DE2553270A1 - EECTOPARASITICIDE AGENT CONTAINING DIPHENYLCARBODIIMIDE - Google Patents

Description

Er-Iz

II (Pha)

2 Nov. 6, 1975

Ectoparasiticidal agents containing diphenylcarbodiimides

The present invention relates to the use of diphenylcarbodiimides, some of which are known, as ectoparasiticides.

The use of the diphenylcarbodiimides used according to the invention as stabilizers of polyurethane plastics against hydrolytic degradation of these polyurethane plastics is already previously known (see Angew. Chem. 7_4, 801 (1962)).

It has not yet become known that diphenylcarbodiimides have an ectoparasiticidal and especially tickicidal effect.

It has been found that the widely known diphenylcarbodiimides the formula

(I)

in which

X for alkyl,

Y for halogen or alkyl and

η stands for an integer from 0 to 3.

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have a strong ectoparasiticidal effect.

Surprisingly, show the diphenylcarbodiimides according to Formula (I) a strong ectoparasiticidal effect. So far, the ectoparasiticidal effect of the diphenylcarbodiimides was appropriate Formula (I) was not yet known.

It is surprising and could not have been foreseen that the invention Compounds represent effective control agents against ectoparasites, especially against ticks. A note The state of the art does not reveal its effectiveness. Phosphoric acid esters in particular have hitherto been used as tickicides and as tickicides against phosphoric acid ester-resistant tick strains in recent years, N-aryl-N'-alkylformamidine, N-alkyl-2-arylimino-pyrrolidines and derivatives of thiourea and other sulfur compounds have become known. Those according to the invention have a similarity to known tickicides did not use diarylcarbodiimides.

It is also surprising and contradicts known experience that the diarylcarbodiimides to be used according to the invention have excellent hydrolytic stability under practical conditions. It is known that diarylcarbodiimides add water under acid or base catalysis with the formation of diarylureas (Chem. Rev. 6_7, 117 (1967)).

The ectoparasiticidal agents according to the invention, containing compounds of the formula (I), are thus a real asset of veterinary medicine.

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2 S b 3 2 7 Q

The diphenylgarbodiimides of the formula (I) to be used according to the invention are precisely defined by the aforementioned formula I, the individual compounds of the formula I being already known or being able to be prepared by processes known per se from the literature. Compare, for example, W. Neumann and P. Fischer, Angew. Chem. 7-4, 801-806 (1962); HG Khorana, Chem. Rev. 53: 145-166 (1953); F. Kurzer and K. Douraghi-Zadeh, Chem. Rev. 6J_, 107-152 (1967).

In the formula (I), X and Y preferably represent straight-chain or branched alkyl with preferably 1 to 6, in particular 1 up to 4 carbon atoms. Examples include methyl, ethyl, n.- and i.-propyl, N.-, I.- and t.-butyl.

Furthermore, the halogen Y is preferably fluorine, chlorine, bromine and iodine, in particular chlorine and bromine.

As examples of the diphenylcarbodiimides which can be used according to the invention of the general formula (I) may be mentioned:

2,6,2 ', 6'-tetramethyl-diphenyl-carbodiimide, m.p. 49-5O ° C

1,4,2 ', 4'-Tetramethyl-dipheny-1-carbodiimide, b.p. 188-192 ° C / O, 4 torr 2, 4,2 ', 4'-tetramethyl 1-6,6'-diisopropyl-diphenyl-carbodiimide

2,4,2 ', 4' -Tetramethy 1 * * 6,6 '-dichloro-diphenyl-carbodiimide 2,2'-Dimethyl-6,6'-diethyl-diphenyl-carbodiimide

2,2 ', 6,6'-Tetraethyl-diphenyl-carbodiimide, b.p. 135-138 ° C / O _f O2 Torr

2,4,2 ', 4'-tetraethyl-diphenyl-carbodiimide 2.2 ·, 6.6 · -Tetraethyl-3,3'-dimethy1-dipheny1-carbodiimide

Bp 197-2OO ° C / 1.5 torr 2.2 ', 6,6'-tetraethy1-3,3 · dichloro-diphenyl-carbodiimide

Bp 166-172 ° C / O, 0.5 torr 2,2 ', 6,6'-tetraethyl-4,4'-dimethyl-diphenyl-carbodiimide

176-178 ° C / 0.035 torr

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2,2'-diisopropyl-diphenyl-carbodiimide

