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Thiazolopyridine derivatives as adenosine receptor antagonists

A technology of derivatives and solvates, applied in the field of thiazolopyridine derivatives, can solve problems such as no inhibition activity

Pending Publication Date: 2022-01-14
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these compounds did not show significant A 2B Inhibitory activity, while only showing good pharmacokinetic properties, but not in mice (animal model of cancer)

Method used

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  • Thiazolopyridine derivatives as adenosine receptor antagonists
  • Thiazolopyridine derivatives as adenosine receptor antagonists
  • Thiazolopyridine derivatives as adenosine receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0242] Example 1: Examples of Compounds of the Invention

[0243] The invention relates in particular to the compounds of Table 2 and their physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including their mixtures in all proportions.

[0244] Table 2 - Examples of Compounds of the Invention

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282] Table 3 - NMR Spectrum of Compounds of the Invention

[0283] The numbers stated here correspond to the compound numbers disclosed in Table 2.

[0284]

[0285]

[0286]

[0287]

[0288]

[028...

Embodiment 2

[0305] Embodiment 2: the preparation and analysis method of the compound of the present invention

[0306] All solvents used were commercially available and used without further purification. The reaction is usually performed under an inert atmosphere of nitrogen using anhydrous solvents. Flash column chromatography is usually performed with silica gel 60 (0.035-0.070mm particle size).

[0307] All NMR experiments were recorded on either a Bruker Mercury Plus 400 NMR spectrometer equipped with a Bruker 400 BBFO probe at 400 MHz or at 300 MHz on a Bruker Mercury Plus 300 NMR spectrometer equipped with a Bruker 300 BBFO probe. All deuterated solvents typically contain 0.03% to 0.05% v / v tetramethylsilane, which is used as a reference signal (for 1 H and 13 C both, set at δ = 0.00).

[0308] LC-MS analysis was performed on a SHIMADZU LC-MS machine consisting of UFLC 20-AD system and LCMS 2020 MS detector. The column used was Shimpack XR-ODS, 2.2 μm, 3.0x50mm. A linear gradi...

Embodiment 3

[0365] Example 3: Test the inhibitory activity of the compounds of the present invention on human adenosine receptors in recombinant cells

[0366] Person A 2A 、A 2B 、A 1 and A 3 Functional activity of the receptor was determined by quantification of cAMP, the second messenger of the adenosine receptor. For this purpose, add the expression A 2A or A 2B Recipient's recombinant HEK293 cells (both Gs coupled to 394-well microtiter plates), test compound and agonist (NECA). After incubation for 15 min, HTRF reagent (cAMP dynamic 2, Cis Bio) was added, and the cellular cAMP level was measured with an ENVISION (Perkin Elmer) plate reader.

[0367] for person A 1 and A 3 receptor, using the expression A 1 or A 3 Recipient of recombinant CHO cells. As both receptors are coupled to the Gi protein, the assay protocol was adjusted:

[0368] Cells were seeded to 384-well plates, and forskolin, test compound and agonist (for A 1 -Acceptor uses CPA, for A 3 - acceptors use IB-...

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PUM

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Abstract

The invention relates to thiazolopyridine derivatives which fall under the general formula I, (I) and the use of the compounds of the present invention for the treatment and / or prevention of hyperproliferative or infectious diseases and disorders in mammals, especially humans, and pharmaceutical compositions containing such compound.

Description

[0001] The present invention relates to thiazolopyridine derivatives belonging to the general formula I, [0002] [0003] and the use of compounds of the invention for the treatment and / or prevention of hyperproliferative or infectious diseases and disorders in mammals, especially humans, and pharmaceutical compositions comprising such compounds. [0004] Background of the invention [0005] Adenosine is a ubiquitous regulator of a variety of physiological activities, particularly within the cardiovascular, nervous and immune systems. Adenosine is structurally and metabolically related to the biologically active nucleotides adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and cyclic adenosine monophosphate (cAMP), and is associated with biochemical methylation It is related to the agent S-adenosyl-L-methionine (SAM), and is structurally related to the coenzymes NAD, FAD, and coenzyme A, as well as to RNA. [0006] Adenosine modulate...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04C07D519/00A61P35/00A61K31/437
CPCC07D513/04C07D519/00A61P35/00A61K45/06A61K9/0019A61K9/08A61K47/02Y02A50/30A61K31/4365A61K31/5377A61P31/00
Inventor E-M·坦策尔克劳埃尔K·席曼A·克雷斯波
Owner MERCK PATENT GMBH
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