CN113679728B - Sulfonamide compound and application thereof in preparation of drugs for treating diabetes and complications - Google Patents

Sulfonamide compound and application thereof in preparation of drugs for treating diabetes and complications Download PDF

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CN113679728B
CN113679728B CN202111036514.9A CN202111036514A CN113679728B CN 113679728 B CN113679728 B CN 113679728B CN 202111036514 A CN202111036514 A CN 202111036514A CN 113679728 B CN113679728 B CN 113679728B
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CN113679728A (en
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陈新平
李纯
吴桐雨
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Lanzhou University
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    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to the technical field of medicines, in particular to a sulfonamide compound and application thereof in preparing medicines for treating diabetes and complications. The structural formula of the sulfonamide compound is shown as a formula (I), and experimental results show that the sulfonamide compound can improve the glucose metabolism of type 2 diabetes mice, improve the sensitivity of insulin and improve insulin resistance, and has a hypoglycemic effect which is 200 times or more than that of metformin when used for treating the type 2 diabetes mice; the content of urine protein, urine creatinine and urea nitrogen in the type 2 diabetes mice is reduced, so that the sulfonamide compound can protect the kidney function of the diabetes mice and treat kidney diseases caused by diabetes; reducing the content of triglyceride and total cholesterol of a type 2 diabetes mouse, regulating the blood lipid level, improving the lipid metabolism of the diabetes mouse, showing that the sulfonamide compound can treat cardiovascular complications of diabetes and can be popularized and applied clinically.

Description

Sulfonamide compound and application thereof in preparation of drugs for treating diabetes and complications
Technical Field
The invention relates to the technical field of medicines, in particular to a sulfonamide compound and application thereof in preparing medicines for treating diabetes and complications.
Background
Diabetes is a metabolic disease characterized by hyperglycemia. Hyperglycemia is caused by defective insulin secretion or impaired biological action, or both. Diabetes is a major disease endangering human health and can be classified into type 1 diabetes and type 2 diabetes. The international diabetes union estimates that about 3.87 million people are currently diagnosed with diabetes, with more than 90% of type 2 diabetes, and it is expected that 5.95 million people will develop diabetes by 2035. Type 2 diabetes is a type of diabetes that is due to relative hyposecretion of insulin, and/or insulin resistance as the primary causative agent. The relative hyposecretion of insulin means that the sugar substances taken by the type 2 diabetes mellitus patients exceed the maximum degree of regulation of the insulin secretion of the organism, so that the glucose in blood is continuously higher; insulin resistance refers to an increase in blood glucose caused by a decrease in the sensitivity of insulin secreted by the patient's islet beta cells in their effector cells (e.g., muscle cells, adipocytes, liver cells, etc.). Currently, treatment regimens for diabetes include drug therapy, dietary therapy, exercise therapy, and general therapy. Available drugs mainly comprise biguanides, sulfonylureas, thiazolidinediones (TZD), meglitinides, dipeptidyl peptidase 4 (DPP-4) inhibitors, sodium-glucose cotransporter (SGLT 2) inhibitors, alpha-glucosidase inhibitors and insulin preparations, but the current situation of diabetes treatment is not ideal, the control rate of diabetes in China is 39.7%, the treatment rate is 25.8%, epidemiological researches of large samples in 2010 in China show that the standard reaching rate is only 16.8% by taking glycosylated hemoglobin <6.5% as a control standard, and patients with blood glucose control failure reach 83.2%.
Meanwhile, a series of complications such as diabetic nephropathy, diabetic skin ulcer, retinopathy, cardiovascular diseases and the like can be generated in the long-term development of diabetes, so that a large economic burden is brought to patients and society, the health of human beings is seriously endangered, and the life quality of the patients is influenced. Among them, diabetic nephropathy, diabetic cardiovascular disease, diabetic retinopathy and diabetic skin ulcer are the most serious complications of diabetes, and there is no ideal medicine for the treatment of diabetic complications clinically.
The sulfanilamide medicine is an artificially synthesized antibacterial medicine, is used for clinical treatment for nearly 50 years, and has the advantages of wide antibacterial spectrum, stable property, simple and convenient use, no consumption of grains during production and the like. In particular, after the discovery of an antimicrobial synergist, trimethoprim (TMP), in 1969, the combination of the sulfamide and the sulfamide can enhance the antimicrobial effect and expand the treatment range, so that the sulfamide is still an important chemotherapeutic drug although a large number of antibiotics are available. The sulfonamides have inhibitory effects on a number of gram-positive and some gram-negative bacteria, nocardia, chlamydia and some protozoa (e.g., plasmodium and amoeba). While for the new application of the sulfonamides, researchers have carried out various researches, for example, patent (CN 201010581743.4) discloses the application of sulfadiazine sodium in preparing medicines for preventing or treating silkworm sepsis, patent (CN 201410477735.3) discloses the application of a sulfadiazine medicine composition in preparing medicines for treating foot odor; patent (cn201410477958. X) discloses the use of a sulfonamide composition in the manufacture of a medicament for the treatment of bromhidrosis. However, no researchers have studied the application of sulfonamides in treating diabetes and complications thereof, and no documents disclose the application of sulfonamides in treating diabetes and complications thereof.
The inventor has unexpectedly found that the sulfanilamide medicines have the curative effect of treating diabetes and also have the curative effect of treating diabetic complications in the research process.
Disclosure of Invention
Aiming at the technical problems, the invention provides a sulfonamide compound and application thereof in preparing medicaments for treating diabetes and complications. The specific technical scheme is as follows:
the first object of the invention is to provide the application of sulfonamide compound shown in formula (I) or tautomer, meso, racemate, enantiomer, diastereoisomer or mixture thereof, or pharmaceutically acceptable salt thereof in preparing medicament for treating diabetes;
R 1 selected from hydrogen atoms, C 1-6 Alkyl, C 1-8 Alkoxy, C 3-6 Cycloalkyl, benzene ring, five-membered or six-membered aromatic heterocycle; wherein, the benzene ring, five-membered or six-membered aromatic heterocycle can be substituted by alkyl, alkoxy, cycloalkyl, halogen, amino, hydroxyl, carboxyl and cyano;
R 2 selected from hydrogen atoms, C 1-6 Alkyl, C 1-8 Alkoxy, C 3-6 Cycloalkyl, benzene ring, five-membered or six-membered aromatic heterocycle; wherein, benzene ring, five-membered or six-membered aromatic heterocycle can be substituted by alkyl, alkoxy, cycloalkyl, halogen, amino, hydroxy, carboxyl and cyano;
R 1 and R is R 2 The N atoms which can be connected with the two can form a five-membered or six-membered heterocyclic ring;
R 3 Selected from hydrogen atoms, C 1-6 Alkyl, C 3-6 Cycloalkyl, benzene ring, five-membered or six-membered aromatic heterocycle; wherein, the benzene ring, five-membered or six-membered aromatic heterocycle can be substituted by alkyl, alkoxy, cycloalkyl, halogen, amino, hydroxyl, carboxyl and cyano;
R 4 ，R 5 ，R 6 ，R 7 respectively selected from hydrogen atom, amino, substituted amino, hydroxy, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, benzene ring, five-membered or six-membered aromatic heterocycle; wherein the benzene ring, five-membered or six-membered aromatic heterocycle can be substituted by alkyl, alkoxy, cycloalkyl, halogen, amino, hydroxy, carboxyl and cyano.
