139486-99-0

Upstream product

• 139487-12-0 5-bromomethyl-1,3,3-trimethylindolin-2-one 
• 38328-94-8 1,3-dihydro-1,3,3,5-tetramethyl-2H-indol-2-one 
• 130723-11-4 4-<3-fluoro-5-(benzyloxy)phenyl>-4-methoxy-3,4,5,6-tetrahydro-2H-pyran 
• 130723-10-3 4-(3-Benzyloxy-5-fluorophenyl)-4-hydroxytetrahydropyran 
• 461-96-1 3,5-difluorobromobenzene 
• 29943-42-8 Tetrahydro-4H-pyran-4-one 
• 130723-09-0 4-(5-fluoro-3-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-pyran 
• 130722-44-0 5-benzyloxy-3-fluorophenyl bromide 

Relevant academic research and scientific papers

BICYCLIC HETEROCYCLIC DERIVATIVES AS 5-LIPOXYGENASE INHIBITORS

The invention concerns a bicyclic heterocyclic derivative of the formula I wherein Q is an optionally substituted 9-membered bicyclic heterocyclic moiety containing 1 or 2 N's and optionally a further N, O or S heteroatom; A1 is a direct link to X1 or (1-3C)alkylene; X1 is oxy, thio, sulphinyl, sulphonyl or imino; Ar is optionally substituted phenylene or pyridylene; R1 is (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and R2 and R3 together form a group of the formula ?A2?X2?A3? which, together with the carbon atom to which A2 and A3 are attached, defines a ring having 5 to 7 ring atoms, wherein each of A2 and A3 is (1-3C)alkylene and X2 is oxy, thio, sulphinyl or sulphonyl; or a pharmaceutically-acceptable salt thereof. The compounds of the invention are inhibitors of the enzyme 5-lipoxygenase

Methoxytetrahydropyrans. A new series of selective and orally potent 5- lipoxygenase inhibitors

Investigation of the SAR of the lead (methoxyalkyl)thiazole 1-[3-(naphth- 2-ylmethoxy)phenyl]-1-thiazol-2-ylpropyl methyl ether (1, ICI 211965) led to the methoxytetrahydropyrans, a new series of 5-lipoxygenase (5-LPO) inhibitors exemplified by the parent compound 4-[3-(naphth-2- ylmethoxy)phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (4f). In vitro 4f inhibited leukotriene C4 (LTC4) synthesis in zymosan-stimulated plasma-free mouse macrophages and LTB4 synthesis in A-23187-stimulated human whole blood (IC50s 0.5 nM and 0.07 μM, respectively). In the rat 4f inhibited LTB4 synthesis in blood ex vivo and in zymosan-inflamed air pouch exudate with an ED50 3 h after oral dosing of 10 mg/kg in each system. In seeking more potent orally active compounds, strategies were explored in congeners of 4f for reducing lipophilicity without sacrificing potency. For example, replacement of 2-naphthyl of 4f by various aza- and oxoheterocycles afforded compounds in which log P is reduced by 1.7-2.3 units while potency in human whole blood in vitro was maintained or enhanced relative to 4f. In addition, the oxoheterocyclic replacements provided compounds with improved oral potency and the preferred compound from this group is 6-[[3-fluoro-5-(4- methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy]methyl]-1-methylquinol-2-one (4y). In the in vitro systems, 4y inhibited LT formation with IC50s in mouse macrophages and human whole blood of 3 nM and 0.02 μM, respectively. 4y did not inhibit the synthesis of cyclooxygenase (CO) products at concentrations up to 500 μM in human blood, a selectivity for 5-LPO over CO of >20 000-fold. In the rat 4y inhibited the formation of LTB4 in blood ex vivo and in inflammatory exudate with ED50s 3 h after oral dosing of 0.9 and 0.3 mg/kg, respectively. 4y was more potent in vitro in human whole blood and in rat blood ex vivo at 3 h than either the 5-LPO inhibitor A-64077 or the FLAP antagonist MK-886. Based on these data 4y (ICI D2138) has been entered into development as an orally active, selective 5-LPO inhibitor for clinical evaluation in inflammatory conditions in which LTs are believed to play a role.