PL160791B1 - Fungicide of synergetic action - Google Patents

Abstract

PURPOSE:To obtain the subject composition, containing a thiazole derivative and acylalanine-based germicide as active ingredients and having both preventive and treating effects on a wide range of plant disease injuries and wide application range with excellent controlling effects even on chemical-resistant germs and long residual effectiveness. CONSTITUTION:A germicidal composition containing (A) a compound expressed by the formula (R<1> and R<2> are H or lower alkyl; R<3> is alkyl, alkenyl, phenyl, furyl or thienyl), e.g., 2-(2,4-dimethylthiazol-5-ylcarbonylamino)-4-methyl-3-penten- enitrile, and (B) an acylalanine-based germicide, e.g., N-(2,6-dimethylphenyl)-N-(2'- methoxyacetyl)-alanine methyl ester, having controlling action on disease injuries caused by oomycetes at (1:0.1)-(1:10), preferably (1:0.5)-(1:5) ratio of the components (A):(B). The above-mentioned composition has ultralow toxicity to warm-blooded animals or fishes without exhibiting phytotoxicity to cultivated plants.

Description

The subject of the invention is a fungicide with a synergistic effect, used in particular in agriculture and horticulture and containing as an active ingredient a new amide derivative of general formula I, in which one of the symbols Y and X represents a sulfur atom and the other represents a carbon atom, Z represents a nitrile group or thioamide, each R ¹ and R 2 is a hydrogen atom, a halogen atom, an alkyl group of 1-6 carbon atoms, a halomethyl group or a phenyl group, and R3 is an alkenyl group of 2-6 carbon atoms, a haloalkenyl group of 2-4 carbon atoms, furyl group, thienyl group, alkoxy group with 1-4 carbon atoms, alkylthio group with 1-4 carbon atoms, alkynyloxy group with 3-5 carbon atoms, alkynylthio group with 3-5 carbon atoms, pyrazolyl group, or unsubstituted or halogen-substituted phenyl group as the first active ingredient and as the second ingredient tetrachloroisophthalonitrile, the content of active ingredients being 0.5-90% by weight and the active ingredients of the first and the other are in a ratio of 1: 1 to 1:30.

Until now, compounds of various chemical structures have been used as agricultural and horticultural fungicides. They contributed to the control of plant diseases and consequently to the development of agriculture. But these traditional chemical fungicides have not been proven to be sufficiently destructive and safe. For example, some dithiocarbamate fungicides such as zinc ethylene bis (dithiocarbamate) (zineb), manganese ethylene bis (maneb) dithiocarbamate (maneb), manganese ethylene bis (dithiocarbamate) and zinc ethylene bis (dithiocarbamate) and bis (mankisethyl) Diazine dithiocarbamate (polycarbamate), N-haloalkyl thioimide fungicides such as N-trichloromethylthio-4-cyclohexane-1,2-dicarbonimide (captan), Nr, 122 ', 2'-tetrachloroethylii-4-cyclohexane-1,2 (captafol) and N-triahloromethylthiophthalimide (folpet), inorganic copper fungicides such as cupric sulfate, basic cupric sulfate, basic cupric chloride and cupric hydroxide, tetrachloroisophthalonitrile (TPN) and 3ahloro-N- (3-chloro-3-triflate) -pyridyl) -2,16-dinitro-4-toyfluooomethylaniline (dichlofluanide) show outstanding efficacy against plant diseases such as fruit trees and vegetables and are widely used as agricultural and horticultural fungicides. However, the above-mentioned chemical compounds mainly show healing properties. Therefore, they have the serious drawback that when a plant disease occurs, these chemicals are not expected to be sufficiently effective. When the use of chemicals to control plant diseases is contemplated in a given situation, the compounds are sprayed to a greater or lesser extent after the onset of plant disease symptoms, and therefore complete disease control is difficult to expect.

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Moreover, the concentrations of these compounds in which they exhibit control activity are very high to be safe for use, and some of these chemicals have significant toxicity to fish.

In order to eliminate the above-mentioned inconveniences, extensive research was undertaken to find new killers. For example, acylalanine fungicides such as N- (2,6-dimethylphenyl) -N- (2'-methoxyacetyl) alanine (metalaxyl) methyl ester, N- (2,6-dimethylphenyl) -N- (2- furoyl) alanine (furalaxyl), N- (2,6 dimethylphenyl) -N-phenylacetyl / alanine (benalaxyl) methyl ester, (2-chloro) -N-2,6-dimethylphenyl) -N (tetrahydro-2-keto-3 -furanyl) acetamide (ofurace) and 2-methoxy-N- (2,6-dimethylphenyl) -N- (2-ketolι-3-oxazoIldinyl-3) acetamide (oxadixyl) as plant disease control agents caused by Oomycetes, which also have excellent healing action and has entered into practical application all over the world. But it has already been found that strains resistant to these chemicals have emerged and their damaging effects have decreased as a result.

Many active benzylamide compounds have been invented and used as herbicides or fungicides. For example, known substituted benzamide derivatives include ethyl N-benzoyl-N- (3,4-dichlorophenyl) -2-aminopropionate (benzylpropethyl) as a herbicide and N- (3-isopropoxyphenyl) -2-methylbenzamide (mepronil) as a fungicide.

Great Britain Patent Specifications No. 2,094,786, No. 2,095,237 and No. 2,107,308 disclose a herbicide and fungicide containing a substituted benzylamide derivative containing a 4-pyridylcarbonyl, 2-furylcarbonyl, 2-thienylcarbonyl or 2-benzofurylcarbonyl group, but are phytotoxic to crops. still a problem.

The object of the present invention was to obtain a composition free from the above-mentioned drawbacks of the known compounds and having excellent properties as an agricultural and horticultural fungicide.

To achieve this goal, extensive work has been done on acylamide derivatives and it has been found that amide derivatives having a thiazole or isothiazole ring have a biological effect that could not be predicted from the above-mentioned compounds and an excellent action against a wide range of plant diseases, and that especially those amide derivatives have both preventive and healing effects in the control of various crops such as potato blight and powdery mildew.

More particularly, the invention relates to a fungicide containing the novel compound which has a preventive and curative effect on a wide range of plant diseases such as fruit tree diseases and vegetables, has an excellent killing effect on resistant fungi, has a wide range of utility and has a long residual effect, has no phytotoxicity to crops and has a very low toxicity to warm-blooded animals and fish, in combination with tetrachloroisophthalonitrile.

The new amide derivatives are represented by the general formula 1, in which all symbols have the above meanings.

In the amide derivative of general formula 1, examples of the alkyl group for R ¹ and R ² are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, t-butyl, n-pentyl, and n-hexyl. Examples of a chloromethyl group are chloromethyl and trifluoromethyl. An alkenyl group R ³ is, for example, vinyl, allyl, propen-1-yl, 2-methylpropen-1-yl, 1-methyl-propen-1-yl, 1-ad-dimethyl-propen-1-yl,

2-ethyl-propen-1-yl or 2-m-propyl-propen-1-yl. A haloalkenyl group is for example

2-chloroethenyl, 2-chloropropen-1-yl or 1-methyl-2-chloropropen-1-yl. Examples of an alkoxy group are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and t-butoxy. Examples of alkylthio groups are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, Il-tert-butylthio and t-butylthio. Exemplary alkynyloxy groups are propen-2-yloxy, 3-methylpropin-2-yloxy and 3-ethylpropin-2-yloxy. Examples of alkynylthio groups are propyne-2-ylthio, 3-methylpropyn-2-ylthio, 3-ethyl-opropin-2-ylthio. Halogen atoms can be, for example, fluorine, chlorine, bromine or iodine.

