An imidazo[1,5-a]pyrazin-8-amine compound, preparation method, pharmaceutical composition and application

A compound and compound structure technology, applied in drug combination, organic chemistry, antineoplastic drugs, etc., can solve the problems of poor solubility, low bioavailability, high plasma protein binding rate, etc., and achieve small side effects, strong inhibitory activity, and good resistance The effect of tumor pharmacological activity

Active Publication Date: 2021-11-02
北京鑫开元医药科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Ibrutinib can selectively and irreversibly form covalent bonds with cysteine ​​residues on BTK, thereby inhibiting the transmission of overactive cell survival signals in B cells and achieving anticancer effects, but it has poor solubility, plasma protein Disadvantages such as high binding rate and low bioavailability

Method used

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  • An imidazo[1,5-a]pyrazin-8-amine compound, preparation method, pharmaceutical composition and application
  • An imidazo[1,5-a]pyrazin-8-amine compound, preparation method, pharmaceutical composition and application
  • An imidazo[1,5-a]pyrazin-8-amine compound, preparation method, pharmaceutical composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] 4-(3-(1-acryloylpyrrol-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-3-oxo-N-(pyridin-2-yl ) piperazine-1-carboxamide

[0093]

[0094] first step:

[0095] Compound 1a (93.0 g, 200.0 mmol), benzyl chloroformate (34.0 g, 200.0 mmol) and diisopropylethylamine (DIPEA) (31.0 g, 240.0 mmol) were dissolved in dichloromethane (500 mL), 25 The reaction was stirred at ℃ for 6 hours, and the reaction was monitored by TLC. After the reaction was completed, water (500 mL) was added to quench the reaction. The organic layer was dried, concentrated, and separated by column chromatography to obtain 85.4 g of compound 1b with a yield of 77.8%. Compound 1b is an off-white solid, and its structural formula is shown in Formula 1b, and other compounds can be deduced accordingly.

[0096] Step two:

[0097] Compound 1b (85.0g, 154.8mmol), compound 1c (31.0g, 154.8mmol), cuprous iodide (5.7g, 30.0mmol), L-Proline (6.9g, 60.0mmol) Dissolve in dimethyl sulfoxide (DMSO) (600mL), heat up to 9...

Embodiment 2

[0107] 4-(3-(1-acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-3-yl)-3- Oxopiperazine-1-carboxamide

[0108]

[0109] first step:

[0110] Compound 1e (5.7 g, 10.0 mmol), N,N'-carbonyldiimidazole (CDI) (1.9 g, 12.0 mmol), diisopropylethylamine (DIPEA) (2.58 g, 20.0 mmol) were dissolved in N, In N-dimethylformamide (DMF) (300mL), the reaction was stirred at room temperature for 60 minutes, then compound 2a (0.9g, 10.0mmol) was added, the temperature was raised to 40°C and the reaction was stirred for 5 hours, and the reaction was monitored by TLC. Add water (30 mL), extract twice with ethyl acetate (100 mL×2), combine the organic layers, dry, concentrate, and separate by column chromatography to obtain 4.2 g of compound 2b with a yield of 61.0%. Compound 2b is an off-white solid.

[0111] Step two:

[0112] Compound 2b (4.0g, 5.8mmol) and palladium carbon (500mg) were dissolved in ethanol (50mL). After hydrogen replacement for 3 times, the reaction...

Embodiment 3

[0117] 4-(3-(1-acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-4-yl)-3- Oxopiperazine-1-carboxamide

[0118]

[0119] first step:

[0120] Compound 1e (5.7 g, 10.0 mmol), N,N'-carbonyldiimidazole (CDI) (1.9 g, 12.0 mmol), diisopropylethylamine (DIPEA) (2.58 g, 20.0 mmol) were dissolved in N, In N-dimethylformamide (DMF) (300mL), the reaction was stirred at room temperature for 60 minutes, then compound 3a (0.9g, 10.0mmol) was added, the temperature was raised to 40°C and the reaction was stirred for 5 hours, and the reaction was monitored by TLC. Add water (30 mL), extract twice with ethyl acetate (100 mL×2), combine the organic layers, dry, concentrate, and separate by column chromatography to obtain 4.6 g of compound 3b with a yield of 66.8%. Compound 3b is an off-white solid.

[0121] Step two:

[0122] Compound 3b (4.5g, 6.5mmol) and palladium carbon (500mg) were dissolved in ethanol (50mL). After hydrogen replacement for 3 times, the reaction...

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Abstract

The invention belongs to the field of medicine, and provides an imidazo[1,5-a]pyrazine-8-amine compound, a preparation method, a pharmaceutical composition and an application. The imidazo[1,5-a]pyrazine-8-amine compound is a compound with the structure of formula I or a pharmaceutically acceptable salt thereof. The formula I structure is: wherein, R 1 Represents a substituted or unsubstituted phenyl or aromatic heterocyclic group. The imidazo[1,5-a]pyrazine-8-amine compound can be used as an effective BTK inhibitor with strong inhibitory activity and less side effects. The pharmaceutical composition comprising the imidazo[1,5-a]pyrazine-8-amine compound also has good antitumor pharmacological activity.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to an imidazo[1,5-a]pyrazine-8-amine compound, a preparation method, a pharmaceutical composition and an application. Background technique [0002] Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase of the Tec kinase family, is a key regulator of B cell development, activation, signal transduction and survival, and plays an important role in B cell receptor signal transduction effect. When activating the B-cell antigen receptor (BCR), BTK is first activated by other tyrosine kinases, resulting in the activation of essential transcription factors for B-cell proliferation and differentiation. In addition, BTK is also involved in B cell migration base adhesion-related receptor signal transduction, including chemokine receptors CXCR4, CXCR5 and adhesion factors. The out-of-control activity of BTK kinase will lead to irregular proliferation of cells and cause cancer. Ab...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61P35/00A61P35/02A61K31/4985
CPCA61P35/00A61P35/02C07D487/04
Inventor 王永广张学魏常俊美苏小庭戴信敏
Owner 北京鑫开元医药科技有限公司
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