Pyrrolopyrimidine ketone compound and preparation method and application thereof

A technology of pyrrolopyrimidones and compounds, applied in the field of pyrrolopyrimidones and their preparation, capable of solving problems such as cardiovascular pathological reactions, hypoglycemia, and β-cell death

Inactive Publication Date: 2017-06-20
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Promoting the secretion of insulin by pancreatic β-cells is the main method for the treatment of T2DM, but the traditional hypoglycemic drugs insulin sensitizers (such as biguanides, thiazolidinediones, etc

Method used

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  • Pyrrolopyrimidine ketone compound and preparation method and application thereof
  • Pyrrolopyrimidine ketone compound and preparation method and application thereof
  • Pyrrolopyrimidine ketone compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0114] Example 1. Synthesis of Compound 1.

[0115]

[0116] Follow the synthetic route below:

[0117]

[0118] 1) Synthesis of compound 1-1:

[0119] Add 520ml of concentrated sulfuric acid into a 100ml eggplant-shaped bottle, add 140g 6-methyluracil in batches under ice bath, and keep the temperature not exceeding 40°C. After all is dissolved, 104ml fuming nitric acid is slowly added dropwise, keeping the temperature not exceeding 15°C. After the dropwise addition was completed, after stirring at room temperature for 30 minutes, the reaction solution was poured into crushed ice, and solids were washed out. After suction filtration, the filter cake is washed with water and acetone and then dried to obtain the target compound 1-1.

[0120] 1H-NMR (400MHz, DMSO-d6): δ 11.79 (1H, s), 11.76 (1H, s), 2.28 (3H, s).

[0121] 2) Synthesis of compound 1-2:

[0122] Add 119g of compound 1-1 and 400mL of N,N-dimethylformamide into a 1000mL two-necked flask, heat and stir in an oil bath at 80°C...

Example Embodiment

[0142] Example 2. Synthesis of Compound 2

[0143]

[0144] Follow the synthetic route below:

[0145]

[0146] 1) Synthesis of compound 2-1:

[0147] Compound 1-7 (303mg, 1.0mmol) was dissolved in 20mL of THF, and 60% sodium hydrogen (48mg, 1.2mmol) was added under nitrogen protection at 0°C, stirred until no gas was generated, and methanesulfonyl chloride (137mg, 1.1 mmol), gradually warm to room temperature and stir for 5 hours, add 50 mL of water to the reaction solution, then extract with 3×80 mL of ethyl acetate, combine the organic layers, and wash with saturated aqueous sodium bicarbonate solution, water and saturated brine in turn, anhydrous sodium sulfate Dry and separate by flash column chromatography to obtain compound 2-1 with a yield of 88%;

[0148] MS: 381.0[M+H + ].

[0149] 2) Synthesis of compound 2:

[0150] The compound 2-1 obtained in the above steps was used as a raw material, referring to the synthesis method of compound 1 in Example 1, compound 2 was synthesize...

Example Embodiment

[0152] Example 3. Synthesis of Compound 3

[0153]

[0154] Follow the synthetic route below:

[0155]

[0156] Using compound 1-7 as raw material, 2-cyano-5-fluorobenzyl bromide instead of methanesulfonyl chloride, referring to the synthesis method of Example 2, compound 3 was synthesized with a yield of 53%;

[0157] MS: 500.2[M+H + ].

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Abstract

The invention relates to a pyrrolopyrimidine ketone compound and a preparation method and application thereof, and belongs to the technical field of medicine. The pyrrolopyrimidine ketone compound having a structural feature of formula I, or a pharmaceutically acceptable salt thereof has a very good inhibition effect on DPP-IV, and almost no effect on activity of DPP-VIII and DPP-IX, can effectively control the blood glucose concentration of diabetic rats, and is safe and low in toxicity through the verification of pharmacological and toxicological tests. After being prepared into a medicine, the compound provided by the invention not only has an obvious efficacy but also has very small side effects, thus greatly improving the administration convenience and patient use compliance, therefore, the compound has obvious advantages compared with the same kind of medicine. The formula is shown in the specification.

Description

technical field [0001] The present invention relates to the technical field of medicine, in particular to a pyrrolopyrimidinone compound and its preparation method and application. 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 1 and type 2. Type 1 diabetes is due to 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 2 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] Promoting the secretion of insulin by pancreatic β-cells is the m...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P3/10A61P3/04
CPCC07D487/04
Inventor 胡文辉曾少高张桂成
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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