Use of tetramethylpyrazine nitrone derivative in prevention or treatment of type 2 diabetes

Abstract

The present invention provides a use of a tetramethylpyrazine nitrone (TBN) derivative in preparation of drugs and in prevention or treatment of type 2 diabetes. Clinical tests show that compared with placebos, a TBN derivative can obviously reduce blood sugar and glycosylated hemoglobin levels in patients with type 2 diabetes.

Description

Application of ligustrazine nitrone derivatives in preventing or treating type 2 diabetes Technical Field

[0001] The present invention belongs to the technical field of biomedicine and relates to the application of ligustrazine nitrone derivatives in preventing or treating type 2 diabetes. Background Art

[0002] Diabetes is a metabolic disease characterized by high blood sugar levels. According to data released by the International Diabetes Federation in 2019, there are 463 million people with diabetes worldwide, and the number of people with diabetes is expected to jump to 700 million by 2045. Diabetes is divided into type 1 diabetes and type 2 diabetes, of which type 2 diabetes accounts for more than 90% of all diabetes cases. In the "Guidelines for the Prevention and Treatment of Type 2 Diabetes in China" issued by the Diabetes Branch of the Chinese Medical Association, based on the results of the national epidemiological survey from 2015 to 2017, the prevalence of diabetes in Chinese adults has reached 11.2%. Diabetes has become a major public health problem that seriously affects the physical and mental health of the Chinese people (Nutrition and Metabolic Management Branch of the China Medical Health Care International Exchange Promotion Association, Clinical Nutrition Branch of the Chinese Nutrition Society, Diabetes Branch of the Chinese Medical Association, etc., "Guidelines for Medical Nutritional Therapy of Diabetes in China (2022 Edition)" [J]. Chinese Journal of Diabetes, 2022, 14(9): 881-933).

[0003] Results from clinical studies on strict blood sugar control, such as the Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS), have shown that strict blood sugar control can reduce the risk of microvascular and macrovascular lesions in diabetic patients (Chinese Society of Diabetes, "Guidelines for the Prevention and Treatment of Type 2 Diabetes in China" (2017 edition) [J]. Chinese Journal of Diabetes, 2018, 10(1): 4-66). The "Guidelines for the Clinical Diagnosis and Treatment of Diabetic Kidney Disease in China" issued by the Expert Group of the Chinese Society of Nephrology pointed out that for all patients with type 2 diabetes and kidney damage, strict and reasonable control of blood sugar levels can delay the onset and progression of the disease (Expert Group of the Chinese Society of Nephrology, "Guidelines for the Clinical Diagnosis and Treatment of Diabetic Kidney Disease in China" [J]. Chinese Journal of Nephrology, 2021, 37(3): 255-304).

[0004] However, the use of various antidiabetic drugs in patients with renal damage is limited. According to the "Chinese Guidelines for the Clinical Diagnosis and Treatment of Diabetic Kidney Disease" issued by the Expert Group of the Chinese Society of Nephrology, patients with diabetic nephropathy should choose oral hypoglycemic drugs based on their renal function and adjust the dose according to the degree of renal damage. Oral hypoglycemic drugs such as gliclazide and glipizide are metabolized in the liver, and the prototype and metabolites are mainly excreted through the kidneys. Therefore, they may accumulate in patients with impaired renal function (Microvascular Complications Group of the Diabetes Society of the Chinese Medical Association, "Clinical Guidelines for the Prevention and Treatment of Diabetic Kidney Disease in China" [J]. Chinese Journal of Diabetes, 2019, 11(1): 15-28). SGLT2 inhibitors act on the renal tubules, inhibiting the reabsorption of glucose by the renal tubules and promoting urinary glucose excretion to exert a hypoglycemic effect. The hypoglycemic effect decreases with impaired renal function (Expert Group of the Nephrology Society of the Chinese Medical Association, "Chinese Guidelines for the Clinical Diagnosis and Treatment of Diabetic Kidney Disease" [J]. Chinese Journal of Nephrology, 2021, 37(3): 255-304).

[0005] Therefore, there is a need to develop new drugs to treat type 2 diabetes.

