CN116850188A - Application of ligustrazine nitrone derivative in preparing medicament for preventing or treating type 2 diabetes - Google Patents
Application of ligustrazine nitrone derivative in preparing medicament for preventing or treating type 2 diabetes Download PDFInfo
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- CN116850188A CN116850188A CN202310609343.7A CN202310609343A CN116850188A CN 116850188 A CN116850188 A CN 116850188A CN 202310609343 A CN202310609343 A CN 202310609343A CN 116850188 A CN116850188 A CN 116850188A
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- 208000001072 type 2 diabetes mellitus Diseases 0.000 title claims abstract description 50
- 239000003814 drug Substances 0.000 title claims abstract description 30
- -1 ligustrazine nitrone derivative Chemical class 0.000 title claims abstract description 15
- FINHMKGKINIASC-UHFFFAOYSA-N tetramethyl-pyrazine Natural products CC1=NC(C)=C(C)N=C1C FINHMKGKINIASC-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 239000008280 blood Substances 0.000 claims abstract description 37
- 210000004369 blood Anatomy 0.000 claims abstract description 36
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 32
- 239000008103 glucose Substances 0.000 claims abstract description 32
- 102000017011 Glycated Hemoglobin A Human genes 0.000 claims abstract description 25
- 108010014663 Glycated Hemoglobin A Proteins 0.000 claims abstract description 25
- 229940079593 drug Drugs 0.000 claims abstract description 7
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 claims description 30
- 206010012601 diabetes mellitus Diseases 0.000 claims description 27
- 206010061481 Renal injury Diseases 0.000 claims description 20
- 208000037806 kidney injury Diseases 0.000 claims description 20
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 16
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
The invention provides application of ligustrazine nitrone derivatives in preparing medicines for preventing or treating type 2 diabetes. Clinical trials have found that ligustrazine nitrone derivatives TBN are capable of significantly lowering blood glucose and glycosylated hemoglobin levels in type 2 diabetics when compared to placebo.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and relates to application of ligustrazine nitrone derivatives in preparation of medicines for preventing or treating type 2 diabetes.
Background
Diabetes is a metabolic disease characterized by hyperglycemia. Diabetes is classified into type 1 diabetes and type 2 diabetes, wherein type 2 diabetes accounts for more than 90% of all diabetes cases.
Clinical research results of severe blood sugar control such as Diabetes Control and Complications Test (DCCT) and british prospective diabetes research (UKPDS) show that the severe blood sugar control can reduce the occurrence risk of microvascular and macrovascular lesions of diabetics (the institute of diabetes of the chinese medical science, the guidelines for prevention and treatment of type 2 diabetes in the chinese version 2017 [ J ], journal of chinese diabetes, 2018,10 (1): 4-66). The Chinese medical science of the expert group of the Chinese medical science of the kidney disease department issues the Chinese medical science of the clinical diagnosis and treatment of diabetes kidney disease guide, which indicates that for all type 2 diabetics with kidney injury, the strict and reasonable control of blood sugar level can delay the occurrence and progress of the disease (Chinese medical science of the expert group of the kidney disease department of the Chinese medical science of the same, chinese medical science of diabetes kidney disease journal of clinical diagnosis and treatment of kidney disease, 2021,37 (3): 255-304).
However, the use of various antidiabetic agents in kidney damaged patients is limited. According to the Chinese guidelines for clinical diagnosis and treatment of diabetic nephropathy issued by the expert group of the kidney disease department of the China medical society, patients with diabetic nephropathy should individually select oral hypoglycemic agents according to the renal function conditions, and adjust the dosage according to the kidney damage degree. Oral hypoglycemic agents such as gliclazide and glipizide are metabolized in the liver, and prototype and metabolites are mainly excreted through the kidneys, so that they may accumulate in patients with impaired renal function (the group of diabetes mellitus division microvascular complications of the Chinese medical society, chinese guidelines for the prevention and treatment of diabetes kidney diseases [ J ]. J.J.J.China J.diabetes, 2019, 11 (1): 15-28.). SGLT2 inhibitors act on the tubules, promote urinary glucose excretion by inhibiting glucose reabsorption by the tubules, and exert a hypoglycemic effect, which declines with reduced renal function (China medical society of the institute of renal diseases expert group, chinese guidelines for clinical diagnosis and treatment of diabetic kidney diseases [ J ]. Chinese J.China J of renal diseases, 2021,37 (3): 255-304).
