GB2083025A - (1R,cis)2,2-dimethyl-3-(2,2-difluoro-ethenyl)-cyclopropane-carboxylic acid derivatives - Google Patents

Abstract

Novel compounds of general formula (I): <IMAGE> which R1 represents an alkyl radical containing from 1 to 5 carbon atoms and which the cyclopropane ring has the (1R, cis) configuration and the benzyl alpha - carbon atom has the (R) configuration are of use as acaricidal agents.

Description

SPECIFICATION (1 R,cis)2,Z-dimethyl-3-(2,2-difluoroethenyl)-cyclopropane-carboxylic acid derivatives This invention relates to new derivatives of (1 R,cis)2,2-dimethyl-3-(2,2-difluoroethenyl)- cyclopropane-carboxylic acid, to a process for preparing them and to their use in the control of acarids.

According to one feature of the present invention there are provided compounds of general formula (I):

(1R, cis) in which'R1 represents an alkyl radical containing from 1 to 5 carbon atoms and in which the cyclopropane ring has the (1 R,cis) configuration and the benzyl (carbon atom has the (R) configuration.

R1 can represent especially the methyl, ethyl, iso-propyl, n-propyl, isobutyl, n-butyl or n-pentyl radical.

Particular features of the invention are the compounds of which the preparation is given further on in the experimental part and especially (1 R)-1-(3-phenoxyphenyl)-ethyl (1 R,cis)2,2-dimethyl-3-(2,2 difluoro-ethenyl)-cyclopropane-carboxylate.

Compounds of general formula (I) are included within the general formulae of à number of different patents, especially of French No. 2,340,925, which describes and claims iiiter alia the compounds of formula (A):

in which X and Y each represent a fluorine atom, R2 may represent a methyl radical and R, represents an alkyl radical containing from 1 to 5 carbon atoms. However, this French Patent No. 2,340,925 does not give any indication of the stereochemistry of the compounds obtained.

We have now found that certain products corresponding to the formula (A), of very particular stereochemistry, namely the compounds of formula (I) in which the cyclopropane ring has the configuration (IR,cis) and the benzyl ar-carbon has the configuration (R), have remarkable acaricidal properties which enable them to be used in the control of acarids which are parasites of animals and plants. Nothing in the prior art suggested that these particular compounds of formula (I) would show such a degree of activity.

According to a further feature of the invention the compounds of formula (I) may be prepared by reacting (IR, cis)2,2-dimethyl-3-(2,2-difluoro-ethenyl)-cyclopropane- 1 -carboxylic acid or a functional derivative thereof with an alcohol of formula (II),

in which R1 is as hereinbefore defined and in which the benzyl carbon has the (R) configuration, whereby the desired compound of formula (I) is obtained.

In a preferred method of carrying out the process of the invention the functional derivative of the acid used is the acid chloride. The esterification may, however, be carried out according to other methods. Thus, for example, (IR, cis)2,2-dimethyl-3-(2,2-difluoro-ethenyl)-cyclopropane-1 -carboxylic acid can be reacted with the alcohol of formula (II) in the presence of dicyclohexylcarbodiimide or of diisopropylcarbodiimide.

As mentioned above, the compounds of general formula (I) according to the invention possess remarkable acaricidal activity and may thus be used to control acarids which ravage plants, such as red and yellow spiders of fruit trees and grape vines and also the acarids which are parasites of animals such as ticks especially of the species Boophilus, of the species Hyalomnia, of the species Amblyomnia and of the species Rhipicephalus. They may also be used to control all kinds of scabies and especially sarcoptic scabies, psoroptic scabies and chorioptic scabies.

According to a still further feature of the invention there are provided acaricidal compositions comprising, as active ingredient, at least one compound of formula (I) according to the invention in association with a carrier or excipient. Such compositions may be presented in a form suitable for administration to plants or animals.

When it is a question of controlling acarids which are parasites of animals, the compounds of general formula (I) according to the invention can also be incorporated in feedstuffs, in association with a nutrient material suitable for animal feeding. The nutrient material will vary according to the animal species for whom the feedstuff is intended; it can, for example, contain cereals, sugars, grain, soyabean-, peanut- and sunflower-seed-cakes, meals of animal origin, e.g. fish meals, synthetic amino acids, mineral salts, vitamins and anti-oxidants.

