Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

1,2,4-substituerte 1,2,3,4-tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as cetp inhibitors for the treatment of atherosclerosis and obesity

A three-substitution and two-substitution technology, which is applied to the active ingredients of heterocyclic compounds, anti-toxic agents, anti-inflammatory agents, etc., can solve the problems of not meeting medical needs, increasing plasma HDL levels, etc.

Inactive Publication Date: 2006-06-28
PFIZER PRODS ETAT DE CONNECTICUT
View PDF117 Cites 7 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a result, there remains an unmet medical need for a well-tolerated drug that significantly increases plasma HDL levels and thereby reverses or slows the progression of atherosclerosis

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 1,2,4-substituerte 1,2,3,4-tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as cetp inhibitors for the treatment of atherosclerosis and obesity
  • 1,2,4-substituerte 1,2,3,4-tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as cetp inhibitors for the treatment of atherosclerosis and obesity
  • 1,2,4-substituerte 1,2,3,4-tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as cetp inhibitors for the treatment of atherosclerosis and obesity

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0301] An alternative method of preparing the desired compound of formula II is from the corresponding compound of formula X by using a chlorinating reagent such as phosphorus(III) chloride or thionyl chloride in a reaction inert solvent such as dichloromethane or chloroform optionally This is achieved by treatment comprising a base such as pyridine, diisopropylethylamine or 2,6-di-tert-butyl-4-methylpyridine at 0°C to 60°C, usually ambient temperature, for 1 to 24 hours, wherein L is (C 1 -C 6 ) alkoxycarbonyl and V, R 1 , R 2 , R 4 , R 5 , R 6 and R 7 as defined above. The non-parasitic formed is then treated with a fine metal powder such as zinc in the presence of an acid or mixed acids such as acetic acid or hydrochloric acid in a suitable solvent or mixed solvents such as methanol, water or tetrahydrofuran at 25°C to 60°C, usually ambient temperature. Chlorine-containing derivatives as a mixture of enantiomers afford the desired products of formula II.

[0302] T...

Embodiment 1

[0589]

[0590] 4-(3,5-Di-trifluoromethyl-benzoyl)-6,7-dimethoxy-2-methyl-2H-quinoline-1-carboxylic acid ethyl ester

[0591] Ethyl 4-diazo-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate (Preparation 7, 0.65 mmol) prepared as above Diethyl ether solution was added to 3,5-bistrifluoromethylbenzoyl chloride (180 mg, 0.65 mmol) and N, N-diisopropylethylamine (120 μl, 0.65 mmol) in diethyl ether solution (15 mL) and heated at room temperature Stir in the dark under nitrogen for 15 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with 3:1 hexane:ethyl acetate to afford partially purified product which was subjected to reverse phase chromatography (linear acetonitrile:water gradient, 55% to 100 % acetonitrile, both phases contained 0.1% formic acid) to give the title compound as a lemon yellow solid (90 mg).

[0592] MS: 518.1[M+H] + measured value

[0593] 1 H-NMR (CDCl 3 ): δ8.26(s, 2H), 8.07(s, 1H), 7.25(brs...

Embodiment 2

[0595]

[0596] (R)-4-[(3,5-Di-trifluoromethyl-phenyl)-hydroxy-methoxycarbonyl-methyl]-2-ethyl-6-trifluoromethyl-2H-quinoline -1-Carboxylic acid ethyl ester

[0597] A solution of 3,5-bis(trifluoromethyl)benzene bromide (0.818 mL, 4.74 mmol) in THF (0.7 mL) was added dropwise to stirred magnesium powder (116 mg, 4.74 mmol) in anhydrous THF ( 4.7 mL) solution to prepare 3,5-bis(trifluoromethylphenyl)magnesium bromide solution. The mixture was then heated to reflux for 1 hour to give a dark solution. A portion of this solution (1.5 mL) was added dropwise at 78 °C to ethyl (R)-2-ethyl-4-methoxycarbonyl-6-trifluoromethyl-2H-quinoline-1-carboxylate (Preparation 10, 133mg, 0.345mmol) in anhydrous THF solution (4mL). After 30 minutes, the mixture was warmed to 0°C and poured into water, extracted with ethyl acetate, and a few drops of 2N hydrochloric acid were added to facilitate separation of the layers. The organic layer was dried over anhydrous sodium sulfate and evaporated...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

Quinoline and quinoxaline compounds of formula I and III, wherein the substituents are as defined in claims 1 and 15, pharmaceutical compositions comprising these compounds and these compounds are effective in raising certain plasma lipid levels, including high-density lipoprotein cholesterol As well as the application of lowering certain other blood lipid levels such as LDL-cholesterol and triglycerides, thus for the treatment of diseases caused by abnormalities of low levels of HDL cholesterol and / or high levels of LDL-cholesterol and triglycerides in mammals, including humans, such as Atherosclerosis and cardiovascular disease.

Description

Background technique [0001] The present invention relates to quinoline and quinoxaline compounds, pharmaceutical compositions containing these inhibitors and their use for raising certain blood lipids including high-density lipoprotein (HDL)-cholesterol levels and lowering certain other blood lipids such as low-density lipoprotein (LDL)-cholesterol and triglyceride levels are therefore used in the treatment of diseases affected by low levels of HDL cholesterol and / or high levels of LDL-cholesterol and triglycerides, as in certain mammals (i.e. plasma Animals containing CETP) including human atherosclerosis and cardiovascular disease. [0002] Atherosclerosis and its associated coronary artery disease (CAD) are the leading causes of death in the industrialized world. Coronary heart disease (CHD) remains the most common cause of death in the United States, accounting for 44% of all U.S. Death, 53% of which are related to coronary heart disease with atherosclerosis. [0003] T...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/14C07D215/12C07D215/50C07D241/42C07D401/04C07D401/06C07D401/12C07D403/06C07D403/10C07D405/06C07D405/12C07D409/06C07D409/12C07D413/06C07D413/10C07D413/12C07D417/06C07D417/12C07D417/14C07D471/04C07D495/04
CPCA61P3/00A61P3/04A61P3/06A61P3/10A61P9/00A61P9/10A61P9/12A61P15/10A61P25/00A61P25/28A61P29/00A61P31/04A61P39/06A61P43/00C07D215/12C07D215/14C07D241/42C07D401/04C07D401/06C07D401/12C07D403/06C07D403/10C07D405/06C07D405/12C07D409/06C07D409/12C07D413/06C07D413/10C07D413/12C07D417/06C07D417/12C07D417/14C07D471/04C07D495/04A61K31/47C07D215/50
Inventor 乔治·张玛丽·T·迪迪乌克贾里·I·芬尼曼拉维·S·加里吉帕蒂瑞安·M·凯利戴维·A·佩里罗杰·B·鲁格里布鲁斯·M·贝克尔迈克尔·P·波拉斯特里
Owner PFIZER PRODS ETAT DE CONNECTICUT
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com