FI107314B - 1-[N-(halo-3-pyridylmethyl)]-N-methylamino-1-alkylamino-2- nitroethylene derivatives for freeing pets from fleas - Google Patents

Abstract

Described are compounds of the formula (I), in which Hal is a halogen such as fluorine, chlorine, bromine or iodine; R1 is hydrogen, C1-C6 alkyl or C3-C7 cycloalkyl; R2 is hydrogen, C1-C6 alkyl or C3-C7 cycloalkyl and R3 is hydrogen or C1-C6 alkyl, for use in a method of controlling fleas on pets, in particular dogs and cats. Systemic application is preferred. Application is carried out by administering an amount effective against fleas of a substance of the formula (I) via the digestive tract or the blood of the host animal, hence administering the substance systemically to the pet, particularly a dog or cat.

Description

107314 1- [N- (halo-3-pyridylmethyl)] -N-methylamino-1-alkylamino-2-nitroethylene derivatives for controlling fleas in domestic animals The invention relates to 1- [N- (halo-3-pyridylmethyl) )] - N-methylamino-1-alkylamino-2-nitroethylene derivatives for use in the control of fleas in domestic animals, especially dogs and cats, with systemic administration being preferred. The Kek-10 invention also relates to a method of preventing flea infestation in dogs and cats, characterized in that said domestic animal, e.g., dog or cat, is systemically dosed against fleas by an effective amount of said compound via gastrointestinal loading or blood.

The 1- [N- (halo-3-pyridylmethyl)] - N -methylamino-1-alkylamino-2-nitroethylene derivatives mentioned above have the following chemical formula I

20

R

NR2R3

Hai --- γ (I)

WELL

25 2 I · · * ·.: Where Hal stands for halogen such as fluorine, chlorine, · · · * · *: bromine or iodine, stands for hydrogen, C 1 -C 6 alkyl or • ·. ···. C 3 -C 7 cycloalkyl, R 2 represents hydrogen, C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl and R 3 represents hydrogen or C 1 -C 6 C 1-4 alkyl.

• · ·

In the context of Formula I,

The following subgroups are preferred because of their · · ······························································································ , chlorine or bromine, in particular chlorine compounds.

Group b: Compounds of formula I wherein R 3 represents hydrogen, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, preferably hydrogen, methyl or ethyl or cyclopropyl, in particular ethyl.

Group c: Compounds of formula I wherein R 2 represents C 1 -C 3 alkyl or cyclopropyl, especially methyl.

Group d: Compounds of Formula I wherein Hal is halogen such as fluorine, chlorine, bromine or iodine, R 1 is hydrogen, methyl, C 3 -C 6 alkyl or C 3 -C 7-15 cycloalkyl, and R 2 is hydrogen or C 1 -C 6 alkyl.

In groups (a) to (d), those compounds in which R3 represents hydrogen are particularly preferred.

Because of its potent systemic activity against fleas, the compound: 1- [N- (6-chloro-3-pyridylmethyl)] -N-ethylamino-1-methylamino-2-nitroethylene is particularly preferred, but also its direct homologues.

.. '. i 25

In the context of the invention, the term alkyl means; • e · • *. · Always depending on the number of carbon atoms given, as follows; • · ·! crude straight-chain or branched groups, e.g.:; ·! · Methyl, ethyl, n-propyl, isopropyl, n-butyl; 30 sec-butyl, tert-butyl, isobutyl, etc. As used herein and hereinafter, "Hal" shall be understood to mean fluorine, chlorine, bromine or iodine, preferably **, fluorine, chlorine or bromine, but above all chlorine. Cycloalkyl, alone or as part of a substituent, means, always depending on the number of carbon atoms given, cyclopropyl, cyclobutyl, cyclopentyl,? 3 cyclohexyl, etc., with cyclopropyl being particularly preferred.

Compounds of the structural type of Formula I, including methods for their preparation, are described in EP-030301389. The compounds of formula I may be prepared according to the methods disclosed in EP-030303838 or analogously to the compounds described therein. This publication discloses a rather limited set of compounds, of which the foregoing compounds refer only to a selected subgroup but are not disclosed as a group. The class of compounds disclosed in EP-0'302'389 is described as insecticide and acaricide. Insects and mites that are harmful to plants are mentioned as a preferred use. There is no reference to the anti-flea effect.

EP-0'302'833 also discloses a group of compounds which are structurally close to, or partially overlapping with, the compounds of formula I above. The major structural difference between the specifically represented compounds and the compounds of formula I is that they contain an unsubstituted pyridyl group of · · ···· in the compounds of formula I. “The pyridyl residue is simply halogenated. The compounds disclosed in EP-0'302'833 state that "·" ί ... they prove to be valuable active ingredients in a pest control y / y, suitable for use in warm blood and plant applications and that they are suitable for pest control. animals and plants. Insects harmful to animals include:. especially the siphonaptera sect (fleas).

· «·· • · · ♦ * ·

It has now surprisingly been found that the coupling of a halogen atom to the pyridyl residue of the compounds of formula I of the above-described * 35 results in an unexpected -_____ and a significant increase in the flea-blocking active 107314; 4 in the mouth. This is clearly evident from a comparison of the parent compounds of the invention with structurally related compounds of the prior art. Corresponding reference values are shown below in biological assays.

The excellent activity of the compounds of the formula I against fleas is so significant that the infestation of fleas in domestic and pet animals, especially; 10 for dogs and cats, remains an insufficiently resolved problem for the veterinarian and the animal owner.

