GB2113091A

GB2113091A - Anthelmintics

Info

Publication number: GB2113091A
Application number: GB08300647A
Authority: GB
Inventors: Joseph Coleman Boray
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1982-01-13
Filing date: 1983-01-11
Publication date: 1983-08-03
Also published as: ZA83186B; IL67659A; DK10583D0; DK10583A; ES518931A0; JPS5936613A; PH19183A; GB2113091B; GB8300647D0; EP0084516A1; EP0084516B1; BG38936A3; MA19678A1; CA1200200A; DE3361358D1; ES8503199A1; AU1031183A

Description

1

GB 2 113 091 A 1

10

SPECIFICATION Anthelmintics

The present invention relates to novel anthelmintic compositions containing as active component an active substance combination, and to the use of the compositions for controlling helminths, particularly trematodes, both in domestic animals and in productive animals.

The active-substance combinations on which the compositions according to the invention are based have a synergistic activity exceeding in an advantageous manner the additive effect of the individual active substances forming the combination. The active-substance combinations comprise the following individual active substances: a compound of the formula I

(I),

10

wherein n is 0 or 1

and a compound of the formula II

r2—x.

TX>

(II),

H

wherein R, is the group —NH—COO—Ra, in which R3 is an alkyl group having 1 to 9 carbon atoms, 15 preferably methyl, or R, is a thiazol-4-yl group, Rz is an alkyl group having 1 to 4 carbon atoms, 15

preferably n-propyl, phenyl unsubstituted or substituted by halogen or alkyl, or it is a cycloalkyl group having 3 to 6 carbon atoms, and X is 0, S, SO, CO, methylene, preferably S or SO, or an —NH—COO group, including the isomers embraced by the formula II, and also the acid addition salts of these compounds.

20 The compounds described in the foregoing as active substance components of the compositions 20 according to the invention are already known individually as being compounds having anthelmintic activity. Compounds of the formula I are described for example in the German Offenlegungsschrift No. 2,815,621, and those of the formula II in Am. Journ. Vet. Res. 37,1515-16 (1976), in the Belgian Patent Specification No., 793 358, and in Vet. Rec. 101, (9) 260—63,1977.

25 The combination of different chemical compounds to produce a synergistic intensification of 25 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 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. 30 The resulting saving in the amounts of active substance applied has both economical and, by virtue of a 30 lessening of environmental contamination, significant ecological advantages. In the administratin of anthelmintics to productive animals, this can means a reduction in the dose applied, with which is simultaneously 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.

35 Helminthic diseases among domestic animals and productive animals are widespread. These 35 diseases lead to a reduction in the growth and in the output of the affected animals, and can even result in their death. A particularly dangerous helminthic disease is Fasciolose, which is caused by parasitic liver flukes (for example Fasciola hepatica, Faciola gigantica and Fascioloides spp.) and which occurs especially in ruminants, such as sheep and cattle. The losses attributable to this helminthic disease can 40 assume considerable proportions, particularly when this disease occurs in epidemic form in herds of 40 cattle. The control and prevention of Fasciolose are therefore looked upon as a serious problem urgently requiring a solution in order to avoid such, above all economically grave, losses in animal production. In spite of the numerous known preparations in the field covering the control of helminths, it has hitherto not been possible to develop active substances which, in addition to having good generatl anthelminthic 45 properties, exhibit a satisfactory action against adult and juvenile Fasciola genera in sheep and cattle 45 while simultaneously having low toxicity.

It has now been found that the active-substance combinatins which are contained in the compositions according to the invention, and which comprise a compound of the formula I and compounds of the formula II, display a high level of anthelmintic activity, having not only a wide

GB 2 113 091 A 2

spectrum of activity against nematodes, cestodes and trematodes, but also a very strongly marked action against Fasciola spp. in domestic animals and in productive animals (ruminants and horses). To be emphasised as being particularly advantageous is the fact that the active-substance combinations on which the compositions according to the invention are based have, even in very small doses, a total 5 action against liver flukes in sheep, especially also against juvenile stages, so that side-effects, which 5 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 against Fasciola hepatica is significantly above the additive action of the individual compounds forming the combinations.

10 The following combinations are to be regarded as being preferred: 10

A) 5-chloro-6-(2', 3'-dichlorophenoxy)-2-methylthiobenzimidazole either with

B) [5-(propylthio)-1 H-benzimidazole-2-yl]-carbamic acid methyl ester ("Albendazoi"), or with

C) [5-(phenylthio)-1 H-benzimidazole-2-yl]-carbamic acid methyl ester ("Fenbendazoi").

