GB2065475A

GB2065475A - Compositions for the control of parasites in warm-blooded animals

Info

Publication number: GB2065475A
Application number: GB8039356A
Authority: GB
Original assignee: Roussel Uclaf SA
Current assignee: Sanofi Aventis France
Priority date: 1979-12-10
Filing date: 1980-12-09
Publication date: 1981-07-01
Also published as: AU3165184A; FR2471187B1; AU6520780A; IT8050334A0; OA06650A; JPS5692818A; FR2471187A1; IT1146066B; ZA807621B; DE3046527A1; AU543379B2; AU561371B2; GB2065475B; NZ195796A; DE3046527C2

Abstract

Compositions adapted for administration to a portion of the surface of the body of a warm-blooded animal comprise, as active ingredient, at least one compound of formula I A-CO2-B (I> wherein A represents a group of formula: <IMAGE> in which values of Z1 and Z2 include methyl radicals and a wide variety of alkyl, cycloalkyl, aromatic, heterocyclic and halogen substituents: and values of B include benzyl radicals and a wide variety of alkyl, alkenyl, cycloalkyl, aromatic, heterocyclic and halogen substituents; said active ingredient being in association with a vehicle capable of permitting passage of the active ingredient through the skin barrier of the animal.

Description

SPECIFICATION Compositions for the control of parasites in warmblooded animals This invention relates to new compositions adapted for administration to a portion of the surface of the body of warm-blooded animals for controlling parasites on the said animals as well as to methods of using such compositions.

The compounds of general formula I, A-CO2-B (I) wherein A represents a group of formula:

Lin which either Z1 and Z2 each represents a methyl radical or Z1 represents a hydrogen atom Z2 represents a radical of formula:

(in which R3 represents a hydrogen or halogen atom and R1 and R2, which may be the same or different, each represents a halogen atom or a C1 8 alkyl radical or, together with the carbon atom to which they are attached, form a C3-6 cycloalkyl radical or a group of formula:

connected to the double bond by the carbon a to the ketone and in which X represents an oxygen or sulphur atom)j; or a group of formula::

(in which Y1 and2, which may be at any of the possible positions on the benzene nucleus and which may be the same or different, each represents a hydrogen or halogen atom, a 0is alkyl radical or a C,-8 alkoxy radical): and B represents a benzyl radical (optionally substituted by one or more substituents selected from C1 4 alkyl radicals, C2 6 alkenyl radicals, C2 6 alkenyloxy radicals, C4-8 alkadienyl radicals, methylenedioxy, benzyl and halogen atoms); a group of formula:

(in which R'1 represents a hydrogen atom or a methyl radical and R'2 represents a monocyclic aryl group or a group of formula -CH,-CECH), especially a 5 - benzyl - 3 - furylmethyl group; a group of formula:

(in which R'3 represents an organic C2~6 aliphatic radical containing one or more carbon-carbon unsaturations, especially a vinyl, propen -1 - yl, buta - 1,3 dienyl or buten - 1 - yl radical); a group of formula:

(in which R'4 represents a hydrogen atom or a group offormulaC=-N or-CECH, R's represents a chlorine atom or a methyl radical and n is0, 1 or 2), especially a 3- phenoxybenzyl, a - cyano - 3 - phenoxybenzyl or a - ethynyl - 3 - phenoxybenzyl group; or a group of formula:

(in which R'6, R'7, R'8 and R'g, which may be the same or different, each represents a hydrogen atom, a chlorine atom or a methyl radical and the symbol Sil indicates an aromatic ring or a dihydro ortetrahydro analogue thereof), are known products; see for example British Patent Specifications Nos.

1,168,798; 1,439,615; 1,439,616 and 1,413,491.

The compounds of general formula I, which may be present in one or more isomeric forms as well as mixtures, thereof, show interesting pesticidal pro perties and especially insecticidal, acaricidal, nematoc idal andlorfungicidal properties. Thus, certain com pounds of formula I display only one of these properties but others display several or indeed all of these properties.

Hitherto the methods of administration known for the compounds of formula I in their use to control parasites of warm-blooded animals were methods of administration by digestive, parenteral or topical routes and consequently only the corresponding compositions were known.

