Alpha-aminoamide derivatives useful in the treatment of psychiatric disorders

Inventors

Izzo, Emanuela • Faravelli, Laura • Barbanti, Elena • Salvati, Patricia

Assignees

Newron Pharmaceuticals SpA

Abstract

The disclosure relates to pharmacotherapy of a psychiatric disorder which is schizophrenia and/or anxiety, wherein schizophrenia includes schizophrenia related disorders such as brief psychotic disorders, delusional disorders, schizoaffective disorders, and schizophreniform disorders, and anxiety includes panic disorders, obsessive-compulsive disorders (OCD), post-traumatic stress disorders (PTSD), social phobia or social anxiety disorders, specific phobia, and generalized anxiety disorders (GAD). The compounds of the disclosure are useful for the treatment of the above psychiatric disorders alone or in combination with other therapeutical agents effective in the treatment of schizophrenia and/or anxiety disorders.

Core Innovation

The disclosure provides alpha-aminoamide derivatives of Formula I, including single optical isomers or mixtures thereof, and pharmaceutically acceptable salts of the single optical isomers or mixtures thereof. The compounds are defined with substituent constraints including n is 1 or 2, R is meta or para to the alpha-aminoamide substituent and is a C3-C6 alkyl or benzyloxy, and the benzyloxy phenyl radical is optionally substituted with fluoro or chloro. Additional substituent variables R1, R2, R3, R4, and R5 are constrained to defined hydrogen, alkyl, or optionally substituted alkyl groups, and representative preferred compound examples are listed.

The disclosure addresses treating schizophrenia and schizophrenia related disorders and treating anxiety and anxiety related disorders, including panic, obsessive-compulsive disorder, post-traumatic stress disorder, social phobia/social anxiety disorder, specific phobias, and generalized anxiety disorder. Schizophrenia related disorders include brief psychotic disorder, delusional disorder, schizoaffective disorder, and schizophreniform disorder. The therapeutic approach comprises administering a therapeutically effective dose of a Formula I compound, or its single optical isomer, mixture, or pharmaceutically acceptable salt, alone or as a combined therapy with adjunct psychiatric/anxiolytic agents.

Ralfinamide, exemplified as (S)-(+)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide (methanesulfonate), is described as exhibiting NMDA antagonism and potent MAO-B inhibition. Representative pharmacological findings described include lack of significant dopamine receptor binding, MAO-B inhibition and NMDA receptor complex inhibition, reversal of MK-801 PPI disruption, attenuation of MK-801-induced hyperlocomotion, and anxiolytic-like effects in open-field testing, including anti-anxiety and anti-OCD-like effects in marble-burying. Combination findings described include synergistic reversal of amphetamine-induced PPI deficits when combined with subthreshold haloperidol.

Claims Coverage

The independent claims cover three treatment uses: schizophrenia or schizophrenia related disorder, anxiety or anxiety related disorder, and schizophrenia combined with anxiety. The compound scope is defined by Formula I substituent constraints or by enumerated stereochemically defined fluorobenzyloxy benzylamino propanamide compounds, with pharmaceutically acceptable salts and adjunct psychiatric/anxiolytic agents in some claims.

Across the independent claims, the main inventive coverage is directed to treating schizophrenia and schizophrenia related disorders, treating anxiety and anxiety related disorders, and treating schizophrenia combined with anxiety by administering therapeutically effective doses of alpha-aminoamide Formula I compounds with constrained substituent variables or by administering enumerated stereochemically defined (S)-(+)/(R)-(-) fluorobenzyloxy benzylamino propanamide derivatives, including pharmaceutically acceptable salts such as methanesulfonic acid, with further dependents allowing adjunct psychiatric/anxiolytic agents.

Stated Advantages

Documented Applications