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Piperazinoltriazole derivatives

A piperazine and compound technology, applied in the field of piperazinotriazole derivatives, can solve the problem of low in vitro activity and target enzyme selectivity, unsatisfactory dipeptidyl peptidase inhibitory activity, and no metformin in hypoglycemic activity Strong and other issues

Inactive Publication Date: 2011-05-11
SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, the inhibitory activity of these compounds on dipeptidyl peptidase in the prior art is not satisfactory enough, the in vitro activity and target enzyme selectivity are still not high, and their hypoglycemic and HbA 1c The activity is not as strong as metformin [Medicinal Research Review, 2009, 29(1), 125-195]

Method used

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  • Piperazinoltriazole derivatives
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preparation example Construction

[0058] In the preparation method of the present invention, each reaction is usually carried out in an inert solvent at 0°C to solvent reflux temperature (preferably room temperature to 80°C). The reaction time is usually 0.1 to 60 hours, preferably 0.5 to 48 hours.

[0059] In a preferred example, the required intermediate of the compound of formula (I) of the present invention can be prepared according to the following route I

[0060] Route I: Preparation of Intermediate I-5a-o

[0061]

[0062]

[0063] Reagents and reaction conditions: a: K 2 CO 3 , CH 3 CN, reflux; b: CuI, Pd(PPh 3 ) 2 Cl 2 ,Et 3 N, DMF; c: SOCl 2 , DCM; d: NaN 3 , DMSO, 150°C; e: TFA, Me 3 SiH.

[0064] (1) In a polar aprotic solvent, at a suitable temperature, commercially available 2-(2,4-dimethoxybenzylamino)ethanol and propyne chloride are reacted in the presence of a base, 2-(N-(2,4-dimethoxybenzyl)-N-(prop-2-ynyl)amino)ethanol (1-1) is obtained. Polar aprotic solvents are selecte...

specific Embodiment approach

[0186] The present invention is explained more specifically in the following Preparations and Examples. It should be understood, however, that these Preparations and Examples are given to illustrate the invention and not to limit the scope of the invention in any way. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Parts and percentages are by weight unless otherwise indicated.

[0187] In all preparations and examples, the melting point was determined with an X-4 melting point apparatus, and the thermometer was not corrected; 1 H-NMR was recorded with a VarianMercury 400 nuclear magnetic resonance instrument, and the chemical shift was expressed in δ (ppm); MS was measured with a Shimadzu LC-MS-2020 mass spectrometer. The silica gel used for separation is not specified and is 200-300 mesh, and the ratio of the eluent is the volume r...

preparation example 1

[0188] Preparation 1: 2-(N-(2,4-dimethoxybenzyl)-N-(prop-2-ynyl)amino)ethanol (I-1)

[0189]

[0190] Dissolve 3-chloropropyne (62.7g, 0.842mol), 2-(2,4-dimethoxybenzylamino)ethanol (148.0g, 0.702mol) in acetonitrile (1500mL), add K 2 CO 3 (176.0 g, 1.276 mol) powder, refluxed overnight. After the reaction was completed, it was filtered, and the filtrate was distilled under reduced pressure. Column chromatography (n-hexane:ethyl acetate=5:1) gave the title compound as a yellow oil (125.8 g, 72%). 1 H NMR (CDCl 3 , 400MHz) δ: 2.23(t, 1H), 2.76(t, 2H), 3.27(d, 2H), 3.62(s, 2H), 3.64(t, 2H), 3.80(s, 6H), 6.41-6.45 (m, 2H), 7.14(s, 1H).

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Abstract

The invention provides piperazinoltriazole derivatives, in particular dipeptidyl peptidase IV inhibitors shown by a formula (I) below. The substituents in the formula are defined in the description. The compounds can be used for treating or preventing diseases associated with dipeptidyl peptidase IV, such as diabetes, obesity and hyperlipidemia. The invention also provides methods for preparing the compounds shown by the formula (I), pharmaceutically acceptable salts of the compounds and medicinal compositions and the use of the compounds, the pharmaceutically acceptable salts of the compounds and the medicinal compositions in the preparation of medicaments for treating or preventing diseases associated with dipeptidyl peptidase IV.

Description

technical field [0001] The present invention relates to a new type of dipeptidyl peptidase IV (Dipeptidyl peptidases, DPP-IV) inhibitor, its preparation method and its use in the preparation and treatment of DPP-IV related disease medicines, especially the preparation and treatment of diabetes, obesity, hyperlipidemia application in medicine. Background technique [0002] Type II diabetes is a common chronic disease characterized by hyperglycemia, and its occurrence is accompanied by insulin resistance in peripheral tissues, a relative decrease in insulin secretion in the body, and an increase in hepatic gluconeogenesis [Exp.Opin.Ther.Patents , 2003, 13(4): 99-51]. Existing drug treatment can't fundamentally solve this problem, therefore, people are looking for new therapeutic drugs, and many new therapeutic targets are being researched, among which dipeptidyl peptidylase IV (DPP-IV) is the target The achievements in drug research are particularly outstanding [Medicinal Re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/4985A61K31/506A61P3/10A61P3/04A61P3/06
CPCY02P20/55
Inventor 卢鹏赵传生朱明杰何宝林於万松史慧敏陈义朗
Owner SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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