Thus, there is a need to develop new drugs for the treatment of diabetes.
Disclosure of Invention
The invention provides application of ligustrazine nitrone derivative or pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating type 2 diabetes.
The technical scheme of the invention is as follows:
the application of ligustrazine nitrone derivative or its pharmaceutically acceptable salt in preparing medicine for preventing or treating type 2 diabetes is provided. The ligustrazine nitrone derivative has a structure shown as the following TBN:
the structure and preparation method of TBN are described in Chinese patent ZL 200810027706.1.
The control of blood glucose is of great importance in the management of diabetes metabolism. Glycosylated hemoglobin (HbA) 1c ) Refers to the non-enzymatic glycosylation of the B chain of hemoglobin, and is the most important indicator reflecting the state of glycemic control. It is generally considered that the glycosylated hemoglobin concentration effectively reflects the average blood glucose level over the past 8 to 12 weeks. HbA 1c Clinically, the method is used as a gold standard for evaluating the long-term blood sugar control condition, and is also an important basis for clinically determining whether to adjust a treatment strategy. HbA1c is 4% -6% of normal reference value. The decrease in HbA1c levels is closely related to the decrease in microvascular complications in diabetics. Type 2 diabetics with lighter age, shorter course of disease, longer life expectancy, and no concomitant cardiovascular disease can control HbA1c targets without hypoglycemia or other adverse effects<6.5% and even as close to normal as possible (Chinese medical society, diabetes division. Chinese guide for prevention and treatment of diabetes type 2, version 2017) [ J ]]Journal of Chinese diabetes 2018,10 (1): 4-67). HbA1c elevation is an independent risk factor of proteinuria of Chinese diabetics, so that strict control of blood sugar is an effective measure for preventing diabetes from proteinuria (China medical society of renal disease expert group, clinical diagnosis and treatment of diabetes renal disease Chinese guidelines [ J)]J.China kidney disease, 2021,37 (3): 255-304).
According to one embodiment of the present invention, the type 2 diabetes is type 2 diabetes with a glycosylated hemoglobin (HbA 1 c) of 6.0% or more, such as glycosylated hemoglobin of 6.2% or more, 6.5%,7.0%,8.0%,8.5%,9.0% or more.
Self blood glucose monitoring can reflect immediate blood glucose levels. Further blood glucose screening should be performed for high risk populations with at least one risk factor, wherein fasting blood glucose screening is a simple and easy method. If the fasting blood glucose is more than or equal to 6.1 mmol/L, it is possible to be a diabetic patient, and oral glucose tolerance test (Chinese medical society, diabetes department, chinese guidelines for prevention and treatment of type 2 diabetes (2017 edition) [ J ]. J.Chinese journal of diabetes 2018,10 (1): 4-66) is recommended. Chinese guidelines for prevention and treatment of type 2 diabetes (2017 edition) recommend that the fasting blood glucose control target for self-blood glucose monitoring of general adult type 2 diabetics be 4.4-7.0 mmol/L.
According to one embodiment of the invention, the type 2 diabetes is type 2 diabetes with a fasting blood glucose of ≡6.1 mmol/L, such as fasting blood glucose of ≡7.0 mmol/L,7.5 mmol/L,8.0 mmol/L,9.0 mmol/L,9.5 mmol/L,10 mmol/L,11 mmol/L,12 mmol/L,13 mmol/L,14 mmol/L,15 mmol/L,16 mmol/L, etc.
Measurement of glycosylated hemoglobin (HbA 1 c) and blood glucose values is a standard procedure in routine medical analysis. The term "fasting" has the general meaning of medical terms.