The applicable weight ratios of compounds of the formula I to compounds of the formula II for the 15 active-substance combinations according to the present invention are within the range of 1 : 50 to 15 50 :1. The combination ratio of 1 :10 to 10 :1 is particularly favourable for bringing into effect the synergistic action.

Tests on sheep infested with Fasciola hepatica

36 sheep were artificially infested with metacercaria of Fasciola hepatica. For this purpose, the 20 metacercaria were injected, in an aqueous 0.4% suspension of carboxymerthyl cellulose, directly into 20 the rumen of the test animals. The animals were divided for medication into approximately equally large groups and into three control groups. After four weeks, the active substances were administered to the animals, in doses of 5 to 10 mg/kg of body weight, according to the specified combination. The sheep were kept during the test in paddock boxes under normal conditions. In order to test the action of the 25 individual active-substance combinations, a count was made in the faeces, using a standard technique, 25 12 to 15 weeks after infestation and 8 to 11 weeks after medication, of the eggs deposited by the liver flukes. The test animals Nos. 1—25, not belonging to group B and control group B' (= animals Nos. 26—36), were subsequently killed, and the number of liver flukes present was determined. The results were as follows:

TABLE 1

EPG*

Adult flukes found by autopsy

Substance

Sheep or mixture

14th

15th

mean

%

No.

(dose mg/kg)

week week number value reduction

1

65

125

12

1

60

23

89.4

3

A (5.0)

0

5

2

10.2

4

10

0

14

5

0

6

5

0

4

7

8

A + C (5.0 + 5.0)

0 0

1.0

99.0

9

0

10

0

10

2

11

5

15

2

12

A + B (5.0 + 4.6)

0

0.8

99.2

13

0

14

0

15

40

300

78

\ /

16

700

500

115

\ /

17

untreated

510

620

119

95.8

x

18

control A'

150

230

62

/\

19

920

240

105

/ \

3

GB 2 113 091 A 3

TABLE 2

EPG*

Adult flukes found by autopsy

Sheep

Substance

12th

13th

mean

%

No.

(dose mg/kg)

week week number value reduction

20

54

21

C (5.0)

—

-

77

71

0

22

82

23

untreated

58

\ /

24

control C'

—

70

25

82

26

360

1110

27

B (4.6)

370

560

_

. -

—* *

28

290

370

29

880

1280

30

710

680

\ /

31

untreated

400

670

\ /

32

control B'

1290

1270

\ /

33

580

660

**"*

—

\/

34

860

850

/\

35

570

410

/ \

36

600

1450

/ \

Key (Tables 1+2)

substance A: 5-chloro-6-(2',3'-dichlorophenoxy)-2-methylthiobenzimidazole,

substance C: [5-(phenylthio)-1H-benzimidazol-2-yl]carbamic acid methyl ester ("Fenbendazol"),

substance B: [5-(propylthio)-1H-benzimidazol-2-yl]carbamic acid methyl ester ("Albendazol").

EPG*: Number of eggs of liver flukes per gram of faeces (week after carrying out of artificial infestation with metacercaria);

**: It is known from the literature that Albendazol in a comparable dose is ineffective against 6-week-old and younger liver flukes (Austral. Vet. J. 55, 431-432, 1979;

Brit. Vet. J. 138, 371-382, 1982).

Results

The active-substance combinations on which the compositions according to the invention are based exhibited a degree of effectiveness of over 99%, even against juvenile Fasciola hepatica. The 5 action of these combinations is therefore significantly above the additive action of the individual 5

compounds forming the combinations.

After administration of therapeutically effective doses of the active-substance combinations,

clinical tests revealed no toxicity symptoms in the test animals.

The active-substance combinations according to the invention are used to control parasitic 10 helminths in domestic and productive animals, such as cattle, sheep, goats, horses, cats and dogs, and 10 also in the red deer preserves. The combinations can be administered either in single doses to the animals, or in repeated doses, the single doses being, depending on the species of animal, preferably between 0.5 and 100 mg per kg of body weight. A better effect can be obtained in some cases by a protracted administration, or smaller complete doses may suffice. The active substances or the mixtures 15 contasining them can also be added to the feed or be introduced into drinking troughs. The finished feed 15 contains the active-substances combinations preferably at a concentratin of 0.005 to 0.1 per cent by weight. The compositions can be 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 of example of customary solid carriers, such as kaolin, talcum, bentonite, sodium 20 chloride, calcium phosphate or cottonseed meal, or by the use of liquids that do not react with the 20 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 combinations can be also injected into the animals subcutaneously, or can be applied by means of the pour-on-method. Furthermore, administration of the active substances to the animals is 25 also possible by means of licking stones (salt) or molasses blocks. 25

