Application of phenolic compound in preparation of hypoglycemic drug or functional food

Abstract

The invention provides an application of a phenolic compound (3-mesoxy-5-pentylpheol) as shown in a formula I or pharmaceutically acceptable salt, ester and solvate of the phenolic compound in preparation of medicines or functional foods for reducing blood sugar and preventing and / or treating diabetes mellitus. The invention also provides a pharmaceutical composition which comprises the compound as shown in the formula I and pharmaceutically acceptable pharmaceutic adjuvants and is used as a pharmaceutical preparation, and the medicine is a hypoglycemic medicine and a medicine for preventing and / or treating diabetes mellitus as shown in the formula I.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical or health product applications, specifically to the application of a phenolic compound in the preparation of drugs or functional foods, and more particularly to the application of a phenolic compound in the preparation of drugs or functional foods for lowering blood sugar, preventing and / or treating diabetes. Background Technology

[0002] Diabetes mellitus is a metabolic disorder characterized primarily by persistent hyperglycemia. It is caused by various pathogenic factors leading to decreased pancreatic function and insulin resistance, resulting in an imbalance of glucose, protein, fat, water, and electrolytes. Clinically, it manifests primarily as polyphagia (excessive hunger), polydipsia (excessive thirst), polyuria (excessive urination), and weight loss—the "three highs and one low" symptoms. According to data from the International Diabetes Federation, the number of adults with diabetes worldwide reached 537 million in 2021, meaning one in ten adults has diabetes. This number is projected to rise to 783 million by 2045. Currently, commonly used treatments include insulin, sulfonylureas, biguanides, thiazolidinediones, alpha-glucosidase inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists. These hypoglycemic drugs are potent and fast-acting, but lack overall therapeutic effects and can cause many adverse reactions, such as loss of appetite, nausea, diarrhea, weight loss, arrhythmia, liver damage, and allergic reactions, making them unsuitable for long-term use by diabetic patients. Therefore, developing novel drugs or functional foods for the treatment of diabetes has broad application prospects and social significance.

[0003] Natural products play a unique role and possess enormous potential in the development of drugs for diabetes treatment. They exhibit characteristics such as lowering blood sugar, improving insulin resistance, and delaying diabetic complications. Their effects are mild and non-toxic, making them a research hotspot in the prevention and treatment of diabetes. Therefore, discovering lead compounds or candidate new drug molecules with hypoglycemic activity from natural products is crucial and urgent. Chinese patent application CN201711167223.7 discloses the application of 5-pentyl-3-methoxyphenol in the preparation of products for the prevention and treatment of diseases induced by oxidative stress or inflammation. However, currently, there are no reports on the effect of 3-methoxy-5-pentylphenol in promoting cellular glucose uptake. Summary of the Invention

[0004] In view of the problems of the prior art, the purpose of the present invention is to provide a novel hypoglycemic drug, and more particularly to provide the application of phenolic compounds in the preparation of hypoglycemic, preventive and / or therapeutic drugs or functional foods for diabetes.

[0005] To achieve this objective, the present invention adopts the following technical solution:

[0006] In a first aspect, the present invention provides the use of phenolic compounds of Formula I or their pharmaceutically acceptable salts, esters, or solvates in the preparation of hypoglycemic, anti-diabetic, and / or therapeutic drugs or functional foods:

[0007]

[0008] Preferably, the blood glucose reduction is to reduce the high blood glucose in type 1 diabetes or type 2 diabetes.

[0009] Preferably, the drug or functional food has the effect of promoting cellular glucose uptake and lowering blood sugar.

[0010] Formula I, known in English as 3-methoxy-5-pentylphenol, can be isolated from *Heterophyllum heterophyllum*, a plant in the Rubiaceae family, and has a high degree of safety.

[0011] Preferably, the drug or functional food further comprises pharmaceutically or food-acceptable excipients, which include any one or a combination of at least two of the following: carrier, diluent, excipient, filler, binder, wetting agent, disintegrant, emulsifier, solubilizer, solvent, osmotic pressure regulator, surfactant, coating material, colorant, pH adjuster, antioxidant, antibacterial agent, or buffer.

