Maleate salts of triazolopyrazine derivatives, compositions, methods of use, and processes of manufacturing the same
Inventors
Choi, Jun Young • PARK, Kyung Eui • Kim, Yeong Mun
Assignees
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Publication Number
US-11987582-B2
Publication Date
2024-05-21
Expiration Date
Abstract
Pharmaceutical compositions and methods of using maleate salts of triazolopyrazine derivatives are provided. In some aspects, the pharmaceutical compositions have improved storage stability and pharmacokinetic properties. The maleate salts of triazolopyrazine derivatives bind competitively to the phosphorylation site of c-MET kinase and can be used for the treatment or prevention of various hyper proliferative disorders.
Core Innovation
The invention relates to novel maleate salts of a triazolopyrazine derivative represented by Chemical Formula 2, corresponding to a free base form represented by Chemical Formula 1. The maleate salt is characterized by defined physical-chemical properties, including chemical purity and water content relationships versus the free base form, and is prepared to substantially retain pharmacokinetic properties relative to the free base.
The maleate salt is described as providing improved solubility-related behavior, reduced hygroscopicity as reflected by lower water content, and improved chemical stability. The document further states improved chemical purity after storage and favorable behavior under specified relative humidity and temperature conditions.
The document also characterizes the maleate salt and its performance using analytical and stability testing such as DSC thermogram, DVS, NMR, and XRPD-type characterization. It further reports c-Met kinase binding and inhibition use, with therapeutic use in disorders associated with increased c-Met kinase activity, including hyperproliferative disorders and specified cancer types.
Claims Coverage
The independent claims define a maleate salt of a triazolopyrazine derivative with quantitative storage-related quality and solubility features, plus pharmaceutical composition, manufacturing, and c-Met kinase inhibition claim families. Across the claims shown, the main inventive features are the maleate salt identity, chemical purity and water content after storage, acidic pH solubility reduction, and administration for c-Met kinase inhibition.
Maleate salt with improved chemical purity after defined storage
A maleate salt of a triazolopyrazine derivative represented by Chemical Formula 2, wherein the maleate salt has a chemical purity of at least about 4.7% greater than a free base form represented by Chemical Formula 1 after about 15 months at 40 °C and 75% relative humidity.
Maleate salt with reduced water content after defined storage
A maleate salt of a triazolopyrazine derivative represented by Chemical Formula 2, wherein the maleate salt has a water content of at least about 22% lower than the free base form represented by Chemical Formula 1 after about 15 months at 40 °C and 75% relative humidity.
Acidic pH solubility reduction in pH 1 to 3
A maleate salt of a triazolopyrazine derivative represented by Chemical Formula 2, wherein the maleate salt is more than 75% less soluble than the free base form represented by Chemical Formula 1 at a pH between 1 and 3.
Gastric media solubility reduction at pH about 1.2 in 0.05 M
A maleate salt of a triazolopyrazine derivative represented by Chemical Formula 2, wherein the maleate salt is more than 75% less soluble than the free base form represented by Chemical Formula 1 at a pH of about 1.2 in 0.05 M gastric media.
Manufacturing method for precipitating the maleate salt
A method for manufacturing a maleate salt of a triazolopyrazine derivative by adding a compound represented by Chemical Formula 1 to a reactor containing a solvent, stirring to form a first solution, adding maleic acid in an equivalent ratio of about 1:1 to about 1:3 with respect to Chemical Formula 1 to form a second solution, stirring to form a third solution, and cooling to obtain a precipitate of the maleate salt represented by Chemical Formula 2.
Pharmaceutical composition with purity-defined maleate salt
A pharmaceutical composition comprising a maleate salt of a triazolopyrazine derivative represented by Chemical Formula 2 and a pharmaceutically acceptable carrier, wherein the maleate salt has a chemical purity of at least about 4.7% greater than a free base form represented by Chemical Formula 1 after about 15 months at 40 °C and 75% relative humidity.
c-Met kinase inhibition by administering purity-defined maleate salt
A method of inhibiting the activity of c-Met kinase in a subject comprising administering a maleate salt of a triazolopyrazine derivative represented by Chemical Formula 2 to a subject in need of treatment for a disorder associated with an increased activity of c-Met kinase, wherein the maleate salt has a chemical purity of at least about 4.7% greater than a free base form represented by Chemical Formula 1 after about 15 months at 40 °C and 75% relative humidity.
