β3 adrenergic agonists

#The current preferred treatment for Type 2, non-insulin dependent diabetes as well as obesity is diet and exercise, with a view toward weight reduction and improved insulin sensitivity. Patient compliance, however, is usually poor. The problem is compounded by the fact that there are currently no approved medications that adequately treat both Type 2 diabetes or obesity.

#One therapeutic opportunity that has recently been recognized involves the relationship between adrenergic receptor stimulation and anti-hyperglycemic effects. Compounds that act as β3 receptor agonists have been shown to exhibit a marked effect on lipolysis, thermogenesis and serum glucose levels in animal models of Type 2 (non-insulin dependent) diabetes. The β3 receptor, which is found in several types of human tissue including human fat tissue, has roughly 50% homology to the β1 and β2 receptor subtypes yet is considerably less abundant. Stimulation of the β1 and β2 receptors can cause adverse effects such as tachycardia, arrhythmia, or tremors. An agonist that is selective for the β3 receptor over the β1 and β2 receptors is, therefore, more desirable for treating Type 2 diabetes or obesity relative to a non-selective agonist.

#However, recent studies have suggested the presence of an atypical β receptor associated with atrial tachycardia in rats (Br. J. of Pharmacol., 118:2085-2098, 1996). In other words, compounds that are not agonists of the β1 and β2 receptors can still modulate tachycardia through activation of a yet to be discovered β4 or through some other unknown pathway.

#Certain compounds of the invention are particularly interesting and are preferred. The following listing sets out several groups of preferred compounds. It will be understood that each of the listings may be combined with other listings to create additional groups of preferred compounds. a) m is 2; b) n is 0 or 1; c) n is 0; d) A1, A2 and A3 are carbon; e) the 6,5 ring system is of the formula:

#f) the 6,5 ring system is of the formula:

#where only one D can be nitrogen; g) the 6,5 ring system is of the formula: