NZ205238A - Synergistic mixtures as anthelmintic - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £05238 205238 Priority Date(s): lO.rf?'.

Publication Date: 2 4 JAN 1986 P.O. Journal. No: NO DRAWINGS Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "ANTHELMINTICS" WE, CIBA-GEIGY AG, a Swiss Corporation of Klybeckstrasse 141, 4002 Basle, Switzerland, hereby declare the invention, for which we pray that a patent may be granted to us,and the method by which it is to be performed, to be particularly described in and by the following statement (follcv/ad I v -?>»<? 1 A ^ 205238 - 1 P>- Case 5-14050/= ANTHELMINTICS The present invention relates to novel synergistic anthelmintic compositions containing as active component 5 an active-substance combination, and to the use of these compositions for controlling helminths, particularly trematodes and nematodes, in domestic animals and in productive animals. compositions according to the invention are based have an unexpected synergistic activity exceeding in a very advantageous manner the additive effect of the individual active substances forming the combination. The active-substance combinations according to the invention comprise 15 the following individual active substances: a compound of the formula I The active-substance combinations on which the n (I) ci \i wherein n is zero or 1, and the compound of the formula II 205238 I—I—I • including the isomers thereof as well as the addition salts thereof embraced by the formula II.

The compounds described in the foregoing as active-5 substance components of the compositions according to the invention are known individually as being compounds having anthelmintic activity. Compounds of the formula I are described for example in the New Zealand Patent Specification No. 186,936, and the compound of the formula II in 10 the U.S. Patent Specifications Nos. 3,274,209, 3,565,907 and 3,579,530, in the GB Patent Specification No. 1,175,270, in Tetrahedron Letters 1967, 1467, and in Am. Journ. Vet. Res. J32, 545 (1971).

The combination of different chemical compounds to 15 produce a synergistic intensification of activity for controlling pests is gaining to an increasing extent in importance because of the possibility the combination offers for effectively counteracting the ever more frequent appearance of resistance of parasites to individual 20 compounds. Consequently, the normally necessitated increase in the amounts of active substance used to overcome this build-up of resistance of the parasites can largely be avoided. The resulting saving in the amounts of active substance applied has both economic and, by virtue of a 25 lessening of environmental contamination, significant ecological advantages. In the administration of anthelmintics to productive animals, this can mean a continuance of the applied dose that can be tolerated or even a , - reduction in the dose applied, with which is simultaneously 205238 associated a lowering of the level of intoxication of the treated animals, with the result that their effective output during the treatment is not impaired.

Helminthic diseases among domestic animals and 5 productive animals are widespread as is well known, and these diseases lead to a reduction in the growth and in the output of the affected animals, and in many cases even result in their death. A particularly dangerous helminthic disease is Fasciolose, which is caused by parasitic liver 10 flukes (for example Fasciola hepatica and Fasciola gigantica), and which occurs especially in ruminants, such as sheep and cattle. The losses attributable to this helminthic disease can assume considerable proportions, particularly when this disease occurs in epidemic form in 15 herds of cattle. The control and prevention of Fasciolose are therefore considered a matter of urgency in order that such, above all economically grave, losses in animal production may be avoided. In spite of the numerous known preparations in the field covering the control of 20 helminths, it has hitherto not been possible to develop active substances which, in addition to having good general anthelminthic properties, exhibit a satisfactory action against adult and juvenile Fasciola genera in sheep and cattle, while simultaneously having low toxicity.

It has now been found that the active-substance combinations which are contained in the compositions according to the invention, and which comprise a compound of the formula I and the compound of the formula II, display a high level of anthelminthic activity, having not 30 only a wide spectrum of activity against nematodes and trematodes, hut also a very strongly marked action against Fasciola hepatica in sheep. To be emphasised as being particularly advantageous is the fact that the active- 205238 substance combinations on which the compositions according to the invention are based have, even in very small doses, a total action against liver flukes in sheep, so that side-effects, which could result in an impairment of the development and of the effective output of the treated animals during the period of treatment, are avoided by virtue of small doses. The action of the active-substance combinations according to the invention against Fasciola hepatica is significantly greater than the additive action of the individual compounds forming the combinations. Furthermore, the broad spectrum of activity induced by the composition specific to the invention is of particular advantage. The animals affected by helminthiasis can thus be treated by a single administration of an active-substance combination according to the invention simultaneously both for nematodes and for trematodes of all development stages. Included also are in particular those nematode strains which show resistance to thiabendazole (2-[4-thiazolyl]-benzimidazole),and in some cases also to other benzimidazole derivatives.