[0006] Summary of the invention:

[0007] The present invention provides use of ligustrazine nitrone derivatives or pharmaceutically acceptable salts thereof in preparing medicines and in preventing or treating type 2 diabetes.

[0008] The drug comprises a therapeutically effective amount of the derivative or a pharmaceutically acceptable salt thereof, or a corresponding pharmaceutical composition. The use in preventing or treating type 2 diabetes comprises administering the drug to a patient in need thereof. The ligustrazine nitrone derivative has the following general formula (I):

[0009] Wherein, R1 and R3 are each independently C1-C6 alkyl; R2 is C1-C6 alkyl or R4 and R5 are each independently sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl.

[0010] In some embodiments, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or n-pentyl.

[0011] Preferably, the ligustrazine nitrone derivative has the structure shown below as TBN:

[0012] The structure and preparation method of the ligustrazine nitrone derivatives, including TBN, are described in the applicant's Chinese patent ZL200810027706.1, the contents of which are hereby incorporated by reference in their entirety.

[0013] Glycated hemoglobin (HbA1c) is an important factor in the management of diabetes mellitus. 1c ) refers to the product of non-enzymatic glycosylation of the hemoglobin B chain and is the most important indicator of blood sugar control. It is generally believed that the concentration of glycosylated hemoglobin can effectively reflect the average blood sugar level in the past 8 to 12 weeks. 1c In clinical practice, it has been used as the gold standard for evaluating long-term blood sugar control and is also an important basis for clinical decisions on whether to adjust treatment strategies. The normal reference value of HbA1c is 4% to 6%. A reduction in HbA1c levels is closely related to the reduction of microvascular complications in diabetic patients. Patients with type 2 diabetes who are younger, have a shorter course of disease, have a longer life expectancy, and do not have cardiovascular disease can control their HbA1c target to <6.5%, or even as close to normal as possible, without hypoglycemia or other adverse reactions (Chinese Medical Association Diabetes Branch, "Guidelines for the Prevention and Treatment of Type 2 Diabetes in China (2017 Edition)" [J]. Chinese Journal of Diabetes, 2018, 10(1): 4-67). Elevated HbA1c is an independent risk factor for proteinuria in Chinese diabetic patients, so strict blood sugar control is an effective measure to prevent proteinuria in diabetic patients (Expert Group of the Chinese Medical Association Nephrology Branch, "Guidelines for the Clinical Diagnosis and Treatment of Diabetic Kidney Disease in China" [J]. Chinese Journal of Nephrology, 2021, 37(3): 255-304).

[0014] According to one embodiment of the present invention, the type 2 diabetes is type 2 diabetes with glycosylated hemoglobin (HbA1c) ≥ 6.0%, such as glycosylated hemoglobin ≥ 6.2%, 6.5%, 7.0%, 8.0%, 8.5%, 9.0%, etc.

[0015] Self-monitoring of blood glucose can reflect the immediate blood glucose level. For high-risk individuals with at least one risk factor, further blood glucose screening should be performed, among which fasting blood glucose screening is a simple and easy method. If the fasting blood glucose is ≥6.1mmol / L, the patient may be diabetic, and an oral glucose tolerance test is recommended (Chinese Medical Association Diabetes Branch "Guidelines for the Prevention and Treatment of Type 2 Diabetes in China (2017 Edition)" [J]. Chinese Journal of Diabetes, 2018, 10(1): 4-66.). The "Guidelines for the Prevention and Treatment of Type 2 Diabetes in China (2017 Edition)" recommends that the fasting blood glucose control target for self-monitoring of blood glucose for general adult patients with type 2 diabetes is 4.4 to 7.0mmol / L.

[0016] According to one embodiment of the present invention, the type 2 diabetes is type 2 diabetes with fasting blood glucose ≥6.1mmol / L, such as fasting blood glucose ≥7.0mmol / L, 7.5mmol / L, 8.0mmol / L, 9.0mmol / L, 9.5mmol / L, 10mmol / L, 11mmol / L, 12mmol / L, 13mmol / L, 14mmol / L, 15mmol / L, 16mmol / L, etc.

