Composition comprising eleganolone or bifurcanol for use in the oral treatment of nemathelminthiasis, and process for the preparation of an anthelmintic

Abstract

The invention relates to a composition for use in the oral treatment of nemathelminthiasis, said composition comprising eleganolone and / or a bifurcanol-type linear diterpene, and a process for preparing a corresponding anthelmintic.

Description

[0001] Composition for use in the oral treatment of nemathelminthiasis and method of preparing an anthelmintic

[0002] 1. Field of the invention

[0003] The field of the invention is that of antiparasitic treatments, in particular against gastrointestinal nematodes.

[0004] More specifically, the invention relates to a composition for use in the oral treatment of nemathelminthiasis and a method for preparing an anthelmintic.

[0005] The invention is intended in particular for pharmaceutical or veterinary use and also finds application in the field of animal feed.

[0006] 2. State of the art

[0007] Gastrointestinal nematodes are a major concern for human and animal health worldwide.

[0008] In livestock, these parasites affect the health of animals by causing loss of appetite, diarrhea, anemia and, in severe cases, death.

[0009] Parasitism also harms productivity and causes significant economic losses in livestock production. In the absence of effective alternative strategies, the control of parasitic nematodes affecting human or animal health relies primarily on the use of chemical anthelmintics. However, their intensive and sometimes inappropriate use has led to the development of anthelmintic resistance.

[0010] Therefore, there is an urgent need to find alternative solutions for sustainable helminth control.

[0011] To prevent the emergence of resistance to anthelmintic drugs, a growing number of studies are now focusing on naturally occurring compounds that can control gastrointestinal nematode populations.

[0012] To combat parasitic infections caused by nematodes, it is now known to use thymol, carvacrol, gamma-terpinene, or terpinenol essential oils. Linear diterpenes, such as eleganolone or bifurcanol, are also known to be present in macroalgae of the species B. bifurcata.

[0013] Studies have shown that eleganolone has antiprotozoal activity against Trypanosoma and Plasmodium (Pais, AC, Saraiva, JA, Rocha, SM, Silvestre, AJ, & Santos, SA (2019). Current research on the bioprospection of linear diterpenes from Bifurcaria bifurcata: From extraction methodologies to possible applications. Marine drugs, 17(10), 556.).

[0014] Another study also showed the antimitotic activity of bifurcanol isolated from B. bifurcata.

[0015] 3. Objectives of the invention

[0016] The invention aims in particular to provide an anthelmintic treatment which is effective against nematode parasites and in particular nematode parasites of the suborders Rhabditina and / or Spirurina, sensitive or resistant to anthelmintics known in veterinary or human medicine, and in particular which is more effective than thymol or carvacrol, and which also preserves the health of the infected host and the environment.

[0017] The invention aims in particular to provide an anthelmintic treatment from compounds of natural origin which is more effective than thymol or carvacrol.

[0018] Another objective of the invention is to provide such a technique which is simple to implement and inexpensive.

[0019] 4. Statement of the invention

[0020] The present invention relates to a composition for use in the oral treatment of nemathelminthiasis, said composition comprising eleganolone and / or a linear diterpene of bifurcanol type.

[0021] The inventors have in fact discovered that eleganolone and / or bifurcanol or a linear diterpene of bifurcanol type alone or combined together prove to have a high efficacy against zooparasitic organisms of the nematodoid type. In the context of the invention, the term "eleganolone" means a linear dipertene present for example in the macroalgae Bifurcaria bifurcata, Cystoseira elegans or Cystoseira balearica having chemical properties and / or a chemical structure analogous to the eleganolones described in the following three scientific publications:

[0022] Li, J., Lan, J., Liu, Z., & Li, Y. (1998). Studies on the synthesis of elegan- type linear diterpenes: the efficient total syntheses of eleganolone, eleganolone acetate, elegandiol, eleganonal, and epoxyeleganolone. Journal of natural products, 61(1), 92-95.

[0023] Gouveia, V., Seca, A. M., Barreto, M. C., & Pinto, D. C. (2013). Di-and sesquiterpenoids from Cystoseira genus: structure, intra-molecular transformations and biological activity. Mini reviews in medicinal chemistry, 13(8), 1150-1159.

[0024] Munoz, J., Culioli, G., & Kôck, M. (2013). Linear diterpenes from the marine brown alga Bifurcaria bifurcata: A chemical perspective. Phytochemistry reviews, 12, 407-424.

