Endoparasiticides tool

 

(57) Abstract:

Features endoparasiticides tool containing cyclic depsipeptide consisting of amino acids and hydroxycarbonic acids as ring links and 6-30 ring atoms, or an optical isomer or racemate, and additionally 2-(cyclohexylcarbonyl)-1, 2, 3, 6, 7, 11b-hexahydro-4H-pyrazino [2,1-a] isoquinoline-4-one or 2-(cyclohexylcarbonyl)-2, 3, 6, 7, 8, 12b-hexahydropyrazino [2,1-a] [2] -benzazepin-4- (1H)-he. This circular depsipeptide and specified derivative of athinaikon or derived benzazepine preferably taken in a weight ratio of from 1:1 to 10:1. The proposed activity means higher than the sum of the activity of known means, containing only one of these two active substances. Thus, the proposed tool allows you to obtain a synergistic effect. 6 C.p. f-crystals, 2 tab.

The invention relates to means for controlling insects, in particular to endoparasiticides tool.

It is well known that cyclic depsipeptide consisting of amino acids and hydroxycarbonic acids as ring links and 6 to 30 ring atoms, can be used for pest control.

And the 18 ring atoms of the General formula I

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where R1is hydrogen, unbranched or branched alkyl with 2 to 8 carbon atoms, hydroxyalkyl, alkanoyloxy, alkoxyalkyl, aryloxyalkyl, mercaptoethyl, alkylthiomethyl, alkylsulfonates, alkylsulfonates, carboxyethyl, alkoxycarbonylmethyl, arylalkylamines, carbamoylethyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, guanidinate, unsubstituted or substituted by one or two residues benzoyloxymethyl or 1 - 4 alkilinity residues, alkoxycarbonylmethyl, 9-fluorenylmethoxycarbonyloxy, alkenyl, cycloalkyl, cycloalkenyl, and unsubstituted or substituted arylalkyl, and as Vice can be called halogen, hydroxyl, alkyl, alkoxy;

R3and R5independently of one another denote hydrogen, an unbranched or branched alkyl with 1 to 8 carbon atoms, hydroxyalkyl, alkanoyloxy, alkoxyalkyl, aryloxyalkyl, mercaptoethyl, alkylthiomethyl, alkylsulfonates, alkylsulfonates, carboxyethyl, alkoxycarbonylmethyl, arylethoxysilanes, carbamoylethyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, guanidinate, unsubstituted or substituted by one or two residues benzyl is l, alkenyl, cycloalkyl, cycloalkenyl, and unsubstituted or substituted arylalkyl, and as Vice can be called halogen, hydroxyl, alkyl, alkoxy;

R2, R4and R6independently of one another denote hydrogen, an unbranched or branched alkyl with 1 to 11 carbon atoms, hydroxyalkyl, alkanoyloxy, alkoxyalkyl, aryloxyalkyl, alkylthiomethyl, alkylsulfonyl, alkylsulfonyl, carboxylic, alkoxycarbonylmethyl, allamoxicillinpills, carbamoylethyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylmethyl, alkenyl, cycloalkyl, cycloalkenyl, and unsubstituted or substituted aryl or arylalkyl, and as Vice can be called halogen, hydroxyl, alkyl, alkoxy,

or their optical isomers or racemates, is known from PCT application N EP 93/01436, class C 07 K 11/02, published 23.12.1993, (WO 93/25543).

Another endoparasiticides tool, containing as active substance depsipeptide formula II

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it is known from N application EP 0 382 173 A2, class C 07 D 273/00, A 61 K 31/395, 1990.

Another endoparasiticides tool, containing as active substance derived depsipeptide General formula III< the R7, R8, R9, R10independently of one another denote hydrogen, alkyl with 1 to 10 carbon atoms or aryl, in particular phenyl, unsubstituted or substituted by hydroxyl, alkoxyl with 1 to 10 carbon atoms or halogen,

or an optical isomer or racemate

it is known from PCT application N JP 93/00286, class C 07 D 273/00, A 61 K 31/395, published 30.09.1993,

Also known endoparasiticides preparations, containing as active substance 2-(cyclohexylcarbonyl)-1,2,3,6,7,11 b - hexahydro-4H-pyrazino[2,1-a]isoquinoline-4-one (see patent GB No. 1 441 554) or 2-(cyclohexylcarbonyl)-2,3,6,7,8,12 b - hexahydropyrazino[2,1-a] [2]-benzazepin-4(1H)-he (see application EP N 134 984).

The disadvantage endoparasiticides means is that their activity is not fully satisfactory.

