Quinoline compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicine synthesis, and provides a quinoline compound as well as a preparation method and application thereof. The chemical structural formula of the quinoline compound is # imgabs0, and the quinoline compound can be used for preventing and controlling plant viruses. The invention also provides an agricultural chemical containing the quinoline compound. The agricultural chemical also contains ningnanmycin. The quinoline compound provided by the invention has the advantages of short synthesis steps, easily available raw materials and easiness in industrial production; the compound has a good inhibition effect on plant viruses, has a protection effect and a treatment effect, is superior to a commercial medicament virazole, and has a commercial prospect; the composition based on the quinoline compound and ningnanmycin has a remarkable synergistic effect, and the resistance risk of a single agent can be reduced. The invention provides a new medicament for preventing and treating plant viruses, and has important practical application value.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a quinoline compound, a preparation method thereof and an agricultural use thereof. Background Art

[0002] Disclosing the information of this background art is intended to enhance the understanding of the overall background of the present invention, and it is not necessarily regarded as an admission or an implication in any form that this information constitutes the prior art already known to those of ordinary skill in the art.

[0003] The parasitic, latent and explosive characteristics of plant viruses have caused significant economic losses to agricultural production and seriously threatened the development of the agricultural economy. After a plant is infected with a plant virus, it often carries the virus for life. Because it is difficult to effectively eradicate, plant virus diseases are also known as "plant cancers". Currently, more than 900 plant viruses are known, among which Tobacco mosaic virus (TMV) is one of the most common and harmful viruses globally and ranks first among the top ten plant viruses in the world. TMV is mainly transmitted through sap and can widely infect tobacco and other solanaceous plants, causing symptoms such as mosaic of plant leaves, growth deformities, retarded plant development and dwarfing, seriously reducing the yield and quality of crops. It is estimated that the economic losses caused by TMV alone globally can reach hundreds of millions of US dollars every year. However, the types of currently highly effective anti-plant virus agents are relatively limited, and there are problems such as insufficient control efficacy and stability. Therefore, developing new antiviral active compounds is an extremely urgent task.

[0004] Quinoline compounds are an important class of nitrogen-containing heterocyclic compounds. The unique "scaffold" function of the skeleton structure of this class of compounds shows potential application value in various fields, such as anti-tumor, anti-malaria parasite and anti-fungal activities. Currently, many pesticides also use quinoline as the skeleton structure. For example, CN107428777A discloses quinoline compounds and their uses in combating phytopathogenic fungi; CN118666858A discloses an agricultural bactericidal composition containing quinoline compounds for controlling fungal diseases of tobacco and rice; CN117402169A discloses a quinoline compound BBPQ7 and its antiviral activity; CN117402170A discloses a quinoline compound that has obvious inhibitory activity against phytopathogenic viruses and can be used as an effective ingredient for a new type of anti-plant virus. In addition, quinoline hydrazone derivatives have insecticidal activity against the larvae of the agricultural pest Spodoptera litura and the pine wood nematode. Therefore, new synthesis and derivatization modifications of the quinoline skeleton structure are expected to provide new lead compounds for the prevention and control of plant virus diseases. Summary of the Invention

[0005] In view of the problems in the prior art, the present invention provides a quinoline compound with the activity of anti-plant pathogenic virus.

[0006] Another object of the present invention is to provide the use of the above quinoline compound in the preparation of agricultural chemicals.

[0007] To achieve the above object, the present invention adopts the following technical solutions.

[0008] A quinoline compound, abbreviated as BDQp9, whose chemical structural formula is shown in formula (I):

[0009]

[0010] The preparation method of the above quinoline compound includes the following steps:

[0011] (1) Under the catalysis of n-pentyltriphenylphosphonium bromide and NaH, heat under reflux in a solvent, and separate to obtain

[0012] (2) And hydrazine hydrate are heated under reflux in acetic acid, and separate to obtain

[0013]

[0014] In step (1), the solvent is N,N-dimethylformamide (DMF).