[0025] Furthermore, within the scope of the invention, the term “linear diterpene of bifurcanol type” means a linear diterpene present for example in the macroalgae Bifurcaria bifurcata and having chemical properties and / or a chemical structure analogous to the compound referenced 39 in the publication by Munoz et al.

[0026] In a preferred embodiment of the invention, said eleganolone or said bifurcanol-type diterpene is present within an extract of Bifurcaria bifurcata, Cystoseira elegans or Cystoseira balearica incorporated into said composition.

[0027] In a particular embodiment of the invention, said extract of Bifurcaria bifurcata, Cystoseira elegans or Cystoseira balearica is an aqueous extract of Bifurcaria bifurcata, Cystoseira elegans or Cystoseira balearica, an extract obtained by compound extraction of Cystoseira elegans or Cystoseira elegans of Cystoseira balearica in a solvent or an extract obtained by extraction of compounds of Bifurcaria bifurcata, Cystoseira elegans or Cystoseira balearica in an oil.

[0028] According to one aspect of the invention, said nemathelminthiasis is caused by organisms of the suborder Rhabditina and / or Spirurina and in particular caused by organisms of the family Ascarididae Heligosomatidae or Trichostrongylidae.

[0029] According to another aspect of the invention, said nemathelminthiasis is caused by organisms resistant to anthelmintics belonging to the group of macrocyclic lactones, such as ivermectin, moxidectin and eprinomectin, and / or to the group of benzimidazoles, such as thiabendazole, and / or to the group of imidazothiazoles, such as levamisole and / or to the group of tetrahydropyrimidines, such as pyrantel.

[0030] The invention also relates to a method for preparing an anthelmintic for oral administration comprising:

[0031] - preparing a composition comprising eleganolone and / or a linear diterpene of bifurcanol type

[0032] - encapsulating said composition in yeast particles or incorporating it into a gelatinized starch matrix.

[0033] 5. List of figures

[0034] Other characteristics and advantages of the invention will appear more clearly on reading the following description of embodiments of the invention, given as simple illustrative and non-limiting examples, and the appended figures among which: Figure 1 is a comparison of the effectiveness of different extracts of Bifurcaria bifurcata from France (frozen) and Portugal (dried) to inhibit the development of Heligmosomoides bakeri larvae. Controls, with water and with 1% DMSO, were carried out. The aqueous extracts, the different organic extracts (heptane, EtOAc and BuOH) and the residual aqueous fraction were tested at 1 g / L. The extracts come either from the batch of frozen algae harvested in France (in August