The objective of the invention is the provision of endoparasiticides means having a higher endoparasiticides activity in comparison with the known.

This problem is solved proposed endoparasiticides product containing cyclic depsipeptide consisting of amino acids and hydroxycarbonic acids as ring links and 6 to 30 ring atoms, or optical iresine[2,1-a]isoquinoline-4-one or 2-(cyclohexylcarbonyl)-2,3,6,7,8,12 b-hexahydropyrazino[2,1-a] [2]- benzazepin-4(1H)-he.

Cyclic depsipeptide and specified derivative of athinaikon or derived benzazepine taken in a weight ratio of from 1:1 to 10:1, preferably 1:1 to 2:1.

Offer endoparasiticides means get a simple mixing of the two active substances. The proposed activity means higher than the sum of the activity of known products containing one of these two active substances. Thus, the proposed tool allows you to obtain a synergistic effect.

The proposed product contains as cyclic depsipeptide preferably the compound of the above General formula I, II, III or IV or its optical isomer or racemate, or a compound of General formula V

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where R11, R14, R17and R20independently of one another denote alkyl with 1 to 8 carbon atoms, halogenated with 1 to 8 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, aralkyl, aryl,

R13, R16, R19and R22independently of one another denote hydrogen or an unbranched or branched alkyl with 1 to 8 carbon atoms, unsubstituted or substituted by a residue from the group comprising hydroxyl, alkoxy with 1 to 4 carbon atoms, carboxyl, carboxamide, imide is e may be substituted with halogen, by hydroxyl, alkyl with 1 to 4 carbon atoms, alkoxyl with 1 to 4 carbon atoms.

R15, R18, R21and R12independently of one another denote hydrogen or unbranched alkyl with 1 to 5 carbon atoms, alkenyl with 2 to 6 carbon atoms, cycloalkyl with 3 to 7 carbon atoms which may be substituted by a residue from the group comprising hydroxyl, alkoxy with 1 to 4 carbon atoms, carboxyl, carbamid, imidazolyl, indolyl, guanidino, mercapto group, alkylthio with 1 to 4 carbon atoms, and aryl or aralkyl, which may be substituted with halogen, hydroxyl, alkyl with 1 to 4 carbon atoms, arcoxia with 1 to 4 carbon atoms,

or an optical isomer or racemate.

In the above formula (I) residues have the following preferred values:

R1, R3and R5independently of one another denote unbranched or branched alkyl with 1 to 8 carbon atoms, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.butyl, tert.butyl, pentyl, isopentyl, Deut. pentyl, hexyl, isohexyl, Deut. hexyl, heptyl, isoheptyl, Deut.heptyl, tert.heptyl, octyl, isooctyl, Deut.octyl, hydroxyalkyl with 1 to 6 carbon atoms, in particular hydroxymethyl, 1-hydroxyethyl, in particular acetoxymethyl, 1-acetoxyethyl, alkoxyalkyl with 1 to 4 carbon atoms in the CNS part m 1 to 6 carbon atoms in the alkyl part, in particular methoxymethyl, 1-methoxyethyl, arylalkylamines with 1 to 4 carbon atoms in alkyloxybenzoic part and 1 to 6 carbon atoms in the alkyl part, in particular benzyloxyethyl, 1-benzyloxyethyl, mercaptoethyl with 1 to 6 carbon atoms, in particular mercaptomethyl, alkylthiols with 1 to 4 carbon atoms in alkylthio-part and 1 to 6 carbon atoms in the alkyl part, in particular methylthioethyl, alkylsulfonyl with 1 to 4 carbon atoms in alkylsulfonyl part and 1 to 6 carbon atoms in the alkyl part, in particular methylsulfinylbutyl, alkylsulfonyl with 1 to 4 carbon atoms in alkylsulfonyl part and 1 to 6 carbon atoms in the alkyl part, in particular methylsulfonylmethyl, carboxyethyl with 1 to 6 carbon atoms in the alkyl part, in particular carboxymethyl, carboxyethyl, alkoxycarbonyl with 1 to 4 carbon atoms in the CNS part and 1 to 6 carbon atoms in the alkyl part, in particular methoxycarbonylmethyl, ethoxycarbonylethyl, allamoxicillinpills with 1 to 4 carbon atoms in the alkyl part, in particular benzyloxycarbonylation, carbamoylethyl with 1 to 6 carbon atoms in the alkyl h is aminobutyl, acylaminoalkyl with 1 to 4 carbon atoms in alkylamino part and 1 to 6 carbon atoms in alkilani part, in particular methylaminopropyl, methylaminomethyl, each acylaminoalkyl with 1 to 4 carbon atoms in each alkylamino part and 1 to 6 carbon atoms in the alkyl part, in particular dimethylaminopropyl, diethylaminomethyl, houndour with 1 to 6 carbon atoms in the alkyl part, in particular grandprey, alkoxycarbonylmethyl with 1 to 4 carbon atoms in the CNS part and 1 to 6 carbon atoms in the alkyl part, in particular tert.butoxycarbonylamino, tert. butoxycarbonylamino, 9-fluorenylmethoxycarbonyloxy with 1 to 6 carbon atoms in the alkyl part, in particular 9-fluorenylmethoxycarbonyloxy, 9-fluorenylmethoxycarbonyl, alkenyl with 2 to 8 carbon atoms, in particular vinyl, allyl, butenyl, cycloalkyl with 3 to 7 carbon atoms, in particular cyclopentyl, cyclohexyl, cycloheptyl, cycloalkyl with 3 to 7 carbon atoms in cycloalkyl part and 1 to 4 carbon atoms in the alkyl part, in particular cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenylalkyl with 1 to 4 carbon atoms in the alkyl part, in particular phenylmethyl, which may be substituted, astatke the particular methoxy or ethoxy, alkyl with 1 to 4 carbon atoms, in particular methyl.

