KR100237714B1 - Novel 2-(piperazin-1-yl)thiazole carboxamide derivatives - Google Patents

Abstract

The present invention relates to a novel 2- (piperazin-1-yl) thiazolecarboxamide derivative represented by the following general formula (I) effective for the control of plant pathogens, a process for its preparation and its use for the control of plant pathogens .

Wherein R ¹ is phenyl, monosubstituted or disubstituted or unsubstituted by halogen, C _1-3 alkyl, C _1-3 haloalkyl or C _1-3 alkoxy, or C _1-3 alkoxycarbonyl or C _1-3 Alkyl, R ² represents straight or branched C _1-5 alkyl or C _1-3 alkoxymethyl, and R ³ represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, C _3-5 alkynyl, C _3-6 cycloalkyl or C _1-3 alkoxyethyl.

Description

[Title of the Invention]

A novel 2- (piperazin-1-yl) thiazolecarboxamide derivative

DETAILED DESCRIPTION OF THE INVENTION [

The present invention relates to a novel 2- (piperazin-1-yl) thiazolecarboxamide derivative represented by the following general formula (I) effective for the control of plant pathogenic bacteria, a process for its preparation and its use for the control of plant pathogens .

Wherein R ¹ is phenyl, monosubstituted or disubstituted or unsubstituted by halogen, C _1-3 alkyl, C _1-3 haloalkyl or C _1-3 alkoxy, or C _1-3 alkoxycarbonyl or C _1-3 Alkyl, R ² represents straight or branched C _1-5 alkyl or C _1-3 alkoxymethyl, and R ³ represents hydrogen, C _1-5 alkyl, C _3-5 alkenyl, C _3-5 alkynyl, C _3-5 cycloalkyl or C _1-3 alkoxyethyl.

The compounds of the general formula (I) according to the invention are useful as an active ingredient in agricultural or horticultural fungicides since they are useful for plant diseases occurring in various plant cycles by plant pathogens. The compounds of general formula (I) according to the present invention are useful for the treatment of diseases such as Pyricularia oryzae, Rhizoctonia solani, Phytophtora infestans, Plasmopra viticola, Botrytis cinerea, Puccinia recondita ), Powdery mildew (Erysiphe graminis), and black blotch (Venturia inequalis), and exhibits excellent drug efficacy especially against blast disease, plague disease, fungus disease and gray mold disease.

As thiazolecarboxamide derivatives similar to the compound of formula (I) according to the present invention, the present inventors have already invented the compounds represented by the following formula (A) in Korean patent application No. 95-36069 and filed a patent application.

Wherein R ¹ represents methyl or ethyl, R ² and R ³ are each independently selected from the group consisting of hydrogen, cyano, hydroxy, formyl, carboxy, carbamoyl which is unsubstituted or substituted by C _1-3 alkyl, C _1-3 alkyl, C _1-3 alkylcarbonyl, C _1-3 haloalkylcarbonyl, C _1-3 alkoxycarbonyl, C _1-3 haloalkoxycarbonyl, piperidinyl, pyridyl, or halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy or C _1-3 alkylcarbonyl, and A represents a phenyl or benzyl which is substituted by a nitrogen atom Represents a 5- to 7-membered heterocyclic ring which may contain at least one oxygen atom or sulfur atom and may be fused with another ring radical or may form a spiro ring.

In addition, the present inventors invented a compound represented by the following general formula (B) in Korea Patent Application No. 96-5597 and filed a patent application.

Wherein R ¹ is phenyl, formyl, or thiophene unsubstituted or substituted by halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, or C _1-3 alkylcarbonyl, C _1-3 alkoxycarbonyl, C _1-3 alkyl, C _1-3 alkylsulfonyl, R ² represents C _1-5 alkyl, C _1-3 haloalkyl or C _1-3 alkoxymethyl, R ³ represents hydrogen, methyl or ethyl.

The compounds of formulas (A) and (B) above all have been found to be effective in combating plant pathogens.

Based on these prior studies and techniques, the present inventors have conducted ongoing research to develop novel compounds that exhibit a broader inhibitory effect on the pathogen-caused pathogen. As a result, (A) and (B) show that compounds prepared by introducing the following specific amide groups exhibit a broad and excellent effect of inhibiting plant pathogens, and have completed the present invention.

Hereinafter, the configuration of the present invention will be described in detail.

The present invention provides a compound having a specific amide group introduced at the 5-position of the thiazole ring, that is, a novel 2- (piperazin-1-yl) thiazolecarboxamide derivative represented by the following general formula (I) .

