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Bruton's tyrosine protein kinase inhibitor and application thereof

A solvate and selected technology, applied in the field of medicine, can solve the problems of infection, cardiotoxicity, hemorrhage, and poor selectivity, and achieve the effects of reducing toxic reactions, improving selectivity, and reducing off-target effects

Pending Publication Date: 2022-02-25
GUANGZHOU BIOTING PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although BTK inhibitors are already on the market for the treatment of certain B lymphocyte malignancies, they have not been successful in autoimmune diseases such as rheumatoid arthritis and lupus erythematosus, allergic diseases such as urticaria, and inflammation
Moreover, these BTK inhibitors are limited in clinical application due to their poor selectivity and high dosage, which can easily lead to adverse reactions such as infection, cardiotoxicity and bleeding (Arch Pharm Res.2019; 42(2): 171-181; LeukLymphoma.2018; 59(7):1554-1564)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094]

[0095] 6-(1-(2-fluoroacryloyl)piperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide was synthesized according to Reaction Formula 1.

[0096] first step:

[0097]

[0098] Compound 1 (4-bromophenyl-phenyl ether 500mg, 2.89mmol), pinacol diboronate (760mg, 3.0mmol), potassium acetate (500mg, 5.1mmol), 1,1-bis(diphenyl Phosphine)ferrocenedichloropalladium dichloromethane complex (160 mg, 0.2 mmol) was dissolved in 1,4-dioxane (20 mL). Nitrogen was sparged for 10 minutes. React at 80°C for 2 hours. Spot plate (pure petroleum ether) was used to monitor the completion of the reaction, and compound 2 was obtained, and the next reaction was carried out without further treatment.

[0099] Step two:

[0100]

[0101] Compound 3 (2,6-dichloronicotinonitrile, 500mg, 2.89mmol), concentrated sulfuric acid (10mL) and water (3mL) were mixed and reacted overnight at 90°C. TLC (PE:EA=1:1) showed that the reaction of starting material was complete. The reaction solution was pour...

Embodiment 2～ Embodiment 15

[0115] Referring to Reaction Formula 1 and the specific synthesis steps of Example 1, the synthesis of Example 2-Example 15 was carried out, and the detailed information is shown in Table 1 below.

[0116] Table 1: Example 2-Example 15

[0117]

[0118]

Embodiment 16

[0120]

[0121] 4-(1-(2-fluoroacryloyl)piperidin-4-yl)-2-(5-phenoxypyridin-2-yl)benzamide was synthesized by referring to Reaction Formula 2.

[0122] The first step: the synthesis of 2-bromo-5-phenoxypyridine

[0123]

[0124] Compound b (561mg, 5.97mmol) was dissolved in dry DMF (6mL), ice bathed, NaH (286mg, 11.93mmol) was added, stirred for 1h, compound a (1.05g, 5.97mmol) was added, reacted overnight at room temperature, water and Extracted three times with ethyl acetate, combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound c (1.2 g, 80%).

[0125] The second step: the synthesis of 5-phenoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine

[0126]

[0127] Dissolve compound c (1.2g, 4.80mmol), compound d (1.83g, 7.20mmol) in dioxane (10mL), add potassium acetate (1.18g, 12.00mmol), tetrakis (triphenylphosphine) palladium (110.89mg ...

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PUM

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Abstract

The invention relates to a compound as shown in a formula (I), and an isomer, a deuterated substance, an active metabolite, a solvate or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition containing the compound or the isomer, the deuterated substance, the active metabolite, the solvate or the pharmaceutically acceptable salt thereof, and a Bruton's tyrosine protein kinase (BTK) inhibitor. The invention also provides application of the substances in treatment of tumors, autoimmune diseases, allergic diseases, inflammation and other diseases caused by BTK abnormality.

Description

technical field [0001] The present invention relates to the field of medical technology, in particular to Bruton's tyrosine protein kinase inhibitors and their use in the treatment of tumors, autoimmune diseases, allergic diseases and inflammation caused by Bruton's tyrosine kinase abnormalities. application. Background technique [0002] Bruton tyrosine kinase (BTK) is a member of the Tec kinase family of tyrosine kinases. BTK is a key kinase in the B cell receptor signaling pathway, which plays a key role in the development and activation of B cells and in the inflammatory signaling pathway. BTK is mainly expressed in hematopoietic cells such as B cells, mast cells and macrophages. Abnormal activation of B cells can promote the occurrence of B cell lymphoma and autoimmune diseases. Therefore, BTK inhibitors have important therapeutic value in diseases such as hematological malignancies, autoimmune diseases, allergic diseases and inflammation (Immunol Rev. 2009; 228(1):5...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D401/14C07D403/04C07D401/10C07D211/34C07D211/58C07D207/08C07D207/14C07D239/47C07D403/12C07D401/12A61P35/00A61P29/00A61P37/08A61P37/02A61K31/506A61K31/505A61K31/4545A61K31/451A61K31/402A61K31/4468
CPCC07D401/04C07D401/14C07D403/04C07D401/10C07D211/34C07D211/58C07D207/08C07D207/14C07D239/47C07D403/12C07D401/12A61P35/00A61P29/00A61P37/08A61P37/02
Inventor 徐伟吴曙光王洪涛
Owner GUANGZHOU BIOTING PHARM TECH CO LTD
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