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Cyclic dinucleotide compound, its preparation method and application

A compound, independent technology, applied in the field of nucleoside analogs, which can solve the problems of intractable effect, loss of activity, low permeability, etc.

Active Publication Date: 2021-08-31
上海弘翊生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] However, natural CDN molecules are not suitable for clinical development. On the one hand, they are easily hydrolyzed in vivo and lose their activity. On the other hand, they are difficult to enter cells to produce pharmacological effects due to their very low permeability. Modifications to obtain more druggable compounds

Method used

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  • Cyclic dinucleotide compound, its preparation method and application
  • Cyclic dinucleotide compound, its preparation method and application
  • Cyclic dinucleotide compound, its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0619]

[0620] The first step: (2R,3S,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-fluoro-2-(2-iso Butyrylamino-6-oxo-1H-purin-9(6H)-yl)tetrahydrofuran-3-yl(2-cyanoethyl)phosphonate (C1-1)

[0621] To (2R,3S,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-fluoro-2-(2-isobutyrylamino -6-Oxo-1H-purin-9(6H)-yl)tetrahydrofuran-3-yl(2-cyanoethyl)diisopropylphosphoramidite (3g, 3.5mmol) in ACN (15mL) Water (0.126 mL, 7 mmol) and 2,2,2-trifluoroacetic acid pyridinium salt (0.811 mg, 4.2 mmol) were added to the solution. The resulting mixture was stirred at room temperature and the progress of the reaction was monitored by LCMS / TLC. After the phosphoramidite was consumed, the reaction mixture containing the product was used in the next step without purification. LCMS (ES, m / z): 775.3 [M+H] +

[0622] The second step: (2R,3S,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-fluoro-2-(2-iso Butyrylamino-6-oxo-1H-purin-9(6H)-yl)tetrahydrofuran-3-ylph...

Embodiment 2-29

[0641] Examples 2 to 29 were prepared according to a method similar to that described in Example 1 above, using the corresponding intermediates (protected nucleosides) in the table below to prepare (2-cyanoethyl)diisopropylphosphoramidites P2-i, (2-cyanoethyl)diisopropylphosphoramidite P1-i prepared from the corresponding methylenecyclopentyl nucleoside analog by oxidation, decyanoethylation, and deprotection Coupling, and then through oxidation, deprotection and ring closure, reoxidation, removal of all protecting groups, salt formation and other steps to obtain the final product;

[0642]

[0643]

[0644]

[0645]

Embodiment 30

[0647]

[0648] The first step: adenosine phosphoramidite P1-1 (17.7g, 20mmol) was dissolved in ACN (200mL) solution. Water (0.72 mL, 40 mmol) and pyridine·TFA (4.64 g, 24 mmol) were added to the solution, and the resulting mixture was stirred at room temperature for 25 minutes. Tert-butylamine was then added, the solution was stirred for 15 minutes, and the solvent was removed in vacuo. Dissolve the residue in 3% DCA in CH 2 Cl 2 A mixture of the solution (150 mL) and water (3.6 mL) was stirred for 20 minutes. The reaction was quenched with MeOH and pyridine. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography using CH 2 Cl 2 / EtOH / MeOH (80 / 15 / 5) as eluent afforded C2-1 (7.15 g; 80% yield). LC-MS: tR=4.92min, m / z=448[M+H] + , m / z=446[M-H] - .

[0649] The second step: in the molecular sieve In the presence of the compound inosine phosphoramidite (7.72g, 10mmol) was added to C2-1 (2.24g...

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Abstract

The invention discloses a cyclic dinucleotide compound, its preparation method and application, in particular to a compound represented by formula (I), its pharmaceutically acceptable salt, its preparation method and its preparation for treatment and / or application in medicine for preventing diseases related to activation of STING protein or application as vaccine adjuvant. The diseases related to activation of STING protein include viral infection, bacterial infection, cancer, immune system-related diseases and the like.

Description

technical field [0001] The present invention relates to nucleoside analogs, in particular to a class of cyclic dinucleotide compounds, a preparation method thereof, a pharmaceutical composition comprising said compound, and a method for preparing a STING (stimulator of interferon gene) regulator thereof Use and use for preparing medicines for treating infectious diseases (especially hepatitis B), autoimmune diseases, cancer, precancerous syndrome and as a vaccine adjuvant. [0002] Background of the invention [0003] Hepatitis B refers to liver cell necrosis and inflammation caused by hepatitis B virus (HBV) infection, which can be divided into acute hepatitis and chronic hepatitis, and can cause a series of complications, such as liver Failure, cirrhosis and hepatocellular carcinoma (HCC). Among them, chronic hepatitis B (CHB) refers to being able to detect hepatitis B surface antigen (hepatitisB surface antigen, HBsAg) and / or HBVDNA positive for at least 6 consecutive mon...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/11C07H19/10C07H1/00C07F9/6571C07F9/6578A61K31/7064A61K31/7076A61K31/708A61K31/675A61P35/00A61P35/02
CPCC07F9/6571C07F9/657136C07F9/65746C07F9/6578C07H1/00C07H19/10C07H19/11Y02P20/55Y02A50/30
Inventor 吴荣光易德武
Owner 上海弘翊生物科技有限公司
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