WO2001095909A1

WO2001095909A1 - New use as antihelmintics of albofungin and analogs

Info

Publication number: WO2001095909A1
Application number: PCT/EP2001/006782
Authority: WO
Inventors: Christoph Kempter; Ulrich Roos; Frank Schroeder; Ernest Lacey; Jennifer Helen Gill; Kirstin Heiland
Original assignee: Novartis Ag; Novartis-Erfindungen Verwaltungsgesellschaft M.B.H.; Microbial Screening Technologies Pty. Limited
Priority date: 2000-06-16
Filing date: 2001-06-15
Publication date: 2001-12-20
Also published as: AU7057701A

Abstract

Described is use of the known compounds of the formula I wherein X is hydrogen or chlorine, against helminths in humans, and preferably in companion and meet-producing animals. These compounds can be used in the manufacture of a composition, which is capable of protecting humans and animals against a broad range of helminths. These compounds are able to reduce, inhibit or otherwise retard growth, viability and/or egg fecundity of said helminths and/or to ameliorate the symptoms of helminth infection. Another aspect of the present invention contemplates a method of controlling helminths in humans and animals, and more particularly nematode, infection, growth, viability and/or egg fecundity and/or ameliorating the symptoms of helminth infection by the administration of a compound of the formula I to helminth-susceptible animals or humans.

Description

NEW USE AS ANTIHELMINTICS OF ALBOFUNGIN AND ANALOGS

The present invention relates to the new use of the known compounds of the formula I as shown below. These compounds can be used in the manufacture of a composition, which is capable of protecting humans and animals against a broad range of helminths. These compounds are able to reduce, inhibit or otherwise retard growth, viability and/or egg fecundity of said helminths and/or to ameliorate the symptoms of helminth infection. Another aspect of the present invention contemplates a method of controlling helminths in humans and animals, and more particularly nematode, infection, growth, viability and/or egg fecundity and/or ameliorating the symptoms of helminth infection by the administration of a compounds of the formula I to helminth-susceptible animals or humans.

The compounds of the formula I have the following chemical structure

wherein X is hydrogen or chlorine. The hydroxy analogue is known as Albofungin (CAS Registry No. 37895-35-5). The chlorine-carrying analogue is known as Chloroalbofungin and Albofungin B (CAS Registry No. 54713-46-1). Both compounds are described, for example, by A. I. Gurevich et al. in Tetrahedron Letters 1974. 2801 -2804. The structure has been revised by Fukushima, k. et al. Bioorg. Khim., 1978, 4, 1418. The Albofungins are described as antibiotics that exhibit a broad activity spectrum against unicellular organisms, especially fungi and bacteria (c.f. Kazutaka Fukushima et al., Tetrahedron Letters 1973, XXVI No.2, 65-69. The known activity spectrum embraces Staphylococcus spp, Bacillus spp, Streptococcus spp, mycobacterium spp, Escherichia coli, Pseudomonas spp, Candida spp, Aspergillus spp and Saccharomyces spp. The compounds I according to the invention are notable for their broad activity spectrum and are valuable active ingredients for use in parasite control, including in particular the control of certain endo-parasites infesting humans and animals whilst being well-tolerated by warm-blooded animals, fish and plants.

It has now been found that the compounds of the formula I exhibit not only a pronounced activity against unicellular pathogens but surprisingly also an excellent activity against a broad range of helminths, which are highly developed multicellular parasites. It turned out that the compounds of the formula I are effective against all developmental stages of helminths in all stages of development, among which the endoparasitic nematodes which can cause severe diseases in mammals and fowl, for example in humans and particularly in companion and meat-producing animals such as sheep, swine, goats, cattle, horses, rabbits, donkeys, dogs, cats, guinea pigs, and cage birds. Typical nematodes having this indication are from the genera : Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Coope a, Ascaris, Bunostomum, Oesophagostomum, Charbertia, Trichuris, Strongylus, Trichomena, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascandia, Oxyuris, Ancylostoma, Uncinana, Toxascaris and Parascaris. A particular advantage of the compounds of formula I is their effectiveness against parasites that are resistant to benzimidazole-based active substances.

Certain species of the genera Nematodirus, Coopeήa and Oesophagostomum attack the intestinal tract of the host animals, whereas others of the genera Haemonchus and Ostertagia parasitise the stomach and those of the genus Dictyocaulus the lung tissue. Parasites of the families Filariidae and Setariidae are found in internal cell tissue and in organs, for example in the heart, blood vessels, lymph vessels and in the subcutaneous tissue. In this connection, particular mention should be made of the dog heartworm, Dirofilaria immitis. The compounds of formula I are highly effective against these parasites. As mentioned above, the compounds of formula I are also suitable for controlling pathogenic parasites in humans, among which parasites there may be mentioned as typical representatives occurring in the alimentary tract those of the genera Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Trichuris and Enterobius. The compounds of this invention are also effective against parasites of the genera Wuchereria, Brugia, Onchocerca and Loa of the Filariidae family, which occur in the blood, in tissue and in various organs and, in addition, against Dracunculus and parasites of the genera Strongyloides and Trichinella which infest, in particular, the gastro-intestinal tract. ln numerous regions of the world, the conditions under which domestic animals and pets are kept greatly encourage the spread of helminths, which may infest all mammals including humans, companion and meet-producing animals. Helminthiases are a serious economic and hygiene problem, especially in domesticated animals. They lead to anaemia, malnutrition, infirmity, weight and production loss, damage to the walls of the intestinal tract and to other organs and may, if not treated, result in the death of the animal affected.

