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BTK (bruton tyrosine kinase) inhibitor and purpose of BTK inhibitor

A technology of solvates and compounds, applied in the field of BTK inhibitors

Inactive Publication Date: 2015-12-16
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no selective BTK inhibitor on the market. The fastest research drug is CC-292, which entered clinical phase II research at the end of October 2013. It serves as an irreversible selective inhibitor of BTK for the treatment of rheumatoid arthritis.

Method used

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  • BTK (bruton tyrosine kinase) inhibitor and purpose of BTK inhibitor
  • BTK (bruton tyrosine kinase) inhibitor and purpose of BTK inhibitor
  • BTK (bruton tyrosine kinase) inhibitor and purpose of BTK inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0161] Example 1: (E)-1-((R)-3-(4-((4-phenoxyphenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl )piperidin-1-yl)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxin[2,3-c]pyrrol-6(3H)-yl)butan-2 -en-1-one

[0162]

[0163] Step 1) Synthesis of N-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine:

[0164] 4-Chloro-1H-pyrazolo[3,4-d]pyrimidine (170 mg, 1.1 mmol) was dissolved in 1,4-dioxane (6 mL) and 4-phenoxyaniline (244 mg, 1.3 mmol) and acetic acid (99 mg, 1.65 mmol), sealed tube at 150 ° C for 12 h, stopped heating, cooled, evaporated the solvent under reduced pressure, and recrystallized (dichloromethane / petroleum ether (V / V)=1 / 20) to obtain Product (145 mg, 43.5%).

[0165] Step 2) (R)-tert-Butyl 3-(4-((4-phenoxyphenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1 - Synthesis of Carboxylate:

[0166] N-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.33 mmol) was dissolved in DMF (5 mL) and tert-butyl 4- Methylsulfonyloxypiperidine-1-carboxylate (184mg,...

Embodiment 2

[0175] Example 2: (R)-1-(3-(4-((4-phenoxyphenyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine- 1-yl)prop-2-en-1-one

[0176]

[0177] Step 1) Synthesis of N-(4-phenoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-4-amine:

[0178] 4-Chloro-1H-pyrazolo[4,3-c]pyridine (1.0 g, 6.5 mmol) was dissolved in n-butanol (30 mL), 4-aminodiphenyl ether (1.27 g, 6.8 mmol) and hydrochloric acid (0.2 mL), and then heated to reflux for about 6 h. After the reaction, the heating was stopped, cooled, the solvent was evaporated under reduced pressure, extracted with dichloromethane (80 mL×3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (V / V)=10 / 1) to obtain the product (1.54 g, 78%).

[0179] Step 2) (R)-tert-Butyl 3-(4-((4-phenoxyphenyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)pip...

Embodiment 3

[0188] Example 3: (R)-1-(3-(4-((4-phenoxyphenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1 -yl)prop-2-en-1-one

[0189]

[0190] Step 1) Synthesis of compound N-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine:

[0191] 4-Chloropyrrolopyrimidine (600mg, 3.9mmol) and 4-phenoxyaniline (796mg, 4.3mmol) were dissolved in n-butanol (10mL), triethylamine (1.65mL, 11.7mmol) was added, and the reaction was refluxed for 25h . The solvent was evaporated under reduced pressure, water (40 mL) was added, extracted with dichloromethane (80 mL×3), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was passed through a silica gel column. Purification by chromatography (dichloromethane / methanol (V / V)=30 / 1) to obtain a yellow solid (1.8 g, 43%).

[0192] MS-ESI: (ESI, pos.ion) m / z: 303.10[M+1] + ;

[0193] Step 2) Compound (R)-tert-butyl 3-(4-((4-p...

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Abstract

The invention provides a BTK (bruton tyrosine kinase) inhibitor compound (compound shown as a formula (I)) and a purpose of the BTK inhibitor compound in medicine. The compound provided by the invention and a medicine composition of the compound can be used for treating diffuse large B cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia.

Description

technical field [0001] The present invention provides a BTK inhibitor, discloses a series of compounds and pharmaceutical compositions thereof, and also discloses that the compounds and pharmaceutical compositions thereof are used for the treatment of autoimmune diseases or disorders, xenoimmune diseases or disorders, and cancer Uses or conditions including lymphoma and inflammatory diseases. Background technique [0002] BTK kinase, a member of the Tec family of non-receptor tyrosine kinases, is a key signaling enzyme expressed in all hematopoietic cell types except T lymphocytes and natural killer cells. BTK plays a crucial role in the B-cell signaling pathway linking cell-surface B-cell receptor (BCR) stimulation to downstream intracellular responses. [0003] Dasatinib, which was launched in 2006, is a multi-target inhibitor, which has a strong inhibitory effect on BTK and is used for the treatment of chronic myeloid leukemia. In addition, PCI-32765, which was approved ...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D519/00A61K31/4545A61P35/00A61P35/02
CPCC07D471/04C07D519/00
Inventor 刘兵柏舜周有柏杨悌平张英俊郑常春蔡少瑜聂飚欧阳罗
Owner SUNSHINE LAKE PHARM CO LTD
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