In the present invention, diabetes is diagnosed based on the results of a venous plasma glucose rather than capillary blood glucose measurement. If no special prompt exists, the blood sugar mentioned by the invention is the venous blood plasma glucose value.
According to one embodiment of the invention, the use is for lowering blood glucose or/and glycosylated hemoglobin in a type 2 diabetic patient.
According to one embodiment of the invention, the type 2 diabetes is type 2 diabetes with kidney damage.
Proteinuria is the primary basis for clinical diagnosis, staging and risk stratification of type 2 diabetics with kidney damage, and is also an important biomarker for assessing disease progression in type 2 diabetics with kidney damage. The Chinese medical society diabetes mellitus department release guidelines for prevention and treatment of type 2 diabetes mellitus (2017 edition) of China indicate that Urinary Albumin Creatinine Ratio (UACR) is a recommended index for diagnosing early kidney injury, and meanwhile, the UACR is more than or equal to 30 mg/g and is defined as kidney injury. The proteinuria stage can be classified by urinary albumin creatinine ratio, e.g., UACR 30-300 mg/g classified as microalbuminuria, UACR >300mg/g classified as macroalbuminuria (chinese medical society, diabetes mellitus type 2 guidelines for control of diabetes (2017 edition) [ J ]. Journal of chinese diabetes, 2018,10 (1): 4-66).
According to one embodiment of the invention, the kidney injury is the degree of kidney injury of urinary albumin/creatinine ratio (UACR) >300mg/g, or the urinary albumin/creatinine ratio (UACR) >300mg/g described as kidney injury.
Further, the kidney injury is urinary albumin/creatinine ratio (UACR) >300mg/g and less than or equal to 5000 mg/g. Still further, the kidney injury is a urinary albumin/creatinine ratio (UACR) of >300mg/g and less than or equal to 3000 mg/g.
The term "Glomerular Filtration Rate (GFR)" is defined as the volume of fluid filtered from glomerular capillaries into the baud's capsule per unit time and is also an important indicator of renal function assessment. According to one embodiment of the invention, the random pre-glomerular filtration rate (eGFR) of the kidney injury is greater than or equal to 45 mL/min/1.73 m 2 。
The pharmaceutically acceptable salts of the invention may be salts of TBN with acids, for example with: hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, phosphoric acid, acetic acid, propionic acid, benzoic acid, caproic 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.
According to one embodiment of the present invention, the TBN as the active pharmaceutical ingredient may be formulated into pharmaceutical compositions (pharmaceutical preparations) using a pharmaceutically acceptable carrier.
According to one embodiment of the invention, the pharmaceutical composition is in the form of any composition suitable for oral, sublingual, topical inhalation (nasal spray), rectal, intramuscular, intradermal, subcutaneous or intravenous administration. Oral administration is preferred.
According to one embodiment of the present invention there is provided the use of TBN or a pharmaceutically acceptable salt thereof in the manufacture of an oral pharmaceutical formulation for the prevention or treatment of type 2 diabetes. The TBN of the present invention or a pharmaceutically acceptable salt thereof may be used in an amount of 10 to 3000 mg per person per time, and the specific administration amount may vary depending on the age, sex and weight of the subject, the specific pathological condition and severity thereof, the administration route or diagnosis.
According to one embodiment of the invention, the term "acceptable carrier" means 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.
If appropriate, the formulations are preferably in discrete dosage units and may be prepared by any method well known in the pharmaceutical arts. All methods include the following steps: the active ingredient is mixed with one or more pharmaceutically acceptable carriers and the product is then shaped into the desired formulation if desired. The pharmaceutical composition may be formulated as: tablets, granules, fine granules, powders, capsules, caplets, soft capsules, pills, oral solutions, syrups, chewable tablets, sugar-coated tablets, effervescent tablets, drops, suspensions, fast-dissolving tablets, oral fast-dispersing tablets, slow-release capsules, enteric-coated tablets, enteric-coated capsules and the like.
