MXPA01003490A - Oral combination of lufenuron and nitenpyram against fleas - Google Patents

Abstract

A veterinary preparation for fleas is described, which consists of an amount that is effective against fleas of a combination of a compound of formula (I), wherein R1 is hydrogen, C1-C6-alkyl or C3-C7-cycloalkyl;R2 is hydrogen, C1-C6-alkyl or C3-C7-cycloalkyl;R3 is hydrogen or C1-C6-alkyl;and A is heterocycly which is unsubstituted or substituted once or repeatedly by identical or different halogen atoms;and a compound of formula (II), wherein X is halogen, X1 is hydrogen or halogen;X2 is hydrogen or halogen;Y is partially or completely halogenated C1-C6-alkoxy, or partially or completely halogenated C1-C6-alkoxy which is interrupted by one oxygen atom, or partially or completely halogenated C2-C6-alkenyl;Y1 is hydrogen or halogen;Y2 is hydrogen or halogen;Y3 is hydrogen or halogen;Z1 is hydrogen or C1-C3-alkyl;and Z2 is hydrogen or C1-C3-alkyl;and a physiologically acceptable formulation excipient.

Description

Oral Combination of Lufenuron and Nitenpyram Against Fleas The present invention relates to veterinary preparations based on a combination of the nitroenamine derivatives of the formula (I) mentioned below, with the benzoylurea derivatives of the formula (II) similarly mentioned below, and their use in systemic control of fleas in domestic animals, as well as the production and use of these preparations and combinations. Therefore, the present invention relates to a veterinary flea control composition, which comprises an amount that is effective against fleas, of a combination of a compound of the formula (I): R3 I 02N-CH = C R2 (I) A R? wherein: RL is hydrogen, alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms; R2 is hydrogen, alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms; R3 is hydrogen or alkyl of 1 to 6 carbon atoms; and A is heterocyclyl which is unsubstituted or substituted once or repeatedly by identical or different halogen atoms; with a compound of the formula (II): wherein X is halogen; Xi is hydrogen or halogen; X2 is hydrogen or halogen; Y is alkyl of 1 to 6 carbon atoms partially or completely halogenated, or alkyl of 1 to 6 carbon atoms completely halogenated which is interrupted by an oxygen atom, or alkenyl of 2 to 6 carbon atoms partially or completely halogenated; Yi is hydrogen or halogen; Y2 is hydrogen or halogen; Y3 is hydrogen or halogen; Zi is hydrogen or alkyl of 1 to 3 carbon atoms; Z2 is hydrogen or alkyl of 1 to 3 carbon atoms, and a physiologically acceptable formulation excipient.

