Veterinary combination and method of controlling fleas

 

(57) Abstract:

The invention relates to the field of veterinary medicine and can be used for controlling fleas in animals. Veterinary combination for controlling fleas contains effective against fleas, the number of combinations of the compounds of formula (I)

where

R1denotes hydrogen, C1-C6alkyl or C3-C7cycloalkyl;

R2denotes hydrogen, C1-C6alkyl or C3-C7cycloalkyl;

R3denotes hydrogen or C1-C6alkyl; and

And indicates heterocyclyl, which is unsubstituted or substituted by one or more identical or different halogen atoms;

and the compounds of formula (II)

where

X denotes halogen;

X1denotes hydrogen or halogen;

X2denotes hydrogen or halogen;

Y denotes a partially or completely halogenated WITH1-C6alkyl or fully halogenated1-C6the alkyl chain of which includes an oxygen atom, or partially or completely halogenated WITH2-C6alkenyl;

YUB> denotes hydrogen or halogen;

Z1denotes hydrogen or C1-C3alkyl; and

Z2denotes hydrogen or C1-C3alkyl, and physiologically acceptable excipient for the combination. Method of controlling fleas on Pets provides a systematic introduction a combination of the p. 1 domestic animal in an amount that is effective against fleas, and the combination administered orally by, and the compound of formula (I) and the compound of formula (II) are administered in separate dosage forms, but at the same time with each other, or first enter the compound of the formula (I), and then make processing a compound of formula (II). The invention provides 99-100% mortality of fleas. 2 S. and 3 C.p. f-crystals, 3 tables.

The present invention relates to veterinary compositions based on the use of a combination of the following nitroenamine derivatives of the formula (I) and also the following derivatives benzoylacetone formula (II), and to their use for system controlling fleas on Pets, and for obtaining and using such compositions and combinations.

Thus, the present invention relates to veterinary compositions for combating fleas">

where R1denotes hydrogen, C1-C6alkyl or C3-C7cycloalkyl;

R2denotes hydrogen, C1-C6alkyl or C3-C7cycloalkyl;

R3denotes hydrogen or C1-C6alkyl;

And indicates heterocyclyl, which is unsubstituted or substituted by one or more identical or different halogen atoms;

and the compounds of formula (II)

where X denotes halogen;

X1denotes hydrogen or halogen;

X2denotes hydrogen or halogen;

Y denotes a partially or completely halogenated C1-C6alkyl or completely halogenated C1-C6the alkyl chain of which includes an oxygen atom, or partially or completely halogenated WITH2-C6alkenyl;

Y1denotes hydrogen or halogen;

Y2denotes hydrogen or halogen;

Y3denotes hydrogen or halogen;

Z1denotes hydrogen or C1-C3alkyl;

Z2denotes hydrogen or C1-C3alkyl, and physiologically acceptable excipient for componentname insecticide.

The most representative compound from the group nitroenamine derivatives of the formula (I) is nitenpyram formula (III)

has the following name in accordance with IUPAC classification: (E)-N-(6-chloropyridin-3-ylmethyl)-N-ethyl-N’-methyl-2-nitrobenzylidene. Nitenpyram and access is described in EP-0302389 in example 41 on page 63. In this published application describes a fairly large group of nitroenamine, among which nitenpyram represents only one representative compound from among the above. These nitroenamine described in the proposal as contact and contact insecticides acaricides. Other nitroenamine described in EP-0302833. From EP-0616494 known that nitenpyram can also be given pet by mouth. In WO 95/33380 proposed synergistic effect of the combination of lufenuron with many other pesticides, including nitenpyram. However, proposed in this application combinations are pesticide compositions intended for the treatment of leaf surface of the plants to protect plants from pest infestation.

In US-5420163 and cited in the patent literature describes Aachener>The compounds of formula (II), where X denotes F, X1denotes 6-F; X2denotes H; Y denotes CF2CHFCF3; Y1denotes 2-F; Y2denotes 3-CL, Y3denotes 5-CL; Z1denotes H, methyl or ethyl; and Z2denotes H, methyl or ethyl, and at least one of Z1and Z2denotes methyl or ethyl, are described in WO 98/19542.

The compounds of formula (II), where X denotes F; X1denotes 6-F; X2denotes H; Y denotes CF2FF3; Y1denotes 2-F; Y2denotes 3-CL, Y3denotes 5-CL; Z1denotes H, methyl or ethyl; and Z2denotes H, methyl or ethyl, and at least one of Z1and Z2denotes methyl or ethyl, are described in WO 98/19542.

The compounds of formula (II), where X denotes F; X1denotes 6-F; X2represents N; Y represents CF2CHFCF3; Y1denotes 3-CL; Y2denotes H, Y3denotes 5-CL; Z1denotes H, methyl or ethyl; and Z2denotes H, methyl or ethyl, and at least one of Z1and Z2denotes methyl or ethyl, are described in WO 98/19543.

The compounds of formula (II), where X denotes F; X1denotes 6-F; X2MBT 2-H or F; Y2denotes 3-CL, Y3denotes 5-CL; Z1represents H; and Z2denotes H, described in WO 98/19995.

The compounds of formula (II), where X denotes F; X1denotes 6-F; X2represents N; Y represents CF=FF3or CF2CF2=FF3; Y1denotes 3-Cl; Y2denotes H, Y3denotes 5-CL; Z1represents H; and Z2denotes H, described in WO 98/19994.

Combinations of the compounds of formula (II), where X denotes F; X1denotes 6-F; X2represents N; Y represents CF2FF3; Y1denotes 3-CL; Y2denotes H, Y3denotes H; Z1represents H; and Z2denotes H, with other anti-parasitic agents are described in WO 98/25466.

One of the famous representative of compounds of formula (II) is lufenuron described in EP-0179021. This compound is an (R,S)-1-[2,5-dichloro-4-(1,1,2,2,3,3,3-hexaphosphate)phenyl]-3-(2,6-differentail)urea.

Another well-known representative compound of the formula (II) is novaluron described in EP-0271923. This connection is represented by (±)-1-[3-chloro-4-(1,1,2-Cryptor-2-cryptometrics)phenyl]-3-(2,6-differentail)urea.

Alkyl group, plicata carbon atoms and they may constitute, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl, and their branched isomers, for example, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl or isohexyl. WITH3-C7cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Typical radicals Y, which are partially or completely halogenated WITH1-C6alkyl or fully halogenated1-C6the alkyl chain of which contains one oxygen atom, or partially or completely halogenated WITH2-C6alkenyl, are:1-C6alkyl radicals are straight chain or branched, partially or completely replaced by identical or different halogen atoms, the carbon chain of which has no gap or includes in one position of the oxygen atom, or WITH2-C6alkeneamine radicals with a straight chain or branched, having the double carbon bond, such as OCF3OC2F5OS3F7OC4F9OC5F11OS6F13, F(CF3)2, F(C2F5)(CF3), OCF(C2F5)(C2F5), F2F3, OCF2OCF(C2F53, F2CF2=FF3, F2(CF3)CF2=FF3, F2Cl3, F2Gl2, OCF2CHF2, OCF2CFCl2, F2ADHD2, OCF2CHClF, co2Snugs2VG, OCF2CHBrF, OCClFCHClF and so on Alkoxyalkyl come from the above alkyl groups. The term "halo" means a halogen and usually denotes fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, especially chlorine, thus partially or fully halogenated Deputy may contain one or more identical or different halogen atoms. Taking into account the number of carbon atoms in each case in a respective group of alkenyl can be either straight chain, for example, vinyl, 1-methylvinyl, allyl, 1-butenyl or 2-hexenyl, or branched, for example, Isopropenyl.

