NOVEL 4-AMINOPYRAZOLO[3,4-d]PYRIMIDINYLAZABICYCLO DERIVATIVES AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME

A technology of amino and compound, applied in the field of pharmaceutical composition containing the derivative

Active Publication Date: 2019-01-04
DAEWOONG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, developed BTK inhibitors show inhibitory activity against BTK as well as various other tyrosine kinases such as EGFR (Epidermal Growth Factor Receptor) and ITK, whereby they show side effects such as skin rash, diarrhea, arthralgia, Myalgia, atrial fibrillation, ecchymosis, and major bleeding (see, Byrd JC et al, N Engl J Med, 2013; 369:1278-9; Byrd JC et al, N Engl J Med, 2014; 371:213-23and O' Brien S et al., Lancet Oncol, 2014; 15:48-58)

Method used

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  • NOVEL 4-AMINOPYRAZOLO[3,4-d]PYRIMIDINYLAZABICYCLO DERIVATIVES AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
  • NOVEL 4-AMINOPYRAZOLO[3,4-d]PYRIMIDINYLAZABICYCLO DERIVATIVES AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
  • NOVEL 4-AMINOPYRAZOLO[3,4-d]PYRIMIDINYLAZABICYCLO DERIVATIVES AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0219] Example 1: Preparation of 1-(6-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-aza Bicyclo[2.2.1]hept-2-yl)prop-2-en-1-one

[0220] Step 1-1: Preparation of tert-butyl 6-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-azabicyclo[2.2.1] Heptane-2-carboxylate

[0221]

[0222]Tert-butyl 6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.0 g, 4.7 mmol) and triphenylphosphine (1.2 g, 4.7 mmol) were dissolved in tetrahydrofuran (18.0 mL), to which diisopropyl azodicarboxylate (920 μL, 4.7 mmol) was slowly added. After stirring the reaction solution for 5 minutes, 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (820 mg, 3.1 mmol) was added and the mixture was heated for 5 minutes until all remaining in the reaction The solid dissolved and was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure. The obtained residue was recrystallized from dichloromethane to obtain the title co...

Embodiment 2

[0233] Example 2: Preparation of 1-(6-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-aza Bicyclo[2.2.1]hept-2-yl)prop-2-yn-1-one

[0234]

[0235] In addition to using the 1-(2-azabicyclo[2.2.1]hept-6-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4 -d] Except pyrimidin-4-amine (60 mg, 0.15 mmol) and propionyl chloride (15 μL, 0.17 mmol), the title compound (45 mg, yield: 66% ).

[0236] 1 H NMR (500MHz, CDCl 3 ):8.32-8.36(m,1H),7.62-7.64(m,2H),7.37-7.40(m,2H),7.07-7.19(m,5H),5.75(s,2H),5.22-5.24(m ,1H),4.71-4.86(m,1H),3.41-3.65(m,1H),3.24-3.38(m,1H),3.01-3.03(m,1H),2.87(s,1H),2.31-2.62 (m,2H), 2.03-2.20(m,1H), 1.72-1.77(m,1H).

Embodiment 3

[0237] Example 3: Preparation of (E)-1-(6-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)- 2-Azabicyclo[2.2.1]hept-2-yl)but-2-en-1-one

[0238]

[0239] In addition to using the 1-(2-azabicyclo[2.2.1]hept-6-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4 -d] The title compound (45 mg, yielding rate: 70%).

[0240] 1 H NMR (500MHz, CDCl 3 ):8.30-8.39(m,1H),7.63-7.65(m,2H),7.37-7.40(m,2H),7.13-7.9(m,5H),6.98-7.09(m,1H),6.05-6.56 (m,1H),5.77(s,2H),5.03-5.19(m,1H),4.51-4.91(m,1H),3.45-3.51(m,1H),3.20-3.31(m,1H),2.51 -2.84 (m, 2H), 2.25-2.47 (m, 1H), 2.15-2.23 (m, 1H), 2.09 (s, 3H), 1.88-1.93 (m, 1H).

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Abstract

The present invention relates to 4-aminopyrazolo[3,4-d]pyrimidinylazabicyclo derivatives and pharmaceutical compositions containing the same, wherein the 4-aminopyrazolo[3,4-d]pyrimidinylazabicyclo derivatives and pharmaceutical compositions containing them not only have BTK inhibitory activity but also has remarkably high selectivity for the inhibitory activity of BTK vs. ITK, and thereby can beusefully used for the prevention or treatment of autoimmune diseases or cancers as BTK inhibitors.

Description

technical field [0001] The present invention relates to a novel 4-aminopyrazolo[3,4-d]pyrimidinyl azabicyclic derivative useful as a Bruton's tyrosine kinase (BTK) inhibitor, and to The pharmaceutical composition of the substance. Background technique [0002] BTK (Bruton's tyrosine kinase) and ITK (interleukin-2 tyrosine kinase), RLK (resting lymphocyte kinase) and BMX (X chromosome bone marrow tyrosine kinase gene) are TEC family tyrosine kinases amino acid kinase, and BTK acts as a regulator of early B cell development as well as mature B cell activation, signaling, and survival. [0003] B cells signal through the B cell receptor (BCR), which recognizes antigens attached to the surface of antigen-presenting cells and is activated into mature antibody-producing cells. However, aberrant signaling through the BCR leads to abnormal B cell proliferation and formation of pathological autoantibodies, which can induce cancer, autoimmune and / or inflammatory diseases. [0004] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D451/02A61K31/519A61K31/46
CPCC07D519/00C07D487/04A61P35/00C07D451/02A61K31/519A61K31/46
Inventor 尹然贞朴贞恩朴蓮沈旻俊房极赞朴埈奭
Owner DAEWOONG PHARM CO LTD
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