Phellinus linteus derivative as well as preparation method and application thereof
By preparing liniment derivatives, the problems of side effects and insufficient blood sugar lowering effect of existing diabetes drugs have been solved, achieving significant blood sugar lowering effect and improved biosafety.
Patent Information
- Application Number
- CN202511227604.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-29
- Publication Date
- 2025-12-16
AI Technical Summary
Existing diabetes medications have side effects, and linalool has a weak hypoglycemic effect. Chemical modification is needed to improve its hypoglycemic effect and enhance its biocompatibility.
A lina serotonin derivative was prepared by using methyl 4-sulfonamide benzoate, cyclohexyl isocyanate, potassium carbonate, lithium hydroxide, sulfoxide and lina serotonin as raw materials, and a series of reactions to obtain a lina serotonin derivative with significant hypoglycemic effect.
The prepared linalool derivatives not only have a significant hypoglycemic effect, but also have good biocompatibility, reducing drug side effects and making them suitable for clinical use as hypoglycemic drugs.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to a kind of Sanghuangsu derivatives, especially to a kind of Sanghuangsu derivatives and its preparation method and application. BACKGROUND
[0002] Diabetes is a common chronic disease, which can seriously affect the physical health and quality of life of patients, mainly including the following aspects: (1) Metabolic disorders: May cause fat, protein, sugar, nucleic acid metabolic disorders, such as dyslipidemia, hyperglycemia, diabetic nephropathy, etc., and can cause cardiovascular system damage, such as atherosclerosis, hypertension, etc.; (2) Microangiopathy: May involve the eye, kidney, heart, cerebral blood vessels and other multiple organs, causing retinopathy, renal failure, myocardial lesions, stroke, etc.; (3) Diabetic foot: If diabetic patients have peripheral neuropathy, foot damage may occur, leading to spontaneous foot ulceration, gangrene, etc., and severe cases may lead to amputation; (4) Other conditions: May also cause common chronic complications such as uremia and cerebrovascular disease, which can cause a significant decline in the quality of life of patients.
[0003] Diabetes treatment drugs such as glimepiride (sulfonylureas), repaglinide (non-sulfonylureas), metformin (biguanides), acarbose (alpha-glucosidase inhibitors), etc. can lower blood sugar through different mechanisms, but may also have some side effects. For example, sulfonylureas and non-sulfonylureas may cause hypoglycemia, biguanides may cause gastrointestinal reactions, and alpha-glucosidase inhibitors may cause abdominal distension and increased gas. Therefore, developing new drug derivatives with hypoglycemic function based on natural active substances has become a research focus in recent years.
[0004] Sanghuangsu is abundant in Moraceae plants, especially the roots, leaves and fruits of mulberry trees. In addition, Brazilian yellow wood, Psidium guajava and other plants parasitized on mulberry trees also contain high levels of Sanghuangsu. Studies have found that Sanghuangsu has good therapeutic effects on a variety of diseases, and can exert antioxidant, anti-diabetic, anti-inflammatory, anti-tumor, anti-hypertensive, anti-bacterial, uric acid-lowering and neuroprotective effects by regulating the activity of many enzymes. In some cases, Sanghuangsu can also reduce the negative side effects of drugs without interfering with their function. However, direct use of Sanghuangsu as a drug for treating hyperglycemia has weak activity, and its hypoglycemic effect still needs to be improved through chemical modification. SUMMARY
[0005] To solve the above technical problems, the present application first proposes a kind of Sanghuangsu derivatives, which not only has significantly improved hypoglycemic effect, but also is beneficial to improving biological safety compared with existing sulfonylurea drugs.
[0006] Based on the second aspect of the present invention, a method for preparing linosin derivatives is also proposed, which can be easily prepared by conventional reaction types, and has the advantages of high reaction efficiency and few process steps.
[0007] Based on a third aspect of the present invention, the application of a linalool derivative in hypoglycemic drugs or preparations is also proposed.
[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A morin derivative has the following molecular structural expression: .
