NL7905723A - Cyclopropyl:amino di:amino triazine derivs. - useful for controlling parasitic diptera larvae in mammals, are administered parenterally - Google Patents

Abstract

Cyclopropylaminotriazines (I) and their salts, which are non-toxic to mammals for parental or percutaneous administration, are new: (where R1 is H, CH3, C2H5 or cyclopropyl; R2 is H or CH3; R3 is H, CH3 or cyclopropyl; and R4 is H or CH3). (I) are useful in the treat-and productive livestock of Class Mammalia, for systemically controlling parasitic insect larvae of the order Diptera which feed on tissues. (I) are administered parenterally or percutaneously e.g. by implant in amts. of 10-50 mg/kg body wt.

Description

- 1 - Ν.0.28.075 CIBA-GEIGY A.G., in Basel, Switzerland.

Method for the preparation of antiparasitically active amino triazines and their preparations for the treatment of mammals to control parasitic Diptera larvae.

The invention relates to a process for the preparation of antiparasitically active aminotriazines for the treatment and treatment of domestic animal production livestock belonging to the group of mammals for the systemic control of parasitic insect larvae of the order Diptera which feed on tissue. 5

The antiparasitically active aminotriazines according to the invention are aminotriazines of the formula 1 in which R ^ a hydrogen atom, a methyl, ethyl or cyclopropyl group, R ^ a hydrogen atom or a methyl group, R ^ a hydrogen atom, a methyl or cyclopropyl group and R ^ a hydrogen atom or a methyl group 10, or an acid addition salt thereof which is not toxic to mammals. The mammals are administered the antiparasitically active compounds or their compositions parenterally or percutaneously.

Acid addition salts of the compounds of formula II are to be understood to mean salts with pharmaceutically suitable acids, for example with strong mineral acids such as hydrochloric or sulfuric acid, or with organic acids such as acetic, tartaric or citric acid.

The compound of formula 1 according to the invention φ due to the particularly high activity against parasitic j; larvae of insects of the order of Dipt era are preferred 2.4-diamino-6-cyclopropylamino-s-triazine. ! ("I The control of Diptera larvae, which" live as parasites in the tissues of the host animals, 7905723 -I- is of particular importance, in particular because of the considerable damage that • Λ i 2 can be caused by the parasites in livestock and in particular in grazing livestock.

The Diutera larvae can enter the tissues of the host animals in various ways. After the Diptera females have laid their eggs, which the animals can lay in or on various parts of the host animal's body, the larvae hatched from the eggs may enter the stomach of the host animals or be licked, the larvae may bore into the pharynx or into the skin of the host animals. However, the eggs can also be housed first on mosquitoes or flies. The larvae develop in the eggs and hatch as soon as the carrier insect has landed on a suitable host animal.

In the case of the live-bearing Diptera species, the larvae can be deposited directly into the nose or eyes of the host animals by the Diptera wifes.

After the larvae have entered the host animals, they can move to the areas of the body they prefer. The larvae can nest, for example, in or under the skin, in the gastrointestinal tract or in the nasal cavities, the pharynx or the frontal sinus of the host animal.

The different types of parasitism by Diptera larvae in animals are called myiasis.

Myiasis can be found in many species of animals, for example in cattle, horses, donkeys, mules, reindeer, sheep, pigs, dogs and cats.

Infection of the host animals by parasitic Diptera larvae, among other adverse effects, can cause a reduction in milk yield, loss of wool, weight loss or even death. If the host animals are affected by skin parasites, which cause swelling in the skin, the result thereof can also cause a depreciation of the skins by perforations, because the swellings have small openings which are enlarged by the larvae before they leave the host animal for pupation.

Since the larvae can attack parts of the body of the host animals in very different ways and in some cases in inaccessible places, the control thereof is a major problem.

