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

Inventors

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

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 invention relates to compounds of a formula, including substituted N-acetyl-L-cysteine (NAC) derivatives and thiocarbonate/sulfanyl-containing amino-acid and amide derivatives, together with pharmaceutically acceptable salts, esters, prodrugs, and related intermediates. The disclosure includes compositions and therapeutic approaches for delivery of the compounds to treat central nervous system (CNS) diseases and conditions, and it also includes prodrug-like scaffolds and piperazine-2,5-dione derivatives containing benzoylsulfanyl/sulfanyl-methyl piperazine-2,5-dione scaffolds.

The patent provides a mechanistic rationale connecting the compounds to oxidative stress and reactive oxygen species reduction, increased glutathione levels, modulation of cystine-glutamate antiporter activity (System x_c− / cystine-glutamate antiporter), and modulation of glutamate signaling. It also describes biological evaluation in human astrocytoma glial cells and in vivo schizophrenia-relevant assays, together with brain pharmacokinetic measurements of NAC and glutathione after oral dosing.

The disclosure states treatment of selected CNS disorders and conditions, including schizophrenia, drug craving and drug addiction, trichotillomania, Huntington’s disease, HIV-associated neurocognitive disorder, hypoxic-ischemic encephalopathy, inherited mitochondrial diseases such as Leigh syndrome, Alpers’ disease, and MELAS, and adrenoleukodystrophy (X-linked), including ABCD1-related disease context. It contrasts the compounds with N-acetyl-L-cysteine (NAC), including stated improvements such as reduced first-pass metabolism and improved CNS penetration.

Claims Coverage

The independent claims cover compounds of formula and pharmaceutically acceptable salts of the compound of formula, with inventive features organized around compound scope, salt scope, pharmaceutical compositions, and therapeutic or biological-function scope. Across the provided claim families, the claims total 4 distinct inventive feature groupings.

The claim coverage centers on compounds of formula and their pharmaceutically acceptable salts, together with pharmaceutical compositions and methods of treatment for selected CNS disorders and conditions. The inventive features also extend to mechanistic endpoints including oxidative stress reduction, glutamate signaling improvement, glutathione level increase, and cystine-glutamate antiporter activity.

Stated Advantages

Documented Applications