Compound, and preparation method and application thereof

A technology of compound and alkyl, applied in the field of compound and its preparation, can solve the problem of loss of physiological activity and so on

Active Publication Date: 2013-06-26
CHENGDU DIAO PHARMA GROUP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

GLP-1 (glucagon-like peptide-1) and its related glucagon-like peptide family members contain amino acids at this position, so they are easily degraded by DPP-IV and lose their physiological activity

Method used

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  • Compound, and preparation method and application thereof
  • Compound, and preparation method and application thereof
  • Compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0145] Example 1: Compound 1 (1,3-bis[(quinolin-2-yl)-methyl]-7-(2-butyn-1-yl)-8-[(R)-3-amino- Preparation of piperidin-1-yl]-xanthine)

[0146] a. Preparation of intermediate 8-bromoxanthine

[0147] Take 15g of xanthine, add 250mL of water and 7.6mL of bromine, heat to 100°C, stop the reaction when the color of bromine disappears, cool the reaction solution to room temperature, filter with suction, wash the filter cake with a small amount of water, and dry in vacuo to obtain product 18.4 g;

[0148] b. Intermediate 7-(2-butyn-1-yl)-8-bromoxanthine

[0149] Weigh 2.3g of 8-bromoxanthine and dissolve it in 30mL DMF, then add 1.75mL DIPEA and 0.9mL 1-bromo-2-butyne successively, heat the reaction solution to 80°C, stop the reaction after 17h, cool to room temperature, and then add 50 mL of water was added to the reaction solution, and a white solid was precipitated, which was filtered with suction, and the filter cake was washed with a small amount of water, and dried in vac...

Embodiment 2

[0157] Example 2: Compound 2(1,3-bis(2-cyanobenzyl)-7-(2-butyn-1-yl)-8-[(R)-3-amino-piperidine-1- base]-xanthine) preparation

[0158] The preparation of compound 2 of the present invention refers to Example 1, but replaces 2-chloromethylquinoline hydrochloride in Example 1 with 2-cyanobenzyl chloride, and prepares the compound corresponding to R in general formula (I). 1 2-cyanobenzyl xanthine.

[0159] A yellow solid was obtained. 1 H NMR (600MHz, DMSO-d 6 ):δ:7.87(d,J=7.8Hz,1H),7.85(d,J=7.2Hz,1H),7.67-7.62(m,2H),7.50-7.45(m,2H),7.39(d, J=7.6Hz,1H),7.29(d,J=8.0Hz,1H),5.32(s,2H),5.24(s,2H),4.97-4.91(m,2H),3.66-3.62(m,1H ),3.56-3.50(m,1H),3.15-3.09(m,2H),2.99-2.96(m,1H),1.93-1.89(m,1H),1.85-1.84(m,1H),1.81(brs ,3H),1.68-1.61(m,1H),1.50-1.43(m,1H).ESI-MS m / z:calc.532.2,found533.2[M+H] +

Embodiment 3

[0160] Example 3: Compound 3 (1,3-bis[(3-methoxycarbonyl)-benzyl]-7-(2-butyn-1-yl)-8-[(R)-3-amino- Preparation of piperidin-1-yl]-xanthine)

[0161] The preparation of compound 3 of the present invention refers to Example 1, but replaces 2-chloromethylquinoline hydrochloride in Example 1 with 3-methoxycarbonyl-benzyl chloride, and prepares the compound corresponding to R in general formula (I). 1 3-Methoxycarbonylbenzyl xanthine to give a yellow solid. 1 H NMR (600MHz, DMSO-d 6 ):δ:8.03-7.98(m,1H),7.89-7.86(m,2H),7.84(d,J=6.8Hz,1H),7.63(d,J=7.9Hz,1H),7.57(d, J=7.7Hz,1H),7.50-7.45(m,2H),5.18(s,2H),5.10(s,2H),4.97-4.90(m,2H),3.83(s,3H),3.82(s ,3H),3.68-3.65(m,1H),3.20-3.12(m,3H),2.01-1.96(m,1H),1.92-1.86(m,1H),1.80(brs,3H),1.71-1.65 (m,1H),1.63-1.58(m,1H).ESI-MS m / z:calc.598.2,found599.2[M+H] +

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Abstract

The invention provides a compound disclosed as Formula I or a pharmaceutically acceptable salt thereof, and a preparation method and application thereof. The new compound provided by the invention can effectively inhibit dipeptidyl peptidase-IV (DPP-IV) activity with better effects than the existing DPP-IV enzyme inhibitor Linagliptin; and meanwhile, the compound has the advantages of higher selectivity for DPP-IV, higher safety and lower toxic or side effect on the DPP inhibitor, and thus, provides a new medicine option for treating or/and preventing diseases related to DPP-IV enzyme activity.

Description

technical field [0001] The present invention relates to a compound and its preparation method and use. Specifically, the present invention relates to a compound capable of inhibiting the activity of dipeptidyl peptidase-IV. Background technique [0002] DPP-IV contains 766 amino acids and is a serine protease located on the surface of cells. It is widely present in various tissues and organs in the body, such as the surface of kidney, intestinal tract, liver, placenta, uterus, prostate, skin and capillary endothelial cells. Its soluble form Also present in plasma and other body fluids. The active site of DPP-IV is the Asp-His-Ser stage, which can selectively cleave peptide chains containing proline and alanine at the amino terminus. However, GLP-1 (glucose-like peptide-1) and its related members of the glucagon-like peptide family contain amino acids at this position, so they are easily degraded by DPP-IV and lose their physiological activity. GLP-1 can promote insulin sec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/04C07D473/06A61K31/522A61P3/10A61P5/50
CPCY02P20/55
Inventor 姬建新郭娜程训官成明陈欣
Owner CHENGDU DIAO PHARMA GROUP
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