Substituted pyridine and pyrazine compounds as PDE4 inhibitors
Inventors
Bollu, Venkataiah • Breitenbucher, James • Kaplan, Alan • Lemus, Robert • Lindstrom, Andrew • VICKERS, Troy • Weinhouse, Michael • Wilson, Mark E. • Zapf, James
Assignees
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Publication Number
US-11279691-B2
Publication Date
2022-03-22
Expiration Date
Abstract
The invention provides a chemical entity of Formula (I), and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods, including metabolic and reaction kinetic studies, detection and imaging techniques, and radioactive treatments; and therapies, including inhibiting PDE4, enhancing neuronal plasticity, treating neurological disorders, providing neuroprotection, treating a cognitive impairment associated with a CNS disorder, enhancing the efficiency of cognitive and motor training, providing neurorecovery and neurorehabilitation, enhancing the efficiency of non-human animal training protocols, and treating peripheral disorders, including inflammatory and renal disorders.
Core Innovation
The disclosure is directed to a specific compound, 5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine, or a pharmaceutically acceptable salt thereof, and provides related example compounds within a substituted heteroheteroaromatic scaffold. The examples include substituted pyridine, pyrazine, pyrimidine, pyrazole, pyridazine, tetrazole, and triazole analogs, with variations such as methoxy, ethoxy, difluoromethoxy, fluoro, chloro, methyl, ethyl, and related side-chain or ring substitutions.
The compounds are characterized by 1H NMR and [M+H] values, and several examples are presented as named compounds with structural depictions and analytical characterization. The disclosure links the compounds to PDE4 enzymatic activity and therapeutic use, including inhibition of PDE4 and PDE4D3.
The therapeutic context includes diseases or medical conditions mediated by PDE4 enzymatic activity and neurological disorders more generally. The document also describes pharmaceutical composition language and compound families and analogs associated with the same core scaffold.
Claims Coverage
The consolidated claim coverage centers on one independent claim directed to a specific compound structure, with dependent claims adding pharmaceutical composition language and therapeutic use. In total, the claim set presents one compound-defining inventive feature, one formulation feature, and two treatment-method features.
Specific substituted pyrimidin-2-amine compound
5-{[5-(3-Chlorophenyl)-6-methoxypyridin-3-yl]methyl}pyrimidin-2-amine, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with effective amount and excipient
A pharmaceutical composition comprising an effective amount of the compound, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.
PDE4-enzymatic-activity-mediated disease treatment
A method of treating a subject with a PDE4-enzymatic-activity-mediated disease or medical condition by administering an effective amount of the compound, with the condition selected from an enumerated group including Alzheimer’s Disease, age associated memory impairment, vascular dementia, Parkinson’s disease, Huntington’s disease, COPD, asthma, rheumatoid arthritis, and psoriasis, among others.
Neurological disorder treatment method
A method for treating a neurological disorder by administering an effective amount of the compound to a subject in need.
Overall, the claims are anchored on the specific substituted pyrimidin-2-amine compound, then extend to pharmaceutical compositions and to treatment methods for PDE4-enzymatic-activity-mediated diseases and neurological disorders.
Stated Advantages
Enhancing neuronal plasticity.
Compounds inhibit PDE4, including PDE4D3.
Behavioral outcomes indicate enhanced contextual memory and 24-hour object recognition memory.
Documented Applications
Therapeutic use as PDE4 inhibitors for treating PDE4-mediated neurological disorders and related indications.
Treatment of Alzheimer’s disease.
Treatment of age associated memory impairment, vascular dementia, Parkinson’s disease, Huntington’s disease, COPD, asthma, rheumatoid arthritis, and psoriasis.
Assessment of PDE4 inhibitor effects on contextual fear conditioning, including freezing behavior and discrimination index.
Assessment of PDE4 inhibitor effects on novel object recognition with 24-hour object recognition memory.
Imaging/immunoassay-related use through isotopically labeled analogs associated with PET and SPECT.
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