New glycosyl carbon glycoside thiadiazoline derivatives, and preparation method and application thereof

Abstract

The application provides a novel glycosyl carbon glycoside thiadiazoline derivative, a preparation method and application thereof, and belongs to the field of pesticides. The structural formula is shown in formula (I) or formula (II). The application takes insect chitin degrading enzyme as a biological target, and synthesizes a novel glycosyl carbon glycoside compound. The glycosyl carbon glycoside compound or a pharmaceutically acceptable salt thereof has good target enzyme inhibition activity and insecticidal activity, and part of the compounds has insecticidal activity on Plutella xylostella and Diatraea grandiosella which is equivalent to that of the control agent diflubenzuron. The compound has high pesticide research value.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pesticides, and particularly relates to a novel glycosyl carbon glycoside thiazolidine derivative and a preparation method and application thereof. BACKGROUND

[0002] Lepidoptera agricultural pests cause serious harm to crops such as corn, sorghum and millet, seriously affecting the quality and yield of crops and causing huge economic losses every year. Chitin is a linear polysaccharide connected by beta-1, 4-glucoside bonds, and is the main structural component of the cuticle of Lepidoptera insects, playing an important role in protecting insects from various stimuli and damage from the external environment. Lepidoptera pests will undergo periodic molting through the degradation process of chitin throughout their life cycle, which is essential for the normal growth and development of Lepidoptera pests. Inhibiting enzymes that degrade the epidermis can cause abnormal molting of Lepidoptera insects, thereby inhibiting the growth and development of insects, and even leading to death. In the process of chitin degradation, glycoside hydrolase family 18 (GH18) chitinase (EC 3.2.1.14) and glycoside hydrolase family 20 (GH20) beta-N-acetylhexosaminidase (Hex; EC 3.2.1.52) play an important role in chitin degradation. Specifically, chitinase can effectively convert long-chain chitin into short-chain chitooligosaccharides. Beta-N-acetylhexosaminidase further hydrolyzes chitooligosaccharides into monosaccharides, thereby achieving the chitin degradation process. Therefore, designing novel pesticides targeting GH18 chitinase and GH20 beta-N-acetylhexosaminidase is a potential pest control strategy. SUMMARY

[0003] The present application provides a novel glycosyl carbon glycoside compound containing N-acetylglucosamine, aminothiourea or 1,3,4-thiadiazole structure, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a preparation method thereof.

[0004] The glycosyl carbon glycoside compound provided by the present application has a structural formula as shown in formula (I) or formula (II), and is respectively denoted as CAUZA-A and CAUZA-B:

[0005]

[0006] R in formula (I) and formula (II) is a substituted or unsubstituted phenyl, benzyl or naphthyl group;

[0007] The substitution can be single substitution or multiple substitution,

[0008] The single substitution position can be 2-position connection, 3-position connection or 4-position connection; the multiple substitution can be specifically double substitution, and the double substitution position can be 3-position connection and 4-position connection;

[0009] each of said substituents is independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, C1-C6 alkyl-substituted amino;

[0010] Further, each of said substituents is independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl, C1-C3 alkyl-substituted amino;

[0011] Still further, each of said substituents is independently selected from the group consisting of any one of chlorine, bromine, methyl, trifluoromethyl, methoxy, N,N-dimethylamino, N,N-diethylamino.

[0012] Specifically, the glycosyl carbon glycoside compound of formula (I) is any one of the following compounds:

[0013]

[0014] The glycosyl carbon glycoside compound of formula (II) is any one of the following compounds:

[0015]

[0016] The compound of formula (I) is prepared by a method comprising the following steps:

[0017] (1) reacting a compound of formula (III) with a compound of formula (IV) in an ethanol solvent to obtain a compound of formula (V);

[0018]

[0019] R in formula (III) has the same definition as R in formula (I);

[0020] R in formula (V) has the same definition as R in formula (I);

[0021] (2) deprotecting the compound of formula (V) under methanolic ammonia conditions to obtain the target compound of formula (I).

