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Pyrazolopyrimidine derivative, preparation method, pharmaceutical composition and application

A technology for pyrazolopyrimidine and derivatives, applied in the field of pyrazolopyrimidine derivatives, which can solve the problems of insufficient biological activity and efficacy, large dosage, and large side effects

Inactive Publication Date: 2016-11-23
ARROMAX PHARMATECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The technical problem to be solved by the present invention is to provide pyrazolopyrimidine derivatives in order to overcome the shortcomings of Bruton's tyrosine kinase inhibitors in the prior art that the biological activity and drug effect are not obvious enough, the dosage is large, and the side effects are large. , preparation method, pharmaceutical composition and use

Method used

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  • Pyrazolopyrimidine derivative, preparation method, pharmaceutical composition and application
  • Pyrazolopyrimidine derivative, preparation method, pharmaceutical composition and application
  • Pyrazolopyrimidine derivative, preparation method, pharmaceutical composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0141] Example 1: (R)-1-[3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine Synthesis of -1-yl]-2-bromoprop-2-en-1-one (compound 1)

[0142]

[0143] Compound 1

[0144] a. Synthesis of (R)-1-Boc-3-(4-amino-3-iodo-1H-pyrazolo[3,4-D]pyrimidin-1-yl)piperidine

[0145]

[0146] 4-Amino-3-iodo-1H-pyrazolo[3,4-D]pyrimidine (10g, 38mmol), (S)-1-Boc-3-hydroxypiperidine (17g, 85mmol), triphenyl Phosphine (20g, 76mmol) was added to a three-necked flask, THF (120ml) was added, the temperature was lowered to 0°C, diisopropyl azodicarboxylate (DIAD) (15.2g, 76mmol) and tetrahydrofuran (THF) (30ml) were added dropwise and mixed solution, the dropwise addition was completed in about 1 h, and slowly rose to room temperature to react overnight. The reaction solution was spin-dried, added water, extracted with ethyl acetate, dried, concentrated and purified by column chromatography to obtain the product (R)-1-Boc-3-(4-amino-3-iodo-1H-pyrazolo[3, 4-D]pyrimidin-...

Embodiment 2

[0160] Example 2: (R)-1-[3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine Synthesis of -1-yl]-2-chloroprop-2-en-1-one (Compound 2)

[0161]

[0162] Compound 2 (72% yield) can be prepared in a similar manner to compound 1, using 2-chloroacrylic acid as a starting material. 1 H-NMR (CDCl 3 , 400MHz, δppm): 8.28(s, 1H), 7.62(d, J=8Hz, 2H), 7.41(t, J=8Hz, 2H), 7.24-7.08(m, 5H), 5.71-5.64(m, 2H),4.98-4.90(m,1H),4.72-4.66(m,0.5H),4.58-4.52(m,0.5H),4.18-4.12(m,0.5H),3.99-3.95(m,0.5H ),3.80-3.78(m,0.5H),3.57-3.52(m,0.5H),3.33-3.28(m,0.5H),2.96-2.90(m,0.5H),2.42-2.25(m,2H) ,2.09-2.01(m,1H),1.85-1.77(m,1H).

Embodiment 3

[0163] Example 3: (R)-1-[3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine Synthesis of -1-yl]-2-fluoroprop-2-en-1-one (Compound 3)

[0164]

[0165] Compound 3 (68% yield) can be prepared in a similar manner to the preparation of compound 1, using 2-fluoroacrylic acid as a starting material. 1 H-NMR (CDCl 3 , 400MHz, δppm): 8.28(s, 1H), 7.62(d, J=8Hz, 2H), 7.41(t, J=8Hz, 2H), 7.24-7.08(m, 5H), 5.71-5.64(m, 2H),4.98-4.90(m,1H),4.72-4.66(m,0.5H),4.58-4.52(m,0.5H),4.18-4.12(m,0.5H),3.99-3.95(m,0.5H ),3.80-3.78(m,0.5H),3.57-3.52(m,0.5H),3.33-3.28(m,0.5H),2.96-2.90(m,0.5H),2.42-2.25(m,2H) ,2.09-2.01(m,1H),1.85-1.77(m,1H).

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Abstract

The invention discloses a pyrazolopyrimidine derivative, a preparation method, a pharmaceutical composition and application. The invention provides the pyrazolopyrimidine derivative as shown in a formula I and stereoisomer or solvate or pharmaceutically acceptable salts or active metabolite or prodrug thereof. The pyrazolopyrimidine derivative as shown in the formula I has good inhibitory activity on Bruton's tyrosine kinase (Btk) and particularly has good in vitro and in vivo inhibitory activity on growth of tumor cells, and a good marketization prospect is achieved. Please see the formula I in the description.

Description

technical field [0001] The present invention specifically relates to pyrazolopyrimidine derivatives, preparation methods, pharmaceutical compositions and uses. Background technique [0002] Bruton's tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, is critical for expression in all hematopoietic cell types except T lymphocytes and natural killer cells signal enzyme. Btk plays a crucial role in the B cell signaling pathway linking cell surface B cell receptor (B-cell receptor, BCR) stimulation to downstream intracellular responses. [0003] Btk is a key regulator of B cell development, activation, signaling and survival (Kurosaki, Curr Op Imm, 2000, 276-281; ​​Schaeffer and Schwartzberg, Curr Op Imm 2000, 282-288). In addition, Btk plays a role in many other hematopoietic cell signaling pathways, such as Toll-like receptor (Tolllike receptor, TLR) and cytokine receptor-mediated TNF-α production in macrophages, immune response in mast cells,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P35/00A61P35/02A61P29/00
CPCC07D487/04
Inventor 洪健许忻乐小勇
Owner ARROMAX PHARMATECH
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