Preferably, said R 4 ，R 5 ，R 6 ，R 7 Respectively selected from hydrogen atoms.
Preferably, said R 1 、R 2 Respectively selected from hydrogen atoms.
Preferably, the compounds of formula (I) include, but are not limited to, the following compounds
Preferably, the diabetes is type 2 diabetes or early stage type 1 diabetes.
A second object of the present invention is to provide the use of a sulfonamide compound of formula (i) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of diabetic complications;
R 1 selected from hydrogen atoms, C 1-6 Alkyl, C 1-8 Alkoxy, C 3-6 Cycloalkyl, benzene ring, five-membered or six-membered aromatic heterocycle; wherein, the benzene ring, five-membered or six-membered aromatic heterocycle can be substituted by alkyl, alkoxy, cycloalkyl, halogen, amino, hydroxyl, carboxyl and cyano;
R 2 selected from hydrogen atoms, C 1-6 Alkyl, C 1-8 Alkoxy, C 3-6 Cycloalkyl, benzene ring, five-membered or six-membered aromatic heterocycle; wherein, benzene ring, five-membered or six-membered aromatic heterocycle can be substituted by alkyl, alkoxy, cycloalkyl, halogen, amino, hydroxy, carboxyl and cyano;
R 1 and R is R 2 The N atoms which can be connected with the two can form a five-membered or six-membered heterocyclic ring;
R 3 selected from hydrogen atoms, C 1-6 Alkyl, C 3-6 Cycloalkyl, benzene ring, five-membered or six-membered aromatic heterocycle; wherein, the benzene ring, five-membered or six-membered aromatic heterocycle can be substituted by alkyl, alkoxy, cycloalkyl, halogen, amino, hydroxyl, carboxyl and cyano;
R 4 ，R 5 ，R 6 ，R 7 respectively selected from hydrogen atom, amino, substituted amino, hydroxy, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, benzene ring, five-membered or six-membered aromatic heterocycle; wherein the benzene ring, five-membered or six-membered aromatic heterocycle can be substituted by alkyl, alkoxy, cycloalkyl, halogen, amino, hydroxy, carboxyl and cyano.
Preferably, the diabetic complications include one or more of gestational diabetes, microangiopathy, skin ulcer, cardiovascular disease and periodontitis.
Preferably, the microvascular lesions are nephropathy and retinopathy.
Preferably, the drug is administered by the following route: sublingual, inhaled, oral or injectable.
The third purpose of the invention is to provide the application of the sulfonamide compound shown in the formula (I) or a tautomer, a meso form, a racemate form, an enantiomer, a diastereomer form or a mixture of the two forms, or pharmaceutically acceptable salts of the sulfonamide compound in the preparation of health care products with auxiliary blood sugar reducing function;
R 1 selected from hydrogen atoms, C 1-6 Alkyl, C 1-8 Alkoxy, C 3-6 Cycloalkyl, benzene ring, five-membered or six-membered aromatic heterocycle; wherein, the benzene ring, five-membered or six-membered aromatic heterocycle can be substituted by alkyl, alkoxy, cycloalkyl, halogen, amino, hydroxyl, carboxyl and cyano;
R 2 selected from hydrogen atoms, C 1-6 Alkyl, C 1-8 Alkoxy, C 3-6 A cycloalkyl group,benzene ring, five-membered or six-membered aromatic heterocycle; wherein, benzene ring, five-membered or six-membered aromatic heterocycle can be substituted by alkyl, alkoxy, cycloalkyl, halogen, amino, hydroxy, carboxyl and cyano;
R 1 and R is R 2 The N atoms which can be connected with the two can form a five-membered or six-membered heterocyclic ring;
R 3 selected from hydrogen atoms, C 1-6 Alkyl, C 3-6 Cycloalkyl, benzene ring, five-membered or six-membered aromatic heterocycle; wherein, the benzene ring, five-membered or six-membered aromatic heterocycle can be substituted by alkyl, alkoxy, cycloalkyl, halogen, amino, hydroxyl, carboxyl and cyano;
R 4 ，R 5 ，R 6 ，R 7 Respectively selected from hydrogen atom, amino, substituted amino, hydroxy, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, benzene ring, five-membered or six-membered aromatic heterocycle; wherein the benzene ring, five-membered or six-membered aromatic heterocycle can be substituted by alkyl, alkoxy, cycloalkyl, halogen, amino, hydroxy, carboxyl and cyano.
The fourth purpose of the invention is to provide the application of the sulfonamide compound shown in the formula (I) or a tautomer, a meso form, a racemate form, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof in preparing health care products for assisting in reducing blood fat;
R 1 selected from hydrogen atoms, C 1-6 Alkyl, C 1-8 Alkoxy, C 3-6 Cycloalkyl, benzene ring, five-membered or six-membered aromatic heterocycle; wherein, the benzene ring, five-membered or six-membered aromatic heterocycle can be substituted by alkyl, alkoxy, cycloalkyl, halogen, amino, hydroxyl, carboxyl and cyano;
R 2 selected from hydrogen atoms, C 1-6 Alkyl, C 1-8 Alkoxy, C 3-6 Cycloalkyl, benzene ring, five-membered or six-membered aromatic heterocycle; wherein the benzene ring, five-membered or six-membered aromatic heterocyclic ring may be substituted by alkyl, alkoxy, cycloalkyl, halogenAmino, hydroxy, carboxy, cyano substitution;
R 1 and R is R 2 The N atoms which can be connected with the two can form a five-membered or six-membered heterocyclic ring;
R 3 Selected from hydrogen atoms, C 1-6 Alkyl, C 3-6 Cycloalkyl, benzene ring, five-membered or six-membered aromatic heterocycle; wherein, the benzene ring, five-membered or six-membered aromatic heterocycle can be substituted by alkyl, alkoxy, cycloalkyl, halogen, amino, hydroxyl, carboxyl and cyano;
R 4 ，R 5 ，R 6 ，R 7 respectively selected from hydrogen atom, amino, substituted amino, hydroxy, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, benzene ring, five-membered or six-membered aromatic heterocycle; wherein the benzene ring, five-membered or six-membered aromatic heterocycle can be substituted by alkyl, alkoxy, cycloalkyl, halogen, amino, hydroxy, carboxyl and cyano.
The beneficial effects of the invention are as follows: the invention provides a new application of a sulfonamide compound, wherein the sulfonamide can improve the glucose metabolism of a type 2 diabetes mouse, improve the sensitivity of insulin, improve insulin resistance, and obviously reduce the blood glucose of the type 2 diabetes mouse, and the blood glucose reducing effect is 200 times or more than that of metformin; meanwhile, the sulfanilamide compound sulfathiazole can reduce the content of urine protein, urine creatinine and urea nitrogen of the type 2 diabetes mice, which indicates that the sulfanilamide compound sulfathiazole can protect the kidney function of the diabetes mice; the sulfonamide compound sulfathiazole can reduce the content of triglyceride and total cholesterol of a type 2 diabetes mouse, regulate the blood lipid level and improve the lipid metabolism of the diabetes mouse. The sulfadiazine can obviously reduce the blood sugar of the type 2 diabetes mice, and has a therapeutic effect on the type 2 diabetes mice; the sulfa compound sulfa-methyl pyrimidine can obviously reduce the blood sugar of type 2 diabetes mice, and has a therapeutic effect on the type 2 diabetes mice. The sulfonamide compound can be used for treating cardiovascular complications of diabetes and can be popularized and applied clinically.
Drawings
FIG. 1 weight change in mice of each group
FIG. 2 blood glucose changes in groups of mice
FIG. 3 urine protein comparison of mice in each group
FIG. 4 urine creatinine comparison of mice in each group
FIG. 5 comparison of urea nitrogen content in mice of each group
FIG. 6 results of 0-120min blood glucose changes in mice of each group
FIG. 7 area under the blood glucose change curve for each group of mice 0-120min
FIG. 8 blood glucose change results for groups of mice 0-120min
FIG. 9 area under the blood glucose change curve for each group of mice 0-120min
Figure 10 comparison of triglyceride levels in mice of each group
FIG. 11 comparison of the low density lipoprotein cholesterol levels of mice in each group
FIG. 12 comparison of total cholesterol levels in groups of mice
FIG. 13 weight change in mice of each group
FIG. 14 blood glucose changes in groups of mice
FIG. 15 weight change in mice of each group
FIG. 16 blood glucose changes in groups of mice
Detailed Description
The following describes the scope of the present invention in detail with reference to specific embodiments, but it should be noted that the scope of the present invention is not limited by the following examples.
Metformin hydrochloride, its chemical name is: 1.1-dimethyldiguanide hydrochloride for patients with type 2 diabetes who are not satisfied with the control of simple diet, especially for those who are obese and associated with hyperinsulinemia, the use of this medicine not only has the effect of reducing blood sugar, but also may have the effect of reducing weight and hyperinsulinemia. The composition can be used for patients with poor curative effects on certain sulfonylureas, such as sulfonylureas, small intestine glycosidase inhibitors or thiazolidinedione hypoglycemic agents, and has better effect than single use. Can also be used for insulin treatment patients to reduce insulin dosage. However, metformin hydrochloride can not cure type 2 diabetes, and has large dosage, long administration period and large side effect, and has no therapeutic effect on diabetic complications.
Streptozocin is also called streptozocin (streptozocin) and has the chemical name of 2-deoxy-2- [ [ (methyl nitrosoamino) carbonyl ] -amino ] -D-glucopyranose, the molecular formula is C8H15N3O7, the molecular weight is 265.22100, light yellow crystalline powder is easy to dissolve in water, but the aqueous solution is extremely unstable at room temperature, and can be decomposed into gas and volatilized after half an hour, so that the streptozocin needs to be prepared at present. Is soluble in lower alcohols and ketones, and insoluble in polar organic solvents. Streptozotocin can damage islet beta cells of animals and reduce insulin secretion, so that the streptozotocin can be used for inducing an animal model of diabetes, generally, large-dose (150 mg/kg/day) single injection can induce type 1 diabetes, small-dose (40-60 mg/kg/day) multiple injection (3-5 days) combined with high-fat feed feeding can induce type 2 diabetes, and in the invention, streptozotocin is used for preparing the animal model.
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 the claimed subject matter belongs. All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the inventive subject matter herein. In the present application, it must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include" and other forms, such as "comprising," "including," and "containing," are not limiting.
In the following examples of the present application, the following terms chinese full scale, english full scale or abbreviations may be used, but whether chinese full scale, english full scale or abbreviations are used, they represent the same compound or medicine or reagent. The method comprises the following steps:
chinese-english contrast abbreviation vocabulary
Unless specifically defined otherwise, the nomenclature and laboratory procedures and techniques related to chemistry, such as analytical chemistry, organic synthetic chemistry, and medical and pharmaceutical chemistry, herein are known to those skilled in the art. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, formulation, drug delivery and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). For example, the reaction and purification techniques may be carried out using a kit with instructions provided by the manufacturer, or according to methods known in the art, or according to the methods described herein. In general, the foregoing techniques and steps may be implemented by conventional methods well known in the art and described in various general or more specific documents, which are cited and discussed in the present disclosure.
Reagents for use in the present invention
Materials used in the present invention
The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that ethyl may be unsubstituted (-CH) 2 CH 3 ) Monosubstituted (e.g. -CH 2 CH 2 F) Polysubstituted (e.g. -CHFCH 2 F、-CH 2 CHF 2 Etc.) or finishFully substituted (-CF) 2 CF 3 ). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =o), meaning that two hydrogen atoms are substituted, oxo does not occur on the aromatic group.
When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0 to 2R, the group may optionally be substituted with up to two R's, and R's in each case have independent options. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.
The term "alkyl" refers to an optionally substituted straight or optionally substituted branched saturated aliphatic hydrocarbon group which is attached to the remainder of the molecule by a single bond. "alkyl" herein may have from 1 to about 8 carbon atoms, for example from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms, or from 1 to 3 carbon atoms. Examples of "alkyl" herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-l-butyl, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl and the like, as well as longer alkyl groups such as heptyl and octyl and the like. As defined herein, when a number range occurs for a group such as "alkyl", for example, "C1-8 alkyl" refers to an alkyl group that may be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, and for example, "C1-4 alkyl" refers to an alkyl group that may be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms. Alkyl groups herein also include those where no numerical range is specified.
