CN101003533A - Derivative of thiadiazoles containing cyclo oxdiazole, synthetic method, and biological activity - Google Patents

Abstract

This invention provides a method for synthesizing 1,2,3-thiadiazole derivatives containing furodiazole ring, and their bioactivity. Fifteen thiadiazole derivatives containing furodiazole ring are synthesized from 1, 2, 3-thiadiazole and 1, 3, 4-furodiazole. This invention discloses chemical structures of these 1, 2, 3-thiadiazole derivatives and their intermediates, their synthesis method, and their inhibitory effect on plant pathogenetic fungi and induced tobacco anti-TMW effect.

Description

The thiadiazoles derivative of Han oxadiazole ring and synthetic method and biological activity

Technical field

Technical scheme of the present invention relates to and contain 1,2-diazole and 3, and the heterogeneous ring compound of 4-diazole is specifically related to [1,2,3] thiadiazoles derivative of Han oxadiazole.

Background technology

1; 3; 4-oxadiazole heterocyclic compounds has multiple biological activity; as anti-inflammatory activity and anti-microbial activity; the contriver once utilized the bioisostere principle to introduce pyridine ring and 1 simultaneously in a part; 3,4-oxadiazole heterocycle has synthesized 5-(3-pyridyl-or 4-pyridyl)-1,3; 4-oxadiazole-2-sulphur acetamides; part of compounds shows that preferably (Fan Zhijin etc. contain 1,3 of pyridine ring to fungicidal activity; synthetic and the bioactivity research of 4-oxadiazole derivative; SCI, 2004,25 (4): 663-666).Because 1,2, the 3-thiadiazoles heterocyclic compounds also has important biological, cotton defoliant [disleave spirit (N-phenyl-N '-1,2,3-thiadiazoles-5-urea, and plant activator Acibenzolar [benzo [1 TDZ)], 2,3]-and thiadiazoles-7-thiocarboxylic acid methyl esters, BTH] and rice field sterilant tiadinil (3 '-chloro-4,4 '-dimethyl-1,2,3-thiadiazoles-5-formylaniline, TDL) waiting commercial kind is exactly 1,2,3-thiadiazoles derivative (chemical structure sees Table 1), we have reported part 1,2 in the patent in early stage, the 3-thiadiazoles derivative has the (Fan Zhijin etc. of fine fungicidal activity, novel [1,2,3] thiadiazoles derivative and preparation method and use thereof, People's Republic of China's national inventing patent, accept the date: on February 20th, 2006, application number: 200610013185.5, the open date of publication number: CN1810808A.: on August 2nd, 2006); Under the subsidy of state natural sciences fund (30270883 and 20672062) and " 973 " plan (2003CB114402) and Tianjin applied basic research planning items (novel anti plant virus medicament Its Mechanisms), in order to enlarge the screening scope, the contriver utilizes the bioisostere principle that oxadiazole and two active groups of thiadiazoles are introduced to have synthesized with design in a part simultaneously to contain [1 of oxadiazole structural unit, 2,3]-derivative of thiadiazoles, and carried out the especially research of fungicidal activity and induced activity of biological assay, measurement result finds that part of compounds has certain fungicidal activity, and the anti-TMV's of majority of compounds evoking tobacco is active relatively poor.

Table 1 is commercial 1,2, the chemical structure of 3-thiadiazoles derivative

Summary of the invention

Technical problem to be solved by this invention is: new 4-methyl-5-(1 ' is provided, 3 ', 4 '-oxadiazole-2 '-yl)-1,2, the synthetic method of 3-thiadiazoles (E series), the activity and the corresponding screening method that provide this compounds to suppress pathogenic fungi also provide activity and the measuring method thereof of measuring such new compound evoking tobacco resisting tobacco mosaic virus simultaneously.

The present invention solves this technical problem the technical scheme that is adopted: the chemical structure of general formula E series with fungicidal activity and induced activity [1,2,3]-thiadiazoles derivative is as follows, and its concrete chemical structural formula represents to see Table 2:

1,2 of the novel Han oxadiazole of table 2 synthetic of the present invention, the chemical structure characteristic of 3-thiadiazoles derivative

2-of the present invention (4 '-methyl isophthalic acid ', 2 ', 3 '-thiadiazoles-5 '-)-5-replacement-1,3, the synthetic method of 4-oxadiazole derivative (E series) is as follows:

Specifically be divided into following steps:

A.4-methyl isophthalic acid, 2, the preparation of 3-thiadiazoles-5-formyl hydrazine:

With 6.9g (40mmol) 4-methyl isophthalic acid, 2,3-thiadiazoles-5-ethyl formate and 44mmol hydrazine hydrate add in the there-necked flask of falling 50ml, reflux 10 hours, stirred overnight at room temperature adds the intact ester of 40ml sherwood oil flush away unreacted in reaction system, suction filtration, the dry yellow solid 4.9g that gets, yield 77.5%, the consumption of this compound can or dwindle by corresponding proportion expansion;

B. novel 2-(4 '-methyl isophthalic acid ', 2 ', 3 '-thiadiazoles-5 '-)-5-replacement-1,3, the preparation of 4-oxadiazole derivative (E series):

In the 100ml there-necked flask, add 5mmol4-methyl isophthalic acid, 2, the POCl that 3-thiadiazoles-5-formyl hydrazine and equimolar substituted carboxylic acid and 7.5ml heavily steamed ₃, 120 ℃ were refluxed 4～6 hours, and were cooled to room temperature, with in the reaction system impouring 80ml frozen water, standing over night is washed the solid that leaches earlier with diluted sodium hydroxide solution under stirring, wash with water again to neutrality, drying then, gets pure product with 200 orders～300 order silica gel column chromatographies, eluent is 60～90 ℃ sherwood oil and an ethyl acetate, according to the difference of product, volume ratio is certain ratio of selecting between 2: 1～5: 1, mensuration product fusing point, ¹Physical and chemical parameters such as H NMR and ultimate analysis, the consumption of this compound can or dwindle by corresponding proportion expansion;

This analog derivative (E series) also can adopt following method synthetic: add the 5mmol4-methyl isophthalic acid in the 100ml there-necked flask, 2,3-thiadiazoles-5-formyl hydrazine and equimolar replacement acyl chlorides and the anhydrous THF of 10ml, refluxed 4～6 hours, be cooled to room temperature, slough solvent under the rotary evaporation decompression, in resistates, add 10mlPOCl then ₃, 120 ℃ were refluxed the POCl that pressure reducing and steaming is excessive 6 hours ₃Be cooled to room temperature, stir down in the thing impouring 80ml frozen water with the remnants of reaction system, fully stir, with 20 * 3 dichloromethane extractions, organic phase is used saturated sodium bicarbonate aqueous solution and washing respectively behind the separatory, suction filtration behind anhydrous sodium sulfate drying, slough solvent under the rotary evaporation decompression, then, get pure product with 200 orders～300 order silica gel column chromatographies, eluent is 60～90 ℃ sherwood oil and an ethyl acetate, according to the difference of product, volume ratio is certain ratio of selecting between 2: 1～5: 1, mensuration product fusing point, ¹Physical and chemical parameters such as H NMR and ultimate analysis, the consumption of this compound can or dwindle by corresponding proportion expansion;