Surprisingly, it has now been found that, with the aid of specific methods of administration, for example preferably by systemic administration, and using a composition that comprises as active ingredients one or more compounds of formula I, it is possible to achieve effective control of the above described helminths. These compositions are fully effective when administered to the host animal systemically, i.e. orally, parenterally, subcutaneously, intramuscularly or intravenously. This can be achieved by controlled periodic administration of the composition. This leads to the death of the parasites inside the host animal and interrupts the continually recurring re-infestation of the host animals in a simple and effective manner. The parasites are killed and prevented from reproducing, and the juvenile stages are prevented from reaching maturity . Infection of host animals is therefore prevented and the area where the host animals live can be kept free of parasites permanently. The most preferred compound due to the more pronounced activity is Albofungin.

The present invention further relates, therefore, to a method of controlling in humans and particularly in companion and meat-producing animals, through a composition comprising at least one compound of formula I in a parasiticidally effective amount, and administered orally, parenterally or by implant to the host animal.

Long-term action is achieved by the compounds of formula I according to the invention using various forms of administration, for example by administering the active ingredient to the animal to be treated internally in a formulated form. "Formulated" in this case means, for example, in the form of a tablet or granules, in liposomes or a capsule, in the form of an emulsion, in microencapsulated form, as an injectable, as an implant or in form of a bolus. It will be understood that all orally administrable compositions may comprise, in addition to customary formulation substances, further additives that encourage the host animal to take the composition orally voluntarily, e.g. suitable odoronts and flavourings.

Percutaneous administration, for example by subcutaneous or intramuscular injection or as a depot preparation in the form of an implant, and topical application, as for example, in pour-on or spot-on form, represent preferred subjects of this invention on account of their being easy to carry out. A further mode of administration is oral administration, e.g. in the form of a tablet. Percutaneous forms of administration are of particular interest and give excellent results.

Percutaneous forms of administration include, for example, subcutaneous, intramuscular and even intravenous administration of injectable forms. In addition to the customary syringes with needles, it is also possible to use needle-less high-pressure syringe devices.

By selection of a suitable formulation it is possible to enhance the ability of the active ingredients to penetrate into the living tissue of the host animal and/or to maintain its availability.

In order to obtain a greatly delayed release of active ingredient, a compound of formula I according to the invention may also be present in a matrix formulation which physically prevents the active ingredient from being released and excreted prematurely, thereby maintaining the bioavailability of the active ingredient. Such a matrix formulation is injected into the body, e.g. intramuscularly or subcutaneously, and remains there as a form of depot from which active ingredient is released continuously. Such matrix formulations are known to a person skilled in the art. They are generally wax-like, semi-solid substances, for example vegetable waxes and polyethylene glycols having a high molecular weight, or solid polymer formulations, for example so-called microspheres.

The rate of release of the active ingredient from the implant and thus the period of time over which the implant exhibits an action is generally determined by the accuracy with which the implant has been calibrated (amount of active ingredient in the implant), the environment around the implant and the polymer formulation from which the implant has been made.

The administration of veterinary medicinal additives to animal food is well known in the field of animal health. It is usual first to prepare a so-called premix in which the active ingredient is dispersed in a liquid or is present in finely divided form in solid carriers. The premix can normally comprise about 1 to 800 mg of compound per kg of premix, depending on the desired final concentration in the food.

Since the compounds of formula I according to the invention may be hydrolysed by the constituents of the food, they should be formulated in a protective matrix, for example in gelatin, before being added to the premix.

The present invention accordingly relates also to the aspect of controlling parasites by administering to the host animal with its food a compound of formula I that has been protected against hydrolysis.

A compound of formula I according to the invention is advantageously administered in a dose of from 0.01 to 800 mg/kg, preferably from 0.1 to 200 mg/kg, especially from 0.5 to 30 mg/kg body weight, based on the weight of the host animal.

A good dose that can be administered regularly to the host animal is from 0.5 to 100 mg/kg, preferably from 0.1 to 40 mg/kg body weight. The administration is effected at suitable intervals depends upon the mode of administration and body weight of the host animal

The total dose may vary for the same active ingredient from one species of animal to another and also within a species of animal, since it depends inter alia on the weight, age and constitution of the host animal.

When used according to the invention, the compound of formula I according to the invention will normally be administered not in pure form but preferably in the form of a composition that comprises, in addition to the active ingredient, constituents that assist administration, suitable constituents being those which are tolerated by the host animal.

Such compositions to be administered in accordance with the invention generally comprise from 0.1 to 99 % by weight, especially from 0.1 to 95 % by weight, of a compound of formula I according to the invention and from 99.9 to 1 % by weight, especially from 99.9 to 5 % by weight, of a solid or liquid, physiologically tolerable carrier, including from 0 to 25 % by weight, especially from 0.1 to 25 % by weight, of a non-toxic dispersant. Whereas commercial products will preferably be formulated as concentrates, the end user will normally employ dilute formulations.

Such formulations may also comprise further ingredients, such as stabilisers, antifoams, viscosity regulators, binders and tackifiers as well as other active ingredients for obtaining special effects.

The physiologically tolerable carriers known from veterinary medicinal practice for oral, percutaneous and topical administration can be used as formulation adjuvants. Some examples are given below.

Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tri- calcium phosphate or calcium hydrogen phosphate, and binders, such as starch pastes using, for example, maize, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxy- methyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Adjuvants are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragee cores can be provided with suitable, optionally enteric, coatings, there being used inter alia concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes, flavourings or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredient.