The term "alkenyl" refers to an optionally substituted straight chain or optionally substituted branched monovalent hydrocarbon radical having at least one c=c double bond. The alkenyl groups have, but are not limited to, 2 to 8 carbon atoms, such as 2 to 6 carbon atoms, 2 to 4 carbon atoms. The double bonds in these groups may be in either cis or trans conformation and should be understood to include both isomers. Alkenyl embodiments include, but are not limited to, vinyl (ch=ch 2 ) 1-propenyl (CH) 2 CH＝CH 2 ) Isopropenyl (C (CH) 3 )＝CH 2 ) Butenyl, and 1, 3-butadienyl, and the like. Alkenyl groups as defined herein are present in the numerical range, e.g. "C 2-8 Alkenyl "refers to alkenyl groups that may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, and alkenyl groups herein are also intended to cover the cases where no numerical range is specified.
The term "alkynyl" refers to an optionally substituted straight or branched chain monovalent hydrocarbon radical having at least one c≡c triple bond. The alkynyl group has, but is not limited to, 2 to 8 carbon atoms, for example 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Examples herein include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl, and the like. Alkynyl groups as defined herein are present in the numerical range, e.g. "C 2-8 Alkynyl "refers to an alkynyl group that may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, and alkynyl herein also encompasses cases where no numerical range is specified.
The term "cycloalkyl" refers to a non-aromatic carbon-containing ring, including a saturated carbocyclic ring (e.g., cycloalkyl) or an unsaturated carbocyclic ring (e.g., cycloalkenyl). Carbocycles include monocycles (having one ring), such as may be monocyclic cycloalkyl; a bicyclic ring (having two rings), for example, may be a bicyclic cycloalkyl; a multicyclic ring (having more than two rings). The rings may be bridged or spiro. Carbocycles (e.g., cycloalkyl or cycloalkenyl) can have 3 to 8 carbon atoms, for example, 3 to about 6 ring-forming carbon atoms or 3 to about 5 ring-forming carbon atoms.
The term "aryl" refers to an optionally substituted aromatic hydrocarbon group having from about 6 to 20, such as from 6 to 12 or from 6 to 10, ring-forming carbon atoms, which may be a monocyclic aryl, bicyclic aryl or more. The bicyclic aryl or more can be a monocyclic aryl fused to other independent rings, such as alicyclic, heterocyclic, aromatic heterocyclic rings. Non-limiting examples of monocyclic aryl groups include monocyclic aryl groups of 6 to about 12, 6 to about 10, or 6 to about 8 ring-forming carbon atoms, such as phenyl; bicyclic aryl is for example naphthyl; polycyclic aryl groups are, for example, phenanthryl, anthracyl, azulenyl.
The term "heteroaryl" refers to an optionally substituted heteroaryl group comprising from about 5 to about 20, such as 5 to 12 or 5 to 10, backbone ring atoms, wherein at least one (e.g., 1-4, 1-3, 1-2) ring atoms are heteroatoms independently selected from heteroatoms in the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but is not limited thereto. Heteroaryl includes monocyclic heteroaryl (having one ring), bicyclic heteroaryl (having two rings), or polycyclic heteroaryl (having more than two rings). In embodiments where two or more heteroatoms are present in the ring, the two or more heteroatoms may be the same as one another, or some or all of the two or more heteroatoms may be different from one another. The bicyclic heteroaryl or more heteroaryl groups may be a monocyclic heteroaryl group fused to other independent rings, such as alicyclic, heterocyclic, aromatic heterocyclic rings (which may be collectively referred to as fused-ring heteroaryl groups). Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.
The term "heterocyclyl" refers to non-aromatic heterocycles, which include saturated or unsaturated heterocycles (containing unsaturation), which do not have a fully conjugated pi-electron system, and which can be classified as non-aromatic monocyclic, fused polycyclic, bridged or spiro ring systems. Wherein one or more (e.g., 1-4, 1-3, 1-2) of the ring-forming atoms are heteroatoms, such as oxygen, nitrogen or sulfur atoms. The heterocycle may include mono-heterocycle (having one ring) or bi-heterocycle (having two bridged rings) or multi-heterocycle (having more than two bridged rings); spiro rings are also included. The heterocyclyl may have 3 to about 20, such as 3 to about 10, 3 to about 8, 4 to 7, 5 to about 8, or 5 to about 6 ring forming atoms. Non-limiting examples of heterocyclyl groups include oxiranyl, thiiranyl, cyclic azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, oxazolidinyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, thiocyranyl, azepanyl, oxepinyl, thiepanyl, oxazabicyclo [2.2.1] heptyl, and azaspiro [3.3] heptyl, and the like.
The term "halo" or "halogen" refers to an optionally substituted group (e.g., alkyl, alkenyl, alkynyl, alkoxy, etc.) in which at least one hydrogen atom is replaced with a halogen (e.g., fluorine, chlorine, bromine, iodine, or a combination thereof). In some embodiments, two or more hydrogens (e.g., difluoromethyl, trifluoromethyl) are replaced with the same halogen as each other; in other embodiments two or more hydrogens (e.g., 1-chloro-1-fluoro-1-iodoethyl) are replaced with halogens that are not identical to each other.
The term "alkoxy" refers to an alkyl ether group (O-alkyl), non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
The term "alkanoyl" refers to a radical formed by the attachment of an alkyl group to-CO-, non-limiting examples of which include formyl, acetyl, propionyl, butyryl, and the like. For example, the term "C 1-6 Alkylacyl "means C 1-6 Alkyl is linked to-CO-. For another example, the term "C 1-4 Alkylacyl "means C 1-4 Alkyl is linked to-CO-.
The term "alkylsulfonyl" refers to alkyl and-SO 2 Non-limiting examples of the term include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, and the like. For example, the term "C 1-6 Alkylsulfonyl "means C 1-6 Alkyl and-SO 2 -a group formed by linking. For another example, the term "C 1-4 Alkylsulfonyl "means C 1-4 Alkyl and-SO 2 -a group formed by linking.
The term "amino" refers to-NH 2 Radicals, -NH (C) 1～6 Alkyl) group or-N (C) 1～6 Alkyl group 2 A group. Specific examples of amino groups include, but are not limited to, -NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-NHC 2 H 5 、-N(C 2 H 5 ) 2 、-N(C 3 H 7 ) 2 、-N(CH 3 )C 2 H 5 Etc.
The term "member" refers to the number of backbone atoms that make up the ring. For example, pyridine is a six-membered ring and pyrrole is a five-membered ring.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutical composition" refers to a biologically active compound optionally admixed with at least one pharmaceutically acceptable chemical ingredient or agent, i.e., a "carrier," which facilitates the introduction of the compound into cells or tissues, including but not limited to stabilizers, diluents, suspending agents, thickening agents, and/or excipients.