We have now found that it is possible to obtain excellent results in the control of parasites on warm-blooded animals by administering these compounds of general formula I according to a method known as the "pour on" method which consists of painting a small surface, and preferably the dorsal spine, of the body of the animal with a solution containing the active product to obtain an effect over the whole body of the animal.

That thins method would be suitable and indeed advantageous for the compounds of general formula I could not have been predicted since this method is of course not generally applicable to any active product but can be applied only to chemical compounds capable of passing through the skin barrier and of migrating whilst either keeping their activity, that is to say without being degraded, or of being degraded into metabolites which are themselves active.

Nothing in the prior art suggests the use of the compounds of general formula I in such a method.

According to one feature of the present invention there are provided compositions adapted for administration to a portion of the surface of the body of a warm-blooded animal comprising, as active ingredient, at least one compound of formula I as hereinbefore defined said active ingredient being in association with the vehicle capable of permitting passage of the active ingredient through the skin barrier of the animal.

According to a further feature of the present invention there is provided a method of treating or preventing an infestation by parasites ofawarm- blooded animal which comprises applying to a portion of the surface of the body of the said animal an effective amount of a compound of formula I in the form of a composition as hereinbefore defined.

As described above the compositions according to the invention can be applied to animals by the "pour on" method and thus, due to this unexpected find ing, such compositions are of great interest industri ally as they enable excellent pesticidal results to be obtained very quickly and in a lasting manner using very small amounts of the compounds of general formula The compositions according to the invention per mit simple, clean and economic application of the compounds of general formula I, showing a number of advantages over the hitherto known compositions for administration by other methods. Thus, whilst administration by the digestive route gives good results, it must be discarded if possible for it can cause gastric disorders and must be reserved particularly for the control of parasites located in the stomach.

Administration by the use of baths also gives quite good results. Unfortunately, however, it requires a fairly large amount of active product and, particularly in the case of pyrethrinoids it is necessary to renew the bath often since these compounds, generally speaking, are easily degraded.

Administration by the parenteral route isto be avoided wherever possible, since it is not easy to inject all the animals of a group.

The compositions according to the invention, however, may easily and quickly be painted on a portion of the body surface of the animal. They can be applied to all warm-blooded animals and especially stock animals such as, for example, cattle, sheep or pigs as well as to domestic animals such as for example dogs and cats.

The compositions according to the invention enable parasites to be combatted, whether they be internal or external parasites. They permit especially the control of acarids e.g. ticks, larvae, nymphae and scabies, helminths, warble flies, insects such as lice, bugs and various kinds of stinging flies.

Among the compositions according to the invention, preferred compositions are those which contain at least one compound of formula I wherein A represents a radical of formula:

especially one in which Z, represents a hydrogen atom and Z2 a radical of formula:

(in which R1, R2 and P2 are as defined above and particularly in which R3 represents a hydrogen atom and more particularly in which R1 and R2 each rep- resent a halogen atom, for example a bromine or chlorine atom).

Particularly preferred as active ingredients of for mula I are (S) a - cyano - 3 - phenoxybenzyl (1 R, cis) - 2,2 - dimethyl - 3 - (2,2 - dibromovinyl) cyclopropane -1 - carboxylate and (S) a - cyano - 3 - phenoxybenzyl (1 R, cis) - 2,2 - dimethyl - 3 - (2,2 - dichlorovinyl) cyclopropane - 1 - carboxylate.

Other compounds of general formula I which may be mentioned include, for example, the following: 3 - phenoxybenzyl (1 R, trans) - 2,2 - dimethyl - 3 (2,2 - dichlorovinyl) cyclopropane - 1 - carboxylate, (RS) a - cyano - 3 - phenoxybenzyl (1 R, cis) - 2,2 dimethyl -3 - (2,2 - dichlorovinyl) cyclopropane - 1 - carboxylate, 5 - benzyl - 3 - furylmethyl (1 R, trans) - 2,2 dimethyl - 3 - cyclopentylidene - methyl - cyclop ropane - 1 - carboxylate, 5 - benzyl - 3 - furylmethyl chrysanthemates in cis or trans form and racemic or optically-active, as well as mixtures thereof, 5 - benzyl - 3 - furylmethyl (1 R, 3S, E) - 2,2 dimethyl - 3 - (2 - oxo - 2,3,4,5 - tetrahydro - 3 thienylidenemethyl) - cyclopropane - 1 - carboxylate, (RS) a - cyano - 3 - phenoxybenzyl (1 R, cis) - 2,2 dimethyl - 3 - (2,2 - dibromovinyl) cyclopropane - 1 carboxylate, a - cyano - 3 - phenoxybenzyl 2 - (4 - chlorophenyl) - 3 - methylbutyrate, and (S) a - cyano - 3 - phenoxybenzyl (1 R, cis) - 2,2 dimethyl - 3 - cyclopentylidene - methyl - cyclop ropane - 1 - carboxylate.