2.2 "-Di-sec.-buty1-diphenyl-carbodiimide 2,2'-di-tert-buty1-diphenyl-carbodiimide 2,2'-di-cyclopenty1-diphenyl-carbodiimide 2,2'-dimethyl-6,6'-di-isopropy-1-diphenyl-carbodiimide

Bp 186-19O ° C / 2, O torr

2,2 ', 6,6' -Tetra-isopropyl-diphenyl-carbodiimide

2,6,2 ', 6'-tetraethy1-3,5,3 *, 5'-tetramethy1-diphenyl-carbodiimide 2,6,2 ', 6'-Tetra-sec-buty1-carbodiimide, bp 170-180 ° C / O, O4 torr 2,6,2 ', 6'-tetra-isopropyl-4,4'-dibromo-diphenyl-carbodiimide

M.p. 115-116 ° C 2,6,2 ', 6'-tetra-isopropy1-4,4'-dichloro-dipheny1-carbodiimide

Mp 100-1O5 ° C

2,2'-di-tert-buty1-4,4'-dimethyl-diphenyl-carbodiimide 2,2'-di-tert. -butyl-4,4'-dimethyl-6,6'-dichloro-diphenyl-carbodiimide 2,2'-dimethy1-4,4'-dicyclohexy1-diphenyl-carbodiimide 2,2'-6,6'-tetracyclopenty1-diphenyl carbodiimide, m.p. 92-95 ° C 2,6-diisopropyl-2 ', 6'-diethy1-diphenyl-carbodiimide 2,6-diisopropyl-2', 4'-dimethyl-diphenyl-carbodiimide 2,6-diisopropyl-2 ', 6'-di-sec-buty1-diphenyl-carbodiimide 2,6-diisopropyl-2'-methyl-6'-chloro-diphenyl-carbodiimide 2,6-diisopropyl-2', 4 ', 5'-trimethyl -diphenyl-carbodiimide 2,6-diisopropyl-2 ', 4', 5'-trimethyl-dipheny1-carbodiimide 2,2'-dimethyl-4 _# 4'-dichloro-dipheny1-carbodiimide, m.p. 50-51 ° C

Up to now unknown diphenyl carbodiimides can easily be prepared by reacting appropriate isocyanates with phosphine oxides .

The reaction can be illustrated by the following individual reaction scheme:

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25b327U

CH ^ CH-CH ₃ CH ^ CH-CH ₃

CH-CH-CH ₃ CH ₃ -CH CH ₃ -CH-CH ₃

Examples of the preparation of new Diphenylcarbodiimiden: 1) 2,6,2 ', 6 ^I -Tetraisopropyl-4,4 ^l dichloro-diphenyl-carbodiimide

a) 2,6-Diisopropyl-4-chlorophenyl isocyanate

376 g of 2,6-diisopropyl-phenyl isocyanate are added with 0.5 g anhydrous, iron-III-chloride added and at 20-40 ° C Initiated 143 g of chlorine. The mixture is then slowly heated to 120 ° C. until the evolution of HCl has ended. After that will be 3 g of anhydrous sodium sulfate were added and the batch was fractionated in vacuo. Bp: 117-12O ° C / 2.5 Torr. Yield 250g.

b) 2,6,2 ', 6'-tetraisopropyl-4,4'-dichloro-diphenylcarbodiimide

40 g of 2,6-diisopropyl-4-chlorophenyl isocyanate are mixed with 3 drops of P-methyl-phospholine oxide and heated to _{100-120 ° C. for about 8 hours until the CO 2 has been} split off. Yield 35g. For cleaning, it can be recrystallized from petroleum ether. F: 100-105 ° C.

Elemental analysis and NMR spectrum are in agreement with the assumed constitution.

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■> ■

2) 2,6, 2 ', 6'-Tetraisopropyl-4,4'-dibromo-diphenyl-carbodiimide a) 2,6-Diisopropyl-4-bromo-phenyl isocyanate

203 g of 2,6-diisopropyl-phenyl isocyanate are mixed with 0.5 g of anhydrous iron (III) chloride and 162 g of bromine are added dropwise at 20 ° C. It is then slowly heated to 120 ° C. until the evolution of gas has ceased. 3.0 g of anhydrous sodium sulfate are then added and the mixture is fractionated in vacuo.
128-135 ° C / 3.0 Torr; Yield 164g.