C. novel 2-(4 '-methyl isophthalic acid ', 2 ', 3 '-thiadiazoles-5 '-)-5-replacement-1,3, the mensuration that 4-oxadiazole derivative (E series) influences the pathogenic fungi growth activity:

Novel 2-of the present invention (4 '-methyl isophthalic acid ', 2 ', 3 '-thiadiazoles-5 '-)-5-replacement-1,3, the measuring method of 4-oxadiazole derivative (E series) fungicidal activity or bacteriostatic activity is as follows:

Adopt thalli growth rate assay method (Mycelium growth rate test), detailed process is, get the 5mg sample dissolution in an amount of dimethyl formamide, then with containing the medicament that a certain amount of polysorbas20 emulsifier aqueous solution is diluted to 500 μ g/ml, reagent agent is respectively drawn 1ml under aseptic condition inject in the culture dish, add the 9ml substratum more respectively, make 50 μ g/ml pastille flat boards after shaking up, do blank with the flat board that adds the 1ml aqua sterilisa, punch tool with diameter 4mm cuts the bacterium dish along the mycelia outer rim, move on the pastille flat board, being equilateral triangle puts, every processing repeats 3 times, culture dish is placed on cultivation in 24 ± 1 ℃ of constant incubators, and colony diameter to be contrasted expands to 2～3cm " Invest, Then Investigate " and respectively handles bacterium dish expansion diameter, averages, relatively calculate relative bacteriostasis rate with blank, comprise more than 20 kind of frequently seen plants pathogenic bacteria for the examination bacterial classification;

Novel 2-D. of the present invention (4 '-methyl isophthalic acid ', 2 ', 3 '-thiadiazoles-5 '-)-5-replacement-1,3, the mensuration that 4-oxadiazole derivative (E series) influences the wheat leaf rust growth activity:

Of the present invention novel 2-(4 '-methyl isophthalic acid ', 2 ', 3 '-thiadiazoles-5 '-)-5-replacement-1,3,4-oxadiazole derivative (E series) is as follows to the measuring method of the fungicidal activity of wheat leaf rust (Urediospore of puccinia recondita Rob.ex Desm.f.sp.puccinia triticina Eriks) or bacteriostatic activity:

Adopt live body plant method (in vivo), detailed process is, with selected susceptible seed, soak 4h with tap water, clean up, place 28 ℃ of constant temperature to break bud 24h, sowing when wheat seedling grows to 1 leaf, 1 heart, promptly can be used for experiment, standby wheat seedling is sprayed water earlier, spray spore powder immediately, the frame of will preserving moisture covers completely with plastic cloth, 20 ± 2 ℃ of controlled temperature, humidity is more than the RH90%, and 24h preserves moisture.The wheat leaf blade of preserving moisture is sprayed compound to be measured, when contrast was fully fallen ill, the vaned sorus number of inquiry agency calculated each processing, comprise the average sorus number of leaf of blank, be calculated as follows out the inhibition effect of test compound wheat leaf rust:

$E=\frac{\mathrm{CK}-T}{\mathrm{CK}}\×100$

Wherein: E is relative effect, unit: %

CK is the average sorus number of blank leaf, unit: heap

T is the average sorus number of treatment group, unit: heap;

Novel 2-E. of the present invention (4 '-methyl isophthalic acid ', 2 ', 3 '-thiadiazoles-5 '-)-5-replacement-1,3, the mensuration of 4-oxadiazole derivative (E series) inducing anti-disease activity:

2-of the present invention (4 '-methyl isophthalic acid ', 2 ', 3 '-thiadiazoles-5 '-)-5-replacement-1,3, the active screening method of 4-oxadiazole derivative (E series) evoking tobacco resisting tobacco mosaic virus (TMV) is as follows:

I. the selection of standard plant inducing anti-disease activator: selecting tiadinil (TDL) and diazosulfide (BTH) is the plant inducing anti-disease activator of standard, the vitro Screening of all compounds adopts 500 μ g/ml, the mensuration of BTH induced activity adopts 100 μ g/ml (Bion 50% WG, purity 50%), TDL (purity is greater than 99.5%) and compound of the present invention adopt 500 μ g/ml;

II. the active screening method of the anti-TMV of new compound evoking tobacco: the mensuration of the direct antiviral activity that exsomatizes adopts half page of method to carry out; It is common cigarette with the seedling age unanimity that live body is induced, 3 basins are one group, cigarette seedling respectively at inoculation pre-treatment in preceding 7 days, processing mode comprises: spray test compound solution 2 to 3 times, each 20ml, the 7th day frictional inoculation TMV on the tobacco leaf that newly grows, place its growth optimal temperature and the following cultivation of illumination after 3 days the cigarette seedling, check incidence, comprehensive scab number is calculated as follows out the inducing anti-disease toxic effect fruit of test compound to TMV, 3 repetitions are established in each processing, and contrast divides blank and standard chemicals treatment to contrast 2 kinds; The relative effect of test compounds is divided into 4 grades: A, B, C, D, and concrete data are the A level: induce effect＞70%, for excellent; B level: induce effect 70～50%, for very; C level: induce effect 30～50%, for poor; D level: induce effect＜30% to be considered as not having and induce effect:

$R=\frac{\mathrm{CK}-I}{\mathrm{CK}}\×100$

Wherein, R is the induce effect of new compound to the anti-TMV of tobacco, unit: %

CK is the average withered spot number of clear water contrast blade, unit: individual

[for induce the average withered spot number of handling rear blade, unit: individual through compound;

The invention has the beneficial effects as follows: 1,2,3-thiadiazoles-5-carboxamides derivatives TDL is a plant inducing anti-disease activator, and the present invention has carried out the optimization of first guide structure to this compound, and new synthetic compound has further been carried out the screening of bacteriostatic activity and the mensuration of induced activity.