[0012] Preferably, the drug dosage form is a capsule, granule, tablet, or oral liquid.

[0013] Preferably, the daily dosage of the phenolic compound is 0.01 to 100 mg / kg based on body weight.

[0014] This invention unexpectedly discovered that phenolic compounds of Formula I, or their pharmaceutically acceptable salts, esters, or solvates, can promote cellular glucose uptake, and can be applied to lower blood sugar or for the prevention and treatment of diabetes. Through cellular glucose uptake experiments, this invention found that the compound 3-methoxy-5-pentylphenol significantly promotes glucose uptake in 3T3-L1 adipocytes. Figure 1 It can lower blood sugar and play a role in the treatment and prevention of type 1 or type 2 diabetes.

[0015] In a second aspect, the present invention provides the use of phenolic compounds of Formula I or pharmaceutically acceptable salts, esters, solvates or combinations thereof, in the preparation of cellular glucose uptake promoters and / or blood glucose lowering agents:

[0016]

[0017] Thirdly, the present invention provides a pharmaceutical composition comprising a phenolic compound of formula I or a pharmaceutically acceptable salt, ester, solvate thereof, and a pharmaceutically acceptable excipient thereof, for use as a pharmaceutical preparation, wherein the pharmaceutical preparation is a hypoglycemic drug or a drug for treating or preventing diabetes.

[0018]

[0019] Preferably, the composition contains 0.001-99.9 wt% of the phenolic compound or its pharmaceutically acceptable salt, ester, or solvate, based on the total weight of the composition.

[0020] Preferably, the daily dosage of the phenolic compound is 0.01 to 100 mg / kg based on body weight.

[0021] Preferably, the pharmaceutically acceptable excipients include any one or a combination of at least two of the following: carrier, diluent, excipient, filler, binder, wetting agent, disintegrant, emulsifier, solubilizer, osmotic pressure regulator, surfactant, coating material, colorant, pH adjuster, antioxidant, antibacterial agent, or buffer, such as a combination of binder and diluent, a combination of disintegrant and filler, a combination of disintegrant, filler, and lubricant, etc. Other arbitrary combinations will not be elaborated here.

[0022] Preferably, the pharmaceutical preparation is a capsule, granule, tablet, or oral liquid.

[0023] The phenolic compounds or their pharmaceutically acceptable salts, esters, and solvates described in this invention can also be used in combination with other drugs to achieve better hypoglycemic effects.

[0024] In this invention, the route of administration of the drug can be selected as oral or sublingual, depending on actual needs.

[0025] This invention unexpectedly discovered that the phenolic compounds shown in Formula I, or their pharmaceutically acceptable salts, esters, and solvates, can significantly promote cellular glucose uptake and can be used to lower blood sugar. This means they can be used to prepare hypoglycemic drugs or functional foods, particularly suitable for the preparation of drugs for the prevention or treatment of diabetes, and can lower hyperglycemia in type 1 or type 2 diabetes. Therefore, it is expected that 3-methoxy-5-pentylphenol can be applied in clinical hypoglycemic agents, diabetes treatment drugs, or functional foods. It has high activity, is suitable for type 1 and type 2 diabetic patients, and since this compound exists in plants such as *Mitragyna diversifolia*, it has low toxicity and high safety. Attached Figure Description

[0026] Figure 1Effects of 3-methoxy-5-pentylphenol on glucose uptake and cell viability in 3T3-L1 adipocytes Specific Implementation

[0027] To more clearly illustrate the present invention, the technical solution is further described below with reference to specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the invention and should not be construed as limiting the invention.

[0028] The processes, conditions, reagents, and experimental methods used in implementing this invention, except as specifically mentioned below, are all common knowledge and general knowledge in the field, and this invention does not have any particular limitations. Experimental methods in the embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer.

[0029] Unless otherwise stated, all technical terms and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. However, in the event of any conflict, the specification containing the definitions shall prevail.

