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Polysubstituted purine compound as well as preparation method and application thereof

A compound and purine technology, applied in the field of polysubstituted purine compounds and their preparation, to achieve the effects of low toxicity, inhibition of cancer proliferation and metastasis, and resistance to drug resistance

Active Publication Date: 2021-10-26
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, no small molecule inhibitors directly acting on ADAR1 have been reported so far.

Method used

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  • Polysubstituted purine compound as well as preparation method and application thereof
  • Polysubstituted purine compound as well as preparation method and application thereof
  • Polysubstituted purine compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Example 1: (2R, 3R, 4S, 5S)-2-(6-amino-2-fluoro-9H-purin-9-yl)-5-(chloromethyl)tetrahydrofuran-3,4-diol ( I-1) synthesis:

[0077]

[0078] At 0°C, 2-fluoroadenosine A-1 (5.70g, 20mmol) was dissolved in acetonitrile (80mL), pyridine (3.22mL, 40mmol) was added, and thionyl chloride (7.25mL , 100mmol), stirred for 4h and raised to room temperature, reacted overnight, TLC monitored that the raw materials were completely consumed, and the solvent was removed by rotary evaporation under reduced pressure, and methanol (120mL), water (12mL), and ammonia water (24mL) were added again, stirred for 0.5h, and reduced pressure Concentrated by rotary evaporation, the product was precipitated in the water phase, filtered to obtain a filter cake, redissolved in a small amount of methanol at 60°C, added dropwise with dichloromethane, cooled to precipitate a solid and suction filtered to obtain a filter cake, washed with cold methanol to obtain the product I-1 as a white solid (5.45 ...

Embodiment 2

[0079] Example 2: 9-((3aR,4R,6R,6aR)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuran[3, Synthesis of 4-d][1,3]bisoxazol-4-yl)-2-fluoro-9H-purin-6-amine (I-2):

[0080]

[0081] Step 1, 2-fluoroadenosine (1.48g, 5mmol) was dissolved in anhydrous acetone (200mL) to form a suspension, anhydrous p-toluenesulfonic acid (4.31g, 25mmol) was added to form a clear solution, and dimethyl Oxypropane (1.04g, 10mmol), after the mixture was stirred at room temperature under nitrogen atmosphere for 4h, cold saturated NaHCO 3 The solution (100 mL) was added to the above mixture; the volatiles were removed under reduced pressure and the residue was dried; the resulting solid was dissolved in acetone (400 mL), stirred for 1 h, then filtered; the volatiles were removed and the crude product was subjected to column chromatography Purified by method to obtain white solid A2 (1.50g, 95%); 1 H NMR (400MHz, DMSO-d 6 )δ8.33(s,1H),7.92(s,2H),6.03(d,J=2.9Hz,1H),5.29(dd,J=6.2,2...

Embodiment 3

[0083] Example 3: ((3aR,4R,6R,6aR)-6-(6-amino-2-fluoro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuran[3,4-d] Synthesis of [1,3]bisoxazol-4-yl)methyl acetate (I-3):

[0084] A2 (0.66g, 2mmol) was dissolved in 10mL DMF, triethylamine (0.83mL, 6mmol), acetic anhydride (0.21mL, 2.2mmol) and DMAP (0.05g, 0.4mmol) were added and reacted at room temperature overnight. TLC monitoring raw material consumption is complete, saturated NH 4 Cl aqueous solution (5 mL) quenched the reaction, the mixture was extracted with ethyl acetate (3 × 30 mL), the combined organic layers were washed with saturated aqueous NaCl solution, anhydrous NaCl 2 SO 4 It was dried, filtered and concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound I-3 (0.66 g, 90%). 1 HNMR (400MHz, DMSO-d 6 )δ8.28(s,1H),7.92(d,J=26.2Hz,2H),6.11(d,J=2.4Hz,1H),5.41(dd,J=6.2,2.5Hz,1H),5.00( dd,J=6.2,3.3Hz,1H),4.45–4.30(m,1H),4.30–4.08(m,2H),1.96(s,3H),1.54(s,3H),1.34(s,3H) .

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Abstract

The invention discloses a polysubstituted purine compound as shown in a formula (I), pharmaceutically acceptable salts thereof, and a preparation method and application of the polysubstituted purine compound. The invention also discloses an obvious inhibition effect of the compound on RNA adenosine deaminase 1 (ADAR1), and the compound can be used for preventing and / or treating cancers or tumor related diseases caused by abnormal enzyme activity, and especially for treating diseases such as prostate cancer, leukemia, breast cancer, multiple myeloma, lung cancer, stomach cancer, ovarian cancer, colon cancer, liver cancer, pancreatic cancer and human glioma.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a multi-substituted purine compound and its preparation method and application. Background technique [0002] Adenosine deaminases acting on RNA enzymes (ADARs) are members of the RNA editing enzyme family, they can act on adenine nucleotides at specific sites on RNA, deamination occurs, and the It is converted into inosine nucleotides, which are mistakenly recognized as guanine nucleotides in organisms and participate in a series of biological processes such as transcription and translation. ADARs include three subtypes, ADAR1, ADAR2, and ADAR3, all of which contain two to three N-terminal double-stranded RNA (double stranded RNA, dsRNA) binding domains and a C-terminal conserved deaminase catalytic domain. ADAR1 and ADAR2 are distributed and expressed in many tissues and organs of the human body, and their structures and functions are currently being studied more. ADAR3 has...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07F9/6561C07H19/167C07H1/00A61K31/675A61K31/7076A61P35/00
CPCC07D487/04C07F9/6561C07H19/167C07H1/00A61P35/00
Inventor 杨鹏王晓李嘉兴朱亚胜闵文剑丁佳雨袁凯
Owner CHINA PHARM UNIV
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