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Novel CXCR4 antagonist with amino acid skeleton as well as preparation and biomedical application of CXCR4 antagonist

An amino acid and group technology, applied in anti-inflammatory agents, antiviral agents, drug combinations, etc., to achieve the effect of novel structure and excellent antagonistic activity

Active Publication Date: 2018-01-19
TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Currently, only one CXCR4 antagonist, plerixafor (AMD3100), has been approved by the FDA as a hematopoietic stem cell mobilizer, combined with granulocyte colony-stimulating factor (G-CSF) for multiple myeloma and Patients with non-Hodgkin's lymphoma are far from being able to meet clinical needs

Method used

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  • Novel CXCR4 antagonist with amino acid skeleton as well as preparation and biomedical application of CXCR4 antagonist
  • Novel CXCR4 antagonist with amino acid skeleton as well as preparation and biomedical application of CXCR4 antagonist
  • Novel CXCR4 antagonist with amino acid skeleton as well as preparation and biomedical application of CXCR4 antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Example 1 Preparation of intermediate 1-3a (HFX50626-5): refer to the enumerated intermediate synthesis route (1)

[0088] 4-cyanobenzaldehyde (10g) was dissolved in methanol (150mL), and N-(3-aminopropyl)cyclohexylamine (12.4mL) and appropriate amount were added to the solution Molecular sieves, the reaction solution was heated to 65°C and stirred for 6 hours. After the reaction solution was cooled to room temperature, sodium borohydride (5.8 g) was added in batches and stirred at room temperature for 1-2 hours. The reaction was quenched with saturated ammonium chloride solution, and the reaction solution was concentrated to dryness. The residue was ultrasonically washed with methanol, filtered, and the filtrate was collected and evaporated to dryness to obtain intermediate 1-1a, which was directly used in the next reaction.

[0089] The crude intermediate 1-1a above was directly dissolved in tert-butanol (100mL) and sodium carbonate solution (2mol / L, 100mL), and Bo...

Embodiment 2

[0091] The preparation of embodiment 2 intermediate 1-3b

[0092] Referring to the enumerated intermediate synthesis route (1), the synthesis method and conditions are similar to the preparation of intermediate 1-3a.

Embodiment 3

[0093] Example 3 Preparation of intermediate 2-3a: refer to the enumerated unnatural amino acid synthesis route (2)

[0094] The amino acid raw material Fmoc-L-Lys(Boc)-OH (5 g) was weighed and suspended in dichloromethane (40 mL), and trifluoroacetic acid (20 mL) was added. After the reaction solution was stirred at room temperature for 1-2 hours, it was spin-dried, and the residue was precipitated with glacial ether. The resulting white precipitate was intermediate 2-1a, which was directly dissolved in methanol (50 mL), and acetone (20 mL) and trifluoroacetic acid (2 mL) were added. After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (11.3 g) was added, and the stirring reaction was continued overnight. The final reaction solution was adjusted to PH 4-6 with hydrochloric acid solution (4mol / L), the concentration reached a certain volume, and extracted with ethyl acetate. The combined organic phases were dried with anhydrous sodium sulfate, filtered...

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PUM

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Abstract

The invention provides compounds represented in formula (I) in the description or pharmaceutically acceptable salts or prodrugs of the compounds. The compounds have novel structure, high efficiency, low toxicity and excellent CXCR4 antagonistic activity, and can block HIV from invading and infecting human target cells, treat or prevent AIDS or mobilize human bone marrow hematopoietic cells, mesenchymal stem cells and stem cells, interfere with CXCL12 / CXCR4 mediated cell migration and adhesion, prevent and treat CXCR4 mediated tumor metastasis, invasion and growth, or block CXCL12 / CXCR4 mediated autoimmune and inflammatory reactions. The compounds can be used as an active ingredient in pharmaceutical composition for preventing and treating HIV in combination with other anti-HIV drugs, or for preventing and treating tumors in combination with other drugs for treating or preventing leukemia, lymphoma, myeloma and solid tumors.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular, the invention relates to a novel CXCR4 antagonist of amino acid skeleton and its preparation and biomedical application. Background technique [0002] Chemokine receptors are a G protein-coupled receptor (GPCR) superfamily with seven transmembrane domain structures, and are usually expressed on the cell membranes of immune cells, epithelial cells, vascular endothelial cells, and nerve cells. One of the CXC chemokine receptors, CXCR4, and its natural ligand, the chemokine CXCL12 (stromal cell-derived factor-1, SDF-1), are widely expressed in a variety of cells and tissues, and they regulate the human immune system and circulatory system. It plays an important role in the nervous system, and their interaction and the signal transduction they mediate are closely related to various diseases such as viral infection, tumor development and metastasis, inflammation and autoimmune disease...

Claims

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Application Information

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IPC IPC(8): C07D213/38C07D215/40C07D233/24C07D401/12C07D401/06C07C279/14A61K31/4439A61K31/4709A61K31/4402A61K31/47A61K31/417A61K31/165A61P31/18A61P35/02A61P35/00A61P35/04A61P37/06A61P29/00C07K5/065C07K5/068A61K38/05
CPCA61K38/05A61P29/00A61P31/18A61P35/00A61P35/02A61P35/04A61P37/06C07C279/14C07D213/38C07D215/40C07D233/24C07D401/06C07D401/12C07D213/56C07D233/64A61K45/06A61K31/165A61K31/417A61K31/4402A61K31/4439A61K31/47
Inventor 黄子为方雄孟倩徐岩朱思雨方笑
Owner TSINGHUA UNIV
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