Salts and pharmaceutical compositions thereof for the treatment of inflammatory disorders
Inventors
Wigerinck, Piet • SABOURAULT, Nicolas Luc
Assignees
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Publication Number
US-10708263-B2
Publication Date
2020-07-07
Expiration Date
Abstract
The present invention discloses salts of a Compound 1: useful in the prophylaxis and/or treatment of inflammatory conditions, autoimmune diseases, proliferative diseases, allergy, transplant rejection, diseases involving degradation and/or disruption of cartilage homeostasis, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 or interferons.
Core Innovation
The disclosure relates to salts and crystalline forms of a compound according to Formula (I), identified as Compound 1, and describes a selective JAK inhibitor, especially JAK1. The document discusses pharmaceutically acceptable salt forms and crystalline materials characterized by X-ray powder diffraction peak positions and XRPD-defined salt formation screens.
The content also describes formation of intermediate brominated triazolo[1,5-a]pyridine thiourea/amine derivatives, including conversion via thiourea formation, cyclization to a bromo-triazolopyridinylamine, and subsequent amide formation followed by hydrolysis. An alternative route further transforms hydroxymethyl and bromomethyl phenyl intermediates using PBr3 bromination and then converts to the thiomorpholine sulfone via nucleophilic substitution, with palladium-catalyzed Suzuki-type coupling used to install a substituted aromatic/thiomorpholine sulfone side chain.
The disclosure emphasizes solid-form characterization and salt form definition for Compound 1 salts, including Compound 1.HCl·3H2O and other salt forms. Stability and dehydration/rehydration behavior under humidity are reported, and XRPD peak information is used to define crystalline forms. The problem addressed is the provision of pharmaceutically acceptable salt forms and crystalline forms suitable for prophylaxis and/or treatment, including improved pharmacological properties relative to less suitable forms.
Claims Coverage
The independent claim set covers one main structural solid-form definition and multiple preparation-route refinements, together with a broader salt-preparation framework. It includes a pharmaceutically acceptable 1:1 free base/maleic acid salt of a compound according to Formula (I) in a crystalline XRPD-defined form, and methods of preparing such salts.
Xrpd-defined 1:1 free base/maleic acid crystalline salt
A pharmaceutically acceptable salt of a compound according to Formula (I) wherein the salt is a 1:1 free base/maleic acid salt in a crystalline form characterized by X-ray powder diffraction peaks at specified 2θ positions, each with ±0.2° tolerance.
Inert solvent precipitation of maleate salt
A method preparing a pharmaceutically acceptable salt by combining the compound of Formula I with maleic acid in an inert solvent and precipitating the resulting salt from the solvent.
Supersaturation and crystallization to obtain maleate salt
A method that combines the compound of Formula I with maleic acid in a suitable solvent, evaporates the solvent to create supersaturation, and then crystallizes to obtain a pharmaceutically acceptable salt.
Solvent-limited preparation for maleate salt
The method is characterized in that the solvent is chosen from acetonitrile, dioxane, THF, acetone, DCM, or MeOH.
Specified Formula I:acid molar ratio range
The salt is obtained by mixing the compound of Formula I with an acid in a molar ratio between 5:1 and 1:5 (Formula I:acid).
Overall, the claim coverage ties a specific 1:1 free base/maleic acid salt of a Formula (I) compound to a crystalline XRPD signature at multiple specified 2θ positions, and supports preparation approaches that include inert-solvent precipitation or supersaturation followed by crystallization, with additional solvent selection and preparation constraints.
Stated Advantages
Improved solubility and exposure versus free base and potentially improved pharmacological profile.
Potentially lower dosage and/or toxicity.
Documented Applications
Prophylaxis and/or treatment of broad inflammatory and immune-related diseases, including autoimmune, allergy, transplant rejection, cartilage-homeostasis disorders, and IL-6- or interferon-associated diseases.
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