[0009] A method for preparing the linalool derivative as described above includes the following steps:
[0010] 1) Methyl 4-sulfonamide benzoate and cyclohexyl isocyanate were mixed in a solvent, potassium carbonate was added and the mixture was reacted. After the reaction was completed, the mixture was purified to obtain intermediate 1. 2) Under ice bath conditions, lithium hydroxide aqueous solution was added dropwise to the dissolved intermediate 1. After complete mixing, the mixture was stirred at room temperature. Then, the aqueous solution was separated, acidified with hydrochloric acid, and purified to obtain intermediate 2. 3) After mixing intermediate 2 and thionyl chloride and reacting, concentrate the mixture to remove excess thionyl chloride and obtain the concentrate. Then add solvent and linalool to continue the reaction and purify the product to obtain the linalool derivative.
[0011] As some preferred examples of the present invention, in step 1), the molar ratio of methyl 4-sulfonamide benzoate and cyclohexyl isocyanate is 1:(3-5), for example, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, etc. Preferably, in step 1), the amount of potassium carbonate used is 2-3 times the molar amount of methyl 4-sulfonamide benzoate, for example, 2.1 times, 2.2 times, 2.3 times, 2.4 times, 2.5 times, 2.6 times, 2.7 times, 2.8 times, 2.9 times, etc.
[0012] As some preferred examples of the present invention, in step 1), the reaction is first carried out with acetone as solvent and heated for 0.5-1 h, then water not exceeding the volume of acetone is added, and the reaction is continued for another 0.5-1 h to end the reaction; preferably, the heating temperature is 40-60℃, for example, 42℃, 45℃, 48℃, 50℃, 52℃, 55℃, 58℃, 60℃, etc. Preferably, after the reaction in step 1) is completed, the filtrate is first separated, then concentrated, and the product is purified by column chromatography to obtain intermediate 1.
[0013] As some preferred examples of the present invention, in step 2), the molar ratio of intermediate 1 to lithium hydroxide is 1:(1.2-1.5), for example, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, 1:1.5, etc.; Preferably, the reaction time between intermediate 1 and lithium hydroxide is 8-24 hours, for example, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, etc.
[0014] Preferably, the solvent used to dissolve intermediate 1 in step 2) is selected from one or more of methanol, ethanol, n-propanol, ethylene glycol, and glycerol; As some preferred examples of the present invention, after the reaction in step 2) is completed, hydrochloric acid is added to acidify the solution to pH 2, and then the organic phase is extracted with chloroform, concentrated and purified to obtain intermediate 2.
[0015] Preferably, the hydrochloric acid concentration is 0.5-2 mol / L.
[0016] As some preferred examples of the present invention, in step 3), the molar ratio of intermediate 2 and sulfoxide dichloride is 1:(50-200), for example 1:60, 1:70, 1:80, 1:90, 1:100, 1:120, 1:140, 1:160, 1:180, 1:190, etc.; Preferably, in step 3), N,N-dimethylformamide is optionally added as a reaction catalyst and an organic solvent is optionally added as a reaction medium when intermediate 2 reacts with thionyl chloride. The amount of N,N-dimethylformamide added, by volume ratio, is 1 / 100 to 1 / 10 of the amount of thionyl chloride added; The organic solvent is preferably 1,4-dioxane; Preferably, in step 3), the reaction conditions for intermediate 2 and thionyl chloride are: stirring at 60-80°C for 3-6 hours; the reaction temperature is, for example, 62°C, 65°C, 68°C, 70°C, 72°C, 75°C, 78°C, 80°C, etc.; the reaction time is, for example, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, etc.
[0017] As some preferred examples of the present invention, in step 3), the amount of linalool added is 1.1-1.3 times the amount of 2 moles of the intermediate, for example, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3 times, etc.; Preferably, after adding morin in step 3), the reaction continues at 60-80℃ for 2-5 hours; the reaction temperature is, for example, 62℃, 65℃, 68℃, 70℃, 72℃, 75℃, 78℃, 80℃, etc.; the reaction time is, for example, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, etc.