[0017] The measurement of glycated hemoglobin (HbA1c) and blood glucose levels is a standard procedure in routine medical analysis. The term "fasting" has a general meaning in medical terms.

[0018] In the present invention, diabetes is diagnosed based on venous plasma glucose rather than capillary blood glucose measurement results. Unless otherwise specified, the blood glucose mentioned in the present invention refers to the venous plasma glucose value.

[0019] According to one embodiment of the present invention, the application is to reduce blood sugar and / or glycosylated hemoglobin in patients with type 2 diabetes.

[0020] According to one embodiment of the present invention, the type 2 diabetes is type 2 diabetes with renal damage.

[0021] Proteinuria is the main basis for clinical diagnosis, staging, and risk stratification of patients with type 2 diabetes and renal damage, and is also an important biomarker for assessing disease progression in patients with type 2 diabetes and renal damage. The "Guidelines for the Prevention and Treatment of Type 2 Diabetes in China (2017 Edition)" issued by the Chinese Society of Diabetes of the Chinese Medical Association states that the urine albumin-to-creatinine ratio (UACR) is a recommended indicator for diagnosing early renal damage, and defines UACR ≥ 30 mg / g as renal damage. The stage of proteinuria can be classified by the urine albumin-to-creatinine ratio, for example, UACR 30-300 mg / g is classified as microalbuminuria, and UACR > 300 mg / g is classified as macroalbuminuria (Chinese Society of Diabetes of the Chinese Medical Association, "Guidelines for the Prevention and Treatment of Type 2 Diabetes in China (2017 Edition)" [J]. Chinese Journal of Diabetes, 2018, 10(1): 4-66.).

[0022] According to one embodiment of the present invention, the renal injury is a renal injury degree of urine albumin / creatinine ratio (UACR)>300 mg / g, or a urine albumin / creatinine ratio (UACR)>300 mg / g described as renal injury.

[0023] Furthermore, the kidney damage is a urine albumin / creatinine ratio (UACR) greater than 300 mg / g and less than or equal to 5000 mg / g. Furthermore, the kidney damage is a urine albumin / creatinine ratio (UACR) greater than 300 mg / g and less than or equal to 3000 mg / g.

[0024] The term "glomerular filtration rate (GFR)" is defined as the volume of fluid filtered from the glomerular capillaries into the Bowman's capsule per unit time and is also an important indicator for evaluating renal function. According to one embodiment of the present invention, the randomized pre-glomerular filtration rate (eGFR) of the renal injury is ≥45 mL / min / 1.73 m 2 .

[0025] The pharmaceutically acceptable salt of the present invention can be a salt formed by a ligustrazine nitrone derivative with an acid, for example, a salt formed with the following acid: hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, phosphoric acid, acetic acid, propionic acid, benzoic acid, hexanoic acid, hydroiodic acid, nitric acid, sulfuric acid, salicylic acid, oxalic acid, malonic acid, tartaric acid, stearic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, cinnamic acid, 2-naphthalenesulfonic acid, succinic acid, D-gluconic acid, dodecylsulfuric acid, pyrosulfuric acid, pyruvic acid, cyclopentanepropionic acid, citric acid, lactic acid or aspartic acid.

[0026] According to one embodiment of the present invention, TBN as an active pharmaceutical ingredient can be formulated into a pharmaceutical composition (pharmaceutical preparation) using a pharmaceutically acceptable carrier.

[0027] According to one embodiment of the present invention, the pharmaceutical composition is in any form suitable for oral, sublingual, topical inhalation (nasal spray), rectal, intramuscular, intradermal, subcutaneous or intravenous administration. Oral administration is preferred.

[0028] According to one embodiment of the present invention, the present invention provides the use of a ligustrazine nitrone derivative or a pharmaceutically acceptable salt thereof in the preparation of an oral pharmaceutical formulation for preventing or treating type 2 diabetes. The dosage of the ligustrazine nitrone derivative or a pharmaceutically acceptable salt thereof of the present invention can be 10-3000 mg / person / time, and the specific dosage can vary depending on the age, sex, and weight of the subject, the specific pathological condition and its severity, the route of administration, or the diagnosis.

