HK1058310A - Anthelminthic agents for the prevention of parasitic infections in humans and animals ii - Google Patents

Description

Anthelmintic agents for the prevention of parasitic infections in humans and animals II

The present invention relates to compositions comprising certain active compounds suitable as anthelmintics and their use for preventing infections of humans or animals with parasitic flatworms during the infection period. The composition is applied to the skin to combat the flat worm, i.e., the stage of infection by cercaria that penetrates the skin into the host.

Various flatworm species cause serious diseases in humans and animals. Especially in tropical countries, infections with blood sucking species lead to chronic diseases and often to death. Important pathogens are Schistosoma mansoni, Schistosoma japonicum and Schistosoma japonicum. Infected are local residents, visitors, staff of humanitarian assistance agencies, and soldiers. At the time of infection of a human, infectious cercaria present in water in open waters enters the human body through the skin.

In temperate climatic countries there is also the problem of infection of humans by different species of schistosoma japonicum and Ornithobilharzia cercaria, which can penetrate the skin and cause dermatitis. These infections occur during amateur activities and fishing, pond farming or land irrigation in inland waters or coasts. In general, in many cases of daily life, contact of the skin with water that may be contaminated/infected is unavoidable.

However, pretreatment of the skin with an insect repellent active according to the present invention prevents the invasion of pathogens.

Several compounds have previously been tested for their suitability for preventing these parasitic infections. However, the substances described so far for the purposes of the present invention are toxic when introduced into the body transdermally or orally:

thus, for example, hexachlorophene has a killing effect on The cercaria of Schistosoma mansoni (Fripp, P.J. and Armstrong, F.I., The efficacy of hexachlorophene skinning as a cercariae repeat, efficacy of hexachlorophene skin cleanser as a cercaria anthelmintic, Southtf African Med.J. 47: 1973, 526-. Hexachlorophene cannot be applied to human skin due to health risks, especially damage to the liver. Contact with the skin and when swallowed is toxic, may cause malformations and may be carcinogenic [ Kommision der Europaischen Gemeinschaften, Richtlinie93/72/EWG vom 1.Sept.1993, suppl.I and II (EUGefahrstoff-Verordnung), 1999, Amtsblatt der EUL258A, 36. Jahrgarg, 16.Okt.1993, 1997 ].

Niclosamide is effective against cercaria invasion [ Bruce, J.I. et al (1992) effectiveness of niclosamide as a potent systemic antisense against ipenetrant (TAP) against Schistosoma mansonii in monkeys (the efficacy of niclosamide as a potent local antisense (TAP) against Schistosoma mansoni cercaria in monkeys). Mem. inst. oswaldo Cruz 87: 28, 1-289], but is suspected of being Toxic because it may cause genetic damage (Registry of top Effects of chemical substructures, National Institute of occupancy safety and Health). Because of its environmental hazard, niclosamide must be excluded from being applied to skin sites exposed to water, because it is particularly harmful to water [ Umwell rendesamt (Hrsg.) Katalog wassergef Stoffe. LTwS-Nr.12.Mai1996, Berlin 1996, and supplemented continuously ]. Thus, the compound has not been commercially used in humans to combat cercaria to date.

N, N-diethyl-m-toluamide (DEET) is active against Schistosoma mansoni cercaria [ Salafsky, B. et al, Evaluation of N, N-diethyl-m-toluamide (DEET) as a topical agent for prevention of Schistosoma mansoni (Evaluation of N, N-diethyl-m-toluamide (DEET) as a topical drug against the prevention of Schistosoma mansoni cercaria penetration). Am.j.trop.med.hyg.58: 1998, 828-834). DEET has some disadvantageous properties.

The effect of the decongestants described so far on the flat worm stage of infection has so far only been tested on the cercaria of the species schistosoma mansoni, i.e. the effectiveness of these compositions on other genera of worms has not yet been demonstrated.

It has now surprisingly been found that the compositions of the invention are suitable for the effective prevention of infection of humans and animals by flatworms, in particular of the genera schistosoma japonicum, schistosoma japonicum and ornithobilharizia, but also of the genera schistosoma japonicum and the like.