R2, R4and R6independently of one another denote unbranched or branched alkyl with 1 to 8 carbon atoms, in particular methyl, ethyl, propyl, isoproyl, butyl, isobutyl, sec.butyl, tert.butyl, pentyl, isopentyl, Deut. pentyl, hexyl, isohexyl, Deut. hexyl, heptyl, isoheptyl, Deut.heptyl, tert.heptyl, octyl, isooctyl, Deut.octyl, hydroxyalkyl with 1 to 6 carbon atoms, in particular hydroxymethyl, 1-hydroxyethyl, alkanoyloxy with 1 to 4 carbon atoms in alkanolamines part m 1 to 6 carbon atoms in the alkyl part, in particular acetoxymethyl, 1-acetoxyethyl, alkoxyalkyl with 1 to 4 carbon atoms in the alkyl part and 1 to 6 carbon atoms in the alkyl part, in particular methoxymethyl, 1-methoxyethyl, arylalkylamines with 1 to 4 carbon atoms in the alkyl part and 1 to 6 carbon atoms in the alkyl part, in particular benzyloxyethyl, 1-benzyloxyethyl, mercaptoethyl with 1 to 6 carbon atoms, in particular mercaptomethyl, alkylthiols with 1 to 4 carbon atoms in alkylthio-part and 1 to 6 carbon atoms in the alkyl part, in particular methylthioethyl, alkylsulfonyl with 1 to 4 carbon atoms in alkylsulfonyl part and 1 to 6 carbon atoms in school part 1 - 6 carbon atoms in the alkyl part, in particular methylsulfonylmethyl, carboxyethyl with 1 to 6 carbon atoms in the alkyl part, in particular carboxymethyl, carboxyethyl, alkoxycarbonyl with 1 to 4 carbon atoms in the CNS part and 1 to 6 carbon atoms in the alkyl part, in particular methoxycarbonylmethyl, ethoxycarbonylethyl, realconsoleonly with 1 to 4 carbon atoms in the CNS part and 1 to 6 carbon atoms in the alkyl part, in particular benzyloxycarbonylation, carbamoylethyl with 1 to 6 carbon atoms in the alkyl part, in particular carbamoylmethyl, carbamoylethyl, aminoalkyl with 1 to 6 carbon atoms, in particular aminopropyl, aminobutyl, acylaminoalkyl with 1 to 4 carbon atoms in alkylamino part and 1 to 6 carbon atoms in the alkyl part, in particular methylaminopropyl, methylaminomethyl, dialkylaminoalkyl with 1 to 4 carbon atoms in each alkylamino part and 1 to 6 carbon atoms in the alkyl part, in particular dimethylaminopropyl, diethylaminomethyl, alkenyl with 2 to 8 carbon atoms, in particular vinyl, allyl, butenyl, cycloalkyl with 3 to 7 carbon atoms, in particular cyclopentyl, cyclohexyl, cycloheptyl, cycloalkenyl with 3-7 carbon atoms in ciclacillin part and 1 to 4 carbon atoms and in which Mami carbon in the alkyl part, in particular phenylmethyl, which may be substituted by residues from the group comprising halogen, in particular fluorine, chlorine, bromine and iodine, hydroxyl, alkoxy with 1 to 4 carbon atoms, in particular methoxy, ethoxy, alkyl with 1 to 4 carbon atoms, in particular methyl.

