NAMPT protein degradation targeted chimera as well as preparation method and application thereof

A technology of protein degradation and chimera, applied in the field of medicine, can solve problems that have not been reported before

Pending Publication Date: 2020-07-28
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] There is no report about the NAMPT protein degradation targeting chimera of the present invention

Method used

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  • NAMPT protein degradation targeted chimera as well as preparation method and application thereof
  • NAMPT protein degradation targeted chimera as well as preparation method and application thereof
  • NAMPT protein degradation targeted chimera as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0131] Example 1 Synthesis of Compound 1

[0132] The preparation method is as follows:

[0133] Step a. Synthesis of tert-butyl 4-((4-nitrophenyl)sulfonyl)piperazine-1-carboxylate:

[0134] Dissolve p-nitrobenzenesulfonyl chloride (2.21g, 10.0mmol) and 1-Boc-piperazine (2.79g, 15.0mmol) in CH 2 Cl 2 (10mL), then add TEA (2mL) dropwise to the solution, stir at room temperature for 1.5h, the reaction solution and 50mL of 2N hydrochloric acid solution are fully mixed, separated, collect the organic phase, evaporate the solvent to obtain a white solid 3.51g, the yield is 95 %. 1 H NMR(600MHz, DMSO-d 6 )δ: 7.78 (d, J = 20.78Hz, 1H), 7.67 (d, J = 20.78Hz, 1H), 3.40-3.37 (m, 4H), 2.89-2.85 (m, 4H), 1.34 (s, 9H) ).

[0135] Step b. Synthesis of tert-butyl 4-((4-aminophenyl)sulfonyl)piperazine-1-carboxylate:

[0136] The compound tert-butyl 4-((4-nitrophenyl)sulfonyl)piperazine-1-carboxylate (3.51g, 9.46mmol) was dissolved in dry CH 2 Cl 2 (30 mL), stirred overnight at room temperature under ...

Embodiment 2～17

[0147] Example 2-17 Synthesis of Compound 2-17

[0148] The operation and feeding are the same as in Example 1.

Embodiment 18

[0149] Example 18 Synthesis of Compound 18

[0150] The preparation method is as follows:

[0151] Step a. Synthesis of (E)-N-(4-(piperidin-4-yl)butyl)-3-(3-pyridyl)acrylamide:

[0152] The compound 4-(4-aminobutyl) piperidine-1-carboxylic acid tert-butyl ester (2.56g, 10.0mmol) and (E)-3-(3-pyridine) acrylic acid (1.49g, 10.0mmol), HATU (5.70g, 15.0mmol), DIPEA (1.90g, 15.0mmol) were dissolved in dry DMF (20mL), reacted at room temperature for 2h, the reaction solution was poured into 200mL saturated sodium chloride solution, and extracted with ethyl acetate (30mL×3), the organic phases were combined and then washed with saturated brine 30mL to remove the remaining DMF, dried over anhydrous sodium sulfate and concentrated, and purified by silica gel column chromatography (eluent, dichloromethane / methanol=100 / 4) , Get 3.10g of white solid, the obtained product is dissolved in dry CH 2 Cl 2 TFA (6 mL) was added to (30 mL), and reacted overnight at room temperature. The reaction solu...

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Abstract

The invention relates to the technical field of medicines, in particular to an NAMPT protein degradation targeted chimera. The NAMPT protein degradation targeted chimera is a compound as shown in a general formula (i) and / or (ii) or pharmaceutically acceptable salt thereof. The invention also relates to a preparation method and application of the NAMPT protein degradation targeted chimera. The compound shows the good NAMPT enzyme inhibition activity, can down-regulate the intracellular and extracellular NAMPT protein levels in a ubiquitin proteasome way to realize tumor inhibition, has the certain broad-spectrum antitumor activity, can obviously inhibit tumor growth, and can be applied to NAMPT mediated tumor diseases.

Description

Technical field [0001] The invention relates to the technical field of medicine, in particular to a NAMPT protein degradation targeting chimera and a preparation method and application thereof. Background technique [0002] Nicotinamide adenine dinucleotide (NAD) is one of the most important coenzymes in the redox process of cells and plays a vital role in the physiological processes of cells. The synthesis of NAD can be achieved through de novo synthesis pathways and three salvage synthesis pathways. In mammals, NAD is mainly obtained from the salvage pathway using nicotinamide as the starting material, and nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme of this pathway. Compared with normal cells, tumor cells have a higher proliferation rate and energy requirements, so NAMPT is in a high expression state, which is an important target in anti-tumor research. Recently, it has been reported in the literature that NAMPT can be secreted outside the cell ...

Claims

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Application Information

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IPC IPC(8): C07K5/027C07K5/03C07K5/033C07K5/078C07D401/12A61K31/496A61K38/05A61K38/06A61P35/00A61P37/04
CPCC07K5/0205C07K5/0207C07K5/021C07K5/06165C07D401/12A61P35/00A61P37/04A61K38/00
Inventor 盛春泉董国强吴颖何世鹏程俊飞黄亚辉陈树强武善超李兴麟马俊辉
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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