Pharmaceutical composition with water-content-defined maleate salt
A pharmaceutical composition comprising a maleate salt of a triazolopyrazine derivative represented by Chemical Formula 2 and a pharmaceutically acceptable carrier, wherein the maleate salt has a water content of at least about 22% lower than the free base form represented by Chemical Formula 1 after about 15 months at 40 °C and 75% relative humidity.
c-Met kinase inhibition by administering water-content-defined maleate salt
A method of inhibiting the activity of c-Met kinase in a subject comprising administering a maleate salt of a triazolopyrazine derivative represented by Chemical Formula 2 to a subject in need of treatment for a disorder associated with an increased activity of c-Met kinase, wherein the maleate salt has a water content of at least about 22% lower than the free base form represented by Chemical Formula 1 after about 15 months at 40 °C and 75% relative humidity.
Pharmaceutical composition with acidic pH solubility reduction
A pharmaceutical composition comprising a maleate salt of a triazolopyrazine derivative represented by Chemical Formula 2 and a pharmaceutically acceptable carrier, wherein the maleate salt is more than 75% less soluble than the free base form represented by Chemical Formula 1 at a pH between 1 and 3.
c-Met kinase inhibition by administering acidic pH solubility-defined maleate salt
A method of inhibiting the activity of c-Met kinase in a subject comprising administering a maleate salt of a triazolopyrazine derivative represented by Chemical Formula 2 to a subject in need of treatment for a disorder associated with an increased activity of c-Met kinase, wherein the maleate salt is more than 75% less soluble than the free base form represented by Chemical Formula 1 at a pH between 1 and 3.
Pharmaceutical composition with gastric media solubility reduction at pH about 1.2
A pharmaceutical composition comprising a maleate salt of a triazolopyrazine derivative represented by Chemical Formula 2 and a pharmaceutically acceptable carrier, wherein the maleate salt is more than 75% less soluble than the free base form represented by Chemical Formula 1 at a pH of about 1.2 in 0.05 M gastric media.
c-Met kinase inhibition by administering gastric media solubility-defined maleate salt
A method of inhibiting the activity of c-Met kinase in a subject comprising administering a maleate salt of a triazolopyrazine derivative represented by Chemical Formula 2 to a subject in need of treatment for a disorder associated with an increased activity of c-Met kinase, wherein the maleate salt is more than 75% less soluble than the free base form represented by Chemical Formula 1 at a pH of about 1.2 in 0.05 M gastric media.
The inventive scope centers on a maleate salt of a triazolopyrazine derivative with quantitative storage-condition stability attributes and marked acidic pH solubility reduction. The claims additionally cover pharmaceutical compositions containing the defined maleate salt, a method of manufacturing the maleate salt by precipitation from a solution with maleic acid, and methods of inhibiting c-Met kinase activity by administering the defined maleate salt to subjects with disorders associated with increased c-Met kinase activity.
Stated Advantages
Chemical purity improved by at least about 4.7% versus the free base after about 15 months at 40 °C and 75% relative humidity.
Water content reduced by at least about 22% versus the free base after about 15 months at 40 °C and 75% relative humidity.
Markedly reduced solubility of the maleate salt versus the free base in acidic pH conditions, including more than 75% less soluble at pH between 1 and 3 and at about pH 1.2 in 0.05 M gastric media.
Substantially retains pharmacokinetic properties relative to the free base.
Documented Applications
Inhibiting the activity of c-Met kinase in a subject with a disorder associated with an increased activity of c-Met kinase, including hyperproliferative disorders and specified cancer types.
Pharmaceutical compositions containing the maleate salt of a triazolopyrazine derivative for administration to treat a disorder associated with increased c-Met kinase activity.
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