The compound of formula I is particularly effective against late blight and powdery mildew of various crops caused by Oomycetes. The main diseases it fights are plague

160 791 potato on potatoes (Phytophtora infestans), potato blight on tomatoes (Phytophthora infestans), blackening of tobacco stalks (Phytopthtora nicotiana var. Nicotiana), reddening of the core of strawberries (Phytophtora sp.), Phytophthora soybean root and stalk phytophthora var. ), grape mildew (Plasmopara viticola), cucumber mildew (Pseudopenospora cubensis), hop mildew (Pseudoperonospora humuli), spinach mildew (Peronospora spinaciae) and rot or blight of various crops caused by aphanomyces, Pythium etc. very low phytotoxicity when applied to crops, which can be seen with other amide derivatives.

The compositions according to the invention are used in suitable form for seed coating, foliar spraying, soil treatment, etc. They show a sufficient effectiveness when used in conventional methods. The dose of the compounds employed and the concentration at which the agent is applied may vary depending on the crop and the disease treated, the degree of disease onset, the formulation in which the compound is applied, the mode of application, and various environmental circumstances. When it is sprayed, a suitable amount of active ingredients is 50-5000 g / ha, preferably 100-2000 g / ha. When the formulation is in the form of a wettable powder or an emulsifiable concentrate it is diluted with water and sprayed on - the dilution ratio is preferably 200 to 100,000, preferably 500-5,000.

The agent of the invention can be used as such, but preferably in the form of a composition with a carrier as well as with a solid or liquid diluent. A carrier as used herein is a synthetic or natural inorganic or organic substance which is included to assist the entry of the active ingredients to the site to be treated and to facilitate storage, transport and handling of the compounds as an active ingredient.

Suitable solid carriers include, for example, clays such as montmorillonite and kaolinite, inorganic substances such as diatomaceous earth, terra alba, talc, vermiculite, gypsum, calcium carbonate, silica gel and ammonium sulphate, vegetable organic substances such as soybean meal, sawdust, wheat flour and urea.

Suitable liquid carriers include, for example, aromatic hydrocarbons such as toluene, xylene and cumene, paraffinic hydrocarbons such as kerosene and mineral oils, halogenated hydrocarbons such as carbon tetrachloride, chloroform and dichloroethane, ketones such as acetone and methyl methyl ketone. ethyl, ethers such as dioxane and tetrahydrofuran, alcohols such as methanol, ethanol, propanol and ethylene glycol, dimethylformamide, dimethyl sulfoxide, and water.

In order to increase the effectiveness of the compositions according to the invention, the excipients described below can be used individually or in a composition depending on the type of preparation, the application situation, etc.

For the purposes of emulsifying, dispersing, spraying, wetting, combining and fixing, for example, anionic surfactants such as lignin sulfonates, alkylbenzene sulfonates, salts of alkyl sulfonates, polyoxyalkylene alkyl sulfates and polyoxyalkylene alkyl ester, polyalkyl ethoxyalkyl ester salts, nonionic polyalkylene alkylene ethoxyalkyl surfactants may be used; polyoxyalkylenealkylamines, polyoxyalkylenealkylamides, polyoxyalkylenealkylthioethers, polyoxyalkylene fatty acid esters, glycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and propylene / polyoxyethylene block polymers, calcium and stearate lubricants; stabilizers such as propyl hydrogen phosphate and methyl cellulose, carboxymethyl cellulose, casein, and acacia. These ingredients are not limited to the specific examples given above.

Typically, the amount of active ingredients of the agent according to the invention is 0.5 to 20% by weight for dusts, 5 to 20% by weight for emulsifiable concentrates, 10 to 90% by weight for wettable powders, 0.1 to 20% by weight for granules and 10 to 90% by weight. % by weight for liquid agents. The amount of carrier is usually 50-99% by weight for dusts, 60-95% by weight for emulsifiable concentrates, 10-90% by weight for wettable powders, 80-90% by weight for granules and 10-90% by weight for liquid agents. The amount of excipient is usually 0.1-20% by weight of dusts, 1-20% by weight for elution concentrates, 0.1-20% by weight for wettable powders, 0.1-20% by weight for granules and 0.1-20% by weight for granules. % by weight for liquid agents.

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The composition of the invention has both preventive and curative activity against a wide range of diseases of fruit trees and vegetables, and shows excellent activity against those plant diseases in which the pathogenic fungus has acquired resistance against traditional fungicidal compounds. Moreover, the agent according to the invention has a sufficiently long residual action and is not phytotoxic. It also has remarkably low toxicity to warm-blooded animals and fish.

In the form of an agro-horticultural fungicide, the composition according to the invention shows activity against a wide range of plant diseases. Examples of plant diseases against which the agent of the invention has an excellent effect are bitter rot (Glomerella cingulata), anthracnose (Elsinoe ampelina), gray mold (Uncinula necator), rust (Phacospora ampelopsidis) and grape downy mildew (Plasmopara viticola), grape mildew (Gymnospora). yemadae), alternaria leaf blotch (Alternaria mali), fruit blotch (Mycosphaerella pomi), scab (Venturia inaequalid) and mildew (Podosphaera leucotricha) apple, anthracnose (Colletotrichum lagenarium), gray mold (Sperehaerothela malica). , powdery mildew (Pseudoperonospora cubensis), phytophthora (Phytophthora melonis), scab (Clandosporium cucumerinum) and bacterial blotch (Pseudomonas lachrymans) of pumpkin, dry spot (Altenaria solani), leaf roll (Cladosporium, fulvica caps) Phytophthora infestans) and tomato mildew (Erysiphe cichoracearum), alternariosis (Alte rnaria japonica), white spot (Cerosporella brassicae) and mildew, rust (Puccinia alli) and mildew (Peronospora destructor) of green onions, spinach, scab (Elsinoe glycinae), red spot (Cercospora morikamniakii) ) soybeans, anthracnose (Colletotrichum lindemuthianum) and rust (Uromnyces appendiculatus) beans, powdery mildew (Peronospora vicinae) field beans, blackening of peduncles (Phytophthora cinotians var. nicotiana) of tobacco, dry spot (Alternaria solani) and potato blight (Phytophthora infestans) of potatoes, downy mildew (Pseudoperonospora humuli) of hops, scrub root (Phytophthora cinnamoni) pineapple, blight of green pepper (Phytophthora humakici) and red pepper blight (Phytophthora humuli) core (Phytophthora fragaria) of strawberries, gray mold (Borytis cinerea) sclerosis disease (Sclerotonia sclerotiorum) and rot of various crops caused by Pythium, etc.

The compositions according to the invention may be used or formulated together with other agriculturally acceptable chemicals, such as fungicides, insecticides, plant growth regulators or fertilizers. The following examples illustrate the effectiveness of the novel compounds in admixture with known compounds as agricultural-horticultural fungicides of the invention. The compounds used in the examples are numbered as given in Table 4 and A is tetrachloroisophthalonitrile (TPN).

Example 1. Tests for controlling powdery mildew on cucumbers (healing effect and residual effect).

Pseudoperonospora cebunis was taken from an amount of a lesion cucumber (cucumber variety "Sagami Hanjiro, third major leaf stage) grown in pots in a greenhouse, and spore suspension of the fungus was prepared using ionized water. The spore suspension was contaminated by spraying the cucumber plant. The contaminated plant pots were kept for 24 hours in a greenhouse and the fixed concentration agent (prepared by preparation of a wettable powder and diluted to a predetermined concentration) was sprayed at a dose of 50 ml into 3 pots using a sprayer (1.0 kg / cm ² ) and air dried. The pots were then transferred to a greenhouse at 18-27 ° C and the lesions were assessed 10 and 18 days later. The results are presented in Table 1.

Assessment standards and disease index data were calculated as shown below.