In the context of the present invention, the concept heterocyclyl denotes an aliphatic or aromatic cyclic radicals containing at least one atom of oxygen, sulfur or nitrogen. Preferred are 5 - and 6-membered heterocycles. Heterocyclyl usually contain substituents, for example, DIOXOLANYL, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrrolyl, peril, shrill, thiazolyl, oxazolyl, oxazolidinyl, imidazolines, imidazolidinyl and dioxane. Preferred are radicals, which are unsubstituted or have one or two halogen atom, in this case, halogen denotes fluorine, chlorine or bromine, especially chlorine. Among these heterocyclic radicals especially pyridyl, thiazolyl and tetrahydrofuryl. However, the most preferred are 6,5-dichloropyridine-3-yl, especially 6-chloropyridin-3-yl, and 5-chlorothiazole-3-yl and tetrahydrofur-3-yl, in particular 6-chloropyridin-3-yl. In the context of the present description specifically mentioned radicals are considered as the preferred options for implementation.

When considering the kinetic characteristics of both classes of substances, namely, nitroenamine derivatives of the formula (I) and derivatives benzoylacetone formula (II), it was found that after the introduction into the organism of an animal benzoylacetone are characterized by a slow increase in their levels in the blood and high levels in the blood for extended periods of time. This means that, although the activity grows very slowly, it remains at a high level for an extended period of time. In General, proizvodi the Denia. However, their effect lasts for several weeks or even several months. In contrast, nitroenamine exert their activity almost immediately after the introduction, but their effect lasts only a few hours or 1-2 days.

Although both classes of compounds are insecticides, they are characterized by completely different mechanisms of action. In fact, both classes of compounds disrupt the life cycle of the insect, but each class of compounds makes it to his specific way. While nitroenamine derivatives belong to the so-called adulticides (imageteam), which act as contact poisons, derived benzoylacetone belong to the class of ovicidal or larvicides depending on the concentration values. This means that nitroenamine derivatives as contact poisons basically kill adult insects living on the animal host, whereas derivative benzoylacetone not affect the adult fleas, but prevents the deposition of eggs, or result in the deposition of sterile eggs, or block the transition from one stage to the next juvenile stages.

Nitroenamine fomula (I) have a very high epost, i.e., topically to the skin of an infected pet. They also have a certain system activity, i.e., if they are infected domestic animal orally, parenterally or by injection. From EP-0616494 known, for example, that nitenpyram in vitro starts to show significant activity after 30 min, i.e., after absorbing the fleas blood containing the insecticide. 100% activity is achieved after 24 hours In this application also describes that after 6 h after oral administration to cats activity nitenpyram against fleas present on cats, reaches 60%, and on the second day after reinfection he still retains 55% activity. From this we can conclude that to achieve full activity nitenpyram you must enter through the mouth at intervals of one or two days that is difficult for the owner of the animal.

Infestation by fleas Pets still represents for the veterinarian and pet owner to the problem, for which so far there is no satisfactory solution.

Fleas have a very complex life cycle. This is also the reason why none of the known methods of dealing with them is not on the fur of a pet and does not affect different juvenile stages of fleas who live not only in animal fur, but also in the floor, carpets, bedding for animals, in chairs, in the garden and in all other places, with which an infected animal comes into contact with, or intended to combat juvenile stages.

Adult cat and dog fleas (Ctenocephalides felis and C. canis) usually live as blood-sucking parasites in wool cat-owner or dog owner. They feed on the blood of an animal host and lay eggs in his hair. However, since these eggs do not have the ability to stick, they usually quickly fall away and can be on the floor, carpets, cages for dogs or cats, chairs, visited the animals in the garden in the back yard and all the places that you visit an infected animal.

This means that all the living area, where there is a pet becomes infected with the eggs of the fleas, of which under normal conditions two days later hatch into larvae. There are three stages of development of larvae, each of which lasts three days. At the last stage, the larva makes a cocoon and becomes a pupa. Under favorable conditions, i.e. at 33°C and at a relative humidity of 65% of the transformation from egg to pupa takes approximately carpets, in the litter, chairs, etc. Young adult fleas remain in these areas until such time as they will not feel the presence of suitable animal host, after which they hatch from the cocoon and try to jump on an animal host. From here, you can see that it takes at least three weeks to a young flea that developed from eggs, was able to infect an animal host.

However, depending on environmental conditions this young flea can remain in its cocoon for several months, perhaps up to a year. On the other hand, in less than optimal conditions, development from egg to adult immature flea may require 4-5 months. To reach sexual maturity fleas require blood as nutrients for the fact that they were capable of reproduction, and, moreover, the blood must belong to the right animal to the owner.

This long life cycle with different stages, which is also partially takes place regardless of an animal host, requires special compositions and methods for controlling fleas, which were hitherto not developed.

Even if the fleas in the fur of a pet can oshki or dog remains constant risk of re-infection after a few weeks or even months again valuewise fleas from the environment of the animal. Starts a vicious circle, leading to constant re-infection, even if the pet is not in contact with infected animals of the same species. The owner of the animal often can't see the end of this process, because it simply detects that it has successfully processed an animal after a short period of time again infected fleas. This often leads to frustration and denial, apparently, inefficient processing.

Infestation by fleas dogs and cats has unpleasant side effects not only on the animal that you want to process, but also on its owner. Flea bites cause, for example, to local skin irritation or annoying itch and often cause serious scratching and damage to the skin, and therefore able to begin a serious infection. A significant number of animals exposed to frequent bites, over time, become allergic to discharge fleas, which leads to severe itching and the appearance of scab on the skin around the bites on the body of the animal. These changes of the skin typically have a diameter of approximately 3 mm or more and often do animals irritable and cause them to itch, so that they partially Terumi Dipylidium, a form of solitaire, which is transmitted infecting fleas, control is very difficult.

Infestation by fleas not only bother infected animal, but also has very unpleasant consequences for the owner, because he finally realizes that his pet behaves in an unusual way and is sick and suffering, and that he should help him. In addition, the owner may be unpleasant consequences if he has to part with an animal, or it dies, or it is temporarily removed from the home environment, as the newly hatched fleas in the floor can even be the need to attack people, if long time no suitable animal host, although they can't reproduce, if the only source of food is human blood. The owner may be bitten by fleas, even if there is a dog or a cat.

In addition, dog or cat fleas or their excrement can cause many people problems with skin similar to allergies, which in many cases force the owner to abandon a pet. Thus, there is constantly the need for effective since they have various shortcomings. If the owner uses against flea combs, the only way is thorough and frequent combing wool of an animal that can take a long time depending on the size of the animal and may be unacceptable to some wildlife species. Also not every owner is willing or able to spend the time necessary for this. In some cases, the relevant shampoos with activity against fleas, cannot be successfully used as, in particular, cats and many dogs not allow the owner to bathem, or it requires great effort. In addition, the effect of such treatment by bathing lasts a maximum of approximately one week, after which all painful procedure must be repeated. The same or very similar problems arise when using immersion in the solution for the destruction of vermin or washing them. The use of dusting powders also usually is not acceptable due to the resistance of the animal, as for uniform treatment of the entire surface of the skin takes a few minutes, the dust inevitably reaches the mouth, nose and eyes. Even with careful application cannot be excluded the possibility that the powder at vdyh is more or less close contact with the composition.