In particular prefer the following values:

R1, R3and R5independently of one another denote unbranched or branched alkyl with 1 to 8 carbon atoms, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, pentyl, isopentyl, Deut.pentyl, hexyl, isohexyl, Deut. hexyl, heptyl, isoheptyl. Deut.heptyl, octyl, isooctyl, Deut. octyl, alkenyl with 2 to 8 carbon atoms, in particular allyl, cycloalkyl with 3 to 7 carbon atoms in cycloalkyl part and 1 to 4 carbon atoms in the alkyl part, in particular cyclohexylmethyl, phenylalkyl with 1 to 4 carbon atoms in the alkyl part, in particular phenylmethyl, R2, R4and R6independently of one another denotes unbranched or branched alkyl with 1 to 8 carbon atoms, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, pentyl, isopentyl, Deut.pentyl, hexyl, isohexyl, Deut. hexyl, heptyl, isoheptyl, Deut.heptyl, octyl, isooctyl, W is alkiline part 1 - 4 carbon atoms in the alkyl part, in particular cyclohexyl-methyl, phenylalkyl with 1 to 4 carbon atoms in the alkyl part, in particular phenylmethyl, which may be substituted by one or more identical or different groups of the aforementioned residues.

In the above formula V residues have the following preferred values:

R11, R14, R17and R20independently of one another denote methyl, ethyl, propyl, isopropyl or n-, sec.-, tert.-butyl,

R13, R16, R19and R22mean hydrogen, unbranched or branched alkyl with 1 to 8 carbon atoms, in particular methyl, ethyl, propyl, ISO-propyl, n-, sec. -, tert. -butyl which may be substituted by a residue from the group including alkoxy with 1 to 4 carbon atoms, in particular methoxy, ethoxy, imidazolyl, indolyl, alkylthio with 1 to 4 carbon atoms, in particular methylthio, ethylthio, phenyl, benzyl or phenethyl, which may be substituted with halogen, in particular chlorine.

R13, R16, R19and R22independently of one another denote hydrogen, methyl, ethyl, n-propyl, n-butyl, vinyl, cyclohexyl which may be substituted by a Deputy from the group comprising methoxy, ethoxy, imidazo is or phenylethyl.

Active substances contained in the proposed tool, get known methods.

With insignificant toxicity to warm-blooded offer tools suitable for combating pathogenic endoparasites which exists in a person, in the field of content and useful breeding, breeding, laboratory, testing, animals in zoos. The funds are active against all or individual stages of development of the pests and against resistant and normally sensitive species. Combating pathogenic endoparasites should reduce the incidence, mortality and increase productivity (for example, in the production of meat, milk, wool, hides, eggs, honey, etc), so the use of the active substances allows a more economical and simple animals. Pathogenic endoparasites are cestodes, trematodes, nematodes, acanthocephala.

The proposed tool can be used both prophylactically and therapeutically.

The application of the proposed tools is carried out directly, i.e. as such or in the form of suitable preparations enterline, parenteral, dermal, through the nose, by processing environment is, for example, collars, ear tags, ribbons for limbs, a marking device.

Enteral application is carried out, for example, orally in the form of powder, tablets, capsules, pastes, additives to water, granules, orally applied solutions, suspensions and emulsions, pills weight from 0.5 to 3.0 g of the additive to feed or drinking water. Dermal the use is carried out, for example, by dipping, nabryzgivaniya or pouring. Parenteral administration is carried out, for example, in the form of injections (intramuscularly, subcutaneously, intravenously, intraperitoneally) or with the help of implants.

Suitable preparations include solutions, such as solutions for injection, oral solutions, concentrates for oral villas after dilution, solutions for use on the skin or supply in the body cavity, for infusion drugs, gels, emulsions and suspensions for oral or dermal application for injection, semi-solid preparations, preparations in which the active substance is processed on the basis of ointments or on the basis of emulsions of the type oil-in-water type or water-in-oil, solid preparations such as powders, pre-prepared mixtures or concentrates, granules, beads, pills, pills weight from 0.5 to

Solutions for injection given intravenously, intramuscularly and subcutaneously.

Solutions for injection produced by dissolving the active substance in a suitable solvent. To the resulting solution may be added such additives target, as, for example, contributing to the dissolution agents, acids, bases, buffer salts, antioxidants, preservatives. The solution is sterile filtered and distinguish.

