FR2579867A1 - - Google Patents

Abstract

THE SUBJECT OF THE INVENTION IS A PROCESS FOR CONTROLLING ENDEMICS TRANSMITTED TO LIVING BEINGS BY PROTOZOA, CHARACTERIZED IN THAT A SUFFICIENT QUANTITY OF THE PYRETHRINOID-TYPE COMPOUND IS APPLIED IN THE SITE WHERE THE PROTOZOARS ARE FOUND SUFFICIENTLY DEVELOPED TO PREVENT THEM. PROTOZOARS. THE PROCESS OF THE INVENTION MAKES IT POSSIBLE TO FIGHT AGAINST MALARIA.

Description

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  The present invention relates to a novel method of controlling protozoa responsible for vertebrate diseases and

  including human and animal endemics.

  The subject of the invention is a method of combating endemics transmitted to living beings by protozoa, characterized in that the place where the protozoa are found is

  pyrethroid compound sufficient to prevent the development of

protozoa.

  Being alive means man, mammals, fish

and birds.

  As protozoa targeted by the present invention, mention may be made of spirochetes, treponemes, amoebae, trypanosomes, haematozoa, especially the haematozoan of malaria or plasmodium.

and leishmanias.

  The invention therefore relates to a method for controlling a wide variety of diseases, such as spirochetosis, diseases caused by treponemes, amoebiasis, malaria, trypanosomiasis or

leishmanoses.

  The pyrethroid compounds contemplated by the invention are compounds that are generally known: they correspond to the general formula ACO2B in which: OI - or A represents a radical:

H3 \ H / 3

  Where Z1 and Z2 each represent a methyl radical, or Z1 represents a hydrogen atom and Z2 represents a radical.

T 3

T _

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  in which Z 3 represents an atom of ydrogen or halogen and either T1 and T2, which are identical or different, represent a hydrogen atom, a halogen atom, an alkoxyl radical or an alkyl radical containing from 1 to 8 carbon atoms , a CF3 or CN radical or a phenyl ring optionally substituted by a halogen, or together form a cycloalkyl radical containing from 3 to 6 carbon atoms or a radical: R B in which B represents an oxygen or sulfur atom: either Z, represents a radical abcd in which a, b, c and d, which are identical or different, each represent a halogen atom, - or Z2 represents a radical D

J-G

  in which D represents a hydrogen or halogen atom, an alkoxyl radical, G represents an oxygen or sulfur atom and J represents either a linear, branched or cyclic alkyl radical, saturated or unsaturated, containing from 1 to 8 carbon atoms, optionally substituted by one or more functional groups, which are identical or different, or an aryl group containing from 6 to 14 carbon atoms, optionally substituted by one or more functional groups

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  identical or different, or a heterocyclic radical optionally substituted with one or more functional groups, which are identical or different, or else A represents a radical: ## STR1 ## in which U, in any position on the benzene ring, represents a halogen atom, an alkyl radical containing from 1 to 8 carbon atoms or an alkoxy radical containing from 1 to 8 atoms of

  carbon, m representing the number O, 1 or 2.

  II - and B represents: - either a benzyl radical optionally substituted with one or more radicals chosen from the group consisting of alkyl radicals containing from 1 to 4 carbon atoms, alkenyl radicals containing from 2 to 6 carbon atoms, radicals alkenyloxy having from 2 to 6 carbon atoms, the alkadienyl radicals containing from 4 to 8 carbon atoms, the methylene dioxy radical and the halogen atoms, - a grouping:

CH2

  in which the substituent R 1 represents a hydrogen atom or a methyl radical and the substituent R 2 is a monocyclic aryl or a group -CH 2 -C = CH and in particular a 5-benzyl-3-furyl methyl group, or a grouping : a R3

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  in which a represents a hydrogen atom or a methyl radical and R3 represents an aliphatic organic radical comprising from 2 to 6 carbon atoms and one or more carbon-carbon unsaturations and in particular the radical -CH2-CH = CH2, -CH2- CH = CH-CH3,