Wherein, R ¹ is halogen, C _1-3 alkyl, C _1-3 haloalkyl or C _1-3 alkoxy by a mono- or disubstituted or unsubstituted phenyl, or C _1-3 alkoxycarbonyl or C _1- represents a _3-alkyl, R ² represents a straight or branched C _1-5 alkyl or C _1-3 alkoxy-methyl, R ³ is hydrogen, C _1-5 alkyl, C _3-5 alkenyl, C _3-5 alkynyl, , C _3-5 cycloalkyl or C _1-3 alkoxyethyl.

Preferred compounds Among the compounds of the formula (I) according to the invention are fluoro are R ^1, trifluoromethyl, methoxy, or mono- or disubstituted by ethoxy or unsubstituted phenyl, or ethoxycarbonyl, or Methyl, R ² represents methyl, ethyl, butyl or methoxymethyl, and R ³ represents hydrogen, ethyl, butyl, propargyl, alkyl, cyclopropyl or methoxyethyl.

The present invention also relates to a process for the preparation of the novel 2- (piperazin-1-yl) thiazolecarboxamide derivatives of the general formula (I).

According to the present invention, the compound of formula (I) can be prepared by reacting the compound of formula (II), which is the starting material, with a piperazine derivative of formula (III) as shown in the following reaction scheme 1.

[Scheme 1]

Wherein R ¹ , R ² and R ³ are the same as defined in formula (I), and X represents halogen or C _1-3 alkylsulfonyl.

As shown in Scheme 1 above, the compound of formula (I) can be synthesized by reacting the compound of formula (II) with a piperazine derivative of formula (III). The reaction of the compound (II) with the compound (III) is preferably carried out in the presence of a solvent and a base. Examples of the base usable in the present reaction include organic bases such as triethylamine, pyridine and the like, and inorganic bases such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate and the like. Further, the piperazine derivative of the general formula (III) used as a reactant may be used in excess to serve as a base.

Examples of the solvent in this reaction include ethers such as diethyl ether, tetrahydrofuran and dimethoxyethane, ketones such as acetone, methyl ethyl ketone and isobutyl methyl ketone, amides such as dimethylformamide and dimethylacetamide, , 1,2-dichloroethane and the like, nitriles such as acetonitrile, propionitrile and butyronitrile, and polar solvents such as methylsulfoxide, and preferably at least one solvent selected from the group consisting of Use ethers or polar solvents.

In the case where the piperazine derivative of the general formula (III) is also used as a base in the above reaction, the compound of the general formula (III) is preferably used in an amount of 2 to 4 equivalents based on the compound of the general formula (II) . The reaction temperature can be varied in the range of 20 ° C to 120 ° C, but preferably the reaction is carried out at a temperature of 20 ° C to 80 ° C.

According to Scheme 1 above, the compound of formula (II) used as a starting material in the reaction can be prepared by first reacting the carboxylic acid compound of formula (VI) with a compound of formula Can be synthesized by acylation into the acid chloride of the general formula (V), and then in the second stage, the acid chloride (V) is reacted with the primary amine of the general formula (IV) in the presence of a base.

[Reaction Scheme 2]

In the above reaction formula, R ² , R ³ and X are the same as defined in the general formula (I) and the reaction scheme 1.

According to the process shown in Scheme 2, the carboxylic acid compound of general formula (VI) is first acylated in the first step to the acid chloride of general formula (V).

Examples of acylating agents that can be used in the first step reaction for producing acid chloride include thionyl chloride (SOCl ₂ ), oxalyl chloride (ClCOCOCl), contaminated phosphorus (PCl ₅ ), and the like. The reaction is preferably carried out at a temperature of -10 ° C to 180 ° C, preferably at a temperature of 0 ° C to 100 ° C, and a reaction time of 30 minutes to 12 hours is suitable. The reaction for producing the acid chloride is preferably carried out in the presence of a solvent. Examples of the solvent used for this purpose include aromatic hydrocarbons such as benzene, toluene and xylene, dichloromethane, 1,2-dichloroethane, Halogenated hydrocarbons such as chloroform and the like can be mentioned. In addition, this reaction can be preferably carried out using N, N-dimethylformamide as a catalyst.