The present invention will more specifically describe the 4-methyl isophthalic acid of Han oxadiazole structural unit by specific preparation and biological activity determination embodiment, 2, synthetic and the biological activity of 3-thiadiazole derivative, but described embodiment only is used for specific description the present invention and unrestricted the present invention, especially its biological activity only illustrates, rather than the restriction this patent, concrete embodiment is as follows:

Embodiment 1

Compound 4-methyl isophthalic acid, 2, the preparation of 3-thiadiazoles-5-formyl hydrazine

With 6.9g (40mmol) 4-methyl isophthalic acid, 2,3-thiadiazoles-5-ethyl formate and 44mmol hydrazine hydrate add in the there-necked flask of falling 50ml, reflux 10 hours, stirred overnight at room temperature then, reaction system yellowly solid, add the intact ester of 40ml sherwood oil flush away unreacted, suction filtration, dry yellow solid 4.9g, the yield 77.5% of getting.

Embodiment 2

Synthetic and the structure of compd E-1 is identified

With 0.79g (5mmol) 4-methyl isophthalic acid, 2,3-thiadiazoles-5-formyl hydrazine and equimolar p-methylbenzoic acid join in the 100ml there-necked flask, add the POCl that 7.5ml heavily steamed ₃, 120 ℃ were refluxed 6 hours, and were cooled to room temperature.Stir down in the reaction system impouring 80ml frozen water, standing over night, the solid that leaches is washed with diluted sodium hydroxide solution earlier, wash to neutrality drying again with water, then, with 200～300 order silica gel column chromatographies, get pure product 0.32g, eluent is 60～90 ℃ sherwood oil and an ethyl acetate, volume ratio is 3: 1, yield 25.0%.Measure fusing point and ¹H NMR, its chemical structural formula and physical and chemical parameter see Table 3 and table 4.By table 3 and table 4 as seen, this compound ¹H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide.

Embodiment 3

Synthetic and the structure of compd E-2 is identified

With 0.32g (2mmol) 4-methyl isophthalic acid, 2,3-thiadiazoles-5-formyl hydrazine and equimolar anisic acid join in the 50ml there-necked flask, add the POCl that 3ml heavily steamed ₃, 120 ℃ were refluxed 6 hours, and were cooled to room temperature.Stir down in the reaction system impouring 80ml frozen water, static spending the night, the solid that leaches is washed with diluted sodium hydroxide solution earlier, wash to neutrality drying again with water, then, with 200～300 order silica gel column chromatographies, eluent is 60～90 ℃ sherwood oil and an ethyl acetate, and volume ratio is 2: 1, get pure product 0.27g, yield 49.2%.Measure fusing point and ¹HNMR, its chemical structural formula and physical and chemical parameter see Table 3 and table 4.By table 3 and table 4 as seen, this compound ¹H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide.

Embodiment 4

Synthetic and the structure of compd E-3 is identified

With 0.32g (2mmol) 4-methyl isophthalic acid, 2, the m-methyl benzoic acid of 3-thiadiazoles-5-formyl hydrazine and 0.29g (2.1mmol) joins in the 50ml there-necked flask, adds the POCl that 4ml heavily steamed ₃, 120 ℃ were refluxed 6 hours, and were cooled to room temperature.Stir down in the reaction system impouring 40ml frozen water, static spending the night, the solid that leaches is washed with diluted sodium hydroxide solution earlier, wash to neutrality drying again with water, then, with 200 orders～300 order silica gel column chromatographies, get pure product 0.09g, eluent is 60～90 ℃ sherwood oil and an ethyl acetate, volume ratio is 5: 1, yield 17.4%.Measure fusing point and ¹H NMR, its chemical structural formula and physical and chemical parameter see Table 3 and table 4.By table 3 and table 4 as seen, this compound ¹H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide.

Embodiment 5

Synthetic and the structure of compd E-4 is identified

With 0.32g (2mmol) 4-methyl isophthalic acid, 2, the o-methoxybenzoic acid of 3-thiadiazoles-5-formyl hydrazine and 0.30g (2mmol) joins in the 50ml there-necked flask, adds the POCl that 5ml heavily steamed ₃, 120 ℃ were refluxed 4.5 hours, and were cooled to room temperature.Stir down in the reaction system impouring 60ml frozen water, static several minutes, the solid that leaches is washed with diluted sodium hydroxide solution earlier, wash to neutrality drying again with water, then, with 200 orders～300 order silica gel column chromatographies, get pure product 0.24g, eluent is 60～90 ℃ sherwood oil and an ethyl acetate, volume ratio is 2: 1, productive rate 44.0%.The mensuration fusing point, ¹H NMR and ultimate analysis, its chemical structural formula and physical and chemical parameter see Table 3 and table 4.By table 3 and table 4 as seen, results of elemental analyses in the limit of error that allows, this compound ¹H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide.

Embodiment 6

Synthetic and the structure of compd E-6 is identified

With 0.32g (2mmol) 4-methyl isophthalic acid, 2,5-methyl-2-phenyl-2H-[1 of 3-thiadiazoles-5-formyl hydrazine and 0.41g (2mmol), 2,3] triazole-4-formic acid joins in the 50ml there-necked flask, adds the POCl that 10ml heavily steamed ₃, 120 ℃ were refluxed 6 hours, and were cooled to room temperature.With in the reaction system impouring 100ml frozen water, add NaOH under stirring, regulate the pH value to neutral, static, suction filtration, drying, then, with 200 orders～300 order silica gel column chromatographies, get pure product 0.27g, eluent is 60～90 ℃ sherwood oil and an ethyl acetate, and volume ratio is 4: 1, yield 41.5%.Measure fusing point and ¹H NMR, its chemical structural formula and physical and chemical parameter see Table 3 and table 4.By table 3 and table 4 as seen, this compound ¹H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide.

Embodiment 7

Synthetic and the structure of compd E-7 is identified

With 0.32g (2mmol) 4-methyl isophthalic acid, 2, the 6-hydroxy niacin of 3-thiadiazoles-5-formyl hydrazine and 0.28g (2mmol) joins in the 50ml there-necked flask, adds the POCl that 10ml heavily steamed ₃, 120 ℃ were refluxed 6 hours, and were cooled to room temperature, with in the reaction system impouring 100ml frozen water, add NaOH under stirring, regulate the pH value to neutral, static, suction filtration, drying, then, get pure product 0.10g with 200 orders～300 order silica gel column chromatographies, eluent is 60～90 ℃ sherwood oil and an ethyl acetate, and volume ratio is 2: 1, productive rate 19.1%.Measure fusing point and ¹H NMR, its chemical structural formula and physical and chemical parameter see Table 3 and table 4.By table 3 and table 4 as seen, this compound ¹H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide.

