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Triazolotriazine derivatives as a2a receptor antagonists

A triazolo and solvate technology, which is applied in the field of triazolotriazine derivatives, can solve problems such as ineffective compensation of tissue damage

Active Publication Date: 2020-04-21
ZHEJIANG VIMGREEN PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In particular, it is worth emphasizing that other inflammatory control mechanisms cannot effectively compensate for the tissue damage caused by the blockage of A2AR signaling. Therefore, A2AR signaling is a very critical non-redundant negative feedback signal control mechanism of immune response (Computational and Structural Biotechnology Journal. 2015, 13, 265–272; Cancer Immunol. Immunother. 2012, 61, 917–26)

Method used

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  • Triazolotriazine derivatives as a2a receptor antagonists
  • Triazolotriazine derivatives as a2a receptor antagonists
  • Triazolotriazine derivatives as a2a receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] 2-(Furan-2-carboxamido)guanidine

[0080]

[0081] 2-Furohydrazide (37.80 g, 300 mmol), S-methylisothiourea sulfate (41.70 g, 150 mmol) were dissolved in NaOH aqueous solution (2%, 1.2 L), and stirred at room temperature for 72 h. After the reaction was completed, filter with suction, wash the filter cake twice with ice water, and dry it for the next step (25.25 g, 51.00% yield). 1 H NMR (500MHz, DMSO-d6) δ: 10.95(s, 1H), 7.56(s, 1H), 6.91(d, J=91.9Hz, 4H), 6.64(s, 1H), 6.45(s, 1H) .

Embodiment 2

[0083] 3-(furan-2-yl)-1H-1,2,4-triazol-5-amine

[0084]

[0085] 2-(Furan-2-carboxamido)guanidine (23.20 g, 138 mmol) was dissolved in DMF (464 mL), heated to 125° C. and stirred overnight. After cooling to room temperature, the solvent was removed under reduced pressure, DCM (200 mL) was added to the residue, and stirred for 30 min. After suction filtration, the filter cake was washed with DCM (20 mL×2), and dried to obtain the target product as a yellow solid (17.37 g, 84.00% yield). 1 H NMR (500MHz, DMSO-d6) δ: 12.13(s, 1H), 7.69(s, 1H), 6.69(d, J=1.8Hz, 1H), 6.54(dd, J=3.0, 1.7Hz, 1H) , 6.03(s, 2H).

Embodiment 2A

[0087] 3-(furan-2-yl)-1H-1,2,4-triazol-5-amine

[0088]

[0089] Sodium methoxide (171.4 g, 3172 mol) and aminoguanidine hydrochloride (175.3 g, 1586 mmol) were added into methanol (1200 mL) at 0° C. and stirred. Methyl furoate (100 g, 793 mmol) was dissolved in methanol (300 mL), and added dropwise to the above reaction solution. The reaction solution was heated to 75°C and stirred overnight. The reaction solution was filtered, and the filtrate was dissolved in water (50 mL) after being concentrated to dryness in vacuo. The pH was adjusted to 4 with 3N hydrochloric acid solution, and the precipitated solid was filtered and dried to obtain the title yellow solid compound (69.2 g, yield 58.1%). The structure was confirmed by H NMR detection. 1 H NMR (500 MHz, DMSO-d6) δ: 12.44 (s, 1H), 7.69 (d, 1H), 6.70 (d, 1H), 6.54 (dd, 1H), 6.03 (s, 2H).

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Abstract

The present invention provides triazolotriazine derivatives of formula (1) as A2A receptor antagonists. Compounds of formula (1) and pharmaceutical compositions including the compounds can be used forthe treatment of disorders related to A2A receptor hyperfunctioning, such as certain types of cancers. The compounds of formula (1) and the methods of preparing the compounds are disclosed in the invention.

Description

technical field [0001] The present invention relates to triazolotriazine derivatives useful as A2A receptor antagonists. The present invention also relates to the preparation methods of these compounds and their pharmaceutical compositions. The compound and its pharmaceutical composition can be used to treat or prevent diseases related to abnormally high activity of A2A receptors, such as immune-tolerant cancers mediated by A2A receptors and related abnormal proliferation of cells. Background technique [0002] Adenosine is a naturally occurring purine nucleoside that modulates various physiological functions. Adenosine binds to purinergic receptors that are members of the G protein-coupled receptor (GPCR) family, including the adenosine A1, A2A, A2B, and A3 receptors (A1R, A2AR, A2BR, and A3R). Among them, the adenosine A2A receptor (A2AR) can couple to adenylate cyclase in a stimulating manner, thereby inducing the signaling pathway of the canonical second messenger, inc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/53A61P35/00
CPCC07D487/04A61P35/00C07D519/00A61K31/53
Inventor 孙三兴赵龙胡崇波陈正树叶进启
Owner ZHEJIANG VIMGREEN PHARMA LTD