CN112336718A - Benzimidazole derivative used as alpha-glucosidase inhibitor and application thereof - Google Patents
Benzimidazole derivative used as alpha-glucosidase inhibitor and application thereof Download PDFInfo
- Publication number
- CN112336718A CN112336718A CN202011115126.5A CN202011115126A CN112336718A CN 112336718 A CN112336718 A CN 112336718A CN 202011115126 A CN202011115126 A CN 202011115126A CN 112336718 A CN112336718 A CN 112336718A
- Authority
- CN
- China
- Prior art keywords
- alpha
- glucosidase
- compound
- activity
- glucosidase inhibitor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of pharmaceutical chemistry, in particular to a compound with alpha-glucosidase inhibition activityN‑(5‑(1H-benzo [ 2 ]d]The imidazole-2-yl) -2-methylphenyl) -2- (2, 4-dimethylphenoxy) acetamide derivative has the following structural general formula:
Description
Technical Field
The invention relates to an alpha-glucosidase inhibitor and application thereof,N-(5-(1H-benzo [ 2 ]d]Use of imidazol-2-yl) -2-methylphenyl) -2- (2, 4-dimethylphenoxy) acetamide as a novel alpha-glucosidase inhibitor.
Background
Diabetes Mellitus (DM) is a disorder of carbohydrate, protein and fat metabolism, which is mainly manifested by hyperglycemia and urine glucose. Clinically, symptoms of polyuria, polydipsia, polyphagia, fatigue, emaciation and the like appear in early stage and after the early stage of the disease develops to the symptom stage. Persistent hyperglycemia can lead to a number of complications, such as blindness, cardiovascular disease, renal failure, and the like. The incidence rate of the disease tends to increase year by year, and the disease becomes one of the serious diseases harming human health.
Diabetes is largely classified into insulin-dependent diabetes (type i diabetes) and non-insulin-dependent diabetes (type ii diabetes). Type I diabetes is a condition in which insulin secretion is reduced due to damage of islet beta cells, and metabolic disorders such as hyperglycemia and beta-ketoacidosis are caused. Type ii diabetes is an insulin-resistant cause, mainly due to insulin resistance. According to the action mechanism of oral hypoglycemic drugs, the oral hypoglycemic drugs can be divided into insulin secretion promoters, insulin sensitizers, dipeptidyl peptidase-IV, alpha-glucosidase inhibitors and the like. The first three representative drugs are glibenclamide, metformin hydrochloride, ciguatine and the like, but are limited because the drugs can cause adverse reactions such as hypoglycemia, nephropathy and the like. The alpha-glucosidase inhibitor does not inhibit the absorption of protein and fat, so that the alpha-glucosidase inhibitor does not cause substance malabsorption and is widely applied to the treatment of type II diabetes.
The subject group carries out virtual screening on a commercial compound library (SPECS), and a compound is obtained by in vitro activity screening in the later stage, can inhibit the activity of alpha-glucosidase, has a novel structure, and can be used as a drug lead for researching and developing anti-type II diabetes drugs.
Disclosure of Invention
The invention aims to provide a novel alpha-glucosidase inhibitor.
In a first aspect of the present invention, there is provided a compound of formula i, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof:
the compound isN-(5-(1H-benzo [ 2 ]d]Imidazol-2-yl) -2-methylphenyl) -2- (2, 4-dimethylphenoxy) acetamide;
in a second aspect of the present invention, a pharmaceutical composition comprises a compound represented by formula I as described in the first aspect, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof; and a pharmaceutically acceptable carrier.
In a third aspect of the present invention, there is provided a compound of formula I as described in the first aspect, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, for use in:
(i) preparing an alpha-glucosidase inhibitor;
(ii) preparing a medicament for preventing and/or treating diseases related to alpha-glucosidase.