Embodiment 8

Synthetic and the structure of compd E-8 is identified

With 0.32g (2mmol) 4-methyl isophthalic acid, 2,1-(4-chloro-phenyl-)-5-n-propyl-1H-pyrazoles-4-formyl chloride of 3-thiadiazoles-5-formyl hydrazine and 0.57g (2mmol) joins in the 50ml there-necked flask, adds the anhydrous THF of 10ml, refluxed 4 hours, and sloughed solvent under the rotary evaporation decompression.In resistates, add 10mlPOCl then ₃, 120 ℃ were refluxed the POCl that pressure reducing and steaming is excessive 6 hours ₃Remaining oily matter is poured in the 80ml frozen water, stirs, and uses 20 * 3 dichloromethane extractions then, organic phase is used saturated sodium bicarbonate aqueous solution and washing respectively behind the separatory, suction filtration behind anhydrous sodium sulfate drying is sloughed solvent under the rotary evaporation decompression, with 200 orders～300 order silica gel column chromatographies, get pure product 0.31g, eluent is 60～90 ℃ sherwood oil and an ethyl acetate, and volume ratio is 4: 1, productive rate 40.1%.Measure fusing point and ¹H NMR, its chemical structural formula and physical and chemical parameter see Table 3 and table 4.By table 3 and table 4 as seen, this compound ¹H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide.

Embodiment 9

Synthetic and the structure of compd E-9 is identified

With 0.16g (1mmol) 4-methyl isophthalic acid, 2, the 2-chloro-6-methylnicotinic acid of 3-thiadiazoles-5-formyl hydrazine and 0.17g (1mmol) joins in the 50ml there-necked flask, adds the POCl that 5ml heavily steamed ₃, 120 ℃ were refluxed 6 hours, and were cooled to room temperature.With in the reaction system impouring 100ml frozen water, add NaOH under stirring, regulate the pH value to neutral, static, suction filtration, drying, then, with 200 orders～300 order silica gel column chromatographies, get pure product 0.14g, eluent is 60～90 ℃ sherwood oil and an ethyl acetate, and volume ratio is 2: 1, productive rate 47.7%.Measure fusing point and ¹HNMR, its chemical structural formula and physical and chemical parameter see Table 3 and table 4.By table 3 and table 4 as seen, this compound ¹HNMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide.

Embodiment 10

Synthetic and the structure of compd E-11 is identified

With 0.32g (2mmol) 4-methyl isophthalic acid, 2, the 6-chlorine apellagrin of 3-thiadiazoles-5-formyl hydrazine and 0.32g (2mmol) joins in the 50ml there-necked flask, adds the POCl that 10ml heavily steamed ₃, 120 ℃ were refluxed 6 hours, and were cooled to room temperature.With in the reaction system impouring 80ml frozen water, add Na under stirring ₂CO ₃, regulate the pH value to neutral, static, suction filtration, drying then, with 200 orders～300 order silica gel column chromatographies, gets pure product 0.08g, and eluent is 60～90 ℃ sherwood oil and an ethyl acetate, and volume ratio is 3: 1, productive rate 14.3%.Measure fusing point and ¹H NMR, its chemical structural formula and physical and chemical parameter see Table 3 and table 4.By table 3 and table 4 as seen, this compound ¹H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide.

Embodiment 11

Synthetic and the structure of compd E-12 is identified

With 0.32g (2mmol) 4-methyl isophthalic acid, 2,5-thiotolene-2-formic acid of 3-thiadiazoles-5-formyl hydrazine and 0.28g (2mmol) joins in the 50ml there-necked flask, adds the POCl that 10ml heavily steamed ₃, 120 ℃ were refluxed 6 hours, and reaction finishes, the POCl that pressure reducing and steaming is excessive ₃With in the resistates impouring 80ml frozen water, stirring makes oily matter become solid, and is static under stirring, suction filtration, dilute sodium hydroxide aqueous solution washing, washing, suction filtration, drying, then, with 200 orders～300 order silica gel column chromatographies, get pure product 0.14g, eluent is 60～90 ℃ sherwood oil and an ethyl acetate, and volume ratio is 3: 1, productive rate 26.5%.Measure fusing point and ¹H NMR, its chemical structural formula and physical and chemical parameter see Table 3 and table 4.By table 3 and table 4 as seen, this compound ¹H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide.

Embodiment 12

Synthetic and the structure of compd E-13 is identified

With 0.47g (3mmol) 4-methyl isophthalic acid, 2, the n-caprylic acid of 3-thiadiazoles-5-formyl hydrazine and 0.43g (3mmol) joins in the 50ml there-necked flask, adds the POCl that 15ml heavily steamed ₃, 120 ℃ were refluxed 6 hours, and reaction finishes, the POCl that pressure reducing and steaming is excessive ₃The back adds the 25ml frozen water, stirs, and adds aqueous sodium hydroxide solution and is neutralized to neutrality, 15 * 2 dichloromethane extractions, washing, the organic phase anhydrous sodium sulfate drying is sloughed solvent under the rotary evaporation decompression, then, with 200 orders～300 order silica gel column chromatographies, get pure product 0.39g, eluent is 60～90 ℃ sherwood oil and an ethyl acetate, volume ratio is 5: 1, productive rate 49.2%.Measure fusing point and ¹H NMR, its chemical structural formula and physical and chemical parameter see Table 3 and table 4.By table 3 and table 4 as seen, this compound ¹H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide.

Embodiment 13

Synthetic and the structure of compd E-14 is identified

With 0.32g (2mmol) 4-methyl isophthalic acid, 2, the styracin of 3-thiadiazoles-5-formyl hydrazine and 0.30g (2mmol) joins in the 50ml there-necked flask, adds the POCl that 10ml heavily steamed ₃, 120 ℃ were refluxed 6 hours, and were cooled to room temperature.With in the reaction system impouring 80ml frozen water, add Na under stirring ₂CO ₃, regulate the pH value to neutral, static, suction filtration, drying then, with 200 orders～300 order silica gel column chromatographies, gets pure product 0.34g, and eluent is 60～90 ℃ sherwood oil and an ethyl acetate, and volume ratio is 3: 1, productive rate 62.9%.Measure fusing point and ¹H NMR, its chemical structural formula and physical and chemical parameter see Table 3 and table 4.By table 3 and table 4 as seen, this compound ¹H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide.

Embodiment 14

Synthetic and the structure of compd E-15 is identified

With 0.47g (3mmol) 4-methyl isophthalic acid, 2, the 4-methyl isophthalic acid of 3-thiadiazoles-5-formyl hydrazine and 0.43g (3mmol), 2,3-thiadiazoles-5-formic acid joins in the 50ml there-necked flask, adds the POCl that 15ml heavily steamed ₃, 120 ℃ were refluxed 6 hours, and reaction finishes, the POCl that pressure reducing and steaming is excessive ₃, with in the resistates impouring 80ml frozen water, add saturated sodium bicarbonate aqueous solution under stirring, regulate the pH value to neutral, static, suction filtration, drying, then, with 200 orders～300 order silica gel column chromatographies, get pure product 0.32g, eluent is 60～90 ℃ sherwood oil and an ethyl acetate, volume ratio is 4: 1, productive rate 40.2%.The mensuration fusing point, ¹H NMR and ultimate analysis, its chemical structural formula and physical and chemical parameter see Table 3 and table 4.By table 3 and table 4 as seen, results of elemental analyses in the limit of error that allows, this compound ¹H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide.