It has been surprisingly found that the compounds of the formula I and the acid addition salts thereof which are not toxic to mammals and the compositions containing these compounds as active components are particularly suitable for combating parasitic Diptera larvae. The active compounds develop a systemic action, that is to say that even with a local application on the host animal, an action against the parasitic Diptera larvae also occurs in parts of the body that have not been treated. Thus, the use of the compounds of Formula 1 allows parasitic Diptera larvae to be effectively controlled even in areas of the body where direct application is particularly difficult or impossible. 15

A particularly effective method of controlling the parasites is by applying a suitable preparation containing the active compound to the animals by applying (pouring or dabbing) the preparation on the body surface of the animals.

The advantages of this method are that the method can be easily carried out by the staff caring for the animals, that the method does not require complicated devices and that the method does not hinder the animals.

Another effective method is to administer the active compound to the animals to be treated by means of an implantation, thereby achieving that the active compound is released gradually.

The compounds of the formula I and the acid addition salts thereof which are not toxic to mammals are advantageously used in a concentration of 10-50 mg / kg body weight. 50

The compounds of the formula I and the acid addition salts thereof which are non-toxic to mammals have in particular a high activity against myiasis-causing larvae of insects of the order Diptera which belong to the following strains: Balliphoridae, Oentridae, Cuterebridae. Gasterophilidae, 35

Sarcophagidae and Hypodermatididae, for example against larvae of 7905723 4 lucilia aye ο., Cochlyomyia hominivorax, Chrysomyia bezziana,

Hypoderma lineata, Hypoderma bovis, Dermatobia hominis, Oedemagena tarandi, Gasterophilus spec ,, Oestrus ovis, Rhinoestrus purpureus, Wohlfahrtia vigil and Cuterebra spec.

The compounds of the formula I according to the invention can be prepared in a manner known per se.

Preferably the compounds according to the invention of the formula I are prepared by a) reacting a 2-cyclopropylamino-4-amino-6-halo-s-triazine of the formula 2 in which and Eg the meanings indicated in formula 1 and X represents a halogen atom, preferably a chlorine atom, with ammonia or a primary and / or secondary amine of the formula V wherein E1 and E1 have the meanings indicated in Formula 1; see fig. 1, or b) conversion of a 2,4-diamino-6-halo-s-triazine of the formula 3 wherein E, R, R, R and R are as defined in formula 1 and X has a halogen atom, preferably represents a chlorine atom, with an eyclopropylamine of the formula 6; see Fig. 2, or c) if in the compounds of formula I E1 has the meaning of E, and Rn has the meaning of E. by reacting a 5 2 4 2-cyclopropylamino-4,6-dihalo-s-triazine with the formula 4 in which X represents a halogen atom, preferably a chlorine atom, with ammonia or a primary and / or secondary amine of the formula 7 wherein E1 'has the meaning of E ^ equal to that of E ^, as in the formula 1 is indicated, and Eg 'has the meaning of Eg which is equal to that of R1 as indicated in formula 1; see fig. 3

The replacement of the halogen atoms with ammonia or primary and / or secondary amines of the formulas 5, 6 and 7 is carried out by dissolving the starting compounds of the formulas 2, 3 and 4 in indifferent solvents, for example acetone, mixtures of acetone and water, butanone-2, dioxane or mixtures of dioxane and water, and by reacting these reaction mixtures under atmospheric pressure or if desired under elevated pressure and at a temperature of 20 - 150 ° C, preferably 50 - 140 ° C with 7905723 5 * ammonia or primary and / or secondary amines.

The starting compounds of formulas 2, 5 and 4 are in most cases known or can be prepared by methods analogous to known methods.

Example I 5 a) 2-Cyclopropylamino-4,6-diamino-s-triazine

A mixture of 100 g of 2-cyclopropylamino-4-amino-5-chloro-s-triazine, 51 S ammonia and 50 ml of dioxane was heated in a vutoclave at 140 ° C for 24 hours. After cooling, the dioxane was removed by suction filtration under reduced pressure, the resulting crystalline residue was washed with water and dried.

The crude product was recrystallized from methanol; mp 219-222 ° C.

b) 2-Cyclopropylamino-4.6-diamino-s-triazine. salt with 2 moles of chlorinated water, acidic. 25 g of 2-cyclopropylamino-4,6-diamino-s-triazine were dissolved in 2000 ml of heated absolute ethanol. The solution was cooled to 15 ° C and further cooled with ice, then hydrogen chloride gas was introduced into the solution until the solution was saturated, with white crystals precipitating. The crystals were isolated by filtration and the crude salt obtained was washed well with a large amount of ether; melting point under decomposition 195 ° C.