Pharmaceutically acceptable carriers must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof, and generally suitable carriers, diluents and excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient employed will depend upon the mode and purpose of administration of the compounds of the invention. The solvent is generally selected based on the solvents (GRAS) that one of skill in the art would consider safe for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents (such as water) and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400 or PEG300), and the like, and mixtures thereof. One or more buffering agents, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, slip agents, processing aids, colorants, sweeteners, flavorants, flavoring agents and other known additives that provide a tailored appearance to the drug (i.e., a compound of the invention or a pharmaceutical composition thereof) or aid in the manufacture of the drug product (i.e., for use in the preparation of a medicament) may also be included.
Advantageous effects
The compound can effectively inhibit the activity of alpha-glucosidase, and is further used for research and development of medicaments for preventing and/or treating diseases related to the alpha-glucosidase.
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
The inventor of the application discovers an alpha-glucosidase inhibitor through virtual screening and activity research on a commercial compound library, and the alpha-glucosidase inhibitor can effectively inhibit the activity of alpha-glucosidase. On the basis of this, the present invention has been completed.
In the present invention, the compound of formula I refers to a compound having the following formula I:
EXAMPLE 1 Effect of Compounds on alpha-glucosidase Activity
Alpha-glucosidase was purchased from Sigma, p-nitrophenyl-alpha-D-glucoside (PNPG) as substrate was purchased from Aladdin, and sodium salt and phosphate salt required for buffer preparation and quencher were purchased from Shanghai Michelin Biotech, Inc. The alpha-glycosidase inhibitory activity is determined by reference to published reported methods. After 99. mu.L of PBS phosphate buffer (pH 6.8) was added to each well of the 96-well plate, 20 mmol of 1. mu.L of the test compound solution or a blank was added to the corresponding well, 25. mu.L of the alpha-glucosidase solution was added thereto, and the plate was incubated at 37 ℃ for 15 min with shaking. Adding 25 mu L of PNPG solution, placing the PNPG solution in a shaking table at 37 ℃ for incubation for 15 min, then adding 50 mu L of 0.2M sodium carbonate solution, measuring the absorbance at 405 nm by using an enzyme-labeling instrument, and calculating the inhibition rate of the compound to be detected on alpha-glycosidase. Then, the compound was prepared at 10 different gradient concentrations and measured again, and the IC of the compound was determined from the inhibition curve50The values (inhibitor concentration at which the enzyme activity was inhibited by 50%) and the results are shown in Table 1.
TABLE 1 inhibitory Activity of Compounds on alpha-glucosidase
| Compound (I) | Inhibition rate (100. mu.M) | IC50（μM） |
| Ⅰ | 82.17% | 21.57 |
| Positive control nojirimycin | 66.54% | 52.02 |
Experimental results show that the compound I has a remarkable inhibition effect on alpha-glucosidase, and the action effect of the compound I is superior to that of positive control nojirimycin.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (3)
1. Alpha-glucosidase inhibitor shown as formula I
Or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention and/or treatment of a disease associated with alpha-glucosidase.
2. The use according to claim 1, characterized in that the medicament for the prevention and/or treatment of α -glucosidase related diseases is a medicament of an α -glucosidase inhibitor.
