A class of heterocyclic compounds with cxcr4 signaling pathway inhibitory activity and application thereof

A heterocyclic compound, a technology for inhibiting activity, applied in the field of diabetic retinopathy, heterocyclic compound, composition containing said compound, brain inflammation, age-related macular degeneration, related diseases

Active Publication Date: 2022-02-11
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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  • A class of heterocyclic compounds with cxcr4 signaling pathway inhibitory activity and application thereof
  • A class of heterocyclic compounds with cxcr4 signaling pathway inhibitory activity and application thereof
  • A class of heterocyclic compounds with cxcr4 signaling pathway inhibitory activity and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] Heterocyclic compound D1, which is synthesized by the following method:

[0096]

[0097] 1) Synthesis of intermediate D1-1

[0098] Ethyl chloroacetoacetate (16.5 g, 100 mmol) and acetamidine hydrochloride (10 g, 106 mmol) were successively dissolved in ethanol (150 mL). 1,8-Diazabicycloundec-7-ene (30.4 g, 200 mmol) was slowly added in an ice-water bath, and stirred overnight at room temperature. Drain the solvent, add dichloromethane (120mL) to dilute, wash with saturated brine (30mL*3), dry the organic phase, and drain the solvent. The residue was dissolved in phosphorus oxychloride (20 mL), and stirred under reflux at 110° C. for 30 min. After cooling to room temperature, most of the phosphorus oxychloride was removed, and the residue was dissolved in ethyl acetate (20 mL) and added dropwise to ice water (100 mL). The aqueous phase was extracted with ethyl acetate (30 mL*3), and the organic phases were combined and dried. After the solvent was spin-dried, th...

Embodiment 2

[0106] Heterocyclic compound D2, which is synthesized by the following method:

[0107]

[0108] 1) Synthesis of intermediate D2-1

[0109] 8-aminoquinoline (200mg, 1.4mmol), intermediate D1-1 (273mg, 1.5mmol), potassium iodide (23mg, 0.14mmol), N,N-diisopropylethylamine (452mg, 3.5mmol) were added into acetonitrile (5 mL) and react overnight at room temperature. Potassium carbonate (386mg, 2.8mmol) was added, the temperature was raised to 90°C, and the reaction was carried out overnight. The reaction solution was spin-dried, added with saturated sodium bicarbonate solution (50 mL), and extracted with dichloromethane (3*20 mL). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The residue was purified by column chromatography (dichloromethane:methanol:ammonia water=100:2:1) to obtain a yellow oily intermediate (230 mg, 58%). 1 H NMR (400MHz, CDCl 3 )δ8.79(d, J=2.8Hz, 1H), 8.11(d, J=8.0Hz, 1H), 7.44(dd, J=8...

Embodiment 3

[0115] Heterocyclic compound D3, which is synthesized by the following method:

[0116]

[0117] 1) Synthesis of intermediate D3-1

[0118] The intermediate 8-aminoquinoline (2.9g, 20mmol) was added to absolute ethanol, heated to 90°C, slowly added dropwise into iodomethane (3.4g, 24mmol), sealed and stirred overnight. The solvent was spin-dried, and saturated sodium bicarbonate (50mL) and dichloromethane (60mL) were added, the aqueous phase was extracted twice with dichloromethane (60mL*2), the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography (petroleum Ether:ethyl acetate=50:1) to obtain yellow oil D3-1 (0.90g, 29.8%).

[0119] 2) Synthesis of intermediate D3-2

[0120] Intermediate D3-1 (158mg, 1.9mmol), dissolved in 10mL acetonitrile, added potassium iodide (31.5mg, 0.19mmol), potassium carbonate (524mg, 3.8mmol), D1-1 (219mg, 2.84mmol), reacted overnight at 80°C , spin-dried to obtain an oil, which was purified...

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PUM

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Abstract

The invention provides a heterocyclic compound with CXCR4 signaling pathway inhibitory activity and application thereof. The heterocyclic compound and its pharmaceutically acceptable salt, isotope, isomer and crystal structure have the structure shown in general formula I: the present invention also provides the application of the above-mentioned heterocyclic compound with CXCR4 signaling pathway inhibitory activity . 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): C07D401/12C07D401/14C07D471/04A61K31/506A61K31/551A61K31/519A61K31/496A61P35/00A61P35/02A61P31/04A61P31/12A61P25/00A61P3/10A61P31/18A61P17/02A61P11/00A61P11/06A61P9/10A61P17/06A61P19/02A61P21/04A61P13/12A61P17/00A61P1/00A61P27/02A61P27/06
CPCC07D401/12C07D401/14C07D471/04A61P35/00A61P35/02A61P31/04A61P31/12A61P25/00A61P3/10A61P31/18A61P17/02A61P11/00A61P11/06A61P9/10A61P17/06A61P19/02A61P21/04A61P13/12A61P17/00A61P1/00A61P27/02A61P27/06
Inventor 张小虎马海阔郑计岳蔺宇
Owner CGENETECH (SUZHOU CHINA) CO LTD
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