Mesylate salts of triazolopyrazine derivatives
Inventors
Choi, Jun Young • PARK, Kyung-eui • Kim, Na Young
Assignees
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Publication Number
US-12084450-B2
Publication Date
2024-09-10
Expiration Date
Abstract
Provided is a mesylate salt of methanesulfonic acid and a triazolopyrazine derivative of formula (1), pharmaceutical compositions thereof, methods of making the salt, and therapeutic use thereof:
Core Innovation
The invention relates to mesylate salts of methanesulfonic acid and a triazolopyrazine derivative of formula (1). The disclosed subject matter includes specific optical and stereochemical forms, including an (S) enantiomer with defined optical purity, and defined mesylate salt forms (Mes1, Mes2, Mes3).
A key aspect is the selection and definition of mesylate salt forms based on physical and analytical properties. The document targets physical stability under defined temperature and relative humidity conditions and specifies chemical purity thresholds for the API. The mesylate salts are characterized by high-throughput X-ray powder diffraction (HT-XRPD) using characteristic peak 2θ ranges, supported by additional analytical characterization methods.
The disclosed mesylate salts are used in pharmaceutical compositions with pharmaceutically acceptable carriers. The document also describes a manufacturing approach for preparing the mesylate salt by forming a solution with a compound of formula (1), adding methanesulfonic acid, and obtaining a precipitate upon cooling. The disclosed formulations and salts are positioned for inhibition of c-Met kinase for hyperproliferative disorders.
Claims Coverage
The document includes two independent claims: one directed to a specific mesylate salt of a triazolopyrazine derivative and one directed to a method for manufacturing that mesylate salt. Across the dependent claims, the inventive features focus on defined stereochemistry/optical purity, selecting specific mesylate salt forms, and imposing characterization/quality constraints (physical stability, API chemical purity, and HT-XRPD peak ranges).
Mesylate salt of methanesulfonic acid with triazolopyrazine derivative of formula (1)
A mesylate salt of methanesulfonic acid and a triazolopyrazine derivative of formula (1).
(S) enantiomer of the triazolopyrazine derivative in the mesylate salt
The mesylate salt in which the triazolopyrazine derivative of formula (1) is the (S) enantiomer.
Mesylate salt in specific salt forms Mes1, Mes2, or Mes3
A mesylate salt wherein the mesylate salt has the specific salt form Mes1, Mes2, or Mes3.
Physical stability of the mesylate salt at defined temperature and RH
A mesylate salt physically stable at 20–50°C and 35–80% relative humidity (RH) for at least 2 days.
API chemical purity threshold for the mesylate salt
The mesylate salt with an API chemical purity of at least about 95%.
HT-XRPD diffraction pattern with characteristic peak 2θ ranges
The mesylate salt having an HT-XRPD diffraction pattern with characteristic peaks at defined 2θ ranges of 15.5–16.0°, 17.5–18.0°, and 21.5–22.0°.
Manufacturing a mesylate salt by solvent solution, methanesulfonic acid addition, and cooling precipitation
A method for manufacturing a mesylate salt comprising adding a compound of formula (1) to a reactor containing a solvent, stirring the compound and the solvent, adding methanesulfonic acid, and cooling the solution to obtain a precipitate of the mesylate salt.
Solvent selection for the manufacturing method
The method where the solvent is selected from acetonitrile, acetone, 1,2-dimethoxyethane, n-heptane, isopropyl alcohol, water, or THF.
Methanesulfonic acid addition at an equivalent ratio range
The method where methanesulfonic acid is added at an equivalent ratio of about 1:1.5 to about 1:2.5 relative to formula (1).
Tighter equivalent ratio range using acetonitrile solvent
The method where the equivalent ratio is about 1:1.9 to about 1:2.3 and the solvent comprises acetonitrile.
Stirring conditions in step (b) of the manufacturing method
The method where stirring in step (b) is performed at about 45 to 55°C for at least about 1 hour.
Overall, the claim coverage concentrates on defined mesylate salts, including stereochemistry/optical purity and named salt forms, combined with physical stability, API chemical purity, and HT-XRPD peak-pattern constraints. A separate independent claim covers manufacturing via solution preparation, methanesulfonic acid addition, and cooling to precipitate the mesylate salt, with dependent claims narrowing solvent choice, equivalent ratio, and stirring conditions.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Use to inhibit c-Met kinase for hyperproliferative disorders.
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