Embodiment 15

Synthetic and the structure of compd E-16 is identified

With 0.32g (2mmol) 4-methyl isophthalic acid, 2, furans-2-formic acid of 3-thiadiazoles-5-formyl hydrazine and 0.22g (2mmol) joins in the 50ml there-necked flask, adds the POCl that 10ml heavily steamed ₃, 120 ℃ were refluxed 6 hours, and reaction finishes, the POCl that pressure reducing and steaming is excessive ₃, with in the resistates impouring 80ml frozen water, add saturated sodium bicarbonate aqueous solution under stirring, regulate the pH value to neutral, static, suction filtration, drying.Then, with 200 orders-300 order silica gel column chromatography, get pure product 0.17g, eluent is 60-90 ℃ sherwood oil and an ethyl acetate, and volume ratio is 3: 1, productive rate 36.7%.Measure fusing point and ¹H NMR, its chemical structural formula and physical and chemical parameter see Table 3 and table 4.By table 3 and table 4 as seen, this compound ¹H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide.

Embodiment 16

Synthetic and the structure of compd E-18 is identified

With 0.32g (2mmol) 4-methyl isophthalic acid, 2, the 1-methyl of 3-thiadiazoles-5-formyl hydrazine and 0.31g (2mmol)-5-ethyl pyrazoles-3-formic acid joins in the 50ml there-necked flask, adds the POCl that 10ml heavily steamed ₃, 120 ℃ were refluxed 6 hours, and reaction finishes, the POCl that pressure reducing and steaming is excessive ₃, with in the resistates impouring 80ml frozen water, add saturated sodium bicarbonate aqueous solution under stirring, regulate the pH value to neutral, static, suction filtration, drying.Then, with 200 orders-300 order silica gel column chromatography, get pure product 0.28g, eluent is 60-90 ℃ sherwood oil and an ethyl acetate, and volume ratio is 1: 1, productive rate 39.5%.Measure fusing point and ¹H NMR, its chemical structural formula and physical and chemical parameter see Table 3 and table 4.By table 3 and table 4 as seen, this compound ¹H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide.

Embodiment 17

Novel 2-of the present invention (4 '-methyl isophthalic acid ', 2 ', 3 '-thiadiazoles-5 '-)-5-replacement-1,3, the bacteriostatic activity of 4-oxadiazole derivative:

The title and the code name of the frequently seen plants pathogenic fungi of the present invention's test see Table 5, and by table 5 as seen, these bacterial classifications have good representativeness.Thalli growth rate method measurement result sees Table 6, table 6 shows, synthetic majority of compounds of the present invention all has bacteriostatic action in various degree to the growth of most of pathogenic fungi of mensuration: when 50 μ g/ml, E1 is 56.0% to the inhibiting rate of Sclerotinia sclerotiorum, is 67.9% to the inhibiting rate of miliary damping-off; E2 is 58.3% to the inhibiting rate of ring rot of apple bacterium.

Embodiment 18

Novel 2-(4 '-methyl isophthalic acid ', 2 ', 3 '-thiadiazoles-5 '-)-5-replaces-1,3, and the 4-_ oxadiazole derivative is to the effect of wheat leaf rust:

The physical and chemical parameter of table 3 The compounds of this invention

Compound	Outward appearance	Molecular formula	m.p./℃	Productive rate %	Ultimate analysis (experimental value/theoretical value)
								C	H	N
					E-1	White crystal	C 12H 10N 4OS				135～136	25.0	Undetermined	Undetermined	Undetermined
E-2	White crystal	C 12H 10N 4O 2S	126～127	49.2				Undetermined	Undetermined	Undetermined
					E-3	White crystal	C 12H 10N 4OS				131～132	17.4	Undetermined	Undetermined	Undetermined
E-4	White crystal	C 12H 10N 4O 2S	156～157	44.0				52.07(52.54)	3.89(3.67)	19.95(20.43)
					E-6	White crystal	C 14H 11N 7OS				159～160	41.5	Undetermined	Undetermined	Undetermined
E-7	White crystal	C 10H 7N 5O 2S	146～147	19.1				Undetermined	Undetermined	Undetermined
					E-8	White crystal	C 17H 15ClN 6OS				98～100	40.1	Undetermined	Undetermined	Undetermined
E-9	White crystal	C 11H 8ClN 5OS	119	47.7				Undetermined	Undetermined	Undetermined
					E-11	White crystal	C 10H 6ClN 5OS				147～148	14.3	Undetermined	Undetermined	Undetermined
E-12	White crystal	C 10H 8N 4OS 2	139～140	26.5				Undetermined	Undetermined	Undetermined
					E-13	Red liquid	C 12H 18N 4OS				Undetermined	49.2	Undetermined	Undetermined	Undetermined
E-14	White crystal	C 13H 10N 4OS	187～188	62.9				Undetermined	Undetermined	Undetermined
					E-15	White crystal	C 8H 6N 6OS 2				134～135	40.2	36.09(36.08)	2.32(2.27)	31.50(31.56)
E-16	White crystal	C 9H 6N 4O 2S	Undetermined	36.7				Undetermined	Undetermined	Undetermined
					E-18	White crystal	C 11H 12N 6OS				Undetermined	39.5	Undetermined	Undetermined	Undetermined