The following combination is to be regarded as being preferred: A) 5-chloro-6-(2',31-dichlorophenoxy)-2-methylthio-benzimidazole with B) L-(-)-2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole ("Levamisol").

The applicable weight ratios of compounds of the formula I to the compound of the formula II for the active-substance combinations according to the present invention are within the range of 1:5 to 5:1. The combination ratio of 1:5 to 1:1 is particularly favourable for bringing into effect the synergistic action. The 2052 amount to be used of the compound of the formula I is preferably below 6 ir.g of active substance (AS)/kg of body weight.

The anthelmintic action of the inventive active-5 substance combinations of compounds of the formula I with the compound of the formula II is demonstrated by the following test.

Test on sheep infested with Fasciola hepatica and nematodes Sheep are artificially infested with metacercaria of Fasciola hepatica. For this purpose, the metacercaria are injected, in a 0.47o aqueous suspension of carboxy-methyl cellulose, directly into the rumen of the test animals. The sheep are simultaneously orally infested 15 each with 10,000 and 5,000 infectious larvae (L 3) of benzimidazole-resistant Trichostrongylus colubriformis and Haemonchus contortus, respectively. The animals are divided for medication into equally large groups and one control group. The active-substance combinations, 20 in which the proportion of active substance of the formula I is 2-5 mg/kg and the proportion of active substance of the formula II is 3-7 mg/kg, are subsequently administered to the test animals. The sheep are kept during the test under normal conditions in paddock boxes. 25 In order to test the action of the individual active- substance combinations, a count is made, using a standard technique, at specific intervals of time after infestation and medication, of the helminth eggs excreted with the faeces. The test animals are subsequently killed and the 30 number of adult helminths present is determined.

The results provided by the medicated groups and the control group are compared for the purpose of making an evaluation. 205238 Results: The active-substance combinations on which the compositions according to the invention are based are 95-100% effective against Fasciola hepatica. The action 5 of these combinations in comparable or even lower doses is therefore significantly above the additive action of the individual compounds forming the combinations.

After administration of the therapeutically effective doses of the active-substance combinations, clinical 10 tests reveal no toxicity symptoms in the test animals; and these animals have moreover a healthy appearance. 2052 3 Example: Comparative test: results Indication: Fasciola hepatica Number of test animals (sheep): 19 Sheep Substance or mixture of substances (dose mg/kg) EPG Adult helminths No. 12th week* ;13 th week'"' ;■ i number mean | value reduction in % ;1 ;210 ;130 ;58 ;2 ;3 ;I (2,5) ;160 120 ;160 180 ;65 51 ;48,5 ;52,7 , ;4 ;20 ;15 ;20 ;5 ;990 ;1140 ;108 ;6 ;7 ;II (6,75) ;160 226 ;250 250 ;71 89 ;92,8 ;9,6 ;8 ;225 ;810 ;103 ;9 ;0 ;0 ;3 ;10 ;11 ;12 ;I + II (2,5 + 6,75) ;' ;170 0 0 ;210 50 30 ;43 19. 27 ;23,0 ;77,6 ' ;13 ;710 ;680 ;99 ;\) ;14 ;15 ;16 ;17 ;untreated control animals ;400 1290 580 860 ;670 1270 660 850 ;60 113 130 99 ;102,6 ;X ;18 ;570 ;410 ;110 ;/ \ ;19 ;1 ;600 ;1450 ;i 116 1 ;/ \ ;Substance I: 5-chloro-6-(21,3'-dichlorophenoxy)-2-methyl- ;thiobenzimidazole, ;Substance II: L-(-)-2,3,5,,6-tetrahydro-6-phenylimidazo-[ 2 , 1-b ] -thiazole ("Levamisol"). ;EPG: number of-eggs per gram of faeces ;* after infestation 2 0 5238 The active-substance combinations according to the invention are used to control parasitic helminths in domestic animals and productive, animalss such as cattle, sheep and goats. The combinations can be administered 5 either in single doses to the animals, or in repeated doses, the single doses being, depending on the species of animal, between 0.5 and 7.5 mg per kg of body weight. A better effect can be obtained in some cases by a protracted administration, or smaller complete doses may 10 suffice. The active substances or the mixtures containing them can also be added to the feed or be introduced into drinking troughs. The finished feed contains the active-substance combinations preferably at a concentration of 0.005 to 0.1 % by weight. The compositions can be 15 administered to the animals perorally in the form of solutions, emulsions, suspensions (drenches), powders, tablets, boluses or capsules. These preparations are prepared by the use for example of customary solid carriers, such as kaolin, talcum, bentonite, sodium chloride, calcium 20 phosphate or cottonseed meal, or by the use of liquids that do not react with the active substances, such as oils and other solvents and diluents harmless to the animal organism. Provided that the physical and toxicological properties of solutions or emulsions permit it, the active-substance 25 combinations can be also injected into the animals for example subcutaneously, or can be applied by means of the pour-on-method. Furthermore, administration of the active substances to the animals is also possible by means of licking stones (salt) or molasses blocks.