Other orally administrable compositions are hard gelatin capsules, or soft sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol. The hard gelatin capsules may comprise the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and, optionally, stabilisers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers may also have been added. Preference is given inter alia to capsules that may easily be bitten through or swallowed without being chewed. Preferred application forms for usage on warm-blooded animals in the control of helminths include solutions, emulsions, suspensions (drenches), food additives, powders, tablets including effervescent tablets, boli, capsules, micro-capsules and pour-on formulations, whereby the physiological compatibility of the formulation excipients must be taken into consideration.

The binders for tablets and boli may be chemically modified polymeric natural substances that are soluble in water or in alcohol, such as starch, cellulose or protein derivatives (e.g. methyl cellulose, carboxymethyl cellulose, ethylhydroxyethyl cellulose, proteins such as zein, gelatin and the like), as well as synthetic polymers, such as polyvinyl alcohol, polyvinyl pyrrolidone etc. The tablets also contain fillers (e.g. starch, microcrystalline cellulose, sugar, lactose etc.), glidants and disintegrants.

If the anthelminthics are present in the form of feed concentrates, then the carriers used are e.g. performance feeds, feed grain or protein concentrates. Such feed concentrates or compositions may contain, apart from the active ingredients, also additives, vitamins, antibiotics, chemotherapeutics or other pesticides, primarily bacteriostats, fungistats, coccidiostats, or even hormone preparations, substances having anabolic action or substances which promote growth, which affect the quality of meat of animals for slaughter or which are beneficial to the organism in another way. If the compositions or the active ingredients of formula I contained therein are added directly to feed or to the drinking troughs, then the formulated feed or drink contains the active ingredients preferably in a concentration of approximately 0.0005 to 0.02 % by weight (5-200 ppm).

Application of the compositions according to the invention to the animals to be treated may take place perorally, parenterally or subcutaneously, the composition being present in the form of solutions, emulsions, suspensions, (drenches), powders, tablets, boli, and capsules.

The compounds of formula I according to the invention may be used alone or in combination with other biocides. They may be combined with pesticides having the same sphere of activity e.g. to increase activity, or with substances having another sphere of activity e.g. to broaden the range of activity. It can also be sensible to add so-called repellents. If the range of activity is to be extended to endoparasites, e.g. wormers, the compounds of formula I are suitably combined with substances having endoparasitic properties. Of course, they can also be used in combination with antibacterial compositions. Since the compounds of formula I are adulticides, i.e. since they are effective in particular against the adult stage of the target parasites, the addition of pesticides which instead attack the juvenile stages of the parasites may be very advantageous. In this way, the greatest part of those parasites that produce great economic damage will be covered. Moreover, this action will contribute substantially to avoiding the formation of resistance. Many combinations may also lead to synergistic effects, i.e. the total amount of active ingredient can be reduced, which is desirable from an ecological point of view. Preferred groups of combination partners and especially preferred combination partners are named in the following, whereby combinations may contain one or more of these partners in addition to a compound of formula I.

Suitable partners in the mixture may be biocides, e.g. the insecticides and acaricides with a varying mechanism of activity, which are named in the following and have been known to the person skilled in the art for a long time, e.g. chitin synthesis inhibitors, growth regulators; active ingredients which act as juvenile hormones; active ingredients which act as adulticides; broad-band insecticides, broad-band acaricides and nematicides; and also the well known anthelminthics and insect- and/or acarid-deterring substances, said repellents or detachers.

Non-limitative examples of suitable insecticides and acaricides are:

1. Abamectin 13. Azinphos M

2. AC 303630 14. Azinphos-methyl

3. Acephat 15. Azocyclotin

4. Acrinathrin 16. Bacillus subtil, toxin

5. Alanycarb 17. Bendiocarb

6. Aldicarb 18. Benfuracarb

7. α-Cypermethrin 19. Bensultap

8. Alphamethrin 20. β-Cyfluthrin

9. Amitraz 21. Bifenthrin lO. Avermectin Bi 22. BPMC

11. AZ 60541 23. Brofenprox

12. Azinphos A 24. Bromophos A 25. Bufencarb 57. Diflubenzuron

26. Buprofezin 58. Dimethoat

27. Butocarboxin 59. Dimethylvinphos

28. Butylpyridaben 60. Dioxathion

29. Cadusafos 61. DPX-MP062

30. Carbaryl 62. Edifenphos

31. Carbof uran 63. Emamectin

32. Carbophenthion 64. Endosulfan

33. Cartap 65. Esfenvalerat

34. Chloethocarb 66. Ethiofencarb

35. Chlorethoxyfos 67. Ethion

36. Chlorfenapyr 68. Ethofenprox

37. Chlorfluazuron 69. Ethoprophos

38. Chlormephos 70. Etrimphos

39. Chlorpyrifos 71. Fenamiphos

40. Cis-Resmethrin 72. Fenazaquin

41. Clocythrin 73. Fenbutatinoxid

42. Clofentezin 74. Fenitrothion

43. Cyanophos 75. Fenobucarb

44. Cycloprothrin 76. Fenobucarb

45. Cyfluthrin 77. Fenothiocarb

46. Cyhexatin 78. Fenoxycarb

47. Cyromazine 79. Fenpropathrin

48. D 2341 80. Fenpyrad

49. Deltamethrin 81. Fenpyroximate

50. Demeton M 82. Fenthion

51. Demeton S 83. Fenvalerate

52. Demeton-S-methyl 84. Fipronil

53. Dibutylaminothio 85. Fluazinam

54. Dichlofenthion 86. Fluazuron

55. Dicliphos 87. Flucycloxuron

56. Diethion 88. Flucythrinat 89. Flufenoxuron 121. Milbemectin

90. Flufenprox 122. Moxidectin

91. Fonophos 123. Naled

92. Formothion 124. NC 184

93. Fosthiazat 125. NI-25, Acetamiprid

94. Fubfenprox 126. Nitenpyram

95. HCH 127. Omethoat

96. Heptenophos 128. Oxamyl

97. Hexaflumuron 129. Oxydemethon M

98. Hexythiazox 130. Oxydeprofos

99. Hydroprene 131. Parathion

100. Imidacloprid 132. Parathion-methyl

101. Insect-active fungi 133. Permethrin

102. Insect-active nematodes 134. Phenthoat

103. Insect-active viruses 135. Phorat

104. Iprobenfos 136. Phosalone

105. Isofenphos 137. Phosmet

106. Isoprocarb 138. Phoxim

107. Isoxathion 139. Pirimicarb

108. Ivermectin 140. Pirimiphos A

109. λ-Cyhalothrin 141. Pirimiphos M

110. Lufenuron 142. Promecarb

111. Malathion 143. Propaphos

112. Mecarbam 144. Propoxur

113. Mesulfenphos 145. Prothiofos

114. Metaldehyd 146. Prothoat

115. Methamidophos 147. Pyrachlophos

116. Methiocarb 148. Pyradaphenthion

117. Methomyl 149. Pyresmethrin

118. Methoprene 150. Pyrethrum

119. Metolcarb 151. Pyridaben

120. Mevinphos 152. Pyrimidifen 153. Pyriproxyfen 172. Thiodicarb

154. RH 5992 173. Thiofanox

155. RH-2485 174. Thionazin

156. Salithion 175. Thuringiensin

157. Sebufos 176. Tralomethrin

158. Silafluofen 177. Triarthen

159. Spinosad 178. Triazamate

160. Sulfotep 179. Triazophos

161. Sulprofos 180. Triazuron

162. Tebufenozide 181. Trichlorfon

163. Tebufenpyrad 182. Triflumuron

164. Tebupirimphos 183. Trimethacarb

165. Teflubenzuron 184. Vamidothion

166. Tefluthrin 185. Vetrazine

167. Temephos 186. XMC (3,5,-Xylylmethylcarbamat)

168. Terbam 187. Xylylcarb

169. Terbufos 188. Yl 5301/5302

170. Tetrachlorvinphos 189. ζ-Cypermethrin

171. Thiafenox 190. Zetamethrin

Non-limitative examples of suitable anthelminthics are named in the following, a few representatives have insecticidal and acaricidal activity in addition to the anthelminthic activity, and are partly already in the above list.

(A1) Praziquantel = 2-cyclohexylcarbonyl-4-oxo-1 ,2,3,6,7,11 b-hexahydro-4H-pyrazino[2,1-α jisoquinoline (A2) Closantel = 3,5-diiodo-N-[5-chloro-2-methyl-4-(a-cyano-4-chlorobenzyl)phenyl]- salicylamide (A3) Triclabendazole = 5-chloro-6-(2,3-dichlorophenoxy)-2-methylthio-1 H-benzimidazole (A4) Levamisol = -(-)-2,3,5,6-tetrahydro-6-phenylimidazo[2,1b]thiazole (A5) Mebendazole = (5-benzoyl-1 H-benzimidazol-2-yl)carbaminic acid methylester (A6) Omphalotin = a macrocyclic fermentation product of the fungus Omphalotus olearius described in WO 97/20857 (A7) Abamectin = avermectin B1 (A8) Ivermectin = 22,23-dihydroavermectin B1

(A9) Moxidectin = 5-O-demethyl-28-deoxy-25-(1 ,3-dimethyl-1 -butenyl)-6,28- epoxy-23-

(methoxyimino)-milbemycin B (A10) Doramectin = 25-cyclohexyl-5-O-demethyl-25-de(1 -methylpropyl)-avermectin A1 a (A11) Milbemectin = mixture of milbemycin A3 and milbemycin A4 (A12) Milbemvcinoxime = 5-oxime of milbemectin Non-limitative examples of suitable repellents and detachers are: (R1) DEET (N, N-diethyl-m-toluamide) (R2) KBR 3023 N-butyl-2-oxycarbonyl-(2-hydroxy)-piperidine (R3) Cvmiazole = N,-2,3-dihydro-3-methyl-1 ,3-thiazol-2-ylidene-2,4-xylidene

The said partners in the mixture are best known to specialists in this field. Most are described in various editions of the Pesticide Manual, The British Crop Protection Council, London, and others in the various editions of The Merck Index, Merck & Co., Inc., Rahway, New Jersy, USA or in patent literature. Therefore, the following listing is restricted to a few places where they may be found by way of example.

(I) 2-Methyl-2-(methylthio)propionaldehyd-0-Methylcarbamoyloxime (Aldicarb), from The Pesticide Manual, 11^th Ed. (1997), The British Crop Protection Council, London, page 26;

(II) S-(3,4-Dihydro-4-oxobenzo[c |-[1 ,2,3]-triazin-3-ylmethyl)O,O-dimethyl-phosphorodithioate (Azinphos-methyl), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 67;

(lll) Ethyl-N-[2,3-dihydro-2₁2-dimethylbenzofuran-7-yloxycarbonyl-(methyl)aminothio]-N- isopropyl-β-alaninate (Benfuracarb), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 96;

(IV) 2-Methylbiphenyl-3-ylmethyl-(Z)-(1 r?S)-c/s-3-(2-chlor-3,3_I3-trif luorprop-1 -enyl)-2,2- dimethylcyclopropancarboxylate (Bifenthrin), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 118;

(V) 2-tert-Butylimino-3-isopropyl-5-phenyl-1 ,3,5-thiadiazian-4-one (Buprofezin), from The Pesticide Manual, 11^mEd. (1997), The British Crop Protection Council, London, page 157;

