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Benzodipyrrolidine compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof

A technology of benzoditetrahydropyrrole and compound, which is applied in the field of medicine and can solve the problem that the drug has not been applied for listing and the like

Active Publication Date: 2020-04-24
INST OF ANALYSIS GUANGDONG ACAD OF SCI (CHINA NAT ANALYTICAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, both of these drugs may not have been approved for marketing by the FDA and in Europe due to safety reasons

Method used

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  • Benzodipyrrolidine compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof
  • Benzodipyrrolidine compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof
  • Benzodipyrrolidine compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Example 1 Synthesis of compound 1

[0073]

[0074] synthetic route:

[0075]

[0076] Synthesis of compound 1-1:

[0077] Tetrabromomethylbenzene (9.0g, 20mmol) was dissolved in 200mL tetrahydrofuran, trifluoroacetamide (9.0g, 80mmol) was added, sodium hydrogen (4.8g, 120mmol, 60wt% in oil) was slowly added at 0°C, and the temperature was gradually raised to room temperature Stir for 30 minutes, then heat up to reflux and stir for 3 hours. After TLC detects that there is no raw material, add 300mL ethyl acetate to the reaction solution for dilution, and the organic phase is washed once with 200mL water and saturated brine successively, then dried with anhydrous magnesium sulfate, pumped After filtration, the filtrate was evaporated to remove the solvent under reduced pressure, and the resulting concentrate was purified by column chromatography (200-300 mesh silica gel, eluent: petroleum ether / ethyl acetate, volume ratio: 4:1) to obtain a white solid (compound 1...

Embodiment 2

[0091] Example 2 Synthesis of compound 2

[0092]

[0093] Using intermediate 1-3 (compound 1-3) as a raw material, replace the raw material methanesulfonyl chloride in Example 1 with trifluoromethanesulfonyl chloride, refer to the synthetic method of the last two steps in Example 1, and synthesize compound 2, the latter two The step yield is 62%; MS: 504.1 [M+H+].

Embodiment 3

[0094] Example 3 Synthesis of compound 3

[0095]

[0096] Using intermediate 1-3 as the raw material, the raw material methanesulfonyl chloride in Example 1 was replaced with the raw material isopropylsulfonyl chloride, referring to the synthesis method of the last two steps in Example 1 to synthesize compound 3, and the yield of the last two steps was 65%. ; MS: 477.1 [M+H+].

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Abstract

The invention discloses a benzodipyrrolidine compound or a pharmaceutically acceptable salt thereof, and a preparation method and application thereof. The benzodipyrrolidine compound disclosed by theinvention has a structure as shown in a formula I, which is described in the specification, in-vitro and in-vivo experiments prove that the compound has a very good selective inhibition effect on DPP-IV, the activity of DPP-VIII and DPP-IX is hardly influenced while the activity of DPP-IV is effectively inhibited, meanwhile, the inhibition rate of a potassium ion channel is relatively low, and itcan be foreseen that the toxicity of the compound is relatively low after the compound is developed into a patent medicine. The benzodipyrrolidine compound provided by the invention has equivalent orhigher biological utilization efficiency compared with a commercially available drug Oldagliptin orally taken once a week, it can be foreseen that the developed compound is expected to achieve a treatment effect of once oral administration for a long time, and the convenience and compliance of patients are greatly improved. The preparation method is simple and suitable for industrial large-scale production, and the raw materials are easily available.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a benzoditetrahydropyrrole compound or a pharmaceutically acceptable salt thereof, a preparation method and application thereof. Background technique [0002] Diabetes mellitus is caused by absolute or relative lack of insulin, resulting in elevated blood sugar, which can lead to serious complications and eventually lead to disability or death of the patient. Clinically, diabetes is divided into type I and type II. Type I diabetes is caused by the destruction of pancreatic β-cells and lack of insulin secretion, which leads to elevated blood sugar. Such patients can only rely on exogenous insulin; type II diabetes is caused by relatively insufficient insulin secretion or imperfect insulin action. Hyperglycemia, its incidence rate accounts for more than 90% of all diabetic patients. Current drug research is mainly aimed at type 2 diabetes mellitus (T2DM). [0003] P...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/403A61P3/04A61P3/10A61P3/08A61P3/06A61P35/00A61P25/00A61P37/00
CPCC07D487/04A61P3/04A61P3/10A61P3/08A61P3/06A61P35/00A61P25/00A61P37/00
Inventor 马艳芳曾少高巫培山石燕丽宋浩军曹宏宝伍俊林刘琳
Owner INST OF ANALYSIS GUANGDONG ACAD OF SCI (CHINA NAT ANALYTICAL
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