  -CH2-CH = CH-CH = CH2, -CH2-CH = CH-CH2-CH3,

- or a grouping: a R3

/ XRE '1

  R'2 in which a represents a hydrogen atom or a methyl radical, R3 retains the same meaning as before, R'1 and R'2, identical or different, represent a hydrogen atom, a halogen atom, an alkyl radical containing from 1 to 6 carbon atoms, an aryl radical containing from 6 to 10 carbon atoms, an alkyloxycarbonyl group containing from 2 to 5 carbon atoms, or a cyano group, or a grouping: H

C -

  B '(Rs) n wherein B' represents an oxygen or sulfur atom, a group - or -CH2- or a sulfoxide group or a sulfone group and R4 represents a hydrogen atom, a -C _ radical; N, a methyl radical, a -CONH2 radical, a -CSNH2 radical or a -C CH radical, R5 represents a halogen atom or a methyl radical and n represents a number equal to 0, 1 or 2, and especially the grouping. 3-phenoxybenzyl, -cyano-3-phenoxybenzyl, o -ethynyl-3-phenoxybenzyl, 3-benzoylbenzyl, 1- (3-phenoxyphenyl) ethyl or o -thioamido-3-phenoxybenzyl, being a group:

2579867

H

C-

CN - a grouping: R6 R7

| S / I | N-CH2

R8

  in which the substituents R6, R7, R8, R9 represent a hydrogen atom, a chlorine atom or a methyl radical and in which S / I symbolizes an aromatic ring or a similar dihydro or tetrahydro ring, ie a group: S - / "- CH2-Cs-CH

CH2-N

o - a grouping: RilH

- R11- R12

  in which R10 represents a hydrogen atom or a CN radical, R12 represents a radical -CH2 - or an oxygen atom, R11 represents

  a thiazolyl or thiadiazolyl radical including 1 a -liaison with -IH-

  can be at any of the available positions, R12 being bonded to R11 by the carbon atom between the sulfur atom and a nitrogen atom, or a group:

I

- or a grouping: F? R1

-C F

  F in which R13 represents a hydrogen atom or a CN radical, or a group:

O 2

4 1

  in which R 13 is defined as above, and the benzoyl radical is in position 3 or 4, or a grouping: R 14 C

R16 10

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  in which R14 represents a hydrogen atom, a methyl, ethynyl or cyano radical and R15 and R16, which are different, represent a hydrogen, fluorine or bromine atom, or a group:

H

R14

I N B

  Wherein R 14 is defined as above, each of R 17 independently represents an alkyl group containing from 1 to 4 carbon atoms, alkoxy containing from 1 to 4 carbon atoms, alkylthio containing from 1 to 4 carbon atoms, alkylsulfonyl containing from 1 to 4 carbon atoms, trifluoromethyl, 3,4-methylene dioxy, chloro, fluoro or bromo, p represents a number equal to 0, 1 or 2

  and B "represents an oxygen atom or a sulfur atom.

  The subject of the invention is particularly a control method characterized in that the multiplication is destroyed or limited.

  pathogenic protozoa of vertebrates and invertebrates.

  Vertebrate vectors include home and mammals such as cattle, sheep, pigs, goats and horses, birds such as poultry, amphibians,

  reptiles, fish and various aquatic species.

  Invertebrate vectors include terrestrial and marine arthropods, including mites, insects,

  molluscs, especially gastropods and worms.

  As insect vectors, we can cite mosquitoes,

  flies, bugs, fleas and lice.

  The control method of the invention, in the case where the protozoa fought are carried by arthropods and in particular by insects, is particularly interesting from an economic and ecological point of view: it is possible to use doses of pyrethroids lower than lethal doses for arthropod vectors. The treatments can be applied in areas of development of these animals different from those of their vertebrate host (ex: water-mosquito) are easier and come back cheaper than the treatments to suppress the insect vectors. Moreover, by not completely eliminating the arthropod, we better respect the balance of

natural environment.

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  The subject of the invention is especially a control method characterized in that protozoa are destroyed which are conveyed

by insects.

  The subject of the invention is therefore a control method as defined above, characterized in that a pyridine-type compound is used.

  thrinoide at a dose lower than the lethal dose of vector insects.

