Substituted phenethylamines with serotoninergic and/or norepinephrinergic activity

Abstract

Chemical syntheses and medical uses of novel inhibitors of the uptake of monoamine neurotransmitters and pharmaceutically acceptable salts and prodrugs thereof, for the treatment and / or management of psychotropic disorders, anxiety disorder, generalized anxiety disorder, depression, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, hot flashes, senile dementia, migraine, hepatopulmonary syndrome, chronic pain, nociceptive pain, neuropathic pain, painful diabetic retinopathy, bipolar depression, obstructive sleep apnea, psychiatric disorders, premenstrual dysphoric disorder, social phobia, social anxiety disorder, urinary incontinence, anorexia, bulimia nervosa, obesity, ischemia, head injury, calcium overload in brain cells, drug dependence, attention deficit hyperactivity disorder, fibromyalgia, irritable bowel syndrome, and / or premature ejaculation are described.

Description

[0001]This application claims the benefit of priority of U.S. provisional applications No. 60 / 895,049, filed Mar. 15, 2007, and No. 60 / 944,399, filed Jun. 15, 2007, the disclosures of which are hereby incorporated by reference as if written herein in its entirety.FIELD[0002]The present invention is directed to inhibitors of the uptake of monoamine neurotransmitters and pharmaceutically acceptable salts and prodrugs thereof, the chemical synthesis thereof, and the medical use of such compounds for the treatment and / or management of psychotropic disorders, anxiety disorder, generalized anxiety disorder, depression, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, hot flashes, senile dementia, migraine, hepatopulmonary syndrome, chronic pain, nociceptive pain, neuropathic pain, painful diabetic retinopathy, bipolar depression, obstructive sleep apnea, psychiatric disorders, premenstrual dysphoric disorder, social phobia, social anxiety disorder, urinary in...

AI Technical Summary

Benefits of technology

[0026]It has been found that the hydrochloride salt Forms A-F of the compound of formula I have high crystallinity, i.e., substantially free of amorphous material. Such salts have the advantage that they provide more reproducible dosing results. The hydrochloride salt Forms A-F of the compound of formula I are substantially hygroscopically stable, which alleviates potential problems associated with weight changes of the active ingredient during the manufacture of capsules or tablets. The hydrochloride Forms A-F of the compound of formula I have the additional advantage that they have a low tendency for concentrated aqueous solution to form viscous mixtures upon standing. The hydrochloride salt Forms A-F of the compound of formula I have rapid kinetic aqueous solubility which simplifies aqueous dosing and make them suitable for injectable dosage forms. Furthermore, the hydrochloride salt Forms A-F of the compound of formula I with enhanced solubility characteristics facilitate the dissolution of solid dosage forms in a timely manner. All of these advantages are specifically described herein for all of the pharmaceutical dosage forms, treatment regimens and therapeutic uses described herein form compounds of formula I.

Problems solved by technology

Because venlafaxine is metabolized by polymorphically-expressed isozymes of cytochrome P450 including CYPs 2C19 and 2D6, and because it can act as an inhibitor of CYP2D6, its application in polypharmacy is necessarily complex and has potential for adverse events.

Venlafaxine also suffers from a short half-life relative to the majority of serotonin reuptake inhibitors.

As a consequence of its 5-11 hour pharmacological half-life, those taking venlafaxine are at significant risk of SRI discontinuation symptoms if the drug is abruptly discontinued.

An extended release formulation of Venlafaxine is also available; however, it does not significantly increase the carryover of drug to the next day.

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