(VI) 2,3-Dihydro-2,2-dimethylbenzofuran-7-yl-methylcarbamate (Carbofuran), from The Pesticide Manual, H^Ed. (1997), The British Crop Protection Council, London, page 186; (VII) 2,3-Dihydro-2,2-dimethylbenzofuran-7-yl-(dibutylaminothio)methylcarbamate

(Carbosulfan), from The Pesticide Manual, H^Ed. (1997), The British Crop Protection Council, London, page 188;

(VIII) S,S'-(2-Dimethylaminotrimethylene)-bis(thiocarbamate) (Cartap), from The Pesticide Manual, 11^,hEd. (1997), The British Crop Protection Council, London, page 193;

(IX) 1-[3,5-Dichloro-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenyl]-3-(2,6-difluoro- benzoyl)-urea (Chlorfluazuron), from The Pesticide Manual, 11^,hEd. (1997), The British Crop Protection Council, London, page 213;

(X) 0,O-Diethyl-0-3,5,6-trichloro-2-pyridyl-phosphorothioate (Chlorpyrifos), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 235;

(XI) (f?S)-α-Cyano-4-fluoro-3-phenoxybenzyl-(1 flS,3f?S;1 ?S_>3 ?S)-3-(2,2-dichlorovinyl)-2,2- di-methylcyclopropancarboxylate (Cyfluthrin), from The Pesticide Manual, 11^,hEd. (1997), The British Crop Protection Council, London, page 293;

(XII) Mixture of (S)-α-Cyano-3-phenoxybenzyl-(_Z)-(1 ?,3/^:?)-3-(2-chloro-3_I3,3-trifluoro- propenyl)-2,2-dimethylcyclopropanecarboxylate and (f?)-α-cyano-3-phenoxybenzyl-(-Z)- (1 ?,3f7)-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate (Lambda-Cyhalothrin), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 300;

(XIII) Racemate consisting of (S)-α-cyano-3-phenoxybenzyl-(1 f7,3 7)-3-(2,2-dichlorovinyl)- 2,2-dimethylcyclopropanecarboxylate and (fl)-α-cyano-3-phenoxybenzyl-(1 S,3S)-3-(2,2- dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate (Alpha-cypermethrin), from The Pesticide Manual, 11^,hEd. (1997), The British Crop Protection Council, London, page 308;

(XIV) Mixture of the stereoisomers of (S)-α-cyano-3-phenoxybenzyl (1 RS,3RS,1RS,3RS)-3- (2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate (zeta-Cypermethrin), from The Pesticide Manual, H^Ed. (1997), The British Crop Protection Council, London, page 314;

(XV) (S)-α-cyano-3-phenoxybenzyl-(1 ?,3r)-3-(2₎2-dibromovinyl)-2,2-dimethylcyclopropane- carboxylate (Deltamethrin), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 344;

(XVI) (4-Chlorophenyl)-3-(2,6-difluorobenzoyl)urea (Diflubenzuron), from The Pesticide Manual, 11 "Εd. (1997), The British Crop Protection Council, London, page 395; (XVII) (1 ,4,5,6,7,7-Hexachloro-8,9,10-trinorbom-5-en-2,3-ylenbismethylene)-sulphite (Endosulfan), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 459;

(XVIII) α-Ethylthio-o-tolyl-methylcarbamate (Ethiofencarb), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 479;

(XIX) 0,0-Dimethyl-0-4-nitro-m-tolyl-phosphorothioate (Fenitrothion), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 514;

(XX) 2-sec-ButylphenyI-methylcarbamate (Fenobucarb), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 516;

(XXI) (HS)-α-Cyano-3-phenoxybenzyl-( 7S)-2-(4-chlorophenyl)-3-methylbutyrate

(Fenvalerate), from The Pesticide Manual, H^Ed. (1997), The British Crop Protection Council, London, page 539;

(XXII) S-[Formyl(methyl)carbamoylmethyl]-0,0-dimethyl-phosphorodithioate (Formothion), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 625;

(XXIII) 4-Methylthio-3,5-xylyl-methylcarbamate (Methiocarb), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 813;

(XXIV) 7-Chlorbicyclo[3.2.0]hepta-2,6-dien-6-yl-dimethylphosphate (Heptenophos), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 670;

(XXV) 1-(6-Chloro-3-pyridylmethyl)-/V-nitroimidazolidin-2-ylidenamine (Imidacloprid), from The Pesticide Manual, 11^,hEd. (1997), The British Crop Protection Council, London, page 706;

(XXVI) 2-lsopropylphenyl-methylcarbamate (Isoprocarb), from The Pesticide Manual, 11 ^hEd. (1997), The British Crop Protection Council, London, page 729;

(XXVII) 0,S-Dimethyl-phosphoramidothioate (Methamidophos), from The Pesticide Manual, 11^,hEd. (1997), The British Crop Protection Council, London, page 808;

(XXVIII) S-Methyl-/V-(methylcarbamoyIoxy)thioacetimidate (Methomyl), from The Pesticide Manual, H^Ed. (1997), The British Crop Protection Council, London, page 815;

(XXIX) Methyl-3-(dimethoxyphosphinoyloxy)but-2-enoate (Mevinphos), from The Pesticide Manual, H^Ed. (1997), The British Crop Protection Council, London, page 844;

(XXX) 0,0-Diethyl-C -nitrophenyl-phosphorothioate (Parathion), from The Pesticide Manual, H^Ed. (1997), The British Crop Protection Council, London, page 926; (XXXI) O,O-Dimethyl-0-4-nitrophenyl-phosphorothioate (Parathion-methyl), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 928;