In the present invention, "tablet" includes uncoated tablets and tablets having one or more coatings. Furthermore, "tablets" include tablets having one, two, three or even more layers, and compression coated tablets, wherein each of the tablet types mentioned above may be uncoated or have one or more coatings. "tablet" also includes mini, melt, chewable, effervescent, orally disintegrating, sustained release, and enteric tablets.
According to one embodiment of the present invention, the desired dose of the oral pharmaceutical formulation of the present invention may conveniently be provided as a divided dose administered once a day or at appropriate intervals (e.g. twice, three or more doses per day).
The invention also provides application of TBN or pharmaceutically acceptable salt thereof and a second therapeutic drug in preparation of drugs for preventing or treating type 2 diabetes. Wherein type 2 diabetes may be as described previously.
According to one embodiment of the invention, TBN may be used in combination therapy with one or more additional therapeutic agents. For combination therapy with more than one therapeutic agent, where the therapeutic agents are in separate dosage formulations or dosage forms, the therapeutic agents may be administered separately or in combination (i.e., simultaneously).
Furthermore, when administered alone, the administration of one therapeutic agent may be performed before or after the administration of the other agent.
When TBN is used in combination therapy with other therapeutic agents, the therapeutically effective amount of the or each other therapeutic agent will depend on the type of drug used. Suitable dosages are known to approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition being treated, and the amount of TBN used.
In one embodiment of the invention, the TBN and the additional therapeutic agent are each administered in a therapeutically effective amount.
Examples of second therapeutic agents that may be associated with a TBN include, but are not limited to, those discussed below, the type and combination of which do not significantly affect the efficacy of their use in combination with a TBN, and therefore agents that are routinely used in the treatment of type 2 diabetes are within the scope of the second therapeutic agents described herein.
In one embodiment of the invention, the second therapeutic agent includes, but is not limited to, biguanides, sulfonylureas, alpha-glucosidase inhibitors, insulin secretagogues, thiazolidinediones, DPP-4 inhibitors, RASS inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists, insulins.
Biguanide hypoglycemic agents are mainly metformin, act by improving the sensitivity of body tissues to insulin, thereby making the body use insulin more effectively, and are the first drugs for controlling blood sugar.
Sulfonylureas include, but are not limited to, glibenclamide, glipizide, gliclazide, gliquidone, glimepiride, tolbutamide, chlorpropamide, acetophenone sulfonylcyclohexamide, tolazamide, and the like.
The alpha-glucosidase inhibitor is hypoglycemic medicine, such as acarbose, epalrestat, voglibose, miglitol, etc.
Insulin secretagogues, hypoglycemic agents, include repaglinide, mitiglinide, and nateglinide.
Thiazolidinediones hypoglycemic agents such as rosiglitazone, troglitazone, ciglitazone, pioglitazone, englitazone.
Hypoglycemic agents including sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, alogliptin, trogliptin, tigliptin, and gemagliptin, and the like.
SGLT-2 inhibitors include dapagliflozin, engagliflozin, canagliflozin, hengliflozin, ai Tuoge gliflozin, bei Shage gliflozin, and the like. The amount of SGLT-2 inhibitor of the present invention may be determined by the clinician based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age of the patient, the weight and health of the patient, and the particular mode and number of administrations may be in accordance with those conventional modes of administration of such agents in the art.
GLP-1 receptor agonists (e.g., exenatide, risinatide, liraglutide, benraglutide, polyethylene glycol lobeltide, exenatide microsphere, cable Ma Lutai, duloxetide, semraglutide, etc.) exert a hypoglycemic effect by agonizing GLP-1 receptor to enhance insulin secretion, inhibit glucagon secretion, etc. The GLP-1 receptor agonist amounts of the invention can be determined by the clinician based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age of the patient, the weight and health of the patient, and the particular mode and number of administrations can be in accordance with those conventional modes of administration of such agents in the art.
Insulin hypoglycemic agents include insulin glulisine, insulin deglutition, insulin glulisine, insulin aspart, insulin glargine, insulin detention, insulin hypo-protamine, human insulin inhalation powder, recombinant human insulin, liver-guided vesicle insulin.
