Pain treatment is often limited by the side effects of currently available medication. For moderate to severe pain, opioids are widely used. These agents are cheap and effective but suffer from serious and potentially life-threatening side effects, most notably respiratory depression and muscle rigidity. In addition, the doses of opioids which can be administered are limited by nausea, emesis, constipation, pruritus and urinary retention, often resulting in patients electing to receive sub-optimal pain control rather than suffer these distressing side effects. Opioids are highly addictive and are scheduled drugs in many territories. There is therefore a demand for new analgesics that have an improved side effect profile compared to opioids, at equi-analgesic doses. Current treatments for neuropathic pain, including opioids, tricyclic antidepressants, serotonin and noradrenaline uptake inhibitors and anticonvulsants are of limited efficacy. There is therefore a demand for new analgesics that have improved efficacy for the treatment of neuropathic pain.
Evidence is accumulating that cannabinoid agonists have potential as analgesic and anti-inflammatory agents. Two types of cannabinoid receptors are implicated, the cannabinoid CB1 receptor, which is located primarily in the central nervous system but which is also expressed by peripheral neurones and to a lower extent in other peripheral tissues, and the cannabinoid CB2 receptor, which is mostly located in immune cells (Howlett, A. C. et al.: International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors. Pharmacol. Rev. 54, 161-202, 2002). While the CB2 receptor has been implicated in modulating the immune and anti-inflammatory response of cannabinoids, cannabinoid receptor agonists, especially those acting at the CB1 receptor have been suggested as useful in the treatment of pain (see Iversen, L. and Chapman, V. Current Opinion in Pharmacology, 2, 50-55, 2002 and references therein). WIN 55, 212-2, the mesylate salt of (R)-(+)-[2,3-dihydro-5-methyl-[(morpholinyl)-methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone was disclosed in U.S. Pat. No. 4,939,138 (Sterling Drug Inc.) as an analgesic agent. The compound is the prototype of aminoalkylindoles (Eissenstat, M. A. et al., J. Med. Chem. 38, 3094-3105, 1995), which are potent cannabinoid CB1 receptor agonists that can produce antinociception with equivalent efficacy to morphine in animal models of acute pain, persistent inflammatory pain and neuropathic pain.
Key structural features of aminoalkylindoles having cannabimimetic properties (Adam, J. and Cowley, P. Expert Opin. Ther. Patents, 12, 1475-1489, 2002) are an aminoalkyl substituent at the 1-position of the indole moiety, and a further bulky substituent in the 3-position of the indole ring, such as exemplified by an aroyl group in the aminoalkylindoles disclosed in U.S. Pat. No. 4,939,138 (Sterling Drug Inc.) and in the more recent WO02060447 ((University of Connecticut), or by a substituted amido-group in the compounds disclosed in WO0158869 (Bristol-Myers Squibb). 1-(Aminoalkyl)indole derivatives having a substituted oxadiazol-5-yl ring at the 3-position were disclosed in WO0236590 (Amrad Operations PTY Ltd.) as cannabinoid receptor modulators and useful as analgesic agents. In WO2004000832, WO2005058327 and WO2005089754 (Akzo Nobel N.V.), 1-[(indol-3-yl)carbonyl]piperazine derivatives and 1-(indol-3-yl) heterocycle derivatives are disclosed as analgesic agents which modulate the cannabinoid receptor.
There remains a need for cannabinoid agonists with improved properties, such as increased water solubility, for use as therapeutic agents.