Due to the complex life cycle of fleas, none of the 15 known methods is completely satisfactory for controlling these highly embarrassing parasites, which not only carry diseases but also cause embarrassing allergies, especially when · most known control methods are based on the! 20 of your active ingredients are dosed into the flea space at various stages. However, due to the complex life cycle of fleas, this pathway is very labor-intensive and cannot actually cover all the states of the body and therefore is equally unreliable.

· ': 25. *: For example, when dealing with adult fleas - * * *; The skin, which is usually accomplished by administering a flea suppressant to the skin of a host animal, completely ignores the various youth of fleas4 • · «· 30 steps that occur not only in the skin of the animal but mainly in the soil, carpets, in the map, on chairs, in the garden and in all other places where the infected animal comes into contact. Adult cat and dog fleas (Cteno- | 35 Cephalides felis and C. canis) usually live on the skin of a host cat or host dog. They take their food.,: From the host animal's blood and lay their eggs on its skin.

107314 5

However, since these eggs are not self-infecting, they tend to fall off quickly and can be found in soil, worms, dog and cat baskets, animal chairs, gardens, backyards, etc.

5 This means that the entire living space of the pet is contaminated with flea eggs, which within two days become larvae. The larvae distinguish between three developmental stages, each lasting three days. In the final step, the larva purrs its housing and becomes a housing. Under favorable conditions, i.e. At 33 ° C and 65% relative humidity, the conversion from egg to shell takes about 8 to 10 days. In the next approximately 8 days, young, ready-made kir-15 put will be formed in the boxes on the ground, carpets, sleeping quarters, chairs, etc. Young, adult fleas remain there until they silence the presence of an acceptable host animal, after which they flutter out of their housing and try to jump on the host animal. Based on this, it takes at least three weeks for the egg to develop into an adult 20 young flea that can re-infect the host animal.

However, such a young flea can remain in its housing for many months, possibly even a year. On the other hand, under less optimum conditions, it may take 4 to 5 weeks to develop from an egg to an adult young flea. Fleas need blood as a nutrient to reach sexual maturity in order to reproduce: and this blood must come from the real host animal. It is usually taken from the secretions of fleas that are usually kept in a host animal. These secretions contain ♦ large amounts of undigested blood.

«·« '!!! With this long life cycle that is separate • * · * »* *. from a host animal, has a significant impact on the successful control of fleas in a host animal.

107314! 6

If only the fleas on the skin of the host animal can be very quickly successfully combated, i.e. when all adult fleas are killed in a very short period of time. '! with the active ingredient, have the cat or dog re-! 5 the risk of infection caused by new hatched blades; ret fleas that have survived in its state.

Flea infestation in dogs and cats does not have any unpleasant sequelae not only for the animal being treated] but also for the animal owner. Such discomfort results in, for example, local irritation or embarrassment of scabies and often severe scabies. A large proportion of animals are allergic to flea secretions, which results in very itchy and rough skin changes around the bite areas. These skin changes] usually have a diameter of about 3 mm or more and often make the animal angry and cause it to scratch, resulting in some hair loss.

20

In addition, flea infected animals are permanently at risk because they are infected with Dipylidium, a species of tapeworm transmitted by fleas. : •••• 25 \. N Flea infestation is not only for the infected person]: «· e • *. · Extremely embarrassing for the animal but also causes i • * * l for the pet owner to experience unpleasant consequences, kur: ·; · he / she eventually identifies these pets as unusual. *; 30 that the animal is sick and suffering and that he must help him. In addition, the pet owner may find it uncomfortable that if they sell the infection - ♦!: * !!! ": · 35 new encapsulated fleas, suitable host for a long time!::: in the absence, they are forced to move to humans, although they can no longer uses human blood as the sole source of nourishment! 107314 7 Although a dog or cat is present, the animal owner may be bitten by fleas.

Dog and cat fleas or their secretions can also cause many people with allergic skin conditions, which in many cases force the pet to give up. Effective control of fleas in dogs and cats was therefore already a wish of everyone.

10 A number of traditional control methods are known, but with various disadvantages. If, for example, flea combs coated with surface insecticide are used, the animal owner has no choice but to comb the animal intensively and frequently, which may require, depending on the size of the animal, a few minutes up to hours and no reconciliation for each animal. Also, every animal owner is not ready to spend their time on this. The use of similar flea-active shampoos is often not appropriate 20 because most cats, but also numerous dogs, do not allow themselves to be laundered or must be cleaned using violence, causing water and active substance to splash and be removed. Furthermore, the effect of such a washing treatment lasts for up to about a week and the thorough treatment must be repeated. The same, or quite similar, - *. Problems occur when cleaning with lubricants ** · *: (dips) or rinses. Also, the use of powders • *; ***. dusting powders are usually not tolerated by the animal without the »i» breast, as it requires some «« ·· ·; *. 30 minutes and the whole coat is treated at the same time, • «* in which case some powder is forced into the mouth,. nose and eyes. Even with careful use, it cannot be avoided that animals and humans get their lives i »» * = * 'powder. In practice, it cannot be avoided that: ·· 35 people are exposed to the substance to greater or lesser extent.

/ · 9 * · »··» 107314 8

When using sprayers, many people may experience an embarrassing surprise because most animals, especially cats, ρεί-τ are already flabby or reacting aggressively to air-spray noise. In addition, the jets also have all the disadvantages listed with the powders 5, with the added fact that they are even finer dispersed in the air and thus more delicious! or the animal's airways. Fleas are often combated with so-called flea collars, for which; guaranteeing a high level of efficiency. This treatment 10 has a particular weakness, particularly locally well limited dosage. Although the lethal effect on the neck and chest region generally reaches 100%, the body parts of the animal, however, are unlikely to be affected. In addition, the effect of these collars is limited in time. Still many of these collars look less attractive and can distract the animal. Nowadays, you can also buy medallions that can be hung at regular collars and should be active. These are even eye-pleasing, but their effect is unsatisfactory because skin contact is insufficient. A few flea-active organophosphorus compounds are also available as Spot-On formulations and can therefore be applied locally to a limited area and skin. They usually have a good effect in the short term! 25 adult fleas, however, when used • »'! substances often have problematic toxic effects. Or -

I »I

»Ganophosphorus compounds are also partially administered orally, {'**: however, they have strict safety margins and should under no circumstances be administered concurrently • M1, * Γ. 30 other organophosphorus compounds. [9

All in all, the methods so far,; $ ***! which are aimed at killing adult fleas, everything i) i

• I I

mucus produces such unsatisfactory results as they; «T '35 depend on what the infected host does--:! patience and skill of the user in it.

· The result of the commercial agent depends entirely on how often and how extensively the user, usually the animal owner, doses the active ingredient to the host animal and how thoroughly he disinfects the environment in which the host animal lives. The methods to date are relatively laborious, time consuming and less effective over time. Short-term suitable agents can achieve complete relief.

What is not adequately taken into account in the appropriate methods or substances for this is that dog and cat paws are re-infected due to the particular life cycle of fleas, firstly because of contact with flea eggs, flea larvae and young adult 15 adults. fleas are unavoidable, secondly, because many pets come in contact with their infected counterparts over and over again.

With conventional agents, the recurrent recurrence of recurrent infection is insufficiently prevented or can be achieved only by the use of large quantities of disinfectants, etc.

It has now surprisingly been found that by means of a particular systemic dosage regimen and by using as active ingredients: compounds of formula I, adult fleas can be useful. : quickly and completely removed and thus can prevent the complex flea development • · * .. I cycle. However, since these agents do not fully diminish their excellent anti-flea effect when systemically administered to the host animal, i.e.

Orally, parenterally, subcutaneously, intramuscularly or intravenously, it is possible to interrupt the continuation of the various ways of pest infestation:: 35 repetitive recurrent infection; • · ... until the all stages of the ◆ 10 107314 juvenile life in the host animal have been killed. Fleas are killed, their li- | regulation is prevented, growth of the adolescent stages is inhibited: the host animal can no longer be infected, which results in. |; dogs and cats can be kept permanently free of fleas. The only inevitable possibility of re-infestation is limited to contact with infected fellow breeders, and this problem can only be solved organically with 100% long-term care. This!' however, the risk is of secondary importance.

It has now been found that with oral doses, parenteral doses, or also containing an effective amount of compounds of Formula I for fleas: the implant can be used to reduce or completely prevent flea infestation in domestic animals such as cats and dogs.

However, it is surprising in the context of the invention that the full effect is achieved even when: the active ingredient is administered to the host animal at a relatively low dose. smelly use and reaches the target adult flea only via the gastrointestinal tract and then suckled blood. Active substance systemic! the complete death of adult fleas I 25 after its administration is now achievable- • | flea destruction. j: • »· 9 * 1 *« · 9 · This combination of systemic use of the active ingredient worked

• O

measures such as disinfecting the residence of the host animal j «· *" 30 may possibly be an even quicker solution to the flea problem; but also without these additional measures; • In a few weeks or at most a month, the flea population has completely disappeared or dropped to the minimum acceptable amount.

• •• 35 she. : The compounds of the formula I have an effect on young flea stages in that the flea larvae that peel |! «· J.

107314 11 flea eggs, are mainly dependent on the secretions of adult fleas as they feed on these feces. However, flea secretions still contain high concentrations of 5 tons of blood thawed by the host animal and thus serve as a protein source for developing fleas. However, because the active substances of formula I kill adult fleas very quickly, the necessary secretions are missing and the juvenile phase lacks the nutrient medium so that they are destroyed before reaching the adult phase. This, too, is crucial to breaking the flea's complex life cycle and preventing the host animal from being continuously re-infected with eggs and hatching larvae that are ubiquitous in its preferred habitat.

15

Thus, the invention relates to two aspects, on the one hand, to the methods already described for preventing flea infestation in domestic animals, and, of course, to the prevention of flea reproduction.

20

It is an object of the invention that the compounds of Formula I are administered such that the adult sucking flea can receive enough of the compounds from the blood of the host animal and the adult flea dies shortly before being able to prepare its secretions as a sufficiently contaminated diet for flea larvae. This can be accomplished with the inventive • · · ·; with active ingredients using different dosage forms e.g.

The active ingredient is prepared by oral administration. In this case, the preparation is in the form of, for example, a powder, a tablet, a granulate, a capsule, an emulsion, a foam. ·· Microencapsulated, etc., whereby the preparation does not need to be ·. * * Strictly administered directly to the animal, but intentionally mixed with its diet, whereby this an-Yj * lifting form is both annoying to the host animal and to the user: Y: 35 It will be appreciated that all compositions for oral administration may contain, in addition to the usual ingredients, other additives which assist the voluntary administration of the host animal, e.g., containing suitable perfume or aromatic agents. Another embodiment of the invention is parenteral administration, e.g., subcutaneous injection or injection long-term preparation (Depotform) for a vein or implant.

Oral administration includes, for example, dog or cat Administering 10 meals containing the active ingredient ready; mixed with, for example, biscuits or snacks, chewable tablets, water-soluble capsules or tablets, in a water-soluble form so that it can be added dropwise to food or other forms added to animal food. Implants also include all devices that can be incorporated into an animal to administer a substance; sex.

Percutaneous dosage forms include, for example, sub-20 cutaneous, dermal, intramuscular and even intravenous dosage forms for injection. In this case, in addition to the conventional needle-type injection syringes, needleless injection devices (Druckstossapparate) may also be appropriate, but also Pour-on and Spot-on preparations. ; By selecting a suitable preparation, it is possible to prevent the acti-j: • 9 i *. *. possible penetration of the vehicle into the living tissue of the animal - • ·. · * ·. or maintain its usability. This is of importance «9 * 9 9 30 when using, for example, very difficult-soluble active '♦ * 11! a substance whose low solubility requires solubility * 9 9 * because the animal's body fluid is only able to dissolve only minor i.

• n · •• i amounts of active ingredient.

V: 35 •; *. The active ingredient may also be in a matrix formulation which is ··. ·. physically disintegrates and maintains the continuing availability of 13,107,314 active ingredient. This matrix preparation is injected into the body and remains there as an Art Depot, which continuously releases the active ingredient. Such matrix preparations are well known to those skilled in the art. Generally waxy, semi-solid substances such as vegetable waxes and high molecular weight polyethylene glycols are concerned.

High availability of the active agent is also achieved by introducing an implant of the active agent into 10 animals. Such implants are widespread in veterinary medicine and often consist of silicone-containing rubber. The active ingredient is then dispersed in a solid rubber or is contained within a rubber hollow body. It should be noted that the active ingredient, which is soluble in the rubber implant, is selected because it is first dissolved in the rubber, after which it continuously exudes from the rubber material into the body fluid of the animal to be treated.

The release of the active agent from the implant, and thus the period of time during which the implant is effective, is generally determined by the accuracy of implant placement (amounts of active agent in the implant), the implant environment, and the polymer preparation from which the implant is manufactured.

25.: The administration of the active ingredient by implant is the subject of the invention. : another preferred embodiment. Such a dosage is also • · .1 · economical and effective because properly sized »· * ,.! the implant provides a constant concentration of active substance in the tissue of 30 animals. Nowadays, ♦ · · ·· ♦ · implants can be manufactured and implanted in a simple manner so that they release the active ingredient at that location for a few months. After implantation, the animal ψ no longer hassle and no more dosing is needed: 35 no worries.

| t «« 107314 14

Use of veterinary additives for animal nutrition; Generally, the so-called Premix (a premix in which the active ingredient is dispersed in a liquid or finely divided in solid carriers) is prepared first. This Premix can usually contain about 1 to 800 mg of substance / kg of Premix depending on the desired final concentration of the nutrient. -: Nose.

In addition, it is known that nutritional ingredients can hydrolyze to rolyse or weaken the active ingredient. Such active ingredients are conventionally prepared in a protective matrix; j; eg gelatin before being added to Premix. | Accordingly, the invention relates to adult fleas removal of livestock, as well as prevention of the development of flea larvae by nutrient barrier, which is equivalent to systemic control before re-infection of livestock, especially fleas. This arrives - j; 20 is administered by administering to said host animal an effective amount of at least one agent of formula I, orally, parenterally or by implantation, against E fleas.

The invention thus also relates to the proliferation of fleas); inhibiting fleas administered to the host animal ak-i * ·· »'· /; by systemic dosing of sealant receive * ·; V. nutrient-contaminated blood containing »1 / ··, an active amount against at least one of the formulas £; * 1

***. 30. This is most easily achieved I

ψ · t> 1 such that an effective amount of the compound of formula I, • 1 ♦ *, is administered to the host animal as a nutritional additive, and in this way a host animal can be reached; .. '. fleas.

V 1 35 II

The compounds of the formula I are administered in a convenient manner in a dose of 0.01 to 800, preferably 1 µL, 1 × 4 µL. , 107314 15 min 0.1 to 200, especially 0.5 to 30 mg / kg of body weight of the host animal, with oral administration being preferred.

A good dose that can be administered to the host animal on a regular basis is 0.5 to 100 mg / kg body weight. The dosage is suitably daily or weekly.

The total dose of the same active ingredient may vary from one animal species to another, and also from one animal species to another, since it depends, e.g. the weight of the animal and the general structure of the animal.

In the use of the invention, the active ingredient is generally not dosed in pure form, but preferably as an agent which, in addition to the active ingredient, contains auxiliary ingredients, such as being acceptable to the host animal. It goes without saying that, in addition to combating adult fleas in accordance with the invention, conventional methods can be used to combat young flea stages, however, the latter is not overwhelmingly necessary.

Such agents for use in accordance with the invention generally contain from 0.1 to 99% by weight, in particular from 0.1 to 95% by weight, of the compound of formula I and from 99.9 to 1% by weight, particularly of 99.9 to 5% by weight. % by weight of solid or liquid, 4 non-toxic additives, plus 0-25% by weight, * t · especially 0.1-25% by weight of non-toxic surfactant.

* 1 1 t · • «4 1 * - ·· '30 Although commercially concentrated substances» ♦ «... ί are inexpensive, the consumer generally uses diluted V 1 substances.

Such substances may further contain other additives, · ·; Y; 35 such as stabilizers, anti-foaming agents, viscose agents, viscosity regulators, binders, adhesives, and other active substances to achieve certain effects.

Veterinary aids may be used as processing aids; 5 oral, parenteral, and implant agents, a few examples are given below.

Suitable carriers are, in particular, excipients such as sugars, e.g. lactose, sucrose, mannitol or sorbic acid, cellulose preparations and / or calcium phosphates. tricalcium phosphate or calcium hydrogen phosphate, incl. substances such as starch paste, e.g. corn, wheat, rice or potato starch, gelatin, [15 tragacanth, methylcellulose and / or, if desired, disintegrating agents such as the starches mentioned above, including carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or a salt thereof, such as sodium alginate. Excipients are primarily flow regulators and lubricants, e.g., silica, talc, stearic acid or its salts such as magnesium or I: calcium stearate, and / or polyethylene glycol. The granulators j may be provided with suitable coatings, possibly gastric fluid resistant, using e.g. concentrated sugar solutions, optionally containing j; .,! · Gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures, or. ii • · I; for the preparation of gastric fluid-resistant coatings, suitable cellulose preparations such as acetyl

MM

# ·; · # Cellulose phthalate or hydroxypropylmethylcellulose; • · «solutions of saftalate. Dyestuffs, flavorings, or pigments may be added to the tablets or granules. Oj1 eg to identify or identify different doses of active ingredient * 35.

• I · · J • «1 1! 17 107314

Other formulations useful for oral administration include gelatin capsules and soft, closed capsules of gelatin and a plasticizer such as glycerol or sorbitol. The capsules may contain the active ingredient in granular form, e.g. in admixture with excipients such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and may optionally contain stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, with the addition of stabilizers. Preferred are e.g. capsules that can be easily bitten in half or swallowed without breaking.

15

Aqueous solutions of a water-soluble form of the active ingredient, e.g., a water-soluble salt, including suspensions of the active ingredient such as corresponding oily injection suspensions, are suitable, for parenteral administration, with suitable lipophilic solvents or carriers such as fatty oils, e.g. fatty acid esters, e.g. ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity-increasing agents, e.g. sodium carboxymethylcellulose, sorbitol and / or dextran, and optionally stabilizers.

The formulations of the invention may be prepared in a manner known per se, e.g. by conventional mixing, granulating, granulating, dissolving or lyophilizing processes. · · ·; ·· system. Thus, pharmaceutical preparations for oral use may be obtained by combining the active ingredient with solid carriers, optionally granulating the resulting mixture, and mixing or granulating, if desired, or after adding suitable excipients, as appropriate. made into tablets or granules.

• · j '107314 18 I.

The following examples illustrate the above invention, without limiting its scope in any way. Hot; the temperature is given in degrees Celsius. : Table: Examples of compounds of formula I according to the invention

R

- 3 I 1 10 .NR2 * 3 f

Hai --- Y (I)

WELL

2 15 ------—------------ 1

Compound No. Hai Rx R2 R3 Sulp. ° C

1.1 6-C1 CH, CH3 H 87-90 1.2 6-Cl C2Ht CH3 H yellow oil 20 1.3 6 -Cl CH3 C2H5 H 112-114 \ 1.4 6-C1 CH, C3H7-H 133-135: 1.5 6- Cl CH on C 4 H 9 H! 1.6 6-C1 CH3 C4H9-t H [

1.7 6-Cl CH, C4H9-s H

25 1.8 6-C1 CH3 C5Hg-n H j:

1.9 6-Cl CH, C6H13-n H

γ. | 1.10 6-F CH, CH3 H 100-100.5 1.11 5-Br CH3 CH3 h 116-117; * · *: 1.12 2-C1 CH3 CH3 h 106-113 j | .n 30 1.13 6 -Cl C3Hv-i CH3 H |; / r, 1.14 6-Cl C4H9 ~ n CH3 H [• · ·

1.15 6-Cl C4Hc-t CH3 H

. 1.16 6-Cl in C4Hc-CH3 H

• · · · ;;; 1.17 6-ci c 6 H: 3-n ch 3 h '* * 1.18 6-Cl cyclopropyl CH 3 H 104-105 | 1.19 6-Cl cyclobutyl CH 3 H i! 1.20 6-Cl cyclopentyl CH 3 H 1; 19 107314

Compound No. Hal R2 R3 M.p. ° C

1.21 6-C 1 cyclohexyl CH 3 H

1.22 6-Cl Cycloheptyl CH 3 H

1.23 6-C1 H CH3 H 158-161 1.24 6-C1 C2 H5 H H 159-161 1.25 6-C1 CH3 H H 202 diff.