The acid chloride (V) obtained in the first step can be subsequently reacted with a primary amine of the general formula (IV) in the presence of a base to give the desired compound of the general formula (II). The second-step reaction can be carried out generally at a temperature range of -30 ° C to 70 ° C, preferably at 0 ° C to 30 ° C, and the reaction time is preferably 30 minutes to 24 hours. Examples of the base preferably used in the second step reaction include organic bases such as pyridine, 4-dimethylaminopyridine, triethylamine, N, N-dimethylaniline, tributylamine, N-methylmorpholine and the like, Potassium carbonate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydride, potassium hydride and the like. This reaction can also be preferably carried out in the presence of a solvent. Examples of the solvent used for this purpose include aromatic hydrocarbons such as benzene, toluene and xylene, dichloromethane, 1,2-dimethyroethane, chloroform and the like Ethers such as halogenated hydrocarbons, ethers such as diethyl ether, dioxane, 1,2-dimethoxyethane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and cyclohexanone, nitriles such as acetonitrile and propionitrile Esters such as methyl acetate, ethyl acetate and the like, polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide and the like can be mentioned.

The carboxylic acid compound of formula (VI) used as starting material in Scheme 2 above can be prepared by the methods described in Korean Patent Applications Nos. 94-39896 and 96-3045 filed by the present inventors .

The above-mentioned preparation methods will be more specifically described in the following Preparation Examples and Examples, and representative examples of the compounds of the general formula (I) according to the present invention prepared according to the method of the present invention are shown in Table 1 below .

[Table 1]

The compound of the general formula (I) according to the present invention exhibits excellent effects in the eradication of various plant pathogenic bacteria such as rice blast, rice paddy rice disease, plague, necrotic disease, gray mold, rust, powdery mildew, Lt; / RTI > Accordingly, the present invention relates to a composition for combating plant pathogens containing the compound of formula (I) as an active ingredient and to a method for combating plant pathogens by applying a compound of formula (I) to a plant or a field thereof will be.

When the compound of the general formula (I) of the present invention is used for the control of plant pathogens, the active compound of the present invention may be compounded with a carrier acceptable for agricultural use, for example, a diluent, a binder, a dispersant, an extender, For example, a formulation acceptable for agricultural use such as a wetting agent, a dispersant, an emulsion, a liquid agent, a suspension, a spray, and the like.

The present invention will be described more specifically by the following Production Examples and Examples. However, these preparation examples and examples are provided only to aid understanding of the present invention, and the scope of the present invention is not limited in any way by them.

[Production Example 1]

Preparation of [4-ethyl-2-methylsulfonyl-thiazole-5-carboxylic acid t-butyl-

5-carboxylic acid (11.8 g, 50 mmol), thionyl chloride (11.5 g, 55 mmol) and dimethylformamide (0.5 ml) were added to chloroform ML), stirred for 2 hours while refluxing, and distilled under reduced pressure to remove the residual thionyl chloride to obtain 4-ethyl-2-methylsulfonyl-thiazole-5-carboxylic acid chloride. The obtained acid chloride was dissolved again in t-butylamine (7.3 g, 100 mmol) in 100 ml of dichloromethane, stirred at room temperature for 2 hours, water was added, the organic layer was separated, dried over anhydrous magnesium and evaporated. The residue was subjected to silica gel column chromatography (eluent hexane: ethyl acetate = 5: 1) to give 11.6 g (40 mmol) of the title compound (yield 80%).

[Production Example 2]

Preparation of [2-bromo-4-methyl-thiazole-5-carboxylic acid (2-methoxy-

2-Bromo-4-methyl-thiazole-5-carboxylic acid (5.6 g, 20 mmol), thionyl chloride (2.6 g, 22 mmol) and dimethylformamide (0.5 ml) were dissolved in dichloromethane The mixture was stirred under reflux for 2 hours and then distilled under reduced pressure to remove the residual thionyl chloride to give 2-bromo-4-methyl-thiazole-5-carboxylic acid chloride. Triethylamine (3.0 g, 30 mmol) was dissolved in 30 ml of dichloromethane together with 2-methoxyethylamine (3.0 g, 40 mmol), and then the acid chloride obtained above was diluted with 10 ml of dichloroethane And gradually dropped. The reaction mixture was stirred at 0 ° C for 10 minutes, water was added, the organic layer was separated, dried over anhydrous magnesium and evaporated to give 5.6 g (20 mmol) of the title compound (yield: 100%).

[Production Example 3]

Preparation of [2-bromo-4-methoxymethyl-thiazole-5-carboxylic acid ethylamide]

2-Bromo-4-methoxymethyl-thiazole-5-carboxylic acid (5.0 g, 20 mmol), thionyl chloride (2.6 g, 22 mmol) and dimethylformamide (0.5 ml) were dissolved in dichloroethane ), Stirred for 2 hours under reflux, and then distilled under reduced pressure to remove the residual thionyl chloride to obtain 2-bromo-4-methoxymethyl-thiazole-5-carboxylic acid chloride. The obtained acid chloride was dissolved again in ethylamine (1.8 g, 40 mmol) in 30 ml of dichloromethane and stirred at room temperature for 30 minutes. Thereafter, the reaction mixture was treated in the same manner as in Preparation Example 1, and the residue was subjected to silica gel column chromatography (eluent nucleic acid: ethyl acetate 3: 1) to obtain 4.5 g (16.2 mmol) of the title compound (yield 81% .

