Double-site irreversible Brutons tyrosine kinase inhibitor

A tyrosine kinase and inhibitor technology, applied in the field of dual-site irreversible Bruton's tyrosine kinase inhibitor, anti-tumor application, which can solve the problems of affecting drug efficacy and increasing patient burden.

Active Publication Date: 2015-08-19
HANGZHOU HERTZ PHARMA
View PDF3 Cites 12 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, during the course of administration, ibrutinib is easily metabolized (oxidatively metabolized into dihydroxylated products by metabolic enzymes or attacked and inactivated by other sulfhydryl-containing enzymes, cysteine, glutathione, etc. ) a

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Double-site irreversible Brutons tyrosine kinase inhibitor
  • Double-site irreversible Brutons tyrosine kinase inhibitor
  • Double-site irreversible Brutons tyrosine kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1. Preparation of key intermediate 4a

[0047]

[0048] Step 1. Synthesis of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (compound 2a)

[0049] 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 1) (2.61g, 10mmol), 4-phenoxyphenylboronic acid (3.85g, 18mmol) and potassium phosphate ( 5.375g, 25mmol) were added to the single-necked bottle successively, 1,4-dioxane (40mL) and water (10mL) were added, and under nitrogen protection, triphenylphosphopalladium (1.76g, 1.5mmol) was added, and reflux reaction 24h. After the reaction was completed, cool to room temperature, stir overnight, a yellow precipitate precipitated out, suction filtered, washed with water (50ml*3), and dried for 24 hours to obtain 2.18g of a yellow solid, which was 3-(4-phenoxyphenyl)-1H-pyrazole And[3,4-d]pyrimidin-4-amine (compound 2a), yield 72%.

[0050] Step 2. 3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester...

Embodiment 2

[0054] Embodiment 2. Preparation of key intermediate 4b

[0055]

[0056] Step 1. Synthesis of 3-(4-(4-methoxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (compound 2b)

[0057] Synthetic steps refer to Example 1 step 1. Using a synthetic method similar to compound 2a, compound 2b (2.56g, yield 77% was prepared from 4-(4-methoxyphenoxy)phenylboronic acid (4.39g, 18mmol) ).

[0058] Step 2. 3-(4-Amino-3-(4-(4-methoxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine- Synthesis of tert-butyl 1-formate (compound 3b)

[0059] Synthetic procedures refer to step 2 of Example 1. Compound 3b (1.26 g, yield 35%) was prepared by a method similar to that of compound 3a.

[0060] Step 3. 3-(4-(4-methoxyphenoxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Synthesis of hydrochloride (compound 4b)

[0061] For the synthetic procedure, refer to step 3 of Example 1. Compound 4b was prepared by a method similar to that of compound 4a (0.59, 65% yield, [...

Embodiment 3

[0062] Embodiment 3. Preparation of key intermediate 4c

[0063]

[0064] Step 1. Synthesis of 3-(4-(3-methoxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (compound 2c)

[0065] Synthetic steps refer to Example 1 Step 1. Using a synthetic method similar to compound 2a, compound 2c (2.49g, yield 75% was prepared from 4-(3-methoxyphenoxy)phenylboronic acid (4.39g, 18mmol) ).

[0066] Step 2. 3-(4-Amino-3-(4-(3-methoxyphenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine- Synthesis of 1-tert-butyl formate (compound 3c)

[0067] Synthetic procedures refer to step 2 of Example 1. Compound 3c (1.25 g, yield 35%) was prepared by a method similar to that of compound 3a.

[0068] Step 3. 3-(4-(3-methoxyphenoxy)phenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Synthesis of hydrochloride (compound 4c)

[0069] For the synthetic procedure, refer to Step 3 of Example 1. Compound 4c (0.61 g, yield 68%, [M+H]=453.3) was prepared by a method similar to that o...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention provides a double-site irreversible Brutons tyrosine kinase inhibitor, a drug combination containing the same and application thereof to the anti-tumor field. The compound provided by the invention has an anti-proliferation inhibiting effect to tumor cell stains such as A549, SGC7901, MCF-7, PC-9 and HL-60, and can be applied to drugs for treating solid tumors or blood cancers related to human or animal cell proliferation; the compound provided by the invention has a better pharmacokinetic property and can be applied to treating solid tumors or blood cancers related to human or animal cell proliferation or autoimmune diseases through oral taking; the compound provided by the invention has a double-site response characteristic.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to a double-site irreversible Bruton's tyrosine kinase inhibitor, a pharmaceutical composition containing it and its application in antitumor. Background technique [0002] Small molecule covalent inhibitors, also known as irreversible inhibitors, are a class of inhibitors that irreversibly bind to target protein residues through covalent bonds to exert their biological functions. Covalent inhibitor drugs have made important contributions to human health over the past few decades. Compared with non-covalent inhibitors, covalent inhibitors enhance the affinity with the target by covalently binding with the target protein, which is the fundamental reason for the high biological activity of covalent inhibitors. In recent years, more attention has been paid to covalent inhibitors due to the emergence of resistance to non-covalent targeting antineoplastic drugs, especially a large number of tini...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07D487/04A61K31/519A61P37/00A61P35/00A61P35/02
CPCC07D487/04
Inventor 周星露韩玲戈震刘兴国罗文华刘冠男
Owner HANGZHOU HERTZ PHARMA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap