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

The patent describes a new group of compounds that are effective in treating certain disorders associated with aggression and impulsivity. These compounds have been found to fully saturate 5-HT2A receptors at a low dose and do not have any side effects such as sedation or cognitive impairment. The compounds can treat disorders associated with dementia, including behavioral or mood disturbances, agitation, irritation, and sleep disturbances, which are often left untreated by current drugs. This discovery gives the compounds a specific advantage for treating these disorders without causing extrapyramidal side effects or cardiovascular safety issues.

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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