Inhibitors of the renin-angiotensin system (RASS inhibitors) are standard strategies for reducing urine proteins and slowing disease progression in type 2 diabetics with kidney damage. ADA guidelines in 2014 suggest that RASS inhibitors are a first-line treatment regimen for a large number of albuminuria in type 2 diabetics with kidney impairment.
According to one embodiment of the invention, the use of TBN or a pharmaceutically acceptable salt thereof in combination with a RASS inhibitor for the manufacture of a medicament for the prevention or treatment of type 2 diabetes; the RASS inhibitor is selected from telmisartan, valsartan, irbesartan, candesartan cilexetil, azilsartan cilexetil, benazepril, captopril, enalapril or perindopril salbutamol.
Within the present invention it is to be understood that the combination, composition or use of the combination according to the invention may be regarded as simultaneous, sequential or separate administration of the active ingredients or components.
In this context, "combined" or "combined" within the meaning of the present invention may include, but is not limited to, both fixed and non-fixed forms and uses, such as the simultaneous, sequential or separate use of components or elements.
The combined administration of the invention may be carried out by administering the active ingredients or components together, for example by administering them simultaneously in a single or two separate formulations or dosage forms. Alternatively, administration may be by sequential administration of the active ingredients or components, e.g., sequential administration of two separate formulations or dosage forms.
For the combination therapy of the invention, the active components or ingredients may be administered separately or formulated together (which means they are formulated in the same formulation or in the same dosage form). Thus, administration of one element of a combination of the invention may be performed before, simultaneously with, or after administration of another element of the combination.
Combination therapy may refer to first-line, second-line or third-line therapy, or initial or supplemental combination therapy or replacement therapy, unless otherwise indicated.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this 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 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 a divergence, the specification (including definitions) will control.
As used herein, the terms "subject" and "patient" are used interchangeably. The subject or patient is a human patient or a human subject.
For the terms "e.g." and "such as" and grammatical equivalents thereof, unless explicitly stated otherwise, it is to be understood as following the phrase "not limited to" or "and not limited to".
As used herein, the term "therapeutically effective amount" or "pharmaceutically effective amount" refers to the amount of an active compound or agent that elicits the medical response in a human 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 improve, alleviate, mitigate, delay, reduce, alleviate or cure one or more of the disease, disorder or syndrome or symptoms, signs or causes thereof.
The subject of TBN administration of the present invention is a human. The term "administering" with respect to a compound or agent refers to introducing the compound into a patient in need of treatment. When TBN is used in combination with one or more other therapeutic agents, "administration" and variants thereof are each understood to encompass the simultaneous and/or sequential introduction of TBN and other therapeutic agents into a patient.
The term "treating" encompasses therapeutic treatment of a patient who has developed the disorder. The therapeutic treatment may be symptomatic treatment that alleviates symptoms of a particular indication, or a treatment that reverses or partially reverses the condition of the indication or stops or slows the progression of the disease. Thus, the compositions and methods of the invention are useful as therapeutic treatments, for example, for a period of time, as well as for chronic treatments.
The terms "prophylactic treatment," "prophylactic treatment," and "prophylaxis" are used interchangeably and include treating a patient at risk of developing a disorder described above, thereby reducing the risk.
It will be appreciated that the amount of the pharmaceutical composition according to the invention to be administered to a patient and to be used in the treatment or prophylaxis according to the 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 medication, and will ultimately be at the discretion of the attendant physician.
As used herein, the term "treatment" also refers to delaying or ameliorating or preventing the progression of a disease (i.e., the known or expected progression of a disease), severity, and/or duration as a result of administration of one or more therapies; or delay or ameliorate or prevent progression of one or more symptoms, clinical manifestations, observations or measurements; or prevent or slow down the negative progression of the pathology assessment (i.e., "manage" without "curing" the disorder).
Description of the embodiments
The present invention is described in detail below by way of specific examples, which are given herein for further illustration of the present invention and are not to be construed as limiting the scope of the present invention. Except for special descriptions, the parts are parts by weight, and the percentages are mass percentages. In the embodiment of the invention, n represents the number of people participating in the test.
