Pyridine heterocyclic compound and application thereof serving as CXCR4 inhibitor

A heterocyclic compound, a technology for inhibiting activity, applied in the fields of brain inflammation, age-related macular degeneration, for, comprising the compound, diabetic retinopathy, heterocyclic compound, related diseases

Active Publication Date: 2019-10-11
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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  • Pyridine heterocyclic compound and application thereof serving as CXCR4 inhibitor
  • Pyridine heterocyclic compound and application thereof serving as CXCR4 inhibitor
  • Pyridine heterocyclic compound and application thereof serving as CXCR4 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Heterocyclic compounds C1 and C2, which are synthesized by the following method:

[0098]

[0099] 1) Synthesis of intermediate C1-2:

[0100] Boc-D-proline (5g, 23mmol), isopropylidene malonate (3.4g, 23mmol) and DMAP (5.7g, 46mmol) were dissolved in 70mL of dichloromethane, under stirring in an ice bath, DCC (4.8 g, 23mmol), stirred at room temperature for 48h. After filtration, 200 mL of dichloromethane and 100 mL of 1N hydrochloric acid solution were added to the filtrate for layering, and the aqueous phase was extracted with dichloromethane. The dichloromethane phases were combined, dried and spin-dried to obtain a yellow oil (9 g, crude product).

[0101] 2) Synthesis of intermediate C1-3:

[0102] Intermediate C1-2 (9 g, crude product) was dissolved in 100 mL of absolute ethanol, and stirred at reflux for 2 h. Ethanol was spin-dried to obtain a liquid, which was purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain a yellow oil...

Embodiment 2

[0111] According to the synthesis method of Example 1, Boc-D-proline was replaced by Boc-L-proline in step 1, and heterocyclic compounds C3 and C4 were synthesized.

Embodiment 3

[0113] Heterocyclic compound C5, which is synthesized by the following method:

[0114]

[0115] 1) Synthesis of intermediate C5-1:

[0116] Intermediate C1-3 (1g, 3.5mmol) and acetamidine hydrochloride (990mg, 10.5mmol) were dissolved in 200mL of ethanol, sodium ethoxide (480mg, 7mmol) was added, and stirred under reflux overnight. Acetic acid was added to adjust the pH to acidic, and extracted three times with dichloromethane (100 mL). The organic phase was dried and spin-dried to obtain a liquid, which was purified by column chromatography (dichloromethane:methanol=20:1) to obtain a colorless oily liquid (930mg, 95%)

[0117] 2) Synthesis of intermediate C5-2:

[0118] Intermediate C5-2 (920mg, 3.3mmol), triethylamine (3.3g, 33mmol), N-methylpiperazine (500mg, 5mmol) were dissolved in 20mL acetonitrile, PyBOP (1.9g, 3.4mmol) was added, and stirred at reflux Overnight, 200 mL of dichloromethane and 200 mL of aqueous sodium bicarbonate were added to separate layers, and...

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PUM

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Abstract

The invention provides a pyridine heterocyclic compound and application thereof serving as a CXCR4 inhibitor. The structure of the heterocyclic compound and the pharmaceutically acceptable salt, isotope, isomer and crystal form thereof is as shown in general formula I. The heterocyclic compound has CXCR4 signal channel inhibitory activity. The heterocyclic compound with the CXCR4 signal channel inhibitory activity can serve as the effective antagonist of CXCR4 signal channels and can be used for treating or preventing diseases responding 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 Applications(China)
IPC IPC(8): C07D401/14C07F7/18C07D471/04A61K31/506A61K31/695A61K31/5377A61K31/551A61K31/496A61P31/18A61P9/10A61P29/00A61P37/08A61P11/00A61P11/06A61P19/02A61P13/12A61P21/04A61P3/10A61P5/14A61P37/06A61P1/00A61P1/04A61P17/06A61P17/00A61P27/02A61P27/06A61P7/06A61P35/00A61P35/02A61P1/16
CPCC07D401/14C07D471/04C07F7/1804
Inventor 张小虎郑计岳马海阔
Owner CGENETECH (SUZHOU CHINA) CO LTD
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