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Publication Number
US-9457014-B2
Publication Date
2016-10-04
Expiration Date
Abstract
Novel cysteine prodrugs and their use in the treatment of diseases and/or conditions, including but not limited to diseases and/or conditions of the Central Nervous System (CNS), including but not limited to schizophrenia, drug craving, drug addiction, bipolar disorder, anxiety, depression, Parkinson's disease, Alzheimer's disease, cognitive dysfunction, multiple sclerosis, Amyotrophic lateral sclerosis (ALS), ischemic stroke, HIV dementia, and Huntington's disease.
Core Innovation
The invention relates to cysteine prodrugs embodied by compounds of Formulas I-VII, and provides expanded chemical scope including pharmaceutically acceptable salts and esters, stereoisomers, enantiomers, diastereoisomers, tautomers, and prodrugs. The compounds are described as cysteine prodrugs intended to address Central Nervous System (CNS) diseases, including schizophrenia, with oral delivery presented as a preferred route.
The disclosure describes prodrug-containing pharmaceutical compositions that include a therapeutically effective amount of the cysteine prodrugs together with pharmaceutically acceptable carriers. It further describes combination regimens that include N-acetyl cysteine (NAC) and/or conventional first- and second-generation antipsychotics for treatment-related use in CNS diseases such as schizophrenia.
The document also provides detailed synthetic strategies for producing cysteine-based dimeric diketopiperazine and mixed-dimer structures. The described approach uses thiazolidinecarboxylic acid/cysteine derivatives to construct diketopiperazine motifs, and includes activated esters/thioesters, peptide-coupling/ester cleavage, S-protection, and phenylacetamide formation as part of the route to diketopiperazine-based structures.
The disclosed chemical concepts further include procysteine-like prodrugs/dimers, stereochemical and cysteine-derived thioester/coupling precursors, and mixed-dimer construction through sulfur activation with leaving groups and coupling to substituted cysteine/phenylacetamide substrates, followed by selective ester hydrolysis. The document outlines a conceptual evaluation approach using methylazoxymethanol (MAM) schizophrenia as a neurodevelopmental model and an attentional set shifting cognitive assay, together with measurement of brain cystine/cysteine/glutathione levels using HPLC with electrochemical detection.
Claims Coverage
The provided partial content identifies independent claims directed to a compound of formula (VIII), including pharmaceutically acceptable salt or ester forms, and a dependent claim directed to a pharmaceutical composition. Two inventive features are identified.
Compound of formula (VIII)
A compound of formula (VIII), or a pharmaceutically acceptable salt or ester thereof.
Pharmaceutical composition with a claim 1 compound
A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
The claim coverage in the provided partial content is centered on a compound of formula (VIII), including pharmaceutically acceptable salt or ester forms, and a pharmaceutical composition that includes the claimed compound and a pharmaceutically acceptable carrier.
Stated Advantages
Reducing required doses when used in combination regimens including N-acetyl cysteine (NAC) and/or conventional first- and second-generation antipsychotics.
Documented Applications
Treatment-related use for Central Nervous System (CNS) diseases including schizophrenia, with oral administration indicated as a preferred route.
Use in combination regimens involving N-acetyl cysteine (NAC) and/or conventional first- and second-generation antipsychotics for CNS diseases such as schizophrenia.
Evaluation in a methylazoxymethanol (MAM) schizophrenia neurodevelopmental model together with an attentional set shifting cognitive assay and brain cystine/cysteine/glutathione measurements using HPLC with electrochemical detection.
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