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4-aminopyrimidine derivatives as cxcr4 inhibitors and their application

A technology of inhibiting activity, alkyl, used in age-related macular degeneration, for, a composition comprising the compound, brain inflammation, heterocyclic compounds, diabetic retinopathy, related diseases, to achieve good drug interaction safety , the effect of weak inhibition

Active Publication Date: 2021-08-27
CGENETECH (SUZHOU CHINA) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although AMD070 entered the second phase of clinical trials, the clinical trials were terminated due to the discovery of hepatotoxicity in preclinical trials

Method used

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  • 4-aminopyrimidine derivatives as cxcr4 inhibitors and their application
  • 4-aminopyrimidine derivatives as cxcr4 inhibitors and their application
  • 4-aminopyrimidine derivatives as cxcr4 inhibitors and their application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Heterocyclic compound A1, which is synthesized by the following method:

[0066]

[0067] 1) Synthesis of intermediate A1-2:

[0068] Intermediate A1-1 (280mg, 1.9mmol, please refer to WO2016128529 for synthesis literature) was dissolved in dichloromethane (10mL), and thionyl chloride (280mg, 2.3mmol) was added dropwise under ice-cooling, stirring was continued overnight, and sodium bicarbonate was added The solution was extracted three times with dichloromethane (50 mL), and the dichloromethane phase was dried and spin-dried to obtain a pale yellow oil (180 mg, 58%).

[0069] 2) Synthesis of intermediate A1-4:

[0070] Intermediate A1-3 (160mg, 1mmol, see WO2006026703 for synthesis literature), Intermediate A1-2 (170mg, 1.05mmol), potassium iodide (16mg, 0.1mmol) and N, N-diisopropylethylamine (320mg, 2.5mmol) was dissolved in 10mL acetonitrile, stirred overnight at room temperature, added 100mL dichloromethane and 50mL sodium bicarbonate aqueous solution for extr...

Embodiment 2

[0074] According to the synthesis method of Example 1, the corresponding amines were used to replace N-methylpiperazine in the last step to obtain heterocyclic compounds A2, A5, A6, A22-A26, A39 and A60.

Embodiment 3

[0076] Heterocyclic compound A3, which is synthesized by the following method:

[0077]

[0078] 1) Synthesis of Intermediate A3-2:

[0079] Ethyl 4-chloroacetoacetate (13g, 79mmol), S-methylisothiourea sulfate (20g, 72mmol), dissolved in 200mL of water, added sodium carbonate (11.5g, 108mmol), stirred overnight at room temperature, added 6N HCl The pH was adjusted to be acidic, and a solid was precipitated, which was filtered and dried to obtain the product (11.1 g, 73%) as a white solid.

[0080] 2) Synthesis of intermediate A3-3:

[0081] Intermediate A3-2 (2.8g, 14.7mmol) was dissolved in 10mL phosphorus oxychloride, stirred at 100°C for 1h, spin-dried, added 100mL ethyl acetate and 100mL sodium bicarbonate aqueous solution for extraction, ethyl acetate was dried and spin-dried. The residue was purified by column chromatography (ethyl acetate:petroleum ether=100:3) to obtain the product (2.4 g, 80%) as a yellow oily liquid.

[0082] 3) Synthesis of Intermediate A3-4:...

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Abstract

The present invention provides a heterocyclic compound with CXCR4 signaling pathway inhibitory activity and its pharmaceutically acceptable salt, isotope, isomer and crystal structure. The compound has the structure shown in general formula I: the present invention also The application of the above-mentioned heterocyclic compound having CXCR4 signaling pathway inhibitory activity is provided. The heterocyclic compound having CXCR4 signaling pathway inhibitory activity of the present invention, as an effective antagonist of CXCR4 signaling pathway, can be used to treat or prevent diseases that respond to CXCR4 receptor antagonism.

Description

technical field [0001] The present invention relates to a heterocyclic compound having CXCR4 inhibitory activity, a composition comprising the compound, a method for preparing the compound, and the use of the compound in medicine, especially for the treatment of CXCR4-responsive The present invention also relates to the use of said compounds in stem cell harvesting methods for diseases antagonized by the body, such as cancer, cancer metastasis, HIV, HIV-related diseases, brain inflammation, diabetic retinopathy, age-related macular degeneration and retinal angiogenesis Uses, including, for example, facilitating the release and mobilization of stem cells, including hematopoietic stem cells, non-hematopoietic stem cells, and progenitor stem cells, prior to harvesting. The invention belongs to the technical field of medicine. Background technique [0002] CXCR4 belongs to seven transmembrane G-protein coupled receptors (GPCR), and its endogenous ligand is chemokine SDF-1 (stro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12C07D401/14C07D405/14C07D487/04C07D491/052A61K31/506A61K31/5377A61K31/551A61P35/00A61P31/18A61P3/10A61P29/00A61P27/02A61P7/00
CPCA61P3/10A61P7/00A61P27/02A61P29/00A61P31/18A61P35/00C07D401/12C07D401/14C07D405/14C07D487/04C07D491/052
Inventor 张小虎郑计岳马海阔
Owner CGENETECH (SUZHOU CHINA) CO LTD
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