The proportions of the lesion area were observed and evaluated for each leaf and the disease severity index (disease index) was determined. For each study area, the lesion index was calculated according to the following equation:

todeks ^choro by = ⁴ⁿ⁴ + ³ⁿ³ + ^2nz + ^ ⁿⁱ + ^Qno

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The following assessment standard has been adopted:

Disease index% damaged area 0%

1 ^ 5%

6-25%

26-50%

51% or more no - number of leaves with a disease index of 0; ni - number of leaves with a disease index of 1; n2 - number of leaves with a disease index of 2; n3 - number of leaves with a disease index of 3; n - number of leaves with a disease index of 4; N = n + n + n2 + n3 + ną.

Example II. Attempt to combat potato blight on tomatoes (healing effect and residual effect).

A zoospore suspension of Phytophthora infestans grown on a slice of potato for 7 days was made and spray-infected with tomatoes (cultivars "Sahaiichi, plant height 20 cm) grown in pots in the greenhouse. The pots with the contaminated plants were kept for 24 hours in a humid chamber at 16 ° C and the agent of a fixed concentration was sprayed (prepared by preparation of a wettable powder and diluted with water to the specified concentration) on the plants at a dose of 50 ml per 3 pots using a sprayer (1.0 kg / cm ² ) and then air-dried. The pots were placed in a greenhouse (temperature 10-20 ° C) and lesions were assessed 10 to 11 days later. The results are presented in Table 2.

Assessment standards and methods for calculating the disease index are shown in Example 1.

Example III. Attempt to combat leaf blotch on tomatoes.

The agent of a specified concentration (obtained by preparing a wettable powder) and diluting with water to a predetermined concentration) was sprayed on tomatoes (cultivars "Sekniichi ¹ *, plant height 20 cm) grown in pots in a greenhouse at a dose of 50 ml for 3 pots with a sprayer. (1.0 kg / cm ² ) and air dried. Alternatia solani spore suspension grown on PSA was infested with tomatoes in pots by spraying. The pots were transferred to a greenhouse (temperature 25-33 ° C) and the lesions were assessed 10 days later. The disease index was determined as in Example 1 and the results are shown in Table 3.

The novel compounds of the formula I show a preventive effect at significantly lower doses than the known killer agents. Accordingly, the compositions of the invention can show a good control effect even when applied to crops after being infected with these diseases. It can therefore significantly change the disease control system in agricultural and horticultural crops and obviously contributes to a great saving in labor for the producer. Since these agents have a good controlling effect when applied by watering the soil, they allow the agent to reach a part of the plant that could not be reached by spraying alone in order to protect it from disease.

The results given in Tables 1 and 2 show that the agro-horticultural fungicidal composition according to the invention shows a significantly superior effect at lower doses than with the known agents.

A synergistic effect is evident when the components are mixed and the residual effect is greatly enhanced.

The results presented in Table 3 show that the agro-horticultural fungicidal composition according to the invention has an excellent effect against a wide range of plant diseases caused by pathogenic fungi such as Alternaria solani, Pseudoperonospora cubenis and Colletotrichum lagenarium, which are taxonomically distant from each other. This means that in the cultivation of crops, the use of an agro-horticultural fungicide according to the invention can combat many simultaneous plant diseases which would be difficult to control simultaneously with known fungicidal compounds.

It should be especially taken into account that the agro-horticultural composition according to the invention shows a much better control effect at lower doses than when using a single compound. This clearly shows a synergistic effect as a result of the mixing of the two main active ingredients of the agent according to the invention.

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Table 1

Test with mildew on cucumbers

Test compound no Concentration active ingredient (ppm) Disease index 10 days later 18 days later 2 100 0 0.7 50 0 1.0 3 100 0 1.0 50 0 1.3 4 100 0 0.7 50 0 1.0 5 100 0 1.0 50 0 1.0 6 100 0 1.0 50 0 1.5 17 100 0 0.8 50 0 0.8 18 100 0 0.6 50 0 0.7 AND 500 3.0 3.1 2 + A 100 + 500 0 0 50 + 500 0 0 6 + A 100 + 500 0 0 50 + 500 0 0 17 + A 100 + 500 0 0 50 + 500 0 0 18 + A 100 + 500 0 0 50 + 500 0 0 Control sample - 3.7 3.7

A - tetrachloroisophthalomtrile

Table 2

Attempt to combat potato blight on tomatoes

Test compound no Concentration active ingredient (ppm) Disease index 10 days later 18 days later 2 100 0 0 50 0 0 6 100 0 0 50 0 0 12 100 0 0 50 0 0 13 100 0 0.6 50 0 0.9 50 100 0 1.0 50 0 1.0 54 100 0 1.0 50 0 1.8 6 + A 100 + 500 0 0 50 + 500 0 0 50 + A 100 + 500 0 0 50 + 500 0 0 2 + A 100 + 50 0 0 50 + 500 0 0 Control sample - 3.6 3.8

A - tetrachloroisophthalomtrile

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Table 3

Attempt to combat dry spot on tomatoes

Test compound no Concentration active ingredient (ppm) Disease index 2 100 2.6 3 100 3.0 4 100 3.1 6 100 3.0 12 100 2.7 18 100 2.9 AND 500 1.0 4 + A 100 + 500 0 6 + A 100 + 500 0 18 + A 100 + 500 0

A - tetrachloroisophthalomtrile

The methods for the preparation of the new amide derivatives of general formula I used as active ingredients of the agent according to the invention are illustrated by the following synthetic examples.

Example IV. Synthesis of N- (alpha-cyanofurfuryl) -2-chloro-4-methylthiazole-5-carboxamide (compound No. 37).

8.8 g of 2-chloro-4-methylthiazole-5-carboxylic acid were suspended in 7 ml of thionyl chloride and 1 drop of Ν, Ν-dimethylformamide was added. The mixture was heated under reflux for 1 hour, then excess thionyl chloride was evaporated under reduced pressure. 10 ml of benzene was added and the mixture was evaporated under reduced pressure. This procedure was repeated three times to obtain 9.7 g of 2-chloro-4-methyloylzole-5-carboxylic acid chloride, which was used in the following reaction without purification.

2-Chloro-4-methyltlazole-5-carboxylic acid chloride (1.6 g) was suspended in 30 ml of pyridine, and 1.3 g of alpha-furylZ-alpha-aminoacetonkryl as the hydrochloride was added. The mixture was stirred at room temperature for 2 hours. After the reaction, the reaction mixture was filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography. Elution with the haxane with ethyl acetate gave 1.79 g (75.2% yield) of the desired N- (alpha-cyanofurfuryl) -2-chloro-4-methyl-thiazole-5-carboxylic acid amide.

Example 5. Synthesis of N- (alpha-cyanofurfuryl) -2,4-d-1-methylylazole-5-carboxylic acid amide (compound No. 2).

9.30 g of k ^^^ in 2,4-dimethylthiazole-5-carboxylic acid was suspended in 90 ml of toluene and 15.0 g of phosphorus pentachloride were added. The mixture was refluxed for 1 hour. The obtained phosphorus oxychloride and toluene were evaporated under reduced pressure to give the acid chloride

2,4-dimethylthiazole-5-carboxylic acid which was used in the following reaction without purification.

6.2 g of alpha- (2-furyl) -alpha-aminoacetonitrile and 6.0 g of triethylamine were dissolved in 120 ml of ethyl acetate, and 2,4-dimethylthiazole-5-carboxylic acid chloride was added dropwise to the solution while stirring. The mixture was stirred at room temperature for 1 hour. 150 ml of water was added and the precipitated triethylamine hydrochloride was dissolved. The ethyl acetate layer was separated, washed with water, dried over sodium sulfate. The dried ethyl acetate layer was distilled off under reduced pressure to remove the solvent. The residue was recrystallized from isopropyl ether to give 11.65 g (90.0% yield) of the desired N- (alphacyanofurfuryl) -2,4-dimethylazole-5-carboxylic acid amide.

Example VI. Synthesis of N- (alpha-cyanofurfuryl) -2,4-diethyliiazole-5-carboxylic acid amide (compound No. 12).