The invention thus relates to

1. A composition for the prevention of helminthic parasites, characterized in that it comprises at least one compound of formula (I)Wherein

Y represents hydrogen, optionally substituted alkyl or a group O-X,

x represents hydrogen, COR¹¹、COOR¹²、R¹³，

R¹Represents an optionally substituted alkyl, alkenyl, cycloalkyl or cycloalkenyl group,

R²、R¹¹、R¹²and R¹³Identical or different and represent optionally substituted alkyl or alkenyl,

R³-R¹⁰identical or different and represents hydrogen or represents optionally substituted alkenyl, where R²And R³Together with the atoms to which they are attached may also form an optionally substituted monocyclic ring

And

n and m are the same or different and are 0 or 1, with the proviso that if n and m are 0, X does not represent hydrogen or R¹³。

2. A composition for the prevention of helminthic parasites according to item 1, characterized in that it comprises at least one compound of formula (1)

Wherein

Y represents hydrogen, C₁-C₆Alkyl or represents a group O-X,

x represents hydrogen, COR¹¹Or R¹³，

R¹Is represented by C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl radical, C₁-C₂-alkyl-C₃-C₇-cycloalkyl, C₁-C₂-alkyl-C₃-C₇Cycloalkenyl in which the cycloalkyl or cycloalkenyl ring of the above radicals is optionally substituted by C₁-C₆-alkyl or C₁-C₆A dialkylene (dialkylene) bridge being at most trisubstituted, or

R¹Is represented by C₁-C₇-alkyl or C₃-C₇-an alkenyl group,

R²、R¹¹、R¹³are the same or different and represent C₁-C₆-an alkyl group,

R³-R⁶are the same or different and represent hydrogen or C₁-C₆-alkyl, wherein R²And R³Together with the atoms to which they are attached may also form a 5-or 6-membered monocyclic ring, and

n represents 1 and m represents 0.

3. A method for controlling helminthic parasites, characterized in that compounds of the formula (I) according to item 1 are applied to helminths and/or their habitat.

4. Use of compounds of formula (I) according to item 1 for controlling parasitic helminths.

5. A process for the preparation of a composition for the prevention of helminthic parasites, characterized in that a compound of formula (I) according to item 1 is mixed with a compatibilizer and/or a surfactant.

In a preferred embodiment, the substituent Y in formula (I) represents hydrogen or C₁-C₆Alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, pentyl or hexyl. In this case, R¹Preferably represents C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl radical, C₁-C₂-alkyl-C₃-C₇-cycloalkyl, C₁-C₂-alkyl-C₃-C₇Cycloalkenyl in which the cycloalkyl or cycloalkenyl ring of the above radicals is optionally substituted by C₁-C₆-alkyl or C₁-C₆The dialkylene bridge is at most trisubstituted.

According to another embodiment, suitable for use in the compositions of the present invention are compounds of formula (I), wherein

Y represents a group O-X,

x represents hydrogen or COR¹¹、COOR¹²Or R¹³，

R¹Represents an optionally substituted alkyl or alkenyl group,

R²、R¹¹、R¹²and R¹³Identical or different and represent optionally substituted alkyl or alkenyl,

R³-R¹⁰identical or different and represents hydrogen or represents optionally substituted alkenyl, where R²And R³May also form, together with the atoms to which they are attached, an optionally substituted monocyclic ring, and

n and m are the same or different and represent 0 or 1, provided that when n and m represent 0, X does not represent hydrogen or R¹³。

Of these compounds, preference is given to compounds of the formula (I), in which

X represents hydrogen, COR¹¹Or R¹³，

R¹Is represented by C₁-C₇-alkyl or C₃-C₇-an alkenyl group,

R²、R¹¹and R¹³Are the same or different and represent C₃-C₆-an alkyl group,

R³-R⁶are the same or different and represent hydrogen or represent C₁-C₆-alkyl, wherein R²And R³Together with the atoms to which they are attached may also form a 5-or 6-membered monocyclic ring, and

n represents 1, and

m represents 0.

In these compounds, R²And R³Together with the atoms to which they are attached particularly preferably form a 5-or 6-membered monocyclic ring, especially a piperazine ring.

Particularly suitable among these compounds are compounds of the formula (Ia)

Wherein

X represents hydrogen, COR¹¹、COOR¹²、R¹³Wherein R is¹¹、R¹²、R¹³Identical or different and represent optionally substituted alkyl, alkenyl, especially hydrogen or C₁-C₄Alkyl radicals, such as the methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl radical, and

R¹is represented by C₁-C₆-alkyl or C₃-C₆-an alkenyl group.

As compounds particularly suitable for use in the compositions of the present invention there may be mentioned in particular the following compounds of formula (I) or formula (Ia):

the compounds of the formulae (I) and (Ia) and their preparation are known from DE OS 3708033.

