Sulphate salts of N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine, preparation thereof and use of the same
Inventors
BURLET, Stéphane • ESTRELLA, Cécilia • BARRIER, Mathieu • Melnyk, Patricia • Sergeant, Nicolas • Buee, Luc • Verwaerde, Philippe
Assignees
ALZPROTECT • Institut National de la Sante et de la Recherche Medicale INSERM • Universite de Lille
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Publication Number
US-10772884-B2
Publication Date
2020-09-15
Expiration Date
Abstract
The present invention relates to sulphate salts of N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine and pharmaceutically acceptable solvates thereof, preparation thereof, pharmaceutical compositions containing them and use of the same in the treatment and/or prevention of neurodegenerative diseases.
Core Innovation
The invention relates to sulphate salts of N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine and pharmaceutically acceptable solvates thereof, including hydrates. The sulphate salt is defined with x equivalents of sulphuric acid (x=0.5–4) and, for the solvate hydrate, a solvate stoichiometry y (preferred hydrate y≈2).
The document emphasizes stable free flowing crystalline powders, defined morphology, and non-hygroscopic solid behaviour. It addresses drawbacks associated with free base and oxalate salts by describing concerns including stability, crystallinity, hygroscopicity, toxicity, and nephrotoxicity, and states that the sulphate salts form stable non-hygroscopic crystalline powders with defined morphology.
The invention further relates to therapeutic effects in neurodegenerative conditions associated with tauopathy and amyloidopathy. The provided data describe modulation of APP metabolism toward non-amyloidogenic pathways, increased APP-CTFs and sAPPα and decreased Aβ1-42, inhibition of pathological Tau phosphorylation, and alleviation of oxidative stress, including reduced lipid peroxidation (LPO).
Claims Coverage
The patent contains three independent claims, each directed to therapeutic administration of a specific sulphate salt of the stated benzimidazol-2-amine or a pharmaceutically acceptable solvate. Across the independent claims, the main inventive chemical feature is the sulphate salt identity, with dependent claims further specifying Formula II with x=0.5–4.
Treating tauopathies by administering a sulphate salt compound
Administering to a patient in need thereof a pharmaceutically effective amount of a sulphate salt of N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine or a pharmaceutically acceptable solvate thereof to treat a disease selected from tauopathies.
Delaying onset of tauopathies by administering a sulphate salt compound
Administering to a patient in need thereof a pharmaceutically effective amount of a sulphate salt of N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine or a pharmaceutically acceptable solvate thereof to delay in the patient the onset of a disease selected from tauopathies.
Inhibiting pathological Tau phosphorylation and alleviating oxidative stress with a sulphate salt compound
Administering to a human patient an effective amount of a sulphate salt of N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine or a pharmaceutically acceptable solvate thereof to inhibit pathological Tau protein phosphorylation while alleviating oxidative stress processes in a human patient in need of treatment for tauopathies.
Across the independent claims, the coverage is directed to therapeutic administration of a specific sulphate salt, or pharmaceutically acceptable solvate, of the stated N-(...)-1H-benzo[d]imidazol-2-amine. The inventive features focus on tauopathy treatment outcomes, including treatment, delaying onset, and inhibition of pathological Tau phosphorylation together with oxidative stress alleviation.
Stated Advantages
Stable free flowing crystalline powders with defined morphology.
Non-hygroscopic solid behaviour.
Reduced oxidative stress, including reduced lipid peroxidation (LPO).
Inhibition of pathological Tau protein phosphorylation (reduced AT100) without affecting AT8.
Modulation of APP metabolism toward non-amyloidogenic pathways, including increased APP-CTFs and sAPPα and decreased Aβ1-42.
No cytotoxicity as reported in the presented preclinical context.
Documented Applications
Treating a disease selected from tauopathies, including ALS with frontotemporal dementia, IBMPFD, frontotemporal lobar degeneration, and frontotemporal dementia with Parkinsonism linked to chromosome 17.
Delaying the onset of a disease selected from tauopathies in a patient, including the same listed tauopathy disorders.
In a human patient in need of treatment for tauopathies, inhibiting pathological Tau protein phosphorylation while alleviating oxidative stress processes.
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