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Piperazidines derivate

A compound and pharmaceutical technology, applied in the field of dipeptidyl peptidase IV inhibitor compounds and DPP-4-related diseases, can solve the problems of not meeting clinical needs, limited varieties of diabetes, etc.

Active Publication Date: 2014-06-04
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Invention patents CN101824036A, CN101417999A, CN101486689A, and CN101899048A disclose a series of DPP-4 inhibitors containing piperazine structures. However, the current effective drugs for treating diabetes are limited and far from meeting clinical needs.

Method used

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  • Piperazidines derivate
  • Piperazidines derivate
  • Piperazidines derivate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] The preparation of embodiment 1 key intermediate formula II

[0059] Chemical reaction formula:

[0060]

[0061] In step (a) to step (f), select compound 1 (C-pyrazin-2-yl-methylamine) as the starting material to prepare compound 8. The specific experimental steps refer to the seventh step in Example 1 of the invention patent CN101824036A to the preparation method of the twelfth step.

[0062] Step (g):

[0063] Add 0.17g of compound 8 into a 100ml single-necked bottle, add 10ml of toluene to dissolve it, then add 0.07g of LR, reflux at 120°C overnight, TLC (PE: EA = I: 1) the reaction of the raw material is complete, evaporate the solvent, and purify by column chromatography , and evaporated to dryness to obtain 0.12 g of compound 9.

[0064] Step (h):

[0065] Add 8.8g NaOH and 180ml of methanol to a 250ml single-necked bottle successively, stir at room temperature to dissolve, add 2.5g of compound 9, heat the oil bath to reflux, TLC (PE:EA=2:1, 2 drops of ace...

Embodiment 2

[0067] The preparation of embodiment 2 compound I-1

[0068] Add about 40 ml of methanol-hydrogen chloride solution (pH≈3) into the single-necked bottle containing 0.6 g of the compound of formula II, and stir overnight at room temperature. TLC (DCM:MeOH=20:1, 2 drops of ammonia) tracked the completion of the reaction, and the reaction solution was concentrated to dryness under reduced pressure to obtain 0.42 g of a yellow solid, namely compound I-1. MS: 481 [M+H].

[0069] H-NMR: δ7.42-7.34(m, 1H), 7.25-7.23(m, 1H), 5.18-5.07(m, 2H), 4.37-4.32(m, 1H), 4.15-4.00(m, 2H) , 3.96-3.92 (m, 2H), 3.26-2.89 (m, 2H), 2.84-2.80 (m, 2H).

Embodiment 3

[0070] The preparation of embodiment 3 compound I-7

[0071] Chemical reaction formula:

[0072]

[0073] Add 0.98g of compound of formula II, 15ml of DMF, 0.75g of triethylamine, 1g of HOBT and 1.41g of EDC·HCl into a 100ml three-necked flask, stir at room temperature for 1h, add 1.0ep of tetrahydrofuran solution of methylamine, and react at 31°C overnight. TLC (DCM: MeOH=20:1, 2 drops of ammonia) followed the completion of the reaction, the reaction solution was poured into 200ml of ice water, a large amount of white solid was precipitated, filtered with suction, the filter cake was washed with water, and dried in vacuum at 45°C to obtain 0.8g of a gray solid, namely is compound 10.

[0074] Referring to the method of Example 2, compound 10 was de-boc-protected to obtain compound I-7.

[0075] MS: 480 [M+H].

[0076] H-NMR: δ7.43-7.35 (m, 1H), 7.26-7.24 (m, 1H), 5.18-5.06 (m, 2H), 4.36-4.31 (m, 1H), 4.16-4.02 (m, 2H), 3.97-3.92 (m, 2H), 3.24-2.87 (m, 2H), 2.87-2.82 (m...

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Abstract

The invention provides a novel piperazine structural dipeptidyl peptidase IV (DPP-4) inhibitor type compound as shown in formula (I). The compound, optical isomers and pharmaceutically acceptable salt of the compound can be used for treating diabetes, in particular non-insulin dependent diabetes and other DPP-4 related diseases; and the definition of each substituent as shown in formula (I) is the same as that in the specification.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and specifically relates to a dipeptidyl peptidase IV (hereinafter referred to as DPP-4) inhibitor compound with a piperazine structure and its application for treating and preventing diabetes and other diseases related to DPP-4. Background technique [0002] Diabetes is a chronic metabolic disease caused by various pathogenic factors such as genetic factors, immune dysfunction, microbial infection and its toxins, free radical toxins, and mental factors. Clinically, it is characterized by hyperglycemia. Can be divided into type 1 diabetes (insulin-dependent), type 2 diabetes (non-insulin-dependent), gestational diabetes and other special types of diabetes. Type 2 diabetes accounts for about 95% of diabetic patients. [0003] At present, the main oral hypoglycemic agents are: sulfonylureas (SU), biguanides, α-glucosidase inhibitors, non-sulfonylurea insulin secretory drugs and insulin sensitizers...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D519/00C07K5/078C07K5/065A61K31/519A61K38/05A61P3/10
CPCA61K38/00C07D487/04C07D519/00C07K5/06191
Inventor 张孝清宋志春包金远蒋玉伟
Owner NANJING HUAWE MEDICINE TECH DEV
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