[0029] According to one embodiment of the present invention, the "acceptable carrier" is intended to be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Examples of pharmaceutically acceptable carriers are known to those skilled in the art.

[0030] If appropriate, the formulation is preferably in discrete dosage units and can be prepared by any method well known in the pharmaceutical art. All methods comprise the steps of mixing the active ingredient with one or more pharmaceutically acceptable carriers and then, if necessary, forming the product into the desired formulation. The pharmaceutical composition can be formulated into the following dosage forms: tablets, granules, fine granules, powders, capsules, caplets, soft capsules, pills, oral solutions, syrups, chewable tablets, sugar-coated tablets, effervescent tablets, drops, suspensions, rapidly dissolving tablets, rapidly dispersible orally tablets, sustained-release tablets, sustained-release capsules, enteric-coated tablets or capsules, etc.

[0031] As used herein, "tablet" includes uncoated tablets and tablets having one or more layers of coating. Furthermore, "tablet" includes tablets having one, two, three, or even more layers, as well as press-coated tablets, wherein each of the aforementioned tablet types may be uncoated or have one or more layers of coating. "Tablet" also encompasses miniature, melt-disintegrating, chewable, effervescent, orally disintegrating, sustained-release, and enteric-coated tablets.

[0032] According to one embodiment of the present invention, the desired dose of the oral pharmaceutical formulation of the present invention may be conveniently provided as a single dose per day or as divided doses administered at appropriate intervals (eg, two, three or more doses per day).

[0033] The present invention also provides the use of the ligustrazine nitrone derivative or a pharmaceutically acceptable salt thereof in combination with a second therapeutic drug in the preparation of a drug and in the prevention or treatment of type 2 diabetes, wherein type 2 diabetes can be as described above.

[0034] According to one embodiment of the present invention, ligustrazine nitrone derivatives can be used in combination therapy with one or more additional therapeutic agents. For combination therapy with more than one therapeutic agent, wherein these therapeutic agents are in separate dosage formulations or dosage forms, these therapeutic agents can be administered alone or in combination (i.e., simultaneously).

[0035] Furthermore, when administered separately, administration of one therapeutic agent can occur before or after administration of the other agent.

[0036] When ligustrazine nitrone derivatives are used in combination therapy with other therapeutic agents, the therapeutically effective amount of the other therapeutic agent or each other therapeutic agent will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by a skilled person based on the condition of the subject, the type of condition being treated, and the amount of ligustrazine nitrone derivative used.

[0037] In one embodiment of the invention, the TBN and the additional therapeutic agent are each administered in a therapeutically effective amount.

[0038] Examples of second therapeutic drugs that can be used in combination with TBN include, but are not limited to, those discussed below. The type and combination of the second drug do not significantly affect the effect of its use in combination with TBN. Therefore, drugs used in conventional treatment of type 2 diabetes are within the scope of the second therapeutic drug described in the present invention.

[0039] In one embodiment of the present invention, the second therapeutic drug includes but is not limited to biguanides, sulfonylureas, α-glucosidase inhibitors, insulin secretagogues, thiazolidinediones, DPP-4 inhibitors, RASS inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists, and insulins.

[0040] Biguanide hypoglycemic drugs are mainly metformin, which works by improving the sensitivity of body tissues to insulin, thereby enabling the body to use insulin more effectively. It is the first choice drug for controlling blood sugar.

[0041] Sulfonylurea hypoglycemic drugs include but are not limited to glibenclamide, glipizide, gliclazide, gliquidone, glimepiride, tolbutamide, chlorpropamide, acetophenonesulfonylcyclohexamide and tolazamide.

[0042] α-glucosidase inhibitors, such as acarbose, epalrestat, voglibose, and miglitol.

[0043] Insulin secretagogues, including repaglinide, mitiglinide, and nateglinide.

[0044] Thiazolidinediones, such as rosiglitazone, troglitazone, ciglitazone, pioglitazone, and englitazone.

[0045] DPP-4 inhibitors (or DPP-IV inhibitors) are hypoglycemic drugs, including sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, alagliptin, trelagliptin, tenegliptin, and gemagliptin.