As solvents can be called physiologically tolerated solvents, such as, for example, water, alcohols like ethanol, butanol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycols, N-methyl-pyrrolidone, and mixtures thereof.

If necessary, the active substance can also be dissolved in physiologically portable vegetable or synthetic oils, suitable for injection.

As conducive to dissolution agents, you can call solvents that promote the dissolution of the active substance in the main solvent or prevent its deposition. As examples polyvinylpyrrolidone, polyoxyethylene castor oil, polyoxyethylene complex sorbitane ethers.

As conservantes">

Oral solutions apply directly. The concentrates used orally after prior dilution to the desired concentration. Oral solutions and concentrates receive the same manner as solutions for injection with the only difference that you can refuse sterility. Solutions for application to the skin put nakayanan, spread, rubbing, nabrasyvaniem or sputtering. These solutions prepared above for solution for injection.

In the process of obtaining may be preferential to add inorganic thickeners, such as, for example, bentonite, colloidal silicic acid, aluminum monostearate, organic thickeners, such as, for example, cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates.

Gels cause or call on the skin or serves in the body cavity. Gels are prepared by mixing the solutions obtained are described for solution for injection way, with so many of the thickener to form a transparent mass with a buttery consistency. As a thickener used the above substances.

Designed for pouring medications or pour nabryzgivajut on Ogre is

Designed for pouring medications get as a result of dissolution, suspension or emulsion of the active substances in a suitable portable skin of solvents or mixtures of solvents. If necessary add additional excipients as, for example, dyes, contributing to the absorption of substances, antioxidative, light stabilizers, adhesives.

As solvents can be called water, alkanols, glycols, polyethylene glycols, polypropylenglycol, glycerol, aromatic alcohols such as, for example, benzyl alcohol, phenylethanol, Phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers, such as, for example, Elgiloy ether alkalophilus, for example, onomatology broadcast dipropyleneglycol, monobutyl ether of diethylene glycol, ketones such as acetone, methyl ethyl ketone, aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oils, dimethylformamide, dimethylacetamide, N-organic, 2,2-dimethyl-4-hydroxy-methylene-1,3-dioxolane.

As the dyes can use any approved for use on animals dyes in the form of a solution or suspension.

Sposobstvuyushhikh, silicone oils, esters of fatty acids, triglycerides, fatty alcohols.

As an antioxidants it is possible to apply the sulfites or metabisulfite, such as, for example, potassium metabisulfite, ascorbic acid, equivalent, butylhydroxyanisole, tocopherol.

Sitosterolemia is, for example, 2-Arenal-benzimidazole-5-acid.

As the adhesives can be applied, for example, cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginate, gelatine.

The emulsion can be applied by the oral, dermal or by injection. They are used or the type of water in the oil or in the form of type oil-in-water. The emulsion obtained by dissolving the active substances either in the hydrophobic or in gyropilot phase, then the phase is subjected to homogenization with the solvent of the other phase with the aid of suitable emulsifiers and, if necessary, additional excipients, such as, for example, promote the absorption of substances, preservatives, antioxidants, light stabilizers that increase the viscosity of the substance.

As the hydrophobic phase (oils) can be called paraffin oil, silicone musicheskie triglycerides as, for example, triglycerides of Caprylic and/or capric acid, a mixture of triglycerides of vegetable fatty acids with 8 to 12 carbon atoms or other specially selected natural fatty acids, mixtures of partial glycerides of unsaturated or saturated fatty acids, which may also contain hydroxyl groups, mono - and diglycerides of fatty acids with 9 to 10 carbon atoms, esters of fatty acids as, for example, telstart, di-n-butyryl-adipat, complex hexyl esters of lauric acid, dipropylenetriamine, esters of a branched fatty acid of medium chain length with saturated fatty alcohols with 16 to 18 carbon atoms, isopropylmyristate, isopropyl, esters of Caprylic and/or capric acids with saturated fatty alcohols with 12 to 18 carbon atoms, isopropylene, complex aerovee esters butyric acids, complex delloye esters of butyric acid, etiloleat, complex ethyl esters of lactic acid, waxy esters of fatty acids, as, for example, the fat duck gland Asses, dibutyl phthalate, complex, isopropyl and the like esters of adipic acid, fatty alcohols such as, for example, isotridecyl alcohol, 2-octyldodecanol, the>As the hydrophilic phase can be called water, alcohols such as propylene glycol, glycerol, sorbitol and their mixtures.