The following compounds of formula (I) are also suitable for use in the present invention,

this compound is known and commercially available.

The active compounds contained in the compositions of the invention have been used in particular as insect repellents against insects and ticks for application to the skin.

The main advantages of using the compounds of the present invention are its high compatibility with the skin, plants and environment and the generally low toxicity of these compounds.

Furthermore, mosquito bites can be advantageously prevented when staying outdoors. Mosquitoes are considered to be unpleasant on the one hand and, on the other hand, may, especially in tropical regions, transmit diseases, such as malaria, various viruses, filariasis and parasites, through their stings. The composition of the invention can prevent the flat insect infection and the mosquito bite at the same time only by using one composition. Thus, the necessity of having to apply two different, possibly incompatible compositions simultaneously on the skin is avoided.

In addition to the active compounds, the compositions according to the invention may contain all the customary auxiliaries and additives for formulations for topical application.

The active compounds can be applied directly or in the form of suitable formulations transdermally or with the aid of shaped bodies containing the active compounds, such as strips (Streifen), sheets (pattern), strips (die), collars, ear ornaments, limb rings (strips), marking devices.

Transdermal administration, for example, is effected by bathing, dipping, spraying, pouring or dripping, washing, shampooing or dusting.

Suitable formulations are:

solutions or concentrates for diluted application, solutions for application to the skin, pour-on formulations, gels;

emulsions and suspensions and semi-solid formulations for dermal application;

formulations wherein the active compound is incorporated in a cream base or in an oil-in-water or water-in-oil emulsion base;

solid preparations, such as powders, shaped bodies containing the active compound.

Solutions for application to the skin are applied by dropping, brushing, wiping, spraying or by dipping, bathing or washing.

The solutions are prepared by dissolving the active compound in a suitable solvent and optionally adding additives such as solubilizers, acids, bases, buffer salts, antioxidants, preservatives.

Suitable solvents which may be mentioned are: physiologically acceptable solvents, such as water, alcohols, for example ethanol, butanol, benzyl alcohol, glycerol, hydrocarbons, propylene glycol, polyethylene glycols, N-methylpyrrolidone and mixtures thereof.

The active compounds can also optionally be dissolved in physiologically acceptable vegetable or synthetic oils.

Suitable solubilizers which may be mentioned are: solvents which promote dissolution of the active compound in the main solvent or which prevent precipitation of the active compound, for example polyvinylpyrrolidone, polyethoxylated castor oil, polyethoxylated sorbitan esters.

Suitable preservatives are: benzyl alcohol, chlorobutanol, parabens, or n-butanol.

Thickening agents may be added in the preparation of the solution. Suitable thickeners are: inorganic thickeners such as bentonite, colloidal silica, aluminium monostearate, or organic thickeners such as cellulose derivatives, polyvinyl alcohol and copolymers thereof, acrylates and methacrylates.

The gel applied or spread on the skin is made to form a clear composition with a cream-like consistency by adding a thickening agent to the solution prepared above. The above-mentioned thickener is used.

Pour-ons and drops are poured or sprayed onto a defined area of the skin to distribute the active compound over the surface of the body.

Pour-on and drop-on formulations are prepared by dissolving, suspending or emulsifying the active compound in a suitable dermatologically acceptable solvent or solvent mixture. Optionally adding other auxiliary agents, such as coloring agent, antioxidant, light stabilizer and binder.

Suitable solvents are: water, alcohols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols, for example benzyl alcohol, phenyl ethanol, phenoxyethanol, esters, for example ethyl acetate, butyl acetate, benzyl benzoate, ethers, for example alkylene glycol alkyl ethers, for example dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether, ketones, for example acetone, methyl ethyl ketone, aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, N-methylpyrrolidone, 2-dimethyl-4-oxy-methylene-1, 3-dioxolane.

Colorants are all colorants approved for animal use that can be dissolved or suspended.

The adjuvant is spreading oil, such as isopropyl myristate, dipropylene glycol pelargonate, silicone oil, fatty acid ester, triglyceride, and fatty alcohol.

The antioxidant is sulfite or pyrosulfite, such as potassium metabisulfite, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole, and tocopherol.

Light stabilizers are, for example, benzophenone and Novantisols ure.

The binders are, for example, cellulose derivatives, starch derivatives, polyacrylates, natural polymers, such as alginates, gelatins.

Emulsions are either water-in-oil or oil-in-water.

