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N-aryl piperidine substituted biphenylcarboxamides as inhibitors of apolipoprotein B

An aryl and alkoxycarbonyl technology, applied in the field of new N-arylpiperidine substituted biphenyl carboxamides, can solve the problem of limited drugs

Inactive Publication Date: 2009-10-14
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, currently available drugs for the treatment of hyperlipidemia are quite limited

Method used

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  • N-aryl piperidine substituted biphenylcarboxamides as inhibitors of apolipoprotein B
  • N-aryl piperidine substituted biphenylcarboxamides as inhibitors of apolipoprotein B
  • N-aryl piperidine substituted biphenylcarboxamides as inhibitors of apolipoprotein B

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A1

[0165] Preparation of intermediate (1)

[0166] At 0°C, 4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid (0.0069mol) was dissolved in dichloromethane (400ml) and oxalyl chloride (0.069mol) and di methylformamide (1 drop). Under nitrogen flow, 4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid (0.0621 mol) was added in portions again. Oxalyl chloride (0.069 mol) and dimethylformamide (1 drop) were added and the reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was filtered, the residue was dissolved in dichloromethane (100ml), and the resulting mixture was added dropwise to 1-(4-aminophenyl)-4-piperidine ethyl acetate (0.069mol), tris A mixture of ethylamine (17.5ml) and dichloromethane (300ml). The reaction mixture was allowed to reach room temperature over 90 minutes. The resulting reaction mixture was washed with water, dried and the solvent was evaporated. The residue was stirred in a hot mixture of hexane and ethyl acetate and the resul...

Embodiment A2

[0170] Preparation of intermediate (3)

[0171] At 0°C, 6-methyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid (0.0025mol) was dissolved in anhydrous dichloromethane (140ml) and ethyl alcohol diacid dichloride (2.4ml) and a few drops of dimethylformamide. The remainder of 6-methyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid (0.0225 mol) was then added in portions under nitrogen flow. The reaction mixture was heated gently to 40 °C until a homogeneous solution was obtained and gas evolution ceased. The mixture was allowed to cool to room temperature, then filtered through a Buchner filter. The filter residue was dissolved in dichloromethane, and then added dropwise to an anhydrous solution of ethyl 1-(4-aminophenyl)-4-piperidine acetate (1 equivalent, 0.025 mol) and triethylamine (3 g) at 0 ° C. Dichloromethane (140ml) solution. The reaction mixture was allowed to warm to room temperature over 90 minutes. The precipitate was filtered off and dried to ...

Embodiment A3

[0175] Preparation of intermediate (5)

[0176] A mixture of ethyl 4-piperidinecarboxylate (0.03mol), 1-fluoro-4-nitro-benzene (0.03mol), potassium carbonate (4.5g) and dimethylformamide (50ml) was reacted at 60°C for 4 hours , then the solvent was evaporated under reduced pressure, and the resulting residue was stirred in water. The resulting yellow solid was filtered off and dissolved in dichloromethane (100ml). The organic layer was dried and the solvent was evaporated. The resulting oil was crystallized from hexane, and the desired product was collected to give 7 g of intermediate (5) (m.p. 70-71°C).

[0177] Preparation of intermediate (6)

[0178] At 25 °C, a mixture of intermediate (5) (0.025 mol) and ethanol (150 ml) was heated under pressure (30 bar = 3.10 6 Hydrogenation overnight at Pa) over catalyst Pd / C 10% (0.5 g). After uptake of hydrogen (3 equivalents), the reaction mixture was filtered and the solvent was evaporated under reduced pressure to yield 6 ...

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PUM

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Abstract

N-aryl piperidine substituted biphenylcarboxamides compounds of formula (I) methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use of said compounds as a medicine for the treatment of hyperlipidemia, obesity and type II diabetes.

Description

technical field [0001] The present invention relates to novel N-arylpiperidine-substituted biphenyl carboxamides having apolipoprotein B inhibitory activity and hypolipidemic activity. The present invention also relates to the preparation method of the compound, the pharmaceutical composition containing the compound and the use of the compound as medicine in the treatment of hyperlipidemia, obesity and type II diabetes. Background technique [0002] Obesity is the cause of many serious health problems such as diabetes and heart disease in adults. In addition, weight loss has also become a problem for more and more people. [0003] Hypercholesterolemia (especially hypercholesterolemia accompanied by elevated concentrations of low-density lipoprotein (hereinafter referred to as LDL) and very low-density lipoprotein (hereinafter referred to as VLDL) in plasma) is associated with premature atherosclerosis and A causal relationship between and / or cardiovascular disease is now w...

Claims

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Application Information

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IPC IPC(8): C07D211/60C07D211/34C07D405/12C07D401/12A61K31/445A61P3/06
CPCC07D211/60C07D401/12C07D405/12C07D211/34A61P3/10A61P3/04A61P3/06A61P43/00A61P9/10C07D401/04
Inventor L·米尔佩尔M·维耶勒沃耶J·T·M·林德斯
Owner JANSSEN PHARMA NV
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