4_

5

10

15

20

25

30

35

40

45

GB 2 113 091 A 4

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 the active substances, also additives, vitamins, antibiotics, chemotherapeutical agents, or other pesticides, chiefly bacteriostatics, fungistatics, coccidiostatics, and also hormone preparations, substances having anabolic activity, or other substances promoting growth, affecting the 5 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 10 the formula I and compounds 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: 1 g granulates (coated granules, impregnated granules and homogeneous granules); water-dispersible concentrates of active substance (wettable powders).

Liquid preparation:

Solutions, pastes, emulsions or dispersions, such as ready-for-use suspensions (drenches).

The particle size of the carriers is advantageously up to about 0.1 mm for dusts and wettable 20 powders, and 0.01—0.5 mm for granulates.

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

To these mixtures can also be added additives stabilising the active-substance combinations,

and/or nonionic, anionic and cationic-active substances, which ensure for example better wettability 25 (wetting agents) and dispersibility (dispersing agents).

EXAMPLE

Water-dispersible powder mixture

25 parts by weight of an active-substance combination of compounds of the formula I

with compounds of the formula II are thoroughtly mixed, in a mixer, with 30

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,

5.3 parts by weight of octylphenylpolyglycol ether, and

2.3 parts by weight of a stearyl-benzimidazole derivative. 35

This mixture is ground in a dowelled disk mill or an air jet mill until the particle size is 5—15 ftm. The wettable powder thus obtained gives a good suspension in water.

1. A synergistic composition for controlling parasic helminths, which composition contains as active component an active-substance combination comprising at least one compound of the formula I 40

Claims

(I)

wherein n is 0 or 1,

and at least one compound of the formula II

(II)

H

wherein R, is the group —NH—COO—R3, in which R3 is an alkyl group having 1 to 9 carbon atoms, 45

GB 2 113 091 A 5

preferably methyl, or R, is a thiazol-4-yi group, R2 is an alkyl group having 1 to 4 carbon atoms,

preferably n-propyl, phenyl unsubstituted or substituted by halogen or alkyl, or it is a cycloalkyl group having 3 to 6 carbon atoms, and X is 0, S, SO, CO, methylene, preferably S or SO, or an —NH—COO group, including the isomers embraced by the formula II, and also the acid addition salts of these 5 compounds, together with suitable carriers and/or distributing agents and diluents. 5
2. A composition for controlling parasitic helminths, according to Claim 1, which contains as active component an active-substance combination comprising: 5-chloro-6-(2',3'-dichlorophenoxy)-2-methylthiobenzimidazole and

[5-(propylthio)-1H-benzimidazole-2-yl]-carbamic acid methyl ester, together with suitable carriers 10 and/or distributing agents and diluents. 10
3. A composition for combating parasitic helminths, according to Claim 1, which contains as active component an active-substance combination comprising: 5-chloro-6-(2',3'-dichlorophenoxy)-2-methyithiobenzimidazole and

[5-(phenylthio)-1H-benzimidazole-2-yl]-carbamic acid methyl ester, together with suitable carriers 15 and/or distributing agents and diluents. 15
4. An anthelmintic composition according to any of Claims 1 to 3, wherein the weight ratio,in the active-substance combination, of compounds of the formula I to compounds of the formula II is 1 : 50 to 50:1.
5. An anthelmintic composiion according to any of Claims 1 to 3, wherein the weight ratio, in the

20 active-substance combination, of compounds of the formula I to compounds of the formula II is 1 :10 to 20 10:1.
6. A composition according to any of Claims 1 to 5 for the treatment of domestic animals and productive animals.
7. A method of controlling parasitic helminths, which method comprises treating the host animal

25 with an effective amount of an active-substance combination according to any of Claims 1 to 5. 25
8. A method according to Claim 7 wherein the helminths are trematodes.
9. A method according to Claim 7 wherein the helminths are liver flukes (Fasciola spp.) in any stages of development.
10. A method according to Claim 9 whereby liver flukes are controlled in the juvenile status.

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1983. Published by the Patent Office, 25 Southampton Buildings, London, WC2A 1AY, from which copies may be obtained.