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4-aminopyrimidine derivatives as adenosine a2a receptor antagonists and uses thereof

A receptor antagonist and aminopyrimidine technology, applied in the field of 4-aminopyrimidine derivatives, can solve the problems of poor pharmacokinetic characteristics, high plasma clearance rate, and short half-life of pyrazole compounds, and achieve good pharmacokinetics The effect of academic characteristics

Active Publication Date: 2020-07-31
SHANGHAI JOYU PHARMATECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

adenosine A 2A The receptor has a better antagonistic effect, which is manifested by its ability to A 2A The affinity is stronger, but its for A 1 The selectivity is also very low, resulting in A 1 In the presence of the receptor, its response to A 2A Receptor selectivity is low
Simultaneously, the pharmacokinetic characteristics of the pyrazole compounds described in this invention are relatively poor, the plasma clearance rate is relatively high, and the half-life in rats is also very short

Method used

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  • 4-aminopyrimidine derivatives as adenosine a2a receptor antagonists and uses thereof
  • 4-aminopyrimidine derivatives as adenosine a2a receptor antagonists and uses thereof
  • 4-aminopyrimidine derivatives as adenosine a2a receptor antagonists and uses thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] The preparation of compound (1), its structural formula is as follows:

[0073]

[0074] The preparation of compound (1) is implemented according to the above-mentioned synthetic route 1:

[0075] The first step, prepare intermediate (A)

[0076] Suspend 4-amino-2,6-dichloropyrimidine (DCAP, 4g, 24.4mmol) in acetic anhydride (80mL, 860mmol), and heat to reflux under stirring for 4 hours. After the reaction solution was cooled, it was concentrated in vacuo, and the residual acetic anhydride was distilled off after adding toluene. The residue was dissolved in ethyl acetate and water, and 10% NaHCO 3 solution until the pH of the solution is 7. The organic layer was washed with saturated brine. After the solvent was recovered, the residue was dissolved in acetic anhydride (40 mL), stirred at 0-5°C for 2 hours, the precipitate was collected by filtration, and dried under vacuum at 40°C to obtain intermediate (A). MS m / z(ESI):206.0[M+1] + .

[0077] Second step, prep...

Embodiment 2

[0088] The preparation of compound (2), its structural formula is as follows:

[0089]

[0090] The preparation of compound (2) is carried out according to the synthetic route 1, and the specific method refers to the example 1. In the 6th step reaction, replace NBS (N-bromosuccinimide) with NCS (N-chlorosuccinimide) for chlorination to obtain compound (2). MS m / z(ESI):263.0[M+1] + , 1 HNMR(400MHz,DMSO-d6) δ8.53(d,1H),8.26(s,1H),7.82(d,1H),7.49(s,1H),7.54(s,2H),6.55(dd,1H ).

Embodiment 3

[0092] The preparation of compound (3), its structural formula is as follows:

[0093]

[0094] Compound (3) was prepared according to Synthetic Route 1. MS m / z(ESI):247.0[M+1] + , 1 HNMR (400MHz,DMSO-d6)δ8.51(d,1H),8.27(s,1H),7.83(d,1H),7.48(s,1H), 7.55(s,2H),6.54(dd,1H ).

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Abstract

Disclosed is a 4-aminopyrimidine derivative used as an adenosine A2A receptor antagonist, having general structural formula (I). R1 is selected from halogen, cyano group, or trifluoromethyl; R2 is selected from pyrazolyl, pyrrolidyl, or pyrazolyl or pyrrolidyl substituted by one or more halogens or C1-3 alkyl groups; R3 is selected from oxazolyl, oxadiazole group, triazole group, or oxazolyl substituted by one or more halogens or C1-3 alkyl groups. The 4-aminopyrimidine derivative provided by the present invention has an obvious antagonistic action on a human-derived adenosine A2A receptor, and can be applied to compositions or combination products for treating diseases or pathological symptoms having responses to the A2A antagonistic action, in particular for treating neurodegenerative disease, extrapyramidal syndrome, depression, hyperkinetic syndrome, sleep disorder, anxiety disorder, diabetes, tumor and other diseases.

Description

technical field [0001] The invention relates to the fields of medicine and organic chemistry, in particular to a 2A 4-aminopyrimidine derivatives of receptor antagonists and uses thereof. Background technique [0002] As an endogenous regulator of most physiological functions in the central (CNS) and peripheral nervous system, adenosine is widely distributed in multiple tissues and organs such as the nervous system, cardiovascular system, digestive system, and respiratory system, and plays a role in regulating various important functions. The role of physiological processes. It exerts its biological effects through a class of membrane-specific receptors, which belong to the superfamily of G protein-coupled receptors. At present, four adenosine receptor subtypes have been identified, which are: A 1 、A 2A 、A 2B and A 3 . where A 1 and A 2A It is a highly expressed receptor, which can produce effects at low levels of adenosine concentration under physiological condition...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/14C07D413/04C07D403/14A61K31/506A61P25/28A61P25/00A61P25/24A61P25/22A61P25/14A61P25/20A61P3/10A61P35/00
CPCC07D403/14C07D413/04C07D413/14
Inventor 钟燕曹西蓉王永临
Owner SHANGHAI JOYU PHARMATECH LTD
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