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Piperazinylpiperidine derivatives as chemokine receptor antagonists

A compound, alkyl technology, applied in the field of compounds that regulate the activity of chemokine receptors such as CCR5 or bind to it, can solve the problem of no effect of infection

Inactive Publication Date: 2007-05-23
INCYTE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The compound specifically inhibits CCR5-mediated HIV-1 infection in U-87 astroglioma cells, but has no effect on infection of CXCR4-expressing cells

Method used

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  • Piperazinylpiperidine derivatives as chemokine receptor antagonists
  • Piperazinylpiperidine derivatives as chemokine receptor antagonists
  • Piperazinylpiperidine derivatives as chemokine receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0129] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Green and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), which is hereby incorporated by reference in its entirety.

[0130] The reaction can be monitored by any suitable method known in the art. For example, product formation can be detected by spectroscopic methods such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13 C), monitoring by infrared spectroscopy, spectrophotometry (eg UV-visible) or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0131] Examples of synthetic routes to compounds of ...

Embodiment 1

[0211] 5-({4-[(3S)-4-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-methylpiperazin-1-yl]-4-methyl piperidin-1-yl}carbonyl)-4,6-dimethylpyrimidine

[0212]

[0213] Step A

[0214] 5-Bromo-1-indanol

[0215] To a solution of 5-bromo-1-indanone (2.0 g, 9.5 mmol) in THF (20 mL) was added NaBH 4 (0.5 g, 12.8 mmol). After stirring overnight at room temperature, water was added to quench the solution. The resulting solution was extracted twice with EtOAc. The combined EtOAc layers were washed with Na 2 SO 4 Dry and concentrate in vacuo to give 2.0 g of the title compound as a solid. MS vs. C 9 h 9 Calculated value of BrO: (M+H) + 212.9; measured value 194.9 (M+H-H 2 O) + , 197.0 (M+H-H 2 O) + .

[0216]

[0217] Step B

[0218] (3S)-3-Methylpiperazine-1-carboxylic acid tert-butyl ester

[0219] To a solution of (2S)-2-methylpiperazine (20.0 g, 0.200 mol) in dichloromethane (300 mL) and triethylamine (20.4 g, 0.202 mol), di-tert-dicarbonate was added dropwise over 5 ho...

Embodiment 2

[0248] 5-({4-[(3S)-4-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-methylpiperazin-1-yl]-4-methyl piperidin-1-yl}carbonyl)-4,6-dimethylpyrimidine

[0249] This compound was prepared essentially as described in Example 1 using appropriate starting materials. MS for C 27 h 36 FN 5 Calculated value of O: (M+H) + 466; found 466.2.

[0250]

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Abstract

The present invention relates to compounds of Formula (I): wherein variable substituents are defined herein, that modulate the activity of or bind to chemokine receptors such as CCR5. In some embodiments, the compounds of the invention are selective for CCR5. The compounds can be used, for example, to treat diseases associated with chemokine receptor expression or activity such as inflammatory diseases, immune diseases and viral infections.

Description

field of invention [0001] The present invention relates to compounds that modulate the activity of or bind to chemokine receptors, such as CCR5. In some embodiments, the compound is selective for CCR5. The compounds can be used, for example, to treat diseases associated with chemokine receptor expression or activity, such as inflammatory diseases, immune diseases, and viral infections. Background of the invention [0002] The migration and transport of leukocytes from blood vessels to diseased tissue is involved in the initiation of the normal disease-fighting inflammatory response. This process, also known as the recruitment of leukocytes, is also involved in the onset and progression of life-threatening inflammatory and debilitating autoimmune diseases. The resulting pathology of these diseases results from the attack of the body's immune system in defense of normal tissues. Therefore, preventing and blocking leukocyte recruitment to target tissues would be a highly eff...

Claims

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Application Information

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IPC IPC(8): A61K31/495
Inventor C·－B·薛G·曹T·黄L·陈K·张A·王D·梅洛尼R·阿南德J·格伦B·梅特卡夫
Owner INCYTE
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