Amide compounds, preparation method and medical use thereof

A compound and pharmaceutical technology, applied in the preparation of organic compounds, carboxylic acid amide preparation, chemical instruments and methods, etc., can solve the problem of low activity of small molecule inhibitors, poor membrane permeability, poor physical and chemical properties of peptidomimetic compounds, etc. question

Active Publication Date: 2015-12-23
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, research on inhibitors of MLL1-WDR5 protein-protein interaction is still in its infancy. The only inhibitors under research are peptidomimetics and a class of small molecule compounds, but peptidomimetic compounds have poor physical and chemical properties and poor membrane permeability. Poor, small molecule inhibitor activity is not high

Method used

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  • Amide compounds, preparation method and medical use thereof
  • Amide compounds, preparation method and medical use thereof
  • Amide compounds, preparation method and medical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Synthesis of N-(2-(4-methylpiperazine)-5-cyanophenyl)-2-chloro-3-methoxybenzenesulfonamide (1):

[0043] In a 25ml eggplant-shaped bottle, 1.0g (6.4mmol) of 2-fluoro-5-cyanoaniline was dissolved in anhydrous dichloromethane, and 2.3g (9.6mmol) of 2-chloro-3-methanol was added dropwise at room temperature. Dichloromethane solution of oxybenzenesulfonyl chloride, and then add 0.77ml (9.6mmol) of pyridine, and react overnight at room temperature. The reaction solution was spin-dried and column chromatographed to obtain 0.97 g of intermediate E as a light yellow solid (yield 48.5%).

[0044] Put 0.2g (0.61mmol) of the above solid in a 25ml eggplant-shaped bottle, dissolve it in 5ml DMF, add 0.088ml (0.8mmol) N-methylpiperazine, then add catalyst 0.14ml (0.8mmol) DIPEA, and react at 80°C for 3 After one hour, the reaction solution was diluted with 40 ml of ethyl acetate, washed twice with water, and the organic phase was collected and chromatographed to obtain 10.15 g of a ...

Embodiment 2

[0047] Synthesis of N-(2-fluoro-4-methoxyphenyl)-2-(4-methylhomopiperazine)-5-cyanophenylsulfonamide (2):

[0048] Using 2-fluoro-5-cyanobenzenesulfonyl chloride, 2-fluoro-4-methoxyaniline, and N-methylhomopiperazine as raw materials, according to the similar method of Example 1, compound 2 was synthesized, and two steps were obtained. rate 30.5%.

[0049] 1 HNMR (300MHz, CDCl 3 )δ8.22(s,1H),7.91(s,1H),7.81(d,J=7.3Hz,1H),7.08(d,J=8.4Hz,1H),6.98(d,J=7.7Hz, 2H),5.28(brs,1H),3.86(s,3H),3.28(t,J=4.3Hz,4H),3.02(m,2H),2.90(m,2H),2.70(s,3H), 1.87(m,2H).

Embodiment 3

[0051] Synthesis of N-(2-(4-methylpiperazine)-5-trifluoromethylphenyl)-2,4,6-trimethylbenzenesulfonamide (3):

[0052] Using 2-fluoro-5-trifluoromethylaniline, 2,4,6-trimethylbenzenesulfonyl chloride, and N-methylpiperazine as raw materials, compound 3 was synthesized according to the method similar to Example 1, two steps Yield 29.2%.

[0053] 1 HNMR (300MHz, CDCl 3 )δ7.98(d, J=2.5Hz, 1H), 7.86(dd, J=8.7, 2.5Hz, 2H), 7.23(d, J=8.7Hz, 1H), 6.98(s, 2H), 3.01( brs,4H),2.73(brs,10H),2.50(brs,4H),2.48(s,3H),2.28(s,3H).

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Abstract

The invention relates to the field of pharmaceutical chemistry, particularly a group of amide compounds (I) and a preparation method therefor and use thereof. Pharmacodynamic experiments prove that the compounds of the invention can be used for preparing medicines for treating leukemia. The formula (I) is shown in the description.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a group of amide compounds and their preparation method and application. The compounds of the invention can be used to prepare medicines for treating leukemia. Background technique [0002] The gene translocation and rearrangement of the 4-position lysine (H3K4) methyltransferase MLL1 of histone H3 forms a fusion gene, expressing MLL fusion protein, which can cause acute myelogenous leukemia (AML) and acute lymphoblastic leukemia Mixed lineage leukemia (ALL). Among them, leukemia caused by MLL1 abnormality accounts for 5-10% of adult AML leukemia and 70% of neonatal ALL leukemia. MLL leukemia has unique clinical characteristics, conventional chemotherapy is unsatisfactory, and the prognosis is poor. Therefore, it is necessary to develop new treatments and drugs for the biological properties of leukemia caused by MLL abnormalities. The occurrence of mixed lineage leukemia requ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C255/60C07C253/30C07C237/40C07C231/14C07C233/80C07D295/155C07D243/08C07D295/096C07D295/135C07D213/74C07D295/13C07D233/61C07D239/26C07D213/56C07C279/12C07C277/08A61K31/495A61K31/551A61K31/277A61K31/167A61K31/496A61K31/40A61K31/506A61P35/02
Inventor 尤启冬孙昊鹏李冬冬陈维琳郭小可张晓进徐晓莉
Owner CHINA PHARM UNIV
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