Example II

a) 2-Cyclopropylamino-4-methylamino-6-amino-s-triazine ♦ 25

A mixture of 12.7 S 2-cyclopropylamino-4-methylamino-6-chloro-s-triazine, 17> 4 S 28% by weight ammonia and 30 ml dioxane was heated in an autoclave at 140 ° C for 4 hours. After cooling, the reaction mixture was poured into 350 ml of a solution of potassium carbonate cooled to 0 ° C in water, after which the mixture was extracted with a mixture of benzene and efcher in a ratio of 1: 1. After the extract was dried over sodium sulfate, the solvents were removed under reduced pressure and the resulting residue was recrystallized from a mixture of isopropanol and hexane; mp 159-162 ° C. 35 7905723

ΰτ V

6 b) 2-Cyclopropylamino-4-methylamino-6-amino-s-triazine, salt with 2 moles of hydrochloric acid.

58 g of 2-cyclopropylamino-4-: methylamino-6-amino-s-triazine were dissolved in 280 ml of chloroform. The solution was cooled to 0-5 ° C with ice, then gaseous hydrogen chloride was introduced into the solution until the solution was saturated, with white crystals precipitating. 280 ml of ether were added to complete the precipitation. The crude hydrochloride was filtered off and recrystallized from methanol; mp 197-199 ° C. 10

Example III

2.4.6-Tris-oyolopropylamino-s-triazine.

A mixture of 20 g of 2-chloro-4,6-bis-cyclopropylamino-s-triazine, 10.1 g of cyclopropylamine and 80 ml of dioxane was heated in an autoclave at 140 ° 0 for 22 hours. The reaction mixture was concentrated to half the volume by volume under reduced pressure, after which 500 ml of water were added to the concentrate.

The mixture was extracted with ethyl acetate, the phase containing the product was dried over sodium sulfate and the solvents were removed under reduced pressure. The residue obtained was recrystallized from a mixture of dioxane and petroleum ether; mp 75-77 ° C.

For example, the compounds of formula 1 shown in the table can be prepared analogously to Examples I to III. 25 7905723 '0 a 7

TABLE

no. Connections Melting point

____________________________ in ° C

1 2-cyclopropylamino-4-amino-6-dimethyl-182-184 amino-s-triazine 2 2,4-bis- (cyclopropylamino) -6-amino-s- 137-140 triazine 3 2-cyclopropylamino-4-methylamino- 6-dime- 164-165 thylamino-s-triazine dihydrochloride 4 2-cyclopropylamino-4,6-bis- (dime thyl- 140-142 amino) -s-triazine 5 2-cyclopropylamino-4-amino-6-ethylamino- 141-145 s-triazine 6 2-cyclopropylamino-4-amino-6-ethylamino- 199-200 s-triazine dihydrochloride 7 2,4-bis- (cyclopropylamino) -6-dime thyl- 136-137 amino-s-trizine

The compounds of the formula (I) or the acid addition salts thereof which are not toxic to mammals can be used as such or together with suitable carriers and / or additives. Suitable carriers and additives can be solid or liquid and are conventional products for the preparation of preparations, for example natural or regenerated products, solvents and / or dispersants.

Compositions containing an active compound according to the invention or an acid addition salt thereof which is not toxic to mammals can be prepared in a manner known per se by dissolving the active compound in suitable solvents and / or intensively mixing and / or grinding the active compounds with suitable carriers, if desired with addition of dispersants or solvents that are indifferent to the active compounds. The active compounds can be incorporated into the following preparations: solid preparations: powders; liquid preparations: a) active compound containing concentrates that can be dispersed in water; wettable powders, pastes and emulsions; B) solutions: suitable for injecting and for pouring or dabbing.