[0030] Among them, compound 3-methoxy-5-pentylphenol was a sample prepared by Zhang Yumei's laboratory at the Xishuangbanna Tropical Botanical Garden, Chinese Academy of Sciences.

[0031] Insulin and other drugs and reagents are purchased from companies such as Sigma.

[0032] Example 1

[0033] Preparation of 3-methoxy-5-pentylphenol

[0034] The collected branches of *Heterophyllum heterophyllum* were dried, pulverized, and extracted with 90% industrial ethanol at room temperature. The extract was then concentrated under reduced pressure to obtain a total ethanol extract. The total extract was extracted sequentially with chloroform, ethyl acetate, and n-butanol to obtain individual fractions. The chloroform extract was separated by silica gel column chromatography, followed by petroleum ether-ethyl acetate gradient elution to obtain five fractions (B1-B5). Fraction B5 was purified by repeated silica gel column chromatography using a Sephadex LH-20 chromatograph to obtain the compound 3-methoxy-5-pentylphenol.

[0035] Mass spectrometry and nuclear magnetic resonance (NMR) analysis were used to confirm the structure. The spectral data of 3-methoxy-5-pentylphenol are as follows: C 12 H 18 O2, ESI-MS m / z 193 [MH] - ; 1 H NMR (600MHz, CD3OD)δH 6.22(1H,d,J=1.7Hz,H-4),6.21(1H,d,J=1.7Hz,H-6),6.16(1H,t,J=2.2Hz,H-2),3.71(3H,s,-OCH3),2.47( 2H,t,J=7.1Hz,H-1'),1.58(2H,p,J=7.6Hz,H-2'),1.34-1.25(4H,m,H-3',4'),0.90(3H,t,J=7.1Hz,H-5'); 13 C NMR (150MHz, CD3OD)δ C 162.4(C-3),159.5(C-1),146.5(C-5),109.0(C-6),106.6(C-4),99.7(C-2),5 5.6(-OCH3),37.2(C-1'),32.8(C-2'),32.4(C-3'),23.8(C-4'),14.6(C-5').

[0036] Example 2

[0037] The effect of 3-methoxy-5-pentylphenol on promoting glucose uptake in adipocytes

[0038] Experimental principle:

[0039] Insulin plays a crucial role in regulating glucose levels in the body. It activates intracellular signal transduction pathways in peripheral tissues (such as adipose tissue and skeletal muscle), thereby initiating glucose uptake. Different insulin stimulation concentrations show a linear relationship with the amount of glucose uptake in adipose tissue / skeletal muscle within the effective range. The potential hypoglycemic activity of the test samples is assessed by detecting cellular glucose uptake.

[0040] Experimental methods:

[0041] Differentiated 3T3-L1 cells were seeded into 96-well plates and incubated for 24 hours. Afterward, the cells were divided into a blank control group, a positive control group (100 nM insulin), and a drug-treated group (3-methoxy-5-pentylphenol, final concentration 40 μM), with three replicates for each sample. After incubation at 37°C for 24 hours, 10 μL of cell culture medium was aspirated, and the glucose concentration in the culture medium was determined using the glucose oxidase-peroxidase method. The absorbance was measured at 505 nm using a microplate reader. Following the glucose uptake assay, CellTiter was used to analyze the glucose concentration. Cell viability was determined using a water-based cell proliferation assay. 20 μL of CellTiter was added to each well. Aqueous solution of cell proliferation assay reagent. After incubation at 37°C for 8 hours, absorbance was measured at 490 nm using an ELISA reader to determine the toxicity of the compound to adipocytes. Glucose uptake rate (Formula 1) and relative cell viability (Formula 2) were calculated using the following formulas.

[0042] Glucose uptake rate (%) = (A1 - A2) / A1 × 100 (Formula 1)

[0043] Where A1 is the absorbance of the initial glucose, and A2 is the absorbance of the blank control, positive control, or sample group.

[0044] Relative cell viability (%) = A2 / A1 × 100 (Formula 2)

[0045] Where A1 is the absorbance of the blank control and A2 is the absorbance of the sample or positive control group.