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The method of Example 5 reacted with 2,4-diethylthiazole-5-carboxylic acid and phosphorus pentachloride to give 2,4-diethylthiazole-5-carboxylic acid chloride quantitatively. The 2,4-diethylthiazole-5-carboxylic acid chloride was used in the following reaction without purification.

2.80 g of alpha - 2-furyl) -alpha-aminoacetonitrile and 6.0 g ^of triethylamine were dissolved in 50 ml of ethyl acetate was added dropwise 2.1 g of 2,4-dimethylthiazol-5-carboxylic acid. The mixture was stirred at room temperature for 1 hour. 150 ml of water was added and the precipitated triethylamine hydrochloride was dissolved. The ethyl acetate layer was separated, washed with water and dried over sodium sulfate. The dried ethyl acetate layer was evaporated under reduced pressure to remove the solvent. The residue was crystallized with n-hexane to give 2.41 g (yield 80.0% - the desired N- (αUa-cyanofurfuryl-f2,4-difmethylthiazole-5-carboxylic acid amide).

Example VII. Synthesis of N- (alpha-cylanoaurfuryl-f2,4-dimethylthiazoI-5-carbOfxylic acid amide (compound No. 2- by using mixed acid anhydride.

4.71 g of 2,4-dimethylthiazole-5-carboxylic acid was suspended in 70 ml of tetrahychrofuran and 6.67 g of triethylamine was added. The mixture was stirred. While cooling to -10 to -5 ° C, 4.10 g of n-butyl chloroformate was added and the mixture was stirred at this temperature for 30 minutes, and then 4.03 g of αlaa- (2-auryl) -alpha-aminoacetonitrile hydrochloride was added. . The mixture was stirred at room temperature for 5 hours and then allowed to stand overnight. The resulting precipitate was filtered off and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography. Elution with hexane / ethyl acetate afforded 4.20 g (53.6% yield - the desired Nf (alpha-furauryl) amide f2.4f-dimethylthiazole-5-carboxylic acid.

Example VIII. Synthesis of N- (alphacyanofurfuryl) f- _> 4-dimethylthiazoleOf5carboxylic acid amide (Compound No. 2- by CDI.

4.0 g of alpha- (2ffuryl-αlfa-αminoαcetonitrile hydrochloride and a mixture of 3.70 g of 50% aqueous NaOH solution and 50 ml of isopropyl ether were stirred at 40 ° C for 1 hour under nitrogen. The isopropyl ether layer was separated. 4.71 g of 2,4-dimethylthiazoI-5-carboxylic acid and 4.88 g of carbonyldiimidazole (CDI- in 50 ml of methylene chloride, while cooling on ice), was added dropwise alpha- (2-furyl) -alpha-aminoacetonitrile in isopropyl ether overnight. room temperature and distilled under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate, separated, washed with water and dried over sodium sulfate. The ethyl acetate layer was distilled under reduced pressure to remove the solvent. The residue was isolated from isopropyl ether to give 5.51. g (70.4% yield of - the desired N- (α-alpha-cyjaIiofurfuryl-2,4-dimethylthiazole-5-kαrboxyl amide).

Example IX. Synthesis of N- (alpha-cilanofurfuryl - 2,4-dimethylthiazoleO 5-carboxylic acid amide (Compound No. 2) by the DCC method.

3.0 g of alpha- (2-furyl-alpha-aminoacetonitrile hydrochloride) and a mixture of 70 g of 50% aqueous NaOH solution in 30 ml of methylene chloride was stirred at 40 ° C for 1 hour under nitrogen atmosphere. Then the methylene chloride layer was separated. while stirring, 2.50 g of 2,4-dimethylthiazole-5-kαrboxylic acid and 3,10g-dicyclohexylcarbodiimide (DCC- in 50 ml of methylene chloride, αlfαf (- furyl - αlfa-aminoαcetonitrile) were added dropwise with ice-cold water cooling for 1 hour. , the mixture was stirred with ice cooling, left overnight at room temperature and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, separated, washed with water and dried over sodium sulfate. The ethyl acetate layer was distilled under reduced pressure to remove the solvent. column chromatography on silica gel Eluting with hexane / ethyl acetate afforded 1.85 g (yield 47.3% of the desired N- (alpha-cyanofurfuryl) -, 4-dimethylthiazole-5-carboxylic acid.

Example X. Synthesis of Nf (alUa-cilanofurfuryl) -3- (methylisothiazole-4-carbOf xylic acid amide (Compound No. 32-.

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1.2 g of alpha- (2-furil) -alpha-arninoacetonitrile ketohydride in 10 ml of pyridine, and 1.1 g of 3-n-ethylisothiazok) f5 (carboxylic acid chloride) was added dropwise while stirring at room temperature. Pyridine was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, separated, washed with water and dried over sodium sulfate. The ethyl acetate layer was distilled under reduced pressure to remove the solvent. The residue was purified by column chromatography on silica gel. Elution with benzene / ethyl acetate gave 1.2 g (70.3% yield of the desired N (alpha (cyanofurfuryl-f3) (methylthiazole (4-carbo (xyl.

Example XI. Synthesis of the acid amide N ((alpha (CyanofurfuryIo- (3 (methylisothiazoIof5-carbO (xyl) (compound No. 34-.

5.0 g of alfaf (2-furyIo) -affafaminoacetonitl · yl hydrochloride dehydrochloride with sodium hydroxide in ethyl acetate as described in Example 6. 2.5 g of pyridine was added, followed by dropwise addition of an ethylacetate solution of 4.0 g of 3-methylisothiazolo (5-carboxylic acid chloride. After the addition, the mixture was stirred for 1 hour. The reaction mixture was washed with water, dilute hydrochloric acid, and dilute aqueous bicarbonate). Sodium sulfate and activated carbon were added to dehydrate and discolor the reaction mixture. The solvent was removed under reduced pressure and the residue was washed with diethyl ether to give 4.5 g (74% yield - the desired acid amide N ((al-cyanofurfuryl) f3 ( methylisophthiazolof5 (k-carboxylic.

Example XII. Synthesis of the acid amide Nf (f (Cyano-3-netylOf2fbutenyl-3-methylisothiazolOf

5-carboxylic acid (compound No. 36-.

To a mixture of 30 ml of water and 30 ml of diethyl ether were added 3 ml of 28% gaseous ammonia, -0 g of sodium cyanide, 4.5 g of ammonium chloride and 0.5 g of triethylbenzylammonium chloride and the mixture was cooled to 5 ° C. While the solution was stirred, 2.8 g of 3-methyl-2-butenal were added dropwise. After the dropwise addition, the mixture was continuously stirred at 15-20 ° C for 5 hours. The ether layer was separated, washed with water and dried over sodium sulfate to give an ether solution of 1-cyanof3-methylph2-butenylamine. 1.0 g of triethylamine was added to the solution, and a solution of 1.1 g of 3-methylisothiazole carboxylic acid chloride in ethyl acetate was added dropwise with stirring at room temperature. After the addition was complete, the mixture was stirred for 1 hour, washed with water, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography. Elution with benzene / ethyl acetate gave 1.0g (63% yield - the desired N (f-cyano-3-netylO (2- (butenyl-f3f-methylisothi-zolph-carboxylic) amide) amide.

Example XIII. Synthesis of the amide Nf (alpha (Cyanobenzyl- (2 (methylisothiazolOf5-carbOf xyl) (compound No. 35-.