Table 4 The compounds of this invention ¹H NMR data

Numbering	1H NMR δ (solvent C DCl 3)
		E-1	2.40(3H，s，CH 3)，3.10(3H，s，thiadiazole-CH 3)，7.29～7.32(2H，d，J＝8.0Hz，benzene-H)，7.94～7.96(2H，d，J＝8.3Hz，benzene-H)
E-2	3.16(3H，s，thiadiazole-CH 3)，3.91(3H，s，-OCH 3)，7.05～7.08(2H，d，J＝8.9Hz，CH＝CH)，8.06～8.09(2H，d，J＝8.9Hz，CH＝CH)
		E-3	2.48(3H，s，CH 3)，3.17(3H，s，thiadaizole-CH 3)，7.40～7.46(2H，m，benzene-H)，7.91～7.98(2H，m，benzene-H)
E-4	3.16(3H，s，thiadiazole-CH 3)，4.01(3H，s，-OCH 3)，7.09～7.16(3H，m，benzene-H)，7.56～7.61(1H，t，J＝8.3Hz，benzene-H)，8.04～8.07 (1H，d，J＝7.7Hz，benzene-H)
		E-6	2.79(3H，s，CH 3)，3.20(3H，s，thiadiazole-CH 3)，7.52～7.57(3H，m，benzene-H)8.14～8.17(2H，d，J＝8.3Hz)
E-7	3.17(3H，s，thiadiazole-CH 3)7.56～7.59(3H，d，J＝8.4Hz，pyridinone-H)，837～8.41(1H，d，J＝8.4Hz，pyridinone-H)，9.13(1H，s， pyridinone-H)
		E-8	0.90～0.95(3H，t，J＝7.3Hz，CH 3)，1.62～1.69(2H，q，J＝7.5Hz，CH 2)，3.05～3.10(2H.t，J＝7.8Hz，CH 2)，7.40～7.43(2H，d，J＝8.7Hz，ben- zene-H)，7.52～7.55(2H，d，J＝8.5Hz，benzene-H)，8.15(1H，s，pyrazole-H)
E-9	2.68(3H，s，CH 3)，3.18(3H，s，thiadiazole-CH 3)，7.32～7.34(1H，d，J＝7.9Hz，Benzene-H)，8.36～8.39(1H，d，J＝7.9Hz，benzene-H)
		E-11	3.18(3H，s，CH 3)，7.56～7.58(1H，d，J＝8.4Hz，pyridine-H)，8.37～8.41(1H，q，J＝8.4Hz，pyridine-H)，9.12～9.13(1H，d，J＝2.4Hz)
E-12	2.60(3H，s，CH 3)，3.14(3H，s，CH 3)，6.88～6.89(1H，d，J＝3.7Hz，H-thiophene)，7.67～7.68(1H，d，J＝3.7Hz，H-thiophene)
		E-13	0.87～0.91(3H，t，J＝6.7Hz，CH 3)，1.30～1.43(8H，m，-(CH 2) 4-)，1.81～1.91(2H，m，CH 2)，2.93～2.98(2H，t，J＝7.5Hz)，3.09(3H，s，CH 3)
E-14	3.16(3H，s，CH 3)，7.08～7.14(1H，d，J＝16.4Hz，CH＝CH)，7.44～7.46(3H，m，benzene-H)，7.60～7.63(2H，m，benzene-H)，7.65～7.70 (1H，d，J＝16.4Hz，CH＝CH)
		E-15	3.17(6H，s，thiadiazole-CH 3)
E-16	3.14(3H，s，CH 3)，6.66-6.67(1H，q，J＝1.8Hz，H-thiophene)，7.31-7.32(1H，d，J＝3.5Hz，H-thjophene)，7.72(1H，d，J＝1.6Hz，H-thio- phene)
		E-18	1.32～1.38(3H，t，J＝7.5Hz，CH 3)，2.67～2.74(2H，d，J＝7.5Hz，CH 2)，3.16(3H，s，thiadiazole-CH 3)，3.93(3H，s，-N-CH 3)，6.79(1H，s，H- pyrazole)

Code name of the plant pathogenic fungi of the test among table 5 the present invention and title

Code name	Chinese	Formal name used at school	Code name	Chinese	Formal name used at school
						A	Sugar beet leaf spot bacteria	Cercospora beticola	Q	Valsa mali	Valsa mali
B	Fusarium moniliforme	Gibberella fujikuroi	R	Glorosprium musarum Cookeet Mass	Glomerella cingulata
						C	Cucumber fusarium axysporum	Fusarium oxysporum	U	Watermelon anthrax bacteria	Colletotrichum lagenarium
D	Peanut Cercospora bacteria	Cercospora arachidicola	V	Apple anthrax bacteria	Glomerella cingulata
						E	Asparagus stem wilt bacteria	Phoma asparagi	W	Cucumber anthracnose	Colletotrichum lagenarium
F	Tomato early blight bacterium	Alternaria solani	X	The pears alternaria	Alternaria kikuchiana
						G	Fusarium graminearum	Gibberella zeae	AE	Cotton-wilt fusarium	Fusarium vasinfectum
I	The ring rot of apple bacterium	Physalospora piricola	AF	Verticillium dahliae	Verticilium dahliae
						J	The bent germ of paddy rice	Ustilaginoidea virens	AD	Corn bottom class germ	Bipolaris maydis
L	Botrytis cinerea pers	Botrytis cinerea	AEA	Phytophthora infestans	Phytophthora infestans
						N	Sclerotinia sclerotiorum	Sclerotinia sclerotiorum	RC	Cereal silk nuclear germ	Rhizoctonia cerealis
O	Apple zonate spot bacterium	Alternaria mali	S	The banana sigatoka leaf spot disease bacterium	Cercosporamusae (Mycosphaerella musicola)
						P	Rice blast fungus	Phyricularia grisea(Cooke)Sacc.
AC	The miliary damping-off germ	Rhizoctonia solani
			AJ	Wheat leaf rust	Urediospore of puccinia.recondita Rob.ex Desm.f.sp.puccinia triticina Eriks

(data are the inhibition percentage/%) to pathogenic bacteria growth to the fungicidal activity of the compound among table 6 the present invention in the table

The test code name	Szg -b	E-2- a	E-2- b	E-2- c	E-3- b	E-4- a	E-6	E-8	E-8- b	E-9- a	E-11	E-12	E-13 -a	E-13 -b	E-14	E-15 -b
																	The structure code name	E-1		E-2		E-3	E-4	E-6	E-8	E-8	E-9	E-11	E-12	E-13		E-14	E-15
μg/ml	50	50	50	50	50	50	50	50	50	50	50	50	50	50	50	50
																	AC	67.9	0	0	0	0	0	0	0	0	22.2	13.3	0	26.6	0	0	0
AE	ND	0	0	0	0	0	0	0	0	0	0	0	0	31.6	23.7	0
																	AJ	ND	ND	0	ND	ND	20	ND	ND	ND	30.0	ND	ND	100	ND	20	ND
B	ND	0	0	0	24.1	17.2	0	31.0	0	17.2	12.5	21.1	21.1	31.6	21.1	21.1
																	C	ND	0	0	0	0	0	0	0	0	0	18.8	31.3	12.5	18.8	36.3	31.3
D	ND	17.6	17.6	17.6	23.5	17.6	17.6	41.2	41.2	23.5	0	9	0	0	27.3	13.6
																	F	18.4	17.6	11.7	0	0	11.7	17.6	17.6	29.4	0	23.7	36.8	31.6	36.8	31.6	44.7
G	ND	37 9	31.0	13.8	24.1	31.0	31.0	48.3	41.4	31.0	10.5	21.1	34.2	13.2	36.8	31.6
																	I	ND	33.3	58.3	0	47.2	33.3	44.4	44.4	55.5	38.9	47.6	39.7	25.4	38.1	46	38.1
J	ND	29.4	29.4	11.7	0	0	0	0	17.6	17 6	0	0	0	0	0	0
																	L	2.1	31.0	13.8	17.2	37.9	13.8	41.4	31.0	17.2	17.2	0	0	0	0	0	0
N	56.0	23.5	29.4	41.2	23.5	23.5	23.5	23.5	29.4	0	32.1	40.5	32.1	0	0	32.1
																	O	ND	37.9	13.8	31.0	41.4	27.6	31.0	27.6	13.8	24.1	38.9	38.9	38.9	49.2	0	0
Q	ND	47.2	44.4	38.9	47.2	41.2	22.2	19.4	33.3	22.2	41.4	0	0	0	20.3	0
																	R	ND	29.4	11.7	0	0	0	0	0	0	0	0	13.8	42.1	0	13.8	13.8
RC	ND	31.0	17.2	13.8	37.9	13.8	37.9	31.0	41.4	13.8	38.5	0	0	19.3	0	0
																	U	ND	0	0	0	0	0	0	0	0	0	27.1	27.1	0	0	0	0
V	ND	0	0	0	0	0	0	0	0	0	0	0	0	0	13.8	0

