Ploretin derivative and application of phloretin derivative in preparation of medicine for treating diabetes and complications of diabetes

Abstract

The invention discloses a phloretin derivative and application of the phloretin derivative in preparation of a medicine for treating diabetes and complications thereof, and relates to the technical field of small molecule medicines. The structure of the phloretin derivative is shown in the specification. Compared with existing phloretin (unmodified) and a clinically common alpha-glucosidase inhibitor (such as acarbose), the phloretin derivative obtained through structural modification can more efficiently inhibit the activity of alpha-glucosidase, further more effectively delays decomposition and absorption of starch substances, has a better stable regulation effect on postprandial blood sugar, and can be used for preparing the phloretin derivative. The core problem that the existing phloretin inhibitory activity is insufficient is solved.

Description

Technical Field

[0001] This invention relates to the field of small molecule drug technology, specifically to a phloretin derivative and its application in the preparation of drugs for diabetes and its complications. Background Technology

[0002] The core danger of diabetes lies in the multi-organ complications caused by long-term hyperglycemia, such as diabetic nephropathy, retinopathy, neuropathy, and diabetic foot. These complications not only significantly reduce patients' quality of life but also lead to end-stage organ damage, posing a huge challenge to clinical treatment. Currently, in clinical blood glucose-lowering strategies, alpha-glucosidase inhibitors have become an important class of drugs for the treatment of type 2 diabetes because they can achieve stable postprandial blood glucose control by delaying the breakdown of carbohydrates in the intestine and reducing glucose absorption.

[0003] While commonly used alpha-glucosidase inhibitors (such as acarbose) can control postprandial blood glucose to some extent, they suffer from limited inhibitory efficiency, and long-term use can easily cause gastrointestinal side effects such as bloating and diarrhea. Furthermore, their intervention effect on diabetic complications is weak, failing to meet the comprehensive treatment needs of "blood glucose control + complication prevention." Phloretin, as a natural polyphenol compound, has become a hot topic for diabetes drug development due to its potential alpha-glucosidase inhibitory activity and wide availability. However, natural phloretin has significant drug-like drawbacks: its alpha-glucosidase inhibitory activity is weak, and its use alone is insufficient to achieve clinical therapeutic effects.

[0004] To improve the performance of phlorizin, existing research has largely focused on single-dimensional structural modifications (such as introducing hydrophilic groups to improve water solubility). However, such modifications often come at the cost of inhibitory activity, failing to achieve synergistic optimization of "activity-drug-likeness" and failing to endow it with the ability to intervene in diabetic complications. Therefore, there is an urgent need in the field to develop a phlorizin derivative that combines highly efficient α-glucosidase inhibitory activity, excellent physicochemical properties and in vivo stability, and can also intervene in diabetic complications, in order to overcome existing technological bottlenecks and provide new solutions for the comprehensive treatment of diabetes. Summary of the Invention

[0005] To address the shortcomings of existing phlorizin in inhibiting α-glucosidase and its poor hypoglycemic effect, a phlorizin derivative with high efficacy in inhibiting α-glucosidase, excellent drug-like properties, and potential applications in the preparation of drugs for diabetes and its complications is proposed.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is: a phlorizin derivative, wherein the phlorizin derivative has the structure shown in Chemical Formula 1:

[0007] The structure of chemical formula 1 is as follows: ;

[0008] R1 in chemical formula 1 is a substituent;

[0009] R1 is selected from any one of the following: alkyl with 1-5 carbon atoms, aryl with 6-10 carbon atoms, and carbonyl with 1-5 carbon atoms.

[0010] Furthermore, the alkyl group having 1-5 carbon atoms is selected from any one of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl.

[0011] Furthermore, the aryl group with 6-10 carbon atoms is selected from phenyl.

[0012] Furthermore, the carbonyl group with 1-5 carbon atoms is selected from: carbonyl group and ethyl carbonyl group.

[0013] Furthermore, the phlorizin derivative is any one of the compounds shown in the following structures:

[0014] ;

[0015] ;

[0016] .

[0017] The pharmaceutical application of a phloretin derivative, including its pharmaceutically acceptable salt, stereoisomer, stable isotopic form, prodrug, or tautomer.

[0018] Application of a phloretin derivative in the preparation of α-glucosidase inhibitors.

[0019] Application of a phloretin derivative in the preparation of drugs for diabetes and its complications.

[0020] Furthermore, the dosage form of the drug is tablets, pills, capsules, oral liquids, or injections.

[0021] Furthermore, the complications are one or more of diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and diabetic foot.

[0022] Compared with the prior art, the beneficial effects of the present invention are:

[0023] 1. Significantly enhances α-glucosidase inhibitory activity and postprandial blood glucose regulation: Compared with existing phlorizin (unmodified) and clinically commonly used α-glucosidase inhibitors (such as acarbose), the phlorizin derivative obtained by the present invention through structural modification can more efficiently inhibit α-glucosidase activity, thereby more effectively delaying the decomposition and absorption of starches, and has a better effect on the stable regulation of postprandial blood glucose, thus solving the core problem of insufficient inhibitory activity of existing phlorizin.

