Napththalene derivatives which inhibit the cytokine or biological activity of microphage migration inhibitory factor (mif)

Example 1

6 7-Dimethoxy-2-naphthalene

2,3-Dimethoxynaphthalene

[0355]

[0356] A suspension of 2,3-dihydroxynaphthalene (5.00g, 0.0312 mol) in water (25 mL) in a three-necked round-bottomed flask was cooled in an ice-bath. Two pressure equilibrating funnels were set up and these charged with dimethyl sulphate (7.20 mL, 9.57 g, 0.0759 mol) and aqueous potassium hydroxide (5.57 g, 0.0993 mol in 17.0 mL of water) respectively. Both of these were added together dropwise over 10 minutes resulting in the suspension first dissolving and then a precipitate forming. The reaction was left overnight at room temperature. The solid was then filtered off, washed with water until the washings were neutral (5×200 mL), and dried to give 2,3-dimethoxynaphthalene (4.09 g, 70% yield) as a white powder;

[0357] Rf: 0.71 (19:1 CHCl3:MeOH), 0.82 (9:1 CHCl3:MeOH), mp: 112-113° C., lit.mp:113-116° C.;

[0358]1H NMR (CDCl3 / TMS): δ 4.01 (s, 6 H, 2×OCH3), 7.13 (s, 2H), 7.33-7.36 (m, 2H), 7.68-7.71(m, 2H); LRESI mass

Example 2

6,7-Dimethloxy-2-acetonaphthone

[0359]

[0360] A suspension of aluminium chloride (6.02g, 0.0451 mol) in sieve-dried nitrobenzene (10 mL) was cooled in an ice-bath and acetyl chloride (3.57 mL, 3.93 g, 0.0501 mol) added over 5 minutes. 2,3-Dimethoxynaphthalene (7.52 g, 0.0400 mol) in nitrobenzenie (25 mL) was then added over 10 minutes. The reaction was stirred for a further 60 minutes at 0° C. and then left overnight at room temperature. The mixture was poured onto a mixture of ice (60 g) and 10% HCl (100 mL). Chloroform (300 mL) was added and the two phases separated. The aqueous was further extracted with chloroform (2×150 mL) and the combined organics then washed with 5% aqueous sodium hydroxide (3×100 mL) and water (2×100 mL), dried (anhydrous Na2SO4), filtered and evaporated under vacuo to give a brown oil. This was flash column chromatographed (silica gel, chloroform) to give 6,7-dimethoxy-2-acetonaphthone (8.51 g. 93% yield) as an orange solid. A sample was further recr

Example 3

6,7-Dimethoxy-2-naphthoic acid

[0363]

[0364] Sodium hypochlorite (55 mL, 12.5% w / v) was first added to sodium hydroxide (1.80 g, 0.0450 mole) dissolved in water (5.5 mL). This solution was gently heated to 45° C. and 6,7-dimethoxy-2-acetonaphthone (2.50 g. 0.0187 mole) then added. Heating was gradually increased until the suspension dissolved at a temperature of 85° C. and the solution was maintained at 85° C. for a further 60 minutes. The solution was then allowed to cool to room temperature and filtered to remove a small amount of orange gum. Small quantities of sodium bisulfite (spatulla ends) were then added to the filtrate until it no longer darkened iodine / starch indicator paper. The solution was then cooled in an ice-bath and concentrated Hcl added drop-wise until a pH of 1. The resultant white precipitate was filtered off, washed with cold water (3×20 mL) and dried under vacuum over a desiccant to give 6,7-dimethoxy-2-naphthanoic acid (2.2601 g, 90% yield as a whit