cxcr4 inhibitors and their applications

A technology selected from and compound, applied in the field of medicine, can solve the problems of less drugs and unable to meet the needs of patients, and achieve the effects of strong inhibitory activity, high biological activity and availability, and long drug effect time

Active Publication Date: 2022-03-29
ZHUHAI NOBEL INST OF BIOMEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, there is a great demand for drugs for stem cell mobilization, HIV infection, hematological tumors, solid tumors and immunodeficiency diseases, but there are few drugs on the market, and they cannot meet the needs of patients

Method used

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  • cxcr4 inhibitors and their applications
  • cxcr4 inhibitors and their applications
  • cxcr4 inhibitors and their applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0137]

[0138] Synthesis of Intermediate 71-2:

[0139] Compound 71-1 (500 mg, 2.92 mmol) was dissolved in THF (30 mL) and H 2 O 30mL, add sodium bicarbonate (294mg, 3.50mmol), di-tert-butyl dicarbonate (764mg, 3.50mmol), and stir at room temperature. TLC followed the reaction until the raw material methyl tranexamic acid disappeared, the reaction was stopped, extracted three times with saturated sodium bicarbonate and DCM, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column (PE:EA=3:1) , to obtain intermediate 6-2 (751 mg).

[0140] Synthesis of intermediate 71-2:

[0141] Dissolve 71-1 (750mg, 2.77mmol) in THF (30mL), cool down to 0°C and stir, slowly add LiAlH4 (211mg, 5.54mmol), stir, and react at room temperature. TLC followed the reaction until the starting material 83-1 disappeared, then stopped the reaction, extracted three times with saturated saline and EA, combined the organic phases, dried over anhydrou...

Embodiment 2

[0167]

[0168] Synthesis of Intermediate 96-2:

[0169] Dissolve compound 96-1 (400mg, 0.84mmol) in 10Ml THF, add 2,4-dichloropyrimidine (125mg, 0.84mmol) and DIEA (129mg, 1.00mmol) successively, stir at room temperature, follow the reaction by TLC, to the starting material 96-1 disappeared, stopped the reaction, extracted three times with saturated saline and DCM, combined the organic phases, dried over anhydrous sodium sulfate, concentrated, and purified by column (DCM:CH 3 OH=30:1), the final product 96-2 (392 mg) was obtained as a yellow solid.

[0170] Synthesis of Intermediate 96-3:

[0171] Compound 96-2 (390mg, 0.66mmol) was dissolved in 20Ml 1,4-dioxane, and 2-aminomethylpyridine (71mg, 0.66mmol), cesium carbonate (323mg, 0.99mmol) and [1 , 1'-bis(diphenylphosphino)ferrocene]palladium dichloride (48mg, 0.066mmol), replaced by N2, heated to 100°C for reaction. TLC followed the reaction until the raw material 96-2 disappeared, stopped the reaction, extracted with...

Embodiment 3

[0179]

[0180] Synthesis of intermediate 17-2:

[0181] Dissolve N-Fmoc-L-alanine (295mg, 0.95mmol) in THF (20Ml), stir, add HATU (431mg, 1.14mmol), HOBT (153mg, 1.14mmol), DIEA (244mg, 1.89mmol) ) and compound 17-1 (528mg, 0.95mmol), stirred at room temperature, TLC followed the reaction until the disappearance of raw material 17-1, stopped the reaction, extracted three times with saturated sodium bicarbonate and DCM, combined the organic phases, dried over anhydrous sodium sulfate, concentrated After column purification (PE:EA=3:1), intermediate 17-2 (679 mg) was obtained.

[0182] Synthesis of Intermediate 17-3:

[0183] Compound 17-2 (650 mg) was dissolved in 1M PIP / THF solution and stirred at room temperature. TLC followed the reaction until the disappearance of raw material 17-2, stopped the reaction, concentrated and purified by column (DCM:CH 3 OH=10:1), to obtain intermediate 17-3 (451 mg).

[0184] Synthesis of intermediate 17-4:

[0185] Compound 17-3 (450m...

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PUM

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Abstract

The invention relates to a compound and its use in preparing medicine, a pharmaceutical composition containing the compound, a medicine carrier and a medicine combination. The compound is a compound as shown in formula (I), its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts Or prodrugs. The compound of the present invention shows strong inhibitory activity on the CXCR4-SDF-1α axis, has good stability in vivo, has good absorption effect and high bioavailability, and can effectively interfere or block the interaction between SDF-1α and CXCR4 The interaction can mobilize hematopoietic stem cells, treat tumor diseases, inflammatory reactions, autoimmune diseases and other effects, and has a good application prospect.

Description

technical field [0001] The present invention relates to the field of medicine. In particular, the present invention relates to CXCR4 inhibitors and uses thereof. More specifically, the present invention relates to compounds, the use of compounds in the preparation of drugs, pharmaceutical compositions, drug carriers, drug combinations, methods for screening drugs and screening targets. Background technique [0002] CXC chemokine receptor 4 (CXCR4) and stromal cell-derived factor 1 (SDF-1) belong to the chemokine CXC subfamily and the chemokine receptor G protein-coupled receptor superfamily, respectively. CXCR4 is an important chemokine receptor widely expressed in a variety of hematopoietic cells (neutrophils, monocytes and macrophages, T, B lymphocytes), hematopoietic stem cells, endothelial precursors in blood and bone marrow cells, blood-derived dendritic cells, and Langerhans cells. At the same time, it is also highly expressed in vascular endothelial cells, neurons ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/38C07D401/12C07D471/04C07F9/6558C07D213/40C07D405/12C07D401/06C07D213/71C07D235/14A61K31/4402A61K31/4709A61K31/506A61K31/517A61K31/4545A61K31/4725A61K31/4439A61K31/675A61K31/4433A61K31/496A61K31/5377A61K31/4406A61K31/551A61K31/4184A61P35/00A61P35/02A61P31/18A61P19/08A61P37/06A61P9/10A61P7/00A61P25/28A61P27/02A61P11/00A61P1/00A61P17/00A61P29/00C12Q1/02
CPCC07D213/38C07D401/12C07D471/04C07F9/65583C07D213/40C07D405/12C07D401/06C07D213/71C07D235/14G01N33/5008C12N2503/02G01N2500/10A61K31/4184A61K31/4402A61K31/4406A61K31/4433A61K31/4439A61K31/4545A61K31/4709A61K31/4725A61K31/496A61K31/506A61K31/517A61K31/5377A61K31/551A61K31/675A61P1/00A61P7/00A61P9/10A61P11/00A61P17/00A61P19/08A61P25/28A61P27/02A61P29/00A61P31/18A61P35/00A61P35/02A61P37/06C07F9/6558C12Q1/02A61K31/00A61K31/33A61K31/435A61K31/495A61P35/04C07D213/36C07D239/24
Inventor 黄子为聂凛凛徐岩谭嘉文梁柏强杨虹叶辉
Owner ZHUHAI NOBEL INST OF BIOMEDICINE CO LTD
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