[0018] The present invention also provides the application of the linalool derivative as described above or the linalool derivative prepared by the method described above in hypoglycemic drugs or preparations.
[0019] The linamycin derivative provided by this invention not only has good biocompatibility, but also has excellent hypoglycemic effect, and is expected to be used as a clinical hypoglycemic drug or preparation without causing serious adverse reactions. Detailed Implementation
[0020] The present invention will be further illustrated below with specific embodiments. These embodiments are merely illustrative and do not limit the scope of the invention.
[0021] Unless otherwise specified, the raw materials and reagents used in the following embodiments of the present invention can be purchased commercially. Example 1
[0022] A method for preparing a linexin derivative includes the following steps:
[0023] 1) Methyl 4-sulfonamide benzoate (215 mg, 1 mmol) and cyclohexyl isocyanate (500 mg, 4 mmol) were mixed in acetone and heated to 40°C. An acetone solution of potassium carbonate (414 mg, 3 mmol) was added, and the mixture was reacted for 1 h. Then, 0.5 times the volume of water (acetone volume) was added, and the reaction was continued with stirring for another 0.5 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated and subjected to column chromatography to obtain intermediate 1.
[0024] 1 H NMR (600 MHz, Chloroform- d ):δ 8.08 – 8.01 (m, 2H), 7.98 – 7.91 (m,2H), 6.35 (s, 1H), 4.29 (d, J = 8.1 Hz, 1H), 3.91 (s, 3H), 3.31 (dp, J = 8.0,4.8 Hz, 1H), 1.78 – 1.68 (m, 2H), 1.67 – 1.55 (m, 2H), 1.55 – 1.39 (m, 6H). 2) Under ice bath conditions, lithium hydroxide (28.8 mg, 1.2 mmol) aqueous solution was added dropwise to a methanol solution of intermediate 1 (340 mg, 1 mmol). After complete mixing, the mixture was stirred and reacted at room temperature for 12 h. Then, the organic solvent was removed by vacuum distillation. The remaining aqueous solution was acidified to pH=2 with 1 mol / L hydrochloric acid and then extracted with chloroform to obtain the organic phase. The organic phase was concentrated and purified to obtain intermediate 2.
[0025] 1 H NMR (600 MHz, Chloroform- d ): δ 13.04 (s, 1H) 8.01 – 7.95 (m, 2H), 7.94 – 7.88 (m, 2H), 6.35 (s, 1H), 4.29 (d, J = 8.0 Hz, 1H), 3.31 (dp, J =8.1, 4.8 Hz, 1H), 1.78 – 1.68 (m, 2H), 1.67 – 1.55 (m, 2H), 1.55 – 1.39 (m, 6H). 3) Intermediate 2 (326 mg, 1 mmol) and thionyl chloride (15.5 g, 0.13 mol) were dissolved in 1,4-dioxane, and a few drops of N,N-dimethylformamide were added as a catalyst. The mixture was reacted at 70 °C for 4 h. After the reaction, excess thionyl chloride and solvent were removed to obtain a concentrate. Then, linalool (362 mg, 1.2 mmol) and 1,4-dioxane were added, and the reaction was continued at 70 °C for 2 h. The product, linalool derivative, was obtained after purification.
[0026] 1 H NMR (600 MHz, Chloroform- d ): δ 9.24 (s, 1H), 8.98 (s, 1H), 8.92 (s, 1H), 8.75 (s, 1H), 8.13 – 8.06 (m, 2H), 8.00 – 7.93 (m, 2H), 7.43 (s, 1H), 7.03 (dd, J = 8.8, 2.2 Hz, 1H), 6.73 (d, J = 2.3 Hz, 1H), 6.35 (s, 1H), 6.27 (d, J = 2.0 Hz, 1H), 6.21 (d, J = 1.8 Hz, 1H), 4.29 (d,J = 8.0 Hz, 1H), 3.31 (dp, J = 8.1, 4.8 Hz, 1H), 1.78 – 1.68 (m, 2H), 1.67 – 1.55 (m, 2H), 1.55 – 1.39 (m, 6H). Example 2
[0027] A method for preparing a linexin derivative includes the following steps: 1) Methyl 4-sulfonamide benzoate (215 mg, 1 mmol) and cyclohexyl isocyanate (375 mg, 3 mmol) were mixed in acetone and heated to 60 °C. An acetone solution of potassium carbonate (276 mg, 2 mmol) was added, and the mixture was reacted for 0.5 h. Then, 0.5 times the volume of water (acetone volume) was added, and the reaction was continued with stirring for 1 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated and subjected to column chromatography to obtain intermediate 1.