The nitroenamine derivatives of the formula (I) and the benzoylurea derivatives of the formula (II) are known insecticides. A prominent representative of the nitroenamines of the formula (I) is nitenpyram of the formula (III): IUPAC Name: (E) -N- (6-chloro-pyridin-3-ylmethyl) -N-ethyl-N '-methyl-2-nitrovinylidene diamine. Nitenpyram and its preparation are described in European Patent Number EP-0,302,389 as Example 41 on page 63. This published application discloses a rather large group of nitroenamines, of which nitenpyram is only one selected representative. These nitroenamines are described therein as contact insecticides and contact acaricides. Additional nitroenamines are disclosed in the European Patent Number EP-A-0, 302, 833. From the Patent European Patent Number EP-0, 616, 494, it is known that nitenpyram can also be administered orally to host animals. The synergistic combination of lufenuron with a number of other pesticides, including also nitenpyram, is proposed in International Publication Number WO 95/33380. However, the combinations proposed therein are plant pesticide compositions for the surface treatment of the leaves of plants against infestation of the pest. A huge number of benzoylureas, which fall under the formula (II), and also their preparation and use, are described in the US Pat. No. 5,420,163, and in the literature cited therein. The compounds of the formula (II), wherein X is F; Xi is 6-F; X2 is H; And it is CF2CHFCF3; Yx is 2-F; Y2 is 3-Cl; Y3 is -Cl; Zi is H, methyl or ethyl; and Z2 is H, methyl or ethyl, and wherein at least Zi or Z2 is methyl or ethyl, are described in International Publication Number WO 98/19542. The compounds of the formula (II), wherein X is F; Xi is 6-F; X2 is H; And it is CF2CHFCF3; And it's 3-Cl; Y2 is H; Y3 is 5- Cl; Zi is H, methyl or ethyl; and Z2 is H, methyl or ethyl, and wherein at least Zx or Z2 is methyl or ethyl, are disclosed in International Publication Number WO 98/19543. The compounds of the formula (II), wherein X is F; Xi is 6-F; X2 is H; Y is CH (CH3) CF2R; R is CF3 or CF2CF3; Yx is 2-H or F; Y2 is 3-Cl; Y3 is 5-Cl; Z is H; and Z is H, are described in International Publication Number WO 98/19995. The compounds of the formula (II), wherein X is F; Xi is 6-F; X2 is H; Y is CF = CFCF3 or CF2CF2 = CFCF3; Yx is 3-Cl; Y2 is H; Y3 is 5-Cl; Zi is H; and Z2 is H; they are described in International Publication Number WO 98/19994. Combinations of a compound of the formula (II), wherein X is F; X? It's 6-F; X2 is H; And it is CF2CFHOCF3; Yx is 3- Cl; Y2 is H; Y3 is H; Zx is H; and Z2 is H; with other antiparasitic agents, are described in the International Publication WO 98/25466. A known representative of formula (II) is lufenuron of European Patent Number EP-0, 179, 021. The substance in question here is (R, S) -1- [2,5-dichloro-4- (1, 1,2,2,3,3,3-hexafluoropropoxy) -phenyl] -3- (2,6-difluorobenzoyl) urea. Another known representative of formula (II) is novaluron of European Patent Number EP-0, 271, 923. The substance in question here is (+) -1- [3-chloro-4- (1, 1, 2- trifluoro-2-trifluoromethoxyethoxy) -phenyl] -3- (2,6-difluorobenzoyl) urea. The alkyl groups present in the definitions of the substituents may be straight or branched chain, depending on the number of carbon atoms, and may be, for example, methyl, ethyl, propyl, butyl, pentyl, or hexyl, as well as their isomers branched, for example isopropyl, isobutyl, secondary butyl, tertiary butyl, isopentyl, neopentyl, or isohexyl. Cycloalkyl of 3 to 7 carbon atoms is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Typical Y radicals, denoting alkyl of 1 to 6 carbon atoms partially or completely halogenated, or alkyl of 1 to 6 carbon atoms completely halogenated which is interrupted by an oxygen atom, or alkenyl of 2 to 6 partial carbon atoms or completely halogenated, are: the straight or branched chain alkyl radicals of 1 to 6 carbon atoms which are partially or completely substituted by identical or different halogen atoms, and whose carbon chain is not interrupted or interrupted at one point by an oxygen atom, or alkenyl radicals of 2 to 6 carbon atoms straight or branched chain with a carbon double bond, such as OCF3, OC2F5, OC3F7, OC4F9, OC5Fn, OC6F? 3, OCF (CF3) 2 , OCF (C2F5) (CF3), OCF (C2F5) (C2FS), OCF2OCF3, OCF2OCF (C2F5) 2, OCF2CHFCF3, OCH (CF3) CF2CF3, OCH (CF3) CF2C2F5, OCF = CFCF3, OCF2CF2 = CFCF3, OCF2 (CF3 ) CF2 = CFCF3, OCF2CCl3, 0CF2CHC12, OCF2CHF2, 0CF2CFC12, OCF2CHBr2, 0CF2CHC1F, OCH2C HBrCH2Br, OCF2CHBrF, OCC1FCHC1F, et cetera. The alkoxy radicals arise from these alkyl groups. Halo denotes halogen, and usually means fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine, especially chlorine, wherein a partially or fully halogenated substituent may contain one or more identical or different halogen atoms. While due consideration is given to the number of carbon atoms contained, depending on the case, in the corresponding group, alkenyl is straight chain, for example vinyl, 1-methylvinyl, allyl, 1-butenyl, or 2-hexenyl, or branched, isopropenyl example. In the context of the present invention, it is understood that heterocyclyl means aliphatic or aromatic cyclic radicals, containing at least one oxygen, sulfur, or nitrogen atom. The 5- and 6-membered heterocycles are preferred. Heterocyclyl usually includes substituents such as dioxolanyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrrolyl, pyrryl, furyl, thienyl, imidazolyl, tetrahydrofuryl, tetrahydropyranyl, dihydrofuryl, dihydropyranyl, isoxazolyl, oxazolyl, thiazolyl, oxazolinyl, oxazolidinyl, imidazolinyl, imidazolidinyl, and dioxanyl. . Preference is given especially to those which are unsubstituted or which have one or two halogen atoms, halogen denoting in this case fluorine, chlorine, or bromine, but especially chlorine. Of these heterocyclic radicals, pyridyl, thiazolyl, and tetrahydrofuryl are especially noteworthy. However, 6,5-dichloropyridin-3-yl, especially 6-chloropyridin-3-yl, are especially preferred., but also 5-chlorothiazol-3-yl and tetrahydrofur-3-yl, in particular 6-chloropyridin-3-yl. The specifically mentioned radicals are to be considered in the context of the present invention as the preferred embodiments. Viewing the kinetics of both classes of substances, those of the nitroenamine derivatives of the formula (I), and those of the benzoylurea derivatives of the formula (II), it is established that, after being applied to an animal, the benzoylureas protrude , due to its slow increase in blood counts and its high blood level for longer periods of time. This means that, although the activity increases very slowly, it remains at a high level for a long time. In general, the benzoylurea derivatives exhibit their complete activity only days or weeks after their administration. However, this effect continues for weeks, or even for several months. In contrast, nitroenamines exhibit their full activity almost directly after their application, but only last a few hours, or at most 1 to 2 days. Although both classes of substances are insecticides, they exhibit a completely different mode of action, both classes of substances, in fact, interrupt the life cycle of the insect, but each class of substance in its own specific way. Although the nitroenamine derivatives are classified as the so-called adulticides that act as contact poisons, the benzoylurea derivatives belong to the class of ovicides or larvicides, depending on the concentration index. This means that the nitroenamine derivatives as contact poisons, primarily kill the adult insects that live on the host animal, while the benzoylurea derivatives leave the adult fleas, but prevent oviposition, or lead to sterile eggs being laid , or block the transition from one stage to the next youth stage. The nitroenamines of the formula (I) are extremely effective if they are administered as contact insecticides, for example externally, that is topically to the hair of the infested host animal. They also exhibit some systemic activity, i.e., if they are applied orally, parenterally, or by injection to the infested host animal. From European Patent Number EP-0, 616, 494, it is known, for example, that nitenpyram shows a first substantial activity after only 30 minutes in the in vi tro test, that is, after feeding the contaminated blood to fleas. 100% activity is obtained after 24 hours. It is also described that, 6 hours after oral administration to cats, nitenpyram achieves a 60% activity against fleas present in cats, and on the second day after a renewed infestation, it still gives an activity of 55 percent. From this, it can be deduced that, in order to achieve a complete activity, nitenpyram should be administered orally at 1 or 2 day intervals, which is hardly reasonable for the caregiver. 1 Flea infestation in domestic animals still represents a problem for the veterinarian and the caregiver that has not yet been satisfactorily resolved. Fleas have a very complete life cycle. This is also the reason why none of the known methods is completely satisfactory in its control. The known methods have as their objective, on the one hand, to control the adult fleas in the hair of the host animal, and to leave completely alone the different juvenile stages of the fleas, which exist not only in the hair of the animal, but also on the floor , in the carpets, in the beds of the animals, in the chairs, in the garden, and in all other places with which the infested animal comes into contact, or they present themselves only to control the juvenile stages. The adult fleas of cats and dogs. { Ctenocephalides felis and C. Canis) live as blood-sucking parasites normally in the hair of the host cat or host dog. They feed on the blood of the host animal, and lay their eggs in their hair. However, because these eggs are not self-adhering, they generally fall quickly, and can be found on the floor, on the rugs, in the dog or cat basket, on the chairs used by the animal, on the garden, in the yard, and therefore, in all the parts to which the infested animal tends to go. 1 This means that the entire living area of the host animals is infested with flea eggs from which larvae are formed under normal conditions within two days. Three stages of development of the larvae can be distinguished, and each lasts 3 days. In the last stage, the larva spins its cocoon, and becomes the chrysalis. Under favorable conditions, that is, at 33 ° C and with a relative humidity of 65 percent, the transformation of the egg into chrysalis takes place in approximately 8 to 10 days. After about 8 additional days, young fleas develop in the pupae that are still on the floor, on the carpets, on the beds, on the chairs, and so on. The young adult fleas remain there until they detect the presence of an acceptable host animal, then hatch from their cocoon, and try to jump on the host animal. From this, it can be seen that it takes at least three weeks for a young flea that has developed from an egg to be in a