Substituted N-acetyl-L-cysteine derivatives and related compounds

Inventors

Neary, Michael • Nieman, James • Tanis, Steven • Lawton, Daniel • Smith, Garry

Assignees

Promentis Pharmaceuticals Inc

Abstract

Novel substituted N-acetyl-L-cysteine (NAC) derivatives and related compounds and methods of using these compounds for the treatment of diseases and/or conditions, including but not limited to diseases and/or conditions of, or involving, the Central Nervous System (CNS), including schizophrenia adrenoleukodystrophy, mitochondrial diseases (e.g. Leigh syndrome, Alpers′ disease, and MELAS), Huntington's disease, trichotillomania, HIV-associated neurocognitive disorder, hypoxic-ischemic encephalopathy, drug craving, and drug addiction.

Core Innovation

The disclosure provides substituted N-acetyl-L-cysteine (NAC) derivatives defined by Formula I and Formula II, including compounds having substituent options R2, R3, and R4. The document frames these derivatives as NAC derivatives intended to enhance efficacy in central nervous system (CNS) and oxidative-stress-related conditions by addressing issues associated with N-acetyl-L-cysteine, including first-pass metabolism and poor blood-brain barrier penetration.

The background rationale links NAC and NAC-derived compounds to modulation of the glutamate-cystine antiporter (System x_c−) and to oxidative stress mitigation through glutathione. The document further describes that oxidative stress and glutathione-related mechanisms are relevant to a range of CNS disorders and conditions including schizophrenia, trichotillomania, drug craving/addiction, Huntington’s disease, HIV-associated neurocognitive disorder, hypoxic-ischemic encephalopathy, adrenoleukodystrophy/X-linked adrenoleukodystrophy, and mitochondrial diseases (Leigh syndrome, Alpers’ disease, MELAS).

Therapeutic approaches are described in terms of administering therapeutically effective amounts of the compounds of Formula I–Formula II, including pharmaceutically acceptable salts/esters/prodrugs, and corresponding pharmaceutical compositions with pharmaceutically acceptable carriers. A brief “Examples” section is also included, with representative compound preparation and analysis being referenced for specific prototypes (including references to Pro-2022, Pro-2023, Pro-2024, Pro-3010, Pro-4006, Pro-4011, Pro-4047, Pro-4051, and Pro-4051a).

Claims Coverage

The provided independent claims cover treating trichotillomania using therapeutically effective administration of a compound of Formula I, and specifically administering salts or esters of the compound of Formula I. Across the independent claims, the inventive features are the specific Formula I compound use for a therapeutic indication and the use of salt/ester forms as the administered compound.

Both independent claims are directed to trichotillomania treatment by administering therapeutically effective amounts of Formula I derivatives, with one independent claim limited to the compound of formula I and the other extending coverage to salt or ester forms of the compound of formula I.

Stated Advantages

Documented Applications