Elemental analysis and NMR spectrum are available with the assumed Constitution in accordance.

*>) 2,6,2 ', 6'-tetra-isopropyl-4,4'-dibromo-diphenyl-carbodiimide

40.0 g of 2,6-diisopropyl-4-bromophenyl isocyanate are with 3 drops of P-methyl-phospholine oxide are added and approx. 4 hours heated to 100-120 ° C. until the (^ development has ended. The product solidifies on cooling. Yield 35 g; F: 115-116 ° C after recrystallization from petroleum ether.

Elemental analyzes and NMR spectrum are available with the assumed Constitution in accordance.

The preparations according to the invention, which in addition to the usual Inert additives containing diphenylcarbodiimides of the formula (I) have strong ectoparasiticidal properties, in particular against ticks which attack animals domesticated as animal ectoparasites, such as cattle and sheep. Simultaneously the active ingredients according to the invention have a low toxicity to warm-blooded animals. They are therefore well suited for combating of animal ectoparasites, in particular ticks.

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As economically important ectoparasites of this type, the particularly play a major role in tropical and subtropical countries, for example: the Australian and South American single host cattle tick Boophilus microplus, the South African cattle tick Boophilus decoloratus / both from the family of the Ixodidae the African multivalent cattle and sheep ticks such as Rhipicephalus appendiculatus jRhipicephalus evertsi, Amblyomina hebraeum, Hyalomma Aruncatum as well as the South American polyvalent beef ticks such as Amblyomma cajennense and Amblyomma americanum.

In the course of time, ticks have been used in numerous areas against the phosphoric acid esters previously used as control agents and carbamates have become resistant, so that the success of the control in many areas is increasingly questionable is provided. There is an urgent need for funds to ensure economic livestock farming in the infested areas with which all stages of development, i.e. larvae, metalarvae, nymphs, metanymphs and adults, also of resistant strains, for example of the genus Boophilus, can be fought safely. To a large extent against the previous phosphoric acid ester agents In Australia, for example, the Mackay, Mt-Alfort and Biarra strains of Boophilus microplus are resistant.

The active ingredients according to the invention are against the normally sensitive as well as against the resistant strains, for example of Boophilus, equally effective. In the usual application on the host animal, they have a direct killing effect on all those parasitizing on the animal Shapes so that the development cycle of the ticks is interrupted in the parasitic phase on the animal.

The deposition of fertile eggs and thus the development and hatching of larvae is inhibited.

The application takes place for example in the dip (bath), whereby the active ingredients in the soiled and the microbial attack exposed to aqueous dip liquid for 6 months and longer.

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2 5 b 3 2 7 over y.

must remain constant- Further forms of application exist in Spray and pour on.

In all application forms have those characterized in the claim Connections complete stability, i.e. a decrease in effectiveness cannot be determined even after 6 months.

The active compounds according to the invention can be used to ectoparasiticides Agents can be formulated in the form of solutions, emulsions, suspensions, powders, pastes and granules. This can be done with the help of techniques known per se are carried out, e.g. by mixing the active ingredients with additives, for example liquid, solid or liquefied gaseous diluents or carriers, optionally using surface-active substances, e.g. emulsifiers and / or dispersants. In the case of using water as an adjuvant Organic solvents can also be used as auxiliaries will.

In addition to water, preferred liquid diluents or carriers are aromatic hydrocarbons, such as xylenes, toluene, benzene or alkyl naphthalenes, chlorinated aromatic or aliphatic hydrocarbons such as chlorobenzenes, chloroethylenes or methylene chloride, and also aliphatic hydrocarbons, such as cyclohexane or paraffins, such as for example mineral oil fractions having boiling ranges from 120 to 400 ⁰ C, preferably 180 to 300 ° C, alcohols, such as butanol or ethylene glycol also their ethers and esters; Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone or strongly polar solvents such as dimethylformamide, dimethyl sulfoxide, pyrrolidone, N-methyl pyrrolidone, or acetonitrile.

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2 5 b 3 2 7 n

Among liquefied gaseous diluents or carriers Liquids are understood that would be gaseous at room temperature and normal pressure, e.g. aerosols, such as e.g. halogenated hydrocarbons. Freon is an example.

Solid diluents or carriers are preferred natural minerals are used, such as kaolins, chalks, talc, quartz, attapulgite, montmorillonite or diatomaceous earth or synthetic minerals such as highly dispersed silica, aluminum oxide or silicates.