  The subject of the invention is especially a method of controlling

  characterized in that the insect vectors are anopheles.

  Anopheles gambiae, Anopheles moucheti, Anopheles funestus, Anopheles hancocki, Anopheles paludis, Anopheles nili, Anopheles littoralis, Anopheles aconitus, Anopheles flavirostris, Anopheles

  mangyanus, anopheles stephensi, etc.

  The invention more particularly relates to a control method characterized in that the protozoa fought are plasmodium, such as for example pl asmodium falciparum, plasmodium

  malariae, plasmodi um vivax, or plasmodium ovale, plasmodi um yoel ii.

  The fight against malaria is of great interest: malaria is still today one of the great scourges of the modern world that is ravaging many countries, especially in Africa, for example in Nigeria, in Upper Volta Cameroon, Congo, Kenya, Ethiopia, Latin America, especially Venezuela and Guatemala, or South-East Asia: the number of children killed by the

  Malaria every year in the world.

  The invention more particularly relates to a process characterized in that the pyrethroid used is deltamethrin; it also relates to a process characterized in that the pyrethrinoid is chosen from the group of photostable or photolabile pyrethrins consisting of tralomethrin, chlorethrin, permethrin, alphamethrin, cyfluthrin, cyhalothrin, fenfluthrin, fencythrin, fenvalerate, and derivatives of

the allethrin of neopynamin.

  The subject of the invention is especially a process characterized in that a very small amount of pyrethroid is used, which is always less than that required to kill the arthropod vector. To fight against protozoa in an aqueous medium according to the process of the invention, compositions containing the

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  pyrethroid in the area where arthropod vectors of protozoa are found on and in swamps, lakes, puddles, canals,

  rivers, in forests, savannahs. To fight against proto-

  zoaires in the living quarters of human beings or animals, pyrethroid compositions are spread by treatment of surfaces, walls, roofs, mosquito nets, etc.,

for example.

  Compositions containing pyrethroid are spread by air, by ground treatment (liquid treatment or dusting) on the vertebrates to be protected and in the premises frequented by humans and vertebrates to be protected as residual treatment or atmosphere on

different housing supports.

  The subject of the invention is also a control method characterized in that a sufficient quantity of pyrethroid compound is directly administered to living beings to prevent the

  development of parasitic protozoa.

  In this particular control method, pyrethrinoid compounds can be advantageously incorporated in beverages

or foods to consume.

  When it comes to controlling protozoan parasites of vertebrates, it is possible to incorporate the products of the invention into drinking water or into food compositions in combination with a nutritive mixture suitable for animal feed. The nutrient mixture may vary depending on the animal species, it may contain cereals, sugars and grains, soybean meal, peanut cake and sunflower meal, animal meal, for example fishmeal,

  synthetic amino acids, mineral salts, vitamins and anti-

  oxidants. The subject of the invention is naturally the compounds intended for carrying out the above process: these compositions are characterized in that they contain a sufficient amount of

  pyrethroid to prevent the development of protozoa.

  The compositions of the invention intended for the treatment of premises preferably contain from 0.05 mg / l to 1 g / 1 of pyrethrinoid; among these preferred compositions, mention may be made especially of

  compositions containing from 0.25 to 5 mg / liter of deltamethrin.

  These compositions are prepared according to the usual processes of the agrochemical or agri-food industry. They can be

  optionally added with one or more other pesticidal agents.

  These compositions may be in the form of powders, granules,

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  suspensions, emulsions, solutions, aerosol solutions, tapes

fuels, baits.

  In addition to the active ingredient, these compositions contain, in general, a vehicle and / or a nonionic surfactant, ensuring, in addition, a uniform dispersion of the constituent substances of the mixture. The vehicle used may be a liquid, such as water, alcohol, hydrocarbons or other organic solvents, a mineral oil, animal or vegetable, a powder such as talc, clays, silicates,

  kieselguhr or a combustible solid.

  The following examples illustrate the invention without limiting it. 1 /. Example of compositions intended for the treatment of swamps: Deltamethrin .................... 0.1 g - Piperonyl butoxide ............ 4 g - Tween 80 ......................... 0.25 g - Topanol -A ............ .