When using sprays, many owners are faced with an unpleasant surprise, as most animals, primarily cats, turned to flight or exhibit violent reaction as soon as they hear the sound of splashing. Moreover, the sprays have all the disadvantages listed for powders, and, in addition, they give a fine dispersion in the atmosphere and therefore inhaled by people and animals. Fleas also often struggle with the so-called collars against fleas, which have good efficiency in the short term. A certain drawback of this treatment is, in particular, is a very limited scope. Insecticidal activity in the neck and chest is usually 100%, however, the deleted parts of the body come under strong attack in addition, these collars have a time limit action. In addition, many of these collars are unattractive and can interfere with the animal. Currently you can buy discs that pereveshivaut on a regular collars and which possess insecticidal activity. They have a nice appearance, but their activity is unsatisfactory as skin contact is the week the Institute of fleas, which is used in the form of compositions applied in the form of spots, and which, therefore, applied to the hair in limited space. In General, they are a good short-term activity against adult fleas, however, the applied composition often create problems related to toxicity level. Organophosphorus compounds are sometimes also be administered orally, however, for them there are strict security restrictions, and under no circumstances they should not be administered simultaneously with other organophosphorus compounds.

In General, we can conclude that by this time developed many methods of killing adult fleas and some of them allow a good control within a short period of time. However, previously underestimated the fact that because of the peculiar life cycle of fleas dogs and cats are always re-infection, on the one hand, due to the fact that contact with the eggs of the fleas, the larvae of fleas and immature adult fleas on the floor or in the immediate environment of the animal is unavoidable, and, on the other hand, due to the fact that many Pets again and again come into contact with infected animals etagere, we have developed special arrangements designed to disinfect places of dogs and cats. However, disinfection is effective only when at the same time handled the animal itself.

Further, on the basis of certain benzoylation, such as lufenuron, we developed a class of compounds that have activity specifically in relation to juvenile stages of fleas. Their use leads to very effective to interrupt the life cycle of fleas, however, it does not occur immediately after the start of treatment.

In General, infestation by fleas Pets is a problem that is not solved satisfactorily until now. The reason for this is described very complex life cycle of fleas, including various juvenile stages, which live not only on the animal host, but also sometimes in its environment, which makes combat much more difficult. This is also the reason why none of the known methods of struggle is not satisfactory from the point of view of long-lasting action. Comprehensive flea prevention at the present time is in parallel using multiple claiming the Sith from the processing not only of the infected animal, for example, dogs or cats, but, in addition, and disinfection of all the places that you visit an infected animal. The owner of the animal must not only perform work for disinfection, but it must also be borne in mind that when this happens pollution active ingredients.

Now, if Pets must be subjected to a full and lasting protection against juvenile and adult stages of the fleas should be used several different methods of processing. For the destruction of adult insects on domestic animal usually applied locally over short intervals of high-speed contact ImageReady, while the fight against juvenile stages is performed with the use of oral administration of drugs prolonged. The destruction of all stages of living surrounded by pet, is carried out by re-disinfection of all places visited by the pet. For a long time for veterinarians and pet owners there is a need for a simple but effective way to fight.

Still various efficiency and, above all, very different on the La ovicidal or larvicides, for example benzoylation kept specialists in this field from a combination of both classes of substances.

In addition, there have been numerous unsuccessful attempts to overcome short time steps, which is very unsatisfactory for practical primeneniya by systemic injections of nitroenamine. It was found that increasing the duration of systemic effects by increasing the concentration of introduced substances can only be achieved to a certain point, because the active substance is excreted too quickly. On the other hand, if it is desirable under the skin or into the muscle to put the form in the form of a depot which releases the active substance in a few weeks, it turns out that the quantity to be injected or implanted, is so large that it becomes unacceptable for a pet, because it causes significant irritation. Therefore, this solution is unacceptable because of ethical or practical reasons. It was also found that increasing the duration by increasing the dose, administered by mouth, is the exclusion is of duration. When ingested by, for example, in the form of tablets, nitroenamine absorbed and dispersed in the blood in the gastrointestinal tract very quickly, but they also quickly eliminated from the body with urine. The half-life in blood of about 7-9 hours for cats and approximately 3-5 h for dogs, is too small in order to increase the efficiency by increasing the dose. After the introduction, there is a very sharp increase in blood levels, as well as a very quick exit curve of the plateau, this is not a significant impact on the increase in the duration of the biological availability. This has a serious impact on medicinal products for systemic use, for example, tablets or solutions for injection. Due to the short duration of pills or injections should be introduced at short intervals of time, preferably every day, this means that the owner of the animal must repeat the treatment or to visit a vet too often. The concept of intensive treatment of this kind requires considerable discipline, and experience suggests that it is already after a short time causes stress to the animal and its owner. This cha is the time the objective was to increase the duration of the systemic effects of this highly active class of compounds, however, it is clear that she was not achieved.

Although nitroenamine derivatives of the formula (I) exhibit sufficient activity against fleas only during the period of time from a few hours up to a maximum of 2 days after administration of the oral route domestic animal, with the invention it has been unexpectedly found that the duration of action is increased at least up to two weeks, when combined with derivatives benzoylacetone formula (II). One would expect that the introduction of lufenuron nitenpyram you must enter the full treatment with weekly intervals to maintain the full broad spectrum of action against all stages of development. However, in this case it is not. Unexpectedly, it was found that treatment nitenpyram provides full protection for 6 weeks. Completely unexpected was that after that there is no re-infection. This is even more surprising since nitenpyram can be entered even with an interval of two weeks.

In General, when creating the present invention, it was found that by systemic administration, e.g. oral, parenteral or with implant, abnormaly (I) and the compound of formula (II), can be completely prevented infestation by fleas Pets, starting from the second week after treatment and throughout the treatment period, while in the environment of a pet fleas are absent for an extended period of time. This is not observed when processing only nitenpyram or only lufenuron.

This desired effect is not achieved only after the injection or insertion of the implant, but also after oral administration, i.e., in a roundabout way through the gastrointestinal tract and through containing insecticide blood.

As the compounds of formula (I) and the compounds of formula (II) are distinguished by their very high activity against fleas, and by combining the compounds of formulae (I) and (II) is achieved not only fast insecticidal activity against adult fleas, but also in respect of all juvenile stages of fleas. Flea larvae, which hatch from eggs of the fleas, mainly feed on faeces of adult fleas. Because the composition of the invention also quickly kill adult fleas, it is necessary excrement, which constitute the staple food of juvenile stages are absent. This is the basis for food in this case is missing, so the juvenile stages of ponies die as a result of contact action.

Thus, the present invention relates to a system devoid of the above problems, and above all to full with activity over a long period of time, the way of dealing with fleas, which begins immediately after injection and lasts for a long period of time.

For the invention it is essential that the composition of the invention are introduced systematically. It is preferable to oral administration, preferably an introduction using tablets or suspensions. High activity is also achieved using other routes of administration, for example, by injection of the compounds included in the composition, or by mixing with food. In the context of the present invention, the term "included in the composition means, for example, included in the composition of powder, tablets, granules, capsules, emulsions, suspensions, foams, microencapsulated form, and so on, in this case, as mentioned above, the composition need not necessarily be administered to the animal directly, it also can be mixed with his food. Of course, all introduced by oral compositions may contain other additives in addition to the usual excipients for the compositions. These additives Upham, the corrigentov and/or improving the taste of the substance.

Due to its simple applicability in practice oral administration is one of the preferred objects of the invention. Another type of injection is parenteral administration, for example, by subcutaneous injection or injection into a vein, or a drug for sustained release (depot) in the form of an implant.