[0046] SGLT-2 inhibitors include dapagliflozin, empagliflozin, canagliflozin, hengagliflozin, ertogliflozin, bexagliflozin, etc. The dosage of the SGLT-2 inhibitors described in the present invention can be determined by the clinician based on the severity of the disease, the response to the disease, any treatment-related toxicity, the patient's age, weight, and health status. The specific administration method and frequency of administration can follow the conventional administration methods of these drugs in the art.

[0047] GLP-1 receptor agonists (such as exenatide, lixisenatide, liraglutide, benaglutide, polyethylene glycol loxenatide, exenatide microspheres, semaglutide, dulaglutide, semaglutide, etc.) exert their hypoglycemic effects by stimulating the GLP-1 receptor to enhance insulin secretion and inhibit glucagon secretion. The dosage of the GLP-1 receptor agonist described in the present invention can be determined by the clinician based on the severity of the disease, the disease response, any treatment-related toxicity, the patient's age, weight, and health status. The specific administration method and frequency of administration can follow the conventional administration methods of these drugs in the art.

[0048] Insulin-based hypoglycemic drugs include insulin glulisine, insulin degludec, insulin lispro, insulin aspart, insulin glargine, insulin detemir, oligosaccharide insulin, human insulin inhalation powder, recombinant human insulin, and liver-directed vesicular insulin.

[0049] Renin-angiotensin system inhibitors (RASS inhibitors) are the standard strategy for reducing proteinuria and delaying disease progression in patients with type 2 diabetes and renal impairment. The 2014 ADA guidelines recommend RASS inhibitors as the first-line treatment for macroalbuminuria in patients with type 2 diabetes and renal impairment.

[0050] According to one embodiment of the present invention, a ligustrazine nitrone derivative or a pharmaceutically acceptable salt thereof is used in combination with a RASS inhibitor in the preparation of a drug for preventing or treating type 2 diabetes; the RASS inhibitor is selected from telmisartan, valsartan, irbesartan, candesartan cilexetil, azilsartan, allisartan medoxomil, benazepril, captopril, enalapril or perindopril salbutamol.

[0051] It is to be understood within the present invention that the combination, composition or combined use according to the present invention may envisage simultaneous, sequential or separate administration of the active ingredients or components.

[0052] In this context, "combination" or "combined" within the meaning of the present invention may include, but is not limited to, fixed and non-fixed forms and uses, such as simultaneous, sequential or separate use of the components or ingredients.

[0053] The combined administration of the present invention can be carried out by administering the active ingredients or components together, for example by administering them simultaneously in a single or two separate preparations or dosage forms. Alternatively, administration can be carried out by administering the active ingredients or components sequentially, for example by administering two separate preparations or dosage forms in succession.

[0054] For the combination therapy of the present invention, the active ingredients or components may be administered separately or formulated together (which means that they are formulated in the same preparation or the same dosage form). Thus, administration of one element of the combination of the present invention may be carried out before, simultaneously with or after administration of another element of the combination.

[0055] Unless otherwise indicated, combination therapy may refer to first-line, second-line, or third-line therapy, or to initial or additional combination therapy or alternative therapy.

[0056] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by one of ordinary skill in the art to which the invention belongs. Methods and materials for use in the present invention are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In the event of any disagreement, the present specification (including definitions) shall prevail.

[0057] As used herein, the terms "subject" and "patient" are used interchangeably. A subject or patient is a human patient or human subject.

[0058] The terms "for example" and "such as" and their grammatical equivalents, unless expressly stated otherwise, should be understood to be followed by the phrase "without limitation" or "and without limitation."

[0059] As used herein, the term "therapeutically effective amount" or "pharmaceutically effective amount" refers to that amount of an active compound or agent that elicits in a human the medical response that a physician or other clinician is seeking. A therapeutically or pharmaceutically effective amount of a compound is at least the minimum amount necessary to ameliorate, alleviate, palliate, delay, reduce, relieve, or cure a disease, disorder, or syndrome, or one or more of its symptoms, signs, or causes.