[0035] 2019), or from the batch of dried seaweed harvested in Portugal (in July

[0036] 2020). The results are from at least three independent experiments, with n = 6 per sample each time. Statistical analyses were performed using a Kruskal-Wallis test with multiple comparison test, with ***p < 0.001. Figure 2 is a comparison of the effectiveness between different extracts of Bifurcaria bifurcata from Portugal with two different preservation processes (drying or freezing) on ​​the inhibition of Heligmosomoides bakeri larvae development. A water control was performed. The aqueous extracts and the different butanol (BuOH) extracts were tested at 1 g / L. The extracts are from a batch of algae that was harvested in November 2021 in Portugal. These algae were either dried (green) or frozen (purple) before extraction. The results are from at least two independent experiments, with n = 6 per sample each time.Statistical analyses were performed using a Kruskal-Wallis test with multiple comparison test, with ***p<0.001. Figure 3 shows the activity of EtOAc extracts from Bifurcaria bifurcata biomass from different batches on the development of Heligmosomoides bakeri larvae. The EtOAc organic fractions were performed directly on the algal biomass from different batches of B. bifurcata. Three of them come from algae harvested in France at different times (March 2022 in brown, June 2021 in turquoise and August 2019 in blue) and frozen before extraction. Two others come from algae harvested in Portugal in November 2021 and either dried (green) or frozen (purple) before extraction. The percentage inhibition of larval development was / 7. bakeri, from the L1 / L2 stage to the L3 stage, is observed in the presence of water (negative control) and these different EtOAc extracts at 0.5 g / L.Figures 4a) and 4b) are 1H (a) and 13C (b) NMR spectra of the heptane fraction of Bifurcaria bifurcata. Two molecules could be identified thanks to the NMR spectra obtained for hydrogen atoms (1H, corresponds to profile a) and carbon atoms (13C, corresponds to profile b), namely eleganolone and bifurcanol, two linear diterpenes. The positions of the hydrogen and carbon atoms are numbered (in orange for eleganolone and in green for bifurcanol), as well as the corresponding peaks on the NMR spectra obtained. Figure 5 illustrates the pharmacological effect of Bifurcaria bifurcata on the nicotine-sensitive acetylcholine receptor of Ascaris suum. Study of the pharmacological effect of an aqueous extract of B. bifurcata as an agonist (a,c) or as an antagonist (b,d) on the nicotinic receptor formed by the ACR-16 subunit of A. suum in the Xenopus laevis egg expression system.(a, b) Representation of the currents recorded using the Two-Electrode Voltage-Clamp technique following the application of 100 pM acetylcholine, 1 g / L and 5 g / L of B. bifurcata aqueous extract alone or in co-application with ACh. The application times of the products are indicated by the horizontal bars (black for ACh and green for B. bifurcata). (c, d) Box-plots representing the currents induced by the application of 100 pM ACh, 1 g / L or 5 g / L of B. bifurcata aqueous extract alone or in co-application with 100 pM ACh. The currents are normalized with the current amplitude obtained at the first application of 100 pM ACh. Figure 6 presents the results of a study of the antagonistic effect of different organic extracts of Bifurcaria bifurcata on the N-AChR of Ascaris suum. Box plots representing the normalized current amplitudes following co-application of organic extracts of B.bifurcata at 0.01 g / L with 100 pM ACh on the ACR-16 receptor of Ascaris suum. The organic extracts used are as follows: Bif AE corresponds to an ethyl acetate extract obtained after extraction with heptane, Bif AEP corresponds to an extraction with ethyl acetate as the first solvent and Bif H corresponds to an extraction with heptane as the first solvent. The currents are normalized to the current induced by the first application of ACh (100 pM). Figure 7 illustrates the pharmacological effect of Bifurcaria bifurcata on the nicotinic-sensitive receptor (N-AChR) and the Mo ran tel-sensitive receptor (M-AChR) of Parascaris equorum. Study of the agonist and antagonist effect of a B. bifurcata extract on the acetylcholine receptors of P.equorum, the N-AChR consisting of the ACR-16 subunit (a) and the M-AChR consisting of the ACR-26 and ACR-27 subunits (b) Box plots representing the normalized current amplitudes following the application of an aqueous extract of B. bifurcata at 1 g / L and 5 g / L or a co-application of B. bifurcata at 1 g / L and 5 g / L with 100 pM ACh. The currents are normalized relative to the current induced by the first application of ACh.

[0037] (100 pM)

[0038] 6. Examples

[0039] 6.1. Bi material

[0040] Two initial batches of Bifurcaria Bifurcata algae with a difference in effectiveness were selected: a first batch of Bifurcaria Bifurcata algae collected in France in August 2019 and frozen and a second batch of Bifurcaria Bifurcata algae collected in Portugal in July 2020 and dried.

[0041] Subsequently, further batches of Bifurcaria Bifurcata seaweed were collected from the French coast in June 2021 and March 2022 and frozen. Similarly, additional batches of seaweed were collected in Portugal in November 2021 and were either dried or frozen.

[0042] 6.2. Organic extractions made from aquatic extracts

[0043] Organic extractions with heptane, ethyl acetate (EtOAc) and butanol (BuOH) were therefore carried out from aqueous extracts of batches of French and Portuguese algae harvested respectively in August 2019 and July 2020.

[0044] The residual aqueous fraction was also recovered.

[0045] The activity of these organic extracts on Heligmosomoides bakeri larvae was studied:

[0046] - effectiveness on larval development

[0047] The obtained heptane EtOAc and BuOH fractions were tested at 1 g / L via a TDL as a first-line assay (Figure 1). A negative control with water was performed, as well as a control with 1% DMSO corresponding to the DMSO concentration of the organic extracts. These two control conditions did not show any inhibition of larval development. A similar test performed on the residual aqueous fraction showed that the active molecules were completely extracted by the organic solvents.

[0048] For both batches of French and Portuguese algae, the heptane and EtOAc fractions completely inhibited the development of larvae.

[0049] The inhibition of larval development is not, however, total with the BuOH extract (99% inhibition of larval development for the extract obtained from the batch of algae collected in France and only 13% for the extract obtained from the batch of algae collected in Portugal).