[Production Example 4]

Preparation of [2-bromo-4-butyl-thiazole-5-carboxylic acid amide]

(2.6 g, 22 mmol) and dimethylformamide (0.5 ml) were dissolved in dichloroethane (10 ml), and the mixture was stirred at < RTI ID = And the mixture was stirred under refluxing for 2 hours, and then distilled under reduced pressure to remove the residual thionyl chloride to obtain 2-bromo-4-butyl-thiazole-5-carboxylic acid chloride. The obtained acid chloride was dissolved again in 30 ml of dichloromethane, and then slowly added dropwise at room temperature to aqueous ammonia (25%, 3.4 g, 24 mmol). The reaction mixture was stirred at room temperature for 1 hour, water was added, and the organic layer was separated and treated in the same manner as in Preparation Example 1. The residue was purified by silica gel column chromatography (eluent hexane: ethyl acetate = 2: 1) 5.1 g (19.4 mmol) of the title compound were obtained (97% yield).

[Example 1]

Synthesis of ethyl 2- [4- (2-methoxy-phenyl) -piperazin-1-yl] -4-ethyl-thiazole-5-carboxylic acid ethylamide (1)

(1 mmol) of 4-ethyl-2-methylsulfonyl-thiazole-5-carboxylic acid ethylamide and 0.27 g (1.1 mmol) of 1- (2- ethoxyphenyl) piperazine hydrochloride were dissolved in tetrahydrofuran , 0.22 g (2.2 mmol) of triethylamine was added, and the mixture was stirred under reflux for 14 hours. The residue was purified by silica gel column chromatography (eluent n- hexane: ethyl acetate = 2: 1) to give the title compound 0.31 g ( 0.8 mmol) (yield 80%).

[Example 2]

Synthesis of ethyl 4-ethyl-2- [4- (4-fluoro-phenyl) -piperazin-1-yl] -thiazole-5-carboxylic acid ethylamide (3)

(1 mmol) of 4-ethyl-2-methylsulfonyl-thiazole-5-carboxylic acid ethylamide and 0.20 g (1.1 mmol) of 1- (4- fluorophenyl) piperazine were dissolved in 4 ml of tetrahydrofuran , 0.11 g (1.1 mmol) of triethylamine was added, and the mixture was stirred under reflux for 14 hours. The residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 2: 1) to give the title compound 0.30 g ( 0.83 mmol) (yield: 83%).

[Example 3]

[2- [4- (2-ethoxy-phenyl) -piperazin-1-yl] -4-ethyl- thiazole-

0.29 g (1.1 mmol) of 1- (2-ethoxyphenyl) piperazine hydrochloride and 0.29 g (1 mmol) of 4-ethyl-2-methylsulfonyl-thiazole- After dissolving in 4 ml of hydrofuran, 0.22 g (2.2 mmol) of triethylamine was added and the mixture was stirred under reflux for 48 hours. The residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 3: 1) to give the title compound 0.31 g ( 0.75 mmol) (yield 75%).

[Example 4]

Synthesis of 4-ethyl-2- [4- (4-fluoro-phenyl) -piperazin-1-yl] -thiazole-

(1.1 mmol) of 1- (4-fluorophenyl) piperazine and 0.29 g (1 mmol) of 4-ethyl-2-methylsulfonyl-thiazole-5-carboxylic acid tert- After dissolving in 4 ml of furan, 0.11 g (1.1 mmol) of triethylamine was added and the mixture was stirred at reflux for 48 hours. The residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 3: 1) to give the title compound 0.31 g ( 0.81 mmol) (81% yield).

[Example 5]

Synthesis of [4-ethyl-2- [4- (2-fluoro-phenyl) -piperazin-1-yl] -thiazole-

(1.1 mmol) of 1- (2-fluorophenyl) piperazine hydrochloride and 0.29 g (1 mmol) of 4-ethyl-2-methylsulfonyl-thiazole- After dissolving in 4 ml of hydrofuran, 0.22 g (2.2 mmol) of triethylamine was added and the mixture was stirred under reflux for 48 hours. The residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 3: 1) to obtain 0.29 g of the title compound 0.76 mmol) (yield 76%).

