Enantioselective synthesis of a cyclobutane analogue of Milnacipran

METHOD FOR SYNTHESIS OF (1S, 2R)-MILNACIPRAN - …

A New Enantioselective Synthesis of Milnacipran and …

The present invention also relates to methods for synthesizing intermediates useful in the non-asymmetric or asymmetric methods for synthesizing enantiomerically enriched milnacipran or congeners thereof.

Asymmetric Synthesis of Enantiomerically Pure Milnacipran …

For additional data we also hand searched reference lists, US Food and Drug Administration medical and statistical reviews and dossiers submitted by pharmaceutical companies.

Review Methods: Study selection, data abstraction, validity assessment, grading the strength of the evidence, and data synthesis were all carried out according to standard Drug Effectiveness Review Project review methods.

Results and Conclusions: We found eligible studies of treatment for fibromyalgia with amitriptyline, nortriptyline, citalopram, fluoxetine, paroxetine, cyclobenzaprine, pregabalin, gabapentin, milnacipran, and duloxetine.

In the past 50 years, there has been an exponential increase in research aiming to elucidate the neurochemical mechanisms responsible for major depressive disorder (MDD). Many plausible hypotheses have been proposed but subsequently found lacking. Much early work investigated the possible causal roles for abnormalities of the brain serotonin (5-HT) and/or norepinephrine (NE) pathways,1-6 largely driven by the marked therapeutic success of 5-HT and NE reuptake inhibitors in the treatment of MDD.2,7,8 However, incremental progress in the neurosciences and clinical investigation along with the rapid development of methods for genetic research has led to a set of more complex causal hypotheses. For example, research suggests that MDD is what geneticists define as a “complex” disease, where illness results from the summation of numerous genetic and environmental factors, each of which have small effects and result in illness only when their combined effects surpass a certain threshold.9 If true, then biochemical and genetic causes of MDD may differ markedly among patients, similar to how genetic and physiologic underpinnings of hypertension or diabetes differ among patients.10 This concept may explain the sometimes inconsistent results in research studies investigating specific biochemical abnormalities in MDD and the outcome of studies testing specific treatments for MDD. The shift to conceptualizing MDD as a complex disorder has also resulted in the current movement to identify more homogeneous subgroups of patients with MDD or endophenotypes.11,12 Finally, if there is great variability in the underlying biochemistry and genetics among patients with MDD, then it may be expected that when studying a large group of people, medications with a broader pharmacologic profile should demonstrate a broader efficacy profile.