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Casein kinase 1[epsilon] inhibitor, pharmaceutical composition and application thereof

A solvate and compound technology, applied in the field of medicine, can solve problems such as lack of substrate specificity and unclear mechanism of action

Active Publication Date: 2020-12-29
HANGZHOU HERTZ PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies have shown that due to the lack of substrate specificity of the CK1 gene, the mechanism by which CK1ε regulates tumor growth and survival is unclear, and may be related to Akt, MYC, β-catenin, etc. (Varghese et al., Scientific Reports, 2018, 8:13621)

Method used

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  • Casein kinase 1[epsilon] inhibitor, pharmaceutical composition and application thereof
  • Casein kinase 1[epsilon] inhibitor, pharmaceutical composition and application thereof
  • Casein kinase 1[epsilon] inhibitor, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0207] Embodiment 1: the synthesis of intermediate 4

[0208]

[0209] Step 1: Add compound 1 (117mmol) and 40mL DMF into a 250mL reaction flask, stir and dissolve at 0°C, then slowly add propionyl chloride (121mmol) dropwise, after the dropwise completion, a large amount of white solid precipitates, continue to keep warm for 1h before adding 200mL of water, stirred for 1 hour, filtered and dried to obtain intermediate 2 as a solid product.

[0210] Step 2: add intermediate 2 (10mmol), H 2 N-B (20mmol), toluene 20mL, add PCl dropwise under stirring at room temperature 3 (10 mmol), after the dropwise addition was completed, the temperature was raised to 110° C. and refluxed overnight. After the reaction was detected by TLC, it was extracted with ethyl acetate and water, dried, concentrated, and the crude product was purified by silica gel column chromatography to obtain the product intermediate 3.

[0211] Step 3: Add intermediate 3 (8mmol), sodium acetate (11.2mmol), and...

Embodiment 2

[0252] Embodiment 2: the synthesis of intermediate 9

[0253]

[0254] Step 1: Add compound 5 (5g, 19mmol), triphenylchloromethane (10.7g, 38mmol), potassium carbonate (10.6g, 76mmol) and 50mL DMF into a 100ml reaction flask, and then heat to 80°C for about 24h Afterwards, the completion of the reaction was detected by TLC, lowered to room temperature, ethyl acetate and water were added, the insoluble matter was removed by filtration, the ethyl acetate layer was separated, and the crude product concentrated under reduced pressure was purified by silica gel column chromatography to obtain 6.75 g of the intermediate product. Body 6, yield 73%.

[0255] Step 2: add intermediate 6 (18mmol), compound 7 (27mmol), potassium carbonate (54mmol), tetrakistriphenylphosphine palladium (0.9mmol), dioxane 135ml, water 45ml respectively in 500ml reaction flask; After stirring, the temperature was raised to 100°C for 14 hours, and the reaction was detected by TLC. After cooling down to ro...

Embodiment 4

[0267] Embodiment 4: the synthesis of intermediate 10

[0268]

[0269] Add 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.2g, 20mmol), potassium carbonate (4.2g, 30mmol) and 100mL DMF respectively in a 500ml reaction flask, stir at room temperature Add compound 4 (8.6g, 26mmol), react at room temperature for about 12h, then detect the completion of the reaction by TLC, add ethyl acetate and water for extraction, wash with water 3 times, separate the ethyl acetate layer, dry over anhydrous sodium sulfate, and concentrate under reduced pressure The final crude product was purified by silica gel column chromatography to obtain intermediate 10 as a white product.

[0270] (Compound 4 is 2-(1-bromoethyl)-3-phenylquinazolin-4(3H)-one, namely R 1 =H)

[0271] 2-(1-(4-Amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-phenylquinazolin-4(3H)-one ; Yield 83%. LC-MS(ESI-MS):510[M+H] + .

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Abstract

The invention discloses a novel substituted pyrazolopyrimidine compound for inhibiting the activity of casein kinase 1[epsilon] (CK1[epsilon]), a stereoisomer or a stereoisomer mixture of the novel substituted pyrazolopyrimidine compound, a pharmaceutically acceptable salt or solvate of the novel substituted pyrazolopyrimidine compound, and application of the compound to preparation of medicine for treating diseases, disorders or symptoms benefiting from the inhibition of the activity of casein kinase 1[epsilon] (CK1[epsilon]). The compound has inhibitory activity on CK1[epsilon] kinase, OCI-LY10 cells and Karpas299 cells, shows good anti-tumor activity in an OCI-LY10 subcutaneous xenogeneic model, shows excellent synergistic anti-tumor activity when being combined with a BTK inhibitor, has good pharmacokinetic properties, and can be applied to treatment of diseases, disorders or symptoms, including cancers, autoimmune diseases and the like, which benefit from inhibition of casein kinase 1[epsilon] activity, alone or in combination with other drugs.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a substituted pyrazolopyrimidine casein kinase 1ε inhibitor, a pharmaceutical composition and application thereof. Background technique [0002] Protein kinases play an important role in signal transduction, and can mediate intracellular signal transduction by phosphorylating substrate proteins, and are an important class of drug targets. Casein kinase 1 (CK1) belongs to the serine-threonine kinase family, and there are seven isoforms in mammals: ɑ, β, γ1, γ2, γ3, δ, and ε. These isoforms are involved in Wnt signal transduction, circadian rhythm, cell signal transduction, membrane transport, DNA replication, DNA damage and RNA metabolism, and can regulate body functions. [0003] The phosphorylated substrates of CK1 are involved in various intracellular regulation. For example, the tumor suppressor factor p53 and the oncogene MDM2 are important proteins that control the abno...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P35/00A61P37/06A61P29/00A61P19/02A61P1/04A61P1/00A61P11/06A61P17/06A61P11/00A61P17/00A61P17/14A61K31/519A61K31/5377
CPCC07D487/04A61P35/00A61P37/06A61P29/00A61P19/02A61P1/04A61P1/00A61P11/06A61P17/06A61P11/00A61P17/00A61P17/14A61P37/00A61K31/519A61K31/5377
Inventor 周星露刘兴国胡苗
Owner HANGZHOU HERTZ PHARMA
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