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3-(n,n-disubstituted amino)propionamide derivatives, preparation method and application in medicine

A propionamide, amine-based technology, used in the field of chemical synthesis of drugs, can solve the problems of clinical research failure, no high affinity, and inability to reduce LDL-C levels.

Active Publication Date: 2020-05-01
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Dalcetrapib is an irreversible non-competitive inhibitor, but it does not have high affinity with CETP (IC50>1000nM). Although Dalcetrapib can slightly increase the level of HDL-C in serum, it cannot reduce LDL-C level, so Dalcetrapib is not an ideal CETP inhibitor, which eventually led to the failure of clinical research
[0007] Although a series of CETP inhibitors for the treatment of atherosclerotic diseases have been disclosed at present, there is no CETP inhibitor drug on the market, and it is still necessary to develop a compound with a novel structure and better efficacy. After continuous efforts, the present invention has a design with The compound of the structure shown in general formula (I), and find that the compound with this type of structure shows excellent CETP inhibitory activity

Method used

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  • 3-(n,n-disubstituted amino)propionamide derivatives, preparation method and application in medicine
  • 3-(n,n-disubstituted amino)propionamide derivatives, preparation method and application in medicine
  • 3-(n,n-disubstituted amino)propionamide derivatives, preparation method and application in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1: Preparation of 3-(3,4-dichlorophenyl-4-fluorobenzyl)amino-1-(4-phenylpiperazinyl)propanamide

[0056] (1) Preparation of 3-(3,4-dichlorophenyl)aminoacrylic acid:

[0057] Add 3,4-dichloroaniline (4.6g) into a 50mL three-necked flask, add (17.0mL) acrylic acid and 10% hydrochloric acid respectively, heat to 50°C, and react for 3h. Heating was stopped, and the reaction solution was slowly poured into a large amount of ice-water mixture, a large amount of light yellow solid was precipitated, which was suction filtered and vacuum-dried to constant weight. After column chromatography (petroleum ether: ethyl acetate: glacial acetic acid = 5:1:0.01), a yellow solid 3-(3,4-dichlorophenyl)aminoacrylic acid (3.5g) was obtained with a yield of 72.10% . Melting point: 49.5-51.2°C.

[0058] (2) Preparation of 1-phenylpiperazine:

[0059] In a 50mL three-neck flask, dissolve 2.1g (20mmol) of diethanolamine in 15mL of dichloromethane, dissolve 7mL (excess) of thionyl ch...

Embodiment 2

[0066] Example 2: Preparation of 3-(3,4-dichlorophenyl-4-fluorobenzyl)amino-1-morpholinopropionamide

[0067] The preparation process of compound 2 is the same as that of compound 1. 1 H-NMR (400MHz, CDCl 3 , ppm) δ: 7.21-7.07 (m, 3H), 7.04-6.93 (m, 2H), 6.73 (d, J = 2.97Hz, 2H), 6.49 (dd, J = 2.97, 8.97Hz, 1H), 4.51 (s,1H),3.77(t,J=7.08Hz,2H),3.69-3.55(m,6H),3.40-3.33(m,2H),2.58(d,J=6.93Hz,2H); ESI- MS(m / z):411.1[M+H] + ,433.1[M+Na] + .

Embodiment 3

[0068] Example 3: Preparation of 3-(4-fluorobenzyl-3,4-dichlorophenyl)amino-N-benzyl-N-methylpropionamide

[0069] The preparation process of compound 3 is the same as that of compound 1. 1 H-NMR (400MHz, CDCl 3 )δ: 7.37-7.27 (m, 3H), 7.24-7.03 (m, 5H), 7.04-6.90 (m, 2H), 6.72 (dd, J=2.94, 21.2Hz, 1H), 6.57-6.36 (m, 1H), 4.60-4.40(m, 4H), 3.89-3.74(m, 2H), 3.03-2.97(m, 3H), 2.72-2.58(m, 2H); ESI-MS(m / z): 445.2[ M+H] + ,467.2[M+Na] + ,483.2[M+K] + .

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Abstract

Provided are a 3-(N,N-disubstituted amino group) propanamide derivative shown in a general formula (I) and a pharmaceutically acceptable salt thereof. Also provided are a 3-(N,N-disubstituted amino group) propanamide compound and a preparation method of a derivative thereof. The general formula (I) has the following structure: R 1, R 2, R 3 and R 4, as described in the specification. Moreover, the compound and a combination thereof can be used as therapeutic agents, and can be used as cholesterylester transfer protein (CETP) inhibitors in particular.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis drugs, and relates to a new class of 3-(N,N-disubstituted amino)propionamide derivatives, a preparation method thereof and its use as a therapeutic agent, especially as a cholesteryl ester transfer protein (CETP) Use of Inhibitors. Background technique [0002] Dyslipidemia refers to the disorder of lipid metabolism in the human body leading to elevated blood cholesterol (CE), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), triglyceride (TG), high Lower density lipoprotein cholesterol (HDL-C). A large number of clinical epidemiological studies have confirmed that dyslipidemia is a direct risk factor for atherosclerosis and coronary heart disease. [0003] Past studies have shown that elevated LDL-C is a major factor in the increased risk of cardiovascular disease (CVD) through the use of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/185C07D213/75C07C237/04C07C237/06C07D209/08C07C311/21C07C311/29C07C231/02C07C231/12C07C303/40A61K31/495A61K31/535A61K31/197A61K31/496A61P9/00
CPCC07C231/02C07C231/12C07C237/04C07C237/06C07C303/40C07C311/21C07C311/29C07D209/08C07D213/75C07D295/185A61K31/495
Inventor 赵冬梅刘春池谢洪磊宋帅白长林马倩倩郝晨洲程卯生
Owner SHENYANG PHARMA UNIVERSITY
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