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C-aryl glucoside derivative, as well as medical composition, preparation method and application thereof

A technology of aryl glycosides and derivatives, applied in the field of C-aryl glycoside derivatives, can solve problems such as adverse reactions, hypoglycemia, decreased insulin secretion, etc.

Inactive Publication Date: 2015-11-04
SHANGHAI DE NOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the most commonly used drugs for type II diabetes are sulfonylureas, biguanides, α-carbosidase inhibitors, and insulins, which have better control of blood sugar elevation and hypoglycemic effects, but are accompanied by many Drug-related adverse reactions, such as weight gain, decreased insulin secretion, hypoglycemia, gastrointestinal adverse reactions, etc.

Method used

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  • C-aryl glucoside derivative, as well as medical composition, preparation method and application thereof
  • C-aryl glucoside derivative, as well as medical composition, preparation method and application thereof
  • C-aryl glucoside derivative, as well as medical composition, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0141] Example 1: Synthesis of 2,3,4,6-tetra-O-(trimethylsilyl)-D-glucopyranone

[0142]

[0143] D-glucono δ-lactone (100.0g, 0.56mol) was dissolved in tetrahydrofuran (700mL), triethylamine (511g, 5.05mol) was added dropwise under ice-cooling and trimethylchlorosilane (427g, 3.93mol ) for about 1 hour, after the dropwise addition was completed, stir in an ice bath for 2 hours, and the system rose to room temperature and stirred overnight. Add ethyl acetate (2L), wash with saturated aqueous sodium dihydrogen phosphate (1L×2), water (1L) and saturated brine (1L×2) respectively, dry the organic phase with anhydrous magnesium sulfate, filter, and The solvent was rotary evaporated under reduced pressure to obtain a colorless oil, added toluene (100mL×2), and distilled under reduced pressure to constant weight to obtain 2,3,4,6-tetra-O-(trimethylsilyl)-D-pyran Glucosone (254 g, 97% yield) was a colorless liquid.

[0144] 1 HNMR (400MHz, CDCl 3 ): δ4.17-4.20(m, 1H), 4.01(d, ...

Embodiment 2

[0146] Embodiment 2: the synthesis of 5-bromo-2-cyanobenzoic acid

[0147]

[0148] Dissolve diisopropylamine (6.67g, 65.9mmol) in tetrahydrofuran (30mL) under nitrogen protection, cool to -30°C, and slowly add n-butyllithium in n-hexane (2.5M, 26.3mL, 65.9mmol ). The reaction system was stirred at -30°C for 30 minutes, then cooled to -70°C, p-bromophenylacetonitrile (10 g, 54.9 mmol) was slowly added dropwise, kept at -70°C for 30 minutes, and then solid carbon dioxide was added. The reaction system was slowly raised to room temperature and stirred overnight. Add water (50mL) and ethyl acetate (100mL), separate the organic phase, extract the aqueous phase with ethyl acetate (100mL×2), combine the organic phases, wash with saturated brine, dry over anhydrous magnesium sulfate, filter, reduce The solvent was removed by rotary evaporation to give 5-bromo-2-cyanobenzoic acid (7.25 g, yield: 58%) as a white solid.

[0149] m / z: [M-H] - 225.9

Embodiment 3

[0150] Embodiment 3: the synthesis of 5-bromo-2-methoxybenzoic acid

[0151]

[0152] 2-Methoxy-5-bromobenzaldehyde (20g, 93.0mmol) was dissolved in acetone (100mL), and after cooling to 5°C, solid potassium permanganate (14.7g, 93.0mmol) was added in portions within 2 hours . After the addition was complete, the reaction system was stirred overnight at room temperature. The mixture was filtered, and the filtrate was adjusted to pH=1 with 5M hydrochloric acid, and a pale yellow solid was precipitated, which was filtered. After vacuum drying, 5-bromo-2-methoxybenzoic acid (10.5 g, yield: 49%) was obtained.

[0153] m / z: [M-H] - 228.9

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Abstract

The invention relates to a C-aryl glucoside derivative, as well as a medical composition, a preparation method and application thereof. The preparation method comprises the following steps of: method I, in a solvent, under the action of alkali, performing a deacetylation protecting group reaction on compounds 1-f; method II: 1, performing a Mitsunobu reaction on components 2-g and (as shown in the description); and 2, performing a deacetylation protecting group reaction on the compounds 2-f obtained in the step 1; and method III: 1, mixing compounds 3-g and (as shown in the description), and performing a nucleophilic substitution reaction; and 2, performing a deacetylation protecting group reaction on the compounds 3-f obtained in the step 1. The medical composition comprises the C-aryl glucoside derivative, salt and / or prodrug of the C-aryl glucoside derivative which are / is acceptable in pharmacy, and auxiliary materials. The invention further relates to the C- aryl glucoside derivative, and application of salt or medical compositions of the C- aryl glucoside derivative, which is acceptable in pharmacy, for preparing SGLT inhibitors. The C- aryl glucoside derivative disclosed by the invention provides a new direction for research of the SGLT inhibitors. (As shown in the description)

Description

technical field [0001] The invention relates to a C-aryl glycoside derivative, its stereoisomer, prodrug or pharmaceutically acceptable salt, its pharmaceutical composition, preparation method and application. Background technique [0002] Diabetes is a type of metabolic disease characterized by hyperglycemia. The global incidence is increasing year by year. Among them, 90% of diabetic patients are type II diabetes, which is caused by excessive hepatic glucose production and peripheral insulin resistance. Hyperglycemia (Advances in Pharmacy, 2003, 27:88-91). At present, the most commonly used drugs for type II diabetes are sulfonylureas, biguanides, α-carbosidase inhibitors, and insulins, which have better control of blood sugar elevation and hypoglycemic effects, but are accompanied by many Drug-related adverse reactions, such as weight gain, decreased insulin secretion, hypoglycemia, gastrointestinal adverse reactions, etc. Therefore, it is necessary to develop safer, mo...

Claims

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Application Information

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IPC IPC(8): C07D407/12A61K31/351A61P3/10A61P3/04A61P9/12A61P3/00
CPCY02P20/55C07D407/12
Inventor 高大新杨和平王培
Owner SHANGHAI DE NOVO PHARMA
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