The above described compositions of the invention may be prepared according to conventional processes in the agrochemical, veterinary and animal feestuff industries. When intended for agrochemical use the compositions may additionally contain if desired one or more other pesticidal agents. Such compositions intended for administration to plants can be presented in the form of, for example, powders, granules, suspensions, emulsions, solutions, aerosols, combustible strips, baits as well as other preparations normally employed for the use of this kind of compound.

In order to increase the biological activity of the active ingredient according to the invention, these compositions may additionally contain conventional synergists used in such cases, such as e.g. 1 (2,5,8-trioxadodecyí)-2-propyl-4,5-methylenedioxy-benzene (piperonyl butoxide), N-(2-ethyl-heptyl) bicyclo[2,2-1 ]-5-heptene-2,3-dicarboximide or piperonyl-bis-2-(2'-n-butoxy-ethoxy)-ethylacetal (tropital).

In addition to the active ingredient these compositions contain, in general, a vehicle and/or a non ionic surface-active agent to ensure uniform dispersion of the substances constituting the mixture. The vehicle used can be a liquid such as e.g. water, an alcohol, a hydrocarbon or other organic solvents, or a mineral, animal or vegetable oil, a powder such as talc, clays, silicates or kieselguhr or a combustible solid such as tabu powder or pyrethrum marc.

In order to control acarids on plants, wettable powders, for foliar spraying, are preferably used containing from 1 to 80 percent of active ingredient or liquids for foliar spraying, containing from 1 to 500 g/l of active ingredient. Powders for foliar spraying can also be used containing from 0.05 to 3 percent of active ingredient.

The acaricidal compositions according to the invention are used to treat plants preferably at doses of from 1 to 100 g of active ingredient per hectare.

The compounds of general formula (I) according to the invention can be used to combat acarids in all the animals attacked by these parasites and especially cattle, sheep, poultry and domestic animals such as dogs and cats.

These compounds of the invention show not only excellent acaricidal activity but also excellent tolerance.

According to a still further feature of the invention there are provided pharmaceutical and veterinary compositions comprising, as active ingredient, at least one compound of formula (I) according to the invention in association with a pharmaceutical carrier or excipient.

The compositions according to the invention can be administered to animals and humans by an external, parenteral or digestive route. They may also advantageously contain a pyrethrinoid synergising agent.

The compositions for use on animals and humans may also be prepared according to conventional techniques.

For local application, for example, solutions may be provided which are emulsifiable in water, which solutions are diluted with water prior to use; they contain, in general, from 1/500 to 1/5 by weight of active ingredient and preferably 1/100 to 1/10, for example 3/100 to 10/100. These solutions contain, most frequently, a large amount of pyrethrinoid synergising agent; they can contain, for example, an amount by weight of piperonyl butoxide of from 2 to 20 times that of the active ingredient and preferably from 5 to 12 times.

These solutions contain, in general, also emulsifying agents such as, for example, those which are known under the commercial names Tween and Span; preferably non-ionic emulsifying agents such as Polysorbate 80 orTriton X 100 are used. These emulsifying agents have the role of promoting wetting and penetration ot the active ingredient into the skin lesions. Preferably an amount by weight of emulsifying agents of from 2 to 20 times that of the active ingredient is used, most preferably from 5 to 10 times.

These solutions can also contain an anti-oxidizing agent soluble in organic solvents such as tocopherol acetate. The active ingredient and the various additives, for example the synergising, emulsifying and anti-oxidizing agents, are in general in solution in an alcohol such as ethyl alcohol or in a mixture of ethyl and isopropyl alcohol or in a mixture of ethyl alcohol, isopropyl alcohol and ethyl acetate.

The posology varies with the animals to be treated, the parasites which they harbour and with the route of administration.