[0060] The subject of administration of the ligustrazine nitrone derivatives of the present invention is a human. The term "administering" with respect to a compound or agent means introducing the compound into the body of a patient in need of treatment. When the ligustrazine nitrone derivatives are used in combination with one or more other therapeutic agents, "administering" and its variants are each understood to encompass the simultaneous and / or sequential introduction of the ligustrazine nitrone derivative and other therapeutic agents into the patient.

[0061] The term "treatment" encompasses therapeutic treatment of a patient already experiencing the condition in question. Therapeutic treatment can be symptomatic treatment to alleviate the symptoms of the specific indication, or causal treatment to reverse or partially reverse the condition of the indication or to halt or slow disease progression. Thus, the compositions and methods of the present invention can be used, for example, as therapeutic treatment over a period of time as well as for chronic treatment.

[0062] The terms "prophylactic treatment," "preventative treatment," and "prevention" are used interchangeably and encompass treating a patient at risk of developing the conditions described above, thereby reducing that risk.

[0063] It will be understood that the amount of the pharmaceutical composition according to the present invention to be administered to a patient and required for use in the treatment or prevention according to the present invention will vary with the route of administration, the nature and severity of the condition to be treated or prevented, the age, weight and physical condition of the patient, concomitant medications, and will ultimately be determined by the resident physician.

[0064] As used herein, the term "treat," ... DETAILED DESCRIPTION

[0065] The present invention is described in detail below through specific examples. It is pointed out that the following examples are only used to further illustrate the present invention and should not be understood as limiting the scope of protection of the present invention. Unless otherwise specified, the parts described in the present invention are all parts by weight and the percentages described are all mass percentages. In the examples of the present invention, n represents the number of subjects participating in the experiment. Example 1 Clinical Trial

[0066] The present invention adopts a multi-center, randomized, double-blind, placebo parallel controlled design.

[0067] The subjects were those who had been taking antidiabetic drugs for 6 months or more and whose HbA1c was ≤9.0%; whose urine albumin / creatinine ratio (UACR) was >300mg / g and ≤3000mg / g in at least 2 of 3 morning urines during the screening period; whose estimated glomerular filtration rate (eGFR) was ≥45mL / min / 1.73m 2 Patients with type 2 diabetes mellitus were selected as research subjects (all signed informed consent).

[0068] In addition to baseline glucose-lowering medication, subjects received a single oral dose of TBN 600mg or 1200mg, compared with a placebo, twice daily for 24 weeks. After 24 weeks of treatment, fasting blood glucose was measured using a biochemical analyzer, and glycated hemoglobin was measured using a BioRad Glycated Hemoglobin Analyzer-High Performance Liquid Chromatography.

[0069] The basic hypoglycemic treatment in the trial is that the patients follow the hypoglycemic treatment regimen they have been taking. These treatment regimens include one or a combination of biguanides, sulfonylureas, α-glucosidase inhibitors, insulin secretagogues, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists, and insulin. For example, the medication status and blood sugar status of some subjects are shown in Table 1 below.

[0070] Table 1 Examples of medication and blood sugar status of some subjects

[0071] Note: qd means once a day, bid means twice a day, tid means three times a day.

[0072] A total of 143 subjects completed the clinical trial, and 140 subjects were included in the FAS set, of which 48 subjects received placebo, 46 ​​subjects received TBN 600 mg / time (twice a day), and 46 subjects received TBN 1200 mg / time (twice a day).

[0073] 106 subjects were treated with GLP-1 receptor agonists, SGLT-2 inhibitors, and / or RASS inhibitors as their primary therapy. Of these subjects, 37 received placebo, 33 received TBN 600 mg twice daily, and 36 received TBN 1200 mg twice daily.

[0074] Thirty-four subjects were not receiving GLP-1 receptor agonists, SGLT-2 inhibitors, and / or RASS inhibitors as part of their baseline treatment. Eleven of these subjects received placebo, 13 received TBN 600 mg twice daily, and 10 received TBN 1200 mg twice daily.

[0075] The results showed that in patients with type 2 diabetes and kidney damage with a urine albumin / creatinine ratio (UACR) >300 mg / g and ≤3000 mg / g, TBN significantly increased glycated hemoglobin relative to baseline in the placebo group, while glycated hemoglobin in the treatment group remained the same or decreased relative to baseline. This shows that TBN can significantly reduce patients' glycated hemoglobin relative to the placebo group. The specific results are shown in Table 2.