[0022] The compound of formula (II) is prepared by a method comprising the following steps:

[0023] 1) reacting a compound of formula (V) with active manganese dioxide in chloroform to obtain a compound of formula (VI);

[0024]

[0025] R in formula (VI) has the same definition as R in formula (II);

[0026] 2) deprotecting the compound of formula (VI) under methanolic ammonia condition to obtain the target compound of formula (II).

[0027] The compound of formula (V) and the compound of formula (VI) in the above method also belong to the protection scope of the present application.

[0028] The present application also provides the use of the glycosyl carbon glycoside aminothiourea of formula (I) or the glycosyl carbon glycoside thiazolium derivative of formula (II) or a pharmaceutically acceptable salt, solvate, hydrate thereof or a composition comprising the same as an insect chitinase inhibitor in the preparation of an insecticide,

[0029] In the use, the insect is a lepidopteran agricultural pest, including Plutella xylostella and Ostrinia nubilalis.

[0030] The present application also provides an insecticide containing the glycosyl carbon glycoside aminothiourea of formula (I) or the glycosyl carbon glycoside thiazolium derivative of formula (II) or a pharmaceutically acceptable salt, solvate, hydrate thereof or a composition comprising the same.

[0031] The insecticide is a pharmaceutically acceptable dosage form, for example: emulsifiable concentrate, wettable powder, suspension concentrate, powder, soluble powder, aqueous solution, water dispersible granule, smoke agent, granule, seed coating agent, etc.

[0032] For example, an insecticidal emulsifiable concentrate is composed of the following mass percentage of substances: 1-10% of the above-mentioned glycosyl carbon glycoside compound or a pharmaceutically acceptable salt thereof, 5-15% of an emulsifier, 0.1-1% of a penetrant, and the rest of solvent.

[0033] The emulsifier is a surfactant, such as Farm Emulsifier 0203B, 0208, GFC, OP-10, Tween-60, etc.

[0034] The solvent can be toluene, xylene, etc.

[0035] For example, an insecticidal wettable powder is composed of the following mass percentage of substances: 15-50% of the above-mentioned glycosyl carbon glycoside compound or a pharmaceutically acceptable salt thereof, 10-20% of a surfactant (such as surfactant NNO), and 30-75% of white carbon black.

[0036] The inventors of the present application take GH18 chitinase and GH20 beta-N-acetylhexosaminidase of Ostrinia furnacalis as targets, take the designed glycosyl naphthimidazole thioglycoside as a lead compound, replace the thioglycoside bond with a more stable carbon glycoside bond, connect acetylglucosamine with different aromatic groups through aminothiourea or 1,3,4 thiadiazole active fragments, synthesize a series of compounds with good activity and selectivity, and achieve good enzyme inhibition activity. Finally, through the insecticidal activity test, it is found that the series of compounds have good insecticidal activity on Ostrinia furnacalis and Plutella xylostella.

[0037] The present application has the advantages that the present application synthesizes novel glycosyl carbon glycoside compounds by taking insect chitin degrading enzyme as a biological target. The glycosyl carbon glycoside compounds or pharmaceutically acceptable salts thereof have good target enzyme inhibition activity and insecticidal activity, and the insecticidal activity of part of the compounds on Plutella xylostella and Ostrinia furnacalis is equivalent to that of the control drug diflubenzuron. The compounds have high pesticide research value. BRIEF DESCRIPTION OF DRAWINGS

[0038] Figure 1 The nuclear magnetic resonance hydrogen spectrum of the compound CAUZA-A-01 prepared in the present application.

[0039] Figure 2 The nuclear magnetic resonance carbon spectrum of the compound CAUZA-A-01 prepared in the present application.

[0040] Figure 3 The nuclear magnetic resonance hydrogen spectrum of the compound CAUZA-B-01 prepared in the present application.

[0041] Figure 4 The nuclear magnetic resonance carbon spectrum of the compound CAUZA-B-01 prepared in the present application. DETAILED DESCRIPTION

[0042] The present application will be further described in detail below in combination with specific embodiments. The examples provided below are only for illustrating the present application, and are not intended to limit the scope of the present application. The examples provided below can serve as a guide for further improvement by those skilled in the art, and do not constitute any limitation on the present application in any way.

[0043] In the following examples, the experimental methods are conventional methods, and are carried out according to the techniques or conditions described in the literature in the art or according to the product instructions, unless otherwise specified. The materials, reagents and the like used in the following examples can be obtained from commercial channels, unless otherwise specified.