790572J

8

Yield preparations are prepared by mixing the active compounds with solid carriers. Suitable carriers are, for example, kaolin, talc, bolus, limburg clay, chalk, limestone, ground limestone, attaclay, diatomaceous earth, precipitated silicic acid, alkaline earth silicates, sodium and potassium aluminum silicates (feldspar and glimmer), calcium and magnesium sulfates, magnesium oxide ground synthetic products, ground vegetable products such as corn meal, sawdust, cellulose powder, plant extract residues, activated carbon, polymers commonly used galenically and the like. These products may or may not be mixed.

Concentrates which are water-dispersible, active compounds, for example wettable powders, pastes and emulsifiable concentrates, are preparations which can be diluted with water to the desired concentration. They consist of an active compound, a carrier, optional additives that stabilize the active compound, surfactants and suds suppressants and optionally solvents. Wettable powders and pastes were prepared by mixing and grinding the active compounds with dispersants and powdery carriers in suitable equipment into a homogeneous mixture. Suitable carriers are, for example, those listed for the solid preparations. In some cases it is effective to use mixtures of different carriers. Dispersants that can be used include, for example, condensation products of sulfonated naphthalene and sulfonated naphthalene derivatives with formaldehyde, condensation products of naphthalene or naphthalene sulfonic acids with phenol and formaldehyde, and also alkali metal, ammonium, and alkaline earth metal salts of alignene sulfonic acid alkylphenyl sulfonic acid and alkaline earth metal salts of dibutyl naphthalene sulfonic acid, fatty alcohol sulfates, such as salts of sulfated hexadecanols, heptadecanols, octadecanolan and salts of sulfated fatty alcohol glycol ethers, sodium salt of olefin alkyl ethyl alcohol, dialert-ethylene glycols, dialert-ethylene glycols, 35 acids.

7905723 .- \ 9

Suitable foaming agents are, for example, polyosiloxanols. The active compounds are mixed, ground, sieved and stretched with the aforementioned additives in such a way that the particle size in wettable powders does not exceed 0.02 - 0.04 mm and in pastes does not exceed 0.03 mm · Emulsifying bar concentrates and pastes are prepared using dispersants such as the aforementioned dispersants, organic solvent? i and water. Examples of suitable solvents are alcohols, dimethyl sulfoxide and mineral oil fractions with a boiling point between 120 and 350 ° C. The solvents should be odorless and indifferent to the active compounds.

Furthermore, the preparations according to the invention can be used in the form of solutions. The suitable organic solvents or solvent mixtures or water are mixed with the active compound or with various active compounds of the formula 1. Aliphatic and aromatic hydrocarbons, carboxylic acid esters, ethers and mineral oils, individually or mixed, can be used as organic solvents.

The pets and the productive live livestock that can be carriers of parasites can be treated in various ways, for example by spraying under spraying (direct hand spraying; spray or nozzles), a bath, pollinators, by pouring (total or partial) , solutions for injecting, an implantation or a collar. 25

Suitable spray dispersion preparations are, for example, wettable powders or emulsifiable concentrates. Emulsifiable concentrates and wettable powders can be used as desired for treatment with spray nozzles or with a bath. Preparations that can be used for the casting method are, for example, wettable powders, emulsifiable concentrates or solutions of the active compounds in paraffin oil, corn oil or rapeseed oil. Injection solutions are obtained by dissolving the active compounds in, for example, diethylsuecinate. Implants 35 may, for example, consist of gelatin capsules filled with active compounds or of a solid preparation containing the active compounds together with synthetic, usually galenically used components Suitable collars are, for example, collars made of synthetic materials in which the active compound is incorporated in a suitable form.

Implants or collars are particularly suitable uses of the treatment in those cases where a slow release of the active compound is desired.

The active compounds of the formula I or the acid addition salts thereof which are non-toxic to mammals can be processed, for example, into the following preparations:

Powder;

The following components are used to obtain a 5% by weight powder: 5 parts by weight of active compound, 15 parts by weight of highly dispersed silica. 94 parts of talc.

The active compound is mixed with the carriers and the mixture is ground.