position to re-infest the host animal. However, depending on environmental conditions, this young flea may also remain in its cocoon for months, possibly up to 1 year. On the other hand, under less optimal conditions, development from the egg to the young adult flea may take 4 to 5 months. To reach their sexual maturity, fleas require blood as the nutrient in order to reproduce, and moreover, this blood must come from the correct host animal. This long life cycle, which passes through different stages, and which can also take place in part independently of the host animal, requires compositions and special methods for thumb control that, until now, have not yet been produced. Even when the fleas in the hair of the host animal can be successfully controlled, that is, if all the adult fleas are annihilated by an appropriate contact venom, the cat or dog is still at risk, for weeks or even months, of a reinfestation. constant by young fleas freshly hatched from the animal's environment. A vicious circle is established, leading to a constant reinfestation, even when the host animal does not come into contact with an animal infested with the same species. The animal's caretaker often can not see the end of this process, because he merely discovers that his apparently successfully treated animal has fleas again after a short time. This often leads to dissatisfaction and withdrawal of apparently ineffective treatment. Infestation with fleas from dogs and cats has unpleasant side effects, not only for the animal to be treated, but also for your caregiver. Flea bites lead, for example, to local irritation of the skin or to an annoying itching, and it often becomes severe scratching and skin injury, which is why a severe infection is consistently established. A large number of bitten animals often become allergic over time to flea excretions, leading to very irritated and crusty skin changes around the mordidcis sites on the animal's body. These skin changes usually have a diameter of about 3 millimeters or more, and often make the animal vicious and make it scratch, so that there is a partial loss of hair consequentially. In addition, flea-infested animals are continually exposed to the danger of becoming infested with Dipylidium, a kind of tape worm that is transmitted by infected fleas, and can only be controlled with great difficulty. Infestation with fleas is not only extremely annoying to the infested animal, but it also has unpleasant consequences for the keeper, because he finally recognizes that his pet is behaving unusually, and must be sick and suffering, and that he must help her. In addition, there may be unpleasant consequences for the keeper if he gets rid of the animal or if he dies or is temporarily removed from the usual environment, because the newly hatched fleas on the floor may even be forced to attack humans if he has not a suitable host animal has been available for a long time, although it can not reproduce if human blood is the only source of food. Even when the dog or cat is present, the caregiver may also be bitten by the fleas. In addition, dog fleas and expenses, or their excretions, can lead to skin problems of the type of allergy of many humans, which in many cases force the owner to get rid of the pet. Therefore, it has always been desirable to effectively control the fleas of dogs and cats. A number of conventional control methods are known, but they have different types of drawbacks. If the caregiver uses combs for fleas, for example, then the only option is to comb the animal thoroughly and often, which can be very time consuming, depending on the size of the animal, and is not patiently accepted by all the animals. Also, not all caregivers are prepared or in a position to devote the necessary time to do this. In certain cases, active shampoos against appropriate fleas can not be used successfully, in particular because cats and numerous dogs do not let caregivers bathe them or only by force. In addition, the effect of this bath treatment lasts at the most about a week, and the whole problematic procedure has to be repeated. The same or very similar problems occur when using dips or rinses. The use of powder dusting is not generally accepted without resistance by the animal, because it takes a few minutes to treat the entire surface of the skin in a uniform manner, and inevitably the powder reaches the mouth, the nose, and the eyes. Even during a careful application, the possibility that the dust can be inhaled by the animal and the human being can not be excluded. It is practically inevitable that the human being also enters into a more or less intense contact with the composition. With the use of dews, for many there will be an unpleasant surprise, because most animals, especially cats, escape or react aggressively as soon as they hear the noise of dew. Moreover, dews also have all the drawbacks mentioned for the powders, and in addition, they are more finely dispersed in the atmosphere, and therefore, are inhaled by humans and animals. Fleas are also frequently controlled with so-called flea collars, which guarantee good effectiveness during a transitory period. A certain weakness of this treatment is in particular the application locally very restricted. The annihilating activity in the neck and chest areas is generally 100 percent; however, the parts of the body that are farther away are difficult to accept. In addition, there is a time limit for the activity of these collars. In addition to this, many of these collars are unattractive and can alter the animal. You can also buy discs today, which hang from the usual necklaces, and they should be active. These are of an attractive appearance, but their activity is unsatisfactory, because contact with the skin is insufficient. There are a few organophosphorus compounds active against fleas also available as applied formulations, and therefore, they are applied to a locally limited hair site. In general, they show good short-term activity against adult fleas, but the composition used often has problematic toxicity values. The organophosphorus compounds were also partly orally administered, but there are strict safety limits on these, and under no circumstances can they be applied at the same time as other organophosphorus compounds. Above all, it can be said that many of the processes of the past were aimed at annihilating adult fleas, and in part gave good control in the short term. However, what was not previously appreciated enough was the fact that, due to the special life cycle of fleas, dogs and cats are always reinfested, on the one hand because contact with the eggs of the fleas is inevitable. fleas, flea larvae, and young adult fleas that are on the ground or in the closest environment of the animal, and on the other hand, because many domestic animals come into contact again and again with the animals infested of the same species. When the need to prevent constant reinfestation was recognized, special compositions were developed, which disinfected the sleeping areas of dogs and cats. Disinfection, however, is only useful if the host animal itself is treated at the same time. In addition, using certain benzoylureas, such as lufenuron, a class of substances was prepared that acted specifically on the juvenile stages of the fleas. Its use interrupts the life cycle of the fleas in a very effective way, but not directly at the beginning of the treatment. In total, the infestation with fleas of domestic animals is still an unsatisfactorily solved problem. It is the very complex life cycle described by fleas, which passes through the different juvenile stages, which live not only in the host animal but also sometimes in its surroundings, which makes control much more difficult. This is also the reason why none of the known methods of control have proven to be satisfactory in the long term. At present, a comprehensive treatment of fleas still stipulates the intense parallel use in time and labor of several methods over long periods of time. The success usually depends on the treatment not only of the infested animal, for example the dog or the cat, but in addition all the places that the infested animal frequents are disinfected. The caretaker of the animal not only has the work, but also must take into consideration the surroundings that are contaminated with the active substances. Until now, if domestic animals were given comprehensive and durable protection against both the juvenile stages of the flea and the adults, several separate treatment methods had to be carried out. To eliminate the adults in the host animal, fast-acting contact adulticides were usually administered in a topical manner at short intervals, while the juvenile stages were normally controlled orally with long-term preparations. The elimination of all the stages that lived in the surroundings of the host animal was carried out by means of the repeated disinfection of all the places frequented by the host animal. Both veterinarians and caregivers have long desired a simple but effective process. The different course of effectiveness, and in particular the very different duration of efficacy of adulticides, such as nitroenamines, compared with ovicides or larvicides, such as benzoylureas, has so far prevented the person skilled in the art from using a combination of both classes of substances . In addition to this, numerous unsuccessful attempts were also made to eliminate the short duration of efficacy, which was rather unsatisfactory for a practical application, in the systemic administration of nitroenamines. It was shown that prologizing the systemic action by raising the concentration of administration can only be achieved to a certain extent, because the active substance is excreted too quickly. On the other hand, if one wanted to insert deposit forms under the skin or in the muscles, which would release the active ingredient for several weeks, the quantities that would have to be injected or implanted would be so large that they would no longer be acceptable for the host animal, because they would lead to substantial irritation. Therefore, this solution is eliminated for ethical and practical reasons. In a similar manner, it was established that long-term efficacy by means of an increased oral administration can not be obtained either, because a larger quantity administered does in fact have no effect on the duration of efficacy. When administered orally, for example as tablets, the nitroenamines are absorbed and dispersed very rapidly in the blood via the gastrointestinal tract, but are thus excreted rapidly in the urine. The half-life in the blood of approximately 7 to 9 hours for the cats, and of approximately 3 to 5 hours for the dogs, is too short for one to achieve an improvement in the effectiveness by means of the elevation of the dose. A very punced elevation in the blood values is observed after its application, and a very rapid flattening of the curve, without a