1.26 5-C1 CH3 CH3 H

10 1.27 4-C1 CH3 CH3 H

1.28 6-Cl Cyclopropyl C 2 H 5 H 144-146 1.29 6-F C 2 H 5 CH 3 H Oil 1.30 6-Br C 2 H 5 CH 3 H 79-80 1.31 6-Cl H CH 3 CH 3 97-98 15 1.32 6-Br CH 3 CH 3 H 130-131 1.33 6-C1 CH3 CH3 CH3 110-112 1.34 6-C1 H C2H5 CH3 87-88 1.35 6-C1 C3H7-i HH resin 1.36 6-C1 HHH 188-190 20 1.37 6-C1 C3H7-n HH 185-186 1.38 6 -C1 C3H7-n H CH3 102-103 1.39 6-C1 C3H7-i H CH3 119-120 1.40 6-C1 cyclopropyl H -cyclo 113-115 propyl 25 ________________ ♦ * · · * ·. · · * · ': 1- [N- (6-chloro-3-pyridylmethyl)] - N -ethylamino-♦ · * · *. l-methylamino-2-nitroethylene.

• ♦ ·.:. Example 1: Tablets containing 25 mg of active ingredient may be prepared as follows:. Ingredients (for 1000 tablets) “· Active substance 25.0 g '35 Lactose 100.7 g ·. · Wheat starch 7.5 g * *. Polyethylene glycol 6000 5.0 g *. · »107314! 20;

Talc 5.0 g F

Magnesium stearate 1.8 g

Demineralized water q.s. | i

Preparation: All solids are first sieved through a sieve with a mesh size of 0.6 mm. After that active! -; those, lactose, talc and half the starches in admixture; a. A second portion of the starch is suspended in 40 ml of water and this suspension is added to polyethylene glycol. 10 ml of a solution in 100 ml of water. The resulting starch glue is added to the masterbatch and the mixture, if necessary after addition of water, is granulated. The granulate is dried overnight; At 35 °, sieved through a sieve with a mesh size of 1.2 mm; mixed with magnesium stearate and pressed with F

15 on both sides to form concave tablets having a diameter of about 6 mm. |:

Example 2: Tablets containing 0.02 g of active ingredient; material, prepared as follows: j; 20 Composition (for 10,000 tablets) [

Active ingredient 200.00 g

Lactose 290.80 g j |

Potato starch 274.70 g j:

Stearic acid 10.00 g t 25 Talc 100.00 g t; \ Magnesium stearate 2.50 g!: * ·: Colloidal silica 32.00 g ji * «j Ethanol g.s |; • * I · ♦ * * n · ♦ ♦; ♦ · ♦

A mixture of the active ingredient, lactose and 194.70 g potato I

•! of starch, moistened with ethanol liv of stearic acid; 9 · · vomit and granulate through a sieve. Dry, followed by addition of the remainder of the potato starch, talc, magnesium; iit | · * 'Sum stearate and colloidal silica and the mixture are compressed into tablets each weighing 0.1 g each; ·, · Optional fracture grooves for finer dosing. ! i j | 107314 21

Example 3: Capsules containing 0.025 g of active ingredient can be prepared as follows:

Composition (for 1000 capsules)

Active substance 25.00 g 5 Lactose 249.80 g

Gelatin 2.00 g

Cornstarch 10.00 g

Talc 15.00 g

Water q.s.

10

The active ingredient is mixed with lactose, the mixture is moistened evenly with an aqueous solution of gelatin and granulated with a sieve of mesh size 1.2-1.5 mm. The granulate is mixed with dried corn starch and 15 talc and filled with 300 mg portions of hard gelatine capsules (size 1).

Example 4: Premix (Nutrient Additive) 20 0.25 parts by weight of active ingredient and 4.75 parts by weight of secondary calcium phosphate, alumina, aerosil, carbonate or lime are mixed homogeneously with 95 parts by weight of animal feed.

25 ..il Example 5: Premix (nutritional supplement) ♦ i i «9 · • ·

ie I

; ·: 0.40 parts by weight of active ingredient and · '** · 5.00 parts by weight of an aerosil / lime mixture (1: 1) were mixed <· !. 30 is homogeneously determined. 94.6 parts by weight of commercially available dry food.

I'll »« - * 1 1 «« r t t «♦ ·> - * 4 t. c 107314 22

Example 6: Emulsifiable Concentrate 20 parts by weight of active ingredient together with 20 parts by weight of emulsifier, e.g., alkylaryl; 5 mixtures of lipol glycol ether with alkylaryl polysulph

with phonates, mix F

60 parts by weight of solvent so. long for the solution; jj is completely homogeneous. Dilution with water gives F emulsions of the desired concentration.

10

Example 7: Solutions (e.g., for use in a beverage supplement 15% by weight of active ingredient in 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane, 15 to 10% by weight of active ingredient in diethylene glycol monoethyl ether, 10% by weight polyethylene glycol in 300 and 5% by weight in glycerol i

Example 8: Soluble Powders F

25 parts by weight of active ingredient, 1 part by weight of sodium lauryl sulphate, 3 parts by weight of colloidal silica gel and | 25 71 parts by weight of urea. jj • • »4 | [

Mix the ingredients and grind until they get - F

• · |;

homogeneous mixture. F

• · * * • e *! ' ♦ · ♦ · 30 Other bio-jj | |; * 11 ^ logically active substances and additives which are: j: • · j: • · o | i * neutral to the active substances and have no adverse effect on the host being treated

... · animal, as well as mineral salts or vitamins. F

35 jj 107314 23

Biological Examples

Example 9: Comparative Test for Action against Ctenocephalldes Fells (Cat Flea) According to the method set forth below, the active ingredient of the invention is 1- [N- (6-chloro-3-pyridylmethyl)] - N-ethylamino-1-methylamino -2-nitroethylene and has the chemical formula .OH,

The substance (A) r J of the invention

il, nhch X J χ

C 1 N 2 NO 2 and also a structurally related compound of the formula CH mentioned in EP-0'302'833.

