Compounds advantageous in the treatment of central nervous system diseases and disorders
Inventors
Pesyan, Amir • Balandrin, Manuel F.
Assignees
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Publication Number
US-10793515-B2
Publication Date
2020-10-06
Expiration Date
Abstract
A series of novel amides showing broad pharmaceutical activity. Compounds described herein are effective as anticonvulsants, chemical countermeasures, and analgesics. Such compounds also show, neuroprotective/neuroreparative effects and activity against spinal muscular atrophy. Such pharmaceutically active compounds show utility in the treatment of central nervous system (“CNS”) diseases and disorders, such as anxiety, depression, insomnia, migraine headaches, schizophrenia, neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's, ALS, and Huntington's disease) spasticity, and bipolar disorder. Furthermore, such compounds may additionally find utility as analgesics (e.g., for the treatment of chronic or neuropathic pain) and as neuroprotective agents useful in the treatment of stroke(s), and/or traumatic brain and/or spinal cord injuries.
Core Innovation
The invention relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of Formula II admixed with at least one of a pharmaceutically acceptable carrier or an excipient. Formula II is defined by substituent variables R1, R2, R3, R5, R4, X, and an integer n=1-4, with enumerated substituent options and a chiral stereocenter in some embodiments.
The invention also relates to novel amide compounds represented by Formula I-IV, with extensive definitions of the amide moiety and substituent variables including R1, R2, R3, R4, R5, Z, and the integer n=1-4. The compounds include optional aryl/heteroaryl groups, including pyrazine, pyridine, and quinoxaline optionally substituted, and chiral stereocenters including R/S enantiomers and racemic mixtures.
The compounds are presented as central nervous system modulators and therapeutic agents for CNS disorders, including anxiety, depression, insomnia, migraine, schizophrenia, neurodegenerative diseases, spasticity, and spinal muscular atrophy. The document further characterizes example compounds and provides biological activity support through anticonvulsant profiles, SMA-related reporter assays, and SMN protein localization to gems.
Claims Coverage
The independent claims cover pharmaceutical compositions defined by a Formula II framework, combined with a pharmaceutically acceptable carrier or excipient, and further refined in dependent claims primarily by stereochemical form. Across the independent claims, the main inventive features are the Formula II compound definition with variable substituents and integer n=1-4, and formulation as an admixed composition.
Formula II pharmaceutical composition with pharmaceutically acceptable carrier or excipient
A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula II admixed with at least one of a pharmaceutically acceptable carrier or an excipient, where Formula II is represented with enumerated definitions of R1, R2, R3, R5, R4, X, and n=1-4.
Formula II pharmaceutical composition with stereochemical specifications
A pharmaceutical composition comprising at least one compound represented by Formula II admixed with at least one of a pharmaceutically acceptable carrier or an excipient, where the Formula II compound includes a chiral stereocenter and is specified as the R enantiomer, the S enantiomer, or as a racemic mixture.
Coverage centers on pharmaceutical compositions containing Formula II compounds defined by enumerated substituent variables and n=1-4, with dependent limitations focusing on whether the Formula II compound is provided as a racemic mixture or as an R or S enantiomer at a chiral stereocenter.
Stated Advantages
Anticonvulsant activity in rodent epilepsy/status epilepticus models.
In vitro cytotoxicity/hepatotoxicity data and assay outcomes.
Analgesic effects in formalin and sciatic nerve ligation related assays.
Mechanistic profiling indicators for compound H, including receptor/channel activity indications and a proposed novel target.
CYP450 inhibition information (Ki values) for compound H.
Neurodegeneration-related assay results, including oxidative stress-related protection/recovery indicators and survival/recovery outcomes in additional models.
Neuroprotective and neuroreparative actions.
Therapeutic treatment of CNS disorders including anxiety, depression, insomnia, migraine, schizophrenia, neurodegenerative diseases, and spasticity.
Therapeutic treatment of spinal muscular atrophy (SMA).
Documented Applications
Anticonvulsant use in rodent epilepsy/status epilepticus models.
In vitro cytotoxicity/hepatotoxicity assessment using ACTIVTox LDH and MTT/LDH related assays.
Analgesic testing including formalin and sciatic nerve ligation effects.
Mechanistic profiling for compound H including receptor/channel activity indications and CYP450 inhibition profiling.
Neurodegeneration-related testing including an in vitro N27 Parkinson model, a Drosophila rotenone survival model, and an MPTP mouse model.
Additional biological reporter/marker assays including SMN2 promoter/exon 7 reporter activity and SMN gem localization assays.
Treatment of central nervous system disorders including anxiety, depression, insomnia, migraine, schizophrenia, neurodegenerative diseases such as Parkinson’s, Alzheimer’s, ALS, and Huntington’s, and spasticity.
Therapy for spinal muscular atrophy (SMA).
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