significant influence on a prolonged bioavailability. This has serious effects on systemically usable preparations, for example tablets or injections. Due to the short duration of efficacy, tablets or injections must be administered at short intervals, preferably every third day, which means that the caregiver has to repeat the treatment or visit the veterinarian too often. A concept of intensive treatment of this kind requires a large amount of discipline, and experience has shown that this causes tension to the animal and the caregiver after only a short time. This often manifests as an aversion to treatment, and leads to a discontinuation of treatment. Accordingly, prolonging the systemic action of this class of extremely active substances was an objective that had been desired for a long time, but apparently had not been achieved. Although the nitroenamine derivatives of the formula (I) exhibit acceptable flea activity, only for a few hours up to a maximum of 2 days when administered orally to a host animal, we have now surprisingly succeeded in extending its efficacy duration to at least two weeks, by its combination with benzoylurea derivatives of the formula (II). It would be expected that, when lufenuwas administered, nitenpyram would have to be administered throughout the treatment period at weekly intervals in order to maintain the full broadband effect against all stages of development. However, this is not the case. Surprisingly, it has been established that a six-week treatment with nitenpyram is completely sufficient. It was totally unexpected that there was no reinfestation of any kind afterwards. This is even more surprising, because nitenpyram can even be given at an interval of two weeks. In summary, it was found, that by means of the systemic administration, for example orally, parenterally, or by implant, of an amount of the combination according to the invention, which is effective against fleas, of a compound of the formula (I) and a compound of the formula (II), the infestation with fleas of the domestic animals can be completely prevented from the second week of treatment and throughout the duration of the treatment, and even the environment of the host animal remains free of fleas during a long time. This does not happen during treatment with nitenpyram alone or with lufenuron alone. This desired effect is thus obtained not only after the injection or with an implant, but also after oral administration, that is, by the round route through the gastrointestinal tract, and therefore, through the contaminated blood Both the compounds of the formula (I) and the compounds of the formula (II) are notorious for their excellent activity against fleas, and by the combination of (I) and (II), not only adult fleas are rapidly annihilated, but also all juvenile stages of fleas. The larvae of fleas that hatch from flea eggs basically feed on the excretions of adult fleas. Because the combinations according to the invention similarly kill adult fleas in a similar manner, the necessary excretions that form the basis of the feed for the juvenile stages are missing. Now this food base is absent, because the juvenile stages are destroyed before they reach the adult stage. In fact, if a few young fleas develop, they are eliminated by the contact action. Accordingly, the present invention relates to a systemic, and therefore stress-free, and particularly comprehensive and long-term control of fleas, which is established immediately after treatment, and continues for a long period of time. What is essential for the invention is that the combinations according to the invention are administered systemically. However, oral application is preferred, especially the administration of tablets or suspensions. Excellent activity is also obtained with other different types of application, for example by injection of the formulated compounds or mixing with the food. In the context of the present invention, formulated means, for example, in the form of a powder, a tablet, a granulate, a capsule, an emulsion, a suspension, a foam, in microencapsulated form, etc., whereby, as already mentioned, the preparation does not necessarily have to be given directly to the animal, but it can also be conveniently mixed with its food. Of course, all compositions that are to be administered orally may contain other additives, in addition to conventional formulating excipients. These additives encourage the desire of consumption by the host animal, for example suitable odorous substances, flavorings, and / or flavor substances. Due to its simple practicability, oral use is one of the preferred aspects of the invention. An additional type of application is parenteral use, for example by subcutaneous injection or injection into the vein, or long-term preparation (deposit form) in the form of an implant. The oral application also includes, for example, the administration of the dog and cat food, which contains the combination according to the invention, of the compounds of the formula (I) and (II), already mixed therein, for example as biscuits or as croquettes, as chewing gum, as water-soluble capsules or tablets, in a water-soluble form that can be dripped on the food, or in other forms that can be mixed with the animal's food. The implants also include all the devices that can be inserted into the body of the animal in order to supply the substance, for example the so-called minipumps. Forms of percutaneous application include, for example, subcutaneous, dermal, intramuscular, and even intravenous administration of the injectable forms. Apart from the usual syringes for injection with needles, needle-type gun-type devices can also be used. By choosing an appropriate formulation, it is possible to improve the penetration power of a combination according to the invention through the living tissue of the animal, or to maintain its availability. This is important, for example, if a less soluble composition is used, whose low solubility requires an improvement measure of solubility, because the body fluids of the animal can only dissolve small amounts of the substance at a time. In addition, a combination according to the invention may also be present in a matrix formulation in order to achieve a very delayed release of the active ingredient., this matrix formulation physically preventing its release and premature secretion, and maintaining the bioavailability of the active ingredient. This matrix formulation is injected into the body, for example intramuscularly or subcutaneously, and remains there as a type of reservoir, from which the active ingredients are continuously released. These matrix formulations are known to the person skilled in the art. These are in general waxy semi-solid substances, for example plant waxes and polyethylene glycols with a high molecular weight. Both compositions of active ingredients can be used either in the same matrix or in different matrices, which are used in different parts of the body if required. The long-term availability of the combination of active ingredients is also achieved by the insertion of an implant of the active substances into the animal. These implants are widely used in veterinary medicine, and often consist of silicone-containing rubber. Here, the active substances are dispersed in the solid rubber or are found inside a hollow rubber element. Care must be taken that a combination according to the invention is selected that is soluble in the rubber implant, because it first dissolves in the rubber, and then is continuously swept from the rubber material to the body fluids of the animal. that is going to be treated. Both kinds of active ingredients can be used either on the same implant or on different implants, and on different parts of the body. The rate of release of the active substances from the implant, and therefore the length of time during which the implant shows activity, is generally determined by the precision of the measurement (amount of active ingredient in the implant) of the implant , the environment of the implant, and the polymeric formulation from which the implant is made. The administration of a combination according to the invention by means of an implant represents a further preferred constituent of the present invention. This type of administration is economical and effective, because a properly dimensioned implant guarantees a constant concentration of the active substance in the tissue of the host animal. Currently, implants can be designed and implanted in a simple manner, so that they are in a position to supply the active ingredient for a few months. After inserting the implant, there is no need to disturb the animal again, and there is no longer any need to worry about dosing. The administration of veterinary medicine additives to animal feed is better known in the field of animal health. Normally, first of all, a so-called premix is produced, where the active substances are dispersed in a liquid, or finely distributed in solid vehicles. This premix can normally contain, depending on the final desired concentration in the food, about 1 to X grams of a nitroenamine of the formula (I), and from about 1 to Y grams of a benzoylurea of the formula (II) per kilogram of premix, wherein X and Y are values between 10 and 15, and depend on the body weight of the host animal. Because the combinations according to the invention can be affected by the constituents in the food, they should preferably be formulated in a protective matrix, for example in gelatin, before being added to the premix. Accordingly, the present invention also relates to the flea control aspect which is characterized by the administration of a combination of active ingredients according to the invention to the host animal with the food. A combination according to the invention is conveniently taken in the following dosages: nitroenamine of the formula (I), from 0.01 to 800 milligrams / kilogram, preferably from 0.1 to 200 milligrams / kilogram, especially from 0.5 to 30 milligrams / kilogram of body weight, based on the host animal; benzoylurea of the formula (II), from 0.01 to 800 milligrams / kilogram, preferably from 0.1 to 200 milligrams / kilogram, especially from 0.5 to 30 milligrams / kilogram of body weight, based on the host animal; where oral administration is preferred over all others. A good dosage that can be administered regularly to the host animal is 0.5 to 100 milligrams / kilogram of the body weight of a nitroenamine of the formula (I), to be given twice, or preferably once a week, and administration Parallel of 0.5 to 100 milligrams / kilogram of body weight of a benzoylurea of the formula (II) given monthly to quarterly. The administration interval for the benzoylurea of the formula (II) can even be extended in a subsequent treatment phase up to half a year, in which the addition of the nitroenamine of the formula (I) can be eliminated even if there is little infestation from the pet's environment.

