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Quinoline compound, pharmaceutical composition, preparation method and application thereof

A technology of compounds and quinolines, applied in the field of pharmaceutical chemical synthesis, can solve the problem of insufficient efficacy of blood lipid-lowering drugs

Inactive Publication Date: 2009-11-04
SHANGHAI INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Therefore, the technical problem to be solved by the present invention is to provide a drug with higher efficacy for the existing HMGCoA reductase inhibitors whose side chain is a lactone structure. Novel hypolipidemic quinoline compound, pharmaceutical composition, preparation method and application thereof

Method used

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  • Quinoline compound, pharmaceutical composition, preparation method and application thereof
  • Quinoline compound, pharmaceutical composition, preparation method and application thereof
  • Quinoline compound, pharmaceutical composition, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: (3R,5S)-7-[4,6,7,8-tetra-(p-isopropylphenylthio)quinolin-3-yl]-3,5-dihydroxy-6( E)-Heptenoic acid (A1)

[0047] (4R,6S)-6-[(E)-2-(4,6,7,8-tetra-p-isopropylphenylthioquinoline-3-)vinyl]-3,4,5, 6-Tetrahydro-4-hydroxy-2H-pyran-2-one 0.5g (0.58mmol) and 5ml THF (tetrahydrofuran) were cooled to 0℃, 1N NaOH 0.8ml (0.8mmol) was added, and stirred for 1h at 0℃ Adjust the pH value to 2 with 1N HCl, concentrate the reaction solution under reduced pressure, add water and ethyl acetate, separate the organic layer, extract the aqueous layer three times with ethyl acetate, combine the organic layers, wash with water until neutral, anhydrous Na 2 SO 4 Dry and concentrate to obtain 0.4 g of solid, yield 78%, Mp (melting point): 118-120°C, [ α ] D 26 = 18.2 (c 1, THF). 1 H NMR(400MHz, DMSO-d 6 )δ1.17-1.11 (m, 18H), 1.25 (d, 6H, J=6.8 Hz), 1.62-1.53 ​​(m, 2H)...

Embodiment 2

[0048] Example 2: (3R,5S)-7-[6-fluoro-7-chloro-4-(m-methoxyphenylthio)quinolin-3-yl]-3,5-dihydroxy-6(E )-Heptenoic acid (A2)

[0049] (4R,6S)-6-[(E)-2-(6-fluoro-7-chloro-4-m-methoxyphenylthioquinolin-3-yl)vinyl]-3,4,5,6 -Tetrahydro-4-hydroxy-2H-pyran-2-one 0.27g (0.58mmol) and 5ml methanol to cool to 10℃, add 1N KOH 0.8ml (0.8mmol), stir for 5h, adjust pH with 1NHCl at 25℃ When the value reached 2, the reaction solution was concentrated under reduced pressure, water and ethyl acetate were added, the organic layer was separated, the aqueous layer was extracted three times with ethyl acetate, the organic layers were combined, washed with water until neutral, anhydrous Na 2 SO 4 Dry and concentrate to obtain 0.26 g of solid, yield 94.7%, Mp: 178-180°C, [ α ] D 26 = 31.8 (c 1, methanol). 1 H NMR(400MHz, DMSO-d 6 )δ1.69-1.59(m, 2H), 2.42-2.25(m, 2H), 3.67(s, 3H), ...

Embodiment 3

[0050] Example 3: (3R,5S)-7-[6-fluoro-4,7-di-m-methoxyphenylthioquinolin-3-yl]-3,5-dihydroxy-6(E)- Heptenoic acid (A3)

[0051] 25℃, 1N NaOH 0.8ml (0.8mmol) was added (4R, 6S)-6-[(E)-2-(6-fluoro-4,7-di-methoxyphenylthioquinolin-3-yl )Vinyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one 0.33g (0.58mmol) and 5ml acetone solution, stir for 8h, use 1N HCl at 0℃ Adjust the pH to 2, concentrate the reaction solution under reduced pressure, add water and ethyl acetate, separate the organic layer, extract the aqueous layer three times with ethyl acetate, combine the organic layers, wash with water until neutral, anhydrous Na 2 SO 4 Dry and concentrate to obtain 0.29 g of solid, yield 85.3%, Mp: 154-156°C, [ α ] D 26 = 21.6 (c 1, methanol). 1 H NMR(400MHz, DMSO-d 6 )δ1.68-1.58(m, 2H), 2.5-2.24(m, 2H), 3.67(s, 3H), 3.78(s, 3H), 4.01(brs, 1H), 4.36(brs, 1H), 4.69 (brs, 1H...

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Abstract

The invention discloses a quinoline compound shown as general formula A, or pharmaceutically accepted solvate, or optical isomer or polymorphic substances of the quinoline compound. In the formula, X is S atom or O atom; M is H, or Na, or NH4or Ca; R1, R2 and R3 are respectively H, halogen and radical shown as general formula D or general formula E; R is H, or halogen, or alkyl group C1-C4 or oxyl group C1-C4. The invention also discloses a pharmaceutical composition, a preparation method of the quinoline compound as well as the application of the pharmaceutical composition in preparing HMG CoA reductase inhibitors or in preparing medicaments for effectively treating or preventing diseases by inhibiting HMG CoA reductase. The quinoline compound and the pharmaceutical composition thereof can produce favorable hypolipemic effect in vivo and can be used for treating diseases related to hyperlipemia.

Description

Technical field [0001] The invention belongs to the technical field of medicinal chemical synthesis, and specifically relates to a new class of quinoline compounds and their pharmaceutical compositions, preparation methods and applications in the field of medicine. Background technique [0002] Since hypercholesterolemia is considered to be the main risk factor for atherosclerosis and cardiovascular diseases, the research of lipid-lowering drugs has been developed rapidly, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) Reductase inhibitors (also known as "statins") are the mainstream products of hypolipidemic drugs (Cai Zhengyan, Zhou Weicheng. Research progress of HMG CoA reductase inhibitors. Chinese Journal of New Drugs. 2006, 15(22): 1907-1911). The fully synthetic statin drugs that have been marketed include fluvastatin, atorvastatin, rosuvastatin and pitavastatin. In the prior art, the structure of a fully synthetic statin drug consists of two parts: the parent ring (quino...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/36C07D215/20A61K31/47A61P9/12A61P3/06A61P9/10
CPCC07D215/233C07D215/20C07D215/36C07D405/06C07D215/22C07D215/26A61P3/00A61P3/06A61P9/00A61P9/10A61P9/12
Inventor 蔡正艳周伟澄郝群施振华盛雨辰施明玉梁清宁
Owner SHANGHAI INST OF PHARMA IND
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