[0076] Table 2 Results of HbA1c (%) of subjects after 24 weeks of treatment (Median)

[0077] In Table 2, RAAS refers to RAAS inhibitors, SGLT-2 refers to SGLT-2 inhibitors, and GLP-1 refers to GLP-1 agonists. Missing indicates the number of cases missing due to subject dropout at the end of the trial.

[0078] LS mean statistical analysis of glycated hemoglobin HbA1c (%) after 24 weeks of TBN treatment was performed for all subjects who completed the clinical trial. The results showed that the relative baseline change rate after 24 weeks of treatment in the placebo group (n=44, baseline 7.31) was 8.34%; the relative baseline change rate after 24 weeks of TBN treatment in the 600 mg group (n=46, baseline 7.47) was 0.67%, and the relative placebo difference was -7.67%, which was statistically significant compared with placebo, P=0.014; the relative baseline change rate after 24 weeks of TBN treatment in the 1200 mg group (n=44, baseline 7.15) was -2.24%, and the relative placebo difference was -10.58%, which was statistically significant compared with placebo, P<0.001.

[0079] LS mean statistical analysis of blood glucose (mmol / L) after 24 weeks of TBN treatment was performed on all subjects who completed the clinical trial. The results showed that the relative baseline change rate after 24 weeks of treatment in the placebo group (n=44, baseline 7.30) was 12.33%; the relative baseline change rate after 24 weeks of TBN treatment in the 600 mg group (n=45, baseline 8.06) was 7.32%, with a difference of -5.01% relative to placebo; the relative baseline change rate after 24 weeks of TBN treatment in the 1200 mg group (n=44, baseline 7.39) was -6.63%, with a difference of -18.96% relative to placebo, which was statistically significant compared with placebo, P=0.009.

[0080] According to the test results, glycated hemoglobin (HbA1c) ≤ 9.0%; urine albumin / urine creatinine ratio (UACR) > 300 mg / g and ≤ 3000 mg / g; random pre-glomerular filtration rate (eGFR) ≥ 45 mL / min / 1.73 m 2 For patients with type 2 diabetes, basic hypoglycemic drugs can no longer control blood sugar levels, and the blood sugar and glycosylation levels of the placebo group have increased significantly.

[0081] Surprisingly, the ligustrazine nitrone derivative TBN can significantly lower blood sugar and glycosylated hemoglobin levels in this type of patients compared with the placebo group, which is of great significance for patients with type 2 diabetes.

Claims

1. Use of a ligustrazine nitrone derivative or a pharmaceutically acceptable salt thereof in preventing or treating type 2 diabetes, comprising administering a therapeutically effective amount of the derivative or a pharmaceutically acceptable salt thereof to a patient in need thereof; wherein the derivative has the following general formula (I): in, R 1 and R 3 Each is independently C1-C6 alkyl; R 2 is C1-C6 alkyl or R 4 and R 5 Each is independently sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl.

2. The use according to claim 1, wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl.

3. The use according to claim 1, wherein the ligustrazine nitrone derivative has the structure shown in TBN below:

4. The use according to claim 1, wherein the type 2 diabetes is type 2 diabetes with glycosylated hemoglobin (HbA1c) ≥ 6.0%, type 2 diabetes with glycosylated hemoglobin (HbA1c) ≥ 6.2%, or type 2 diabetes with glycosylated hemoglobin (HbA1c) ≥ 6.5%.

5. The use according to claim 4, wherein the type 2 diabetes is type 2 diabetes with glycosylated hemoglobin (HbA1c) ≤ 9.0%.

6. The use as claimed in claim 1, wherein the type 2 diabetes is type 2 diabetes with fasting blood glucose ≥ 6.1 mmol / L, type 2 diabetes with fasting blood glucose ≥ 7.0 mmol / L, or type 2 diabetes with fasting blood glucose ≥ 7.5 mmol / L.