[Example 6]

Synthesis of [4-ethyl-2- [4- (3-trifluoromethyl-phenyl) -piperazin-1-yl] -thiazole-

(1.1 mmol) of 1- (3-trifluoromethyl) piperazine hydrochloride and 0.29 g (1.1 mmol) of 4-ethyl-2-methylsulfonyl-thiazole-5-carboxylic acid tert- After dissolving in 4 ml of tetrahydrofuran, 0.22 g (2.2 mmol) of triethylamine was added and the mixture was stirred under refluxing for 48 hours. The residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 3: 1) to give 0.33 g of the title compound 0.75 mmol) (yield 75%).

[Example 7]

Synthesis of [2- [4- (2-ethoxy-phenyl) -piperazin-1-yl] -4-methyl-thiazole-5-carboxylic acid (2- methoxy- ]

(1.0 mmol) and 0.27 g (1.1 mmol) of l- (2-ethoxyphenyl) piperazine hydrochloride were added to a solution of 2-bromo-4-methyl-thiazole- Mmol) was dissolved in 4 ml of tetrahydrofuran, 0.22 g (2.2 mmol) of triethylamine was added, and the mixture was stirred under reflux for 36 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium and evaporated, and the residue was recrystallized from methanol to give 0.28 g (0.73 mmol) of the title compound (yield: 70%).

[Example 8]

Synthesis of [2- [4- (2-ethoxy-phenyl) -piperazin-1-yl] -4-methyl-thiazole-5-carboxylic acid (2- methoxy- ]

0.21 g (1.1 mmol) of 1- (2-methoxyphenyl) piperazine hydrochloride and 0.28 g (1.0 mmol) of 2-bromo-4- methylthiazole-5-carboxylic acid Mmol) was dissolved in 4 ml of tetrahydrofuran, 0.11 g (1.1 mmol) of triethylamine was added, and the mixture was stirred under reflux for 36 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium and evaporated, and the residue was recrystallized from methanol to give 0.28 g (0.73 mmol) of the title compound (yield: 73%).

[Example 9]

Synthesis of [2- [4- (2-ethoxy-phenyl) -piperazin-1-yl] -4-methyl-thiazole-5-carboxylic acid (2-methoxy- ]

0.28 g (1.0 mmol) of 2-bromo-4-methyl-thiazole-5-carboxylic acid (2-methoxy- 1.1 mmol) was dissolved in 4 ml of tetrahydrofuran, 0.33 g (3.3 mmol) of triethylamine was added, and the mixture was stirred under reflux for 36 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate, and evaporated. Recrystallization of the residue from methanol gave 0.25 g (0.67 mmol) of the title compound (yield 67%).

[Example 10]

Synthesis of [4- [5- (2-methoxy-ethylcarbamoyl) -4-methyl-thiazol-2-yl] -piperazine-1-carboxylic acid ethyl ester (14)

(1.0 mmol) of 1-piperazinecarboxylic acid ethyl ester and 0.47 g (3.0 mmol) of 2-bromo-4-methyl-thiazole-5-carboxylic acid (2- methoxy- After dissolving in 4 ml of tetrahydrofuran, the mixture was stirred under reflux for 36 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated, dried over anhydrous magnesium and evaporated, and the residue was recrystallized from methanol to give 0.32 g (0.85 mmol) of the title compound (yield 85%).

[Example 11]

Synthesis of 4-butyl-2- (4-phenyl-piperazin-1-yl) thiazole-5-carboxylic acid amide (15)

(1.0 mmol) of 2-bromo-4-methyl-thiazole-5-carboxylic acid amide and 0.48 g (3.0 mmol) of 1-phenylpiperazine were dissolved in 4 ml of tetrahydrofuran, And the mixture was stirred under reflux. The residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 1: 1) to give the title compound 0.31 g ( 0.90 mmol) (yield 90%).

[Example 12]

Methoxy-ethyl) - amide (16) [0157] < EMI ID = 36.1 > / RTI >

(1.0 mmol) and l- (2-ethoxyphenyl) piperazine hydrochloride 0.27 g (1.0 mmol) were added to a solution of 2-bromo-4-methoxy-methyl-thiazole- g (2.2 mmol) was dissolved in 4 ml of tetrahydrofuran, 0.22 g (2.2 mmol) of triethylamine was added, and the mixture was stirred at reflux for 6 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from a mixed solution of n-hexane and ethyl acetate (volume / volume = 5/1) 0.36 g (0.82 mmol) of the compound was obtained (yield 82%).