3. Acetylcholinesterase inhibitors of formula I
Or pharmaceutically acceptable salts thereof, in the preparation of medicaments for preventing and/or treating diabetes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011115126.5A CN112336718A (en) | 2020-10-19 | 2020-10-19 | Benzimidazole derivative used as alpha-glucosidase inhibitor and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011115126.5A CN112336718A (en) | 2020-10-19 | 2020-10-19 | Benzimidazole derivative used as alpha-glucosidase inhibitor and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112336718A true CN112336718A (en) | 2021-02-09 |
Family
ID=74362087
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011115126.5A Pending CN112336718A (en) | 2020-10-19 | 2020-10-19 | Benzimidazole derivative used as alpha-glucosidase inhibitor and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112336718A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101087769A (en) * | 2004-10-15 | 2007-12-12 | 拜尔药品公司 | Preparation and use of biphenyl-4-yl-carbonylamino acid derivatives for the treatment of obesity |
| EP2061767A1 (en) * | 2006-08-08 | 2009-05-27 | Sanofi-Aventis | Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use |
| CN109336887A (en) * | 2018-09-07 | 2019-02-15 | 中山大学 | A kind of benzimidazole and chiral heterocycle class compound and its preparation method and application |
| CN111393372A (en) * | 2020-05-12 | 2020-07-10 | 中国药科大学 | Benzimidazole derivative and preparation method and application thereof |
-
2020
- 2020-10-19 CN CN202011115126.5A patent/CN112336718A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101087769A (en) * | 2004-10-15 | 2007-12-12 | 拜尔药品公司 | Preparation and use of biphenyl-4-yl-carbonylamino acid derivatives for the treatment of obesity |
| EP2061767A1 (en) * | 2006-08-08 | 2009-05-27 | Sanofi-Aventis | Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use |
| CN109336887A (en) * | 2018-09-07 | 2019-02-15 | 中山大学 | A kind of benzimidazole and chiral heterocycle class compound and its preparation method and application |
| CN111393372A (en) * | 2020-05-12 | 2020-07-10 | 中国药科大学 | Benzimidazole derivative and preparation method and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| EMRE MENTEŞE ET AL.: "Synthesis, α-glucosidase inhibition and in silico studies of some 4-(5-fluoro-2-substituted-1H-benzimidazol-6-yl)morpholine derivatives", 《BIOORGANIC CHEMISTRY》 * |
| NIK KHAIRUNISSA NIK ABDULLAH ZAWAWI ET AL.: "Benzimidazole derivatives as new a-glucosidase inhibitors and in silico studies", 《BIOORGANIC CHEMISTRY》 * |
| 葛珍等: "新型2-芳基苯并咪唑类α-淀粉酶抑制剂的理论设计研究", 《计算机与应用化学》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPWO2004050122A1 (en) | Preventive or therapeutic agent for diseases caused by hyperglycemia | |
| CZ20011006A3 (en) | Medicament and pharmaceutical preparation for treating parkinsonism, ADHD and micro-adenomas | |
| EP2525793B1 (en) | Alpha-2 adrenergic agonist having long duration of intraocular pressure-lowering effect | |
| EP0771195B1 (en) | Method of inhibiting nitric oxide formation | |
| CN107987033B (en) | Application of vanillin and isomer thereof in preparation of NA inhibitor | |
| JP6412241B2 (en) | Liver function improvement method | |
| EP1004304A1 (en) | Composition containing ascorbic acid | |
| US20200215068A1 (en) | Treatment of type i and type ii diabetes | |
| CN112336718A (en) | Benzimidazole derivative used as alpha-glucosidase inhibitor and application thereof | |
| RU2056416C1 (en) | Derivatives of thiourea, pharmaceutical composition and method of treatment | |
| CN104582701B (en) | The method to lose weight | |
| US20060194810A1 (en) | Methods of treating ischemic related conditions | |
| JP4096122B2 (en) | Method for inhibiting cardiac fibroblast proliferation and cardiac fibrosis | |
| JP6657101B2 (en) | Compounds for the treatment of diabetes and disease complications resulting therefrom | |
| CN112225740A (en) | Pyrazolopyrimidinone derivative serving as alpha-glucosidase inhibitor and application thereof | |
| CN112190582A (en) | Novel alpha-glycosidase inhibitor and application thereof | |
| JPH10101566A (en) | Medicine for protecting retina | |
| CN112300190A (en) | Novel alpha-glycosidase inhibitor and application thereof | |
| KR100219972B1 (en) | Method of reducing tissue damage associated with ischemia | |
| US20090076067A1 (en) | Pharmaceutical composition comprising azarhodacyanine compound as active ingredient | |
| TWI246424B (en) | Use of 2-imidazolyl-substituted carbinols for the production of a medicament for the treatment or prophylaxis of diseases caused by ischemic conditions | |
| CN101801373B (en) | Antidiabetic pharmaceutical composition | |
| CN115043825A (en) | Oxadiazole compound and preparation method, application and product thereof | |
| JP2007504198A (en) | Composition comprising benzo [g] quinoline derivative and prostaglandin derivative | |
| EP3441070A1 (en) | Drug for preventing or treating lactic acidosis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20210209 |
|
| WD01 | Invention patent application deemed withdrawn after publication |