The amount of active product of formula Ito be applied to the animal will vary depending upon the condition of the animal to be treated, the species, the environment as well as the result sought. In general, however it will be desirable to administer from 0.5 to 10 mg of the compound of formula I per kg of bodyweight of the treated animal. The number of treatments which should be carried out will also vary depending upon the same parameters as those which have been set out above to determine the amount of product to be administered. As illustrated hereinafter, however, excellent results may be obtained with a single application.

The compositions according to the invention contain a vehicle permitting passage of the active ingredient through the skin barrier. Particular vehicles which may be mentioned are solutions, preferably oily solutions, alcoholic solutions, especially ethanolic and isopropanolic solutions, solutions in esters of monocarboxylic acids, especially isopropyl myristate, in esters of dicarboxylic acids or else solutions of esters of aliphatic acids, in general with glycols.All these solutions preferably contain a dispersing agent such as, e.g. dimethylformamide, dimethylsulphoxide or dimethylacetamide or some other dispersing agents known in the pharmaceutical industry to facilitate passage through the skin barrier, insofar as the solubility of the compounds of general formula I permits this, such as, for example, pyrrolidin - 2 - one, N - alkyl - pyrrolidin - 2 - ones, methyl ethyl ketone, acetone, polyethyleneglycols and their ethers and esters, propylene glycol and synthetic triglycerides.

The oily solutions used preferably contain a vegetable oil such as e.g. olive oil, peanut oil, sesame oil, pine oil, linseed oil or castor oil.

A particularly preferred vehicle for the compositions according to the invention is an oily solution of dimethylformamide.

The compositions according to the invention may, for example, contain from 1 to 5% by weight of active ingredient, from 0.1 to 50% by weight of dispersing agent and from 98.9 to 45% by weight of solvent.

The compositions according to the invention may if desired, include an emulsifying agent and/or a surface-active agent.

The use and activity of the compositions according to the invention may be illustrated as follows: EXPERIMENTAL PART In the experimental part set out hereinafter, (S) a - cyano - 3- phenoxybenzyl (1 R, cis) - 2,2 diemthyl - 3 - (2,2 - dibromovinyl) cyclopropane - 1 - carboxylate is called product "A"; (S) a - cyano - 3 - phenoxybenzyl (1 R, cis) - 2,2 dimethyl - 3 - (2,2 - dichlorovinyl) cyclopropane - 1 - carboxylate is called product "B" and (S) a - cyano - 3 - phenoxybenzyl (1 R, cis) - 2,2 dimethyl - 3 - cyclopentylidene - methyl - cyclopropane - 1 - carboxylate is called product "C".

Test 7: Study of the acaricidalactivity of Product B on the calf: activity on "Boophilus Micro p lus" The activity was investigated in the following test: calves were infested with ticks of the species "Boophilus Microplus". The ticks are in all the stages of development. The dorsal spine of the animals is painted on day D, using a solution containing either 5 mg or 10 mg of Product B per kg weight of animal treated. The live ticks are counted on days D (before treatment), D+1, D+2, D+4 and D+7 and the presence or absence of larvae and nymphae is observed.

The results obtained are as follows:

DOSE Days 5 mglkg 10 mglkg 123 adult ticks 61 adult ticks D larvae (many) larvae (many) nymphae nymphae 2 adult ticks 3 adult ticks D+1 larvae and nymphae larvae andnymphae 0 adulttick 0 adulttick D+2 larvae and nymphae larvae and nymphae 0 adult tick 0 aduitflck D+4 larvae and nymphae larvae and nymphae O adult tick 0 adult tick D+7 neither larvae nor neither larvae nor nymphae nymphae Conclusion: Product B shows excellent activity in the control of ticks of the species "Boophilus Micro plus".