Oral administration includes, for example, the introduction of food for dogs or cats that contains a combination according to the invention already mixed compounds of formulas (I) and (II), for example, in the form of biscuits or tidbits, gum, water-soluble capsules or tablets, water-soluble forms that can be added in the form of droplets in the feed, or in other forms that can be mixed with animal feed. Implants also include all devices that can be introduced into the body of the animal for delivery of a substance, for example, so-called Minnesota.

Form for intradermal injection include, for example, forms for subcutaneous, cutaneous, intramuscular and even intravenous injectable forms. In addition to this conventional syringes with needles can be used device type rifles without and which of the combinations according to the invention through the living tissue of an animal or to maintain its availability. This is important, if applied poorly soluble composition, the low solubility which requires funds to increase the solubility, since the total water body of the animal is able to dissolve only small amounts of the substance over time.

In addition, the combination according to the invention can also be present in the matrix composition to provide a significant slow release of the active substance, with the matrix composition is physically prevents vysvobojdenie and premature separation of the active substance and retains its biological availability. The matrix composition is injected into the body, for example subcutaneously or intramuscularly, and it remains there in the form of a depot from which continuously releases the active substances. Such matrix compositions known to specialists in this field. Usually they are a waxy semi-solid substances, for example, vegetable waxes and polyethylene glycols with a large molecular weight. Compositions containing the active substance may be either a single matrix or in different matrices, which if necessary can be used in different parts of the body.

The rate of release of active substances from the implant and the resulting time during which the implant has an activity is usually determined by the precision of the implant (the number of the active substance in the implant), the environment in which is placed the implant, and a polymer composition which is used to implant.

Introduction the combination according to the invention with implant is another preferred component of the present invention. This type of introduction is ekonomiczna in the tissue of an animal host. Currently, the implants can be created and implanted in a simple way, and they can release the active substance in a few months. After insertion of the implant, there is no need again to disturb the animal and also not have to worry about the input dose of medication.

In the field of veterinary medicine is well known, the introduction of additives in animal feed. Usually, first of all, prepare a so-called premix in which the active substances dispersed in a liquid or evenly distributed in hard copy. This premix can usually contain depending on the desired final concentration in the feed is from about 1 to X g nitroenamine formula (I) and from about 1 to Y g benzoylacetone formula (II) per 1 kg of premix, where X and Y have values from 10 to 15 depending on the body weight of an animal host.

Because the effectiveness of the combinations according to the invention can be influenced by components of the feed, preferably enclosed in a protective matrix, for example, gelatin, before adding to the premix.

The present invention also relates to a method of controlling fleas, characterized by the introduction of the animal to the owner of the combination of active substances according to the Institute of formula (I) from 0.01 to 800 mg/kg, preferably from 0.1 to 200 mg/kg, most preferably from 0.5 to 30 mg/kg of body weight of an animal host; benzoylacetone formula (II) from 0.01 to 800 mg/kg, preferably from 0.1 to 200 mg/kg, most preferably from 0.5 to 30 mg/kg of body weight of an animal host; however, oral administration is preferred in comparison with other routes of administration.

Acceptable dose, which can regularly be entered domestic animal, is 0.5-100 mg of nitroenamine formula (I)/kg body weight twice or preferably once a week with the parallel introduction of 0.5-100 mg benzoylacetone formula (II)/kg body weight once in one to three months. The interval between the introduction of benzoylacetone formula (I) may even be increased at a later stage of treatment up to six months, with the addition of nitroenamine formula (I) can be excluded, if contamination of the environment pet, slightly.

The introduction of a combined composition comprising nitroenamine formula (I) and benzoylacetone formula (II) can be done in many different ways.

The user, veterinarian, treating, or the owner of the animal, may be specially designed for this primer, tablets containing certain single dose of the active substance to be applied according to a certain scheme introduction, or specifically characterized by standard doses, for example, tablets that contain both active substances in one tablet in the appropriate concentrations, and which should be entered at specified intervals of time.

The total dose of the same active substance may vary depending on animal species and even within one species, because it depends, among other things, the weight, age and Constitution of a pet.

In the composition of the combinations according to the invention the active substances are usually entered not in pure form, but is preferably in the form of a composition or formulation, which contains in addition to the current substance enhancing the efficiency of introduction of the components or excipients for the compositions, however, such components are acceptable for a pet.

Such compositions or formulation used according to the invention usually contain from 0.1 to 99 wt.%, preferably from 0.1 to 95 wt.% nitroenamine formula (I) or benzoylacetone formula (II) or both dejstvo media containing from 0 to 25 wt.%, preferably from 0.1 to 25 wt.% non-toxic surfactants.

Whereas for sale preferably prepared products as concentrates, the end user typically uses dilute compositions.

Such compositions for specific purposes may also contain other additives, such as stabilizers, protivovspenivayushchie agents, viscosity regulators, binders or adhesives, as well as other active ingredients.

Excipients that can be used for compositions that are physiologically acceptable carriers known in veterinary medicine and used for oral and parenteral administration and for injection through the implant. Some examples are given below.

Suitable carriers are in particular fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, preparations based on cellulose and/or calcium phosphates, for example tricalcium phosphate or acid phosphate of calcium, in a broader sense, also binders, such as starch pastes, based on, for example, corn, wheat, rice or potato krahm the crystals, in a broad sense also carboxymethylate starch, cross-linked polyvinylpyrrolidon, agar, alginic acid or its salt, such as sodium alginate. As the excipients can primarily be applied substances that improve the fluidity and oil, for example, silicic acid, talc, stearic acid or its salts, such as magnesium stearate or calcium, and/or polyethylene glycol. At the core of the tablets can be coated with suitable appropriate resistant to the action of gastric juices coating, using, inter alia, concentrated sugar solutions, which may include gum Arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or solutions for the coatings on the basis of suitable organic solvents or mixtures of solvents, or for the preparation of resistant to the action of gastric juices coatings, solutions of suitable cellulose preparations, such as cellulose acetate phthalate or phthalate of hydroxypropylmethylcellulose. The tablets or coatings for tablets can be added dyes, corrigentov or pigments, for example for identification purposes or to indicate different doses of active ingredient.

Other compositions for pereraadio of gelatin and a plasticizer, such as glycerol or sorbitol. Capsules with solid coating can contain the active substance in the form of granules, for example, in a mixture with fillers, such as lactose, binders, such as starches, and/or substances that improve the slip, such as talc or magnesium stearate, and, if necessary, with stabilizers. Capsules, soft coated active substance is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, may also be added stabilizers. Among other preferred forms are capsules that can be easily chewed and swallowed whole.

Compositions for parenteral administration are primarily aqueous solutions of active ingredients in water-soluble form, for example, in the form of soluble salts, in a broad sense also suspensions of the active substances, such as appropriate oily suspension for injection containing suitable lipophilic solvents or carriers, such as oils, for example sesame oil, or synthetic fatty acid esters, for example, etiloleat, or triglycerides, or aqueous suspension for injection is optionally stabilizers.

The compositions of the present invention can be prepared with well-known methods, for example using conventional mixing, granulation, coating, dissolving or lyophilization.

Pharmaceutical compositions for oral administration can be prepared, for example, by consolidating existing (it) substances with solid carriers, optionally pelletizing the resulting mixture and processing the mixture or granules, if desired or necessary, to obtain tablets or cores tablets after the addition of suitable excipients.

The introduction of the combinations according to the invention can be carried out either by preparation of both active substances in the form of a true mixture, separate dosage forms, and the introduction of its domestic animal, or by introducing a pet active ingredients in separate dosage forms, so that the active substances are mixed with each other only in the shared water body, especially in blood. The latter method has the advantage that the active agents can also be administered through various time intervals. For example, benzoylacetone, which has the efficiency for DL is more General short-term effect, can be entered with a few shorter time intervals. This method leads to the reduction of the used quantity of active substances.