For use by a parenteral route preferably solutions are used and prepared doses are from 0.5 to 10 mg of active ingredient per kg of weight of animal to be treated. In the majority of cases excellent results are obtained with doses of 0.5 to 4 mg of active ingredient per kg of weight of animal to be treated. For administration by a sub-cutaneous or intramuscular route the active ingredient is dissolved in an excipient suitable for this use, such as a mixture of benzyl benzoate and peanut oil. Solutions for injection can also, if desired, contain additives such as (E-tocopherol acetate and piperonyl butoxide.

For use by the oral route, capsules may, for example be provided. Preferred doses are from 0.5 mg to 25 mg of active ingredient per kg of weight of animal to be treated. As indicated previously, it can be convenient for veterinary use, to use the compounds according to the invention in admixture with a balanced nutrient material for animals. Such feedstuffs for animals may, for example, contain from 100 to 500 mg of active substance per kg of food. These foods may also, if desired, contain a synergising agent.

The following non-limiting Examples serve to illustrate the present invention.

EXAMPLE 1 (1 R)- 1 -(3-phenoxyphenyl)-ethyl (1R, cis) 2,2-dimethyl-3-(2,2-difluoro-ethenyl)cyclopropane- 1 carboxylate.

Into a mixture of 1.8 g of (1 R, cis) 2,2-dimethyl-3-(2,2-difluoro-ethenyl)-cyclopropane-1- carboxylic acid chloride, 30 cm3 of benzene and 1.94 g of ar(R)-methyl-3-phenoxybenzyl alcohol (prepared according to the process indicated in French Patent Application 2,423,488) is introduced, drop by drop at 200C, a mixture of 3 cm3 of pyridine and 6 cm3 of benzene. The resultant mixture is agitated for 2 hours at 200C then poured into a 1 N aqueous solution of hydrochloric acid and extracted with ether. The organic extracts are combined, washed with water, dried and concentrated to dryness under reduced pressure.The residue is chromatographed on silica eluting with a cyclohexane/petroleum ether mixture (B.Pt. 30 --75 C) (1:1) and 2.3 g of(1R)-1-(3-phenoxyphenyl)-ethyl (1 R, cis) 2,2 dimethyl-3-(2,2-difluoro-ethenyl)-cyclopropane-1 -carboxylate are obtained.

[arl=+1O8 + 5 (C=0.1%, benzene) IR Spectrum (chloroform) Absorption at 1741 cm- attributed to

Absorption at 1720 cm-1 attributed to > C=O Absorptions at 1585 cm-','1489 cm1 attributed to

NMR Spectrum (deuterochloroform) - Peaks at 1 1.12--1. 7 p.p.m. attributed to the hydrogens of the geminal methyls.

- Peaks at 1.45-1.56 p.p.m. attributed to the hydrogens of the methyl at a of the metaphenoxybenzyl.

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

- Peaks at 4.3-4.9 p.p.m. attributed to the ethylenic hydrogen.

- Peaks at 5.6-5.7-5.8-5.9 p.p.m. attributed to the hydrogen situated at ar of the metaphenoxyphenyl.

- Peaks at 6.75 p.p.m. attributed to the hydrogens of the aromatic nuclei.

EXAMPLE 2 (iR)- 1 -(3-phenoxyphenyl)-propyl (1 R, cisJ-2,2-dimethyl-3-{2,2-difluoro-ethenyl)-cyclopropc1ne- 1 - carboxylate.

Into a mixture of 1.8 g of (1 R, cis)2,2-dimethyl-3-(2,2-difluoro-ethenyl)-cyclopropane-1-carboxylic acid chloride, 30 cm3 of benzene and 1.92 g of (1 R)-(3-phenoxyphenyl)-propanol (prepared according to the process indicated in French Patent Application 2,423,488) is introduced a solution of 2 cm3 of pyridine and 2 cm3 of benzene. The resultant mixture is agitated for 2 hours 30 minutes, then poured into a 1 N aqueous solution of hydrochloric acid. The benzene phase is separated by decanting and the aqueous phase is extracted with benzene. The organic phases are combined, washed, dried and concentrated to dryness under reduced pressure.The residue is chromatographed on silica eluting with a mixture of benzene and petroleum ether (B.Pt. = 300-750C (1:1) and 2 g of (1 R)-1-(3- phenoxyphenyl)-propyl (1 R, cis) 2,2-dimethyl-3-(2,2-difluoro-ethenyl)-cyclopropane- 1 -carboxylate are obtained.