(XXXII) S-6-Chloro-2,3-dihydro-2-oxo-1 ,3-benzoxazol-3-ylmethyl-0,0-diethyl-phosphor- dithioate (Phosalone), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 963;

(XXXIII) 2-Dimethylamino-5,6-dimethylpyrimidin-4-yl-dimethylcarbamate (Pirimicarb), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 985;

(XXXIV) 2-lsopropoxyphenyl-methylcarbamate (Propoxur), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 1036;

(XXXV) 1 -(3,5-Dichloro-2,4-dif luorophenyl)-3-(2,6-dif luorobenzoyl)urea (Tef lubenzuron), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 1158;

(XXXVI) S-tert-butylthiomethyl-O,0-dimethyl-phosphorodithioate (Terbufos), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 1165;

(XXXVII) Ethyl-(3-tett-butyl-1-dimethylcarbamoyl-1 H-1 ^^-triazol-δ-yl-thioj-acetate, (Triazamate), from The Pesticide Manual, 11^,hEd. (1997), The British Crop Protection Council, London, page 1224;

(XXXVIII) Abamectin, from The Pesticide Manual, 11^,hEd. (1997), The British Crop Protection Council, London, page 3;

(XXXIX) 2-sec-butylphenyl-methylcarbamate (Fenobucarb), from The Pesticide Manual, H^Ed. (1997), The British Crop Protection Council, London, page 516;

(XL) /V-tert.-butyl-/V-(4-ethylbenzoyl)-3,5-dimethylbenzohydrazide (Tebufenozide), from The

Pesticide Manual, 11^,hEd. (1997), The British Crop Protection Council, London, page

1147; (XLI) (±)-5-Amino-1-(2,6-dichloro- ,α, -trifluoro-p-tolyl)-4-trifluoromethyl-sulphinylpyrazol-3- carbonitrile (Fipronil), from The Pesticide Manual, 11^lhEd. (1997), The British Crop

Protection Council, London, page 545; (XLII) ( ?S)-α-cyano-4-fluoro-3-phenoxybenzyl(1 f?S,3f?S;1 HS,3/=.S 3-(2.2-dichlorovinyl)-2.2- dimethylcyclopropanecarboxylate (beta-Cyfluthrin), from The Pesticide Manual, H^Ed.

(1997), The British Crop Protection Council, London, page 295; (XLIII) (4-Ethoxyphenyl)-[3-(4-fluoro-3-phenoxyphenyl)propyl](dimethyl)silane (Silafluofen), from The Pesticide Manual, 11^mEd. (1997), The British Crop Protection Council, London, page 1105; (XLIV) tert. -butyl (E)- -(1 ,3-dimethyl-5-phenoxypyrazol-4-yl-methylenamino-oxy)-p-toluate

(Fenpyroximate), from The Pesticide Manual, 11^,hEd. (1997), The British Crop Protection

Council, London, page 530; (XLV) 2-tørt.-butyl-5-(4-tert.-butylbenzylthio)-4-chloropyridazin-3(2H)-one (Pyridaben), from

The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page

1161; (XLVI) 4-[[4-(1,1-dimethylphenyl)phenyl]ethoxy]-quinazoline (Fenazaquin), from The

Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page

507; (XLVII) 4-Phenoxyphenyl-(f?S)-2-(pyridyloxy)propyl-ether (Pyriproxyfen), from The Pesticide

Manual, 11^,hEd. (1997), The British Crop Protection Council, London, page 1073; (XLVIII) 5-Chloro-Λ/-{2-[4-(2-ethoxyethyl)-2,3-dimethylphenoxy]ethyl}-6-ethylpyrimidin-4- amine (Pyrimidifen), from The Pesticide Manual, 11^thEd. (1997), The British Crop

Protection Council, London, page 1070; (XLIX) (E)-/V-(6-chloro-3-pyridylmethyl)-/V-ethyl-V-methyl-2-nitrovinylidenediamine

(Nitenpyram), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection

Council, London, page 880; (L) (E)-/V¹-[(6-chloro-3-pyridyl)methyl]-/V^?-cyano-/V¹-methylacetamidine (NI-25, Acetamiprid), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 9; (LI) Avermectin B^ from The Pesticide Manual, H^Ed. (1997), The British Crop Protection

Council, London, page 3; (Lll) an insect-active extract from a plant, especially (2r?₎6aS,12aS)-1,2,6,6a,12,12a- hexhydro-2-isopropenyl-8,9-dimethoxy-chromeno[3,4-£>]furo[2,3-/7]chromen-6-one

(Rotenone), from The Pesticide Manual, H^Ed. (1997), The British Crop Protection

Council, London, page 1097; and an extract from Azadirachta indica, especially azadirachtin, from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection

Council, London, page 59; and (Llll) a preparation which contains insect-active nematodes, preferably Heterorhabditis bacteriophora and Heterorhabditis megidis, from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 671; Steinernema feltiae, from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 1115 and Steinernema scapterisci, from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 1116;

(LIV) a preparation obtainable from Bacillus subtilis, from The Pesticide Manual, 11 ^thEd. (1997), The British Crop Protection Council, London, page 72; or from a strain of Bacillus thuringiensis with the exception of compounds isolated from GC91 or from NCTC11821; The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 73;

(LV) a preparation which contains insect-active fungi, preferably Verticillium lecanii, from The Pesticide Manual, 11^,hEd. (1997), The British Crop Protection Council, London, page 1266; Beauveria brogniartii, from The Pesticide Manual, 11^,hEd. (1997), The British Crop Protection Council, London, page 85 and Beauveria bassiana, from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 83;