[0050] Post-hatching larval mortality test

[0051] The anthelmintic activity of the organic fractions was then further investigated using the post-hatching larval mortality test (Table 1). The three organic extracts were tested at different concentrations. While the BuOH extracts and residual aqueous fractions showed little impact on larval mortality even at 3 g / L, the EtOAc extracts were effective at 1 g / L and the heptane extracts had full activity at 0.5 g / L.

[0052] Table 1: Comparison of the nematicidal activity of different extracts of Bifurcaria bifurcata from France (frozen) and Portugal (dried) on freshly hatched larvae of Heligmosomoides bakeri

[0053] _ „ , C „oncentration Z -,one Mortal .ity • p-value

[0054] Extract type, France vs

[0055] (g / L) geographic (%± SD) Portugal

[0056] Control - 0 - 0.065 ± 0.34 France (cong) 12 ± 7 15 France (cong.) 100 ± 0 00 d

[0057] Results are from three independent experiments, with n=6 per sample each time.

[0058] The values ​​represent the mean mortality (%) ± standard deviation. nd: not determined These results indicate that the active molecules are mainly present in the heptane and EtOAc extracts, regardless of the origin of the batch of algae.

[0059] Factors influencing in vitro activity

[0060] To further explore the latest results obtained, and to determine which factor between the harvesting location or the algae preservation process most impacts in vitro biological activity, two batches of Bifurcaria Bifurcata algae harvested in November 2021 in Portugal were studied with different pre-treatments (drying or freezing). A TDL was carried out on the aqueous extracts of these two batches at 1 g / L as well as on the BuOH fractions at 1 g / L which correspond to the organic fractions where a difference in activity had been previously observed (Figure 2). The results obtained show a strong difference in activity between these two extracts, whether for the aqueous extracts or the BuOH extracts: the extract from frozen Portuguese algae shows a strong inhibition of larval development (88% for the aqueous extract and 85% for the BuOH fraction) unlike the batch of dried algae (< 10% for both extracts).These results demonstrate that the algae preservation process plays a major role in the availability or alteration of active molecules and therefore in the biological activity of the extracts.

[0061] 6.3. Organic extractions carried out from alaue biomass

[0062] Organic extractions were carried out directly on batches of algae harvested in France in August 2019 and in March and June 2021 and frozen as well as on batches of Portuguese algae harvested in 2021 (dried or frozen), concentrating the active compounds in the organic fractions without going through a first aqueous extraction step.

[0063] Test results with a TDL of 0.5 g / L EtOAc fraction are shown in Figure 3.

[0064] These show that there is no difference in activity between the batches studied and that all completely inhibit the development of larvae at a concentration of 0.5 g / L. It can be concluded that an extraction carried out directly from the algae biomass is substantially as effective as an aqueous extraction, regardless of the batch of algae used. 6.4. Exploration of the modes of action involved

[0065] 6.4.1. Characterization of active molecules

[0066] Samples of the heptane fraction were sent to a specialized NMR (Nuclear Magnetic Resonance) platform at the University of Western Brittany, France (UBO), in order to characterize the active molecules in these organic fractions of B. bifurcata.

[0067] Analysis of the NMR spectra (1H and 13C) made it possible to identify two different molecules present in this extract: eleganolone and a linear diterpene of the bifurcanol type (Figure 4).

[0068] 6.4.2. Exploration of modes of action by electrophysiology in Xenopus eggs Following the identification of eleganolone and a linear diterpene of the bifurcanol type in an extract of B. bifurcata, the mechanism and mode of action that could be involved in the observed biological activities were investigated. It has been shown in the scientific literature that certain terpenes target cholinergic receptors. Based on this work, the inventors investigated what the effects of B. bifurcata extracts could be on different receptors known to be the target of anthelmintics in two species of gastrointestinal nematodes, A. suum, a parasite of pigs, and P. equorum, a parasite of horses. These receptors are hetero- or homopentamers, therefore composed of 5 different or identical subunits.Several receptor families were therefore chosen, including nicotine-sensitive cholinergic receptors composed of the ACR-16 subunit of A. suum or P. equorum, and a Morantel-sensitive cholinergic receptor composed of the ACR-26 and ACR-27 subunits of P. equorum. These receptors were expressed on the surface of Xenopus laevis eggs, and electrophysiological measurements were performed to determine the potential agonist or antagonist effect of aqueous and organic extracts of B. bifurcata applied to these receptors.