[tl]D = to122.50 + 3.50 (c = 0.5%, benzene).

NMR Spectrum (deuterochloroform) - Peaks at 0.75-0.86-0.98 p.p.m. attributed to the hydrogens of the methyl of the ethyl.

- Peaks at 1.1-1.2 p.p.m. attributed to the hydrogens of the geminal methyls.

- Peaks from 1.6 to 2.0 p.p.m. attributed to the hydrogens of the methylene of the ethyl.

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

- Peaks from 4.3 to 4.9 p.p.m. attributed to the ethylenic hydrogen.

EXAMPLE 3 A caricidal activity on plants of the product of Example 1.

Adulticidal test on Tetranychus urticae (yellow spider).

Bean plants are used comprising two leaves which are treated with a Fisher pistol at different doses of the product to be tested. After drying these plants are infested at a rate of 25 females of yellow spiders of Tetranychus urticae per leaf and 50 individuals per dose tested, then kept at 220--230C and 6065% RH (relative humidity) under permanent artificial light. The counts of the live and dead acaridae are carried out 24, 48 and 72 hours after treatment. The results obtained are expressed in percentage mortality after 72 hours. At the dose of 1.5 g/hl the insecticidal efficacy of the product is 100% after 72 hours. At 1 g/hl it is 98% and at 0.75 g/hl it is still 96%.

Conclusion: The product of Example 1 shows remarkable acaricidal activity on Tetranichus urticae.

Adulticidal test on Pananochus ulmi (red spider) Apple tree leaves are used, of which the leaf-stalk dips into water, treated with a Fisher pistol at a dose of 5 g/hl of the product to be tested. After the spray has dried these leaves are infested at a rate of 25 females of red spider and 100 individuals per dose tested, then kept at 220--230C and 78% + 10% RH (relative humidity), under permanent artificial light. The counts of the live and dead acaridae are carried out 24 hours after treatment. Under these conditions the product tested shows total efficacy of 100% on the acaridae studied.

Conclusion: The product of Example 1 shows remarkable activity on Pananochus ulmi.

EXAMPLE 4 Study of the acaricidal activity of the Product of Example 1 in parasites of animals.

a) Study of the activity on larvae of Boophilus Microplus: The substance to be tested is dissolved in a mixture of dimethylformamide, emulsifiers and Arcopal so as to obtain a 10% emulsifiable concentrate. This concentrate is diluted with water to obtain solutions of the desired concentration of 100, 10 and 1 p.p.m.

By means of a spraying tower the different solutions above are sprayed onto larvae of tropical cattle ticks, of Boophilus Microplus type and after 24 hours the percentage mortality is determined by counting the dead and live larvae.

The results are as follows:

Doses of product of Example 1 in p.p.m. % mortality 100 100 10 100 1 100 Conclusion: The product of Example 1 shows remarkable activity.

b) Study of the activity on the inhibition of the reproduction of Boophilus Microplus ticks.

Females of Boophilus Microplus, ready to lay, are immersed for five minutes in the solutions prepared above, then they are -taken to a heated enclosure for laying.

a) The percentage of ticks which have not laid, b) the amount of eggs laid by comparison with a control and c) the percentage of larvae which have hatched out are determined.

Dependiny on the numbers obtained, the percentage inhibition of reproduction is calculated: 100% denotes that the inhibition is total and 0% that the reproduction is identical to that obtained with the controls. Obtained are:

Doses in p.p.m.

(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 Conclusion: The product of Example 1 shows remarkable activity.

EXAMPLES OF COMPOSITIONS EXAMPLEA Preparation of a soluble concentrate.

A homogeneous mixture is made up, consisting of: - Product of Example 1 0.25 g - Piperonyl butoxide 1 g -Tween 80 0.25 g -TopanolA 0.1 g water 98.4g EXAMPLE B Preparation of an emulsifiable concentrate.