(LVI) a preparation which contains insect-active viruses, preferably Neodipridon Sertifer NPV, from The Pesticide Manual, 11^,hEd. (1997), The British Crop Protection Council, London, page 1342; Mamestra brassicae NPV, from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 759 and Cydia pomonella granulosis virus, from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 291;

(CLXXXI) 7-Chloro-2₎3,4a,5-tetrahydro-2-[methoxycarbonyl(4-trifluoromethoxyphenyl)- carbamoyl]indole[1,2e]oxazolin-4a-carboxylat e(DPX-MP062, Indoxycarb), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 453;

(CLXXXII) /V-tert.-butyl-Λ/-(3,5-dimethylbenzoyl)-3-methoxy-2-methylbenzohydrazide (RH- 2485, Methoxyfenozide), from The Pesticide Manual, 11^thEd. (1997), The British Crop Protection Council, London, page 1094; and

(CLXXXIII) (Λ/'-[4-methoxy-biphenyl-3-yl]-hydrazinecarboxylic acid isopropyl ester (D 2341), from Brighton Crop Protection Conference, 1996, 487- 493;

(CLXXXIV) Spinosad is a mixture of Spinosyn A and Spinosyn D; US-5,362,634;

(R2) Book of Abstracts, 212th ACS National Meeting Orlando, FL, August 25-29 (1996), AGRO-020. Publisher: American Chemical Society, Washington, D.C. CONEN: 63BFAF. As a consequence of the above details, a further essential aspect of the present invention relates to combination preparations for the control of parasites on warm-blooded animals, characterized in that they contain, in addition to a compound of formula I, at least one further active ingredient having the same or different sphere of activity and at least one physiologically acceptable carrier. The present invention is not restricted to two-fold combinations.

Anthelminthic compositions of this type, which are used by the end user, similarly form a constituent of the present invention.

In each of the processes according to the invention for pest control or in each of the pest control compositions according to the invention, the active ingredients of formula I can be used in all of their steric configurations or in mixtures thereof.

The invention also includes a method of prophylactically protecting mammals and fowl, for example humans and particularly companion and meat-producing animals such as sheep, swine, goats, cattle, horses, rabbits, donkeys, dogs, cats, guinea pigs, and cage birds, against parasitic helminths, which is characterised in that the active ingredients of formula I or the active ingredient formulations prepared therefrom are administered to the animals as an additive to the feed, drinking water or also in solid or liquid form, orally, by injection or parenterally. The invention also includes the compounds of formula I according to the invention for usage in one of the said processes.

The following examples serve merely to illustrate the invention without restricting it.

In particular, preferred formulations are made up as follows: (% = percent by weight)

Formulation examples

1. Emulsion concentrates a) b) c)

Albofungin or Chloroalbofungin 25 % 40 % 50 %

Ca dodecylbenzene sulphonate 5 % 8 % 6 % castor oil polyethylene glycol ether

(36 mols ethylene oxide) 5 % - - tributylphenolpolyethylene glycol ether

(30 mols ethylene oxide) - 12 % 4 % cyclohexanone - 15 % 20 % xylene mixture 65 % 25 % 20 % From these concentrates, emulsions of any desired concentration may be prepared by diluting with water.

2. Emulsion concentrates a) b) c)

Albofungin or Chloroalbofungin 10 % 8 % 60 % octylphenol polyethylene glycol ether

(4-5 mols ethylene oxide) 3 % 3 % 2 %

Ca dodecylbenzene sulphonate 3 % 4 % 4 % castor oil polyethylene glycol ether

(35 mols ethylene oxide) 4 % 5 % 4 % cyclohexanone 30 % 40 % 15 % xylene mixture 50 % 40 % 15 %

From these concentrates, emulsions of any desired concentration may be prepared by diluting with water.

3. Suspension concentrate

Albofungin or Chloroalbofungin 40 % ethylene glycol 10 % nonylphenol polyethylene glycol ether

(15 mols ethylene oxide) 6 %

Na ligninsulphonate 10 % carboxymethylcellulose 1 %

37% aqueous formaldehyde solution 0.2 % silicone oil in the form of a 75% aqueous emulsion 0.8 % water 32 %

The finely ground active ingredient is intimately mixed with the admixtures. In this way, a suspension concentrate is obtained, from which suspensions of any desired concentration can be prepared by diluting with water.

4. Granulate a) b)

Albofungin or Chloroalbofungin 5 % 10 % kaolin 94 % - highly dispersed silicic acid 1 % - . attapulgite 90 %

The active ingredient is dissolved in methylene chloride, sprayed onto the carrier and the solvent subsequently concentrated by evaporation under vacuum. Granulates of this kind can be mixed with the fodder.

5. Granulate

Albofungin or Chloroalbofungin 10 %

Na ligninsulphonate 2 % carboxymethylcellulose 1 % kaolin 87 %

The active ingredient is mixed with the admixtures, ground and moistened with water. This mixture is extruded and then dried in a stream of air.

6. Granulate

Albofungin or Chloroalbofungin 3 % polyethylene glycol (mw 200) 3 % kaolin 94 %

(mw = molecular weight)

The finely ground active ingredient is evenly applied in a mixer to the kaolin which has been moistened with polyethylene glycol. In this way, dust-free coated granules are obtained.

7. Tablets or boli

I Albofungin or Chloroalbofungin 33.00 % methyl cellulose 0.80 % highly dispersed silicic acid 0.80 % corn starch 8.40 %

II crystalline lactose 22.50 % corn starch 17.00 % microcrystalline cellulose 16.50 % magnesium stearate 1.00 %

I Methyl cellulose is stirred into water. After the material has swollen, silicic acid is stirred in and the mixture homogeneously suspended. The active ingredient and the corn starch are mixed. The aqueous suspension is worked into this mixture and kneaded to a dough. The resulting mass is granulated through a 12 M sieve and dried.