You can also make an introduction with the use of available animal owner's packaging, in which a separate dosage forms contain different amounts of benzoylacetone and nitroenamine derived, while the consumer realizes introduction according to a certain scheme introduction.

Thus, in the combinations according to the invention or use of the compounds of formulas (I) and (II) according to the invention the active substances in dosage form can be a true mixture, however, they can also be entered individually and form a mixture within a host organism. Fundamental is the fact that they continue to are present together during certain periods of time in the host organism, resulting in the desired effect.

Preferred compounds of formulas (I) and (II) according to the present invention are presented in the following tables 1 and 2.

Preferred are, in particular, the following combinations of the 1.01 and 2.10; 1.01 and 2.11; 1.01 and 2.12; and 2.13 1.01; 1.01 and 2.14; and 2.15 1.01; 1.01 and 2.16; 1.01 and 2.17; 1.01 and 2.18; and 2.19 1.01; 1.01 and 2.20; 1.01 and 2.21; 1.01 and 2.22; 1.01 and 2.23; 1.01 and 2.24; 1.01 and 2.25; 1.01 and 2.28; 1.01 and 2.29; 1.01 and 2.30; 1.01 and 2.31; 1.01 and 2.32; 1.01 and 2.33; 1.01 and 2.34; 1.02 and 2.01; 2.02 1.02 and; 1.02 and 2.03; 1.02 and 2.04; 2.05 1.02 and; 1.02 and 2.06; 1.02 and 2.07; 2.08 1.02 and; 1.02 and 2.09; 1.02 and 2.10; 1.02 and 2.11; 2.12 1.02 and; 1.02 and 2.13; 1.02 and 2.14; and 2.15 1.02; 1.02 and 2.16; 2.17 1.02 and; 1.02 and 2.18; 2.19 1.02 and; 1.02 and 2.20; 1.02 and 2.21; 1.02 and 2.22; 1.02 and 2.23; 1.02 and 2.24; and 2.25 1.02; 1.02 and 2.28; 1.02 and 2.29; 1.02 and 2.30; 1.02 and 2.31; 1.02 and 2.32; 1.02 and 2.33; 1.02 and 2.34; 1.03 and 2.01; 2.02 1.03 and; 1.03 and 2.03; 1.03 and 2.04; 2.05 1.03 and; and 2.06 1.03; 1.03 and 2.07; 2.08 1.03 and; 1.03 and 2.09; 1.03 and 2.10; and 2.11 1.03; 1.03 and 2.12; and 2.13 1.03; 1.03 and 2.14; 2.15 1.03 and; 1.03 and 2.16; 2.17 1.03 and; 1.03 and 2.18; and 2.19 1.03; 1.03 and 2.20; 1.03 and 2.21; 1.03 and 2.22; 1.03 and 2.23; 1.03 and 2.24; 1.03 and 2.25; 1.03 and 2.28; 1.03 and 2.29; 1.03 and 2.30; 1.03 and 2.31; 1.03 and 2.32; 1.03 and 2.33; 1.03 and 2.34; 1.04 and 2.01; 2.02 1.04 and; and 2.03 1.04; 2.04 1.04 and; 1.04 and 2.05; 2.06 1.04 and; 1.04 and 2.07; 2.08 1.04 and; 1.04 and 2.09; 1.04 and 2.10; 1.04 and 2.11; 2.12 1.04 and; 1.04 and 2.13; 2.14 1.04 and; 1.04 and 2.15; 1.04 and 2.16; 2.17 1.04 and; 1.04 and 2.18; 2.19 1.04 and; 1.04 and 2.20; 1.04 and 2.21; 1.04 and 2.22; 1.04 and 2.23; 1.04 and 2.24; 1.04 and 2.25; 1.04 and 2.28; 1.04 and 2.29; 1.04 and 2.30; 1.04 and 2.31; 1.04 and 2.32; 1.04 and 2.33; 1.04 and 2.34; 1.05 and 2.01; 2.02 1.05 and; 1.05 and 2.03; 1.05 and 2.04; 1.05 and 2.05; 1.05 and 2.06; 2.07 1.05 and; 1.05 and 2.08; 1.05 and 2.09; 1.05 and 2.10; 1.05 and 2.11; 2.12 1.05 and; 1.05 and 2.13; 1.05 and 2.14; and 2.15 1.05; 1.05 and 2.16; 2.17 1.05 and; 1.05 and 2.18; and 2.19 1.05; 1.05 and 2.20; 1.05 and 2.21; 1.05 and 2.22; 1.05 and 2.23; 1.05 and 2.24; 1.05 and 2.25; 1.05 and 2.28; 1.05 and 2.29; 1.05 and 2.30; 1.05 and 2.31; 1.05 and 2.32; 1.05 and 2.33; 1.05 and 2.34; 1.06 and 2.01; 2.02 1.06 or; 1.06 and 2.03; 1.06 and 2.04; 2.05 1.06 or; 1.06 and 2.06; 2.07 1.06 or; 1. the 2.22; 1.06 and 2.23; 1.06 and 2.24; 1.06 and 2.25; 1.06 and 2.28; 1.06 and 2.29; 1.06 and 2.30; and 2.31 1.06; 1.06 and 2.32; 1.06 and 2.33; 1.06 and 2.34; 1.07 and 2.01; 2.02 1.07 and; 1.07 and 2.03; 1.07 and 2.04; 2.05 1.07 and; 1.07 and 2.06; 1.07 and 2.07; 2.08 1.07 and; 1.07 and 2.09; 1.07 and 2.10; 1.07 and 2.11; 2.12 1.07 and; 1.07 and 2.13; 2.14 1.07 and; 1.07 and 2.15; 1.07 and 2.16; 2.17 1.07 and; 1.07 and 2.18; and 2.19 1.07; 1.07 and 2.20; 1.07 and 2.21; 1.07 and 2.22; 1.07 and 2.23; 1.07 and 2.24; 1.07 and 2.25; 1.07 and 2.28; 1.07 and 2.29; 1.07 and 2.30; 1.07 and 2.31; 1.07 and 2.32; 1.07 and 2.33; 1.07 and 2.34; 1.08 and 2.01; 2.02 1.08 and; 1.08 and 2.03; 1.08 and 2.04; 2.05 1.08 and; 1.08 and 2.06; 1.08 and 2.07; 2.08 1.08 and; 1.08 and 2.09; 1.08 and 2.10; 1.08 and 2.11; 2.12 1.08 and; 1.08 and 2.13; 1.08 and 2.14; and 2.15 1.08; 1.08 and 2.16; 2.17 1.08 and; 1.08 and 2.18; and 2.19 1.08; 1.08 and 2.20; 1.08 and 2.21; 1.08 and 2.22; 1.08 and 2.23; 1.08 and 2.24; 1.08 and 2.25; 1.08 and 2.28; 1.08 and 2.29; 1.08 and 2.30; 1.08 and 2.31; 1.08 and 2.32; 1.08 and 2.33; 1.08 and 2.34; and 2.01 1.09; 1.09 and 2.02; 1.09 and 2.03; 1.09 and 2.04; 2.05 1.09 and; 1.09 and 2.06; 1.09 and 2.07; 2.08 1.09 and; 1.09 and 2.09; 1.09 and 2.10; 1.09 and 2.11; 2.12 1.09 and; 1.09 and 2.13; 1.09 and 2.14; and 2.15 1.09; 1.09 and 2.16; 2.17 1.09 and; 1.09 and 2.18; and 2.19 1.09; 1.09 and 2.20; 1.09 and 2.21; 1.09 and 2.22; 1.09 and 2.23; 1.09 and 2.24; 1.09 and 2.25; 1.09 and 2.28; 1.09 and 2.29; 1.09 and 2.30; 1.09 and 2.31; 1.09 and 2.32; 1.09 and 2.33; 1.09 and 2.34; 1.10 and 2.01; 2.02 1.10 and; 1.10 and 2.03; 1.10 and 2.04; 2.05 1.10 and; 1.10 and 2.06; 1.10 and 2.07; 2.08 1.10 and; 1.10 and 2.09; 1.10 and 2.10; 1.10 and 2.11; 2.12 1.10 and; 1.10 