[0028] 2) Under ice bath conditions, lithium hydroxide (36 mg, 1.5 mmol) aqueous solution was added dropwise to a methanol solution of intermediate 1 (340 mg, 1 mmol). After complete mixing, the mixture was stirred and reacted at room temperature for 20 h. Then, the organic solvent was removed by vacuum distillation. The remaining aqueous solution was acidified to pH=2 with 2 mol / L hydrochloric acid and then extracted with chloroform to obtain the organic phase. The organic phase was concentrated and purified to obtain intermediate 2.
[0029] 3) Intermediate 2 (326 mg, 1 mmol) and thionyl chloride (5.95 g, 0.05 mol) were dissolved in 1,4-dioxane, and a few drops of N,N-dimethylformamide were added as a catalyst. The mixture was reacted at 60 °C for 6 h. After the reaction, excess thionyl chloride and solvent were removed to obtain a concentrate. Then, linalool (332 mg, 1.1 mmol) and 1,4-dioxane were added, and the reaction was continued at 60 °C for 5 h. The product, linalool derivative, was obtained after purification. Example 3
[0030] A method for preparing a linexin derivative includes the following steps: 1) Methyl 4-sulfonamide benzoate (215 mg, 1 mmol) and cyclohexyl isocyanate (625 mg, 5 mmol) were mixed in acetone, heated to 50°C, and a solution of potassium carbonate (345 mg, 2.5 mmol) in acetone was added and reacted for 1 h. Then, water with a volume equal to 0.5 times that of acetone was added, and the reaction was continued with stirring for another 1 h. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated and subjected to column chromatography to separate intermediate 1.
[0031] 2) Under ice bath conditions, lithium hydroxide (31.2 mg, 1.3 mmol) aqueous solution was added dropwise to a methanol solution of intermediate 1 (340 mg, 1 mmol). After complete mixing, the mixture was stirred and reacted at room temperature for 24 h. Then, the organic solvent was removed by vacuum distillation. The remaining aqueous solution was acidified to pH=2 with 0.5 mol / L hydrochloric acid, and then extracted with chloroform to obtain the organic phase. The organic phase was concentrated and purified to obtain intermediate 2.
[0032] 3) Intermediate 2 (326 mg, 1 mmol) and thionyl chloride (23.8 g, 0.2 mol) were dissolved in 1,4-dioxane, and a few drops of N,N-dimethylformamide were added as a catalyst. The mixture was reacted at 80 °C for 3 h. After the reaction, excess thionyl chloride and solvent were removed to obtain a concentrate. Then, linalool (392 mg, 1.3 mmol) and 1,4-dioxane were added, and the reaction was continued at 80 °C for 3 h. The product, linalool derivative, was purified to obtain the product.
[0033]
Application Example
[0034] Drug preparation: Prepare a 0.8 wt% CMC-Na solution, dissolve the linalool derivative prepared in Example 1 in the CMC-Na solution, and prepare low-dose experimental group solutions and high-dose experimental group solutions with drug concentrations of 2 mg / mL and 4 mg / mL, respectively; then dissolve metformin in the CMC-Na solution to prepare a positive control solution with a drug concentration of 2 mg / mL; dissolve linalool in the CMC-Na solution to prepare a raw material control solution with a drug concentration of 2 mg / mL.
[0035] In vivo experiments: Each drug solution was administered to rats in the corresponding groups at a dosage of 1 ml / 10 g via gavage for 8 consecutive weeks. The control group and the model group were administered an equal volume of CMC-Na solution. Blood glucose and body weight of all rats were recorded every 2 weeks. The results are shown in Tables 1 and 2.