  ...... 0.1 g..DTD: - Xylene ........................... q.s. for 1 liter.

  2 /. Example of compositions for the treatment of premises: Deltamethrin .................... 5 mg - Vercoryl S ............... ........ 899 g - Topanol A ...................... 16 g - Emcol ........... ..........

  ..... 35 g 3 /. Experimentation "in vitro on cultures of plasmodium falciparum Culture is performed in cypules of polystyrene plates for tissue cultures placed at 37C in an oven at .DTD: CO2 (6%) using modified medium RPMI 1640.

  Each cup contains 0.7 ml of the parisian human blood suspension (baseline parasitaemia rate: 0.3%). The incubation is continued for 48 hours without renewal of medium. The antiplasmodium products to be tested are added before incubation in the survival medium. The results are read on smears after MGG-specific staining and enumeration of parasitized red blood cells. The counts are approximately 3,000 RBCs per well. The products to be tested are introduced into 3 cups per concentration studied.

  The results obtained are summarized in Table 1.

  The parasitized red blood cells contain either trophozoites (young form), schizonts young or old, or meerozoites (in 11i 22579867

  rosace), all forms of plasmodium.

  The conclusion that can be drawn is that a marked activity on the development of plasmodium occurs with the dose of

0.75 / Ig / ml.

TABLE 1

  I IConcentra INHeReHeHeHeHeReHeReHeReHeReHeReHeNtS Imaties Imaties Iparasitémielparasité- i 101 I (in g / ml) Parasitized idumbrs (in%) Imitated by I I I I I I I I I I I I I I I I I

I I (%) I

  Idelmathrinel I I I I I I I I I I I I I I I I I I I I I I I (I) I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I

I I I I I I I I

I! I I

  EXAMPLE 4 Effect of pyrethrinids on the sporogonic cycle

in anopheles.

  The model chosen was the A. stephensi-P.y-yoelii couple whose

  cycle can be easily maintained on white mouse.

Plasmodium yoelii yoel i i.

  Plasmodium of rodents, P.y. yoelii is from Africa

Central.

  - Maintenance of the cycle of P.y. yoelii.

  Maintenance of the OF1 white mouse strain was achieved by intravenous inoculation of sporozoites obtained according to the protocol

following: -

  - After checking on a sample that 75 to 80% of female anopheles in a cage are carrying sporozoites in their salivary glands, 120 to 150 females are killed and then roughly dissected

  in order to keep only the head and the thorax.

  - These are deposited in a "potter" of Thomas containing 4 ml of RPMI

  1640 maintained at 4 C then finely ground.

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  - The ground material obtained is centrifuged a first time at 1500 rpm

(800 g) for 5 minutes.

  2 ml of supernatant are recovered in syringes, the rest is recentrifuged for 5 minutes at 1500 rpm and 1 ml of the supernatant is recovered. After checking the presence of sprozoites, 0.5 ml of the supernatant per mouse is inoculated intravenously, ie a total of 4 to 6

  mouse according to the results of the second centrifugation.

  On a donor mouse, which has previously been verified to have parasitaemia of at least 40% of red blood cells, 1 ml of blood is withdrawn by retro-orbital sinus puncture using a heparinized pasteur pipette. This blood is mixed in a watch glass with 1 ml of RPMI 1640 supplemented with a drop of heparin. Then we inoculate

  intraperitoneally 0.2 to 0.5 ml of this mixture per mouse.

  This method of infestation of mice has the disadvantage of increasing at each new passage the virulence of the plasmodial strain and especially to make it gradually lose its ability to produce infectious gametocytes. We therefore limited ourselves to taking mice infested only

sporozoites.

  The infectivity of the mice is checked from the 3rd day after the blood smear inoculation. The criteria are: presence of immature gametocytes and microgamites stage O and 1, absence of degenerate gametocytes whose cytoplasm is dotted with small vacuoles

round.

  The mice recognized as infectious are trapped in a flexible mesh and put in a cage containing about 150 females

  anopheles less than one week old.