Wettable powder: 20 parts by weight of the active compound are added with 5 parts by weight of a dispersant, for example sodium lignin sulfonate, 5 parts by weight of a wetting agent, for example dibutylnaphtha-1-sulfonic acid, 10 parts by weight of kaolin and 50 parts by weight of kaolin mixed, after which the mixture is ground. 25

Emulsifiable concentrate; 20 parts of the active compound are mixed with 20 parts of an emulsifying agent, for example, a mixture of an alkyl aryl polyglycol ether with alkylarylsulfonic acids and 60 parts of a solvent, until a completely homogeneous solution is obtained. . By mixing with water, this concentrate produces an emulsion of the desired concentration.

Solutions

MWMMWMÉM

Solution for the method of casting.

10 parts of active compound 35 55 parts of "Solketal" (trade name, 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane) 7905723 11 20 parts of benzyl benzoate 15 parts of polyethylene glycol 300.

The active compound is dissolved in the mixture of Solketal and polyethylene glycol 300 with constant stirring and heating, after which the benzylhenzoate is added. 5

Solution for injecting.

10.0 parts of active compound 3.6 parts of acetic acid 86.4 parts of water suitable for injection.

The acetic acid and water are added to the active compound 10 and the mixture is stirred until all components are dissolved. The solution is then filtered and sterilized by an appropriate method. pH of the solution: 5.0.

Other biocidal active compounds or preparations which are compatible with the active compounds according to the invention and which are suitable for treating the animals can be added in the preparation of the above preparations.

. Trial 1.

Application according to the casting method on livestock. 5-100 ml of a suitable preparation containing per kg body weight up to 100 mg of an active compound of the formula 1 or a non-toxic acid addition salt thereof were poured onto the backs of the cattle. Blood samples were taken from the jugular vein at certain intervals. These samples were mixed with a determined culture medium, after which this mixture was applied to newly hatched larvae I of luoilia sericata. The larval killing activity was observed after 72 hours.

In the present experiment, the compounds of the formula I and the non-toxic acid addition salts thereof had a particularly large larval killing activity.

Trial 2.

Application of solutions suitable for injecting to livestock.

The animals were injected subcutaneously with a suitable preparation of an active compound of the formula 1 or of a non-toxic acid addition salt thereof. Blood samples were taken from the jugular vein at certain intervals 7905723. The samples were mixed with a given culture medium and the mixture was applied to newly hatched larvae I of Lucilia sericata. The larval killing activity was determined after 72 hours. In the present experiment, the compounds of the formula I and the non-toxic acid addition salts thereof had a particularly large larval killing activity.

7905723

Claims (6)

Process for the preparation of antiparasitically active aminotriazines or their acid addition salts, characterized in that aminotriazines of the formula I or the acid addition salts thereof are prepared in a manner known per se, in which 5 E ... J a hydrogen atom, a methyl, ethyl or eyclopropyl group, Eg a hydrogen atom or a methyl group, E ^ a hydrogen atom, a methyl or eyclopropyl group and E ^ a hydrogen atom or a methyl group. 2. Process according to claim 1, characterized in that aminotriazines of the formula I are prepared in which E 2, Eg, E and E represent hydrogen atoms. 3 4 Method for controlling parasites occurring in mammals, in particular parasitic insects of the order Liptera, which occur in the tissues of the animals, characterized in that the parasites are controlled with aminotriazines of the formula 1 in which the substituent and the Claims 1 and 2 have meanings or with the acid addition salts thereof which are non-toxic to the mammals or their preparations by administering the active compounds or preparations containing the active compounds to the animals parenterally or percutaneously or the respective preparation casting the body surface of the animals to be treated. · 4. Method according to claim 3, characterized in that the administration is carried out by implantation of the active compound with a carrier which is physiologically suitable for the animal to be treated. Process for the preparation of antiparasitic working preparations, characterized in that the aminotriazines of the formula 1 in which the substituents have the meanings set out in claims 50 1 and 2 and / or their acid addition salts which are not toxic to mammals a carrier and optionally other additives in a suitable form. 6. Formed antiparasitic active preparation prepared according to the method of claim 5 · 35 79 0 5723 - =