/ 3 compound (B) / NHCH2 of the prior art

k J X

N2O2 is compared to an untreated control group for testing fleas.

• · · · · * · ,; Test Method: 20 adult fleas of Ctenocephalides felis are housed in a shallow, round cage closed by a gauze on both sides. This cage is now placed in · · · · /; ·. a container closed below with a paraffin membrane. This vessel contains blood containing 1.0 ppm of active ingredient and the temperature is constant to 37 °. Fleas get blood through the membrane. 24 and 48 hours after the initial X * 35 examination. Determining the population ·; : percentage reduction (% activity) from the comparison performed with treated blood and treated with 24 I; 1073 '4 Floodless (Control) Flea of the Dead ··! . 24 hours after treatment, the blood is changed to new, including treated blood, and the test is continued! fleas still alive. Also a control group! 5 untreated blood is changed after 24 hours.

Results: Fleas in all three groups [(control! Group / untreated blood); (Group A / blood treated with substance A according to the invention) and (Group B / blood treated with prior art compound B)] began to draw blood as soon as they were added to the experimental design. The behavior of the control group and group B (prior art) remained virtually unchanged during the test. Instead, within half an hour after starting the experiment, the first j; toxic effects.

After 24 hours, the following individual findings were observed; 20 blots with each 2x20 flea population (% mortality): j

Substance ppm Active Substance_Test 1 Test 2 Test 3 Test 4 j B 1.0 0% 5% 0% 0% A 1.0 100% 95% 95% 100% j Cont. 0.0 0% 0% 0% 0%; • - - .....- j »» · o • ·

Example 10: In Vivo Comparative Assay for Ctenopfra-i, ·, ···. lides against fells (cat flea) • · • · ·

30 I

* Ί ”In this comparative study, as in Example 9, the substance A of the invention is again tested against a prior art, closely resembling substance B in cats. j: 35 25 107314

Testing of other compounds of the formula I exemplified in the Table gives absolutely comparable results.

5 Test Method: 6 female goats, aged 1-2 years and weighing 3.0 to 4.0 kg, are divided into three groups with two animals each. One group, which is also infected with fleas but left untreated, serves as a control group. One of the remaining groups receives test substance A, the other substance B in a gelatin capsule directly into the pharynx at a dose of 10 mg / kg body weight. Each active ingredient is premixed with lactose in a ratio of 1: 1. Immediately after dosing of active substances, cats are infected with up to 20 fleas (16 female and 4 male) at the withers. Additional flea infestations, each with 20 fleas, are performed on substance A on days +2, +4 and +6. In cats treated with substance B and in the control group, no further infection with fleas was necessary because all first infected fleas were alive.

Flea eggs were collected and counted daily. The number of dead fleas found daily was also calculated daily. The results of the two treated groups were compared with each other as well as with the control group.

»I« «« «•« »i« «« i «« i «« «i« «« i «« «i« «« i «« «i« «i« «« i «« «i« «« i «« i «« «i« r «1« rt. * 1 e · * · · 26

1073 U

Results: The number of dead fleas found and egg production are shown in the following table--; in size 1 and 2! 5 Table 1: Number of dead fleas

Substance Cats No. Dead fleas on days 0 +1 +2 +3 + 4 +5 +6 +7 +8 + 9!

10 A 325 12 * 1 0 * 11 5 * 0 2 * 0 0 C

343 9 * 1 0 * 8 2 '· 0 2 * 0 0 C

B 351 0 * 1000 0 0 0 0 0 256 0 * 0000 0 0 0 0 0 15 __________________________; kontrol. 339 0 * 0000 0 0 0 0 0 599 0 * 0000 0000 Ci Infection 20 with Flea 20

By substance A, as early as 6 hours after infection, 60% of the first 20 fleas were dead. Even on the second day, after another 20 flea infestations, there were | still 55% dead. The effect of Substance A decreased only by a month! On the 25th day to about 10%. In contrast, there was no significant difference between the control group in cats and the group treated with substance B, »• J. Substance B is detected at low test concentrations- * ♦ · i! * ♦ ·. for ineffective and oral administration of fleas!

«E II

* «30 against useless. !: 4! '• · · · • · ♦ * · ♦ 4 t j' «· 4 * !; «« 107314 27

Table 2: Egg production

Substance Cats No. Egg production on days +2 +3 +4 +5 +6 +7 +8 +9 5 _____ A 325 0 * 0 0 * 0 37 * 233 250 370 343 0 * 0 0 * 60 0 * 186 240 283 B 351 240 306 403 423 350 333 343 290 10 266 106 266 386 313 286 290 326 303 controls. 339 60 133 186 300 310 313 290 233 599 96 110 156 146 166 116 200 170 15 * infection with 20 fleas

After the first and second flea infestations, no flea eggs were detected in the substance-treated group. In the Cat-treated group and in the control-20 group, female fleas produced a normal number of eggs, with no significant difference observed.

A comparative experiment shows that substance A has a good systemic activity against adult fleas, lasting about 3-4 days. By contrast, Substance B can be considered to be completely ineffective at the dose tested. However, it could not be expected in advance that simple halogenation of the pyridyl group would provide such a significant effect on the improvement of systemic anti-flea activity.

