Salt and crystal form of compound having agonistic activity to S1P5 receptor

Inventors

Otani, Shuhei • FUJITO, Takayuki • IMURA, Naoko • KIJIMA, Hideomi • PARENT, Stephan D. • Bevill, Melanie Janelle • JOHNSON, COURTNEY S. • Houston, Travis Lee

Assignees

Ono Pharmaceutical Co Ltd

Abstract

Compound I as defined, having high S1P5 receptor-selective agonist activity on the S1P1 receptor, and the crystal forms of Compound I, the salts of Compound I, and the crystal forms of salts thereof are provided as drug substances of pharmaceuticals.

Core Innovation

The disclosure provides 1-[[(3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid and focuses on its salt and solid-state forms. The salts are specified as mono(4-hydroxybenzoate) salt, mono-tryptophan salt, or a hemisuccinate salt, and the disclosure further includes crystal forms and related hydrate/cocrystal forms, including a named free crystal D.

The disclosure addresses the lack of prior-art description of the salts and crystals of the stated compound in the disclosed forms and the resulting lack of defined solid-state identities for these drug substance forms. It emphasizes improved selectivity for S1P5 agonism over S1P1 and relates this to shortcomings of prior art concerning receptor selectivity and lack of described solid-form variants.

To establish identity and definition of the solid forms, the disclosure provides physicochemical characterization using powder X-ray diffraction and differential scanning calorimetry. Crystal identity is defined via PXRD 2θ peak sets and DSC endothermic or exothermic transition temperatures, and chemical stability is reported using residual rates to support suitability as a pharmaceutical drug substance.

The disclosure connects the compound and its forms to biological relevance by reporting example crystal preparations and biological and PK evidence associated with S1P5-mediated disease relevance. It enumerates pharmaceutical compositions and describes prevention and treatment use for S1P5-mediated diseases, notably neurodegenerative conditions such as multiple system atrophy and Parkinson’s disease, through administration of the compound.

Claims Coverage

The document includes one independent claim directed to a compound in specific salt forms, with dependent claims refining those salt forms using solid-state characterization constraints. The inventive features therefore center on the defined compound salt options and their characterization, with additional dependent coverage extending to pharmaceutical compositions and treatment methods for S1P5-mediated diseases.

Overall claim coverage is anchored in the defined azetidine-3-carboxylic acid compound provided as specified salts, with dependent claims strengthening definition using PXRD 2θ peak conditions and DSC endothermic peak onset or peak temperatures. Further dependent coverage includes treatment methods for S1P-mediated diseases via administration of the compound to a mammal.

Stated Advantages

Documented Applications