1.2 g of chlo) alpha-benzylc-flfa-aminoacetonitrile was suspended in 20 ml of ethyl acetate and 7 ml of 10% NaOH was added dropwise at a temperature below 10 ° C. The mixture was stirred at this temperature for 10 minutes, and then a solution of 0.8 g of 3-methylisothiazoleOf5 (carboxylic acid chloride in ethyl acetate was added dropwise at 0 ° C. After completion of the dropwise addition, the mixture was stirred for 30 minutes. The ethyl acetate layer was washed with water and the solvent was distilled off). The residue was purified by column chromatography on silica gel Elution with benzene / ethyl acetate gave 1.0g (77% yield - the desired Nf (alpha-cyanobenzyl-f3-methylisothiazole-5-carboxylic acid amide).

Example XIV. Synthesis of the amide Nf [-lfaffinof (1-pyrazoyl) methyl] -3-methyl-isophthiazolph-5-carboxylic acid (compound No. 46-.

0.7 g of Nf acid amide (cyanonethyl- (3-methylisothiazole (carboxylic acid) dissolved in 30 ml of ethyl acetate. 0.8 g of bromine was added and the mixture was stirred for 30 minutes, then cooled in an ice bath. A mixture of 0.3 was added to the reaction mixture while stirring. g of pyrazole, 1.0 g of triethylmine and 5 ml of ethyl acetate. The mixture was stirred for 30 minutes. The ethyl acetate layer was washed with water and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with benzenene / ethyl acetate. The result was 0.75 g ( yield 78%) of the desired bis-amide N- [alpha-cyanOf alpha (1-pyrazolyl) methyl] -3-methylisothiazole-5-carboxyl.

Example XV. Synthesis of N- [alpha-cyano-alpha- (1-pyrazolyl / methyl] 2,4-dimethylthiazole-5-carboxylic acid amide (compound No. 38).

(1) Synthesis of N-cyanomethyl-2,4-dimethyl-thiazole-5-carboxylic acid amide.

A mixture of 10 g of 2,4-dimethylisothiazole-5-carboxylic acid, 13.6 g of thionyl chloride and ml of toluene was cooled with ice, and 8.4 g of Ν, Ν-dimethylformamide was added with stirring. The mixture was stirred for 3 hours at 3-5 ° C and then for 1 hour at 20 ° C and 200 ml of toluene and 37 g of triethylamine were added. Acetyl acetate solution of aminoacetonitrile with ethyl acetate and gradually added NaOH to the mixture cooled with ice. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried, and the solvent was distilled off under reduced pressure to remove the solvent. The residue was purified by column chromatography with silica gel eluting with hexane / ethyl acetate. 6.6 g (63% yield) of N-cyanomethyl-2,4-diethylthiazole-5-carboxylic acid amide were obtained.

(2) Synthesis of N- [alpha-cyano-alpha- (1-pyrazolyl) methyl] 2,4-dimethylthiazole-5-carboxylic acid amide.

1.0 g of N-cyanomethyl-2,4-dimethylthiazole-5-carboxylic acid amide was dissolved in 30 ml of ethyl acetate. 0.3 ml of bromine was added and the mixture was refluxed until the dark brown color with bromine disappeared. The reaction mixture was cooled in an ice bath, and at this temperature 0.5 g of pyrazole, 2.0 g of triethylamine and 10 ml of ethyl acetate were added. The mixture was stirred at room temperature for 2 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexane / ethyl acetate. 0.74 g (54.9% yield) of the desired N- [alpha-cyano-alpha- (1-pyrazolyl / methyl] 2,4-dimethylthiazole-5-carboxylic acid amide was obtained.

Example XVI. Synthesis of N- (alpha-cyano-ethoxymethyl) -2,4-dimethylthiazole-5-carboxylic acid amide (compound No. 39).

1.0g of N-cyanomethyl-2,4-dimethylisothiazole-5-carboxylic acid amide was dissolved in 30 ml of ethyl acetate. 0.3 ml of bromine was added and the mixture was refluxed until the dark brown color of bromine disappeared. The reaction mixture was cooled in an ice bath, and at this temperature 1.0 g of ethanol, 2.0 g of triethylamine and 10 ml of ethyl acetate were added. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography eluting with hexane / ethyl acetate. 0.53 g (43.1% yield) of the desired N- (alpha-cyano-alpha-ethoxyethyl) -2,4-dimethylthiazole-5-carboxylic acid amide was obtained.

Example XVII. Synthesis of N - [(alpha-thiocarbamoyl) furfuryl] -3-methylisothiazole-5-carboxylic acid amide (Compound No. 47).

1.0 g of N- (alpha-cyanofurfuryl) -3-methylisothiazole-5-carboxylic acid amide was dissolved in 30 ml of tetrahydrofuran and 0.6 ml of triethylamine was added. While stirring at room temperature, hydrogen sulfide gas was introduced into the mixture. 5 hours later, the solvent was evaporated from the reaction mixture under reduced pressure. Water was added to the residue. The precipitated crystals were collected by filtration to obtain 1.1 g of the desired N - [(alpha-thiocarbamoyl) furfuryl] -3-methylisothiazole-5-carboxylic acid amide.

Typical examples of the new amide derivatives of general formula I used as one of the active ingredients of the agent according to the invention are shown in Table 4 below.

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Table 4

Relationship no group formula 11 R substituent ³ WITH . Melting point, ° C NMR (100 MHz, s) 1 2 3 4 5 6 1 pattern 2 pattern 4 CN Oil (CDCla) 2.72 (3H, s), 6.24-6.66 (3H, m), 7.34-7.49 (1H, m), 7.97 (1H, br d), J = 7Hz), 8.04 (lH.s) 2 pattern 3 pattern 4 CN 100.5-101.5 (CDCl) 2.61 (3H, s), 2.64 (3H, s), 6.34 (1H, d, J = 8.0Hz), 6.40 (1H, m), 6.58 (1H , m), 7.48 (1H, m), 7.96 (1H, d, J = 8.0Hz) 3 pattern 3 pattern 5 CN 99-100 (CDCU) 1.85 (6H, s), 2.71 (6H, s), 5.34 (1H, d, J = 8.0Hz), 5.68 (1H, t, J = 8.0Hz) . 6.16 (1H, d, J = 8.0Hz) 4 pattern 3 pattern 5 CN 115.5-118.5 (CDCla) 2.66 (6H, s), 6.42 (1H, d, J = 9.0 Hz), 6.98 (2H, m), 7.34 (1H, d, J = 8.0Hz) . 7.38 (1H, d. J = 9.0Hz) 5 pattern 3 pattern 7 CN 90 93 (CDCla) 2.60 (6H, s), 6.18 (1H, d, J = 9.0Hz), 6.68 (1H, d, J = 9.0Hz), 7.0-7.1 ( 1H, m), 7.28-7.44 (2H, m) 6 pattern 3 formula 8 CN 132-135 (CDCla) 2.61 (6H, s), 6.18 (1H, d, J = 9.0Hz), 6.81 (1H, d, J = 9.0Hz), 7.28-7.52 ( 5H, m) 7 pattern 9 pattern 4 CN Oil (CDCla) 2.72 (3H, s), 6.26 (1H, d, J = 8.0Hz), 6.36 (1H, m), 6.54 (broad d, J = 4Hz), 6, 95 (1H, d, J = 8.0Hz), 7.43 (1H, broad d, J = 4Hz), 8.65 (1H, s) 8 pattern 9 formula 8 CN Oil (CDCla) 2.62 (3H, s), 6.16 (1H, d, J = 8.0Hz), 7.2-7.5 (5H, m), 8.46 (1H, s) 9 pattern 10 pattern 4 CN 99-102 (CDCla) 1.40 (3H, t, J = 8Hz), 2.70 (3H, s), 3.00 (2H, q, J = 8Hz), 6.36 (1H, broad d, J = 8Hz ), 6.4-6.7 (2H, m), 6.78 (1H, br d, J = 8Hz), 7.42 (1H, m) 10 pattern 10 pattern 6 CN 90.5- 91.6 (CDCla) 1.34 (3H, t, J = 7Hz), 2.68 (3H, s), 2.98 (2H, q, J = 7Hz), 6.41 (1H, d, J = 8Hz) , 6.61 (1H, br d, J = 8Hz), 6.96-7.12 (1H, m), 7.23-7.48 (2H, m) 11 pattern 10 formula 8 CN Oil (CDCla) 1.36 (3H, t, J = 7Hz), 2.66 (3H, s), 2.96 (2H, q, J = 7Hz), 6.22 (1H, d, J = 8Hz) , 6.46 (IH, broad d, J = 8Hz), 7.12 ^ 7.60 (3H, m) 12 formula 11 pattern 4 CN 114.5-115.5 (CDCla) 1.30 (3H, t, J = 8Hz), 1.38 (3H, t, J = 8Hz), 2.98 (2H, q, J = 8Hz), 3.09 (2H, q, J = 8Hz), 6.28 (1H, d, J = 8Hz), 6.40 (1H, m), 6.56 (2H, m), 7.48 (1H, m) 13 formula 11 pattern 6 CN 117-118 (CDCla) 1.31 (3H, t, J = 8Hz), 1.39 (3H, t, J = 8Hz), 2.97 (2H, q, J = 8Hz), 3.05 (2H, q, J = 8Hz), 6.29 (1H, d, J = 9Hz), 6.74 (1H, br d, J = 9Hz), 7.00 (1H, m), 7.2-7.4 ( 2H, m) 14 formula 11 formula 8 CN 79- 81 (CDCla) 1.26 (3H, t, J = 8Hz), L34 (3H, t, J = 8Hz), 2.92 (2H, q, 3 j = ^), 3.0 (2H, q, 3 = 8Hz), 6.21 (1H, d, 3 = 8Hz), 6.67 (1H, d, J = 9Hz), 7.20-7.50 (5H, broad s) 15 pattern 12 pattern 4 CN Oil (CDCla) 1.02 (3H, t, J = 7Hz), 1.80 (2H, m, J = 7Hz), 2.68 (3H <s), 2.91 (2H, t, J = 7Hz) , 6.31 (IH, d, J = 8Hz), 6.42, 6.59, 7.47 (1H, m each), 6.80 (1H, broad d, J = 8Hz) 16 pattern 12 pattern 6 CN Oil (CDCla) 1.00 OH, t, J = 7 Hz), 1.78 (2H, m,