II All 4 excipients are mixed thoroughly. ill The preliminary mixes obtained according to I and II are mixed and pressed into tablets or boli. 8. Injectables

A. Oily vehicle (slow release)

1. Albofungin or Chloroalbofungin 0.1 -1.0 g peanut? oil ad 100 ml

2. Albofungin or Chloroalbofungin 0.1-1.0 g sesame oil ad 100 ml

Preparation: The active ingredient is dissolved in part of the oil whilst stirring and, if required, with gentle heating, then after cooling made up to the desired volume and sterile- filtered through a suitable membrane filter with a pore size of 0.22 mm.

B. Water-miscible solvent (medium rate of release) Albofungin or Chloroalbofungin 0.1 -1.0 g 4-hydroxymethyl-1 ,3-dioxolane (glycerol formal) 40 g

1 ,2-propanediol ad 100 ml

An active ingredient from table 1 0.1 -1.0 g glycerol dimethylketal 40 g

1 ,2-propanediol ad 100 ml

Preparation: The active ingredient is dissolved in part of the solvent whilst stirring, made up to the desired volume and sterile-filtered through a suitable membrane filter with a pore size of 0.22 mm.

C. Aqueous solubilisate (rapid release)

1. Albofungin or Chloroalbofungin 0.1-1.0 g polyethoxylated castor oil (40 ethylene oxide units) 10 g

1 ,2-propanediol 20 g benzyl alcohol 1 g aqua ad inject.

2. Albofungin or Chloroalbofungin 0.1-1.0 g polyethoxylated sorbitan monooleate (20 ethylene oxide units) 8 g 4-hydroxymethyl-1 ,3-dioxolane (glycerol formal) 20 g benzyl alcohol 1 g aqua ad inject.

Preparation: The active ingredient is dissolved in the solvents and the surfactant, and made up with water to the desired volume. Sterile filtration through a suitable membrane filter with a pore size of 0.22 micron. The aqueous systems may also preferably be used for oral and/or intraruminal application. The compositions may also contain further additives, such as: stabilisers, e.g. where appropriate epoxidised vegetable oils (epoxidised coconut oil, rapeseed oil, or soybean oil); antifoams, e.g. silicone oil; preservatives; viscosity regulators; binders; tackifiers, as well as fertilisers or other active ingredients to achieve special effects.

Further biologically active substances or additives, which are neutral towards the compounds of formula I and do not have a harmful effect on the host animal to be treated, as well as mineral salts or vitamins, may be added to the compositions described.

The following examples serve to illustrate the invention. They do not limit the invention. The letter 'h' stands for hour.

Biological Examples:

1. In-vivo test on Trichostrongylus colubriformis and Haemonchus contortus on Mongolian gerbils (Meriones unguiculatus) using subcutaneous injection

Six to eight week old Mongolian gerbils are infected by artificial feeding with ca. 2000 larvae each of the 3^rd stage of Trichostrongylus colubriformis and Haemonchus contortus. 6 days after infection, the gerbils are treated by subcutaneous injection into the neck area with the test compounds, dissolved in a mixture of 2 parts DMSO and 1 part polyethylene glycol 400, in quantities of 32, 3.2 and 0.32 mg/kg. On day 9 (3 days after treatment), when most of the

Haemonchus contortus that are still present are larvae of the late 4^th stage and most of the

Trichostrongylus. colubriformis are immature adults, the gerbils are necropsied in order to count the worms. The efficacy is calculated as the % reduction of the number of worms in each gerbil, compared with the geometric average of number of worms from 6 infected and

Placebo - treated gerbils.

In this test, complete reduction in nematode infestation is achieved with Albofungin and

Chloroalbofungin even at the lowest test concentration of 3.2 mg/kg.

If the same test is repeated and Albofungin/Chloroalbofungin are administered orally the reduction of nematode infestation at the lowest dose of 3.2 mg/kg is as follows:

Claims

What we claim is

, An anthelmintic composition comprising a compound of formula

wherein X is hydrogen or chlorine, and at least one physiologically tolerable carrier.

2. An anthelmintic composition according to claim 1 , comprising from 0.1 to 99 % by weight of a compound of formula I according to claim 1 and from 99.9 to 1 % by weight of a solid or liquid, physiologically tolerable carrier, including from 0 to 25 % by weight of a non-toxic dispersant.

3. An anthelmintic composition according to either claim 1 or claim 2, which is in a form suitable for being administered to the animals as an additive to the feed, drinking water, or in solid or liquid form suitable for being administered to the animals orally or by injection or parenterally.

4. A combination preparation for controlling helminths and other parasites, comprising, in addition to a compound of formula I according to claim 1 , at least one further biocide having the same or a different direction of action and at least one physiologically tolerable carrier.

5. A method of controlling helminths in humans, in companion and meat-producing animals, which method comprises administering to a warm-blooded animal a parasiticidally effective compound of formula I according claim 1.

6. A method according to claim 5, comprising the systemic application of a compound of formula I according claim 1.

7. A method according to claim 5, wherein a compound of formula I according claim 1 is administered in a dose of from 0.01 to 800 mg/kg body weight, based on the host animal.

8. The use of a compound of formula I according claim 1 in a method of controlling helminths in humans, in companion and meet-producing animals.

9. The use of a compound of formula I according to claim 1 in the manufacture of a veterinary medicinal preparation against helminths.