[0044] Example 1, preparation and structure identification of compound CAUZL-A-01, R = Ph.

[0045]

[0046] In 50 mL round bottom flask was added 1-C-(2-acetamido-2-deoxy-3,4,6-tri-O-acetyl- -D-glucopyranosyl)-propan-2-one (1.0 g, 2.58 mmol); 4-phenyl-3-aminothiourea (0.43 g, 2.58 mmol, 1.0 eq), 20 ml absolute ethanol. Stirred at 80 °C for 8 hours, after completion of reaction concentrated, the concentrate was passed through column chromatography to get white solid 0.94 g, yield 67.9%.

[0047] Structural confirmation data: 1 H NMR (500 MHz, Chloroform-d) δ 9.47 (s, 1H, -NH-), 8.60 (s, 1H, -NH-), 7.63 (d, J = 7.6 Hz, 2H, -PhH), 7.33 - 7.26 (m, 2H, -PhH), 7.18 - 7.11 (m, 1H, -PhH), 6.00 (d, J = 9.3 Hz, 1H, -NH-), 5.07 - 4.92 (m, 2H, -CH2-), 4.18 - 3.89 (m, 3H, H-1, H-3, H-4), 3.68 - 3.49 (m, 2H, H-2, H-5), 2.64 - 2.42 (m, 2H, -CH2-), 2.02 - 1.81 (m, 15H, -CH3). 13 C NMR (125 MHz, CDC13) δ 205.37, 175.37, 175.31, 170.61, 170.56, 170.48, 169.87, 169.84, 169.73, 169.65, 169.48, 169.22, 168.36, 168.31, 168.20, 149.18, 148.09, 137.22, 137.00, 127.69, 127.61, 124.90, 124.83, 123.36, 122.94, 76.55, 74.88, 74.81, 74.10, 73.26, 73.22, 72.74, 67.38, 67.33, 67.07, 61.35, 61.22, 61.10, 59.41, 53.12, 52.62, 52.11, 44.95, 39.17, 32.93, 30.06, 28.67, 23.71, 22.31, 22.15, 19.88, 19.71, 19.61, 19.59, 16.09, 13.18.

[0048] In a 50 mL round-bottom flask was added the product from (1) (0.94 g, 1.7 mmol), 10 mL of methanol, 10 mL of saturated methanolic ammonia solution, and the reaction was stirred for 4 h. The reaction was concentrated and purified by column chromatography to give 0.69 g of a white solid in 95.6% yield.

[0049] Structural confirmation data: 1 H NMR (500 MHz, Chloroform-d) δ 10.00 (d, J = 442.1 Hz, 1H, -NH), 9.21 (s, 1H, -NH), 7.76 - 7.41 (m, 3H, -PhH), 7.32 (q, J = 9.4, 8.6 Hz, 2H, -PhH), 7.18 (q, J = 11.4, 9.5 Hz, 1H, -NH), 5.62 - 5.06 (m, 2H, -OH), 4.50 (d, J = 199.0 Hz, 1H, -OH), 3.87 (d, J = 52.5 Hz, 2H, -CH2-), 3.68 (s, 2H, H-1, H-3), 3.56 (d, J = 35.5 Hz, 2H, H-2, H-4), 3.32 (d, J = 26.4 Hz, 1H, H-5), 2.80 - 2.27 (m, 2H, -CH2-), 2.01 (d, J = 10.9 Hz, 6H, -CH3). 13 C NMR (125 MHz, CDC13) δ 175.76, 172.49, 172.21, 153.02, 138.42, 137.67, 128.75, 128.61, 126.13, 124.36, 80.05, 77.33, 75.37, 70.46, 69.65, 60.30, 55.39, 35.24, 30.85, 29.71, 24.92, 23.52, 23.43, 17.17. HR-MS (ESI) m / z: calcd for C 18 H 26 N4O5S [M+H] + , 411.1702; found, 411.1698.

[0050] Other compounds of the series CAUZL-A were prepared according to the above method. Their compound numbers, corresponding substituent groups, physicochemical data are shown in Table 1, and the structure-identified nuclear magnetic resonance hydrogen spectrum, mass spectrum data are shown in Table 2.