As emulsifiers it is possible to use nonionic surfactants, for example, polyoxyethylene castor oil, polyoxyethylene complex monocarbonyl ester of oleic acid, a complex monocarbonyl ester of stearic acid, complex monoglyceride ester of stearic acid, polyoxyethylene, alkylphenol ether, impolitically surfactants, for example, the disodium salt of N-lauryl -- iminodipropylamine acid or lecithin, anionic surfactants, for example, sodium lauryl sulfate, fireslate fatty alcohol series, monoethanolamine salt complex polyglycolether mono/dialkylamino ether orthophosphoric acid, cationic surfactants, for example, chloride, cetyltrimethylammonium.

As a further auxiliary substances can be called increasing viscosity and stabiliausia emulsion substances, such as, for example, carboxymethylcellulose, methylcellulose and other derivatives of cellulose and starch, polyacrylates, al and maleic anhydride, the polyethylene glycols, waxes, colloidal silicic acid or mixtures of these substances.

The suspension can be applied by the oral, dermal or by injection. It is a result of the suspension of the active substance in the liquid medium, if necessary, with the addition of additional excipients, such as, for example, wetting, dyes, contributing to the absorption of substances, preservatives, antioxidants, light stabilizers.

As liquid carriers can use any homogeneous solvents or mixtures thereof.

As wetting (dispersant), you can apply the above surfactants.

As a further auxiliary substances can be called the above remedies.

Semi-solid preparations can be given oral or dermal. They differ from the above-described suspensions and emulsions only its higher viscosity.

For solid preparations, the active substance is mixed with suitable carriers, if necessary, with addition of auxiliary substances, and the resulting mixture was transferred into a desired shape.

As carriers can be called any fiziolechenie substances are, for example, sodium chloride, carbonates such as calcium carbonate, a bicarbonate, aluminum oxide, silicic acid, alumina, deposition or colloidal silicon dioxide, phosphates. Organic substances are, for example, sugar, cellulose, foodstuffs and feed means as, for example, milk powder, meat and bone flour, bakery flour, grind grain, starches.

As auxiliary substances can apply the above preservatives, antioxidants and colorants, and lubricants, such as, for example, magnesium stearate, stearic acid, talc, bentonite, contributing to the collapse of substances such as, for example, starch or cross crosslinked polyvinylpyrrolidone, binders such as, for example, starch, gelatin or linear polyvinylpyrrolidone, and dry binders, such as, for example, microcrystalline cellulose.

The active substance may be present in the preparations in a mixture with synergists or other active substances active against pathogenic endoparasites. Such active substances are, for example, L-2,3,5,6-tetrahydro-6-phenyl-imidazothiazole, benzimidazolecarbamate, Pyrantel.

Ready for use drugs saaty, which are diluted before use contain the active substance in concentrations from 0.5 to 90 wt.%, preferably 5 to 50 wt.%.

In General, appeared to be preferential to give the proposed tool in amounts from about 10 to 100 mg of active substance per 1 kg of body weight per day to achieve effective results. Preferably using a mixture of active substances in quantities of 10 - 50 1 mg per kg of body weight.

The following examples explain the invention and its positive effect.

In these examples have the following endoparasiticides tools:

The tool is A (known).

A preparation containing as an active substance depsipeptide above formula (II), i.e. cyclo-(MeLeu-D-Lac-Me-Leu-D-PhLac-Me - Leu-D-Lac-MeLeu-D-PhLac) - where MeLeu means N-methyl-L-leucine, D-Lac - D-lactic acid, and F-PhLac - D -- phenylalanyl acid.

Tool (known).

A preparation containing as an active substance 2-(cyclohexylcarbonyl)-1,2,3,6,7,11 b-hexahydro-4H-pyrazino[2,1-a] ISO - quinoline-4-one.

Tool (known).

A preparation containing as an active substance 2-(cyclohexylcarbonyl)-2,3,6,7,8,12 b-hexahydropyrazino[2,1 - a] [2] benzazepin-4-(1H)-he.

The medium is rmula (II), where Z denotes morpholinyl, i.e. cyclo-(MeLeu-D-Lac-MeLeu-D-p-MorPhLac-MeLeu-D-Lac-MeLeu-D-p-MorPhLac)-, and MeLeu, D-Lac or D-PhLac have the above significance, and D-p-Mor-Phlac means D -- morpholino-phenylalanyl acid.

The tool I (according to the invention).

A preparation containing as active substances cyclo-(MeLeu-D-Lac-MeLeu-D-PhLac-MeLeu-D-Lac-MeLeu-D-PhLac) - where MeLeu, D-Lac or D-PhLac have the above significance, and 2-(cyclohexylcarbonyl)-1,2,3,6,7,11 b-hexahydro-4H-pyrazino[2,1 - a]ISO-quinoline-4-one mass ratio of 1:1.