[0069] Cholinereceptor N-AChR of Ascaris suum The first receptor that was studied is a cholinergic receptor of the parasite A. suum composed of 5 ACR-16 subunits forming a nicotine-sensitive receptor. It was expressed on the surface of Xenopus eggs and currents were measured using the Two-Electrode Voltage-Clamp method to determine the response of the receptor following the application of the natural ligand (100 pM of ACh) or following the application of aqueous extracts of B. bifurcata (at 1 g / L and 5 g / L) alone or in co-application with ACh.

[0070] The effect of an aqueous extract of B. bifurcata as an agonist on the nicotinic receptor formed by the ACR-16 subunit of A. suum in the Xenopus laevis egg expression system is illustrated in Figure 5 a), which shows examples of current signals recorded using the Two-Electrode Voltage-Clamp technique following the application of 100 pM acetylcholine, 1 g / L and 5 g / L aqueous extract of B. bifurcata alone or in co-application with ACh and in Figure 5 c) is a bar graph representation of the measured current values ​​and the dispersion observed on the measurements, following the application of 100 pM acetylcholine (ACh), 1 g / L and 5 g / L aqueous extract of B. bifurcata alone or in co-application with ACh

[0071] The effect of an aqueous extract of B. bifurcata as an antagonist on the nicotinic receptor formed by the ACR-16 subunit of A. suum in the Xenopus laevis egg expression system is illustrated in Figure 5 b), which presents examples of current signals recorded using the Two-Electrode Voltage-Clamp technique following the application of 100 pM acetylcholine, 1 g / L and 5 g / L of aqueous extract of B. bifurcata alone or in co-application with ACh and Figure 5 d), which is a bar graph representation of the measured current values ​​and the dispersion observed on the measurements, following the application of 100 pM acetylcholine (ACh), 1 g / L and 5 g / L aqueous extract of B. bifurcata alone or in co-application with ACh

[0072] It should be noted that in Figures 5c) and 5d), the current values ​​were normalized with the current amplitude obtained at the first application of 100 pM ACh. First, two successive applications of ACh at 100 pM were carried out in order to control the replicability of the effect of the natural ligand on the receptor. The observed results show that the receptor is correctly expressed on the surface of Xenopus eggs and that the effect is stable because the current amplitudes are comparable.

[0073] Application of the aqueous extract of B. bifurcata alone shows that there is no direct agonist effect on the N-AChR receptor of Ascaris suum. Indeed, no current amplitude is observed following the application of 5 g / L or 1 g / L of extract.

[0074] Conversely, when the B. bifurcata extract is applied at the same time as 100 pM of ACh, a decrease in the current amplitude normally obtained with ACh alone is observed. Indeed, when co-applied with 5 g / L of B. bifurcata, the current obtained is reduced by approximately 90% compared to ACh alone, and with 1 g / L of B. bifurcata, the current is reduced by approximately 50%. These results show a dose-dependent antagonistic effect of the aqueous extract of B. bifurcata. It is important to note here that after the different applications of the extracts of interest, the receptors recover correctly because the current amplitudes obtained with the third application of ACh are comparable to those of the first application of ACh.

[0075] To complement the initial results obtained, organic fractions of B. bifurcata were also tested on the N-AChR receptor of Ascaris suum (Figure 6). The first applications of ACh alone demonstrate stability of the current amplitudes obtained between the two applications. The fractions tested come from extracts obtained with the ethyl acetate solvent (Bif AE), using EtOAc directly without prior extraction with heptane (Bif AEP) and with the heptane solvent (Bif H). The extracts were tested at 0.01 g / L in co-application with 100 pM of ACh. It is observed that with the co-application of the Bif AE extract and ACh, a slight decrease in current is observed (approximately 10%) compared to ACh alone. The Bif AEP extract shows a decrease of approximately 25% of the current obtained compared to ACh alone. This result highlights a better efficiency of the fraction extracted with EtOAc directly and not after a first extraction with heptane.Finally, the co-applied heptane fraction induced a stronger antagonistic effect than the ethyl acetate fractions, inducing a decrease of approximately 75% of the current compared to ACh alone. A complete recovery of the receptors was observed with the last application of ACh alone. The results obtained showed that the organic fractions were significantly more effective than the aqueous fractions in inducing an antagonistic effect on these cholinergic receptors, and in particular the heptane fraction.

