CN112370455A - Sulfonamide derivative as alpha-glucosidase inhibitor and application thereof - Google Patents
Sulfonamide derivative as alpha-glucosidase inhibitor and application thereof Download PDFInfo
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- CN112370455A CN112370455A CN202011115115.7A CN202011115115A CN112370455A CN 112370455 A CN112370455 A CN 112370455A CN 202011115115 A CN202011115115 A CN 202011115115A CN 112370455 A CN112370455 A CN 112370455A
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- glucosidase
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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- 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
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- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Medicinal Chemistry (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
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Abstract
The invention relates to the field of pharmaceutical chemistry, in particular to 2-methyl-3-oxo-substituted beta-glucosidase with alpha-glucosidase inhibiting activityN- (5,6,7, 8-tetrahydronaphthalen-2-yl) -3, 4-dihydro-2H-benzo [ 2 ]b][1,4]The oxazine-6-sulfonamide derivative has the following structural general formula:
Description
Technical Field
The invention relates to an alpha-glucosidase inhibitor and application thereof, 2-methyl-3-oxo-N- (5,6,7, 8-tetrahydronaphthalen-2-yl) -3, 4-dihydro-2H-benzo [ 2 ]b] [1,4]Use of oxazine-6-sulfonamides as novel alpha-glucosidase inhibitors.
Background
Diabetes Mellitus (DM) is a group of carbohydrate, protein and fat metabolism disorder diseases caused by absolute or relative insufficient secretion and/or insulin utilization disorder of insulin, and takes hyperglycemia as a main marker. The clinical manifestations are "more than three and one less", i.e. polydipsia, diuresis, polyphagia, weight loss, high blood sugar, glucose contained in urine, etc., which can cause multisystem damage after a long period of disease, slow and chronic pathological changes, hypofunction and failure of tissues and organs, and acute and severe metabolic disorders in severe cases. The prevalence and incidence of diabetes is currently rising dramatically worldwide.
The etiology of diabetes has not been systematically elucidated. Research has proved that alpha-glucosidase is one of the key hydrolases for decomposing oligosaccharides and disaccharides into glucose, and alpha-glucosidase inhibitors have significant effects on lowering postprandial blood glucose and treating diabetes. The alpha-glucosidase inhibitor competes with saccharides at the brush edge of the small intestine epithelium for the activity of hydrolase so as to slow down the speed of carbohydrate hydrolysis to generate monosaccharide, and has obvious effects on reducing blood fat, delaying the occurrence of coronary heart disease and the like. At present, alpha-glycosidase inhibitors on the market at home comprise acarbose, voglibose and miglitol, and are widely used for treating type 2 diabetes.
In the process of developing a new drug, a subject group carries out virtual screening of an alpha-glucosidase inhibitor on a commercial compound library (SPECS), and obtains a sulfonamide derivative from the product by enzyme level activity screening in the later period.
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 is 2-methyl-3-oxo-N- (5,6,7, 8-tetrahydronaphthalen-2-yl) -3, 4-dihydro-2H-benzo [ 2 ]b] [1,4]Oxazine-6-sulfonamide;
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 obviously inhibit alpha-glucosidase, and can be used for preparing a medicament 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 of a commercial compound library, and the alpha-glucosidase inhibitor can effectively inhibit the activity of alpha-glucosidase, and the activity of the alpha-glucosidase inhibitor is obviously superior to that of a control drug. 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 | 88.21% | 16.03 |
| Positive control nojirimycin | 66.54% | 52.02 |
Experimental results show that the compound I has a remarkable inhibiting effect on alpha-glucosidase, and the action effect of the compound I is superior to that of positive control medicament 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 |