The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness of the free acid and free base of the specified compound and that are biologically or otherwise undesirable. Salts in the present invention may be mentioned, unless otherwise indicated, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Non-limiting examples of metal salts include, but are not limited to, salts of alkali metals, such as sodium, potassium, and the like; salts of alkaline earth metals, such as calcium salts, magnesium salts, barium salts, and the like; aluminum salts, and the like. Non-limiting examples of salts with organic bases include, but are not limited to, salts with trimethylamine, triethylamine, pyridine, picoline, 2, 6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, and the like. Non-limiting examples of salts formed with inorganic acids include, but are not limited to, salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Non-limiting examples of salts formed with organic acids include, but are not limited to, salts formed with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Non-limiting examples of salts with basic amino acids include, but are not limited to, salts with arginine, lysine, ornithine and the like. Non-limiting examples of salts formed with acidic amino acids include, but are not limited to, salts formed with aspartic acid, glutamic acid, and the like.
Pharmaceutically acceptable salts can be synthesized from the parent compound, which contains an acid or base, by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
The term "treating" and other similar synonyms include alleviating, alleviating or ameliorating symptoms of a disease or disorder, preventing other symptoms, ameliorating or preventing underlying metabolic causes that lead to symptoms, inhibiting a disease or disorder, e.g., arresting the development of a disease or disorder, alleviating a disease or disorder, ameliorating a disease or disorder, alleviating symptoms that result from a disease or disorder, or halting symptoms of a disease or disorder, and in addition, the term may include prophylactic purposes. The term also includes obtaining a therapeutic effect and/or a prophylactic effect. The therapeutic effect refers to curing or ameliorating the underlying disease being treated. In addition, the cure or amelioration of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, e.g., an improvement in patient condition is observed, although the patient may still be affected by the underlying disease. In terms of prophylactic effect, the composition or compound may be administered to a patient at risk of a particular disease, or even if a disease diagnosis has not been made, to a patient exhibiting one or more physiological symptoms of the disease.
Example one, the effect of sulfathiazole on the treatment of diabetes and complications thereof in mice
1. Animal feeding
Experimental animals: SPF grade C57BL/6N male mice of 8 weeks old, weighing 18-22 g, were never used as any drug before the experiment and were purchased from the animal institute of Lanzhou, national academy of agricultural sciences. The experimental animals are adaptively raised for one week in an environment with 24-26 ℃ and 12h/12h day and night law alternation, diet is given to the animals and free drinking water is carried out, and then grouping experiments are carried out.
2. Medicine and reagent:
the medicines used in the invention are as follows: sulfathiazole (Sulfathiazole); metformin hydrochloride (Metformin hydrochloride, metaformin); streptozocin (STZ).
Preparation of the reagent: the preparation method comprises the following steps: solution A was prepared by adding 2.1g of citric acid to 100mL of distilled water, and solution B was prepared by adding 2.94g of sodium citrate to 100mL of distilled water. Mixing the solution A and the solution B according to the ratio of 1:1.32 or 1:1, adjusting the PH to 4.2-4.5, and filtering the mixed solution by a filter with the diameter of 2.22 mu m.
Sulfathiazole solution (1 mg/kg): after DMSO is dissolved, the mixture is diluted to the required concentration by normal saline
Third step metformin hydrochloride solution (200 mg/kg): is prepared from physiological saline
Model establishment of type 2 diabetes in C57BL/6N mice
80 mice were randomly divided into three groups:
normal feed group (SD): after feeding for three weeks with the common feed, 12 patients were injected with a citric acid buffer solution (the injection dose is the same as the STZ solution described below) in the abdominal cavity, and the patients were not prohibited from water for 12 hours after the injection of the citric acid buffer solution, and the injections were carried out according to the same time period of 9:00am-10:00am, once a day for five days, and the patients were fed after the injection of the citric acid buffer solution for 2 hours. The mice were then fed with normal feed for three more weeks and fasted without water for 10h, and tested for fasting blood glucose between 7:30pm and 9:00 pm.
High fat diet group (HFD): 12 animals were fed with the high-fat feed for three weeks, and then, the solution was intraperitoneally injected with a citric acid buffer solution (the injection dose was the same as that of the STZ solution described below), and the solution was not kept for 12 hours until the injection of the citric acid buffer solution, and the injection was carried out once a day for five days according to the same period of 9:00am-10:00am, and the solution was fed after 2 hours of the injection of the citric acid buffer solution. The mice were then fed with high fat diet for a further three weeks with no water withdrawal for 10 hours and tested for fasting glycemia between 7:30pm and 9:00 pm. The purpose of this group was to demonstrate that the type 2 diabetes model was induced by high fat diet in combination with STZ, rather than high fat diet alone.
Model group 2 diabetes mellitus: after feeding for three weeks with high fat diet, the STZ solution was intraperitoneally injected at a dose of 50mg/kg (STZ was dissolved in a citric acid buffer solution, which was formulated as a 5% strength solution). The injection is carried out once a day for five days continuously according to the same time period of 9:00am-10:00am, and the injection is carried out after the injection is carried out for 2 hours, and then the injection is carried out for 30 minutes after the injection of the STZ solution. Then feeding the mice with high-fat feed for three weeks, detecting the fasting blood glucose of the mice between 7:30pm and 9:00pm, picking out the mice with the Model group fasting blood glucose of more than 15.0mmol/L, then feeding the mice with common feed for one week, detecting the fasting blood glucose again, and the mice with the fasting blood glucose of still more than 15.0mmol/L can be considered to be successful in the type 2 diabetes Model, 18 mice are picked out as type 2 diabetes Model mice, and all the mice are fed with common feed after the experimental formality begins.
The 18 mice with successful modeling were randomly divided into 3 groups, the 12 normal feed mice were randomly divided into 2 groups, the 12 high-fat feed mice were divided into 2 groups, and 7 groups were divided, and after the experiment was formally started, all the mice were fed with normal feed. The specific grouping and administration conditions are as follows:
model group: injecting an equal volume of physiological saline into the abdominal cavity;
model+metaformin group: lavage of 200mg/kg metformin hydrochloride;
model+sulfathiazole group: intraperitoneal injection of 1mg/kg of sulfathiazole compound;
SD (normal feed) group: injecting an equal volume of physiological saline into the abdominal cavity;
sd+sulfathiazole (Sulfathiazole) group: intraperitoneal injection of 1mg/kg of sulfathiazole compound;
HFD (high fat diet) group: injecting an equal volume of physiological saline into the abdominal cavity;
hfd+sulfathiazole (Sulfathiazole) group: intraperitoneal injection of 1mg/kg of sulfathiazole compound;
all mice were dosed once daily for 13 weeks, during which time the mice were observed for growth and life, and the mice were examined weekly for body weight and blood glucose changes.
4. Detection index
4.1 body weight and fasting blood glucose test
Before and after administration, after 10 hours of fasting without water control, the body weight and fasting blood glucose are monitored in the same time period (7:30 pm-9:00 pm), and the body weight value is recorded by weighing with a balance; and cutting the tail to obtain a proper amount of blood, measuring the blood sugar content by using a glucometer (glucose oxidase method), and reading and recording the blood sugar value.
