A group of 1-substituted-1, 8-naphthyridine formamide derivatives and preparation and application thereof

A kind of technology of naphthyridine carboxamide and derivatives, applied in the field of pharmacy

Inactive Publication Date: 2013-07-03
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The 1-substituted-1,8-naphthyridine carboxamide derivatives of the present invention can significantly increase the expression of ABCA1 and SR-BI, and have obvious

Method used

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  • A group of 1-substituted-1, 8-naphthyridine formamide derivatives and preparation and application thereof
  • A group of 1-substituted-1, 8-naphthyridine formamide derivatives and preparation and application thereof
  • A group of 1-substituted-1, 8-naphthyridine formamide derivatives and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] (a) Synthesis of 2-(2,6-dichloro-nicotinoyl)-3-(3-hydroxy-4-methoxyanilino)-ethyl acrylate

[0037] Add ethyl 2,6-dichloronicotinoyl acetate (10g, 38.2mmol) to 20mL of acetic anhydride, then add triethyl orthoformate (11.2g, 76.3mmol), heat up to 120°C and stir for 2 hours, The reaction solution was evaporated under reduced pressure to remove the solution, then cooled to room temperature, 20 mL of dichloromethane was added, after stirring evenly, 3-hydroxy-4-methoxyaniline (3.7 g, 26.7 mmol) was added, and the reaction was performed for 2 hours. Wash the filter cake with a small amount of ether, and dry the filter cake in vacuum to obtain 6.3 g of yellow powder solid, with a yield of 40.1%.

[0038] 1 H-NMR(DMSO)δ:1.01(t,J=7.2Hz,3H),3.79(s,3H),3.98-4.01(m,2H),6.04(s,1H),6.60(d,J=7.2 Hz,1H),6.91(d,J=7.2Hz,1H),7.73(d,J=7.4Hz,1H),8.17(d,J=7.4Hz,1H),8.63(d,J=13.8Hz, 1H),12.35(d,J=13.8Hz,1H).MS m / z:412.17[M+H] + .

[0039](b) Synthesis of ethyl 1-(3-hydroxy-4-methoxyphe...

Embodiment 2

[0061] (a) 1-[3-(3-bromopropoxy)-4-methoxyphenyl]-7-(dimethylamino)-1,4-dihydro-4-oxo-1,8 Synthesis of -naphthyridine-3-(3,5-difluorophenyl)carboxamide

[0062] Prepared according to the method of step (g) of Example 1, using the product of step (f) of Example 1 and 1,3-dibromopropane to obtain 1-[3-(3-bromopropoxy)-4-methane Oxyphenyl]-7-(dimethylamino)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-(3,5-difluorophenyl)carboxamide compound, It is in the form of white powder with a yield of 76%.

[0063] 1 H-NMR (CDCl 3 ):1.97-1.98(m,2H),3.09(s,6H),3.56-3.57(m,2H),3.80(s,3H),4.07-4.08(m,2H),6.52(t,J=1.2 Hz,1H),6.65(d,J=5.6Hz,1H),7.09(d,J=6.0Hz,1H),7.23(dd,J 1=6.0Hz,J 2 =1.6Hz,1H),7.35(d,J=1.6Hz,1H),7.37(d,J=1.2Hz,1H),7.39(d,J=1.6Hz,1H),8.41(d,J=6.0 Hz,1H),8.70(s,1H).MS m / z:588.32[M+H] + .

[0064] (b) 1-{3-[3-(N-methylmorpholine bromide)]propoxy-4-methoxyphenyl}-7-(dimethylamino)-1,4-dihydro Synthesis of -4-oxo-1,8-naphthyridine-3-(3,5-difluorophenyl)carboxamide

[0065] Pre...

Embodiment 3

[0068] (a) 1-[3-(5-Bromopentyloxy)-4-methoxyphenyl]-7-(dimethylamino)-1,4-dihydro-4-oxo-1,8 Synthesis of -naphthyridine-3-(3,5-difluorophenyl)carboxamide

[0069] Prepared according to the method of step (g) of Example 1, using the product of step (f) of Example 1 and 1,5-dibromopentane to obtain 1-[3-(5-bromopentyloxy)-4- Methoxyphenyl]-7-(dimethylamino)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-(3,5-difluorophenyl)carboxamide compound , in the form of off-white powder, with a yield of 77%.

[0070] 1 H-NMR (CDCl 3 ):1.29-1.30(m,2H),1.78-1.80(m,4H),3.08(s,6H),3.50-3.51(m,2H),3.80(s,3H),4.06-4.07(m,2H ),6.51(t,J=1.2Hz,1H),6.65(d,J=5.6Hz,1H),7.08(d,J=6.0Hz,1H),7.26(dd,J 1 =6.0Hz,J 2 =1.6Hz,1H),7.35(d,J=1.6Hz,1H),7.36(d,J=1.2Hz,1H),7.39(d,J=1.6Hz,1H),8.46(d,J=6.0 Hz,1H),8.71(s,1H).MS m / z:616.36[M+H] + .

[0071] (b) 1-{3-[5-(Pyridine bromide)pentyloxy]-4-methoxyphenyl}-7-(dimethylamino)-1,4-dihydro-4-oxo Synthesis of -1,8-naphthyridine-3-(3,5-difluorophenyl)carboxamide

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Abstract

The invention relates to a group of 1-substituted-1, 8-naphthyridine formamide derivatives, and a preparation method and an application thereof. The biological experimental studies show that the tested compounds in the derivatives remarkably inhibit the apical sodium-dependent bile acid transporter (ASBT) at the cellular level, and have increased effect on the expression of ABCA1 (ATP-binding cassette transporter A1) and SR-BI (scavenger receptor type B class I), thereby being expected to be developed to become a clinically effective medicament for treating associated cardiovascular diseases.

Description

Technical field: [0001] The invention belongs to the field of pharmacy, and specifically relates to a group of naphthyridine carboxamide derivatives and applications thereof. Background technique: [0002] Cardiovascular disease is listed as the first of the three major diseases (cardiovascular disease, tumor, infectious disease) that threaten human health today. Atherosclerosis (AS) is the pathological basis of cardiovascular diseases, and it is related to the occurrence and development of many diseases. The occurrence of AS is closely related to the abnormality of serum cholesterol and low-density lipoprotein. The liver and gastrointestinal system are the main organs for cholesterol and lipoprotein metabolism. The reverse cholesterol transport (RCT) process and the enterohepatic circulation of bile acids play a very important role in the absorption and metabolism of cholesterol and lipids. [0003] Currently, clinically used lipid-lowering drugs mainly include niacin, fi...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D519/00A61K31/4375A61K31/444A61K31/5377A61K31/4545A61K31/4995A61P9/10A61P3/06A61P1/16
Inventor 邵荣光王玉成司书毅刘洪涛何红伟蔡仕英许艳妮王菊仙白晓光徐长亮
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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