[0076] Roiou choline receptors N -AC h R and M-AChR of Parascaris equorum

[0077] The second receptors studied are cholinergic receptors of P. equorum, one sensitive to nicotine (N-AChR) and composed of the ACR-16 subunit, the other sensitive to Morantel (M-AChR) and composed of the ACR-26 and ACR-27 subunits. These receptors were also expressed on the surface of Xenopus eggs and the currents were measured using the Two-Electrode Voltage-Clamp method to determine the receptor response following the application of the natural ligand (100 pM of ACh) or following the application of aqueous extracts of B. bifurcata (at 1 g / L and 5 g / L) alone or in co-application with ACh (Figure 7).

[0078] The results obtained on these two receptors are very similar. They indicate that the application of aqueous extracts of B. bifurcata does not have a direct agonist effect. A slight effect is nevertheless observed for the 5 g / L extract on the Peq-M-AChR receptor with a current intensity of approximately 10% compared to the current intensity obtained with the natural ligand.

[0079] Concerning the antagonistic effects observed, during the co-application of 100 pM of ACh and 5 g / L of B. bifurcata, a decrease in current intensity of approximately 40% is observed on both receptors Peq-N-AChR and Peq-M-AChR. For the concentration of B. bifurcata at lg / L in co-application with AChR, a decrease of approximately 10% is observed for both receptors. These results show that there is also a dose-dependent antagonistic effect of the aqueous extract of B. bifurcata on the receptors of P. equorum. The results initially observed on a cholinergic receptor of the parasite A. suum, are confirmed here on another species of animal parasite of veterinary importance.

Claims

CLAIMS 1. A composition for use in the oral treatment of nematode helminthiasis, said composition comprising eleganolone and / or a linear diterpene of the bifurcanol type.

2. Composition for use in the oral treatment of nemathelminthiasis according to claim 1, characterized in that said eleganolone or said diterpene of bifurcanol type is present within an extract of Bifurcaria bifurcata, Cystoseira elegans or Cystoseira balearica incorporated in said composition.

3. Composition for use in the oral treatment of nemathelminthiasis according to claim 2, characterized in that said extract of Bifurcaria bifurcata, Cystoseira elegans or Cystoseira balearica is an aqueous extract of Bifurcaria bifurcata, Cystoseira elegans or Cystoseira balearica, an extract obtained by extraction of compounds from Bifurcaria bifurcata, of Cystoseira elegans or Cystoseira balearica in a solvent or an extract obtained by extraction of compounds of Bifurcaria bifurcata, Cystoseira elegans or Cystoseira balearica in an oil.

4. Composition for use in the oral treatment of nemathelminthiasis according to any one of claims 1 to 3, characterized in that said nemathelminthiasis is caused by organisms of the suborder Rhabditina and / or Spirurina and in particular caused by organisms of the family Ascarididae, Heligosomatidae or Trichostrongylidae.

5. Composition for use in the oral treatment of nemathelminthiasis according to any one of claims 1 to 4, characterized in that said nemathelminthiasis is caused by organisms resistant to anthelmintics belonging to the group of macrocyclic lactones, such as ivermectin, moxidectin and eprinomectin, and / or to the group of benzimidazoles, such as thiabendazole, and / or to the group of imidazothiazoles, such as levamisole and / or to the group of tetrahydropyrimidines, such as pyrantel.

6. Composition for use in the oral treatment of nemathelminthiasis according to any one of claims 1 to 5, characterized in that said nemathelminthiasis is intestinal nemathelminthiasis.

7. Process for the preparation of an anthelmintic intended to be administered orally comprising: - preparing a composition suitable for use in the oral treatment of nemathelminthiasis comprising eleganolone and / or a linear diterpene of the bifurcanol type, - encapsulating said composition in yeast particles or incorporating it into a gelatinized starch matrix.

8. Process for preparing an anthelmintic according to claim 7, characterized in that said anthelmintic is effective against organisms of the suborder Rhabditina and / or Spirurina and in particular organisms of the family Ascarididae, Heligosomatidae or Trichostrongylidae.

9. A process for preparing an anthelmintic according to any one of claims 7 and 8, characterized in that said anthelmintic is effective against organisms resistant to anthelmintics belonging to the group of macrocyclic lactones, such as ivermectin, moxidectin and eprinomectin, and / or to the group of benzimidazoles, such as thiabendazole, and / or to the group of imidazothiazoles, such as levamisole and / or to the group of tetrahydropyrimidines, such as pyrantel.

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