4.2 detection of diabetic nephropathy related indicators
At week 11 of administration, the 24-hour urine volume, urine protein content, urinary creatinine and urea nitrogen content of the mice were measured according to the kit instructions.
4.3 intraperitoneal injection glucose tolerance and insulin tolerance detection
At 12 weeks of administration, insulin resistance was measured, and after each group of mice had fasted for 6 hours without water deprivation, blood glucose levels were measured with a glucometer as blood glucose levels at 0min (BG 0), and then insulin was intraperitoneally injected at 0.3U/kg, blood glucose levels at 15, 30, 60 and 120min (BG 15, BG30, BG60 and BG 120) after insulin injection were recorded, respectively, IPITT curves were drawn with Graphpad prism software, and the area under the curve AUC was calculated for the total of blood sampling periods of 0 to 120 min.
At 12 weeks of administration, glucose tolerance test was performed, each group of mice was fasted without water control for 12 hours, the blood glucose level was measured with a glucometer the next day as the blood glucose level at 0min (BG 0), then 1g/kg glucose was intraperitoneally injected, the blood glucose levels at 15, 30, 60 and 120min (BG 15, BG30, BG60 and BG 120) after glucose injection were respectively measured and recorded, an IPGTT curve was drawn, and the area under the total curve AUC for the blood sampling period of 0 to 120min was calculated.
5. Preparation of dissected mice and specimens
On the 13 th weekend, after the mice fasted for 12 hours, the eyeballs were taken out to take blood, the whole blood added with anticoagulant was stood at 4 ℃ for 2 days, then the supernatant was sucked up, and then the supernatant was centrifugally sucked up under the conditions of 4 ℃,1000g and 10min, and then sub-packaged (avoiding repeated freeze thawing) and stored in a refrigerator at-80 ℃ for standby. Pancreatic tissue, liver tissue, kidney tissue, heart tissue and spleen tissue are taken, placed on ice, and after physiological saline is washed clean, fixed in 4% paraformaldehyde solution (> 24 h), and stored in a refrigerator at 4 ℃ for later use. Dehydrating with gradient alcohol, embedding in paraffin wax, and slicing; hematoxylin-eosin staining and after sealing, the images were observed and photographed under a microscope (magnification of 200).
5.1 detection of cardiovascular disease related indicators of diabetes
The content of total cholesterol, triglyceride and low density lipoprotein cholesterol in the blood plasma is measured according to the instruction of the kit.
5.2 glycosylated hemoglobin detection
The glycosylated hemoglobin content of the mice was measured according to the kit instructions.
5.3 detection of fasting serum insulin (Fasting Serum Insulin, FINS) content
The fasting serum insulin content of the mice was measured, and the content of FINS in the serum was measured as described with reference to the mouse INSESA kit.
6. Data processing
Experimental data were statistically analyzed using SPSS23.0 software, data expressed as (x±s), and group comparisons were made pairwise using One-way ANOVA and LSD-t methods. p <0.05 is considered statistically significant.
7. Experimental results
7.1 Effect of sulfathiazole on body weight and blood sugar in type 2 diabetic mice
As shown in fig. 1, the weights of the SD group, sd+sulfashiazole group, HFD group, and hfd+sulfashiazole group mice continued to be higher than the Model group, but there was no significant difference between the groups; there was no significant difference in body weight between the Model + sulfashiazole group, the Model + metaformin group and the Model group.
As shown in fig. 2, blood glucose of SD group, sd+sulfashiazole group, HFD group and hfd+sulfashiazole group mice was always maintained within a normal range (< 7 mmol/L); the blood glucose duration was significantly higher in Model mice than in SD mice (# # P < 0.001); from week 1 treatment initiation to week 13, model+sulfthiazole group mice showed significantly lower blood glucose than Model group at weeks 3, 4, 8, 9, 11, 12, 13 (< 0.05; P <0.01, < P <0.001,; except for weeks 5 and 10, the blood glucose of mice in the model+metaformin group was significantly lower than that in the Model group (< 0.05; <0.01; < 0.001;); according to the experimental result of blood sugar change, sulfathiazole can obviously reduce the blood sugar of a type 2 diabetes mouse, has a blood sugar reducing effect 200 times higher than that of metformin, and can be used for preparing a medicament for treating diabetes.
7.2 Effect of sulfathiazole on type 2 diabetic mouse kidneys
Urine was measured in each of the above groups at 11 weeks of treatment, and as shown in fig. 3, urine protein of SD group mice was substantially identical to sd+sulfthiazole group and lower than Model group (Model group vs.sd group # P < 0.001); the HFD group and HFD+Sulfathiazole group have substantially the same urine protein content and are lower than the Model group; the Model + sulfthiazole group has lower urine protein than the Model group, indicating that sulfthiazole can reduce urine protein content in type 2 diabetic mice; the model+Metformin group mice had slightly higher urine proteins than the Model group. As shown in fig. 4, there was no inter-group difference in urine protein content among SD group, sd+sulfashiazole group, HFD group and hfd+sulfashiazole group; the Model + sulfashiazole group mice had lower urinary creatinine levels than the Model group, indicating that sulfashiazole can reduce creatinine levels in the urine of type 2 diabetic mice; the mice in the Model + meta-min group had a lower urinary creatinine content than the Model group. As shown in fig. 5, there was no inter-group difference in urea nitrogen content between SD group, sd+sulfthiazole group and hfd+sulfthiazole group, but the urea nitrogen content of HFD group was substantially identical to the Model group, indicating that high fat diet resulted in increased urea nitrogen in mice; the urea nitrogen content of mice in the model+Sulfathiazole group is lower than that of mice in the Model group, which indicates that Sulfathiazole can reduce the urea nitrogen content of mice with type 2 diabetes; from the experimental results shown in fig. 3-5, it can be seen that the sulfathiazole can reduce the content of urine protein, urine creatinine and urea nitrogen in the type 2 diabetic mice, so that the sulfathiazole can be used for protecting the renal function of the diabetic mice and treating the renal diseases caused by diabetes.