and 2.13; 2.14 1.10 and; 1.10 and 2.15; 1.10 and 2.16; 2.17 1.10 and; 1.10 and 2.18; 2.19 1.10 and; 1.10 and 2.20; 1.10 and 2.21; 1.10 and 2.22; 1.10 and 2.23; 1.10 and 2.24; 1.10 and 2.25; 1.10 and 2.28; 1.10 and 2.29; 1.10 and 2.30; 1.10 and 2.31; 1.10 and 2.32; 1.10 and 2.33; 1.10 and 2.34; and 2.01 1.11; 1.11 and 2.02; and 2.03 1.11; 1.11 and 2.04; 2.05 1.11 and; 1.11 and 2.06; 1.11 and 2.07; 2.08 1.11 and; 1.11 and 2.09; 1.11 and 2.10; 1.11 and 2.11; 2.12 1.11 and; 1.11 and 2.13; and 2.14 1.11; 1.11 and 2.15; and 2.16 1.11; 1.11 and 2.17; 1.11 and 2.18; 2.19 1.11 and; 1. the 2.02; 1.12 and 2.03; 1.12 and 2.04; 2.05 1.12 and; 1.12 and 2.06; 1.12 and 2.07; 2.08 1.12 and; 1.12 and 2.09; 1.12 and 2.10; 1.12 and 2.11; 2.12 1.12 and; 1.12 and 2.13; 1.12 and 2.14; 1.12 and 2.15; 1.12 and 2.16; 2.17 1.12 and; 1.12 and 2.18; 2.19 1.12 and; 1.12 and 2.20; 1.12 and 2.21; 1.12 and 2.22; 1.12 and 2.23; 1.12 and 2.24; 1.12 and 2.25; 1.12 and 2.28; 1.12 and 2.29; 1.12 and 2.30; 1.12 and 2.31; 1.12 and 2.32; 1.12 and 2.33; 1.12 and 2.34; 1.13 and 2.01; 2.02 1.13 and; 1.13 and 2.03; 1.13 and 2.04; 2.05 1.13 and; 1.13 and 2.06; 1.13 and 2.07; 2.08 1.13 and; 1.13 and 2.09; 1.13 and 2.10; 1.13 and 2.11; 2.12 1.13 and; 1.13 and 2.13; 2.14 1.13 and; 1.13 and 2.15; 1.13 and 2.16; 2.17 1.13 and; 1.13 and 2.18; 2.19 1.13 and; 1.13 and 2.20; 1.13 and 2.21; 1.13 and 2.22; 1.13 and 2.23; 1.13 and 2.24; and 2.25 1.13; 1.13 and 2.28; 1.13 and 2.29; 1.13 and 2.30; 1.13 and 2.31; 1.13 and 2.32; 1.13 and 2.33; 1.13 and 2.34; 1.14 and 2.01; 2.02 1.14 and; 1.14 and 2.03; 1.14 and 2.04; 2.05 1.14 and; 1.14 and 2.06; 1.14 and 2.07; 2.08 1.14 and; 1.14 and 2.09; 1.14 and 2.10; 1.14 and 2.11; 2.12 1.14 and; 1.14 and 2.13; 1.14 and 2.14; 2.15 1.14 and; 1.14 and 2.16; 2.17 1.14 and; 1.14 and 2.18; 2.19 1.14 and; 1.14 and 2.20; 1.14 and 2.21; 1.14 and 2.22; 1.14 and 2.23; 1.14 and 2.24; 1.14 and 2.25; 1.14 and 2.28; 1.14 and 2.29; 1.14 and 2.30; 1.14 and 2.31; 1.14 and 2.32; 1.14 and 2.33; 1.14 and 2.34; 1.15 and 2.01; 2.02 1.15 and; 1.15 and 2.03; 1.15 and 2.04; 2.05 1.15, and; 1.15 and 2.06; 1.15 and 2.07; 2.08 1.15, and; 1.15 and 2.09; 1.15 and 2.10; 1.15 and 2.11; 2.12 1.15 and; 1.15 and 2.13; 1.15 and 2.14; 1.15 and 2.15; 1.15 and 2.16; 2.17 1.15 and; 1.15 and 2.18; 1.15 and 2.19; 1.15 and 2.20; 1.15 and 2.21; 1.15 and 2.22; 1.15 and 2.23; 1.15 and 2.24; 1.15 and 2.25; 1.15 and 2.28; 1.15 and 2.29; 1.15 and 2.30; 1.15 and 2.31; 1.15 and 2.32; 1.15 and 2.33; 1.15 and 2.34; 1.16-2.01; 2.02 1.16 and; 1.16-2.03; 1.16-2.04; 1.16-2.05; 2.06 1.16 and; 1.16-2.07; 2.08 1.16 and; 1.16-2.09; 1.16-2.10; 1.16-2.11; 2.12 1.16 and; 1.16-2.13; 2.14 1.16 and; 1.16-2.15; 1.16-2.16; 2.17 1.16 and; 1.16-2.18; 2.19 1.16 and; 1.16-2.20; 1.16-2.21; 1.16-2.22; 1.16-2.23; 1.16-2.24; 1.16-2.25; 1.16-2.28; 1.16-2.29; 1.16-2.30; 1.16-2.31; 1.16-2.32; 1.16-2.33; 1. the 2.14; 1.17 and 2.15; 1.17 and 2.16; 2.17 1.17 and; 1.17 and 2.18; and 2.19 1.17; 1.17 and 2.20; 1.17 and 2.21; 1.17 and 2.22; 1.17 and 2.23; 1.17 and 2.24; 1.17 and 2.25; 1.17 and 2.28; 1.17 and 2.29; 1.17 and 2.30; 1.17 and 2.31; 1.17 and 2.32; 1.17 and 2.33; 1.17 and 2.34; 1.18 and 2.01; 2.02 1.18 and; 1.18 and 2.03; 1.18 and 2.04; 2.05 1.18 and; 1.18 and 2.06; 2.07 1.18 and; 1.18 and 2.08; 1.18 and 2.09; 1.18 and 2.10; 1.18 and 2.11; 2.12 1.18 and; 1.18 and 2.13; 2.14 1.18 and; 1.18 and 2.15; 1.18 and 2.16; 2.17 1.18 and; 1.18 and 2.18; 2.19 1.18 and; 1.18 and 2.20; 1.18 and 2.21; 1.18 and 2.22; 1.18 and 2.23; 1.18 and 2.24; 1.18 and 2.25; 1.18 and 2.28; 1.18 and 2.29; 1.18 and 2.30; 1.18 and 2.31; 1.18 and 2.32; 1.18 and 2.33; 1.18 and 2.34; 1.19 and 2.01; 2.02 1.19 and; 1.19 and 2.03; 1.19 and 2.04; 2.05 1.19 and; 1.19 and 2.06; 1.19 and 2.07; 2.08 1.19 and; 1.19 and 2.09; 1.19 and 2.10; 1.19 and 2.11; 2.12 1.19 and; 1.19 and 2.13; 1.19 and 2.14; and 2.15 1.19; 1.19 and 2.16; 2.17 1.19 and; 1.19 and 2.18; and 2.19 1.19; 1.19 and 2.20; 1.19 and 2.21; 1.19 and 2.22; 1.19 and 2.23; 1.19 and 2.24; 1.19 and 2.25; 1.19 and 2.28; 1.19 and 2.29; 1.19 and 2.30; 1.19 and 2.31; 1.19 and 2.32; 1.19 and 2.33; 1.19 and 2.34; 1.20 and 2.01; 2.02 1.20 and; 1.20 and 2.03; 1.20 and 2.04; 2.05 1.20 and; 1.20 and 2.06; 2.07 1.20 and; 1.20 and 2.20; 1.20 and 2.09; 1.20 and 2.10; 1.20 and 2.11; 2.12 1.20 and; 1.20 and 2.13; 1.20 and 2.14; and 2.15 1.20; 1.20 and 2.16; 2.17 1.20 and; 1.20 and 2.18; 1.20 and 2.19; 1.20 and 2.20; 1.20 and 2.21; 1.20 and 2.22; 1.20 and 2.23; 1.20 and 2.24; 1.20 and 2.25; 1.20 and 2.28; 1.20 and 2.29; 1.20 and 2.30; 1.20 and 2.31; 1.20 and 2.32; 1.20 and 2.33; 1.20 and 2.34; 1.21 and 2.01; 2.02 1.21 and; 1.21 and 2.03; 1.21 and 2.04; 2.05 1.21 and; 1.21 and 2.06; 1.21 and 2.07; 2.08 1.21 and; 1.21 and 2.09; 1.21 and 2.10; 2.11 1.21 and; 1.21 and 2.12; 2.13 1.21 and; 1.21 and 2.14; 2.15 1.21 and; 1.21 and 2.16; 2.17 1.21 and; 1.21 and 2.18; 2.19 1.21 and; 1.21 and 2.20; 1.21 and 2.21; 1.21 and 2.22; 1.21 and 2.23; 1.21 and 2.24; 1.21 and 2.25; 1.21 and 2.28; 1.21 and 2.29; 1.21 and 2.30; 1.21 and 2.31; 1.21 and 2.32; 1.21 and 2.33; 1.21 and 2.34.