J = 7Hz), 2.66 (3H, s), 2.89 (2H, t, J = 7Hz), 6.41 (IH, d, J = 8Hz), 6.62 (1H, broad d, J = 8Hz), 7.0-7.4 (3H, m)

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1 2 3 4 5 6 17 pattern 13 pattern 4 CN Oil (CDCla) 1.30 (3H, t, J = 7Hz), 2.69 (3H, s), 3.47 (2H, q, J = 7Hz), 6.29 (1H, d, J = 8Hz) , 6.29-6.72 (3H, m), 7.28-7.71 (lH, m) 18 pattern 13 pattern 6 CN 124.5-125.8 (CDCla) 1.20 (3H, t, J = 8Hz), 2.67 (3H, s), 2.96 (2H, q, J = 8Hz), 6.53 (1H, d, J = 7Hz) , 7.00-7.72 (3H, m), 9.61 (1H, broad d, J = 7Hz) 19 pattern 13 formula 8 CN 111-112 (CDCU) 1.27 (3H, t, J = 7Hz), 2.67 (3H, s), 3.03 (2H, q, J = 7Hz), 6.22 (1H, d, J = 8Hz) , 6.66 (1H, br d, J = 8Hz), 7.20-7.64 (5H, s) twenty pattern 14 pattern 4 CN 117-118 (CDCU) 0.96 (3H, t, J = 8Hz), 1.74 (2H, m), J = 8Hz), 2.70 (3H, s), 3.02 (2H, t, J = 8Hz ), 6.32 (1H, d, J = 8Hz), 6.45, 6.60, 7.70 (1H, m each), 6.88 (1H, broad d, J = 8Hz) 21 pattern 14 pattern 6 CN 117.6-119 (CDCU) 0.96 (3H, t, J = 8Hz), 1.54 (2H, m, J = 8Hz), 2.68 (3H, s), 3.01 (2H, t, J = 8Hz) , 6.44 (1H, d, J = 8Hz), 6.90-7.50 (4H, m) 22 pattern 14 pattern 18 CN 93- 94 (CDCU) 0.93 (3H, t, J = 8Hz), 1.70 (2H, m, J = 8Hz), 2.66 (3H, s), 2.98 (2H, t, J = 8Hz) , 6.25 (1H, d, J = 9Hz), 6.84 (1H, broad t, J = 9Hz), 7.28-7.74 (5H, m) 23 pattern 15 pattern 4 CN 105-107 (CDCU) 2.77 (3H, s), 6.23 (1H, d, J = 8Hz), 6.45 (1H, m), 6.62 (1H, m), 6.93 (1H, broad d, J = 8Hz), 7.50 (1H, m) 24 pattern 15 pattern 6 CN Oil (CDCU) 2.76 (3H, s), 6.39 (1H, d, J = 8Hz), 6.90-7.13 (2H, m), 7.36-7.48 (2H, m) 25 pattern 16 pattern 4 CN 98.5- 99.0 (CDCU) 1.34 (3H, t, J = 8Hz), 3.20 (2H, q, J = 8Hz), 6.30 (1H, d, J = 8Hz), 6.42 (1H, m ), 6.60 (1H, m), 6.72 (1H, br d, J = 8Hz), 7.48 (1H, m), 7.74 (1H, s) 26 pattern 17 pattern 4 CN 147-151 (CDCU) 2.74 (3H, s), 6.26 (2H, d, J = 8Hz), 6.3-6.7 (4H, m), 7.3-7.5 (3H, m) , 7.8-7.9 (2H, m) 27 pattern 17 pattern 6 CN 162-163 (CDCU) 2.64 (3H, s), 6.26 (1H, d, J = 8Hz), 6.8 (1H, m), 7.1-7.3 (5H, m), 7.7 (2H, m), 9.24 (1H, broad d, J = 8Hz) 28 pattern 17 formula 8 CN 138-139 (CDCU) 2.73 (3H, s), 6.25 (1H, d, J = 8Hz), 6.66 (1H, broad d, J = 8Hz), 7.36-7.62 (8H, m ), 7.82-7.97 (2H, m) 29 pattern 18 pattern 4 CN 233.5-234.5 (CDCU) 2.72 (3H, s), 6.40 (1H, d, J = 8Hz), 6.45-6.68 (2H, m), 7.32-7.87 (6H, m) , 9.78 (1H, broad d, J = 8Hz) thirty pattern 18 pattern 6 CN 216.5-218.0 (CDCU) 2.73 (3H, s), 6.51 (1H, d, J = 7Hz), 6.83-7.79 (8H, m), 9.82 (1H, broad d, J = 7Hz ) 31 pattern 18 formula 8 CN 220.5-221.5 (CDCU) 2.70 (3H, s), 6.25 (1H, d, J = 7Hz), 7.04-7.74 (10H, m), 9.67 (1H, broad d, J = 7Hz ) 32 pattern 19 pattern 4 CN 126-127 (CDCU) 2.62 (3H, s), 6.26 (1H, d, J = 8Hz), 6.38 (lH, t, J = 2Hz), 6.54 (lH, d, J = 2Hz) , 7.44 (1H, d, J = 2Hz), 7.50 (1H, d, J = 8Hz), 9.00 (1H, s) 33 pattern 19 pattern 5 CN Oil (CDCU) 1.84 (6H, s), 2.68 (2H, s), 5.34 (1H, d, J = 8Hz), 5.70 (1H, t, J = 8Hz), 7.30 (1H, d, J = 8Hz), 9.08 (lH, s) 34 pattern 20 pattern 5 CN 136-137 (DMSO-de) 2.87 (1H, s), 6.44 (1H, d, J = 8Hz), 6.50 (1H, t, J = 2Hz), 6.62 (1H, d, J = 2Hz), 7.74 (1H, d, J = 2Hz), 7.76 (1H, s), 10.02 (1H, d, J = 8Hz) 35 pattern 20 formula 8 CN 1 ^ ^< ^^ 131 (DMSO-d6) 2.54 (3H, s), 6.40 (1H, broad), 7.4-7.7 (5H, m), 7.84 (1H, s), 10.0 (1H, broad) )