7.3 Effect of sulfathiazole on insulin resistance in type 2 diabetic mice
The mice in each group were tested for insulin resistance at week 11 of treatment, and as shown in FIG. 6, the trend of blood glucose changes was substantially consistent in SD, SD+Sulfathiazole, HFD, and HFD+Sulfathiazole mice within 0-120 min; at 0min, 15min, and 30min, the model+sulfashiazole group mice showed significantly lower blood glucose than the Model group (P < 0.05;p < 0.01), indicating that the model+sulfashiazole group mice were more sensitive to insulin than the Model group; at 0min, 15min, 30min, the model+Metformin group mice had lower blood glucose than the Model group; within 60-120min, the blood glucose of the model+Sulfathiazole, model+Metformin, and Model mice did not change substantially. As shown in FIG. 7, there was no significant difference between the SD group, SD+Sulfathiazole group, HFD group and HFD+Sulfathiazole group in the area under the blood glucose change curve of 0 to 120 min; the area under the blood glucose change curve of Model group 0-120min is larger than that of SD group (# # P < 0.001); the area under the blood glucose change curve of the model+Sulfathiazole group 0-120min is smaller than that of the Model group (P < 0.05); the area under the 0-120min blood glucose change curve of the model+Metformin group is smaller than that of the Model group, which shows that the sulfathiazole can improve the glucose metabolism of the type 2 diabetes mice and also can improve the sensitivity of insulin and improve the insulin resistance.
7.4 Effect of sulfathiazole on glucose tolerance in type 2 diabetic mice
The mice in each group are subjected to glucose tolerance detection at 11 weeks of treatment, as shown in fig. 8, the blood sugar change trend of the mice in the SD group, the SD+Sulfathiazole group and the HFD group is basically consistent within 0-120min, and the blood sugar of the HFD+Sulfathiazole group is slightly higher than that of the HFD group at 30min and 60 min; the blood glucose rise rate of the model+sulfashiazole group is slower than that of the Model group within 0-30min, and the blood glucose is obviously lower than that of the Model group at 0min, 15min, 30min and 60min (P <0.05; P < 0.01), which indicates that the regulation capacity of the model+sulfashiazole group on glucose in the body is stronger than that of the Model group; the model+metaformin group showed lower blood glucose than the Model group at 0min (< 0.05). As shown in FIG. 9, the area under the blood glucose change curve of 0-120min was substantially identical for the SD group, SD+Sulfathiazole group and HFD+Sulfathiazole group, with HFD+Sulfathiazole group being higher than HFD group; the area under the blood glucose change curve of Model group 0-120min is larger than that of SD group (# # P < 0.001); the area under the 0-120min blood glucose change curve of the model+Sulfathiazole group is smaller than that of the Model group (P is smaller than 0.01), and the area under the 0-120min blood glucose change curve of the model+Metformin group is smaller than that of the Model group, so that the Sulfathiazole can improve the glucose metabolism and regulate the glucose balance in the body.
7.5 Effect of sulfathiazole on the cardiovascular System of type 2 diabetes
As shown in fig. 10, the SD group, sd+sulfashiazole group, HFD group and hfd+sulfashiazole group have no inter-group difference in the content of triglycerides; the Model + sulfthiazole group has a lower triglyceride content than the Model group, indicating that sulfthiazole can reduce the triglyceride content of type 2 diabetic mice; the triglyceride content of mice in the model+Metformin group was slightly higher than that of mice in the Model group. As shown in fig. 11, there was no inter-group difference in low-density lipoprotein cholesterol content in SD group, sd+sulfashiazole group, HFD group and hfd+sulfashiazole group mice; the low density lipoprotein cholesterol content of mice from the model+Sulfathiazole group was slightly lower than that of mice from the Model group, indicating that Sulfathiazole can reduce the low density lipoprotein cholesterol content of type 2 diabetic mice; mice from the Model + meta-group had lower low-density lipoprotein cholesterol than mice from the Model group. As shown in fig. 12, the SD group, sd+sulfashiazole group, HFD group and hfd+sulfashiazole group were substantially uniform in total cholesterol content; model + sulfashiazole group mice total cholesterol content ratio Model group; the total cholesterol content of mice in the model+Metformin group was slightly lower than that of mice in the Model group. The sulfonamide compound sulfathiazole can reduce the content of triglyceride and total cholesterol of a type 2 diabetes mouse, regulate the blood lipid level and improve the lipid metabolism of the diabetes mouse, and the sulfonamide compound sulfathiazole can treat cardiovascular complications of diabetes.
Example two, effect of sulfadiazine on treatment of diabetes and complications thereof in mice
1. The animal feeding pattern is as shown in example one:
2. medicine and reagent:
the medicines used in the invention are as follows: sulfadiazine (Sulfadiazine); metformin hydrochloride (Metformin hydrochloride, metaformin); streptozocin (STZ).
Preparation of the reagent: the preparation method comprises the following steps: solution A was prepared by adding 2.1g of citric acid to 100mL of distilled water, and solution B was prepared by adding 2.94g of sodium citrate to 100mL of distilled water. Mixing the solution A and the solution B according to the ratio of 1:1.32 or 1:1, adjusting the PH to 4.2-4.5, and filtering the mixed solution by a filter with the diameter of 2.22 mu m.
The preparation method comprises the following steps of: dissolving DMSO, diluting with physiological saline to desired concentration
Metformin hydrochloride solution (200 mg/kg): is prepared from physiological saline
Model establishment of type 2 diabetes in C57BL/6N mice
Model group 2 diabetes mellitus: after feeding for three weeks with high fat diet, the STZ solution was intraperitoneally injected at a dose of 50mg/kg (STZ was dissolved in a citric acid buffer solution, which was formulated as a 5% strength solution). The injection is carried out once a day for five days continuously according to the same time period of 9:00am-10:00am, and the injection is carried out after the injection is carried out for 2 hours, and then the injection is carried out for 30 minutes after the injection of the STZ solution. Then feeding the mice with high-fat feed for three weeks, detecting the fasting blood glucose of the mice between 7:30pm and 9:00pm, picking out the mice with the Model group fasting blood glucose of more than 15.0mmol/L, then feeding the mice with common feed for one week, detecting the fasting blood glucose again, and the mice with the fasting blood glucose of still more than 15.0mmol/L can be considered to be successful in the type 2 diabetes Model, 18 mice are picked out as type 2 diabetes Model mice, and all the mice are fed with common feed after the experimental formality begins.
The 18 type 2 diabetic mice successfully modeled were randomly grouped into 3 groups, and the normal mice were grouped into 1 group, and were totally divided into 4 groups, 6 groups each, and the specific grouping and administration conditions were as follows:
model group: lavage an equal volume of physiological saline;
model+meta group: lavage of 200mg/kg metformin hydrochloride;
model+Sulfadiazine (Sulfadiazine) group: lavage 1mg/kg sulfadiazine compound;
SD (normal feed) group: lavage an equal volume of physiological saline;
all mice were dosed once daily for 3 weeks, during which time the mice were observed for growth and life, and the mice were examined weekly for body weight and blood glucose changes.
4. Detection index
4.1 body weight and fasting blood glucose test
Before and after administration, after 10 hours of fasting without water control, the body weight and fasting blood glucose are monitored in the same time period (7:30 pm-9:00 pm), and the body weight value is recorded by weighing with a balance; and cutting the tail to obtain a proper amount of blood, measuring the blood sugar content by using a glucometer (glucose oxidase method), and reading and recording the blood sugar value.