[0046] The experimental results are shown in Figure 1 The results showed that, compared with the blank control group, 40 μmol / L of the compound 3-methoxy-5-pentylphenol significantly promoted glucose uptake by adipocytes (p<0.05). At the same time, at this concentration, 3-methoxy-5-pentylphenol had no significant effect on the viability of 3T3-L1 adipocytes, and the difference was not statistically significant (p>0.05).

[0047] Example 3

[0048] Capsules: Mix 1g of compound 3-methoxy-5-pentylphenol with 0.5g of lactose and 0.1g of magnesium stearate until homogeneous, sieve, mix evenly, and fill the resulting mixture into 20 hard gelatin capsules. Capsule weight: 80mg, content: 50mg / capsule.

[0049] Example 4

[0050] Granules: Mix 1g of compound 3-methoxy-5-pentylphenol with 1g of lactose and 0.6g of starch evenly, moisten with water, sieve the moistened mixture and dry it, sieve it again, and then make the mixture into granules and pack them into 20 bags, each bag weighing 130mg, with a content of 50mg / bag.

[0051] Example 5

[0052] Tablets: Mix 1g of compound 3-methoxy-5-pentylphenol with 0.6g of lactose and 0.5g of starch, moisten with water, sieve and dry the moistened mixture, sieve again, add 0.1g of magnesium stearate, mix well, compress into tablets, and compress into 20 tablets. Tablet weight: 110mg, content: 50mg / tablet.

[0053] Example 6

[0054] Oral ampoules: Add 1g of compound 3-methoxy-5-pentylphenol to the conventional additives used in the preparation of oral solutions and purified water, and make up to 0.1L. Under aseptic conditions, fill 20 ampoules, each containing 5ml, with a content of 50mg / ampoule.

[0055] The above descriptions are merely several embodiments of this application and are not intended to limit this application in any way, i.e., they do not imply that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of raw materials for the product of the present invention, additions of auxiliary components, and selection of specific methods, all fall within the protection and disclosure scope of the present invention. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

Claims

1. The use of phenolic compounds of Formula I or their pharmaceutically acceptable salts, esters, or solvates in the preparation of hypoglycemic, preventive, and / or therapeutic drugs or functional foods for diabetes:

2. The application as described in claim 1, characterized in that, The blood sugar reduction refers to lowering the high blood sugar levels in type 1 or type 2 diabetes.

3. The application as described in claim 1, characterized in that, The drug or functional food has the effect of promoting cellular glucose uptake.

4. The application as described in claims 1 to 3, characterized in that, The drug or functional food also contains pharmaceutically or food-acceptable excipients, including any one or a combination of at least two of the following: carriers, diluents, excipients, fillers, binders, wetting agents, disintegrants, emulsifiers, solubilizers, osmotic pressure regulators, surfactants, coating materials, colorants, pH adjusters, antioxidants, antibacterial agents, or buffers. Preferably, the drug dosage form is a capsule, granule, tablet, or oral liquid. Preferably, the daily dosage of the phenolic compound is 0.01 to 100 mg / kg based on body weight.

5. The use of phenolic compounds of Formula I or their pharmaceutically acceptable salts, esters, or solvates in the preparation of cellular glucose uptake promoters and / or hypoglycemic drug formulations:

6. A pharmaceutical composition comprising a phenolic compound of formula I or a pharmaceutically acceptable salt, ester, solvate thereof, and a pharmaceutically acceptable excipient, for use as a pharmaceutical preparation, wherein the pharmaceutical preparation is a hypoglycemic agent, a drug for treating and / or preventing diabetes.

7. The composition according to claim 6, characterized in that, The composition contains 0.001-99.99 wt% of the phenolic compound or its pharmaceutically acceptable salt, ester, or solvate, based on the total weight of the composition. Preferably, the daily dosage of the phenolic compound is 0.01 to 100 mg / kg based on body weight.

8. The composition according to claim 6, characterized in that, The pharmaceutical preparation is a capsule, granule, tablet, or oral liquid.

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