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1 2 3 4 5 6 36 pattern 20 pattern 5 CN 123-125 (DMSO-d6) 1.78 (6H, d, J = 2Hz), 2.48 (3H, s), 5.3-5.8 (2H, m), 7.74 (1H, s), 9 .58 (1H, d, J = 8Hz) 37 pattern 21 pattern 4 CN 90-91 (CDCl5) 2.55 (3H, s), 6.24 (1H, d, J = 8Hz), 6.55 (2H, m), 7.52 (1H, m), 8.06 (1H, d , J = 8Hz) 38 pattern 22 pattern 23 CN 140-141 (CDCl3) 2.67 (3H, s), 6.30-6.40 (1H, m), 7.20 (1H, d, J = 8Hz), 7.60-7.66 (1H, m) , 7.72-7.80 (1H, m), 8.30 (1H, d, J = 8Hz) ' 39 pattern 22 -OC2H3 CN 89- 90 (CDCls) 1.30 (3H, t, J = 7Hz), 2.70 (3H, s), 2.73 (3H, s), 3.71 (2H, q, J = 7Hz), 6.10 (1H, d, J = 10Hz), 6.95 (1H, d, J = 10Hz) 40 pattern 22 -OCHzC ^ CH CN Oil (CDCls) 2.25-2.59 (1H, m), 2.71 (6H, s), 4.31 (2H, d, J = 3Hz), 6.31 (1H, d, J = 9Hz) . 7.04 (1H, d, J = 9Hz) 41 pattern 22 -SC2H3 CN Oil (CDCls) 1.37 (3H, t, J = 8Hz), 2.68 (3H, s), 2.70 (3H, s), 2.87 (2H, q, J = 8Hz), 6.15 (1H, d, J = 9Hz), 6.96 (1H, d, J = 9Hz) 42 pattern 22 -OCsHz (n) CN Oil (CDCls) 0.93 (3H, t, J = 7Hz), 1.80 (2H, m), J = 7Hz), 2.68 (3H, s), 2.91 (2H, t, J = 7Hz ), 6.31 (1H, d, J - 8Hz), 6.42, 6.59, 7.47 (1H, m each), 6.80 (1H, broad d, J = 8Hz) 43 pattern 22 -OCH3 CN Oil (CDCl5) 2.66 (3H, s), 2.68 (3H, s), 3.38 (3H, s), 5.95 (1H, d, J = 9Hz), 7.08 (1H, d , J = 9Hz) 44 pattern 22 -SC3H7O) CN 105-106 ° C (CDCU) 1.36 (3H, d, J = 6Hz), 1.39 (3H, d, J = 6Hz), 2.65 (3H, s), 2.68 (3H, s), 3.25 (1H, m, J = 6Hz), 6.09 (1H, d, J = 9Hz), 7.03 (1H, broad d, J = 9Hz) 45 pattern 20 pattern 23 CN 134-136 (DMSO-de) 2.56 (3H, s), 6.40 (1H, t, J = 2Hz), 7.64 (1H, d, J = 8Hz), 7.70 (1H, d, J = 2Hz), 7.86 (lH, s), 7.94 (lH, d, J = 2Hz), I0.99 ((H, d, J = 8Hz) 46 pattern 19 pattern 23 CN 1 ^^ 178 (DMSO-de) 2.60 (3H, s), 6.40 (1H, t, J = 2 Hz), 7.60 (1H, d, J = 8 Hz), 7.66 (1H, d, J = 2Hz), 7.96 (lH, d, J = 2Hz), 9.62 ((H, s), 10.56 ((H, d, J = 8Hz) 47 pattern 20 pattern 4 39 163-167 (DMSO-d6) 2.48 (3H, s), 5.92 (1H, d, J = 7.5 Hz), 6.34-6.52 (2H, m), 7.62 (1H, s) , 7.87 (1H, s), 9.13 (1H, d, J = 7.5Hz), 9.54 (1H, s), 9.82 (1H, s) 48 pattern 22 pattern 4 39 96.5- 99.0 (DMSO-d6) 2.58 (3H, s), 2.63 (3H, s), 5.94 (1H, d, J = 8.5Hz), 6.41 (2H, s), 7.57 (1H, s), 8.16 (1H, d, J = 8.5Hz), 9.60 (1H, s), 9.98 (1H, s) 49 pattern 24 pattern 4 CN 129.5-130 (CDCls) 2.70 (3H, s), 4.9 (2H, s), 6.22 (1H, d, J = 8Hz), 6.32-6.64 (2H, m), 7.08 (1H, broad d, J = 8Hz), 7.40-7.48 (1H, m) 50 pattern 25 pattern 4 CN 118.0-119.0 (CDCls) 1.240 (6H, d, J = 7Hz), 2.63 (3H, s), 3.63 (1H, qt, J = 7Hz), 6.16 (tH, d, J = 8Hz), 6 , 16-6.68 (2H, m), 6.55 (1H, br d, J = 8Hz), 7.16-7.39 (1H, m) 51 pattern 25 pattern 6 CN Oil (CDCls) 1.28 (6H, d, J = 7Hz), 2.64 (3H, s), 3.72 (1H, qt, J = 7Hz), 6.33 (IH, d, J = 8Hz) , 6.60 (1H, br d, J = 8Hz), 6.75-7.22 (3H, m) 52 pattern 25 formula 8 CN 95.0- 98.0 (CDCls) 1.21 (6H, d, J = 7Hz), 2.57 (3H, s), 3.61 (IH, qt, J = 7Hz), 6.08 (IH, d, J = 8Hz) , 6.61 (1H, br d, J = 8Hz), 7.10-7.24 (5H, m) 53 pattern 26 pattern 4 CN Oil (CDCls) 2.68 (3H, s), 6.23 (1H, d, J = 8Hz), 6.12-6.62 (2H, m), 7.20-7.44 (1H, m) . 7.90 (1H, br d), 8.01 (1H, s) 54 pattern 13 pattern 5 CN 90.5- 92.0 (CDCls) 1.27 (3H, t, J = 8Hz), 1.81 (6H, s), 2.65

(3Η, s), 3.01 (2H, q, J = 8Hz), 5.47 (1H, d, J = 8Hz), 5.60 (1H, broad d, J = 8Hz), 6.48 ( 1H, broad d, J = 8Hz)