Preferred emulsifiers are: nonionic and anionic emulsifiers, such as polyoxyethylene fatty acid esters, Polyoxyethylene fatty alcohol ethers, e.g. alkylaryl polyglycol ethers, alkyl sulfonates, alkyl sulfonates, aryl sulfonates.

Preferred dispersants are, for example, lignin and sulphite waste liquor and methyl cellulose in question.

The ectoparasiticidal or tickicidal agents according to the present invention contain 0.1 to 95 percent by weight, preferably 0.5 to 90 percent by weight active ingredient.

For the purpose of application, they can be diluted with water, for example. Depending on the application, you can the concentrations can be varied over a wide range, i.a. from 10 to 50,000 ppm, preferably 50 to 10,000 ppm.

Other additives such as disinfectants or insecticides can be added to the ready-to-use formulation will.

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The tickicidal effect of the agents according to the invention should be through the following application examples are documented:

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Example A. *

In-vitro tick test on Boophllus microplus

3 parts of active ingredient are made with 7 parts of a mixture equal parts by weight of ethylene glycol monomethyl ether and nonylphenol polyglycol ether mixed. The emulsion concentrate thus obtained is diluted with water to the desired application concentration.

Tolerated fully sucked female ticks are put into this active substance preparation of the species Boophilus microplus (Biarra strain) immersed for one minute. After diving 25 female specimens each one transfers the individual ticks in plastic dishes, their The bottom is covered with a filter paper disc.

After 35 days, the effectiveness of the active compound preparation is determined by determining the inhibition of the laying of fertile eggs compared to the laying of untreated control ticks. The effect is given in % , where 100% means that no more fertile eggs have been laid and OJi means; that the ticks laid eggs in the normal way like the untreated control ticks.

Active ingredient concentration Effect in% in ppm A) 4,096 100 2,048 80 1,024 40 512 25th 256 O B) 10,000 100 1,000 0

A) = 2,6,2 ', 6'-tetraisopropyl-diphenylcarodiimide

B) = 2,6 , 2 ', 6'-tetraethyl-3,3'-dimethyl-diphenylcarbodiimide

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Example B.

In-vivo tick test on Boophilus microplus

3 parts of active ingredient are mixed with 7 parts of a mixture of equal parts by weight of ethylene glycol monomethyl ether and nonylphenyl polyglycol ether mixed. The emulsion concentrate obtained in this way is mixed with water to the desired application: concentration diluted.

Cattle are sprayed with the active ingredient preparation obtained in this way, those with resistant tick larvae of the species Boophilus microplus, Biarra strain, several times (infection 12x at a distance of 2 days) have been infected.

The effect of the active ingredient preparation is determined by determination the number of adult female ticks that develop on the treated cattle. That number will compared to the number of adult female ticks that develop on untreated cattle. A connection is more effective, the fewer female ticks develop after treatment.

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-4 O CD OO NJ

CD CO CD

Boophilus microplus (Biarra-Stanm): All development stages in vivo (cattle) Active ingredients according to the invention / effectiveness in hand spray for various applications

Active ingredient Active ingredient
concentr.
in ppm. Number of ticks with fertile clutches Days before
Treat.
-2 - +0 Days after treatment + 1-3 + 4-6 + 7-9 + 10-12 + 13-15 + 16-18 + 19-21 1-21 A) 5,000
3,000
1,000 768
415
425 23
50
301 1
11
55 11
47
111 20th
43
55 13th
3
19th 5
0
0 0
0
0 73
154
541 unibehandel
te control
len 1286 1464 792 659 224 2048 784 724 6745

A) = 2,6,2 \ 6 ^l -Tetxaisqpropyl-diphenylcarbodiiinid

Claims (3)

Claims 1) Ectoparasiticidal agent, characterized by a content of at least one diphenylcarbodiimide of the formula (D in which X for alkyl, y for halogen or alkyl and η stands for an integer from 0 to 3, 2) method of making an ectoparasiticidal agent, characterized in that diphenylcarbodiimides according to the formula in claim 1 with inert, non-toxic, pharmaceutical suitable carriers mixed. 3) method for combating ectoparasites, characterized in that that diphenylcarbodiimides according to the formula in claim 1 are administered to animals which are infected with ectoparasites To suffer. Le A 16 747 - 14 - 09322/0964