When the anthelmintic compositions are in the form of feed concentrates, the main carriers used are feed materials, such as hay, production feed, fodder grain or protein concentrates. The feed can contain, in addition to 205238 the active substances, also additives, vitamins, antibiotics, chemotherapeutical agents, or other pesticides, chiefly bacteriostatics, fungistatics, coccidlostatics; and also hormone preparations, substances having anabolic activity, or other substances promoting growth, affecting the quality of the meat of slaughter cattle, or being in some other way beneficial for the organism. They can also be combined with insecticides and acaricides, by virtue of which the action of the compositions is broadened and adapted to suit the given circumstances.

The anthelmintic compositions according to the invention are produced in a manner known per se by the intimate mixing and grinding of the active-substance combinations, comprising compounds of the formula I and the compound of the formula II, with suitable carriers, optionally with the addition of dispersing agents or solvents which are all inert to the active substances.

The anthelmintic compositions according to the invention can be used for example in the following preparations: Solid preparations: granulates (coated granules, impregnated granules and homogeneous granules); water-dispersible concentrates of active substance (wettable powder).

Liquid preparations: solutions, pastes, emulsions, particularly ready-for-use suspensions (drenches).

The particle size of the carriers is advantageously up to about 0.1 mm for dusts and wettable powders, and 0.01 - 0.5 mm for granulates.

The concentration of the active-substance combinations in the solid preparations is 0.5 to 80%, and 0.5 to 50% 205238 in the liquid preparations.

To these mixtures can also be added additives stabilising the active-substance combinations, and/oi. nonionic, anionic and cationic substances, which ensure 5 for example better wettability (wetting agents) and dispersibility (dispersing agents).

Example Water-dispersible powder mixture parts by weight of an active-substance combination 10 of compounds of the formula I with the compound of the formula II are thoroughly mixed, in a mixer, with 7.5 parts by weight of an absorbent carrier, for example silicic acid, 59.4 parts by weight of a carrier, for example bolus alba or kaolin, 0.5 part by weight of oleic acid, .3 parts by weight of octylphenylpolyglycol ether, and 2.3 parts by weight of a stearyl-benzimidazole derivative This mixture is ground in a dowelled disk mill or an air-jet mill until the particle size is 5-15 /pm. The wettable powder thus obtained gives a good suspension in water. 205238 - ].i -

Claims (9)

WHAT WE CLAIM IS.. WHAT-ifr CLAIMED IG ;

1. A synergistic composition for controlling parasitic helminths, which composition contains as active component an active-substance combination comprising at least one 5 compound of the formula I CI \ CK A I I • • < ^ ^ / /* ~ * N.-S -v / If Y (0>n CH. (I), 10 wherein n is zero or 1, and the compound of the formula II A A (id . .1 -vf" including the isomers thereof, as well as the addition salts thereof, embraced by the formula II, wherein the weight ratio of ccnpounds of the formula I to the compound of the formula II in the active-substance combination is 1:5 to 5:1, together with suitable carriers and/or dispersing and diluting agents.

2. A composition according to Claim 1 for controlling parasitic helminths, which contains as active component 15 an active-substance combination comprising 5-chloro-6- (2 1,3 ' -dichlorophenoxy) -2-methylthiobenziniidazole and L-(-)-2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]-thiazole, together with suitable carriers and/or dispersing and 20 diluting agents. ^ c.- "crisisi A 205238 - 12 -

3. A composition according to Claim 1 or 2, wherein the weight ratio of compounds of the formula I to the 5 compound of the formula II in the active-substance combination is 1:5 to 1:1.

4. A composition according to any one of Claims 1-3 for controlling trematodes.

5. A composition according to any one of Claims 1-3 for 10 controlling liver flukes (Fasciola hepatica).

6.. A method of controlling parasitic helminths, which method comprises treating the non-human host animal with an effective amount of an active-substance combination according to any one of Claims 1-3. 15

7. A method according to Claim 6 wherein the helminths are trematodes.

8. A method according to Claim 6 wherein the helminths are liver flukes (Fasciola hepatica) .

9. A method according to Claim 6, wherein the proportion 20 of the compound of the formula I in the active-substance combination is less than 6 mg of AS/kg of body weight. BALDWIN, SON & CAREY "~ATO«^EY^&R^^Pfl,CANTS Yi c \ I" 3 10CT 19855$ V /