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1 2 3 4 5 6 55 pattern 13 pattern 27 CN 113-116 (CDCIs) 1.32 (3H, t, J = 8Hz), 2.75 (3H, s), 3.11 (2H, q, J = 8Hz), 6.58 (1H, d, J = 8Hz) , 6.92 (1H, br d, J = 8Hz), 7.5-7.8 (8H, m), 7.88 (1H, m) 56 pattern 13 pattern 28 CN 115-119 (CDCIs) 1.30 (3H, t, J = 8Hz), 2.75 (3H, s), 3.10 (2H, t, J = 8Hz), 6.44 (1H, d, J = 8Hz) , 7.20 (1H, br d, J = 8Hz), 6.62 (4H, m) 57 pattern 13 pattern 29 CN 146-148 (CDCIs) 1.29 (3H, t, J = 8Hz), 2.73 (3H, s), 3.08 (2H, q, J = 8Hz), 6.40 (1H, d, J = 8Hz) , 7.08 (1H, br d, J = 8Hz), 7.64 (4H, s) 58 pattern 30 pattern 31 CN Oil (CDCIs) 6.30 (1H, d, J = 8Hz), 6.1-6.62 (2H, m), 7.18-7.46 (1H, m), 8.14 (1H, broad d , J = 8Hz), 8.35 (1H, s), 8.86 (1H, s) 59 pattern 31 pattern 4 CN 88- 89 (CDCIs) 1.28 (3H, t, J = 8Hz), 1.37 (6H, d, J = 7Hz), 3.03 (2H, q, J = 8Hz), 3.18 (1H, sx, J = 7Hz), 6.24 (1H, broad d, J = 7Hz), 6.33 (1H, d, J = 7Hz), 6.16-6.2 (2H, m), 7.28-7 .52 (1H, m) 60 pattern 31 pattern 6 CN (CDCIs) 1.30 (3H, t, J = 8Hz), 1.39 (6H, d, J = 7Hz), 3.06 (2H, q, J = 8Hz), 3.25 (1H, qt, J = 7Hz), 6.41 (2H, singIet similar), 6.92-7.46 (3H, m) 61 pattern 31 formula 8 CN 11 ^^ 116 (CDCIs) 1.29 (3H, t, J = 8Hz), 1.38 (6H, d, J = 6Hz), 3.05 (2H, q, J = 8Hz), 3.32 (1H, qt, J = 6Hz), 6.25 (2H, singIet similar), 7.20-7.60 (5H, m) 62 pattern 32 pattern 4 CN 108.5-109.5 (CDCIs) 1.28 (3H, t, J = 7Hz), 1.43 (9H, s), 3.05 (2H, q, J = 7Hz), 6.24 (1H, d), 6.10 -6.58 (3H, m), 7.20-7.46 (1H, m) 63 pattern 32 pattern 6 CN 145-146 (CDCIs) 1.29 (3H, t, J = 8Hz), 1.43 (9H, s), 3.06 (2H, q, J = 8Hz), 6.39 (2H, similar to singIeta), 6 . 90-7.44 (3H, m) 64 pattern 32 formula 8 CN 126-127 (CDCIs) 1.30 (3H, t, J = 8Hz), 1.44 (9H, s), 3.08 (2H, q, J = 8Hz), 6.22 (2H, similar to singIeta), 7 . 20-7.64 (5H, m) 65 pattern 13 pattern 35 CN 118-120 (CDCIs) 1.26 (3H, t, J = 7Hz), 2.65 (3H, s), 2.97 (2H, q, J = 7Hz), 6.28 (1H, d, J = 8Hz) , 6.46 (1H, br d, J = 8Hz), 7.0-7.6 (4H, m) 66 pattern 33 pattern 4 CN semi-permanent (CDCIs) 6.28 (1H, d, J = 8Hz), 6.02-6.68 (2H, m), 7.11 (1H, broad d, J = 8Hz), 7.20-7.44 (1H, m) 67 pattern 34 pattern 4 CN 10 (6-107 (CDCIs) 2.89 (3H, s), 6.36 (1H, d, J = 8Hz), 6.36-6.68 (2H, m), 7.36-7.56 (1H, m) 8.14 (1H, br d, J = 8Hz), 8.51 (1H, s) 68 pattern 34 formula 8 CN 94-94.5 (CDCIs) 2.88 (3H, s), 6.31 (1H, d, J = 8Hz), 7.30-7.68 (5H, m), 8.15 (1H, broad d, J = 8Hz ), 8.46 (IH, s) 69 pattern 34 formula 8 CN 101-104 (CDCIs) 2.86 (3H, s), 6.44 (1H, d, J = 8Hz), 6.90-7.10 (1H, m), 7.22-7.45 (2H, m) 8.16 (1H, br d, J = 8Hz), 8.44 (1H, s) 70 pattern 36 pattern 6 CN 128.0-129.0 (CDCIs) 2.65 (3H, s), 6.42 (1H, d, J = 8Hz), 6.76 (1H, d, J = 8Hz), 7.0-7.2 (2H, m) . 7.4 (IH, s) 71 pattern 37 pattern 4 CN 92.5-93.0 (CDCIs) 2.70 (3H, s), 6.31 (1H, d, J = 8Hz), 6.52 (1H, dd, J = 3.0, 1.0Hz), 7.55 (1H, d, J = 1Hz) 72 pattern 38 pattern 6 CN 131.5-132.0 (CDCIs) 2.67 (3H, s), 6.41 (1H, d, J = 8Hz), 6.77 (1H, d, J = 8Hz), 7.0-7.2 (IH, m) , 7.3-7.35 (2H, m) 73 pattern 38 pattern 4 CN 130.5-131.0 (CDCIs) 2.66 (3H, s), 6.35 (1H, d, J = 8Hz), 6.62 (1H, dd, J = 3Hz), 6.71 (1H, d, J = 3Hz) , 6.76 (1H, d, J = 8Hz), 7.52 (IH, d, J = 1Hz) 74 pattern 38 pattern 6 CN 130.5-131.0 (CDCIs) 2.63 (3H, s), 6.41 (1H, d, J = 8Hz), 6.77 (IH, d, J = 8Hz), 7.15 (IH, m), 7.3 -7.5 (2H, m)

s II -c-nh ₂ N Cl N U ch ₃ MODEL 39 MODEL 33 MODEL 34 n .ch ₃ i- ^ T N AT MODEL 29 MODEL 30 MODEL 38 NC ₉ Hc 'S ^H 7- £ X ^{2 5} NC _{9 Ha} N CHo ^cl ^ 'X FORMULA 3) MODEL 32 MODEL 35 MODEL 36 Cl Cl Br MODEL 37 MODEL 27 MODEL 28

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^N '-c3 ^H 7 ^CH r- ^ K N-, ^cH3 ~ ^ K ^N = l -nJJ N CHoCl ^Ch 3 (C MODEL 25 MODEL 26 MODEL 23 PATTERN 24 N CH 3 ³ _ lj N CtHc ² MODEL 17 MODEL 11 N ^CH 3 N ../ ^C 2 ^H 5 CW _S X MODEL 19 N CH3 MODEL 13 MODEL 18 N Cł-k MODEL 12 N CFo ³ N CH3 ęr PATTERN 21 o ,, .N n-CoH ₇ MODEL 15 MODEL 20 PATTERN 14 ⁿ > ^H 3 CH3 N CoHc

MODEL 22

MODEL 16 ^C 2 ^H 5 ^S.

N CHo

MODEL 10

MODEL 9

MODEL 6

-CH = C

C ^h 3

MODEL 8

CH3

PATTERN 5 is

MODEL 7

MODEL U

YQJCCNNHCH 'N

Z z

'R'

PATTERN 1 o- / 'CH3 S.

PATTERN 2

CH3

MODEL 3

Publishing Department of the UP RP. Circulation of 90 copies. Price: PLN 10,000

Claims (1)

Patent claim A fungicide with a synergistic effect, used in particular in agriculture and horticulture, and containing a diluent or an excipient and / or an excipient and an active ingredient, characterized in that the first active ingredient comprises at least one amide derivative of the general formula I, wherein one of X and Y represents a sulfur atom and the other represents a carbon atom, Z represents a nitrile or thioamide group, each R and R ² represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a halomethyl group or a phenyl group, and R ³ is alkenyl group with 2-6 carbon atoms, haloalkenyl group with 2-4 carbon atoms, furyl group, thienyl group, alkoxy group with 1-4 carbon atoms, alkylthio group 1-4 carbon atoms, an alkynyloxy group with 3-5 carbon atoms, an alkynylthio group with 3-5 carbon atoms, a pyrazolyl group or an optionally halogen-substituted phenyl group, and the second active ingredient is tetrachloroisophthalonitrile, the active ingredient content being 0.5- 90% by weight and the first and second active ingredients are in the ratio of 1: 1 to 1:30.