[0024] 2. Improve the drug-like properties of phlorizin and overcome the limitations of existing derivatives: In response to the shortcomings of existing phlorizin, such as poor water solubility, low oral bioavailability, and rapid in vivo metabolism, as well as the limitations of existing phlorizin derivatives that focus on a single property (such as only improving water solubility), the structural modification of this invention achieves comprehensive optimization of drug-like properties, which not only improves the physicochemical properties and in vivo stability of the molecule, but also ensures the activity, achieving a synergistic improvement in "activity-drug-like properties".

[0025] 3. Expanding the potential for intervention in diabetic complications and meeting comprehensive clinical needs: Existing diabetes treatment drugs often have limited effects on intervention of complications. However, the phloretin derivative of this invention can be used in the preparation of drugs for diabetes and its complications (such as diabetic nephropathy, retinopathy, etc.). It can protect target organs while lowering blood sugar, making up for the clinical shortcomings of existing drugs that cannot simultaneously address "blood sugar control + complication prevention", and providing a new direction for comprehensive diabetes treatment. Attached Figure Description

[0026] Figure 1 This is the NMR spectrum of phloretin derivative 1 of the present invention. Detailed Implementation

[0027] The technical solution of the present invention will now be clearly and completely described with reference to the accompanying drawings. Obviously, the described embodiments are merely some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0028] Example 1

[0029] Preparation of phlorizin derivative 1:

[0030] ;

[0031] CAS number of compound 1: 200878-68-8;

[0032] CAS number of compound 2: 119754-15-3;

[0033] Under a nitrogen atmosphere, 10 g of compound 1, 5.10 g of compound 2, and 120 mL of a dioxane / diisopropylamine (80 mL / 40 mL) mixed solvent were added to the reaction system. After stirring until homogeneous dispersion, 0.36 g of palladium acetate, 0.32 g of tri-tert-butylphosphine, and 0.30 g of CuI were added. The temperature was raised to 90 °C, and the reaction was stirred for 6 h. The solvent was evaporated to dryness, and the mixture was subjected to silica gel column chromatography (using a mixed solution of petroleum ether and ethyl acetate as the eluent). After evaporation to dryness, 10.01 g of compound 3 was obtained. The mass spectra of compound 3 were M / Z MS+1:404.

[0034] ;

[0035] CAS number of compound 4: 13533-12-5;

[0036] Under nitrogen protection, 10.01 g of compound 3, 6.94 g of compound 4, and 130 ml of toluene were stirred until homogeneous. Then, 4.77 g of sodium tert-butoxide and 1.43 g of tetra(triphenylphosphine)palladium were added, stirred until homogeneous, heated to 120 °C, and refluxed for 12 h. After the reaction was complete, the mixture was filtered hot using silica gel to remove salts and catalyst. The filtrate was cooled to room temperature, the solvent was evaporated, and the solution was subjected to silica gel column chromatography (using a mixture of petroleum ether and ethyl acetate as eluent). The solution was evaporated to dryness to obtain 11.80 g of phlorizin derivative 1. Mass spectra of phlorizin derivative 1 were obtained at M / Z MS+1:600, and NMR data are shown below. Figure 1 .

[0037] Examples 2-6

[0038] In Examples 2-6, phlorizin derivative 2-phlorizin derivative 6 were prepared sequentially, following the preparation method of Example 1, except that compound 2 was replaced, and the rest remained the same as in Example 1. For details, please refer to Table 1.

[0039] Table 1

[0040] Comparative Example 1: ;

[0041] Comparative Example 2: (Phosporalin);

[0042] Comparative Example 3: Acarbose.

[0043] Performance testing:

[0044] 1. IC50 of α-glucosidase 50 Value determination:

[0045] The compounds prepared in the examples and comparative examples were dissolved in DMSO to prepare a 20 mmol / L stock solution, which was then serially diluted to 5 μmol / L, 10 μmol / L, 50 μmol / L, 100 μmol / L, 300 μmol / L, 600 μmol / L, and 1000 μmol / L. Different concentrations of the compound (10 μL), 0.5 U / ml enzyme solution (40 μL), and 0.1 mM, pH 6.8 phosphate buffer (100 μL) were pre-incubated in 96-well plates at 37°C for 10 min. Then, 50 μL of substrate (pNαGP, 0.6 mM) was added to each well, and the plates were incubated at 37°C for 20 min. The absorbance was measured at 405 nm to detect changes in enzyme activity, and the data are shown in Table 2.

[0046] Table 2 <![CDATA[IC of α-glucosidase 50 > Example 1 28.56 Example 2 32.14 Example 3 15.87 Example 4 38.62 Example 5 31.79 Example 6 42.35 Comparative Example 1 60.37 Comparative Example 2 192.64 Comparative Example 3 561.24

[0047] α-glucosidase IC 50 The lower the value, the stronger the α-glucosidase inhibitory activity. The phlorizin derivatives prepared in Examples 1-6 of this invention exhibit significantly superior inhibitory activity compared to the comparative examples: compared to the commonly used clinical drugs Comparative Example 3 (acarbose), the unmodified Comparative Example 2 (phlorizin), and Comparative Example 1 (an existing phlorizin derivative), the IC50 values ​​of Examples 1-6 are concentrated in the range of 15.87-42.35 μmol / L, demonstrating superior α-glucosidase inhibitory ability. This verifies that the structural modification of phlorizin in this invention effectively solves the problem of insufficient phlorizin activity in the prior art. Regardless of the substituent, the derivatives of this invention maintain α-glucosidase inhibitory activity far exceeding that of existing controls, providing crucial data support for their application in diabetes treatment (lowering blood sugar by delaying carbohydrate breakdown).

[0048] 2. Oral glucose tolerance test:

[0049] Five- to six-week-old C57 / BL mice were used as experimental subjects. They were allowed one week to acclimatize to the experimental environment before the formal experiments. Animal experiments were conducted in a specific pathogen-free (SPF) environment. C57 / BL mice were randomly divided into three groups: the example group, the comparative group, and the control group, with eight mice in each group. All mice were fasted for 12 hours before the oral glucose tolerance test, during which time they had free access to water. The compounds prepared in the examples and comparative examples were dissolved in physiological saline containing 10% DMSO. The gavage dose was set at 20 mg / kg. Mice in the control group were administered an equal volume of physiological saline by gavage. Five minutes after administration, blood glucose levels were measured in each group of mice at 30 and 60 minutes after gavage administration of a starch solution at a dose of 2 mg / kg. The data are shown in Table 3.

[0050] Table 3 30-minute blood glucose 60-minute blood glucose Example 1 4.5 4.0 Example 2 4.8 4.3 Example 3 4.2 3.8 Example 4 5.1 4.5 Example 5 4.7 4.2 Example 6 5.3 4.7 Comparative Example 1 5.9 5.0 Comparative Example 2 8.7 7.2 Comparative Example 3 6.8 6.0 Blank group 16.2 13.1

[0051] Table 3 shows the blood glucose data (unit: mmol / L) from the oral glucose tolerance test, clearly demonstrating that the phloretin derivatives prepared in Examples 1-6 of this invention significantly improved postprandial blood glucose regulation compared to the blank group and the comparative examples, and exhibited a clear correlation with the α-glucosidase inhibitory activity shown in Table 2. The blank group, having received no drug intervention, had blood glucose levels as high as 16.2 and 13.1 at 30 and 60 minutes postprandial, respectively, reflecting the peak and decline pattern of blood glucose under normal starch breakdown and absorption. Comparative Example 2 (protocorretin), due to its weaker α-glucosidase inhibitory activity, showed a blood glucose level lower than the blank group but still at a relatively high level. Comparative Example 3 (clinical drug acarbose) and Comparative Example 1 showed further reductions in blood glucose levels, but still lower than the example groups. The blood glucose levels of the derivatives in Examples 1-6 were all concentrated in the range of 3.8-5.3. Overall data shows that the phlorizin derivative obtained by structural modification in this invention can effectively inhibit α-glucosidase in vivo, delay starch decomposition and absorption, thereby stabilizing postprandial blood glucose. Moreover, the effect is better than existing phlorizin and the clinically commonly used drug acarbose, providing in vivo experimental support for its practical application in the treatment of diabetes.

[0052] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A phloretin derivative, characterized by, The phloretin derivative is a compound shown in the following formula 1: The structure of the chemical formula 1 is: ; R1 in the formula 1 is a substituent; The R1 is selected from any one of an alkyl group having 1-5 carbon atoms, an aryl group having 6-10 carbon atoms, and a carbonyl group having 1-5 carbon atoms.

2. The phloretin derivative according to claim 1, characterized in that, The alkyl group having 1-5 carbon atoms is selected from any one of a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and a tert-butyl group.

3. The phloretin derivative according to claim 1, wherein The aryl group having 6-10 carbon atoms is selected from a phenyl group.

4. The phloretin derivative according to claim 1, wherein The carbonyl group having 1-5 carbon atoms is selected from a carbonyl group and an ethyl carbonyl group.

5. The phloretin derivative according to claim 1, wherein The phloretin derivative is any one of the following compounds: ； ； 。 6. Use of a phloretin derivative in the preparation of an α-glucosidase inhibitor.

7. Use of a phloretin derivative in the preparation of a drug for diabetes and its complications.

8. Use of a phloretin derivative according to claim 7 for the preparation of a medicament for diabetes mellitus and its complications, characterized in that, The dosage form of the drug is a tablet, a pill, a capsule, an oral solution, or an injection.

9. Use of a phloretin derivative according to claim 7 in the manufacture of a medicament for diabetes and its complications, characterized in that, The complications are one or more of diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and diabetic foot.

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