The following examples and claims are used for the illustration is lsia.

In the examples below, the compositions of the concept of the compound of formula (I) represents (E)-N-(6-chloro-3-pyridylmethyl)-N-ethyl-N’-methyl-2-nitrobenzylidene or (R,S)-1-[2,5-dichloro-4-(1,1,2,2,3,3,3-hexaphosphate)phenyl]-3-(2,6-differentail)urea.

Example 1

Tablets containing 25 mg of the compounds of formula (I) or (II) or both active ingredients, can be prepared as follows:

Composition (for 1000 tablets), g:

Active substance 25,0

Lactose 100,7

Obtaining

First, active ingredients sieved through a sieve with a mesh size of 0.6 mm, Then mix the active ingredient, lactose, talc and half of the starch. The second half of the starch is suspended in 40 ml of water and this suspension is added to the boiling solution of the polyethylene glycol in 100 ml of water. The obtained starch paste is added to a mixture containing the active substance, and the mixture granularit, adding required water. The granulate is dried overnight at 35°C, passed through a sieve with a mesh size of 1.2 mm, mixed with magnesium stearate and pressed, receiving, biconvex tablets with a diameter of approximately 6 mm

Example 2: Tablets, containing 0.02 g of compound of formula (I) or (II)), year:

Active substance 200,00

Lactose 290,80

Potato starch 274,70

Stearic acid 10,00

Talc 200,00

Magnesium stearate 2,50

Colloidal dioxide 32,00

Silicon ethanol q.s.

The mixture containing the compound of formula (I), lactose and 194,70 g of potato starch, moisturize ethanol solution of stearic acid and granularit through a sieve. After drying, add while mixing the rest of the potato starch, talc, magnesium stearate and colloidal silicon dioxide and the mixture is pressed, receiving tablets weighing 0.1 g each, which can be fitted with dividing grooves for a more precise control of the dose.

Example 3

Capsules containing 0.025 g of compound of formula (I) or (II) or both active ingredients, can be prepared as follows:

Composition (for 1000 capsules), g:

Active substance 25,00

Lactose 249,80

Gelatin 2,00

Corn starch 10,00

Talc 15,00

Q water.s.

Current(s) substance(s) is mixed with the lactose, the mixture is uniformly moistened with an aqueous solution of gelatin and granularit through a sieve with razmara who each fill gelatin capsules with solid floor (size 1).

Example 4

Premix (additive to feedstuff)

0,25.h. the active substance and 4.75 wt.h. secondary acidic calcium phosphate, alumina, Aerosil, carbonate or clay mixed to a homogeneous state with 95 wt.h. feed for the animal.

Example 5

Premix (additive to feedstuff)

to 0.40 wt.h. the active substance and 5.00 wt.h. a mixture of Aerosil/clay (1:1) mixed to a homogeneous state with a 94.6 wt.h. commercially available dry fodder.

Example 6

Emulsion concentrate

20 wt.h. the active substance is mixed with 20 wt.h. emulsifier, for example, a mixture of simple alkylarylsulphonates ether alkylarylsulfonate, and 60 wt.h. solvent until then, until the solution becomes completely homogeneous. Emulsions of the desired concentration is obtained by dilution with water.

Example 7

Solutions (for example, for use as an additive for drinking)

15 wt.% the active substance, 10 wt.% the active ingredient in monoethylene ether of diethylene glycol, 10 wt.% polyethylene glycol 300 and 5 wt.% glycerol, 60 wt.% water.

Example 8

Soluble powder

25 wt.h. the active substance, 1 wt.h. l is ismalia together until a homogeneous state.

The described compositions can be added to other biologically active substances or additives which are neutral with respect to the active substances and no harmful effects to be processed animal host, as well as mineral salts or vitamins.

Similar to the compositions described above in examples 1-8 can also be prepared with other compositions on the basis of active substances of the formula (I) and/or (II).

Biological examples

Example B1

Comparison of the activity of one lufenuron and combinations nitenpyram and lufenuron in respect of a dog infected fleas in the environment corresponding to the actual conditions.

Place: Department of Parasitology and dermatology veterinary College, Toulouse, Toulouse, France.

Study type: Activity against fleas.

Time: Spring-fall 1997.

Test animals: 20 dogs, healthy hounds (Beagles) from the same litter.

Parasites: the cat flea Ctenocephalides felis.

Method: the Test using as a control placebo; the blind test; simulation of the natural environment (home).

Processing method: Determination affectation as appetizing round, biconvex tablets with a notch with a weight of 100 mg (11.4 mg of active substance) for dogs weighing from 1.0 to 11.0 kg and a weight of 500 mg (57 mg active substance) for dogs weighing from 11,1 to 57 kg

Lufenuron was introduced in the form of marketed tablets PROGRAMM containing 204,9 mg lufenuron for dogs weighing from 7 to 29 kg

Placebo: the above appetizing round biconvex, scored tablets with a weight of 100 and 500 mg, containing no active ingredient.

In the experience of simulated conditions existing in the home environment. For this purpose, used 4 separate and clean from a medical point of view the premises. In them were the recreation area, lined with straw, and they had a small space on the outside. The room was lit by natural light. In every room we were placed in 5 healthy dogs and each of them were infected three times a week 50 svezhevyrosshimi fleas until then, until the dogs were not formed a permanent population of fleas. After that, each group of dogs were subjected to various treatments.