Example 1 clinical trial
The present invention employs a multicenter, randomized, double-blind, placebo-controlled design.
Test object: the hypoglycemic medicine is taken regularly for 6 months or more, and the glycosylated hemoglobin (HbA 1 c) is less than or equal to 9.0 percent; and urine albumin/urine creatinine ratio (UACR) occurs at least 2 times in 3 morning urine during the screening period>300mg/g is less than or equal to 3000 mg/g; the random pre-glomerular filtration rate (eGFR) is more than or equal to 45 mL/min/1.73 m 2 Type 2 diabetics of (1) were subjects (all signed informed consent).
Subjects were given TBN 600 mg or 1200 mg orally in a single dose, placebo controlled, twice a day for 24 weeks (24W) on a hypoglycemic basis. After 24 weeks of treatment, the fasting blood glucose was detected by a biochemical analyzer and the glycosylated hemoglobin was detected by a Berle glycosylated hemoglobin meter-high performance liquid chromatography.
The basic treatment of the hypoglycemic agents in the test is that patients take the treatment schemes according to the hypoglycemic agents adopted by the patients, wherein the treatment schemes comprise one or a combination of biguanides, sulfonylureas, alpha glucosidase inhibitors, insulin secretagogues, thiazolidinediones, DPP 4 inhibitors, SGLT2 inhibitors, GLP 1 receptor agonists and insulins, for example, the administration conditions and blood sugar conditions of partial subjects are shown in the following table 1.
Table 1 examples of partial subject dosage and blood glucose conditions
qd is once a day, bid is twice a day, tid is three times a day.
143 subjects completed the clinical trial, 140 subjects included in FAS set, of which 48 subjects received Placebo (Placebo) treatment, 46 subjects received TBN 600 mg/time (twice a day) treatment, and 46 subjects received TBN 1200 mg/time (twice a day) treatment.
106 subjects used GLP-1 receptor agonists, SGLT-2 inhibitors and/or RASS inhibitors in the basal treatment. Of these subjects, 37 received placebo treatment, 33 received TBN 600 mg/time (twice a day) and 36 received TBN 1200 mg/time (twice a day) treatment.
34 subjects did not use GLP-1 receptor agonists, SGLT-2 inhibitors and/or RASS inhibitors in the basal treatment. Of these subjects, 11 received placebo treatment, 13 received TBN 600 mg/time (twice a day) and 10 received TBN 1200 mg/time (twice a day) treatment.
The results show that: in type 2 diabetics with a kidney injury level of urinary albumin/creatinine ratio (UACR) of >300mg/g and less than or equal to 3000 mg/g, the placebo group had significantly elevated glycosylated hemoglobin relative to baseline, while the administration group had leveled or reduced glycosylated hemoglobin relative to baseline, and it was seen that TBN significantly reduced glycosylated hemoglobin in the patients relative to placebo group, with the specific results shown in Table 2.
Table 2 results of glycosylated hemoglobin HbA1c (%) after 24 weeks of treatment (Median)
In Table 2, RAAS refers to RAAS inhibitors, SGLT-2 refers to SGLT-2 inhibitors, GLP-1 refers to GLP-1 agonists. Missing represents the number of cases Missing due to subject shedding at the end of the trial.
LS mean statistical analysis was performed on glycosylated hemoglobin HbA1c (%) after 24 weeks of TBN treatment for all subjects completing the clinical trial, and the results showed that: placebo group (n=44, baseline 7.31) had a rate of change from baseline of 8.34% over 24 weeks of treatment; 600 The rate of change of the base line relative to the base line after 24 weeks of TBN treatment was 0.67% for the mg group (n=46, base line 7.47), the difference of-7.67% relative to the placebo, which is statistically significant compared to placebo, and the rate of change of the base line relative to the base line after 24 weeks of TBN treatment was-2.24% for the 1200 mg group (n=44, base line 7.15), the difference of-10.58% relative to the placebo, which is statistically significant compared to placebo, and P < 0.001.