Test 2: Insecticidal activity of Pro duct A: activity on cattle lice Cattle are infested with lice. They are treated by painting their dorsal spine with 40 ml (per animal) of a solution containing 0.5% of product A. A single treatment is carried out. Very good results are obtained.

Test 3: Study ofthe acaricidalactivity of product C The tests are carried out according to the same process as in Test 1 on cattle infested artificially with ticks (Mexico variety in all stages of development) with the following treatments: 2 bulls each with 5 mglkg, 2 bulls each with 2.5 mglkg, 2 bulls untreated serving as controls.

The reduction in the number of ticks on the treated animals is determined in % by comparison with the control animals.

Dose Control 5 mglkg 2.5 mg/kg Number of ticks on each ofthe 1745 3886 20 131 (=100%) 2 bulls % reduction in the number of 91.3 80.7 ticks Conclusion: It follows from the results above that product C has very remarkable activity in the control of ticks.

Test 4: Test of tolerance ofproductA: adminis- tered by "pour on ", in the cow Healthy cows are treated by painting their dorsal spines with 20 ml of a solution containing 50 50 g/l of product A. A daily local examination is carried out for 10 days. It is observed that product A is perfectly well tolerated.

The following non-limiting example serves to illustrate a composition according to the invention.

Example 1: Example of composition A compositions was prepared, corresponding to the following formulation: Product ............................. B 1700 mg Dimethylformamide ........................ 40 cc Olive oil 40 cc

Claims

1. Compositions adapted for administration to a portion of the surface of the body of a warm-blooded animal comprising, as active ingredient, at least one compound of formula I A-CO2-B (I) wherein A represents a group offormula:

[in which either, and Z2 each represents a methyl radical orZ, represents a hydrogen atom and Z2 represents a group of formula:

(in which R3 represents a hydrogen or halogen atom and R, and R2, which may be the same or different, each represents a halogen atom or a C,-8 alkyl radical or, together with the carbon atom to which they are attached, form a C3-6 cycloalkyl radical or a group of formula::

connected to the double bond by the carbon a to the ketone and in which X represents an oxygen or sulphur atom)J; or a group of formula:

(in which Y1 and2, which may be at any of the possible positions on the benzene nucleus and which may be the same or different, each represents a hydrogen or halogen atom, a C1~8 alkyl radical or a 0i- alkoxy radical: and B represents a benzyl radical (optionally substituted by one or more substituents selected from C1-4 alkyl radicals, 02-6 alkenyl radicals, 02-6 alkenyloxy radicals, C4-S alkadienyl radicals, methylenedioxy radicals, benzyl radicals and halogen atoms); a group of formula:

(in which R'1 represents a hydrogen atom or a methyl radical and R'2 represents a monocyclic aryl group or a group of formula CH2C-=CH); a group of formula:

(in which R'3 represents an organic 02-6 aliphatic radical containing one or more carbon-carbon unsaturations); a group of formula:

(in which R'4 represents a hydrogen atom or a group of formula -CN or C-OH, R's represents a chlorine atom our a methyl radical and n isO, 1 or2); our a group of formula:

(in which R'6, R'7, R's and R'g, which may be the same or different, each represents a hydrogen atom, a chlorine atom or a methyl radical and the symbol S/I indicates an aromatic ring or dihydro ortetrahydro analogue thereof); said active ingredient being in association with a vehicle capable of permitting passage of the active ingredient through the skin barrier of the animal.

2. Compositions as claimed in claim 1 wherein, in the compound of formula I, A represents a group of formula:

in which Z1 and Z2 are as defined in claim 1.

3. Compositions as claimed in claim 2 wherein, in the compound of formula 1, Z, represents a hydrogen atom and Z2 represents a radical of formula:

(in which Rl, R2 and R3 are as defined in claim 1).

4. Compositions as claimed in claim 3 wherein, in the compound of formula I, R3 represents a hydrogen atom.

5. Compositions as claimed in claim 4wherein, in the compound of formula I, R, and R2 each represents a halogen atom.

6. Compositions as claimed in claim 5 wherein, in the compound of formula I, R1 and R2 each represents a bromine atom ora chlorine atom.