Control group 1 was not given active substance, and gave only a placebo, and she served as a control group for comparison. Group 2 was given lufenuron in monthly dose corresponding to the instructions on the package, and once a week were given a placebo. Group 3 was given lufenuron in monthly dose corresponding to the instructions on the package, and once a week for 6 weeks packing, and twice a week for 6 weeks additionally gave nitenpyram.

The trial was carried out blindly, however, the processing and evaluation of results was carried out by different people who were not familiar with the Protocol of experience.

All four groups were estimated population of fleas by counting twice a week before the first treatment and once a week during the experience.

The activity of test compounds in a simulated home environment was determined according to the following formula:

After the first injection of nitenpyram all fleas with the exception of one individual died within 16-24 days, however, when processing observed significant differences. The results are summarized in table 3.

You can see that the activity in group 2, which were treated only lufenuron was very low up to 28 days compared with groups 3 and 4 and achieved satisfactory for practical use level after approximately 84 days. In contrast, the activity in groups 3 and 4 was from the beginning a much higher and reached the maximum value at most after 28 days. The results for groups 3 and 4 insignificantly differed among themselves, i.e., no detection is the combination for controlling fleas, contains effective against fleas, the number of combinations of the compounds of formula (I)

where R1denotes hydrogen, C1-C6alkyl or C3-C7cycloalkyl;

R2denotes hydrogen, C1-C6alkyl or C3-C7cycloalkyl;

R3denotes hydrogen or C1-C6alkyl;

And indicates heterocyclyl, which is unsubstituted or substituted by one or more identical or different halogen atoms;

and the compounds of formula (II)

where X denotes halogen;

X1denotes hydrogen or halogen;

X2denotes hydrogen or halogen;

Y denotes a partially or completely halogenated WITH1-C6alkyl or fully halogenated1-C6the alkyl chain of which includes an oxygen atom, or partially or completely halogenated WITH2-C6alkenyl;

Y1denotes hydrogen or halogen;

Y2denotes hydrogen or halogen;

Y3denotes hydrogen or halogen;

Z1denotes hydrogen or C1-C3alkyl;

the I.

2. Method of controlling fleas on Pets, providing systemic injection of a combination of the p. 1 domestic animal in an amount that is effective against fleas.

3. The method according to p. 2, where the combination is administered through the mouth.

4. The method according to p. 2, where the compound of formula (I) and the compound of formula (II) are administered in separate dosage forms, but at the same time with each other.

5. The method according to p. 2, where you first enter the compound of the formula (I), then proceed to process the compound of formula (II).

 

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The invention relates to agriculture, in particular animal health, and can be used to control ectoparasites on birds
The invention relates to the field of veterinary medicine

The invention relates to chemical-pharmaceutical industry, in particular to the creation and production of medicines protivochesotocnaya

The invention relates to medicine

FIELD: organic chemistry, fungicides.

SUBSTANCE: invention describes a fungicide mixture containing carbamate of the formula (Ia):

and copper-containing fungicide taken in synergistically active amount. Also, invention describes a method for control of phytopathogenic fungi and applying compounds for a synergistic mixture eliciting the fungicide properties. Fungicide mixtures provide inhibition of phytophthora infection in tomato plants.

EFFECT: improved method for control, valuable fungicide properties of mixtures.

8 cl, 6 tbl, 3 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to herbicidal composition containing synergetically effective amounts of (A) and (B) components, wherein (A) has formula II (R1 is C1-C6-alkyl, substituted with halogen; R2, R3 and R4 are hydrogen; R5 is rest of formula -B1-Y1, wherein B1 is direct bond and Y1 is acyclic C1-C6-hydrocarbon or cyclic C3-C6-hydrocarbon; F is -CH2-CH2-, -CH2-CH2-CH2- and CH2-O-; X are independently halogen or C1-C4-alkoxy; n = 0-2; and (B) represents one or more herbicides, selected from group containing isoprothuron, flufenacet, anylophos, ethoxysulphuron, mecoprop-(P), ioxinyl, florazulam, pendimethalin, MV 100, etc. Also disclosed is method for weed controlling using abovementioned composition.

EFFECT: composition with improved herbicidal action.

12 cl, 23 ex, 23 tbl

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention describes insecticide composition comprising the active amount of one pyridine compound of the formula (I)

or its salt wherein Y represents halogenalkyl group comprising from 1 to 2 carbon atoms and halogen atoms from 1 to 5; m = 0; Q represents compound of the formula:

wherein X represents oxygen atom; R1 and R2 represent independently hydrogen atom, alkyl group comprising from 1 to 6 carbon atoms and substituted with cyan-group, and one insecticide taken among carbofuran, carbosulfan, cipermethrin, bifentrin, acetamiprid, chlorfauazuron, fluphenoxuron, piriproxiphen, spinosad, emamectine benzoate, avermectin, buprophezin and fipronil taken in the weight ratio of compound of the formula (I) and other insecticide = from 1:2 to 100:1. The composition provides stable and strong effect and eradicates insects.

EFFECT: strong insecticide effect of composition.

4 cl, 11 tbl, 5 ex

FIELD: agriculture, fungicides.

SUBSTANCE: claimed method includes treatment of contaminated cultural plants or cultivation area thereof with effective amount of composition, containing A) N-sulfonylvaline amide of formula I 1, wherein R1 represents hydrogen or haloprenyl; and R1 represents C1-C4-alkyl, in combination with B) methalaxyl, or fluozinam, or mancoceb, or chlorithalonyl, or strobyluzine, or pyraclostrobine, or acibenzolar-S-methyl, or dimethoform, or fludioxonyl, or cimoxanyl, or imazalyl in synergistically effective amounts. Fungicide composition containing effective combination of A and B in synergistically effective amounts in combination with agriculturally acceptable carrier and optionally with surfactant.

EFFECT: composition of increased fungicidal action due to synergic effect.

8 cl, 12 ex

FIELD: agriculture, fungicides.

SUBSTANCE: claimed method includes treatment of contaminated cultural plants or cultivation area thereof with effective amount of composition, containing A) N-sulfonylvaline amide of formula I 1, wherein R1 represents hydrogen or haloprenyl; and R1 represents C1-C4-alkyl, in combination with B) methalaxyl, or fluozinam, or mancoceb, or chlorithalonyl, or strobyluzine, or pyraclostrobine, or acibenzolar-S-methyl, or dimethoform, or fludioxonyl, or cimoxanyl, or imazalyl in synergistically effective amounts. Fungicide composition containing effective combination of A and B in synergistically effective amounts in combination with agriculturally acceptable carrier and optionally with surfactant.

EFFECT: composition of increased fungicidal action due to synergic effect.

8 cl, 12 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention describes a synergetic composition with the effective content of components (A) and (B) wherein (A) means herbicide chosen from the group of compounds of the formula (I): wherein R1, R2, R, X, Y and Z have values given in the invention claim or their salts; (B) means one or some herbicides among the following groups: (B1) selective herbicides with activity in some dicotyledonous cultures against monocotyledonous and dicotyledonous weeds; (B2) selective herbicides with activity in some dicotyledonous cultures against dicotyledonous weeds; (B3) selective herbicides with activity in some dicotyledonous cultures with preferable effect against monocotyledonous weeds. Also, invention describes a method for control against weeds using the proposed composition. Using the combination of proposed herbicides results to the synergetic effect.

EFFECT: valuable herbicide properties of composition.

3 cl, 7 tbl, 2 ex

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