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-10537569-B2
Publication Date
2020-01-21
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, and pharmaceutically acceptable solvates including hydrates, of N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine. It addresses stability and crystallization issues associated with the free base and with prior oxalate salts, and states that sulphate salt selection is associated with stable solid-state properties and crystalline powders with defined morphology.
The invention contrasts prior oxalate salts requiring high equivalents of acid and discusses concerns including reducing active payload and raising nephrotoxicity concerns. In comparison, the sulphate salts are described as yielding stable, non-hygroscopic, crystalline powders with defined morphology and improved solid-state properties, and Formula II specifies sulphate stoichiometry x for the sulphate salts.
The invention also describes functional neurobiology of the sulphate salts, including modulation of APP metabolism toward non-amyloidogenic pathways. It states that the sulphate salts increase APP-CTFs and sAPPα while decreasing Aβ1-42 without changing APP expression and without neurotoxicity, and that they alter pathological Tau phosphorylation and alleviate oxidative stress, including lowering lipid peroxidation (LPO).
Claims Coverage
The independent claim covers a disease-delaying or treatment method with a sulphate salt of a defined benzimidazole-amine, including pharmaceutically acceptable solvates, for two selected diseases, and it is tied to the sulphate stoichiometry defined in Formula II.
Disease delaying or treating with a specified sulphate salt
A method for delaying the onset of or treating a disease selected from Alzheimer's disease and Parkinson's disease by administering 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.
Stoichiometry-defined sulphate salt according to Formula II
The sulphate salt is characterized by Formula II, in which the sulphate is expressed as (H2SO4)x and x is limited to 0.5–4, including a pharmaceutically acceptable solvate thereof.
The claims scope method-based use of the specified benzimidazole-amine sulphate, or pharmaceutically acceptable solvate, to delay onset or treat Alzheimer's and Parkinson's diseases, with a key inventive element being the stoichiometry constraint of the sulphate salt according to Formula II (x = 0.5–4).
Stated Advantages
Provides stable, non-hygroscopic, crystalline powders with defined morphology.
Improves solid-state properties.
Modulates APP metabolism toward non-amyloidogenic pathways by increasing APP-CTFs and sAPPα while decreasing Aβ1-42 without changing APP expression and without neurotoxicity.
Alleviates oxidative stress, including lowering lipid peroxidation (LPO).
Documented Applications
Delaying the onset of or treating Alzheimer's disease by administering a pharmaceutically effective amount of the sulphate salt or a pharmaceutically acceptable solvate thereof.
Treating Parkinson's disease by administering a pharmaceutically effective amount of the sulphate salt or a pharmaceutically acceptable solvate thereof.
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