Tool II (according to the invention).

A preparation containing as active substances cyclo-(MeLeu-D-Lac-MeLeu-D-PhLac-MeLeu-D-Lac-MeLeu-D-PhLac) - where MeLeu, D-Lac or D-PhLac have the above significance, and 2-(cyclohexylcarbonyl)-2,3,6,7,8,12 b-hexahydro-pyrazino[2,1 - a][2]benzazepin-4-(1H)-he mass ratio of 1:1.

Tool III (according to the invention).

A preparation containing as active substances cyclo-(MeLeu-D-Lac-MeLeu-D-p-MorPhLac-MeLeu-D-Lac-MeLeu-D-p-PhLac) - where MeLeu, D-Lac or D-p-MorPhLac have the above significance, and 2-(cyclohexylcarbonyl)-1,2,3,6,7,11 b-hexahydro-4H-pyrazino[2,1 - a]ISO-quinoline-4-one mass ratio of 1:1.

Tool IV (according to the invention).

A preparation containing as active substances cyclo-(MeLeu-D-Lac-MeLeu-D-p-MorPhLac the draw-pyrazino[2,1 - a][2]benzazepin-4-(1H)-he mass ratio of 1:1.

Example 1. The test nematodes in vivo Ancylostoma caninum in dogs.

Puppies short-legged hound infect ancylostomidae species Ancylostoma caninum. To infect dogs orally give A. caninum in 250 L3-larvae.

After prepatent period (or if there are steps larvae during prepatent period) the above remedies are given orally in gelatin capsules.

Activity funds is determined by two methods.

1. Counting spin-off together with the dung eggs of helminths before giving funds and after their testimony.

2. Determining the percentage of activity in the critical test by the formula:

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In table. 1 shows the effective dose means (mg/kg), which provides 100% activity by both methods for determining the activity.

Comparison of the results of experiments 1 - 3, 5, 6, and 1, 2, 4 and 7, 8 demonstrates the synergies achieved by the proposed means I - IV.

Example 2. The test nematodes in vivo Ancylostoma tubaeforme in cats.

Cats infect ancylostomidae species Ancylostoma tubaeforme. To infect cats orally give A. tubaeforme in the form of 250 L3-larvae or through the skin in the form of 500 L3-larvae.

After prepatent period (and the new capsules.

Activity funds is determined by two methods.

1. Counting spin-off together with the dung eggs of helminths before giving funds and after their testimony.

2. Determining the percentage of activity in the critical test by the formula:

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In table. 2 shows the effective dose means (mg/kg), which provides 100% activity by both methods for determining the activity.

Comparison of the results of experiments 1 - 3, 5, 6, and 1, 2, 4 and 7, 8 demonstrates the synergies achieved by the proposed means I - IV.

1. Endoparasiticides tool containing cyclic depsipeptide consisting of amino acids and hydroxycarbonic acids as ring links and 6 to 30 ring atoms, or an optical isomer or racemate, characterized in that it further comprises 2-(cyclohexylcarbonyl)-1,2,3,6,7,11 b-hexahydro-4H-pyrazino[2,1-a]isoquinoline-4-one or 2-(cyclohexylcarbonyl)-2,3,6,7,8,12 b-hexahydropyrazino[2,1-a][2]-benzazepin-4(1H)-he.

2. Means under item 1, characterized in that the cyclic depsipeptide and specified derivative of athinaikon or derived benzazepine taken in a weight ratio of from 1:1 to 10:1, preferably 1:1oC 2:1.

3. Tool for PP.1 and 2, from the where R1is hydrogen, unbranched or branched alkyl with 2 to 8 carbon atoms, hydroxyalkyl, alkanoyloxy, alkoxyalkyl, aryloxyalkyl, mercaptoethyl, alkylthiomethyl, alkylsulfonates, alkylsulfonates, carboxyethyl, alkoxycarbonylmethyl, allamoxicillinpills, carbamoylethyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, guanidinate, unsubstituted or substituted by one or two residues benzyloxycarbonyl or 1 to 4 alkyl residues, alkoxycarbonylmethyl, 9-fluorenylmethoxycarbonyloxy, alkenyl, cycloalkyl, cycloalkenyl, and unsubstituted or substituted arylalkyl, and as Vice can be called halogen, hydroxyl, alkyl, alkoxy;

