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BTK inhibitor and uses thereof

A solvate, compound technology, applied in the field of BTK inhibitors

Active Publication Date: 2016-03-16
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 inhibitor and uses thereof
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  • BTK inhibitor and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0163] Example 1(E)-1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-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

[0164]

[0165] Step 1) Synthesis of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine:

[0166] 1H-pyrazolo[3,4-d]pyrimidin-4-amine (15.0 g, 111.1 mmol) was dissolved in DMF (150 mL), and N-iodosuccinimide was slowly added to the reaction solution (37.5 g, 166.6 mmol), and the reaction was stirred at 80 °C for 12 h. Heating was stopped, cooled, water (40 mL) was added to the reaction solution, suction filtered, the solid was washed with water (80 mL), washed with ethanol (60 mL), and dried to obtain a yellow solid (24.9 g, 86%).

[0167] Step 2) Synthesis of (S)-tert-butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate:

[0168] (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate (1.50 g, 7.47 mmol) was dissolved in dichloromethane (30 mL), and then triethylamine (1.35 mL, 9.71 mL) was added ...

Embodiment 2

[0188] Example 2 (S, E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piper Pyridin-1-yl)-4-(2-oxo-6-azaspiro[3.3]heptane-6-yl)but-2-en-1-one

[0189]

[0190] (R,E)-1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1 -yl)-4-bromobut-2-en-1-one (200mg, 0.37mmol) was dissolved in DMF (15mL), and 2-oxo-6-aza-spiro[3,3]heptane was added Salt (0.14g, 0.75mmol) and potassium carbonate (149mg, 1.50mmol), react at 60°C for 4h. The solvent was evaporated under reduced pressure, water (20 mL) was added, extracted with dichloromethane (50 mL×3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the crude product was separated and purified by column chromatography (2 Chloromethane / methanol (V / V)=10 / 1) to give a white powder (79mg, 40%).

[0191] MS-ESI: (ESI, pos.ion) m / z: 276.7[M / 2+1] + ;

[0192] 1 HNMR (400MHz, CDCl 3 ): δ7.63(d, J=7.6Hz, 2H), 7.38(...

Embodiment 3

[0193] Example 3 (R, E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piper Pyridin-1-yl)-6-morpholinylhex-2-en-1-one

[0194]

[0195] Step 1) Synthesis of 4-((tert-butyl(dimethyl)silyl)oxy)butan-1-ol:

[0196]Dissolve butane-1,4-diol (6.5 g, 72 mmol) in dichloromethane, add tert-butyl(dimethyl)chlorosilane (5.4 g, 36 mmol), and slowly add triethylamine ( 5mL, 35.9mmol), then stirred at room temperature for 5h, extracted with dichloromethane (150mL×3), washed with saturated brine (60mL), dried over anhydrous sodium sulfate, and evaporated to remove the solvent under reduced pressure to obtain the product (6.82g, 93% ).

[0197] Step 2) Synthesis of 4-((tert-butyl(dimethyl)silyl)oxy)butyraldehyde:

[0198] Under nitrogen protection, oxalyl chloride (10 mL), dichloromethane (150 mL) were added, and DMSO (5 mL) was slowly added dropwise at -78 °C. After stirring for 15 min, 4-((tert-butyl) was slowly added at -78 °C. (dimethyl)silyl)oxy)butan-1-ol (6....

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Abstract

The present invention provides a BTK inhibitor compound (having s structure represented by a formula (I)) and uses of the BTK inhibitor compound in medicines. According to the present invention, the compound and the pharmaceutical composition can be used for treatment of diffuse large B-cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia. The formula (I) is defined in the specification.

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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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/00C07D487/04A61K31/519A61K31/5377A61P35/00A61P35/02
CPCC07D487/04C07D519/00
Inventor 刘兵柏舜张英俊郑常春杨悌平周有柏
Owner SUNSHINE LAKE PHARM CO LTD
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