[0015] In step (1), the above intermediate Can be prepared by the prior art; preferably, its preparation method includes the following steps:

[0016] (i) Under anaerobic conditions, 3,4-(methylenedioxy)acetophenone and diethyl carbonate are heated under reflux in a solvent under the catalysis of NaH to obtain

[0017] (ii) And triethyl orthoformate are heated under reflux in the presence of acetic anhydride to obtain

[0018]

[0019] (iii) React with 3,4-(methylenedioxy)aniline in a solvent to obtain

[0020]

[0021] (iv) And diphenyl ether are heated under reflux to obtain

[0022]

[0023] In step (i), the solvent is tetrahydrofuran (THF); in step (ii), the solvent is isopropanol.

[0024] In step (1), the separation step is as follows: HCl is added to remove NaH, the reaction solution is concentrated to dryness under reduced pressure, dichloromethane is added for extraction, the organic layer is washed with NaHCO 3 3, the organic layer is concentrated to dryness and then passed through a silica gel column chromatography with a methanol and dichloromethane eluent in a volume ratio of 1:20.

[0025] In step (2), the separation step is as follows: after the reaction is complete, HCl is added to remove hydrazine hydrate, dichloromethane is added for extraction, the organic layer is washed with NaHCO 3 3, the organic layer is concentrated to dryness and then passed through a silica gel column chromatography with a methanol and dichloromethane eluent in a volume ratio of 1:20.

[0026] Use of the above quinoline compound in controlling plant viruses. The plant virus is a virus of the family Virgaviridae; preferably a virus of the genus Tobamovirus or Tobravirus; more preferably, the plant virus is tobacco mosaic virus (TMV).

[0027] An agrochemical containing the above quinoline compound. The agrochemical also contains other active ingredients and / or inert ingredients. Preferably, the active ingredient is an antiviral ingredient; more preferably, the active ingredient is ningnanmycin. When the mass ratio of the quinoline compound BDQp9 to ningnanmycin is 8:2 - 2:8, a synergistic effect is achieved, and when the mass ratio of BDQp9 to ningnanmycin is 6:4 - 4:6, the synergistic effect is more significant.

[0028] The present invention has the following advantages:

[0029] The quinoline compound BDQp9 provided by the present invention has a short synthesis route, easily available raw materials, and is easy for industrial production; the quinoline compound BDQp9 has an inhibitory effect on plant viruses, and has a protective and therapeutic effect after being applied to plants, and is superior to the commercial agent ribavirin, with good biological activity and commercial prospects; the present invention also provides a composition based on the above quinoline compound, containing ningnanmycin, and the two have a significant synergistic effect, which can reduce the resistance risk of a single agent. The present invention provides a new agent for the control of plant viruses and has important practical application value. Description of the Drawings

[0030] Figure 1 is the 1 1H NMR spectrum of compound BDQp9;

[0031] Figure 2 is the HRMS spectrum of compound BDQp9. Detailed implementation manners

[0032] The present invention will be further described below in conjunction with embodiments and the accompanying drawings, but the present invention is not limited by the following embodiments.

[0033] Synthesis of compound BDQp9 in Example 1

[0034] (1) Synthesis of 1a

[0035]

[0036] Take a centrifuge tube, add dry THF (15 mL), add 3,4-(methylenedioxy)acetophenone (S0, 30 mmol), and stir to dissolve at 0 °C to obtain a S0 solution;

[0037] Take another clean 100 mL flask, and successively add NaH (60% mineral oil, 4.8 g, 120 mmol), anhydrous THF (25 mL), and diethyl carbonate (19.4 mL, 120 mmol);

[0038] Under nitrogen protection, slowly drop the S0 solution into the above flask within 5 min, and heat and reflux at 70 °C; Petroleum ether: ethyl acetate (PE:EA = 1:5, v / v) is used as the developing agent, and thin layer chromatography (TLC) is used to monitor the reaction progress. After refluxing for 6 h, add 1 mol / L HCl (30 mL) to the reaction mixture to remove the excess NaH to end the reaction;

[0039] Add water (20 mL) to the above system, extract with ethyl acetate 3 times, 20 mL each time; the organic layer is extracted with saturated NaCl solution again; the organic layer is dried with Na 2 SO 4 Dry, spin-dry the solvent with a rotary evaporator at 48 °C, and pump dry with an oil pump to obtain a yellow-brown oily substance 1a, with a yield of 72.2%.

[0040] (2) Synthesis of 2a

[0041]

[0042] Take a 50 ml round-bottom flask, add compound 1a (5.1 g, 21.6 mmol), CH(OEt) 3 (18 mL, 108 mmol), Ac 2 O (11 mL, 108 mmol), reflux at 140 °C for 16 h; add 25 mL of water to the reaction product, extract with EA, and dry the organic layer with anhydrous Na 2 SO 4 Dry, and then purify by column chromatography (PE:EA = 3:1, v / v) to obtain compound 2a, with a yield of 62.9%.

[0043] (3) Synthesis of 3a

[0044]

[0045] Take a 50 mL round-bottom flask, add compound 2a (4.0 g, 13.59 mmol), add 25 mL of isopropanol, then add 3,4-(methylenedioxy)aniline (1.12 g, 8.15 mmol). After reacting for half an hour, monitor the reaction progress by TLC (EA:PE = 2:1, v / v). After 4 h, the reaction is complete. Filter the reaction system under reduced pressure, wash the filter cake with ethanol, dry it with an oil pump, and purify it by column chromatography (PE:EA = 3:1, v / v) to obtain white precipitate 3a with a yield of 47.8%.

[0046] (4) Synthesis of 4a

[0047]

[0048] In 5 × 10 mL high-temperature reaction tubes, add 5 mL of diphenyl ether and 0.3 g of compound 3a to each tube. React under reflux at 260 °C and monitor the reaction progress using TLC with petroleum ether:ethyl acetate (PE:EA = 1:5, v / v). After 5 h, the reaction is complete. Add PE to extract the reaction system 3 times, 20 mL each time, precipitate black solid, filter to obtain the solid and wash it with ethyl acetate to get black solid 4a with a yield of 63.9%.

[0049] (5) Synthesis of 5h

[0050]

[0051] Take a 50 mL round-bottom flask, add compound 4a (400 mg), add NaH (42.73 mg, 1.07 mmol), add DMF (20 mL), add n-pentyltriphenylphosphonium bromide (1.05 g, 2.55 mmol), and reflux at 80 °C. Use methanol:dichloromethane (MeOH:DCM = 1:10, v / v) as the developing solvent for TLC to monitor the reaction progress. After 8 h, the reaction is complete. Add 1 mol / L HCl (30 mL) to remove NaH. Rotate and evaporate the reaction solution to dryness, add DCM (20 mL) for extraction, wash the organic layer with NaHCO 3 wash, evaporate the organic layer to dryness and pass through a chromatography column (MeOH:DCM = 1:20, v / v) to obtain brown solid 5h.

[0052] (6) Synthesis of BDQp9

[0053]

[0054] Add 200 mg of compound 5h to a high-temperature reaction tube, add 5 mL of acetic acid, add 18 μL of hydrazine hydrate, reflux at 80 °C and monitor the reaction progress by TLC (MeOH:DCM = 1:10). After the reaction is complete, add 1 mol / L HCl (30 mL) to remove hydrazine hydrate, add DCM (20 mL) for extraction, and wash the organic layer with NaHCO 3 After the organic layer is dried by evaporation and subjected to column chromatography (MeOH:DCM = 1:20, v / v), a yellow solid BDQp9, the target compound, is obtained as a yellow solid with a yield of 37%; 1 1H NMR (600 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.15 (d, J = 14.1 Hz, 2H), 7.90–7.86 (m, 3H), 7.80 (ddd, J = 12.7, 8.5, 1.4 Hz, 6H), 7.73 (ddd, J = 8.4, 7.4, 3.6 Hz, 6H), 7.69–7.61 (m, 2H), 7.16 (d, J = 8.0 Hz, 1H), 6.48 (s, 2H), 6.18 (s, 2H), 5.00 (t, J = 7.8 Hz, 2H), 3.70 (t, J = 14.8 Hz, 2H), 2.14 (s, 2H), 1.73 (d, J = 7.0 Hz, 2H). MS (ESI) for C 40 H 33 O 4 N 3 P + [M] + , calculated 650.2203, found 650.2061; its 1 1H NMR and HRMS are shown respectively as Figure 1-2 follows.

[0055] Antiviral Activity of Compound BDQp9 in Example 2

[0056] After accurately weighing compound BDQp9, dissolve it in DMSO solution to prepare a 5×10 5 μg / mL stock solution, and then dilute it to the required concentration with an aqueous solution containing 0.1% Tween 80; Ribavirin is directly diluted with water using the preparation.

