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3-(N, N-disubstituted amino) propanamide derivative and preparation method and use thereof in medicine

A double substitution and propionamide technology, applied in the field of chemical synthesis of drugs, can solve the problems of clinical research failure, failure to produce high affinity, and inability to reduce LDL-C levels

Active Publication Date: 2017-03-22
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) propanamide derivative and preparation method and use thereof in medicine
  • 3-(N, N-disubstituted amino) propanamide derivative and preparation method and use thereof in medicine
  • 3-(N, N-disubstituted amino) propanamide derivative and preparation method and use thereof in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1: Preparation of 3-(3,4-dichlorophenyl-4-fluorobenzyl)amino-1-(4-phenylpiperazinyl)propanamide

[0058] (1) Preparation of 3-(3,4-dichlorophenyl)aminoacrylic acid:

[0059] 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.

[0060] (2) Preparation of 1-phenylpiperazine:

[0061] In a 50mL three-neck flask, dissolve 2.1g (20mmol) of diethanolamine in 15mL of dichloromethane, dissolve 7mL (excess) of thionyl ch...

Embodiment 2

[0068] Example 2: Preparation of 3-(3,4-dichlorophenyl-4-fluorobenzyl)amino-1-morpholinopropionamide

[0069] 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

[0070] Example 3: Preparation of 3-(4-fluorobenzyl-3,4-dichlorophenyl)amino-N-benzyl-N-methylpropionamide

[0071] 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

An object of the present invention is to provide a novel 3-(N, N-disubstituted amino) propanamide derivative shown as a general formula (I) and a pharmaceutically acceptable salt thereof. Another object of the present invention is to provide a preparation method of the 3-(N, N-disubstituted amino) propanamide derivative compound and the derivative thereof. The general formula (I) is as follows: R1, R2, R3 and R4 are as described in the specification and claims. The present invention also provides use of the compound and the composition thereof as a therapeutic agent particularly as a cholesteryl ester transfer protein (CETP) inhibitor.

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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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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