[0036] Table 1. Fasting blood glucose levels in rats (mmol / L)
[0037] Table 2. Rat body weight (g)
[0038] The above in vivo rat experiments show that the linalool derivative provided by this invention has a more significant therapeutic effect on improving blood glucose levels in T2DM model rats compared with the raw linalool. Furthermore, after 4 weeks of experimentation, it exhibits a superior hypoglycemic effect compared with the same concentration of the positive control drug metformin.
[0039] Furthermore, the experiments in Table 2 show that, during the experimental period, the linalool derivatives provided by this invention tend to better control the weight of rats, thereby having a certain inhibitory effect on pre-obesity.
[0040] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several improvements and additions without departing from the method of the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention.
Claims
1. A morin derivative, characterized in that, It has the following molecular structural expression: 。 2. A method for preparing the linalool derivative as described in claim 1, characterized in that, Includes the following steps: ； 1) Methyl 4-sulfonamide benzoate and cyclohexyl isocyanate were mixed in a solvent, potassium carbonate was added and the mixture was reacted. After the reaction was completed, the mixture was purified to obtain intermediate 1. 2) Under ice bath conditions, lithium hydroxide aqueous solution was added dropwise to the dissolved intermediate 1. After complete mixing, the mixture was stirred at room temperature. Then, the aqueous solution was separated, acidified with hydrochloric acid, and purified to obtain intermediate 2. 3) After mixing intermediate 2 and thionyl chloride and reacting, the mixture is concentrated to remove excess thionyl chloride and obtain a concentrate. Then, solvent and linalool are added to continue the reaction and the product linalool derivative is obtained after purification.
3. The method for preparing the linalool derivative according to claim 2, characterized in that, In step 1), the molar ratio of methyl 4-sulfonamide benzoate to cyclohexyl isocyanate is 1:(3-5); Preferably, in step 1), the amount of potassium carbonate used is 2-3 times the molar amount of methyl 4-sulfonamide benzoate.
4. The method for preparing the linalool derivative according to claim 2 or 3, characterized in that, In step 1), the reaction is first carried out with acetone as solvent and heated for 0.5-1 h. Then, water with an amount not exceeding the volume of acetone is added and the reaction is continued for another 0.5-1 h to end the reaction. Preferably, the heating temperature is 40-60℃. Preferably, after the reaction in step 1) is completed, the filtrate is first separated, then concentrated, and the product is purified by column chromatography to obtain intermediate 1.
5. The method for preparing the linalool derivative according to any one of claims 1-4, characterized in that, In step 2), the molar ratio of intermediate 1 to lithium hydroxide is 1:(1.2-1.5); Preferably, the reaction time between intermediate 1 and lithium hydroxide is 8-24 hours.
6. The method for preparing the linalool derivative according to claim 5, characterized in that, After the reaction in step 2) is completed, hydrochloric acid is added to acidify the solution to pH 2, and then chloroform is used to extract the organic phase. The organic phase is then concentrated and purified to obtain intermediate 2.
7. The method for preparing the linalool derivative according to any one of claims 1-6, characterized in that, In step 3), the molar ratio of intermediate 2 to sulfoxide is 1:(50-200); Preferably, in step 3), N,N-dimethylformamide is optionally added as a reaction catalyst when intermediate 2 reacts with thionyl chloride; Preferably, in step 3), the reaction conditions for intermediate 2 and thionyl chloride are: stirring at 60-80°C for 3-6 hours.
8. The method for preparing the linexin derivative according to claim 7, characterized in that, In step 3), the amount of linalool added is 1.1-1.3 times the amount of 2 moles of the intermediate; Preferably, after adding morin in step 3), the reaction continues at 60-80℃ for 2-5 hours.
9. The use of a linalool derivative as described in claim 1 or a linalool derivative prepared by the method of any one of claims 2-8 in a hypoglycemic drug or preparation.