|---|---|---|---|
| CN202011115115.7A CN112370455A (en) | 2020-10-19 | 2020-10-19 | Sulfonamide derivative as alpha-glucosidase inhibitor and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011115115.7A CN112370455A (en) | 2020-10-19 | 2020-10-19 | Sulfonamide derivative as alpha-glucosidase inhibitor and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112370455A true CN112370455A (en) | 2021-02-19 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011115115.7A Pending CN112370455A (en) | 2020-10-19 | 2020-10-19 | Sulfonamide derivative as alpha-glucosidase inhibitor and application thereof |
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| CN (1) | CN112370455A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114469957A (en) * | 2022-04-15 | 2022-05-13 | 山东第一医科大学第一附属医院(山东省千佛山医院) | Application of compound in preparation of alpha-glucosidase inhibitor |
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| CN101133040A (en) * | 2005-01-27 | 2008-02-27 | 瑟维尔实验室 | Novel heterocyclic oxime derivatives, method for preparing same and use thereof as hypoglycaemic or hypolipidemic agents |
| CN101754687A (en) * | 2007-05-29 | 2010-06-23 | Vero科学有限责任公司 | Therapeutic treatment for metabolic syndrome, type 2 diabetes, obesity, or prediabetes |
| WO2010150840A1 (en) * | 2009-06-24 | 2010-12-29 | 大日本住友製薬株式会社 | N-substituted-cyclic amino derivative |
| CN102510867A (en) * | 2009-10-20 | 2012-06-20 | 诺瓦提斯公司 | Glycoside derivative and uses thereof |
| CN103339111A (en) * | 2010-07-29 | 2013-10-02 | 诺瓦提斯公司 | Bicyclic acetyl-CoA carboxylase inhibitors |
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| CN106632216A (en) * | 2016-12-30 | 2017-05-10 | 中山大学 | Xanthone sulfonamide derivative as well as preparation method and application thereof |
| CN106715395A (en) * | 2014-07-30 | 2017-05-24 | 豪夫迈·罗氏有限公司 | 6-amino-5,6,7,8-tetrahydronaphthalen-2-yl or 3-aminochroman-7-yl derivatives as taar modulators |
| CN111646941A (en) * | 2020-07-17 | 2020-09-11 | 天津科技大学 | Sulfonamide derivative and preparation method and application thereof |
-
2020
- 2020-10-19 CN CN202011115115.7A patent/CN112370455A/en active Pending
Patent Citations (10)
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| CN1930152A (en) * | 2004-01-09 | 2007-03-14 | 卡地拉健康护理有限公司 | 1,3-dioxane derivatives and analogues thereof useful in the treatment of I.A. obesity and diabetes |
| CN101133040A (en) * | 2005-01-27 | 2008-02-27 | 瑟维尔实验室 | Novel heterocyclic oxime derivatives, method for preparing same and use thereof as hypoglycaemic or hypolipidemic agents |
| CN101754687A (en) * | 2007-05-29 | 2010-06-23 | Vero科学有限责任公司 | Therapeutic treatment for metabolic syndrome, type 2 diabetes, obesity, or prediabetes |
| WO2010150840A1 (en) * | 2009-06-24 | 2010-12-29 | 大日本住友製薬株式会社 | N-substituted-cyclic amino derivative |
| CN102510867A (en) * | 2009-10-20 | 2012-06-20 | 诺瓦提斯公司 | Glycoside derivative and uses thereof |
| CN103339111A (en) * | 2010-07-29 | 2013-10-02 | 诺瓦提斯公司 | Bicyclic acetyl-CoA carboxylase inhibitors |
| CN103619170A (en) * | 2011-05-04 | 2014-03-05 | 默沙东公司 | Amino-pyridine-containing spleen tyrosine kinase (SYK) inhibitors |
| CN106715395A (en) * | 2014-07-30 | 2017-05-24 | 豪夫迈·罗氏有限公司 | 6-amino-5,6,7,8-tetrahydronaphthalen-2-yl or 3-aminochroman-7-yl derivatives as taar modulators |
| CN106632216A (en) * | 2016-12-30 | 2017-05-10 | 中山大学 | Xanthone sulfonamide derivative as well as preparation method and application thereof |
| CN111646941A (en) * | 2020-07-17 | 2020-09-11 | 天津科技大学 | Sulfonamide derivative and preparation method and application thereof |
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|---|
| KAVITHA BHARATHAM ET AL.: "Binding mode analyses and pharmacophore model development for sulfonamide chalcone derivatives, a new class of a-glucosidase inhibitors", 《JOURNAL OF MOLECULAR GRAPHICS AND MODELLING》 * |
| 郭时印等: "1-脱氧野尻霉素对α-葡萄糖苷酶的抑制作用机制", 《食品科学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114469957A (en) * | 2022-04-15 | 2022-05-13 | 山东第一医科大学第一附属医院(山东省千佛山医院) | Application of compound in preparation of alpha-glucosidase inhibitor |
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