[0057] 1. In Vivo Passivation Effect

[0058] Select Xanthi tobacco at the 4-6 leaf stage with uniform growth. After mixing and incubating compound BDQp9 with the TMV virus particle solution for 30 min, inoculate by rubbing, with a virus concentration of 20 μg / mL. Measure using the half-leaf method. On the right side of the same leaf, inoculate the mixture of the compound and the virus, and on the left side, inoculate the virus with the same concentration and 0.1% Tween 80 aqueous solution as a control. After inoculation, rinse with running water, and repeat each treatment 3 times. After 4-5 d, count the number of leaf lesions and calculate the inhibition rate:

[0059] Inhibition rate (%) = [(number of control necrotic lesions - number of treated necrotic lesions) / number of control necrotic lesions] × 100%.

[0060] 2. Protective effect in vivo

[0061] Select Xanthi tobacco at the 4-6 leaf stage with uniform growth. Measure using the half-leaf method. Spray the medicament on the right side of the same leaf, and spray 0.1% Tween 80 aqueous solution on the right side as a blank control. After 24 h, sprinkle carborundum (500 mesh) on the leaf surface, dip a writing brush in the virus solution, and inoculate the TMV virus by rubbing the whole leaf, with a virus concentration of 10 μg / mL. After inoculation, rinse with running water. Repeat each treatment 3 times. After 4-5 d, count the number of leaf lesions and calculate the inhibition rate in the same way.

[0062] 3. Therapeutic effect in vivo

[0063] Select Xanthi tobacco at the 4-6 leaf stage with uniform growth. Inoculate the TMV virus by rubbing the whole leaf with a writing brush, with a virus concentration of 10 μg / mL. After inoculation for 2 h, rinse with running water. After the leaf surface is dried, measure using the half-leaf method. Spray the medicament on the right side of the same leaf, and spray 0.1% Tween 80 aqueous solution on the right side as a control. Repeat each treatment 3 times. After 4-5 d, count the number of leaf lesions and calculate the inhibition rate in the same way.

[0064] Table 1 Anti-TMV activity results of quinoline derivative BDQp9

[0065]

[0066] As can be seen from Table 1, compound BDQp9 has good inhibitory activity against TMV in all three modes of action. Compound BDQp9 has the strongest inactivation activity against TMV, followed by the therapeutic activity. Moreover, at the same concentration, the in vivo inactivation and therapeutic activities of compound BDQp9 against TMV are better than those of the commercial medicament ribavirin and slightly higher than those of the commercial medicament ningnanmycin. In summary, as a novel-structured virus inhibitor, compound BDQp9 has great potential for development and application.

[0067] Example 3 Combined antiviral activity of compound BDQp9 and ningnanmycin

[0068] After accurately weighing compound BDQp9, dissolve it in DMSO solution to prepare a 5×10 5 μg / mL mother liquor for standby; dilute the ningnanmycin preparation with water to 5×10 5 μg / mL mother liquor for standby. Then, prepare a series of medicament combination solutions with a total effective concentration of 300 μg / mL from the two compound mother liquors in different proportions.

[0069] 1. In vivo inactivation effect

[0070] Select Xanthi tobacco at the 4-6 leaf stage with uniform growth. After mixing and incubating different proportions of the medicament combination solution with the TMV virus particle solution for 30 min, perform rubbing inoculation with a virus concentration of 20 μg / mL. Use the half-leaf method for determination. On the right side of the same leaf, inoculate the mixture of the compound and the virus, and on the left side, inoculate the same volume of clear water as a control. After inoculation, rinse with running water, and repeat each treatment 3 times. After 4-5 d, count the number of leaf lesions and calculate the inhibition rate.

[0071] 2. In vivo treatment effect

[0072] Select Xanthi tobacco at the 4-6 leaf stage with uniform growth. Use a writing brush to rub-inoculate the whole leaf with TMV virus at a concentration of 10 μg / mL. After 2 h of inoculation, rinse with running water. After the leaf surface is dried, use the half-leaf method for determination. On the right side of the same leaf, spray different proportions of the medicament combination solution, and on the right side, spray the same volume of clear water as a control. Repeat each treatment 3 times. After 4-5 d, count the number of leaf lesions and calculate the inhibition rate.

