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NEPT compound and preparation method and application thereof

A compound and reaction technology, applied in the field of NEPT compounds and their preparation and application, can solve the problems of lack of effective treatment methods and limited treatment methods for advanced hepatocellular carcinoma, and achieve a clear mechanism of action, mature technology, and less liver toxicity and side effects Effect

Active Publication Date: 2015-03-11
SHENZHEN GRADUATE SCHOOL TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although hepatocellular carcinoma detected at an early stage can be cured by liver transplantation and liver resection, only a small number of cases can be treated. recurrence after surgery
What is even more frustrating is that most patients are diagnosed at an advanced stage of cancer, and currently there is a lack of effective treatment methods for advanced hepatocellular carcinoma, and the options for treatment are extremely limited. Therefore, further exploration of molecular mechanism and develop novel targeted therapeutics based on it

Method used

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  • NEPT compound and preparation method and application thereof
  • NEPT compound and preparation method and application thereof
  • NEPT compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1. Synthesis of N-(4-((2-(2-(naphthalene-1-yl)acetamido)ethyl)carbamoyl)piperidin-4-yl)-6-(trifluoromethyl) Nicotinamide (NEPT, compound 6a)

[0042] The synthetic route is as follows:

[0043]

[0044] In a 50mL single-mouth bottle, add 250mg (1.02mmol) 1a, 863mg (2.55mmol) Fmoc-OSu, 10mL THF / H 2 O (1:1, v / v), adjust the pH to between 8-9 with saturated sodium carbonate solution, stir for 18 hours at room temperature; extract the resulting solution with ether (2×5mL), adjust the pH to 5.0 with concentrated hydrochloric acid for the aqueous solution About, a white viscous solid is formed, filtered and dried to obtain a white solid 2a. The NMR characterization data is consistent with the results reported in the literature.

[0045] In a 200mL single-neck flask, add 1.87g (10mmol) of naphthaleneacetic acid 1b, an equimolar amount of N-hydroxysuccinimide HOSu, and dissolve it in 50mL of chloroform; an equimolar amount of DIC in 15mL of chloroform, Slowly drip the above ...

Embodiment 2

[0049] Example 2. Synthesis of N-(1-benzyl-4-((2-(2-(3-fluorophenyl)acetamido)ethyl)carbamoyl)piperidin-4-yl)-6- (Trifluoromethyl) Nicotinamide (6h)

[0050] First, synthesize compound 1c according to the following synthetic route;

[0051]

[0052] In a 100mL single-mouth bottle, add 2.16g (10mmol) 1-benzyl-4-cyano-4-hydroxypiperidine, excess (about 10g) ammonium carbonate, 40mL ethanol / water (1:1, v / v) , The mixture was stirred and reacted at 60°C, and white needle-like crystals were gradually formed. After about 12 hours, the formed crystals were filtered and washed with hot water; in a 250mL single-neck flask, add 4.0g lithium hydroxide and 50mL deionized water. After stirring and dissolving, add the white needle-like crystals obtained above, heat to reflux for 48 hours; cool to room temperature, filter to remove the white solid precipitate formed, and the filtrate is rotary evaporated to remove the solvent to obtain a mixture of inorganic salt and 1c. Add anhydrous methanol. ...

Embodiment 3

[0069] Example 3. The compound inhibits tumor cell proliferation activity in vitro

[0070] The logarithmic growth phase of human liver cancer cells HepG2 and leukemia cells K562 (the above cells were purchased from the Cell Bank of the Type Culture Collection Committee of the Chinese Academy of Sciences, and the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences). 2×10 5 Inoculated into 96-well plate at a density of pieces / mL, 99μL / well, at 37°C, 5% CO 2 After culturing in the incubator for 4 hours, add the compound prepared in the embodiment of the present invention to each well to make the final concentration of 50μmol / L, 25μmol / L, 10μmol / L, 5μmol / L, 1μmol / L and 0.5μmol / L respectively. 6 concentration gradients; each compound has five replicate wells, and both negative and positive controls are set. The negative control is a 1% DMSO solution by volume; after 48 hours of action, add MTT (5mg / ml) solution, 10μL / Well, continue to...

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Abstract

The invention discloses a NEPT compound and a preparation method and the application thereof. The NEPT compound is shown as formula I. This preparation method of the NEPT compound shown as the formula I comprises the following steps: (1) a compound shown as formula II reacts with ethylenediamine to obtain a compound shown as formula III; (2) a compound shown as formula IV reacts with 9-fluorene methyl-N-succinimido carbonate under alkaline conditions to obtain a compound shown as formula V; (3) the compound shown as the formula III reacts with the compound shown as the formula V in the presence of a condensing agent to obtain a compound shown as formula VI; (4) a deprotection reaction of the compound shown as the formula VI is carried out in the presence of an organic alkali to obtain a compound shown as formula VII; and (5) the compound shown as the formula VII reacts with a compound shown as formula VIII in the presence of the condensing agent to obtain the compound shown as the formula I; wherein, X is C, a first chemical group or a second chemical group (the first chemical group and the second chemical group are shown in the specification), and a compound shown as the formula I in which the X is NH is obtained by deprotection of the compound shown in the formula I in which the X is the second chemical group under acidic conditions. The invention also provides the application of the compound shown in the formula I in preparation of drugs for prevention and / or treatment of tumour.

Description

Technical field [0001] The invention relates to a NEPT compound and its preparation method and application. Background technique [0002] Liver cancer is a very harmful disease. It has the characteristics of a large number of cases, lack of effective treatment methods, and high mortality. Especially in my country, the number of cases and deaths of liver cancer ranks first in the world. Of primary liver cancer, 90% are hepatocellular carcinoma (HCC), which causes approximately 700,000 deaths worldwide each year, and is the third leading cause of cancer-related deaths. Although early detection of hepatocellular carcinoma can be cured by liver transplantation and liver resection, only a small number of cases can be treated. For example, in Asia, such cases account for less than 10% of cases, and as many as 50% of patients It relapsed after the operation. What’s more frustrating is that most patients are already in the advanced stage of cancer when they are discovered, and the curr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12C07D211/66C07D409/12C07D213/82C07C237/24C07C231/14A61K31/455A61K31/4468A61K31/4535A61K31/166A61P35/00A61P35/02A61P1/16
Inventor 蒋宇扬金锋高丹张存龙谭春燕
Owner SHENZHEN GRADUATE SCHOOL TSINGHUA UNIV
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