7. The use according to any one of claims 4 to 6, wherein the type 2 diabetes is type 2 diabetes with renal damage.

8. The use of claim 7, wherein the urine albumin / creatinine ratio (UACR) of kidney damage is >300 mg / g, the urine albumin / creatinine ratio is >300 mg / g and ≤5000 mg / g, or the urine albumin / creatinine ratio is >300 mg / g and ≤3000 mg / g.

9. The use according to claim 7, wherein the eGFR is ≥ 45 mL / min / 1.73 m 2 .

10. The use according to any one of claims 1 to 9, wherein the use is for reducing blood sugar and / or glycosylated hemoglobin levels in patients with type 2 diabetes.

11. Use of a ligustrazine nitrone derivative or a pharmaceutically acceptable salt thereof in the prevention or treatment of type 2 diabetes, wherein the ligustrazine nitrone derivative or a pharmaceutically acceptable salt thereof is combined with a second therapeutic drug, wherein the second therapeutic drug is selected from one or a combination of biguanides, sulfonylureas, α-glucosidase inhibitors, insulin secretagogues, thiazolidinediones, DPP-4 inhibitors, RASS inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists, and insulins; wherein the derivative has the following general formula (I): in, R 1 and R 3 Each is independently C1-C6 alkyl; R 2 is C1-C6 alkyl or R 4 and R 5 Each is independently sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl.

12. The use according to claim 11, wherein the ligustrazine nitrone derivative has the structure shown in TBN below:

13. The use according to claim 11 or 12, wherein the second therapeutic drug is selected from one or a combination of RASS inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists.

14. The use according to claim 13, wherein the SGLT2 inhibitor is selected from dapagliflozin, empagliflozin, canagliflozin, hengagliflozin, ertogliflozin or bexagliflozin; the GLP-1 receptor agonist is selected from exenatide, lixisenatide, liraglutide, benaglutide, polyethylene glycol loxenatide, exenatide microspheres, semaglutide, dulaglutide or semaglutide; the RASS inhibitor is selected from telmisartan, valsartan, irbesartan, candesartan cilexetil, azithromycin, alisartan medoxomil, benazepril, captopril, enalapril or perindopril salbutamol.

15. The use according to any one of claims 11 to 14, wherein the type 2 diabetes is type 2 diabetes with glycosylated hemoglobin (HbA1c) ≥ 6.0%, type 2 diabetes with glycosylated hemoglobin (HbA1c) ≥ 6.2%, or type 2 diabetes with glycosylated hemoglobin (HbA1c) ≥ 6.5%.

16. The use according to claim 15, wherein the type 2 diabetes is type 2 diabetes with glycosylated hemoglobin (HbA1c) ≤ 9.0%.

17. The use according to any one of claims 11 to 14, wherein the type 2 diabetes is type 2 diabetes with fasting blood glucose ≥ 6.1 mmol / L, type 2 diabetes with fasting blood glucose ≥ 7.0 mmol / L, or type 2 diabetes with fasting blood glucose ≥ 7.5 mmol / L.

18. The use according to any one of claims 11 to 14, wherein the type 2 diabetes is type 2 diabetes with renal damage.

19. The use according to claim 18, wherein the renal injury has a urine albumin / creatinine ratio (UACR)>300 mg / g, a urine albumin / creatinine ratio>300 mg / g and ≤5000 mg / g, or a urine albumin / creatinine ratio>300 mg / g and ≤3000 mg / g.

20. The use according to claim 18, wherein the eGFR is ≥ 45 mL / min / 1.73 m 2 .

21. The use according to any one of claims 11 to 20, wherein the use is for reducing blood sugar and / or glycosylated hemoglobin levels in patients with type 2 diabetes.

22. The use according to any one of claims 1 to 10 and 11 to 20, wherein the pharmaceutically acceptable salt is selected from hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, phosphoric acid, acetic acid, propionic acid, benzoic acid, hexanoic acid, hydroiodic acid, nitric acid, sulfuric acid, salicylic acid, oxalic acid, malonic acid, tartaric acid, stearic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, cinnamic acid, 2-naphthalenesulfonic acid, succinic acid, D-gluconic acid, dodecylsulfuric acid, pyrosulfuric acid, pyruvic acid, cyclopentanepropionic acid, citric acid, lactic acid or aspartic acid.

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