Novel compositions and methods

Abstract

The present invention relates to use of particular substituted heterocycle fused gamma-carbolines as described herein, in free, pharmaceutically acceptable salt or prodrug form, and pharmaceutical composition comprising the same optionally in combination with one or more agents, for the prophylaxis or treatment of one or more disorders associated with dementia, particularly behavioral or mood disturbances (e.g., agitation / aggression), psychosis, depression and sleep disturbances among others in patients suffering from dementia.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a national phase application filed under 35 U.S.C. §371 of International Application No. PCT / US2013 / 036515, filed on Apr. 14, 2013, which International Application claims priority from U.S. Provisional Application Nos. 61 / 624,293, 61 / 624,292 and 61 / 624,291, all filed on Apr. 14, 2012; and U.S. Provisional Application Nos. 61 / 671,723 and 61 / 671,713, both filed on Jul. 14, 2012, the contents of each of which are incorporated by reference in their entirety.TECHNICAL FIELD[0002]The present invention relates to use of particular substituted heterocycle fused gamma-carbolines as described herein, in free, pharmaceutically acceptable salt or prodrug form, and pharmaceutical composition comprising the same, optionally in combination with one or more agents, for the prophylaxis or treatment of one or more disorders associated with dementia, particularly behavioral or mood disturbances (e.g., agitation / aggression), psychosis, de...

AI Technical Summary

Benefits of technology

[0008]It has been discovered that the Compounds of the Invention (i.e., the Compounds of Formula I as described hereinbelow) fully saturate 5-HT2A receptors at a low dose. Altered serotonergic function has consistently been implicated in the pathophysiology of aggression. In animal models, 5-HT2A antagonists attenuate aggressive & impulsive behaviors. Human platelet 5-HT2A levels are associated with aggression in personality disordered patients, but not in healthy control subjects. Postmortem studies also show that 5-HT2A receptor expressions in prefrontal cortical regions are correlated positively with lifetime aggression in subjects who committed suicide. Orbitofrontal 5-HT2A receptor availability is greater in patients with current physical aggression compared with patients without current physical aggression and healthy control subjects. Specific genetic polymorphisms of 5-HT2A receptors are associated with aggression and impulsivity. These Compounds also exhibit efficacy in reducing behavioral disturbances such as agitation and irritability as well as sleep disturbances and symptoms of depression and psychosis. Due to their low off target receptor interactions, the Compounds of the Invention have reduced sedation, cognitive impairment, motor impairment and lower risk of falls. Therefore, Compound of Formula I as described below are effective in treating 5-HT2A related disorders without having the extrapyramidal side effects, psychomotor sedation, cognitive impairment or cardiovascular safety issues such as QTc prolongation. This discovery gives the Compounds of the current Invention particular utility in the treatment or prophylaxis of one or more disorders associated with dementia, particularly behavioral or mood disturbances such as agitation, irritation, aggressive / assaultive behavior, anger, physical or emotional outbursts and sleep disturbances, which conditions are often left untreated by current marketed drugs, as well as psychosis and depressive disorders in dementia patients.

Problems solved by technology

Currently, there is no cure or standard of treatment for dementia.

While these drugs improve mental function (such as memory, attention, social interaction, reasoning ability, language ability, and ability to perform activities of daily living), they often cause side effects including stomach upset, diarrhea, nausea, vomiting, muscle cramps, fatigue, difficulty falling or staying asleep or excess sleepiness, depression, bradycardia and other side effects.

In addition, these drugs do not treat affective symptoms and / or other behavior disruptions such as mood swing, agitation, aggressive / assaultive behavior and paranoia which are common in dementias.

In fact, some studies have shown that memantine, a drug approved for Alzheimer's disease and often used for dementias in general, may have some adverse effects on neuropsychiatric functioning, particularly agitation / aggression, delusions or hallucinations.

These untreated and sometimes aggravated behavioral disruptions often prevent the patients from integrating back into society, causing further distress to the caregivers and eventually leading to the patients' institutionalization.

However, antipsychotic drugs such as haloperidol, risperidone and quetiapine are associated with serious side effects including extrapyramidal side effects (akinesia or akathisia), bone marrow suppression, seizure, orthostatic hypotension, insomnia, sedation, somnolence and weight gain.

Many atypical antipsychotic agents also have a higher risk of heart failure.

Therefore, the use of these antipsychotic agents in combination with anticholinesterase inhibitor or NMDA receptor antagonist is undesirable.

In addition to behavior and mood disturbances, many dementia patients, particularly those at a more serious stage of the disease also commonly experience sleep disturbances wherein the patients either have difficulty falling asleep, maintaining sleep or experience changes in their sleep-wake cycle / pattern.

While agents such as temazepam (Restoril), zolpidem (Ambien), or zaleplon (Sonata), or sedating antidepressants, such as trazodone (Desyrel, Molipaxin), may be useful in managing insomnia, failure of these drugs to improve sleep quality in addition to the associated risk of falling due to drowsiness and psychomotor impairment caused by these agents render them undesirable for dementia, particularly Alzheimer's patients.

These references, however, do not teach use for the treatment or prophylaxis of disorders associated with dementia, particularly behavioral or mood disturbances such as agitation, irritation, aggressive / assaultive behavior, anger, physical or emotional outbursts and psychosis and sleep disorders associated with dementia.

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