ND: undetermined

What biological assay was tested the results are shown in Table 6, table 6 shows, the part [1 that the present invention finds, 2,3] thiadiazoles derivative has certain fungicidal activity or bacteriostatic activity to wheat leaf rust, wherein E-13-a is 100% to the inhibiting rate of wheat leaf rust, and its fungicidal activity is not as good as commercial contrast medicament m-tetrachlorophthalodinitrile, but this is to find that first this compounds that contains the oxadiazole structural unit has the growth-inhibiting effect to wheat leaf rust.

Embodiment 19

Novel 2-of the present invention (4 '-methyl isophthalic acid ', 2 ', 3 '-thiadiazoles-5 '-)-5-replacement-1,3, the effect of the derivative induced tobacco resisting tobacco mosaic virus of 4-oxadiazole:

What biological assay was tested the results are shown in Table 7, table 7 shows, the plant inducing anti-disease activator BTH of standard and tiadinil and of the present invention [1,2,3] thiadiazoles derivative under isolated condition to TMV unrestraint effect, but BTH can evoking tobacco produces the resistance to TMV, and tiadinil also can evoking tobacco produces the resistance to TMV, but effect is poor than BTH; Major part of the present invention [1,2,3] thiadiazoles derivative does not have the activity of the anti-TMV of evoking tobacco.

The activity of the compound evoking tobacco resisting tobacco mosaic virus among table 7 the present invention

The medicament title	Concentration μ g/mL	Antiviral effect % exsomatizes	Concentration μ g/mL	Blade face inducing anti-disease toxic effect fruit %
					BTH	100	0	100	95
TDL	500	0	500	50
					E-1	500	Not detected	500	Not detected
E-2	500	Not detected	500	Not detected
					E-3	500	Not detected	500	Not detected
E-4	500	Not detected	500	Not detected
					E-6	500	Not detected	500	Not detected
E-7	500	Not detected	500	Not detected
					E-8	500	Not detected	500	Not detected
E-9	500	Not detected	500	Not detected
					E-11	500	Not detected	500	Not detected
E-12	500	Not detected	500	Not detected
					E-13	500	0	500	0
E-14	500	0	500	0
					E-15	500	Not detected	500	Not detected
E-16	500	Not detected	500	Not detected
					E-17	500	0	500	20
E-18	500	0	500	20

Annotate: data are average results of 3 experiments in the table

Claims (6)

1. the novel nitrogen-containing sulfur heterocyclic compound 1,2, and the 3-thiadiazoles derivative is characterized in that: have following chemical structural formula:

2. described novel 1,2 of the oxadiazole structural unit that contains of claim 1, the synthetic method of the intermediate of 3-thiadiazoles derivative and synthetic this compounds is characterized in that total synthetic route is:

Specifically be divided into following steps:

A.4-methyl isophthalic acid, 2, the preparation of 3-thiadiazoles-5-formyl hydrazine:

With 6.9g (40mmol) 4-methyl isophthalic acid, 2,3-thiadiazoles-5-ethyl formate and 44mmol hydrazine hydrate add in the there-necked flask of falling 50ml, reflux 10 hours, stirred overnight at room temperature then, reaction system yellowly solid, add the intact ester of 40ml sherwood oil flush away unreacted, suction filtration, the dry yellow solid 4.9g that gets, yield 77.5%, the consumption of this compound can enlarge or dwindle in proportion;

B. novel 2-(4 '-methyl isophthalic acid ', 2 ', 3 '-thiadiazoles-5 '-)-5-replacement-1,3, the preparation of 4-oxadiazole derivative (E series):

In the 100mL there-necked flask, add 5mmol4-methyl isophthalic acid, 2, the POCl that 3-thiadiazoles-5-formyl hydrazine and equimolar substituted carboxylic acid and 7.5ml heavily steamed ₃, 120 ℃ were refluxed 4～6 hours, and were cooled to room temperature, with in the reaction system impouring 80ml frozen water, standing over night is washed the solid that leaches earlier with diluted sodium hydroxide solution under stirring, wash with water again to neutrality, drying then, gets pure product with 200 orders～300 order silica gel column chromatographies, eluent is 60～90 ℃ sherwood oil and an ethyl acetate, according to the difference of product, volume ratio is certain ratio of selecting between 2: 1～5: 1, mensuration product fusing point, ¹Physical and chemical parameters such as H NMR and ultimate analysis, the consumption of this compound can or dwindle by corresponding proportion expansion;

This analog derivative (E series) also can adopt following method synthetic:

In the 100mL there-necked flask, add the 5mmol4-methyl isophthalic acid, 2,3-thiadiazoles-5-formyl hydrazine and equimolar replacement acyl chlorides and the anhydrous THF of 10ml refluxed 4～6 hours, were cooled to room temperature, sloughed solvent under the rotary evaporation decompression, added 10mlPOCl then in resistates ₃, 120 ℃ were refluxed the POCl that pressure reducing and steaming is excessive 6 hours ₃Be cooled to room temperature, stir down in the thing impouring 80ml frozen water with the remnants of reaction system, fully stir, use 20 * 3 dichloromethane extractions then, organic phase is used saturated sodium bicarbonate aqueous solution and washing respectively behind the separatory, suction filtration behind anhydrous sodium sulfate drying, slough solvent under the rotary evaporation decompression, then, get pure product with 200 orders～300 order silica gel column chromatographies, eluent is 60～90 ℃ sherwood oil and an ethyl acetate, according to the difference of product, volume ratio is certain ratio of selecting between 2: 1～5: 1, mensuration product fusing point, ¹Physical and chemical parameters such as H NMR and ultimate analysis, the consumption of this compound can or dwindle by corresponding proportion expansion.

