Substance P is an 11-amino acid neuropeptide present reportedly involved in various pathological conditions including asthma, inflammation, pain, psoriasis, migraine, dyskinesia, cystitis, schizophrenia, emesis and anxiety, due to its localizations and functions. Substance P is an agonist for the NK1 receptor, and causes intracellular signal transduction through its interaction with the NK1 receptor.
The NK1 receptor has been reported to be implicated in various disorders and diseases, and various NK1 antagonists have been developed for the purpose of treating or preventing such disorders and diseases. For example, Kramer et. al. (Science 281 (5383), 1640-1645, 1988) reports clinical trials for NK1 receptor antagonists in the treatment of anxiety, depression, psychosis, schizophrenia and emesis, Gesztesi et al. (Anesthesiology 93 (4), 931-937, 2000) also reports the use of NK1 receptor antagonists in the treatment of emesis
U.S. Pat. No. 6,297,375 to Hoffmann-La Roche describes a class of 4-phenyl-pyridine compounds that are NK1 antagonists which are useful for treating CNS disorders, such as depression, anxiety or emesis. Netupitant is a selective NK1 receptor antagonist among these 4-phenyl-pyridine compounds, and is currently under clinical development in combination with palonosetron 5-HT3 receptor antagonist) for the prevention of chemotherapy-induced-nausea and vomiting (CINV) by Helsinn Healthcare.
Mono-N-Oxide derivatives of 4-phenyl-pyridine compounds are described in U.S. Pat. No. 6,747,026 to Hoffmann-La Roche. These N-Oxide derivatives are reportedly intended to overcome limitations on the parent compounds that would otherwise limit their clinical usefulness, such as solubility or pharmacokinetic limitations. However, no physicochemical or biological data of the mono-N-Oxide derivatives are reported in the '026 patent.
U.S. Pat. No. 5,985,856 to the University of Kansas describes water soluble N-phosphoryloxymethyl derivatives of secondary and tertiary amines, and the use of such derivatives to improve the solubility profiles of loxapine and cinnarizine. The '856 patent does not disclosure how the N-phosphoryloxymethyl moiety would affect other critical attributes of the drug product, such as stability, local tolerance at the site of administration, bioavailability, metabolism or toxicity.
In view of the above, there is a need to find new derivatives of 4-phenyl-pyridine compounds that are effective NK1 receptor antagonists, with enhanced physicochemical and/or biological properties.