R3and R5independently of one another denote hydrogen, an unbranched or branched alkyl with 1 to 8 carbon atoms, hydroxyalkyl, alkanoyloxy, alkoxyalkyl, aryloxyalkyl, mercaptoethyl, alkylthiomethyl, alkylsulfonates, alkylsulfonates, carboxyethyl, alkoxycarbonylmethyl, allamoxicillinpills, carbamoylethyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, guanidinate, unsubstituted or substituted by one or two residues benzyloxycarbonyl loukil, cycloalkyl, and unsubstituted or substituted arylalkyl, and as Vice can be called halogen, hydroxyl, alkyl, alkoxy;

R2, R4and R6independently of one another denote hydrogen, an unbranched or branched alkyl with 1 to 11 carbon atoms, hydroxyalkyl, alkanoyloxy, alkoxyalkyl, aryloxyalkyl, alkylthiomethyl, alkylsulfonates, alkylsulfonates, carboxyethyl, alkoxycarbonylmethyl, allamoxicillinpills, carbamoylethyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylmethyl, alkenyl, cycloalkyl, cycloalkenyl, and unsubstituted or substituted aryl or arylalkyl, and as Vice can be called halogen, hydroxyl, alkyl, alkoxy,

or an optical isomer or racemate.

4. Tool for PP.1 and 2, characterized in that it contains as cyclic depsipeptide compound of formula II

< / BR>
or an optical isomer or racemate.

5. Tool for PP.1 and 2, characterized in that it contains as cyclic depsipeptide compound of formula III

< / BR>
where Z - N-morpholinyl, nitro, amino, mono - or dimethylamino,

or its optical isomer or the Chida compound of formula IV

< / BR>
where R7, R8, R9, R10independently of one another denote hydrogen, alkyl with 1 to 10 carbon atoms or aryl, in particular phenyl, unsubstituted or substituted by hydroxyl, alkoxyl with 1 to 10 carbon atoms or halogen,

or an optical isomer or racemate.

7. Tool for PP.1 and 2, characterized in that it contains as cyclic depsipeptide compound of General formula V

< / BR>
where R11, R14, R17and R20independently of one another denote alkyl with 1 to 8 carbon atoms, halogenated with 1 to 8 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, aralkyl, aryl;

R13, R16, R19and R22independently of one another denote hydrogen or an unbranched or branched alkyl with 1 to 8 carbon atoms, unsubstituted or substituted by a residue from the group comprising hydroxyl, alkoxy with 1 to 4 carbon atoms, carboxyl, carboxyamide, imidazolyl, indolyl, guanidino, mercaptopropyl, alkylthio with 1 to 4 carbon atoms, and aryl or aralkyl, which may be substituted with halogen, hydroxyl, alkyl with 1 to 4 carbon atoms, alkoxyl with 1 to 4 carbon atoms;

R15, R18, R21and R12independently each is l 3 - 7 carbon atoms which may be substituted by a residue from the group comprising hydroxyl, alkoxy with 1 to 4 carbon atoms, carboxyl, carbamid, imidazolyl, indolyl, guanidino, mercaptopropyl, alkylthio with 1 to 4 carbon atoms, and aryl or aralkyl, which may be substituted with halogen, hydroxyl, alkyl with 1 to 4 carbon atoms, alkoxyl with 1 to 4 carbon atoms,

or an optical isomer or racemate.

 

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The invention relates to the compound of formula (I):

< / BR>
where

Ar is chosen from the group including

(a) phenyl, naphthyl and diphenyl, each of which optionally contains from one to three substituents selected from the group including:

C1-4alkyl, C1-4halogenated, C1-4hydroxyalkyl, C1-4alkoxy, C1-4halogenoalkane, C2-4alkoxyalkane, C1-4alkylthio, hydroxy, halogen, cyano, amino, C1-4alkylamino, di (C2-8) alkylamino, C2-6alkanolamine, carboxy, C2-6alkoxycarbonyl, phenyl, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halogenoalkane, cyano group or halogen, phenoxy, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halogenoalkane, cyano and halogen; phenylthio group, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halog is selected from the group including C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halogenoalkane, cyano and halogen;

(b) furyl, benzo (b) furyl, thienyl, benzo/b/thienyl, pyridyl and chenail, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, halogen, C1-4alkoxy, hydroxy, phenyl, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halogenoalkane, cyano or halogen, phenoxy group, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halogenoalkane, cyano group and halogen; phenylthio group, optionally containing from one to three substituents selected from the group comprising C1-4alkyl, C1-4halogenated, C1-4alkoxy, C1-4halogenoalkane, cyano and halogen

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< / BR>
in which

R1is a hydrogen atom;

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R3is a hydrogen atom or halogen;

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