The arrangement under which a preparation in combination of a nitroenamine of the formula (I) and a benzoylurea of the formula (II) is administered can be carried out in many different ways. The user, whether the treating veterinarian or the caregiver, may have specially designed packages at his disposal, where separate unit doses are present for each active ingredient, for example tablets containing a single specific dose of the active ingredient, and that they have to be applied according to certain administration scheme, or where specially characterized unit doses are present, for example tablets containing both active ingredients in the same tablet and in the relevant concentrations, and which have to be administered at intervals dices. The total dose of the same active ingredient can vary from one animal species to another, and even within a species, because it depends, among other things, on the weight, age, and constitution of the host animal. With the combinations according to the invention, the active ingredients are usually not applied in a pure form, but preferably in the form of a composition or preparation containing, in addition to the active ingredient, constituents of the application enhancers or formulation excipients. , where these constituents are beneficial to the host animal.

These compositions or preparations to be used according to the invention normally contain from 0.1 to 99 weight percent, especially from 0.1 to 95 weight percent of a nitroenamine of the formula (I) or of a benzoylurea of the formula (II), or of both active ingredients, and 99.9 to 1 weight percent, especially 99.9 to 5 weight percent of a solid or physiologically acceptable liquid carrier, including 0 to 25 weight percent, especially from 0.1 to 25 weight percent of a non-toxic surfactant. Although it is preferred to formulate commercial products as concentrates, the end user will normally use diluted formulations. These compositions may also contain other additives, such as stabilizers, antifoaming agents, viscosity regulators, binders or thickeners, as well as other active ingredients, in order to achieve special effects. The formulation excipients that can be used are the physiologically acceptable vehicles known from veterinary medicine for oral and parenteral administration, and for administration by implants. Later on, a few examples are mentioned here. Suitable carriers are in particular fillers, such as sugars, for example lactose, sucrose, mannitol, or sorbitol, cellulose preparations, and / or calcium phosphates, for example calcium triphosphate or calcium acid phosphate, in a broader sense also binders, such as starch pastes using, for example, corn starch, wheat starch, rice starch, or potato starch, gelatin, tragacanth, methylcellulose, and / or, if desired, disintegrants, such as the aforementioned starches, in a wider sense also starch; carboxymethyl, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. The excipients 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. Tablet cores may be provided, where appropriate, with suitable coatings resistant to gastric juices, using, among other things, concentrated sugar solutions, which may comprise gum arabic, talcum, polyvinylpyrrolidone, polyethylene glycol, and / or dioxide. of titanium, or coating solutions in organic solvents or mixtures of suitable solvents, or, for the preparation of coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes, flavors, or pigments may be added to tablets or tablet coatings, for example, for identification purposes, or to indicate different doses of the active ingredient. Additional orally administrable preparations are hard capsules consisting of gelatin, and also sealed soft capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol. The hard capsules may contain the active ingredient in the form of granules, for example mixed with fillers, such as lactose, binders, such as starches, and / or brighteners, such as talc or magnesium stearate, and where appropriate, stabilizers. In soft capsules, the active ingredients are preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil, or liquid polyethylene glycols, and in the same manner stabilizers can be added. Among other forms, capsules that can be both easily chewed and swallowed are preferred. Formulations suitable for parenteral administration are especially aqueous solutions of the active ingredients in a water soluble form, for example a water soluble salt, in the broadest sense also suspensions of the active ingredients, such as appropriate injectable oil suspensions, using solvents or suitable lipophilic vehicles, such as oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate, or triglycerides, or injectable aqueous suspensions containing viscosity-increasing agents, for example sodium carboxymethylcellulose, sorbitol, and / or dextran, and where appropriate, stabilizers. The compositions of the present invention can be prepared from; a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving, or lyophilizing processes. Pharmaceutical compositions for oral administration can be obtained, for example, by combining the active ingredients with solid carriers, granulating a resulting mixture where appropriate, and processing the mixture or granules, if desired or necessary. , to form tablets or tablet cores following the addition of suitable excipients. The administration of the combinations according to the invention can take place either by the transformation of both active ingredients as a true mixture in a single dosage form, and administration to the host animal, or by administration to the host animal, in of separate dosages, such that the active substances only mix with each other in body fluids, especially in the blood. The latter method has the advantage that the active substances can also be applied with different time delays. For example, benzoylurea, which is effective for long periods of time, can be applied at longer intervals, and the shorter acting nitroenamine derivative can be applied at slightly shorter intervals. This procedure leads to a reduction in the amount of active substance used. It is also conceivable to have applications where a package for the caregiver is available, wherein the individual dosage forms contain different amounts of benzoylurea and nitroenamine derivative, and the user follows an administration scheme. Accordingly, in the combinations according to the invention, or in the use of the compounds of the formulas (I) and (II) according to the invention, the active ingredients in the dosage form can represent true mixtures, but also they can be administered individually and form mixtures only when they are in the host organism. What is crucial is that they are present together during certain periods when later in the host organism, in such a way that the desired effect is present. The preferred compounds of formulas (I) and (II) within the context of the present invention are shown in the following Tables 1 and 2. Table 1; Compounds of the formula (I), where A is: 1. 01 6-C1 H C2H5 H CH3 1.02 6-C1 5-Cl C2H5 H CH3 1.03 6-C1 5-FC, H5 H CH, 1.04 6-C1 4-F C2H5 H CH3 1.05 6-C1 H CH3 H CH3 1.06 6 -C1 5-Cl CH3 H CH3 1.07 6-C1 2-F CH3 H CH3 1.08 6-C1 4-F CH3 H CH3 1.09 6-C1 HHH CH3 1.10 6-C1 5-Cl HH CH3 1.11 6-C1 5-FHH CH3 1.12 6-C1 4-FHH CH3 1.13 6-C1 H nC3H7 H CH3 1.14 6-C1 5-Cl nC3H7 H CH3 1.15 6-C1 5-F nC3H7 H CH3 1.16 6-C1 4-F nC3H7 H CH3 1.17 6- C1 H iC3H7 H CH3 1.18 6-C1 H C2H5 CH3 CH3 1.19 6-C1 5-Cl C2H5 CH3 CH3 1.20 6-C1 5-F C2H5 CH3 CH3 1.21 6-C1 4-F C2H5 CH3 CH3 Table 2: Benzoi lureas pr ef erid [ace of the formula (I I): 2. 11 F 6-F H H H CF 2 CHFCF 3 3-Cl H 5-Cl 2. 12 F 6-F H H CH 3 CF 2 CHFCF 3 3-Cl H 5-Cl 2. 13 F 6-F H H C 2 H 5 CF 2 CHFCF 3 3-Cl H 5-Cl 2. 