Substituted N-acetyl-L-cysteine derivatives and related compounds
Inventors
Neary, Michael • Nieman, James • Tanis, Steven • Lawton, Daniel • Smith, Garry
Assignees
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Publication Number
US-10961187-B2
Publication Date
2021-03-30
Expiration Date
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 substituted N-acetyl-L-cysteine (NAC) derivative compounds defined by Formulas I and II, including compounds having specified R-group substituents and representative specific structures. The compounds include salts, esters, prodrugs, enantiomers, as well as isomer and solvate forms, and the disclosure positions these NAC derivative compounds as CNS-relevant agents.
The background portion describes limitations associated with parent NAC, including first-pass metabolism and poor blood-brain barrier penetration. It further connects NAC-derivative functionality to central glutamate-cystine exchange and the System x_c− / cystine-glutamate antiporter, and to oxidative stress and glutathione-related pathways involving reactive oxygen species (ROS).
The invention proposes oral CNS-focused uses for the substituted NAC derivatives, particularly treating schizophrenia and drug craving/drug addiction, with additional CNS-related disorders described in the disclosure. The method includes administering a therapeutically effective amount of a compound of formula I to a human in need thereof for the claimed condition.
The document also relates to synthetic intermediates and multiple prodrug candidates, including N53 thiocarbonate and prodrugs identified as Pro-4051/Pro-4051a, Pro-4047, Pro-4011, Pro-4006, and related examples. It provides characterization data for these prodrug candidates and representative intermediates used to support the prodrug development, together with in vitro and in vivo functional results evaluating CNS-relevant targets and oral dosing outcomes.
Claims Coverage
The provided independent claim coverage includes two inventive features. One centers on treating trichotillomania by administering a therapeutically effective amount of a compound of formula I to a human in need thereof, and the other covers the same treatment with oral administration and related release and dosing refinements.
Treating trichotillomania with a compound of formula I
Administering a therapeutically effective amount of the compound of formula I to a human in need thereof to treat trichotillomania.
Oral administration and release characteristics
The method includes orally administering the compound of formula I, including in a composition that releases it in a delayed manner and in a solid dosage form using an enteric coating.
Multiple daily doses and specified daily dosage range
The method includes administering the therapeutically effective amount of the compound of formula I in multiple daily doses, with a daily dosage ranging from about 0.0001 to about 2,000 mg/kg.
The claim coverage centers on trichotillomania treatment using a therapeutically effective amount of a compound of formula I, with refinements for oral administration, delayed or enteric release, multiple daily doses, and a specified daily mg/kg dosage range.
Stated Advantages
Overcomes limitations of the parent NAC associated with first-pass metabolism and poor blood-brain barrier penetration.
Supports CNS-relevant activity through links to central glutamate-cystine exchange, the System x_c− / cystine-glutamate antiporter, and oxidative stress/glutathione pathways.
Provides oral administration concepts for delivering the compounds for CNS-focused treatment.
Documented Applications
Treating trichotillomania by administering a therapeutically effective amount of a compound of formula I to a human in need thereof.
Treating schizophrenia.
Treating drug craving and drug addiction.
CNS-related oxidative-neurodegenerative and mitochondrial disease contexts are referenced in the disclosure background, including Huntington’s disease and mitochondrial diseases such as Leigh syndrome, Alpers’ disease, and MELAS.
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