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-9562018-B2
Publication Date
2017-02-07
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 a sulphate salt of N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine and pharmaceutically acceptable solvates, including hydrates. The sulphate salts are described as forming stable, non-hygroscopic crystalline powders with defined morphology and improved formulation attributes.
Salt stoichiometry is addressed using sulphuric acid equivalents x in a Formula II concept (H2SO4)x and solvate/hydrate parameter y in a Formula III concept (H2SO4)x(H2O)y, with defined parameter ranges used to specify the sulphate salt and its solvates. The background motivates the sulphate salt approach due to problems identified with the free base and with oxalate salts, including stability/crystallinity issues, required counter-ion equivalents, and potential nephrotoxicity concerns.
The disclosed sulphate salts are linked to modulation of APP metabolism, including increasing non-amyloidogenic APP processing metabolites and decreasing Aβ1-42. The document further links these effects to changes in pathological Tau phosphorylation and oxidative stress, including lipid peroxidation (LPO), and provides supportive in vitro and in vivo data.
Claims Coverage
The independent claim covers the sulphate salt of the specified benzimidazole-amine compound and pharmaceutically acceptable solvates. The claim set includes five inventive features, with dependent claims adding quantitative definition by introducing sulphuric-acid equivalent parameter x and water-equivalent parameter y, plus an embodiment as a medicament.
Sulphate salt of N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine
A sulphate salt of N-(3-(4-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine and pharmaceutically acceptable solvates thereof.
Sulphuric-acid equivalent parameter x in Formula II
The sulphate salt defined by Formula II where the number of equivalents of sulphuric acid is defined by x.
Narrower sulphuric-acid equivalent range for x
The sulphate salt where x is between 1.5 and 2.5, including pharmaceutically acceptable solvates.
Hydrate/solvate specification using water-equivalent parameter y in Formula III
A sulphate salt corresponding to Formula III where x is defined as in the prior claim and y is the number of equivalents of water with y ranging from 0.5 to 5.
Medicament containing the sulphate salt or its solvate
A medicament containing a sulphate salt as defined and/or a pharmaceutically acceptable solvate of that sulphate salt.
Across the inventive features, the claim set defines the compound as a sulphate salt, specifies solvate scope, and further constrains the salt and hydrate composition using parameter x (sulphuric acid equivalents) and parameter y (water equivalents), with an embodiment that includes formulation as a medicament.
Stated Advantages
Forms stable, non-hygroscopic crystalline powders with defined morphology.
Improved formulation attributes.
Motivated improvement relative to free base and oxalate salts, addressing stability/crystallinity, counter-ion equivalent requirements, and potential nephrotoxicity concerns.
Documented Applications
Neurodegenerative diseases and amyloid/tau-related conditions, including Alzheimer’s disease, dementia with Lewy bodies (DLB), amyloid angiopathies, tauopathies, and Parkinson’s disease.
Pharmaceutical compositions for use in the above conditions, including combination therapy adjuncts for Alzheimer’s disease with agents such as acetylcholinesterase inhibitors and NMDA antagonist (memantine).
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