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High-efficient DPP (dipeptidyl peptidase)-IV inhibitor

A technology selected from, alkyl, applied in the field of medicine, can solve problems such as inactivation and short half-life

Active Publication Date: 2013-04-17
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, as the substrate of DPP-IV, GLP-1 has a very short half-life, and will be rapidly cut and inactivated by DPP-IV within 1-2 minutes after secretion

Method used

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  • High-efficient DPP (dipeptidyl peptidase)-IV inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Embodiment 1. Synthesis of compound 4

[0089]

[0090] Synthesis of Compound 4-0:

[0091] Add 6-chlorouracil (15g, 102.4mmol) and 250mL DMF into a 500mL eggplant-shaped bottle, add 15mL DIEA after dissolving, stir evenly, add 1-bromo-2-butyne (9.85mL, 112.64mmol) dropwise, and react The solution was stirred overnight at 25°C. After the reaction is complete, add ice water, filter with suction, wash the filter cake with water and ether, and then dry it to obtain the target product.

[0092] 1H NMR (400MHz, CDCl 3 )δ8.85(s, 1H), 5.91(s, 1H), 4.75(d, J=2.0Hz, 2H), 1.82(t, J=2.4Hz, 3H). MS 199.82[M+H]+.

[0093] Synthesis of Compound 4-1:

[0094] Under nitrogen protection, 60% NaH (54mg, 3.78mmol) was added to a 100mL eggplant-shaped flask, anhydrous DME / DMF (2:1) solution was added at 0°C, and after stirring at 0°C for 10 minutes, 1-(2- Butyne)-6-chlorouracil (500mg, 2.52mmol) in 10ml of anhydrous DME / DMF (2:1) solution. After the addition was completed, anhydro...

Embodiment 2

[0099] Embodiment 2. Synthesis of compound 3

[0100]

[0101] Synthesis of compound 3-1:

[0102] Using benzyl bromide as a raw material, refer to the synthetic method of compound 4-1 in Example 1 to prepare compound 3-1.

[0103] 1 H NMR (400MHz, CDCl 3 )δ7.43-7.19(m, 5H), 5.97(s, 1H), 5.42(s, 2H), 4.60(s, 2H), 1.77(s, 3H). MS 289.07[M+H] + .

[0104] Synthesis of compound 3:

[0105] Compound 3-1 obtained in the above step was used as a raw material, and with reference to the synthetic method of compound 4 in Example 1, compound 3.

[0106] 1 H NMR (400MHz, CDC l 3 )δ7.46-7.22(m, 5H), 5.33(s, 2H), 5.20(s, 1H), 4.40(s, 2H), 3.22(m, 3H), 2.96(m, 1H), 2.62(m , 1H), 2.42(m, 1H), 1.90(m, 1H), 1.77(s, 3H), 1.60(m, 1H), 1.22(m, 1H).MS 353.2[M+H] + .

Embodiment 3

[0107] Embodiment 3. Synthesis of compound 5

[0108]

[0109] Synthesis of Compound 5-1:

[0110] Using 2-chloromethylbenzimidazole as raw material, refer to the synthetic method of compound 4-1 in Example 1 to prepare compound 5-1.

[0111] 1 H NMR (400MHz, CDCl 3 )δ7.58(m, 2H), 7.23(m, 2H), 5.99(s, 1H), 5.40(s, 2H), 4.75(d, J=2.4Hz, 2H), 1.79(t, J=2.4 Hz, 3H).MS 329.10[M+H] + .

[0112] Synthesis of Compound 5:

[0113] Compound 5-1 obtained in the above step was used as a raw material, and with reference to the synthetic method of compound 4 in Example 1, compound 5.

[0114] 1 H NMR (400MHz, CDCl 3 )δ7.47(m, 2H), 7.14(m, 2H), 5.31(s, 2H), 5.18(s, 1H), 4.40(s, 2H), 3.21(m, 3H), 2.95(m, 1H ), 2.61(m, 1H), 2.43(m, 1H), 1.92(m, 1H), 1.75(s, 3H), 1.61(m, 1H), 1.21(m, 1H). MS 393.45[M+H ] + .

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Abstract

The invention belongs to the technical field of medicines, relates to a high-efficient DPP (dipeptidyl peptidase)-IV inhibitor, and specifically relates to a compound taking uracil as a mother nucleus, or a salt thereof, a preparation method, a composition and an application of the compound as the DPP-IV inhibitor in prevention or treatment of diseases which benefit from DPP-IV inhibition. The compound disclosed by the invention has a very good selective inhibition effect against DPP-IV and has very low cardiotoxicity, thereby being a DPP-IV inhibitor type medicament with great prospects.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a compound with uracil as the core or its salt, its preparation method, composition and this type of compound as a dipeptidyl peptidase (DPP-IV) inhibitor in the prevention or treatment of Use in the treatment of a disease that would benefit from inhibition of DPP-IV. 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 rat...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D401/14A61K31/513A61K31/517A61P3/10A61P3/06A61P3/00A61P3/04A61P35/00A61P25/00A61P37/02
Inventor 胡文辉曾丽丽曾少高刘飞徐宏江
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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