.9 ppm attributed to ethylene hydrogen.

Peaks at 5.6-5.7-5.8-5.9 ppm attributed to the hydrogen located at metaphenoxyphenyl.

Peaks at 6.75 ppm attributed to the hydrogens of the aromatic nuclei. Example 2:

1R, Cis-2,2-dimethyl-3- (2,2-difluoroëthênyljcyclo-propane-l-carboxylate of (1 R) -l- (3-phenoxyphenyl) propyl

In a mixture of 1.8 g of 1R acid chloride, cis-2,2-dimethyl-3- (2,2-difluoroethenyl) cyclopropane-1-carboxylic, 30 cm3 of benzene and 1.92 g of 1 R- (3-phenoxyphenyl) propanol (prepared according to the process indicated in French patent application No. 2423488), a solution of 2 cm3 of pyridine and 2 cm3 of benzene is introduced, stirred for 2 h, pouring the reaction mixture on an aqueous solution N of hydrochloric acid, separating the benzene phase by decantation, extracting the aqueous phase with benzene, combining the organic phases, washing them, drying them, concentrating them to dryness under reduced pressure, Chromatography the residue on silica, eluting with a benzene / petroleum ether mixture (bp = 30-75 ° C) (1/1) and obtains 2 g of 1R, cis-2,2-dimethyl-3- (2,2-difluoroethenyl) cyclopropane (1R) -1- (3-phenoxyphenyl) propyl -l-carboxylate. [a] D = +122.5 + 3.5 ° (c = 0.5%, benzene)

NMR spectrum (deuterochloroform)

Peaks at 0.75-0.86-0.98 ppm attributed to methyl methyl hydrogens.

Peaks at 1.1-1.2 ppm attributed to the hydrogens of the twin methyls. Peaks of 1.6 to 2.0 ppm attributed to ethylene methylene hydrogens.

Peaks at 1.6-2.0 ppm attributed to the hydrogens in positions 1 and 2 of the cyclopropyl.

Peaks of 4.3 to 4.9 ppm attributed to ethylene hydrogen.

Miticide activity on plants of the product of Example 1

Adulticide trial on Tetranychus urticae (yellow spider)

Bean plants with two leaves are used which are treated with a Fisher spray gun at different doses of the product to be tested. After drying, these plants are infested with 25 females of Tetranychus urticae yellow spiders per leaf and 50 individuals per dose tested, then kept at 22-23 ° C 60-65% RH (relative humidity) under permanent artificial light. Counts of living and dead mites are made 24, 48 and 72 hours after treatment. The results obtained are expressed as a percentage of mortality after 72 h. At a dose of 1.5 g / hl, the insecticidal efficacy of the product is 100% after 72 h. At 1 g / hl, it is 98%, at 0.75 g / hl it is still 96%.

Conclusion: The product of Example 1 exhibits remarkable miticide activity on Tetranychus urticae.

Adulticide trial on Panonichus ulmi (red spider)

Apple leaves are used, the petioles of which soak in water, treated with a Fisher pistol at a dose of 5 g / hl of the product to be tested. After spray drying, these leaves are infested with 25 females of the red spider and 100 individuals per dose tested, then maintained at 22-23 C, 78+ 10% RH, under permanent artificial light. Counts of living and dead mites are made 24 hours after treatment. Under these conditions, the product tested has a total effectiveness of 100% on the mites studied.

Conclusion: The product of Example 1 exhibits remarkable activity on Panonichus ulmi.

Study of the acaricidal activity of the product of Example 1 in animal parasites a) Study of the activity on the larva of Boophilus microplus:

The substance to be tested is dissolved in a mixture consisting of dimethylformamide, emulsifiers and Arcopal so as to obtain a 10% emulsifying concentrate. This concentrate is diluted with water to obtain solutions of desired concentration of 100, 10 and 1 ppm.

By means of a spraying tower, the various solutions above are sprayed on larvae of ticks of tropical oxen, of the Boophilus microplus type, and the percentage of dead and living larvae is determined after 24 hours. mortality.

The results are as follows:

Doses of product of Example 1 (ppm)

Mortality (%)

100

100

10

100

1

100

Conclusion: The product of Example 1 exhibits remarkable activity.

b) Study of the activity on the inhibition of the reproduction of Boophilus microplus ticks:

Females of Boophilus microplus ready to lay for 5 min are immersed in the solutions prepared above, then they are brought to a heated enclosure for laying.

A) the percentage of ticks which have not laid eggs is determined, b) the quantity of eggs laid according to a control, c) the percentage of larvae which have hatched.

The percentage of inhibition of reproduction is calculated on the basis of the figures obtained; 100% means that the inhibition is total and 0% that the reproduction is identical to that obtained with the controls. We obtain:

Doses (ppm)

(product of example 1)

Inhibition (%)

100

100

50

100

25

100

12.5

100

6.2

100

3.1

70

1.5

26

0.75

20

0.38

10

0.19

18

5

10

15

20

25

30

35

40

45

50

55

60

65

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Conclusion: The product of Example 1 exhibits remarkable activity.

Examples of compositions:

Example A: Preparation of a soluble concentrate 5 A homogeneous mixture of:

Product of Example 1 0.25 g

Piperonyl butoxide 1 g

Tween 80 0.25 g

TopanolA 0.1 g io

Water 98.4 g Example B: Preparation of an emulsifiable concentrate Intimately mixed:

Product of Example 1 0.015 g 15

Piperonyl butoxide 0.5 g

Topanol A 0.1 g

Xylene 95.885 g

Tween 80 3.5 g

Example C: Preparation of a smoke composition 20

Product of Example 1 0.25 g

Tabu powder 25 g

Cedar leaf powder 40 g

Pine wood powder 33.75 g

Bright green 0.5 g p-Nitrophenol 0.5 g

Example D: Ixodicidal composition

A solution was prepared, the composition of which is as follows:

Product of Example 1 5 g 30

25

Piperonyl butoxide Polysorbate 80 Triton X 100 Tocopherol acetate Ethanol q.s.p.

25 g 10 g 25 g 1 g 100 ml

This solution is used for external use after dilution in 50 times its volume of water.

Example E: Ixodicidal composition

Compositions corresponding to the following formula were prepared: Product of Example 1 j jqq g

Dimethylformamide '40 mi

Olive oil 40 ml

Example F: Compound feed for animals

As a basic balanced food, use is made of corn, dehydrated alfalfa, wheat straw, molasses palm kernel meal, urea, a vitamin-based mineral condiment.

This food contains at least 11% crude protein materials (including 2.8% provided by urea), 2.5% fat and at most 15% cellulosic materials, 6% mineral materials and 13% of humidity.

The food used corresponds to 82 fodder units per 100 kilos and contains, for 100 kilos: 910,000 IU of vitamin A, 91,000 IU of vitamin D3, 156 mg of vitamin E and 150 mg of vitamin C.

400 mg of product of Example 1 was incorporated into this food per kilo.

R