14 F 6-F H CH 3 H CF 2 CHFCF 3 3-Cl H 5-Cl 2. 15 F 6-F H CH 3 CH 3 CF 2 CHFCF 3 3-Cl H 5-Cl 2. 16 F 6-F H CH 3 C 2 H 5 CF 2 CHFCF 3 3-Cl H 5-Cl 2. 17 F 6-F H C 2 H 5 H CF 2 CHFCF 3 3-Cl H 5-Cl 2. 18 F 6-F H C 2 H 5 CH 3 CF 2 CHFCF 3 3-Cl H 5-Cl 2. 19 F 6-F H C 2 H 5 C 2 H 5 CF 2 CHFCF 3 3-Cl H 5-Cl 2. 20 F 6-F H H H CH (CH 3) C 2 F 5 3-Cl H 5-Cl 2. 21 F 6-F H H H CH (CH 3) C 2 F 5 3-Cl 2-F 5-Cl 2. 22 F 6-F H H H CH (CH 3) C 2 F 4 CF 3 3-Cl H 5-Cl 2. 23 F 6-F H H H CH (CH 3) C 2 F 4 CF 3 3 Cl 2 -F 5-Cl 2. 24 F 6-F H H H CF = CFCF 3 3-Cl H 5-Cl 2. 25 F 6-F H H H CF 2 CF 2 = CFCF 3 3-Cl H 5-Cl 2. 28 F 6-F H H H CF 3 2-Cl 5-Cl H 2. 29 F 6 -FHHH CFjCHClF 2-Cl 5-Cl H 2.30 F 6 -FHHH CF2CHCHC12 2-Cl 5-Cl H 2.31 F 6 -FHHH CF, CHCFBr 2-Cl 5-Cl H 2.32 FHHHH CF2CHFCF3 2-Cl 5-Cl H 2.33 Cl HHHH CF2CHFCF3 2-Cl 5-Cl H 2.34 F 6-C1 HHH CF2CHFCF3 2-Cl 5-Cl H Particularly preferred are the following combinations of compounds of the formula (I) and of the formula (II): 1.01 and 2.01; 1.01 and 2.02; 1.01 and 2.03; 1.01 and 2.04; 1.01 and 2.05; 1.01 and 2.06; 1.01 and 2.07; 1.01 and 2.08; 1.01 and 2.09; 1.01 and 210; 1.01 and 211; 1.01 and 2.12; 1.01 and 2.13; 1.01 and 2.14; 1.01 and 2.15; 1.01 and 2.16; 1.01 and 2.17; 1.01 and 2.18; 1.01 and 2.19; 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; 1.02 and 2.02; 1.02 and 2.03; 1.02 and 2.04; 1.02 and 2.05; 1.02 and 2.06; 1.02 and 2.07; 1.02 and 2.08; 1.02 and 2.09; 1.02 and 210; 1.02 and 211; 1.02 and 2.12; 1.02 and 2.13; 1.02 and 2.14; 1.02 and 2.15; 1.02 and 2.16; 1.02 and 2.17; 1.02 and 2.18; 1.02 and 2.19; 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; 1.02 and 2.25; 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; 1.03 and 2.02; 1. 03 and 2.03; 1.03 and 2.04; 1.03 and 2.05; 1.03 and 2.06; 1.03 and 2.07; 1.03 and 2.08; 1.03 and 2.09; 1.03 and 210; 1.03 and 211; 1.03 and 2. 12; 1.03 and 2.13; 1.03 and 2.14; 1.03 and 2.15; 1.03 and 2.16; 1.03 and 2.17; 1.03 and 2.18; 1.03 and 2.19; 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; 1.04 and 2.02; 1.04 and 2.03; 1. 04 and 2.04; 1.04 and 2.05; 1.04 and 2.06; 1.04 and 2.07; 1.04 and 2.08; 1.04 and 2.09; 1.04 and 210; 1.04 and 211; 1.04 and 2.12; 1.04 and 2. 13; 1.04 and 2.14; 1.04 and 2.15; 1.04 and 2.16; 1.04 and 2.17; 1.04 and 2.18; 1.04 and 2.19; 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; 1.05 and 2.02; 1.05 and 2.03; 1.05 and 2.04; 1.05 and 2.05; 1.05 and 2.06; 1.05 and 1. 07 and 2.19; 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; 1.08 and 2.02; 1.08 and 2.03; 1.08 and 2.04; 1.08 and 2.05; 1.08 and 2.06; 1.08 and 2.07; 1.08 and 2.08; 1.08 and 2.09; 1.08 and 210; 1.08 and 211; 1.08 and 2.12; 1.08 and 2.13; 1.08 and 2.14; 1.08 and 2.15; 1.08 and 2.16; 1.08 and 2.17; 1.08 and 2.18; 1.08 and 2.19; 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; 1.09 and 2.01; 1. 09 and 2.02; 1.09 and 2.03; 1.09 and 2.04; 1.09 and 2.05; 1.09 and 2.06; 1.09 and 2.07; 1.09 and 2.08; 1.09 and 2.09; 1.09 and 210; 1.09 and 211; 1.09 and 2.12; 1.09 and 2.13; 1.09 and 2.14; 1.09 and 2.15; 1.09 and 2.16; 1.09 and 2.17; 1.09 and 2.18; 1.09 and 2.19; 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; 1.10 and 2.02; 1.10 and 2.03; 1.10 and 2.04; 1.10 and 2.05; 1.10 and 2.06; 1.10 and 2.07; 1. 10 and 2.08; 1.10 and 2.09; 1.10 and 210; 1.10 and 211; 1.10 and 2.12; 1.10 and 2.13; 1.10 and 2.14; 1.10 and 2.15; 1.10 and 2.16; 1.10 and 2.17; 1.10 and 2.18; 1.10 and 2.19; 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; 1.11 and 2.01; 1.11 and 2.02; 1.11 and 2.03; 1.11 and 2.04; 1.11 and 2.05; 1.11 and 2.06; 1.11 and 2.07; 1.11 and 2.08; 1.11 and 2.09; 1.11 and 210; 1.11 and 211; 1.11 and 2.12; 1.11 and 2.13; 1.11 and 2.14; 1.11 and 2.15; 1.11 and 2.16; 1.11 and 2.17; 1.11 and 2.18; 1.11 and 2.19; 1.11 and 2.20; 1.11 and 2.21; 1.11 and 2.22; 1.11 and 2.23; 1.11 and 2.24; 1.11 and 2.25; 1.11 and 2.28; 1.11 and 2.29; 1.11 and 2.30; 1.11 and 2.31; 1.11 and 2.32; 1.11 and 2.33; 1.11 and 2.34; 1.12 and 2.01; 1.12 and 2.02; 1.12 and 2.03; 1.12 and 2.04; 1.12 and 2.05; 1.12 and 2.06; 1.12 and 2.07; 1.12 and 2.08; 1.12 and 2.09; 1.12 and 210; 1.12 and 211; 1.12 and 2.12; 1.12 and 2.13; 1.12 and 2.14; 1.12 and 2.15; 1.12 and 2.16; 1. 12 and 2.17; 1.12 and 2.18; 1.12 and 2.19; 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; 1.13 and 2.02; 1.13 and 2.03; 1.13 and 2.04; 1.13 and 2.05; 1.13 and 2.06; 1.13 and 2.07; 1.13 and 2.08; 1.13 and 2.09; 1.13 and 210; 1.13 and 211; 1.13 and 2.12; 1.13 and 2.13; 1.13 and 2.14; 1.13 and 2.15; 1.13 and 2.16; 1.13 and 2.17; 1. 13 and 2.18; 1.13 and 2.19; 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; 1.13 and 2.25; 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; 1.14 and 2.02; 1.14 and 2.03; 1.14 and 2.04; 1.14 and 2.05; 1.14 and 2.06; 1.14 and 2.07; 1.14 and 2.08; 1.14 and 2.09; 1.14 and 210; 1.14 and 211; 1.14 and 2.12; 1.14 and 2.13; 1.14 and 2.14; 1.14 and 2.15; 1.14 and 2.16; 1.14 and 2.17; 1.14 and 2.18; 1. 14 and 2.19; 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; 1.15 and 2.02; 1.15 and 2.03; 1.15 and 2.04; 1.15 and 2.05; 1.15 and 2.06; 1.15 and 2.07; 1.15 and 2.08; 1.15 and 2.09; 1.15 and 210; 1.15 and 211; 1.15 and 2.12; 1.15 and 2.13; 1.15 and 2.14; 1.15 and 2.15; 1.15 and 2.16; 1.15 and 2.17; 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 and 2.01; 1. 16 and 2.02; 1.16 and 2.03; 1.16 and 2.04; 1.16 and 2.05; 1.16 and 2.06; 1.16 and 2.07; 1.16 and 2.08; 1.16 and 2.09; 1.16 and 210; 1.16 and 211; 1.16 and 2.12; 1.16 and 2.13; 1.16 and 2.14; 1.16 and 2.15; 1.16 and 2.16; 1.16 and 2.17; 1.16 and 2.18; 1.16 and 2.19; 1.16 and 2.20; 1.16 and 2.21; 1.16 and 2.22; 1.16 and 2.23; 1.16 and 2.24; 1.16 and 2.25; 1. 16 and 2.28; 1.16 and 2.29; 1.16 and 2.30; 1.16 and 2.31; 1.16 and 2.32; 1.16 and 2.33; 1.16 and 2.34; 1.17 and 2.01; 1.17 and 2.02; 1.17 and 2.03; 1.17 and 2.04; 1.17 and 2.05; 1.17 and 2.06; 1.17 and 2.07; 1. 17 and 2.08; 1.17 and 2.09; 1.17 and 210; 1.17 and 211; 1.17 and 2.12; 1.17 and 2.13; 1.17 and 2.14; 1.17 and 2.15; 1.17 and 2.16; 1.17 and 2. 17; 1.17 and 2.18; 1.17 and 2.19; 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; 1.18 and 2.02; 1.18 and 2.03; 1.18 and 2.04; 1.18 and 2.05; 1.18 and 2.06; 1.18 and 2.07; 1.18 and 2.08; 1. 18 and 2.09; 1.18 and 210; 1.18 and 211; 1.18 and 2.12; 1.18 and 2.13; 1. 18 and 2.14; 1.18 and 2.15; 1.18 and 2.16; 1.18 and 2.17; 1.18 and 2.18; 1.18 and 2.19; 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; 1.19 and 2.02; 1.19 and 2.03; 1.19 and 2.04; 1.19 and 2.05; 1.19 and 2.06; 1.19 and 2.07; 1.19 and 2.08; 1.19 and 2.09; 1. 19 and 210; 1.19 and 211; 1.19 and 2.12; 1.19 and 2.13; 1.19 and 2.14; 1.19 and 2.15; 1.19 and 2.16; 1.19 and 2.17; 1.19 and 2.18; 1.19 and 2.19; 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; 1.20 and 2.02; 1.20 and 2.03; 1.20 and 2.04; 1.20 and 2.05; 1.20 and 2.06; 1.20 and 2.07; 1.20 and 2.08; 1.20 and 2.09; 1.20 and 210; 1.20 and 211; 1.20 and 2.12; 1. 20 and 2.13; 1.20 and 2.14; 1.20 and 2.15; 1.20 and 2.16; 1.20 and 2.17; 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; 1.21 and 2.02; 1.21 and 2.03; 1.21 and 2.04; 1.21 and 2.05; 1.21 and 2.06; 1.21 and 2.07; 1.21 and 2.08; 1. 21 and 2.09; 1.21 and 210; 1.21 and 211; 1.21 and 2.12; 1.21 and 2.13; 1.21 and 2.14; 1.21 and 2.15; 1.21 and 2.16; 1.21 and 2.17; 1.21 and 2.18; 1.21 and 2.19; 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; and 1.21 and 2.34. The following examples and patent claims illustrate the present invention, but in no way limit its scope. Temperatures are given in degrees Celsius. In the following formulation examples, the term the compound of the formula (I) represents (E) -N- (6-chloro-3-pyridylmethyl) -N-ethyl-N '-methyl-2-nitrovinylidene diamine or (R, S) -1- [2,5-dichloro-4- (1,1,2,2,3,3,3-hexafluoropropoxy) -phenyl] -3- (2,6-difluorobenzoyl) urea.