[Example 13]

Synthesis of ethyl 4- [5- (2-methoxy-ethylcarbamoyl) -4-methoxymethyl-thiazol-2-yl] -piperazine-1 -carboxylic acid ethyl ester [

0.30 g (1.0 mmol) of 1-piperazinecarboxylic acid ester and 0.30 g (1.0 mmol) of 2-bromo-4-methyl-thiazole-5-carboxylic acid (2- methoxy- After dissolving in 4 ml of hydrofuran, the mixture was stirred under reflux for 6 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from a mixed solution of n-hexane and ethyl acetate (volume / volume = 5/1) 0.36 g (0.92 mmol) of the compound was obtained (yield 82%).

[Example 14]

Synthesis of ethyl 2- (4- (2-ethoxy-phenyl) -piperazin-1-yl] -4-methoxymethyl-thiazole-

(1.1 mmol) of 1- (2-ethoxyphenyl) piperazine hydrochloride and 0.28 g (1.0 mmol) of ethyl 2-bromo-4-methylthiazole- , 0.22 g (2.2 mmol) of triethylamine was added, and the mixture was stirred under reflux for 6 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from a mixed solution of n-hexane and ethyl acetate (volume / volume = 3/1) 0.33 g (0.81 mmol) of the compound was obtained (yield 81%).

[Example 15]

Synthesis of 4-methoxymethyl-2- (4-phenyl-piperazin-1-yl) -thiazole-5-carboxylic acid ethylamide (23)

(1.0 mmol) of 2-bromo-4-methoxy-methyl-thiazole-5-carboxylic acid ethylamide and 0.18 g (1.1 mmol) of 1-phenylpiperazine were dissolved in 4 ml of tetrahydrofuran , 0.11 g (1.1 mmol) of triethylamine was added, and the mixture was stirred under reflux for 6 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from a mixed solution of n-hexane and ethyl acetate (volume / volume = 3/1) 0.32 g (0.9 mmol) of the compound was obtained (90% yield).

[Example 16]

Synthesis of ethyl 2- [4- (2-fluoro-phenyl) -piperazin-1 -yl] -4-methoxymethyl-thiazole-

(1.1 mmol) of 1- (2-bromophenyl) piperazine hydrochloride and 0.28 g (1.1 mmol) of 2-bromo-4- methoxy-methyl- After dissolving in 4 ml of furan, 0.22 g (2.2 mmol) of triethylamine was added and the mixture was stirred under reflux for 6 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from a mixed solution of n-hexane and ethyl acetate (volume / volume = 3/1) 0.30 g (0.78 mmol) of the compound was obtained (yield 78%).

[Example 17]

Synthesis of [2- [4- (2-ethoxy-phenyl) -piperazin-1-yl] -4-methoxymethyl-thiazole-5-carboxylic acid cyclopropylamide 28]

(1.1 mmol) of 1- (2-ethoxyphenyl) piperazine hydrochloride and 0.29 g (1.1 mmol) of 2-bromo-4-methoxy-methyl-thiazole- After dissolving in 4 ml of hydrofuran, 0.22 g (2.2 mmol) of triethylamine was added and the mixture was stirred under refluxing for 4 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from a mixed solution of n-hexane and ethyl acetate (volume / volume = 3/1) 0.35 g (0.85 mmol) of the compound was obtained (yield: 85%).

[Example 18]

Synthesis of [2- [4- (2-fluoro-phenyl) -piperazin-1-yl] -4-methoxymethyl-thiazole-5-carboxylic acid cyclopropylamide 31]

(1.1 mmol) of 1- (2-fluorophenyl) piperazine hydrochloride and 0.29 g (1.1 mmol) of 2-bromo-4-methoxymethyl-thiazole-5-carboxylic acid cyclopropylamide in tetrahydro After dissolving in 4 ml of furan, 0.22 g (2.2 mmol) of triethylamine was added and the mixture was stirred under refluxing for 4 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from a mixed solution of n-hexane and ethyl acetate (volume / volume = 3/1) 0.31 g (0.81 mmol) of the compound was obtained (yield 81%).

[Example 19]

Synthesis of 4-methoxymethyl-2- (4-phenyl-piperazin-1-yl) -thiazole-5-carboxylic acid prop-

(1.0 mmol) of 2-bromo-4-methoxy-methyl-thiazole-5-carboxylic acid prop-2-ynylamide and 0.18 g (1.1 mmol) of 1-phenylpiperazine were dissolved in tetrahydrofuran , 0.11 g (1.1 mmol) of triethylamine was added, and the mixture was stirred under reflux for 4 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from a mixed solution of n-hexane and ethyl acetate (volume / volume = 2/1) 0.35 g (0.95 mmol) of the compound was obtained (95% yield).