Intimately mixed are: - Product of Example 1 0.015 g - Piperonyl butoxide 0.5 g -TopanolA 0.1 g -Xylene 95.885g -Tween 80 3.5 g EXAMPLE C Preparation of a fumigating composition.

- Product of Example 1 0.25 g -Tabupowder 25g - Cedar-needle powder 40 g - Pine-wood dust 33.75 9 - Brilliant green 0.5 g -p-nitrophenol 0.5 g EXAMPLE D Ixodicidal composition A solution is prepared of which the composition is as follows: - Product of Example 1 5 9 - Piperonyl butoxide 25 g - Polysorbate 80 10 9 -- Triton X 100 25g Tocopherol acetate 1 g Ethanol q.s. for 100 ml This solution is employed for external use after dilution in 50 times its volume of water.

EXAMPLE E Ixodicidal composition Compositions are prepared corresponding to the following formulation: - Product of Example 1 1.700 g dimethylformamide 40 ml - olive oil 40 ml EXAMPLE F Foodstuff for animals.

As basic balanced food there is used a mixture of maize, dehydrated lucerne, wheat straw, cake of cabbage-palm molasses, urea and a mineral/vitamin additive.

This food contains at least 11% crude protein substances (of which 2.8% are contributed by the urea),2.5% of fatty substances and at most 1 5% of cellulose substances, 6% of mineral substances and 13% water.

The food used corresponds to 82 fodder units per 100 kilos and contains, per 100 kilos, 910,000 I.U. of vitamin A, 91,000 I.U. of vitamin D,, 1 56 mg of vitamin E and 1 50 mg of vitamin C.

Incorporated in this food are 400 mg of the product of Example 1 per kg.

Claims (17)

1. Compounds of general formula (I):

(lR, cis) in which R1 represents an alkyl radical containing from 1 to 5 carbon atoms and in which the cyclopropane ring has the (1 R, cis) configuration and the benzyl ci-carbon atom has the (R) configuration.

2. ( 1 R)-1 -(3-phenoxyphenyl)-ethyl ( 1 R, cis)2,2-dimethyl-3-(2,2-difluoro-ethenyl)-cyclopropane-- carboxylate.

3. (1 R)- 1 -(3-phenoxyphenyl)-propyl (1 R, cis)2,2-dimethyl-3-(2,2-difluoro-ethenyl)-cyclopropane- carboxylate.

4. A process for the preparation of compounds as claimed in claim 1 which comprises reacting (1 R, cis)2,2-dimethyl-3-(2,2-difluoro-ethenyl)-cyclopropane- 1 -carboxylic acid or a functional derivative thereof with an alcohol of formula (all):

in which R1 is as defined in claim 1 and in which the benzyl carbon atom has the (R) configuration, whereby the desired compound of formula (I) is obtained.

5. A process as claimed in claim 4 wherein ( 1 R, cis)-2,2-dimethyl-3-(2,2-difluoro-ethenyl) cyclopropane-1-carboxylic acid chloride is reacted with the alcohol of formula (it).

6. A process for the preparation of compounds as claimed in claim 1 substantially as herein described.

7. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in Example 1 or Example 2.

8. Compounds as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 4 to 7.

9. Compounds as claimed in claim 1 for use as acaricidal agents.

1 0. Acaricidal compositions comprising, as active ingredient, at least one compound as claimed in claim 1 in association with a carrier or excipient.

11. Compositions as claimed in claim 10 in a form suitable for administration to plants.

12. Compositions as claimed in claim 10 in a form suitable for administration to animals.

13. Animal feedstuffs comprising at least one compound as claimed in claim 1 in association with a nutrient material.

14. Pharmaceutical and veterinary compositions comprising, as active. ingredient, at least one compound as claimed in claim 1 in association with a pharmaceutical carrier or excipient.

1 5. Compositions and feedstuff as claimed in any one of claims 10 to 14 substantially as herein described.

1 6. Compositions and feedstuff substantially as herein described in any one of Examples A to F.

17. A method of treating a site, other than a human or animal body, infested with or susceptible to infestation by acarids which comprises administering to the said site an effective amount of a compound as claimed in claim 1.

1 8. Each and every novel method, process, compound and composition herein disclosed.