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Chemokine receptor antagonists and methods of use thereof

A compound and aliphatic-based technology, applied in anti-inflammatory agents, anti-viral agents, organic chemistry, etc., can solve problems such as unsuccessful development

Inactive Publication Date: 2005-02-23
MILLENNIUM PHARMA INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Receptor antagonists for larger proteins such as chemokines and C5a have not been successfully developed to date

Method used

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  • Chemokine receptor antagonists and methods of use thereof
  • Chemokine receptor antagonists and methods of use thereof
  • Chemokine receptor antagonists and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0234] Example 1: 4-(4-chlorophenyl)-1-[3-(10,11-dihydro-5H-

[0235] Dibenzo[a,d]cyclohepten-5-ylidene)propyl]piperidin-4-ol

[0236] To a solution of 5-(3-bromopropylene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (described in JP48-030064) (200mg) in DMF (10ml) 4-(4-Chlorophenyl)-4-hydroxypiperidine (230 mg), potassium carbonate (360 mg) and potassium iodide (50 mg) were added. The mixture was stirred at 70°C for 24 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was separated, washed with saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:1) to give the title compound (250 mg). 1 H-NMR (CDCl 3 )d: 1.65-2.11(5H, m), 2.32-3.10(8H, m), 3.22-6.67(4H, m), 5.87(1H, t), 7.03-7.44(12H, m).MS m / z : 444(M+1).

Embodiment 2

[0237] Example 2: 4-(4-chlorophenyl)-1-[3-(6,11-dihydrodibenzo[b,e]

[0238] Oxaheptin-11-ylidene)propyl]piperidin-4-ol

[0239]The title compound was prepared following the procedure of Example 1, except that 11-(3-bromopropylene)-6,11-dihydrodibenzo[b,e]oxepin was used instead of 5-(3-bromopropylene base)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene. 1 H-NMR (CDCl 3 )d: 1.61-2.16 (5H, m), 2.37-2.80 (8H, m), 5.22 (2H, brs), 5.70 (0.6x1H, t), 6.03 (0.4x1H, t), 6.73-6.90 (2H, m), 7.09-.7.45 (10H, m). MS m / z: 446 (M+1).

Embodiment 3

[0240] Example 3: Membrane preparation and binding detection of chemokine binding

[0241] Membranes were prepared using THP-1 cells (ATCC #TIB202). Cells were collected by centrifugation and washed twice with PBS (phosphate buffered saline). Cell pellets were frozen at -70 to -85°C. The frozen pellet was placed in an ice-cooled medium containing 5mM HEPES (N-2-hydroxyethylpiperazine-N'-2-ethane-sulfonic acid) pH 7.5, 2mM EDTA (ethylenediaminetetraacetic acid), each 5g / ml Aprotinin, leupeptin and chymostatin (protease inhibitors), and 100g / ml PMSF (phenylmethylsulfonyl fluoride - also a protease inhibitor) were dissolved in lysis buffer at a concentration of 1 to 5×10 7 cells / ml. This step lyses the cells. Mix the suspension well and resuspend any frozen cell pellets. Centrifuge at 400xg for 10 minutes at 4°C to remove nuclei and cell debris. Transfer the supernatant to a clean test tube and centrifuge at 25,000xg for 30 minutes at 4°C to collect membrane fragments. ...

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Abstract

Disclosed are novel compounds and a method of treating a disease associated with aberrant leukocyte recruitment and / or activation. The method comprises administering to a subject in need an effective amount of a compound represented by structural formula (I) or physiologically acceptable salt thereof.

Description

[0001] related application [0002] This application is a continuation-in-part of U.S. Application Serial No. 09 / 989,086, filed November 21, 2001, which is a continuation-in-part of U.S. Application Serial No. 09 / 989,086, filed July 28, 2000 / 627,886, U.S. Application Serial No. 09 / 627,886 is a continuation-in-part of U.S. Application Serial No. 09 / 362,837, filed July 28, 1999, U.S. Application Serial No. 09 / 362,837 is 1999 Continuation-in-Part of U.S. Application Serial No. 09 / 235,102, filed January 21, 1998, which is a part of U.S. Application Serial No. 09 / 148,823, filed September 4, 1998 Continuing the application, the entirety of the aforementioned related application is hereby incorporated by reference. Background of the invention [0003] Chemotactic cytokines, or chemokines, are a family of pro-inflammatory mediators that promote the recruitment and activation of various lineages of leukocytes and lymphocytes. They can be released by activation of various tissues. S...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/044A61KA61K31/4353A61K31/438A61K31/4427A61K31/451A61K31/4523A61K31/4525A61K31/4535A61K31/4545A61K31/496A61K31/506A61K31/527A61K31/537A61K31/5377A61K31/55A61K31/5513A61PA61P1/00A61P1/04A61P3/10A61P9/00A61P9/10A61P11/06A61P13/12A61P19/02A61P25/28A61P29/00A61P31/18A61P37/02A61P37/08A61P43/00C07DC07D211/52C07D221/00C07D223/00C07D223/20C07D313/00C07D313/12C07D337/00C07D337/12C07D401/06C07D401/14C07D405/00C07D405/06C07D409/06C07D451/00C07D471/04C07D491/00C07D491/04C07D493/04C07D495/04C07D497/04C07D513/04C07D519/00
CPCC07D491/04C07D211/46C07D211/52C07D401/06C07D401/14C07D405/06C07D409/06C07D471/04C07D491/044C07D493/04C07D495/04C07D519/00A61P1/00A61P1/04A61P11/00A61P11/06A61P13/00A61P13/12A61P17/06A61P19/00A61P19/02A61P25/00A61P25/28A61P29/00A61P3/00A61P3/10A61P31/00A61P31/18A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P7/00A61P9/00A61P9/10A61K31/4353
Inventor 杰伊·R·卢利中里宜资大岛悦男杰拉尔丁·C·B·哈里曼肯尼斯·G·卡尔森修米尔·勾西艾米·M·艾尔德卡伦·M·马蒂尔
Owner MILLENNIUM PHARMA INC
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