Chemoattractant Protein-1 Antagonists

Dioxo-9H-Purin-8-yl-Phenyl Derivatives, Their Preparation, and Their Use in the Treatment of Inflammatory Conditions and Immune Disorders 

Daluge et al., US Patent 7,002,012 (February 21, 2006) Assignee SmithKline Beecham Corporation Utility Treatment of Respiratory Disorders 

Cyclohexanemethylamine (68.66 g) and 200 ml 5M NaOH were stirred at — 10°C, then treated with phosgene (30.0 g) dissolved in 600 ml toluene, and stirred 20 minutes. A solid that formed was isolated, washed with 1500 ml water, dried, and the product isolated in 95% yield as a white powder, mp = 150—152°C. 

The Step 1 product (54.5 g) was treated with cyanoacetic acid dissolved in 260 ml acetic anhydride, then heated 2 hours to 80°C, and concentrated. The residual oil was dried by evaporation three times with 400 ml water/ethyl alcohol, 1 9, then dissolved in a mixture of 600 ml ethyl alcohol and 300 ml water at 80°C. The solution pH was raised to 10 using 10% aqueous NaHCOs, then diluted with 75 ml water, and colorless crystals isolated. The crystals were washed three times with 500 ml, dried, and the product isolated in 94% yield, mp = 138—141 °C. 

The Step 2 product (25.0 g) was dissolved in 440 ml apiece glacial acetic acid, water, and ethyl alcohol, then heated to reflux and NaN02 (5.65 g) added. Upon slowly cooling to ambient temperature, a lavender precipitate was isolated, which was washed with water/ethyl alcohol, 1 1, dried, and the product isolated as light purple crystals in 86% yield, mp = 240-243°C. 

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Gong JH, Clark-Lewis I (1995) Antagonists of monocyte chemoattractant protein 1 identified by modification of functionally critical NH2-terminal residues. J Exp Med 181 631-640 Gonzalez-Scarano F, Martin-Garcia J (2005) The neuropathogenesis of AIDS. Nat Rev Immunol 5 69-81... 

Gong JH, Ratkay LG, Waterfield JD, Clark-Lewis I (1997) An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-lpr mouse model. J Exp Med 186 131-137... 

McQuibban GA, Gong JH, Wong JP, Wallace JL, Clark-Lewis I, Overall CM. Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood 2002 100(4) 1160-1167. 

The isoxazole 200 is an important intermediate in the synthesis of a guanine-cytosine (G-C) DNA base hybrid <1999JOC8479> and the isoxazole 201 is an antagonist of the monocyte chemoattractant protein-1 (MCP-1) function <2002W0060900>. 

Abbreviations AIA, adjuvant-induced arthritis CIA, collagen-induced arthritis IL, interleukin ENA, Epithelial-neutrophil activating protein MIP, macrophage inflammatory protein MCP, monocyte chemoattractant protein EPS, lipopolysaccharide TNF, tumor necrosis factor IFN, interferon TGF, transforming growth factor IL-1 Ra, interleukin-1 receptor antagonist OSM, Oncostatin M. 

Chemokines Chemokines comprise a superfamily of small proteins that demonstrate a wide variety of biological and pathological functions [7], Many reports have shown that chemokines and their receptors regulate cell differentiation, proliferation, and migration. In this section, chemoattractant activity and small-molecular antagonists are focused on and described concisely as follows. 

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