[0051] Table 1 Compound numbers, substituent groups, physicochemical data of some compounds of the series CAUZL-A

[0052]

[0053] Table 2 CAUZA-A series of partially compounds NMR hydrogen spectrum, mass spectrum data

[0054]

[0055]

[0056]

[0057]

[0058] Example 2, preparation and structural identification of compound CAUZA-B-01, R = Ph

[0059]

[0060] (1) In a 50 mL round-bottom flask was added (2R, 3S, 4R, 5S, 6S)-5-acetylamino-2- (acetyloxymethyl)-6-((E)-2-(2(phenylaminomethoxy)hydrazino)propyl)tetrahydro-2H- pyran-3, 4-diethylate (1.0 g, 1.86 mmol); active manganese dioxide (1.6 g, 18.6 mmol, 10.0 eq), 20 ml of chloroform. Stirring at room temperature for 5 hours, after the reaction was completed, the manganese dioxide was removed by filtration, the filtrate was dissolved under reduced pressure, and the crude product was obtained by column chromatography to obtain a yellow solid 0.69 g, yield 69.6%.

[0061] Structural confirmation data: 1 H NMR (500 MHz, Chloroform-d) δ 7.46 (dd, J = 8.8, 7.0 Hz, 2H, -PhH), 7.31 - 7.27 (m, 2H, -PhH), 7.26 (d, J = 1.9 Hz, 1H, -PhH), 5.72 (dd, J = 9.3, 3.0 Hz, 1H, -NH-), 5.05 - 4.91 (m, 2H, -CH2-), 4.15 (dd, J = 12.3, 6.2 Hz, 1H, H-3), 4.08 - 3.93 (m, 2H, H-1, H-5), 3.56 (td, J = 10.1, 2.0 Hz, 1H, H-4), 3.47 (ddd, J = 9.9, 6.2, 2.2 Hz, 1H, H-2), 2.63 (dd, J = 15.5, 10.1 Hz, 1H, -CH2-), 2.36 (dd, J = 15.5, 2.0 Hz, 1H, -CH2-), 2.10 (s, 3H, -CH3), 2.02 (d, J = 5.2 Hz, 6H, -CH3), 1.94 (s, 3H, -CH3), 1.83 (s, 3H, -CH3). 13C NMR (126 MHz, CDC13) δ 174.52 (s), 171.60 (s), 170.88 (s), 170.44 (s), 169.29 (s), 148.09 (s), 129.48 (d), 126.97 (s), 120.95 (d), 108.38 (s), 76.16 (s), 75.95 (s), 73.96 (s), 68.37 (s), 62.35 (s), 53.68 (s), 41.56 (s), 27.28 (s), 23.25 (s), 20.81 (s), 20.65 (s), 20.59 (s).

[0062] (2) In a 50 mL round-bottom flask, add the product from (1) (0.69 g, 1.30 mmol), 10 mL of methanol, 10 mL of saturated methanolic ammonia solution, react for 4 h, concentrate, and purify by column chromatography to obtain 0.48 g of a yellow solid, yield 90.7%.

[0063] Structural confirmation data: 1 H NMR (500 MHz, Chloroform-d) δ 10.00 (d, J = 442.1 Hz, 1H, -NH), 9.21 (s, 1H, -NH), 7.76 - 7.41 (m, 3H, -PhH), 7.32 (q, J = 9.4, 8.6 Hz, 2H, -PhH), 7.18 (q, J = 11.4, 9.5 Hz, 1H, -NH), 5.62 - 5.06 (m, 2H, -OH), 4.50 (d, J = 199.0 Hz, 1H, -OH), 3.87 (d, J = 52.5 Hz, 2H, -CH2-), 3.68 (s, 2H, H-1, H-3), 3.56 (d, J = 35.5 Hz, 2H, H-2, H-4), 3.32 (d, J = 26.4 Hz, 1H, H-5), 2.80 - 2.27 (m, 2H, -CH2-), 2.01 (d, J = 10.9 Hz, 6H, -CH3). 13 C NMR (125 MHz, CDC13) δ 175.76, 172.49, 172.21, 153.02, 138.42, 137.67, 128.75, 128.61, 126.13, 124.36, 80.05, 77.33, 75.37, 70.46, 69.65, 60.30, 55.39, 35.24, 30.85, 29.71, 24.92, 23.52, 23.43, 17.17.

[0064] Other compounds of general formula CAUZA-B were prepared according to the above method. Their compound numbers, corresponding substituent groups, physicochemical data are shown in Table 3, and the structure-identified nuclear magnetic resonance hydrogen spectrum and mass spectrum data are shown in Table 4.

[0065] Table 3 Compound numbers, substituent groups, physicochemical data of some compounds of CAUZA-B series

[0066]

[0067] Table 4 Nuclear magnetic resonance hydrogen spectrum and mass spectrum data of some compounds of CAUZA-B series

[0068]

[0069]

[0070]

[0071]

[0072] Example 3, Preparation of emulsifiable concentrate with 1-10% content of compound CAUZA-A-01

[0073] In a 100 mL volumetric flask, 1-10 g of compound CAUZA-A-01, 5-15 g of Tween 80, and 0.1-1 g of fatty alcohol polyoxyethylene ether were added, and then toluene was added to volume to obtain an emulsifiable concentrate with a content of 1-10%.

[0074] Emulsifiable concentrates of other compounds of general formula CAUZA-A and CAUZA-B can be prepared according to the above method.

[0075] Example 4, Preparation of wettable powder with 15-50% content of compound CAUZA-A-01

[0076] Take 15-50 g of compound CAUZA-A-01, 10-20 g of sodium dodecyl benzene sulfonate, and 30-75 g of white carbon black, mix and crush to obtain a wettable powder with a content of 15-50%.

[0077] Wettable powders of other compounds of general formula CAUZA-A and CAUZA-B can be prepared according to the above method.

[0078] Example 5, Enzyme inhibition activity determination of compounds of general formula CAUZA-A and CAUZA-B

[0079] Enzyme activity assay method: 4-methylumbelliferyl N,N'-diacetyl-β-D-chitobioside was used as the test substrate for OfChtl, OfChtll, and OfChi-h. pNP-β-GlcNAc was used as the test substrate. The enzyme was mixed with the enzyme activity assay buffer (20 mM NaH2PO4, pH = 6.5) in a 96-well plate to a final volume of 54 μL, 6 μL of 5 mM pNP-β-GlcNAc was added to initiate the reaction, and the mixture was incubated at 30°C for 20 min. The reaction was terminated by adding 60 μL of 0.5 M sodium carbonate, and the absorbance was measured at 450 nm.

[0080] Compound inhibition activity assay method: The enzyme was incubated with different concentrations of inhibitors at room temperature for 10 min, and the enzyme activity was measured by the above method at concentrations of 0.1 mM and 0.2 mM, respectively. The inhibition activities of some compounds on insect chitin-degrading enzymes are shown in Tables 5 and 6.

[0081] Example 6, determination of the insecticidal activity of compounds of general formula CAUZL-A and CAUZL-B

[0082] Determination method: The test Plutella xylostella Linnaeus and Ostrinia furnacalis were treated by the drop method and the leaf immersion method, respectively, and the results were checked after 3 days and 2 days, respectively. The individuals that could not crawl normally were considered dead, and the corrected mortality rate (%) was calculated. Compared with the control agent, the toxicity of the agent was determined. The insecticidal activity data of some compounds are shown in Tables 7 and 8.

[0083] The following test targets were used:

[0084] Plutella xylostella Linnaeus and Ostrinia furnacalis were purchased from commercial channels and were raised in a room with corresponding feed. The raising conditions were room temperature (27 ± 1) °C, humidity of 80%, light intensity of 2000 lux, and light time of 12 h per day. Under the indoor raising conditions, the 3rd instar larvae with consistent instar, body weight, and physiological conditions were used for the agent activity screening test.