LS mean statistical analysis was performed on blood glucose (mmol/L) after 24 weeks of TBN treatment for all subjects completing the clinical trial and showed that: placebo (n=44, baseline 7.30) had a rate of change from baseline of 12.33% over 24 weeks of treatment; 600 The rate of change of the base line after 24 weeks of TBN treatment was 7.32% for the mg group (n=45, base line 8.06), 5.01% for the placebo, and-6.63% for the 1200 mg group (n=44, base line 7.39) after 24 weeks of TBN treatment, 18.96% for the placebo, with statistical significance for p=0.009 compared to placebo.
From the test results, glycosylated hemoglobin (HbA 1 c) is less than or equal to 9.0%; and urinary albumin/urinary creatinine ratio (UACR)>300mg/g is less than or equal to 3000 mg/g; the random pre-glomerular filtration rate (eGFR) is more than or equal to 45 mL/min/1.73 m 2 The basal hypoglycemic agent has failed to continue to control blood glucose levels, placebo group blood glucose and glycosylation in type 2 diabeticsThe level is greatly improved.
Surprisingly, TBN was able to significantly lower blood glucose and glycosylated hemoglobin levels in this class of patients relative to placebo, which is of great significance to type 2 diabetics.
Claims (27)
1. Application of ligustrazine nitrone derivative or pharmaceutically acceptable salt thereof in preparing medicament for preventing or treating type 2 diabetes with kidney injury; the ligustrazine nitrone derivative has a structure shown as the following TBN:
。
2. the use according to claim 1, wherein: the type 2 diabetes is type 2 diabetes with glycosylated hemoglobin HbA1c more than or equal to 6.0%.
3. The use according to claim 1, wherein: the type 2 diabetes is type 2 diabetes with glycosylated hemoglobin HbA1c more than or equal to 6.2%.
4. The use according to claim 1, wherein: the type 2 diabetes is type 2 diabetes with glycosylated hemoglobin HbA1c more than or equal to 6.5%.
5. The use according to claim 1, wherein: the type 2 diabetes mellitus is type 2 diabetes mellitus with fasting blood glucose not less than 6.1 mmol/L.
6. The use according to claim 1, wherein: the type 2 diabetes mellitus is type 2 diabetes mellitus with fasting blood glucose not less than 7.0 mmol/L.
7. The use according to claim 1, wherein: the type 2 diabetes mellitus is type 2 diabetes mellitus with fasting blood glucose not less than 7.5 mmol/L.
8. The use according to claim 1, wherein: urinary albumin/creatinine ratio (UACR) for kidney injury >300 mg/g.
9. The use according to claim 1, wherein: the kidney injury is that the ratio of urine albumin/creatinine is more than 300mg/g and less than or equal to 5000 mg/g.
10. The use according to claim 1, wherein: the kidney injury is that the ratio of urine albumin/creatinine is more than 300mg/g and less than or equal to 3000 mg/g.
11. The use according to claim 1, wherein: the kidney injury glomerulus filtration rate (eGFR) is more than or equal to 45 mL/min/1.73 m 2 。
12. The use according to any one of claims 1-11, wherein: the use is for lowering blood glucose and/or glycosylated hemoglobin levels in a type 2 diabetic patient.
13. The application of ligustrazine nitrone derivative or pharmaceutically acceptable salt thereof in combination with a second therapeutic drug in preparing a drug for preventing or treating type 2 diabetes with kidney injury; the second therapeutic drug is selected from one or a combination of a plurality of biguanides, sulfonylurea, alpha-glucosidase inhibitor, insulin secretagogue, thiazolidinedione, DPP-4 inhibitor, RASS inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist and insulin, and the ligustrazine nitrone derivative has a structure as shown in the following TBN:
。
14. the use according to claim 13, wherein: the second therapeutic agent comprises one or a combination of a plurality of RASS inhibitor, SGLT2 inhibitor and GLP-1 receptor agonist.