Example 1: Tablets containing 25 milligrams of the compound of the formula (I) or (II), or both active substances, can be produced as follows: Constituents (for 1000 tablets) active ingredient 25.0 grams lactose 100.7 grams wheat starch 7.5 grams polyethylene glycol 6000 5.0 grams talc 5.0 grams magnesium stearate 1.8 grams demineralized water cs Preparation: First of all, all the solid ingredients are forced through a sieve with a mesh size of 0.6 mm. Then the active ingredient, lactose, talc, and half of the starch are mixed. The other half of the starch is suspended in 40 milliliters of water, and this suspension is added to a boiling solution of the polyethylene glycol in 100 milliliters of water. The obtained starch paste is added to the main quantity, and the mixture is granulated, if necessary adding water. The granulate is dried overnight at 35 ° C, forced through a sieve of a mesh size of 1.2 millimeters, mixed with magnesium stearate, and compressed into biconcave tablets with a diameter of approximately 6 millimeters.

Example 2; Tablets containing 0.02 grams of the compound of the formula (I) or (II), or both active substances, can be produced as follows: Constituents (for 10,000 tablets) active ingredient 200.00 grams lactose 290.80 grams potato starch 274.70 grams stearic acid 10.00 grams talc 200.00 grams magnesium stearate 2.50 grams colloidal silicon dioxide 32.00 grams ethanol q.s.