·· ♦ M »» • «4

I «I

The compounds shown in the tables as the inventive and related substances and having the physical values of,,,,, and, have comparable fleas. '· 35, as well as the agent of the invention; A. Surprisingly, the compounds 1.1 - 1.4, 1.10 - »* are particularly surprising. 1.12, 1.18, 1.28, 1.29 and 1.36-1.40.

* · »· I ·.

r: * «· <»

Claims (20)

1073V 28; A method of fleas, preferably adult fleas; for systemic combating in domestic animals, characterized in that for fleas an effective amount of a compound of formula I R3 ^ 11 nr2r, 10 Hai —L— | d > NO 2: wherein Hal represents halogen such as fluorine, chlorine, bromine or iodine, R 1 represents hydrogen, C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl, R 2 represents hydrogen, C 1 -C 6 alkyl tallow C 3 -C 7 cycloalkyl and R 3 represents hydrogen or C 1 -C 6 alkyl, is administered systemically to said animal., | preferably orally, parenterally, or implant; In 20 t form. jl Method according to claim 1, characterized in that the active ingredient is a compound of formula I i wherein Hal is in the 6-position and means | 25 preferably fluorine, chlorine, or bromine, especially if. I do chlorine. * 1 • · · Process according to Claim 1, characterized in that the active ingredient is a compound of the formula I, wherein R 1 represents hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, preferably hydrogen, methyl or t V 1 cyclopropyl, especially methyl. • · · • · ·. ···. Process according to Claim 1, characterized in that the active ingredient is a compound of the formula I * 1 1 *: wherein R 2 represents C 1 -C 1 alkyl or · 1: cyclopropyl, in particular methyl. 107314 29 Process according to claim 1, characterized in that the active ingredient is a compound of formula I according to any one of claims 2 to 4, wherein R 3 represents hydrogen. 5 A method according to claim 1, characterized in that the pet animal is a dog or a cat. Method according to one of Claims 1 to 6, characterized in that the active ingredient-containing substance is orally administered in regular unit doses. A method according to any one of claims 1 to 6, characterized in that the active ingredient is administered to the host animal in amounts ranging from about 0.01 mg / kg to about 800 mg / kg body weight. 9. The method of claim 8, wherein the active agent is administered to the host animal in amounts ranging from about 0.1 mg / kg body weight to about 200 mg / kg body weight. I; 10. The method of claim 9, wherein the active agent is administered to the host animal in amounts of about 0.5 mg / kg body weight each time. to about 30 mg / kg body weight. • · »· · The method according to any one of claims 8 to 10, characterized in that the active ingredient is orally administered to a cat or dog. The method according to any one of claims 1 to 6, characterized in that the cat or dog is dosed. the active ingredient is regularly dosed from 0.5 mg / kg body weight to 100 mg / kg body weight. • · · • · · 1 · · 10731 {1 30 1 A systemic agent for preventing flea infestation in domestic animals, preferably dogs and cats, characterized in that the food contains fleas; an effective amount of a compound of formula I: 5 E R l. nr2r3 I-lal ---- | V (I); '\ 10 N ° 2; wherein Hal represents a halogen such as fluorine, chlorine, bromine or iodine, R 3 represents hydrogen, C 1 -C 8 alkyl or C 3 -C 7 cycloalkyl, R 2 represents hydrogen, C 1 -C 8 alkyl or C 3 -C 7 cycloalkyl and R 3 represents hydrogen or C 1 -C 6 -alkyl. Substance according to Claim 13, characterized in that it covers both dog and cat food. An agent according to claim 13, characterized in that the active ingredient is a compound of formula I according to any one of claims 2-4. j • 1 · '• · • * 16. Compound of Formula I Hal-1-Y (I) j NO E 2 j wherein Hal represents halogen such as fluorine, chlorine, bromine or iodine, R x represents hydrogen, C 1 -C 8 alkyl or · ': C 3 - Use of C 7 -cycloalkyl, R 2 for hydrogen, C 1 -C 8 -alkyl or C 3 -C 7 -cycloalkyl and R 3 for hydrogen or C 1 -C 10 107314 31 alkyl for use in a method for systemically controlling fleas, preferably adult fleas, in domestic animals. 17. Compound R of formula I. NR2R3 Hal-- Y (I) 10 \ NO2 wherein Hal represents halogen such as fluorine, chlorine, bromine or iodine, Rx represents hydrogen, C1-C8 alkyl or C3-C7 cycloalkyl, R2 represents hydrogen, C1-C8 or C 3 -C 7 cycloalkyl and R 3 represents hydrogen or C 1 -C 8 alkyl, for use in the preparation of a systemically administrable preparation for domestic animals for controlling parasitic fleas. 20 18. Package containing a compound of formula I R / NR1R3 =: ··! 25 HaI_t J i (l> • · NO. ···. 2 • ♦ • ♦ * ·· ♦ where Hai means halogen such as fluorine, chlorine, »» »·; * j *: bromine or iodine, Rx means hydrogen , C 1 -C 8 alkyl or 30 C 3 -C 7 cycloalkyl, R 2 represents hydrogen, C 1 -C 7 alkyl or C 3 -C 7 cycloalkyl and R 3 represents hydrogen or C 1 -C 8 -C ... alkyl, in unit doses for oral use against fleas in a domestic animal , characterized in that the active ingredient is ready for use in unit doses: *: 35 from about 0.01 mg / kg body weight to about 800 mg / kg body weight. : lo. 32 10. z | 14