  - Evaluation of the action of deltamethrin dissolved in mosquito larval rearing water on the development of sporozoites

  of Pharmodium in the adult mosquito.

  The impregnation with deltamethrin at the LD50 or at lower doses is carried out on non-infectious mosquito larvae raised in water. The surviving adults are then carried on mice infected with the plasmodiun for taking blood meals. Since the complete evolution of the plasmodium sporogonic cycle can not be judged on the presence of oocysts in the stomach of the adult, it seemed preferable to continue the experiment by evaluating the effect of deltamethrin on the percentage of

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  mosquitoes carrying sporozoites in the salivary glands. The

  dissections were performed 14 days after the blood meal.

  The results are reported on the following table: Series a :. Dose of deltamethrin used: 2.10-4 mg / l (LD 50 of mosquito larvae).

  The control group was infected first.

  None of the 19 mosquitos dissected in the treated lot carried sporozoites, whereas in the teimoin lot, 14 out of 20

  were. The difference is obviously very significant.

  O Series b: Dose of deltamethrin used: 2.10-4 mg / l (LD 50 of

mosquito larvae).

  The control lot was infested first.

  Again, no mosquitoes were found carrying sporozoites in the treated lot (0/42), whereas more than 50% of the mosquitos out of two were in the control group (16/31). The difference is obvious

very significant.

CONCLUSION:

  The complete sporogonic cycle can not be achieved in

  0 insects having been in contact with deltamethrin.

  TABLEAUJ: Distribution of sporozoite-carrying mosquitos in salivary glands by control and treated groups

by deltamethrin.

I I I I I I I I

  I Series I Dose I Lot I Negative I Positive I Effective I

I I I I I I I I

  Control I 1 I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I 10

I.I I I I I I

  I 1 I I I I I I I I I I I I I 12.10-4mg / 1 treated 1I 42 I O I i42 I

I! I I I

Example 5

  An experiment similar to that of Example 4) was carried out on larval Anopheles using a dose of

14 25

-55

  deltethrin lnfral; tale of 2.5 10 -5mg /.

  It was also found that the complete sporogonic cycle could not be achieved in adult insects having been in contact with larvae.

with deltadthrIne.

Example 6

  The experiment of Example 4 was carried out on anopheles in the adult state, in contact with a glass support treated at an infralithal dose of deltamithrin of 2.5 × 10 -9 g / l. It was also found that the complete sporogonic cycle could not be achieved

  in insects that have come into contact with deltamethrin.

Claims (6)

  1 /. A method of controlling endemics transmitted to living beings by protozoa, wherein the protozoan site contains a sufficient amount of pyrethroid compound to inhibit the development of protozoa. 2 /. Control method according to claim 1, characterized in that the multiplication of the protozoa is destroyed or limited   pathogens of vertebrates and invertebrates.   3 /. Control method according to claim 2 characterized in that   that protozoa are carried by insects.   4 /. A control method according to claim 3, characterized in that a pyrethroid-type compound is used at a lower dose   at the lethal dose of vector insects.    /. Process according to Claim 3 or 4, characterized in that   insect vectors are anopheles.   6 /. Control method according to one of the claims   1 to 5 characterized in that the protozoa being fought are plasmodium.   /. Control method according to any one of claims 1   at 6 characterized in that the pyrethroid used is the del tamethri ne.   8 /. Control method according to any one of claims 1   characterized in that the pyrethroid is selected from the group of the following compounds: tralomethrin, cypermethrin, permethrin, alphamethrin, cyfluthrin, cyhalothrin, fenfluthrin, fencythrin and fenvalerate and the derivatives thereof.   1 allethrin and neopynamin.   /. Control method according to one of the claims   1 to 8, characterized in that a quantity of pyrethrin is used.   less than that required to kill the vector arthropod.    /. Control method according to one of the claims   i to 8, characterized in that a sufficient quantity of pyrethroid compound is directly administered to living beings.   to prevent the development of plasmodium. 16 2579867   11 /. The compositions intended for the implementation of the process   according to any one of claims i to 10 characterized in   what they contain a sufficient amount of pyrethroid for   prevent the development of protozoa.