[Example 20]

Synthesis of [4- [4-methoxymethyl-5- (prop-2-ynylcarbamoyl) -thiazol-2-yl] piperazine-1-carboxylic acid ethyl ester (38)

(1.0 mmol) of 2-bromo-4-methoxy-methyl-thiazole-5-carboxylic acid prop-2-ynylamide and 0.47 g (3.0 mmol) of 1-piperazinecarboxylic acid ethyl ester And dissolved in 4 ml of tetrahydrofuran, followed by stirring under reflux for 4 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from a mixed solution of n-hexane and ethyl acetate (volume / volume = 2/1) 0.34 g (0.94 mmol) of the compound was obtained (94% yield).

[Example 21]

Synthesis of 4-methoxymethyl-2- (4-phenyl-piperazin-l-yl) -thiazole-5-carboxylic acid allylamide (43)

0.29 g (1.0 mmol) of 2-bromo-4-methoxy-methyl-thiazole-5-carboxylic acid allylamide and 0.18 g (1.1 mmol) of 1-phenylpiperazine were dissolved in 4 ml of tetrahydrofuran , 0.11 g (1.1 mmol) of triethylamine was added, and the mixture was stirred under reflux for 6 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from a mixed solution of n-hexane and ethyl acetate (volume / volume = 5/1) 0.35 g (0.94 mmol) of the compound was obtained (94% yield).

[Example 22]

Synthesis of 4-methoxymethyl-2- (4-phenyl-piperazin-1-yl) -thiazole-5-carboxylic acid allylamide (45)

0.29 g (1.0 mmol) of 2-bromo-4-methoxymethyl-thiazole-5-carboxylic acid allylamide and 0.30 g (3.0 mmol) of 1-methylpiperazine were dissolved in 4 ml of tetrahydrofuran, And the mixture was stirred under reflux for 6 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from a mixed solution of n-hexane and ethyl acetate (volume / volume = 5/1) 0.30 g (0.96 mmol) of the compound was obtained (yield: 96%).

¹ H NMR data of the individual compounds of the general formula (I) synthesized in the above examples are shown in Table 1.

[Biological Test Example]

In order to examine the protective effect of the novel compounds represented by the general formula (I) according to the present invention on the plant diseases caused by the plant pathogenic bacteria, the following bacteria were selected for the fungicidal activity.

Rice blast (RLB) (Pyricularia oryzae)

Rice sheath blight (RSB) (Rhizoctonia solani)

Cucumber Gray mold (CGM) (Botrytis cinerea)

Tomato Plague (TLB) (Phytophtora infestans)

Wheat Red Rust (WAR) (Puccinia recondita)

Barley powdery mildew (BPM) (Erysiphe graminis)

The control strain was examined for the above strain by the following method. After dissolving the test compound in 10% acetone solution, 5 ml of the test compound was sprayed onto the host plants of a certain size. To this solution was added 250 ppm of Tween-20. The plants sprayed with the medicament were allowed to stand at room temperature for 24 hours to volatilize the solvent and water, and then the pathogens prepared as in Test Examples 1 to 6 below were inoculated and the control value was calculated according to the following equation Respectively.

(Control Valuc,%) = {1- (lesion area ratio of treatment / lesion area ratio of control)} x 100

All experiments were repeated twice and grades were divided according to the criteria shown in Table 2 below and are shown in Table 3 below.

[Table 2]

[Test Example 1]

[Germicidal effect on rice blast fungus]

The strain Pyricularia oryzae was inoculated into a rice bran agar medium (rice bran 20 g, dextrose 10 g, agar 15 g, distilled water 1 L) and cultured in a 26.2 ° C. incubator for 2 weeks. The surface of the pathogen-grown medium was scratched with a rubber blanket to remove air hyphae and spores were formed on a fluorescent lighted shelf (26-28 ° C) for 48 hours. The resulting conidia were treated with sterilized distilled water to give a certain concentration of spore suspension (10 ⁶ spores / ml), and then the solution was allowed to flow to Nakdongbyeon (3-4 leaves) sensitive to drug-treated rice blast as described above And sprayed sufficiently. The inoculated rice was kept in a humid to dark state, and after 5 days in a constant temperature and humidity room with a relative humidity of 90% or more and a temperature of 26.2 ° C, the area of onset was calculated. The pathologist examined the area of the diseased lesion formed on fully developed leaves just below the uppermost leaf of 3-4 leaf stage rice according to the standard deviation percentage.