3. claim 1 is described contains 1,3, and the bioactive screening method of novel [1,2,3] thiadiazoles derivative of 4-oxadiazole structural unit is as follows:

Novel 2-A. of the present invention (4 '-methyl isophthalic acid ', 2 ', 3 '-thiadiazoles-5 '-)-5-replacement-1,3, the mensuration that 4-oxadiazole derivative (E series) influences the pathogenic fungi growth activity:

Adopt thalli growth rate assay method (Mycelium growth rate test), detailed process is, get the 5mg sample dissolution in an amount of dimethyl formamide, then with containing the medicament that a certain amount of polysorbas20 emulsifier aqueous solution is diluted to 500 μ g/mL, reagent agent is respectively drawn under aseptic condition in 1mL or the 0.5mL injection culture dish, add 9mL or 9.5mL substratum more respectively, make 50 μ g/mL or 25 μ g/mL pastille flat boards after shaking up, do blank with the flat board that adds the 1mL aqua sterilisa, do blank with the flat board that adds the 1mL aqua sterilisa, punch tool with diameter 4mm cuts the bacterium dish along the mycelia outer rim, move on the pastille flat board, being equilateral triangle puts, every processing repeats 3 times, culture dish is placed in 24 ± 1 ℃ of constant incubators cultivates, and " Invest, Then Investigate " was respectively handled bacterium dish expansion diameter in 48 hours, average, relatively calculate relative bacteriostasis rate with blank.Early epidemic disease (Alternaria), asparagus stem withered (Phoma asparagi solani), apple are taken turns 22 kinds of line (Physalosporapiricola) and peanut foxiness (Cercospora arachidicola) etc. to comprise gibberella saubinetii (Gibberella zeae), tomato for the examination pathogenic fungi;

Novel 2-B. of the present invention (4 '-methyl isophthalic acid ', 2 ', 3 '-thiadiazoles-5 '-)-5-replacement-1,3, the mensuration that 4-oxadiazole derivative (E series) influences the wheat leaf rust growth activity:

Of the present invention novel 2-(4 '-methyl isophthalic acid ', 2 ', 3 '-thiadiazoles-5 '-)-5-replacement-1,3,4-oxadiazole derivative (E series) is as follows to the measuring method of the fungicidal activity of wheat leaf rust (Urediospore of puccinia.recondita Rob.ex Desm.f.sp.puccinia triticina Eriks) or bacteriostatic activity:

Adopt live body plant method (in vivo), detailed process is, with selected susceptible seed, soak 4h with tap water, clean up, place 28 ℃ of constant temperature to break bud 24h, sowing when wheat seedling grows to 1 leaf, 1 heart, promptly can be used for experiment, standby wheat seedling is sprayed water earlier, spray spore powder immediately, the frame of will preserving moisture covers completely with plastic cloth, 20 ± 2 ℃ of controlled temperature, humidity is more than the RH90%, and 24h preserves moisture.The wheat leaf blade of preserving moisture is sprayed compound to be measured, when contrast was fully fallen ill, the vaned sorus number of inquiry agency calculated each processing, comprise the average sorus number of leaf of blank, be calculated as follows out the inhibition effect of test compound wheat leaf rust:

$E=\frac{\mathrm{CK}-T}{\mathrm{CK}}\×100$

Wherein: E is relative effect, unit: %

CK is the average sorus number of blank leaf, unit: heap

T is the average sorus number of treatment group, unit: heap;

Novel 2-C. of the present invention (4 '-methyl isophthalic acid ', 2 ', 3 '-thiadiazoles-5 '-)-5-replacement-1,3, the mensuration of 4-oxadiazole derivative (E series) inducing anti-disease activity:

4-methyl isophthalic acid of the present invention, 2, the active screening method of 3-thiadiazoles derivative evoking tobacco resisting tobacco mosaic virus (TMV) is as follows:

I. the selection of standard plant inducing anti-disease activator: selecting tiadinil (TDL) and diazosulfide (BTH) is the plant inducing anti-disease activator of standard, the vitro Screening of all compounds adopts 500 μ g/mL, the mensuration of BTH induced activity adopts 100 μ g/mL (Bion 50%WG, purity 50%), TDL (purity is greater than 99.5%) and compound of the present invention adopt 500 μ g/mL;

II. the active screening method of the anti-TMV of new compound evoking tobacco: the mensuration of the direct antiviral activity that exsomatizes adopts half page of method to carry out; It is common cigarette with the seedling age unanimity that live body is induced, 3 basins are one group, cigarette seedling respectively at inoculation pre-treatment in preceding 7 days, processing mode comprises: spray test compound solution 2 to 3 times, each 20mL, the 7th day frictional inoculation TMV on the tobacco leaf that newly grows, place its growth optimal temperature and the following cultivation of illumination after 3 days the cigarette seedling, check incidence, comprehensive scab number is calculated as follows out the inducing anti-disease toxic effect fruit of test compound to TMV, 3 repetitions are established in each processing, and contrast divides blank and standard chemicals treatment to contrast 2 kinds; The relative effect of test compounds is divided into 4 grades: A, B, C, D, and concrete data are the A level: induce effect＞70%, for excellent; B level: induce effect 70～50%, for very; C level: induce effect 30～50%, for poor; D level: induce effect＜30% to be considered as not having and induce effect:

$R=\frac{\mathrm{CK}-I}{\mathrm{CK}}\×100$

Wherein, R is the induce effect of new compound to the anti-TMV of tobacco, unit: %

CK is the average withered spot number of clear water contrast blade, unit: individual

I is for inducing the average withered spot number of handling rear blade, unit: individual through compound.

4. the described novel 2-of claim 1 (4 '-methyl isophthalic acid ', 2 ', 3 '-thiadiazoles-5 '-)-5-replaces-1,3, and 4-oxadiazole derivative is to the restraining effect of plant pathogenic fungi growth.

5. the described novel 2-of claim 1 (4 '-methyl isophthalic acid ', 2 ', 3 '-thiadiazoles-5 '-)-5-replaces-1,3, and 4-oxadiazole derivative is to the restraining effect of wheat leaf rust growth.

6. the described novel 2-of claim 1 (4 '-methyl isophthalic acid ', 2 ', 3 '-thiadiazoles-5 '-)-5-replaces-1,3, and the derivative induced tobacco of 4-oxadiazole is to the resistant effect of tobacco mosaic virus (TMV) (TMV).