5. Experimental results:
5.1 influence of sulfadiazine on body weight and blood sugar in type 2 diabetic mice
As shown in fig. 13, there was no significant difference in body weight between SD, model, model+metaformin, and model+sulfadia mice. As shown in fig. 14, the blood glucose of SD group mice was always maintained within the normal range (< 7 mmol/L); the blood glucose duration of Model mice was significantly higher than that of SD mice (#p < 0.01;#p < 0.001); at weeks 1 and 3, the model+sulfadia zine group mice had significantly lower blood glucose than the Model group (< 0.05); on weeks 1, 2 and 3, the blood glucose of mice in the model+meta group was significantly lower than that of mice in the Model group (P <0.01; P < 0.001), indicating that sulfadiazine has therapeutic effect on type 2 diabetes mice.
Embodiment III, effect of Sulfomethylpyrimidine on treating diabetes and complications thereof in mice
1. The animal feeding pattern is as shown in example one:
2. medicine and reagent:
the medicines used in the invention are as follows: sulfa-methyl pyrimidine (Sulfamerazine); metformin hydrochloride (Metformin hydrochloride, metaformin); streptozocin (STZ).
Preparation of the reagent: the preparation method comprises the following steps: solution A was prepared by adding 2.1g of citric acid to 100mL of distilled water, and solution B was prepared by adding 2.94g of sodium citrate to 100mL of distilled water. Mixing the solution A and the solution B according to the ratio of 1:1.32 or 1:1, adjusting the PH to 4.2-4.5, and filtering the mixed solution by a filter with the diameter of 2.22 mu m.
The preparation method comprises the following steps of: dissolving DMSO, diluting with physiological saline to desired concentration
Metformin hydrochloride solution (200 mg/kg): is prepared from physiological saline
Model establishment of type 2 diabetes in C57BL/6N mice
Model group 2 diabetes mellitus: after feeding for three weeks with high fat diet, the STZ solution was intraperitoneally injected at a dose of 50mg/kg (STZ was dissolved in a citric acid buffer solution, which was formulated as a 5% strength solution). The injection is carried out once a day for five days continuously according to the same time period of 9:00am-10:00am, and the injection is carried out after the injection is carried out for 2 hours, and then the injection is carried out for 30 minutes after the injection of the STZ solution. Then feeding the mice with high-fat feed for three weeks, detecting the fasting blood glucose of the mice between 7:30pm and 9:00pm, picking out the mice with the Model group fasting blood glucose of more than 15.0mmol/L, then feeding the mice with common feed for one week, detecting the fasting blood glucose again, and the mice with the fasting blood glucose of still more than 15.0mmol/L can be considered to be successful in the type 2 diabetes Model, 18 mice are picked out as type 2 diabetes Model mice, and all the mice are fed with common feed after the experimental formality begins.
The 18 type 2 diabetic mice successfully modeled were randomly grouped into 3 groups, and the normal mice were grouped into 1 group, and were totally divided into 4 groups, 6 groups each, and the specific grouping and administration conditions were as follows:
model group: lavage an equal volume of physiological saline;
model+meta group: lavage of 200mg/kg metformin hydrochloride;
model+Sulfamerazine (Sulfamethazine) group: lavage 1mg/kg of sulfamethazine compound;
SD (normal feed) group: lavage an equal volume of physiological saline;
all mice were dosed once daily for 3 weeks, during which time the mice were observed for growth and life, and the mice were examined weekly for body weight and blood glucose changes.
4. Detection index
4.1 body weight and fasting blood glucose test
Before and after administration, after 10 hours of fasting without water control, the body weight and fasting blood glucose are monitored in the same time period (7:30 pm-9:00 pm), and the body weight value is recorded by weighing with a balance; and cutting the tail to obtain a proper amount of blood, measuring the blood sugar content by using a glucometer (glucose oxidase method), and reading and recording the blood sugar value.
5. Experimental results:
5.1 influence of Sulfomethylpyrimidine on body weight and blood glucose in type 2 diabetic mice
As shown in fig. 15, there was no significant difference in body weight between SD, model, model+metaformin, and model+sulfamazine mice. As shown in fig. 16, blood glucose was always maintained within the normal range (< 7 mmol/L) for SD group mice; the blood glucose duration of Model mice was significantly higher than that of SD mice (#p < 0.01;#p < 0.001); at weeks 1 and 2, the blood glucose was lower in the model+sulfamerazine group than in the Model group, and at week 3, the blood glucose was significantly lower in the model+sulfamerazine group than in the Model group (< 0.05); on weeks 1, 2 and 3, the blood glucose of mice in the model+meta group was significantly lower than that of mice in the Model group (P <0.05; P <0.01; P < 0.001), indicating that sulfamethazine has therapeutic effect on type 2 diabetic mice.
Conclusion(s)
In conclusion, the sulfonamide compound sulfathiazole disclosed by the invention can improve the glucose metabolism of a type 2 diabetic mouse, improve the sensitivity of insulin and improve insulin resistance, can obviously reduce the blood glucose of the type 2 diabetic mouse, and has the effect of reducing the blood glucose by 200 times or more than that of metformin; the effect of the sulfonamide compound for reducing blood sugar also has remarkable effect in sulfadiazine and sulfadimidine; meanwhile, the sulfanilamide compound sulfathiazole can reduce the content of urine protein, urine creatinine and urea nitrogen of the type 2 diabetes mice, which indicates that the sulfanilamide compound sulfathiazole can protect the kidney function of the diabetes mice; the sulfonamide compound sulfathiazole can reduce the content of triglyceride and total cholesterol of a type 2 diabetes mouse, regulate the blood lipid level and improve the lipid metabolism of the diabetes mouse. . The sulfadiazine can obviously reduce the blood sugar of the type 2 diabetes mice, and has a therapeutic effect on the type 2 diabetes mice; the sulfa compound sulfa-methyl pyrimidine can obviously reduce the blood sugar of type 2 diabetes mice, and has a therapeutic effect on the type 2 diabetes mice. The sulfonamide compound can be used for treating cardiovascular complications of diabetes and can be popularized and applied clinically.

Claims (2)

1. The application of the sulfonamide compound in preparing the medicine for treating the type 2 diabetes is characterized in that the sulfonamide compound is sulfa-methyl pyrimidine.
2. The use of claim 1, wherein the medicament is administered by the route: sublingual, inhaled, oral or injectable.
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Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
THE USE OF SULFADIAZINE AND SULFATHIAZOLE IN DIABETES MELLITUS;CHARLES W. STYRON等;《The Journal of the American Medical Association》;19420425;第118卷(第17期);第1423-1427页 *

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