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Publication Number
US-9340483-B2
Publication Date
2016-05-17
Expiration Date
Abstract
The present invention relates to use of DHA analogs and their pharmaceutical compositions for treating ALS, by administering these compounds or pharmaceutical compositions to subjects in need thereof.
Core Innovation
The invention relates to chemical scope and forms for compounds of Formula I and related Formula I-IV compounds defined with atropic isomers, tautomeric forms including all tautomeric forms, and crystal polymorphs or crystal forms. The scope further includes hydrated and anhydrous forms as well as solvates, including hydrate and specific solvates such as ethanol solvates and acetone solvates, with characterizations including X-ray diffraction and IR spectral data.
The invention further defines analogs, derivatives, and bioisosteres, including 10,17-dihydroxyl DHA derivatives where Formula I serves as a core scaffold framework. Additional chemical embodiments include isotopes and protecting groups, including oxygen protecting groups and nitrogen protecting groups, with inclusion of stereochemical and geometric (E/Z) considerations described for representative compounds including Compound 2 and related isomers.
The invention addresses oxidative stress associated with amyotrophic lateral sclerosis (ALS), where reducing oxidative stress is linked to reducing cell death, reducing neurodegeneration, and increasing cell survival. The compounds reduce oxidative stress in ALS by increasing survival of motor neurons and astrocytes, and the document discusses alleviating symptoms and clinical signs, prolonging survival, and mechanistic links to cell death reduction and improved viability of motor neurons and astrocytes.
The invention also describes pharmaceutical and combination therapy frameworks for ALS using the Formula I compounds, including medicament use for treating, preventing, or delaying ALS and for alleviating symptoms and clinical signs. The document further frames combination therapy by optionally administering a second active therapeutic agent selected from a listed set of therapeutic agents, and it includes composition and formulation considerations with routes including intrathecal, intracerebroventricular (ICV), and intranasal.
Claims Coverage
The provided claims include two independent methods that cover administering therapeutically effective amounts of compounds of Formula I, or pharmaceutically acceptable salts, esters, solvates, hydrates, or prodrugs, to reduce oxidative stress associated with ALS. Across the independent claims, the inventive features are directed to at least 39% motor neuron survival and at least 22% astrocyte survival, respectively, in the context of ALS oxidative stress reduction.
Formula I for reducing oxidative stress in ALS by increasing motor neuron survival
Administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, ester, solvate, hydrate or prodrug thereof, such that reducing oxidative stress associated with ALS comprises one or more of reducing cell death, reducing neurodegeneration, or increasing cell survival, wherein the cell is a motor neuron and the method increases motor neuron survival by at least 39%.
Formula I for reducing oxidative stress in ALS by increasing astrocyte survival
Administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, ester, solvate, hydrate or prodrug thereof, such that reducing oxidative stress associated with ALS comprises one or more of reducing cell death, reducing neurodegeneration, or increasing cell survival, wherein the cell is an astrocyte and the method increases astrocyte survival by at least 22%.
Both independent claims cover ALS treatment by administering a therapeutically effective amount of a Formula I compound to reduce oxidative stress, with the claim-defining performance metrics tied to increasing survival of the relevant neural cell type: at least 39% for motor neurons or at least 22% for astrocytes.
Stated Advantages
Reduces oxidative stress associated with ALS by reducing cell death and/or reducing neurodegeneration and/or increasing cell survival.
Increases motor neuron survival by at least 39%.
Increases astrocyte survival by at least 22%.
Alleviates symptoms and clinical signs of ALS.
Prolongs survival of a subject with ALS.
Documented Applications
Treating, preventing, or delaying amyotrophic lateral sclerosis (ALS), including alleviating ALS symptoms and clinical signs and prolonging survival.
Combination therapy for ALS in which the Formula I compound is administered with an optional second active therapeutic agent selected from a specified list of second active agents or combinations thereof.
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