They can be prepared by dissolving the active compound in a hydrophobic or hydrophilic phase and homogenizing this phase together with the solvent of the other phase, in the presence of suitable emulsifiers and optionally further auxiliaries, such as colorants, bioabsorption-promoting substances, preservatives, antioxidants, photostabilizers, viscosity-increasing substances.

Mention may be made, as hydrophobic phases (oils): paraffin oil, silicone oil, natural vegetable oil such as sesame oil, almond oil, castor oil, synthetic triglyceride such as caprylic/capric diglyceride, having C_8-12Triglyceride mixtures of vegetable fatty acids of chain length or other specifically selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated and optionally hydroxyl-containing fatty acids, C₈/C₁₀-mono-or diglycerides of fatty acids.

Fatty acid esters, e.g. ethyl stearate, di-n-butyryl adipate, hexyl laurate, dipropylene glycol pelargonate, branched fatty acids of medium chain length and having C₁₆-C₁₈Esters of saturated fatty alcohols of chain length, isopropyl myristate, isopropyl palmitate, having C₁₂-C₁₈Octanoic/decanoic acid esters of saturated fatty alcohols of chain length, isopropyl stearate, oleyl oleate, decyl oleate, ethyl lactate, waxy fatty acid esters, such as dibutyl phthalate, diisopropyl adipate, ester mixtures of the latter family, in particular fatty alcohols, such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.

Fatty acids such as oleic acid and mixtures thereof.

Mention may be made, as hydrophilic phase: water, alcohols such as propylene glycol, glycerin, sorbitol, and mixtures thereof.

Mention may be made, as emulsifiers: nonionic surfactants, such as polyethoxylated castor oil, polyethoxylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyethoxylated stearate, alkylphenol polyglycol ethers; amphoteric surfactants such as disodium N-lauryl- β -iminodipropionate or lecithin; anionic surfactants such as sodium lauryl sulfate, fatty alcohol ether sulfates, monoethanolamine salts of mono/dialkyl polyglycol ether orthophosphate; cationic surfactants, such as cetyltrimethylammonium chloride.

Other suitable adjuvants include: substances which increase the viscosity and stabilize the emulsion, such as carboxymethylcellulose, methylcellulose and other cellulose derivatives and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, methyl vinyl ether and maleic anhydride copolymers, polyethylene glycols, waxes, colloidal silica or mixtures of the aforementioned substances.

Suspensions may be prepared by suspending the active compound in a liquid vehicle, optionally together with other adjuvants, such as wetting agents, colorants, bioabsorption-promoting substances, preservatives, antioxidants, light stabilizers.

Suitable liquid excipients are all homogeneous solvents and solvent mixtures.

Suitable wetting agents (dispersants) may be mentioned the surfactants mentioned above.

Other auxiliaries may be mentioned those mentioned above.

Semisolid formulations for transdermal administration differ from the above-mentioned suspensions and emulsions only in that they have a high viscosity.

To produce solid preparations, the active compounds are mixed with suitable carrier materials, optionally with the addition of auxiliaries, and the mixture is brought into the desired form.

All physiologically acceptable solid inert substances can be mentioned as carriers. Suitable for this purpose are inorganic and organic substances. The inorganic substances are, for example, common salt, carbonates, such as calcium carbonate, bicarbonates, alumina, silica, clays, precipitated or colloidal silica, phosphates.

Auxiliaries are the preservatives, antioxidants and colorants already mentioned above.

Other suitable auxiliaries are lubricants (Schmier und gleitmttel), for example magnesium stearate, stearic acid, talc, bentonite.

Furthermore, it is desirable that such protective agents have a sufficient protective effect even after prolonged contact with water, for example after swimming, washing or fishing. For this purpose, the compositions according to the invention may also contain water-barrier or water-repellent substances.

Suitable water-repellent substances are those of sunscreens which have been used to protect users from ultraviolet radiation from the sun (e.g. US 5518712 and US 4810489). The purpose is to maintain the sunscreen effect after the user has swim or has sweated vigorously, etc. Sunscreens and insect repellents comprising such waterproof or water-barrier substances are known (US 5716602). However, no compositions containing anthelmintics have been described to date.

Accordingly, a water repellent substance is also included in the composition of the present invention. They may be fat-soluble, water-insoluble substances and compounds which improve the adhesion of the composition to the skin.

Polymers such as polyvinylpyrrolidone, polyacrylates, silicone rubbers, etc., may be included as water-repellent components, for example, in amounts of 1 to 50% by weight in the skin care product.