[0085] Table 5, inhibition rate (%) of some compounds of CAUZA-A series at a concentration of 100 μM

[0086]

[0087] Table 6, Inhibition rate (%) of some compounds of CAUZA-B series at 100 μM concentration

[0088]

[0089] Table 7, Insecticidal activity (%) of some compounds of CAUZL-A, CAUZL-B series against Plutella xylostella at 500 mg / L concentration

[0090] Compound Lethality (%) Compound Lethality (%) CAUZA-A-01 46.52±3.5 CAUZA-B-01 57.46±5.01 CAUZA-A-02 48.15±6.44 CAUZA-B-02 53.60±6.03 CAUZA-A-03 74.07±6.44 CAUZA-B-03 7.20±2.00 CAUZA-A-04 59.26±6.45 CAUZA-B-04 76.80±6.40 CAUZA-A-05 69.14±7.73 CAUZA-B-05 65.20±8.20 CAUZA-A-06 83.93±7.72 CAUZA-B-06 82.60±8.15 CAUZA-A-07 70.37±6.43 CAUZA-B-07 61.33±7.00 CAUZA-A-08 38.89±7.84 CAUZA-B-08 38.13±6.41 CAUZA-A-09 63.13±4.94 CAUZA-B-09 76.80±7.59 CAUZA-A-10 72.33±7.82 CAUZA-B-10 30.40±5.39 CAUZA-A-11 77.78±6.51 CAUZA-B-11 26.54±8.20 CAUZA-A-12 74.09±6.415 CAUZA-B-12 71.00±5.60 CAUZA-A-13 72.22±7.8 CAUZA-B-13 65.20±7.00 CAUZA-A-14 60±7.8 CAUZA-B-14 76.80±8.02 CAUZA-A-15 74.41±6.35 - - diflubenzuron 74.07±6.45 diflubenzuron 76.96±3.35

[0091] Table 8, Insecticidal activity (%) of some compounds of CAUZL-A, CAUZL-B series against Ostrinia nubilalis at 500 mg / L concentration

[0092]

[0093] The present application has been described in detail. For those skilled in the art, the present application can be implemented in a wider range under the same parameters, concentrations and conditions without departing from the spirit and scope of the present application and without unnecessary experiments. Although the present application gives special examples, it should be understood that the present application can be further improved. In summary, according to the principle of the present application, the present application is intended to include any change, use or improvement of the present application, including changes made by conventional techniques known in the art, which deviates from the scope disclosed in the present application.

Claims

1. A glycosyl carboxylic acid compound of formula (II) or a pharmaceutically acceptable salt thereof, or a composition comprising thereof: In formula (II), R is a substituted or unsubstituted phenyl or naphthyl group; The substitution can be a single substitution or multiple substitutions; Each of the substituents is independently selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, halogen-substituted C1-C6 alkyl groups, and C1-C6 alkyl-substituted amino groups.

2. A method for preparing the glycosyl C-glycoside compound of formula (II) in claim 1, comprising the following steps: 1) The compound shown in formula (V) was reacted with active manganese dioxide in chloroform to obtain the compound shown in formula (VI); The definitions of R in equation (V) and R in equation (VI) are the same as the definition of R in equation (II); 2) The compound shown in formula (VI) was deprotected under methanol and ammonia conditions to obtain the target compound shown in formula (II).

3. The method according to claim 2, characterized in that, The compound represented by formula (V) is prepared by a method comprising the following steps: The compound shown in formula (III) was reacted with the compound shown in formula (IV) in an ethanol solvent to give the compound shown in formula (V); The definition of R in formula (III) is the same as the definition of R in formula (II) of claim 1; The definition of R in formula (V) is the same as the definition of R in formula (II) of claim 1.

4. The compound shown in formula (VI), R represents a substituted or unsubstituted phenyl or naphthyl group; The substitution can be a single substitution or multiple substitutions; Each of the substituents is independently selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, halogen-substituted C1-C6 alkyl groups, and C1-C6 alkyl-substituted amino groups.

5. The use of the glycosyl carboxylic acid compound of formula (II) of claim 1 or a pharmaceutically acceptable salt thereof or a composition comprising the thereof as an inhibitor of insect chitin-degrading enzymes in the preparation of insecticides.

6. The application according to claim 5, characterized in that, In this application, the insects are lepidopteran agricultural pests, including diamondback moth and corn borer.

7. An insecticide comprising a glycosyl carboxylic acid compound of formula (II) of claim 1 or a pharmaceutically acceptable salt thereof or a composition comprising the same.

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