[Test Example 2]

[Sterilization effect on rice sheath blight]

After a proper amount of bran was placed in a 1 L culture bottle and sterilized, the agar of the Rhizoctonia solani AG-1 pathogen (Rhizoctonia solani AG-1) grown in potato agar medium for 3 days was inoculated, and the cultured hyphae were finely ground After incubation at 28.1 ℃ for 5 days, the cells were incubated at 28.1 ℃ for 5 days. The incidence survey was carried out in accordance with the ratio of area percentage of diseased lesions to the area ratio of diseased lesions in the leaf sheath of 2-3 leaf stage seedlings.

[Test Example 3]

[Germicidal effect against tomato plague]

Phytophthora infestans of tomato blight were placed on a rye B agar medium (60 g of rye, 20 g of sucrose, 50 g of β-sitosterol, 15 g of agar, 1 l of distilled water) and light treatment was carried out at 20 ° C. for 16 hours, And cultured for 14 days in an incubator. After the sterile distilled water was added to the plate, the reagent spoon was used to separate it from the germ layer. The concentration of harvested zoosporangia was adjusted to ⁵ × 10 ⁴ / ml and used as an inoculation source. The inoculum was inoculated with 3 ml of each drug-treated tomato seedlings as described above. The inoculated plants were allowed to develop for 5 days on a wet condition at 20 ° C, and then the percentage of the lesion area was examined.

[Test Example 4]

[Sterilization effect on cucumber gray mold]

The pathogen (Botrytis cinerea KC1) of the cucumber gray mold disease isolated from the tomato was inoculated into a rice bran agar medium (RPA), followed by a 16 hour blank treatment and an 8 hour dark treatment in an incubator at 20 ° C to form conidium spores. The spores formed in the medium were poured into a potato liquid medium (200 g of potato, 20 g of dextrose and 1 l of distilled water), spores were scraped, and the spores were harvested by using a gauze to adjust the spore concentration to 1 × 10 ⁶ / ml and used as an inoculation source . The inoculated seeds were inoculated with 3 ml of the spray-treated seedlings of the first crop of cucumber as described above, and the inoculated plants were treated for 4 days in a wet condition at 20 캜 for 4 days. Respectively.

[Test Example 5]

[Germicidal effect against wheat red rust (WAR)]

The pathogen (Puccinia recondita) of wheat red rust was directly subcultured to the plant in the laboratory. 15-lipped wheat seeds (silver waves) were sown in disposable pots (diameter: 6.5 cm) and the 7-day-old one-leaf wheat cultivated in the greenhouse was treated with the drug as described above and subjected to wet treatment at 20 ° C for 1 day Then, the spores of the pathogens were inoculated and transferred to a constant temperature and humidity chamber at 20 ° C, where the relative humidity was 70%, to induce the onset, and the onset was examined 10 days after the inoculation. The incidence of lesions was examined 10 days after the inoculation with the blastocyst spores.

[Test Example 6]

[Germicidal effect on barley powdery mildew (BPM)]

Pathogen () of barley powdery mildew was used by subculture in laboratory. Barley seeds (Dongbori No. 1) were sown in a disposable pot (diameter: 6.5 cm) at 15 rupees, and the barley of a one-leaf stage cultivated in a greenhouse (25 ° C) for 7 days was treated with the drug as described above and the powdery mildew spores Respectively. The inoculated plants were transferred to a constant temperature and humidity chamber at a relative humidity of 50% and 22-24 ° C to induce the onset for 7 days.

The results specified in the respective test examples are shown in the following Table 3.

[Table 3]

Claims (2)

A 2- (piperazin-1-yl) thiazolecarboxamide derivative represented by the following general formula (I): Wherein, R ¹ is halogen, C _1-3 alkyl, C _1-3 haloalkyl or C _1-3 alkoxy by a mono- or disubstituted or unsubstituted phenyl, or C _1-3 alkoxycarbonyl or C _1- represents a _3-alkyl, R ² represents a straight or branched C _1-5 alkyl or C _1-3 alkoxy-methyl, R ³ is hydrogen, C _1-5 alkyl, C _3-5 alkenyl, C _3-5 alkynyl, , C _3-5 cycloalkyl or C _1-3 alkoxyethyl. The method of claim 1, wherein, R ¹ is fluoro, trifluoromethyl, methoxy, or mono- or disubstituted by ethoxy, or represents an unsubstituted phenyl, or ethoxycarbonyl or methyl, R ² is methyl, ethyl , Butyl or methoxymethyl, and R ³ represents hydrogen, ethyl, butyl, propargyl, alkyl, cyclopropyl or methoxyethyl.