STEREOISOMERS OF p-HYDROXY-MILNACIPRAN, AND METHODS OF USE THEREOF

摘要

The present invention relates generally to the enantiomers ofpara-hydroxy-­ milnacipran or congeners thereof. Biological assays revealed that racemic para-hydroxy-­milnacipran is approximately equipotent in inhibiting serotonin and norepinephrine uptake (IC50 = 28.6 nM for norepinephrine, IC50 = 21.7 nM for serotonin). Interestingly, (+) para-­hydroxy-milnacipran is a more potent inhibitor of norepinephrine uptake than serotonin uptake (IC50 = 10.3 nM for norepinephrine, IC50 = 22 nM for serotonin). In contrast, (-)­ para-hydroxy-milnacipran is a more potent inhibitor of serotonin uptake compared to norepinephrin uptake (IC50 = 88.5 nM for norepinephrine, IC50 = 40.3 nM for serotonin). The invention also relates to salts and prodrug forms of the aforementioned compounds. In certain embodiments, the compounds of the present invention and a pharmaceutically acceptable excipient are combined to prepare a formulation for administration to a patient. Finally, the present invention relates to methods of treating mammals suffering from various afflictions, e.g., depression, chronic pain, or fibromyalgia, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention.