Purine compound containing bicyclic group, and preparation method thereof

A technology of compound and ring group, applied in the field of purine compound containing bicyclic group and its preparation

Inactive Publication Date: 2019-08-06
GUANGZHOU ESA BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, DOT1L inhibitors are still in the early stage of research and development, and there are no approved drugs. The present invention provides drugs for the treatment of various tumors caused by the abnormal activity of DOT1L, which has great practical significance

Method used

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  • Purine compound containing bicyclic group, and preparation method thereof
  • Purine compound containing bicyclic group, and preparation method thereof
  • Purine compound containing bicyclic group, and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] 9-[(3aR,4R,6R,6aR)-6-([[6-(5-tert-butyl-1H-1,3-benzimidazol-2-yl)spiro[3.3]heptane-2- Base](propan-2-yl)amino]methyl)-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxolane-4 -yl]-9H-purin-6-amine (1):

[0093]

[0094] Its preparation reaction route is as follows Figure 10 As shown, the method is as follows:

[0095] The first step: [(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-methyl-tetrahydro-2H-furo[3,4- d] Synthesis of [1,3]dioxolan-4-yl]methanol (I-2):

[0096] To (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol (adenosine, I-1,50.0g, 187mmol) in acetone (1L) solution, add p-toluenesulfonic acid (96.6g, 561mmol) and triethyl orthoformate (83.1g, 561mmol) successively, the resulting solution was stirred at room temperature 14 hours, then basified to pH≈8 with saturated aqueous potassium carbonate solution. The reaction mixture was filtered and the filtrate was further concentrated in vacuo until a white solid appeared. The solid ...

Embodiment 2

[0109] Examples 2a / b, 2a and 2b

[0110] (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-({[(2R,6R) / (2R,6S)-6-(5-tert-butyl Base-1H-1,3-benzimidazol-2-yl)spiro[3.3]heptane-2-yl](propan-2-yl)amino}methyl)oxolane-3,4-ol (2a / b), (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-({[(2R,6R)-6-(5-tert-butyl Base-1H-1,3-benzimidazol-2-yl)spiro[3.3]heptane-2-yl](propan-2-yl)amino}methyl)oxolane-3,4-ol (2a) and (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-({[(2R,6S)-6-(5-tert-butyl- 1H-1,3-benzimidazol-2-yl)spiro[3.3]heptane-2-yl](propan-2-yl)amino}methyl)oxolane-3,4-ol (2b ):

[0111]

[0112] Its preparation reaction scheme is as follows Figure 11 As shown, the method is as follows:

[0113] At 0°C, 9-[(3aR,4R,6R,6aR)-6-([[6-(5-tert-butyl-1H-1,3-benzimidazol-2-yl)spiro[3.3] Heptane-2-yl](propan-2-yl)amino]methyl)-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxa Cyclopentan-4-yl]-9H-purin-6-amine (Example 1, 700 mg, 1.14 mmol) was dissolved in 2.5 N hydrogen chloride in methanol (15 mL), a...

Embodiment 3

[0116] Examples 3a / b, 3a and 3b

[0117] (2R,3R,4S,5R)-2-(6-Amino-9H-purin-9-yl)-(S / R)-5-({[(2R,6R)-6-(5-tert-butyl Base-1H-1,3-benzimidazol-2-yl)spiro[3.3]heptane-2-yl](propan-2-yl)nitroso}methyl)oxolane-3,4 -alcohol (3a / b), (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-(S)-5-({[(2R,6R)-6 -(5-tert-butyl-1H-1,3-benzimidazol-2-yl)spiro[3.3]heptane-2-yl](propan-2-yl)nitroso}methyl)oxetane Pentan-3,4-ol (3a) and (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-(R)-5-({[(2R, 6R)-6-(5-tert-butyl-1H-1,3-benzimidazol-2-yl)spiro[3.3]heptane-2-yl](propan-2-yl)nitroso}methyl ) oxolane-3,4-ol (3b):

[0118]

[0119] Its preparation reaction scheme is as follows Figure 12 As shown, the method is as follows:

[0120] To (2R,3R,4S,5R)-2-(6-amino-9H-purin-9-yl)-5-({[(2R,6R)-6-(5-tert-butyl-1H-1 ,3-benzimidazol-2-yl)spiro[3.3]heptane-2-yl](propan-2-yl)amino}methyl)oxolane-3,4-ol (2a, 20mg, 0.03mmol) in dioxane / water (2mL / 0.6mL) solution was added 3-chloroperoxybenzoic acid (mCPBA, 6mg), the resu...

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Abstract

The invention provides a purine compound containing a bicyclic group which is shown as a formula (I) and a formula (II) and a pharmaceutically acceptable salt, and a preparation method thereof. The compound is an inhibitor of histone methyltransferase DOT1L, and can be used for treating diseases caused by the abnormity of enzyme activity, such as tumor.

Description

technical field [0001] The invention relates to a purine compound containing a bicyclic group, a pharmaceutically acceptable salt thereof and a preparation method thereof. Background technique [0002] DOT1L (Disruptor of telomeric silencing 1-like) is a histone methyltransferase (Histone methyltransferase), its function is to promote the methylation of Lys79 (lysine 79, H3K79) in histone H3 molecule. DOT1L plays an important role in gene regulation processes such as telomere silencing and transcription elongation, and its molecular mechanism is through binding with RNA polymerase II (RNA polymerase II) and E3 in histone H2B molecules Genetics and epigenetics regulatory molecules such as pantothenate ligase (E3ubiquitin ligase ofhistone H2B) interact to achieve this. In addition, DOT1L is also involved in the regulation of DNA damage and cell cycle. DOT1L plays an important role in the pathogenesis of tumors, such as breast cancer, head and neck cancer, neuroblastoma, brai...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H1/00C07H19/16C07H19/167A61K31/7076A61P35/00
CPCC07H1/00C07H19/16C07H19/167A61P35/00Y02P20/55
Inventor 李静荣李安虎
Owner GUANGZHOU ESA BIOTECH
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