15. The use according to claim 14, wherein: the SGLT2 inhibitor is selected from dapagliflozin, engagliflozin, canagliflozin, hengagliflozin, ai Tuoge gliflozin or Bei Shage gliflozin; the GLP-1 receptor agonist is selected from exenatide, risperidin, liraglutide, benraglutide, polyethylene glycol lobeltide, exenatide microsphere, cable Ma Lutai, duloxetide or semraglutide; the RASS inhibitor is selected from telmisartan, valsartan, irbesartan, candesartan cilexetil, azilsartan cilexetil, benazepril, captopril, enalapril or perindopril salbutamol.
16. The use according to any one of claims 13-15, wherein: the type 2 diabetes is type 2 diabetes with glycosylated hemoglobin HbA1c more than or equal to 6.0%.
17. The use according to claim 16, wherein: the type 2 diabetes is type 2 diabetes with glycosylated hemoglobin HbA1c more than or equal to 6.2%.
18. The use according to claim 16, wherein: the type 2 diabetes is type 2 diabetes with glycosylated hemoglobin HbA1c more than or equal to 6.5%.
19. The use according to any one of claims 13-15, wherein: the type 2 diabetes mellitus is type 2 diabetes mellitus with fasting blood glucose not less than 6.1 mmol/L.
20. The use according to claim 19, wherein: the type 2 diabetes mellitus is type 2 diabetes mellitus with fasting blood glucose not less than 7.0 mmol/L.
21. The use according to claim 19, wherein: the type 2 diabetes mellitus is type 2 diabetes mellitus with fasting blood glucose not less than 7.5 mmol/L.
22. The use according to claim 13, wherein: the urinary albumin/creatinine ratio UACR of the kidney injury is >300 mg/g.
23. The use according to claim 13, wherein: the kidney injury is that the ratio of urine albumin/creatinine is more than 300mg/g and less than or equal to 5000 mg/g.
24. The use according to claim 13, wherein: the kidney injury is that the ratio of urine albumin/creatinine is more than 300mg/g and less than or equal to 3000 mg/g.
25. The use according to claim 13, wherein: the glomerulus filtration rate of the kidney injury is more than or equal to 45 mL/min/1.73 m 2 。
26. The use according to any one of claims 13-15, 17-18, 20-21 or 22-25, wherein: the use is for lowering blood glucose and/or glycosylated hemoglobin levels in a type 2 diabetic patient.
27. The use according to any one of claims 1-11, 13-15, 17-18, 20-21 or 22-25, wherein: the pharmaceutically acceptable salt is selected from the group consisting of salts of TBN with: hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, phosphoric acid, acetic acid, propionic acid, benzoic acid, caproic 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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1363274A (en) * | 2002-01-08 | 2002-08-14 | 李瑞峰 | Application of ligustrazine and aminoguanidin in treating II-type diabetes and its complication |
| CN107157999A (en) * | 2017-05-27 | 2017-09-15 | 青岛海蓝医药有限公司 | Application of the ligustrazine nitrone derivative in diabetes complicated disease is prevented and treated |
| US20220202812A1 (en) * | 2019-11-22 | 2022-06-30 | Qingdao Hailan Pharmaceuticals Co., Ltd. | Use of ligustrazine nitrone derivatives in treatment and prevention of diabetic complication diseases |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1363274A (en) * | 2002-01-08 | 2002-08-14 | 李瑞峰 | Application of ligustrazine and aminoguanidin in treating II-type diabetes and its complication |
| CN107157999A (en) * | 2017-05-27 | 2017-09-15 | 青岛海蓝医药有限公司 | Application of the ligustrazine nitrone derivative in diabetes complicated disease is prevented and treated |
| CN115887460A (en) * | 2017-05-27 | 2023-04-04 | 青岛海蓝医药有限公司 | Application of ligustrazine nitrone derivative in preventing and treating diabetic complication diseases |
| US20220202812A1 (en) * | 2019-11-22 | 2022-06-30 | Qingdao Hailan Pharmaceuticals Co., Ltd. | Use of ligustrazine nitrone derivatives in treatment and prevention of diabetic complication diseases |
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