7. Compositions as claimed in claim 6 wherein the active ingredient comprises (S) a - cyano - 3 phenoxybenzyl (1 R, cis) 2,2- dimethyl - 3 - (2,2dibromovinyl) cyclopropane -1 - carboxylate.

8. Compositions as claimed in claim 6 wherein the active ingredient comprises (S) a - cyano - 3 phenoxybenzyl (1 R, cis) 2,2- dimethyl - 3 - (2,2 - dichlorovinyl) cyclopropane - 1 - carboxylate.

9. Compositions as claimed in claim 1 wherein the active ingredient comprises a compound of formula I selected from the following: 3- phenoxybenzyl (1 R, trans) 2,2 - dimethyl - 3- (2,2 dichlorovinyl) - cyclopropane -1 - carboxylate, (RS) a - cyano - 3 - phenoxybenzyl (1 R, cis) 2,2 dimethyl - 3 - (2,2- dichlorovinyl) - cyclopropane - 1 - carboxylate, 5 - benzyl - 3 - furylmethyl (1 R, trans) 2,2 - dimethyl 3. cyclopentylidene - methyl - cyclopropane - 1 carboxylate, 5 - benzyl - 3 - furylmethyl chrysanthemates in cis or trans form and racemic or optically-active, as well as mixtures thereof, 5 - benzyl - 3 - furlymethyl (1 R, 3S, E) - 2,2- dimethyl - 3 - (2- oxo - 2,3,4,5 - tetrahydro - 3 - thienylidenemethyl) - cyclopropane -1 - carboxylate, (RS) a - cyano - 3 - phenoxybenzyl (1 R, cis) - 2,2 dimethyl - 3 - (2,2- dibromovinyl) cyclopropane - 1 - carboxylate, a - cyano - 3 - phenoxybenzyl 2 - (4 - chlorophenyl) - 3- methylbutyrate, and (S) a - cyano - 3 - phenoxybenzyl (1 R, cis) - 2,2dimethyl - 3 - cyclopentylidene - methyl - cyclop ropane - 1 - carboxylate.

10. Compositions as claimed in any preceding claim wherein the vehicle comprises an oily solution.

11. Compositions as claimed in claim 10 wherein the vehicle comprises an oily solution of a dispersing agent.

12. Compositions as claimed in claim 11 wherein the dispersing agent comprises dimethylformamide, dimethylsulphoxide or dimethylacetamide.

13. Compositions as claimed in claim 11 or claim 12 wherein the oily solution comprises a vegetable oil.

14. Compositions as claimed in any preceding claim including an emulsifying agent and/or a sur face active agent.

15. Compositions as claimed in any preceding claim for use in the control of parasites.

16. Compositions as claimed in claim 15 for use in the control of acarids.

17. Compositions as claimed in any preceding claim adapted for administration to a part of the dorsal spine of the animal.

18. Compositions as claimed in any preceding claim containing from 1 to 5% by weight of active ingredient, from 0.1 to 50% by weight of dispersing agent and from 98.9 to 45% by weight of solvent

19. Compositions as claimed in claim 1 substantially as herein described.

20. Compositions substantially as herein described in the Example.

21. A method of treating or preventing an infestation by parasites of a warm-blooded animal which comprises applying to a portion of the surface of the body of the said animal an effective amount of a compound of formula I in the form of a composition as defined in claim 1.

22. A method as claimed in claim 21 wherein the compound of formula lis applied in the form of a composition as defined in any one of claims 2 to 9.

23. A method as claimed in claim 21 or claim 22 wherein the compound of formula I is applied to the dorsal spine of the animal or a part thereof.

24. A method as claimed in any one of claims 21 to 23 wherein from 0.5 to 10 mg of the compound of formula I are applied per kg bodyweight of the animal.

25. A method as claimed in any one of claims 21 to 24 for the treatment or prevention of an infestation by acarids.

26. A method as claimed in any one of claims 21 to 25 wherein the animal is selected from cattle, sheep, pigs, dogs and cats.

27. A method as claimed in claim 21 substantially as herein described.

28. A method as claimed in any one of claims 21 to 27 wherein the compound of formula lis applied in the form of a composition as claimed in any one of claims 10to 14.

29. Each and every novel method, process, composition and product herein disclosed.