[0073] Inhibition rate (%) = [(number of control necrotic spots - number of treated necrotic spots) / number of control necrotic spots] × 100%

[0074] Table 2 Anti-TMV activity results of the compound BDQp9 and ningnanmycin compound composition

[0075]

[0076] As can be seen from the results in Table 2, the combined use of quinoline derivative BDQp9 and ningnanmycin has a good inhibitory effect on TMV. When the two are combined at different mass ratios, there is a certain synergistic effect on the inhibitory activity against TMV; and when the mixing ratio is 8:2 - 4:6, the in vivo inactivation activity against TMV is 68.1% - 74.9%. Especially when the mixing ratio is 5:5, the in vivo inactivation activity against TMV is as high as 82.6%; when the mixing ratio is 8:2 - 2:8, the in vivo therapeutic effect on TMV is 54.0 - 68.9%, which is higher than the biological activities of the two compounds used alone. Especially when the mixing ratio is 5:5 - 4:6, a significant synergistic effect is shown. Therefore, the combined use of quinoline derivative BDQp9 and ningnanmycin can effectively inhibit TMV; especially when the ratio between the two is between 4:6 - 4:6, it can significantly enhance the effect, thereby slowing down the generation of drug resistance caused by the single use of the agent.

[0077] The above description is only for the embodiments of the present application and is not intended to limit the present application. For those skilled in the art, various changes and modifications can be made to the present application. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present application shall be included within the scope of the claims of the present application.

[0078] In the scope disclosed in the present application, the endpoints and any values of the range are not limited to the exact range or value. These ranges or values should be understood to include values close to these ranges or values. For numerical ranges, between the endpoint values of each range, between the endpoint values of each range and a single point value, and between single point values, they can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed in the present application.

Claims

1. A quinoline compound, whose chemical structure is shown in formula (I):

2. A method for preparing a quinoline compound as claimed in claim 1, characterized in that: The following steps are involved: (1) and n-pentyltriphenylphosphonium bromide are heated to reflux in a solvent under the catalysis of NaH to separate and obtain (2) and hydrazine hydrate in acetic acid and heated to reflux to separate and obtain 3. The preparation method according to claim 2, characterized in that: In step (1), the solvent is N,N-dimethylformamide; In step (1), the separation step is: adding HCl to remove NaH, the reaction solution is spin-dried to dry the solvent, dichloromethane is added to extract, the organic layer is washed with NaHCO3, the organic layer is spin-dried, and then passed through a silica gel chromatography column with methanol and dichloromethane in a volume ratio of 1:20 as the eluent; In step (2), the separation step is: adding HCl to remove hydrazine hydrate, adding dichloromethane to extract, adding NaHCO3 to wash the organic layer, and after the organic layer is spin-dried, passing through a silica gel chromatography column with methanol and dichloromethane in a volume ratio of 1:20 as the eluent.

4. The preparation method according to claim 2, characterized in that: In step (1), The preparation method comprises the following steps: (i) Under oxygen-free conditions, 3,4-(methylenedioxy)acetophenone and diethyl carbonate are heated under reflux in a solvent under the catalysis of NaH to obtain (ii) and triethyl orthoformate in the presence of acetic anhydride and heated under reflux to obtain (iii) and 3,4-(methylenedioxy)aniline in a solvent to obtain (iv) and diphenyl ether under reflux to obtain 5. The preparation method according to claim 4, characterized in that: In step (i), the solvent is tetrahydrofuran (THF); in step (ii), the solvent is isopropanol.

6. Use of the quinoline compound as claimed in claim 1 in preventing and controlling plant viruses.

7. The use according to claim 6, characterized in that: The plant virus is a virus of the Virgaviridae family; preferably, a virus of the genus Tobamovirus or Tobravirus; more preferably, the plant virus is a tobacco mosaic virus.

8. An agricultural chemical containing the quinoline compound according to claim 1, characterized in that: The agricultural chemicals also contain other effective ingredients and / or inert ingredients.

9. The agricultural chemical according to claim 8, characterized in that The active ingredient is an antiviral ingredient; more preferably, the active ingredient is Ningnanmycin.

10. The agricultural chemical according to claim 8, characterized in that The mass ratio of the quinoline compound to Ningnanmycin is 8:2-2:8, preferably 6:4-4:6.

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