Compositions for topical application can be formulated as sprays, solutions, creams, ointments or layered or film-forming compositions according to methods known for the preparation of cosmetics (Schrader, K. (1979) Grundlagen und rezepturener kosmetika. dr. alfred huig Verlag, Heidelberg).

Upon application, the article of the present invention is applied uniformly and completely to the skin in the appropriate amount for the application.

Of course, the compositions of the invention are also suitable for use in animals to prevent infection of the animals by parasites of these genera. The compositions of the present invention are useful for pets, such as dogs and cats, and for commercial animals, such as cattle, pigs, sheep, and the like.

In the application of the compositions according to the invention, in general from 0.03 to 1mg, preferably from 0.03 to 0.1mg and particularly preferably from 0.04 to 0.06mg of active compound per square centimeter of skin are applied. Thereby prophylactically protecting against skin-invading worms and their pre-stages. Repeated applications of the active compound are necessary if the user remains in the water for a long time.

The compositions of the present invention are illustrated by the following examples, which are not intended to limit the invention.

Biological examples

Activity against Schistosoma mansoni cercaria

[ Final concentration of active Compound 500. mu.l/l ]

For infection, each snail (Biomphalaria glabrata) was incubated overnight with 8 miracidiums in 10 ml water. The snail was irradiated with light in the dark about 6-9 weeks after infection to obtain cercaria, and then emerged cercaria were collected in 2 hours.

Water (1 or 2ml, see below) containing cercaria was added to the test portions, each containing approximately 100-150 cercaria.

Mu.l of active compound are mixed thoroughly with 25. mu.l of PEG300, then 9ml of culture water are added and the aliquot is shaken vigorously. After (later) the addition of 1ml cercariae suspension, the survival of the cercariae was observed immediately with a stereo magnifier in each case. The activity of the active compounds was assessed on the following scale: 0 ═ no effect over the entire measurement period of 120 minutes; 1-weak action (movement of cercaria is greatly reduced); 2-good effect (cercaria move only slightly and bend); 3-strong action (cercaria completely immobilized).

Evaluation of the different compounds of the invention:

compound (I) Evaluation value

Claims (5)

1. A composition for the prevention of helminthic parasites, characterized in that it comprises at least one compound of formula (I)

Wherein

Y represents hydrogen, optionally substituted alkyl or represents a group O-X,

x represents hydrogen, COR¹¹、COOR¹²、R¹³，

R¹Represents an optionally substituted alkyl, alkenyl, cycloalkyl or cycloalkenyl group,

R²、R¹¹、R¹²and R¹³Identical or different and represent optionally substituted alkyl or alkenyl,

R³-R¹⁰identical or different and represents hydrogen or represents optionally substituted alkenyl, where R²And R³Together with the atoms to which they are attached may also form an optionally substituted monocyclic ring

And

n and m are the same or different and are 0 or 1, with the proviso that if n and m are 0, X does not represent hydrogen or R¹³。

2. A composition for combating helminthic parasites according to claim 1, characterized in that it comprises at least one compound of formula (I)

Wherein

Y represents hydrogen, C₁-C₆Alkyl or represents a group O-X,

x represents hydrogen, COR¹¹Or R¹³，

R¹Is represented by C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl radical, C₁-C₂-alkyl-C₃-C₇-cycloalkyl, C₁-C₂-alkyl-C₃-C₇Cycloalkenyl in which the cycloalkyl or cycloalkenyl ring of the above radicals is optionally substituted by C₁-C₆-alkyl or C₁-C₆The dialkylene bridge being up to trisubstituted, or

R¹Is represented by C₁-C₇-alkyl or C₃-C₇-an alkenyl group,

R²、R¹¹、R¹³are the same or different and represent C₁-C₆-an alkyl group,

R³-R⁶are the same or different and represent hydrogen or C₁-C₆-alkyl, wherein R²And R³Together with the atoms to which they are attached may form a 5-or 6-membered monocyclic ring, and

n represents 1 and m represents 0.

3. A method for controlling helminthic parasites, characterized in that compounds of the formula (I) according to claim 1 are applied to helminths and/or their habitat.

4. Use of compounds of formula (I) according to claim 1 for controlling parasitic helminths.

5. A process for the preparation of a composition for the prevention of helminthic parasites, characterized in that a compound of formula (I) according to claim 1 is mixed with a compatibilizer and/or surfactant.