Methods and compositions for stimulating neurogenesis and inhibiting neuronal degeneration using isothiazolopyrimidinones
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Publication Number
US-9592234-B2
Publication Date
2017-03-14
Expiration Date
Abstract
The present invention provides methods and compositions comprising compounds useful for stimulating neurogenesis. The methods and compositions comprising compounds are also useful for inhibiting neuronal degeneration. Thus, the present invention can be used in the treatment of diseases and conditions characterized by neuronal loss and reduced neurogenesis including Alzheimer's disease, stroke, traumatic brain injury, traumatic nerve injury, and depression. This invention is useful for research products including single agents or mixtures of agents to promote, proliferate, differentiate, or maintain neurons from stem or progenitor cells.
Core Innovation
The invention relates to neurology methods and pharmaceutical compositions using isothiazolopyrimidinone compounds to stimulate neurogenesis and inhibit neuronal degeneration. The disclosure targets diseases and conditions associated with neuronal loss, including neurodegenerative disease, brain injury, nerve injury, psychiatric disorders, and aging, and includes Alzheimer’s disease, stroke, traumatic brain injury, traumatic nerve injury, depression, and Parkinson’s disease as example conditions.
A compound is provided having a structure defined by a scaffold with multiple substituent variables. The structure includes R1 as an optionally substituted aryl group, L as [CH2]1-6, X as S, SO2, O, or NH, and additional variable substituent positions including Y, Z, T, and n where n is 2 or 3. The disclosure includes Formula I and additional enumerated compound formulas (II–XII) illustrating specific isothiazolo[4,5-d]pyrimidin-7(6H)-one derivatives derived from the Formula I framework.
The disclosure further describes pharmaceutical compositions comprising the isothiazolopyrimidinone compounds, including pharmaceutically acceptable salts, solvates, and hydrates, with pharmaceutically acceptable carriers or excipients. It also relates to therapeutic administration in mammals and humans in an effective amount to stimulate neurogenesis and/or inhibit neuronal degeneration, and includes kit and administration route concepts.
Claims Coverage
The document includes independent claim scope focused on a defined isothiazolopyrimidinone compound structure and on therapeutic administration of a pharmaceutical composition containing that compound to stimulate neurogenesis and/or inhibit neuronal degeneration. The inventive content centers on the constrained chemical scaffold and therapeutic use in mammals, then in humans, and then for selected human conditions.
Isothiazolopyrimidinone scaffold with defined substituent options
A compound having a structure with R1 optionally substituted aryl, L as [CH2]1-6, X as S, SO2, O, or NH, Y and Z as defined substitution variables, T as O, S, or NR1, and n as 2 or 3, with each R1 independently selected.
Effective-amount administration for neurogenesis stimulation and/or neuronal degeneration inhibition in a mammal
A method of stimulating neurogenesis and/or inhibiting neuronal degeneration in a mammal by administering a pharmaceutical composition comprising the compound, or pharmaceutically acceptable salts, hydrates, or solvates, in an effective amount, optionally including a pharmaceutically acceptable excipient or carrier.
Human administration
The method is performed using a human mammal.
Human patient treatment for selected conditions
The method is for a human patient having a condition selected from neurodegenerative disease, brain injury, nerve injury, psychiatric disorders, or aging.
Claim coverage is anchored by a constrained isothiazolopyrimidinone scaffold defined through the permitted values of R1, L, X, Y, Z, T, and n, and is extended through therapeutic method claims requiring administration of a pharmaceutical composition in an effective amount to stimulate neurogenesis and/or inhibit neuronal degeneration, first in mammals, then in humans, and for a listed set of human conditions.
Stated Advantages
Stimulating neurogenesis.
Inhibiting neuronal degeneration.
Controlled release via biodegradable or non-biodegradable carriers and polymer degradation, including enzymatic or non-enzymatic hydrolysis.
Reversible thermal gelation at physiological temperature to support pharmaceutical delivery.
Documented Applications
Treatment methods for neurogenesis stimulation and/or neuronal degeneration inhibition in mammals and humans for neurodegenerative disease, brain injury, nerve injury, psychiatric disorders, and aging, including Alzheimer’s disease, stroke, traumatic brain injury, traumatic nerve injury, depression, and Parkinson’s disease.
Application to neurodegeneration including peripheral neuropathy from irradiation and chemotherapy.
Evaluating neurogenesis/neuroprotection and toxicity profiling in documented examples and models, including a behavior aging model and transgenic Alzheimer’s model.
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