A mixture of a compound of the formula (I), lactose, and 194.70 grams of potato starch is moistened with an ethanolic solution of stearic acid, and granulated through a sieve. After drying, the remaining potato starch, talc, magnesium stearate, and colloidal silicon dioxide are mixed, and the mixture is compressed into tablets each weighing 0.1 grams, to which they can be provided. Divide notches for finer dosage adjustment.

Example 3; Capsules containing 0.025 grams of a compound of the formula (I) or (II), or both active substances, can be produced as follows: Constituents: (for 1,000 capsules) active ingredient 25.00 grams lactose 249.80 grams gelatin 2.00 grams corn starch 10.00 grams talcum 15.00 grams water q.s.

The active ingredients are mixed with the lactose, the mixture is moistened uniformly with an aqueous solution of the gelatin, and is granulated through a sieve having a mesh size of 1.2 to 1.5 millimeters. The granulate is mixed with the dried corn starch and the talc, and 300 milligram portions of it are filled into hard gelatin capsules (size 1).

Example 4: Premix (food additive) 0.25 parts by weight of the active ingredient, and 4.75 parts by weight of secondary calcium phosphate, alumina, aerosil, carbonate or lime, are mixed until homogeneous with 95 parts by weight of a food for animals.

Example 5: Premix (food additive) 0.40 parts by weight of the active ingredient, and 5.00 parts by weight aerosil / lime (1: 1) are mixed to homogeneity with 94.6 parts by weight of a commercial dry food.

Example 6; Emulsifier concentrate 20 parts by weight of the active ingredient are mixed with parts by weight of an emulsifier, for example a mixture of alkylaryl polyglycol ether with alkylaryl polysulfonates, and with 60 parts by weight of a solvent, until the solution has been completely homogenized. By diluting with water, emulsions of a desired concentration are obtained. Example 7; Solutions (for example, to be used as a beverage additive) 15 weight percent of the active ingredient, 10 weight percent of the active ingredient in diethylene glycol monoethylether, 10 weight percent polyethylene glycol 300, and 5 weight percent of glycerol.

Example 8: Soluble powder 25 parts by weight of active ingredient, 1 part by weight of sodium lauryl sulfate, 3 parts by weight of colloidal silica gel, and 71 parts by weight of urea.

The constituents are mixed and ground together} : homogeneous Biologically active substances or additional additives, which are neutral towards the active ingredients, and which do not have a harmful effect on the host animal, as well as mineral salts or vitamins, can be added to the compositions described. Additional preparations can also be prepared with the active substances of the formula (I) and / or (II) in a manner analogous to the formulations described above of Examples 1 to 8. Biological Example Example Bl; Comparison between the activity of lufenuron alone and the combination of nitenpyram and lufenuron against dog fleas in a contaminated environment corresponding to the actual conditions. Location: Department of Parasitology and Dermatology of the Toulouse Veterinary School, Toulouse, France. Type of study: Flea activity. Period: primary to autumn 1997. Tested animals: 20 healthy Beagles dogs of the same reproduction. Parasite: cat flea Ctenocephalides felis Procedure: Blind test controlled with placebo; simulation of the natural environment (domestic). Method of treatment: Determination of efficacy in a contaminated environment following the oral administration of tablets. Test substances: Nitenpiram as tasty and flavored round biconvex tablets of 100 milligrams (11.4 milligrams of active substance) for dogs of 1.0 to 11.0 kilograms, and 500 milligrams (57 milligrams of active substance) for dogs of 11.1 to 57 kilograms.was.

Lufenuron was administered in the form of commercially available PROGRAM®M tablets containing 204.9 milligrams of lufenuron for dogs of 7 to 29 kilograms of body weight. Placebo: Tasty and flavored biconvex round tablets of 100 and 500 milligrams as above, but without the active ingredient.

In the study, the existing conditions in the home were simulated. For this purpose, 4 isolated and clinically clean rooms were used. They contained a sleeping area arranged with straw and a small corridor to the outside. The rooms were subjected to natural light conditions. Five healthy dogs were placed in each room, and each was infected three times a week with 50 newly hatched fleas, until the dogs had a constant population of fleas. Subsequently, each group of dogs underwent a different treatment. Control group 1 was not given any active ingredient, but only a placebo, and served as the reference group. Group 2 was given lufenuron in a monthly dosage according to package instructions, and once a week it was given a placebo. Group 3 was given lufenuron in a monthly dosage according to package instructions, and once a week nitenpyram was additionally given over a period of 6 weeks. To group 4 is; He gave lufenuron in a monthly dosage according to package instructions, and twice a week he was given nitenpyram over a period of 6 weeks. This was a blind test, where the treatment and evaluation were performed by different people who did not know the test protocol. In all four groups, the flea population was determined by counting them twice a week before the first treatment, and once a week during the treatment. The activity of the test substances was determined under simulated conditions of the home according to the following formula: (number of fleas in the control group) • (number of fleas in the treated group) activity in% = (number of fleas in the control group) After the first administration of nitenpyram, all fleas except one died within 16 to 24 days, but clear differences were present throughout the treatment. The results are summarized in table 1.

Table 1: Activity (% in relation to control) of groups 1 to 4 after the first treatment.

As it could be seen, the activity of group 2, which had been treated exclusively with lufenuron, was very low until day 28 compared to groups 3 and 4, and only reached a satisfactory level for practical use after approximately 84 days. In contrast, the activity of groups 3 and 4 was considly higher from the beginning, and reached a full effect after at most 28 days. Groups 3 and 4 were not significantly different from one another, that is, no substantial differences were established in once or twice weekly administration of nitenpyram.

Claims (7)

1. A veterinary flea control composition, which comprises an amount that is effective against fleas, of a combination of a compound of the formula (I): R, 02N-CH = C R2 (I). FL wherein: Ri is hydrogen, alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms; R2 is hydrogen, alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms; R3 is hydrogen or alkyl of 1 to 6 carbon atoms; and A is heterocyclyl which is unsubstituted or substituted once or repeatedly by identical or different halogen atoms; with a compound of the formula (II): wherein: X is halogen; Xi is hydrogen or halogen; X2 is hydrogen or halogen; Y is alkyl of 1 to 6 carbon atoms partially or completely halogenated, or alkyl of 1 to 6 carbon atoms completely halogenated which is interrupted by an oxygen atom, or alkenyl of 2 to 6 carbon atoms partially or completely halogenated; Yx is hydrogen or halogen; Y2 is hydrogen or halogen; Y3 is hydrogen or halogen; Zi is hydrogen or alkyl of 1 to 3 carbon atoms; and Z2 is hydrogen or alkyl of 1 to 3 carbon atoms, and a physiologically acceptable formulation excipient.

2. A method for controlling fleas in domestic animals, wherein a combination according to claim 1 is administered systemically to the pet in an amount that is effective against fleas.

3. A process according to claim 2, wherein the combination is administered orally.

4. The process according to claim 2, wherein the compound of the formula (I) and that of the formula (II) are administered in separate dosage forms but in parallel.

5. The process according to claim 2, wherein the compound of the formula (I) is applied first of all, and subsequently the treatment with the compound of the formula (II) begins.

6. The use of a combination of a compound of the formula (I): FL -N, 02N -CH = C FL I (I). wherein: Ri is hydrogen, alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms; R2 is hydrogen, alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms; R3 is hydrogen or alkyl of 1 to 6 carbon atoms; and A is heterocyclyl which is unsubstituted or substituted once or repeatedly by identical or different halogen atoms; with a compound of the formula (II): wherein: X is halogen; Xi is hydrogen or halogen; X2 is hydrogen or halogen; Y is alkyl of 1 to 6 carbon atoms partially or completely halogenated, or alkyl of 1 to 6 carbon atoms completely halogenated which is interrupted by an oxygen atom, or alkenyl of 2 to 6 carbon atoms partially or completely halogenated, - Yi is hydrogen or halogen; Y2 is hydrogen or halogen; Y3 is hydrogen or halogen; Zi is hydrogen or alkyl of 1 to 3 carbon atoms; and Z2 is hydrogen or alkyl of 1 to 3 carbon atoms, for the production of a veterinary preparation for the control of fleas in domestic animals.

7. The use of the veterinary preparation according to claim 1, or of the combination of active ingredients contained therein, in the control of fleas in domestic animals.