Polymorphic forms of triazolopyrazine derivatives and method of preparing the same
Inventors
Jeong, Seong-Hoon • Kim, Ki-Hyun • KIM, Nam-Ah
Assignees
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Publication Number
US-10538529-B2
Publication Date
2020-01-21
Expiration Date
Abstract
A crystalline modification of triazolopyrazine derivatives binds to a hepatocyte growth factor (HGF) to activate phosphorylation, thereby significantly inhibiting the activity of c-Met kinase triggering cell proliferation, migration, and formation of new blood vessels. Therefore, the compound of the present application may be effectively used for the treatment or prevention of various hyper proliferative disorders mediated by hyper proliferation activation of cells and excessive angiogenesis.
Core Innovation
The patent relates to polymorphic/crystalline modifications of a triazolopyrazine derivative defined as Chemical Formula 1. It identifies crystalline modification types I–VII by angles of 2θ representing X-ray diffraction (XRD) peaks, measured using Cu-Kα1 radiation with a tolerance of ±0.1°. The crystalline modification types are described as binding HGF and inhibiting c-Met kinase activity.
The background problem addressed is that c-Met activation by hepatocyte growth factor (HGF) involves phosphorylation activation, and c-Met-driven tumor cell proliferation, migration, and angiogenesis are associated with hyper proliferative disorders and cancer. The patent states that the crystalline modification types I–VII of Chemical Formula 1 bind HGF and inhibit c-Met kinase activity.
The crystalline modification types I–VII are associated with therapeutic suppression of c-Met-driven tumor cell proliferation, migration, and angiogenesis. The patent provides XRD fingerprints for each crystalline modification type and pharmaceutical compositions with pharmaceutically acceptable carriers and excipients.
Claims Coverage
The independent claims are directed to crystalline modification type I, type II, type III, type IV, type V, type VI, and type VII of the compound of Chemical Formula 1, with each independent claim defining the crystalline identity by a defined set of XRD peak angles (2θ) measured using Cu-Kα1 radiation with ±0.1° tolerance. Across the family, the inventive features are the specific XRD fingerprint constraints for each crystalline modification type.
Crystalline modification type I XRD fingerprint
A crystalline modification type I compound of Chemical Formula 1 wherein angles of 2θ representing XRD peaks of the crystalline modification include 3.35°, 6.75°, 7.94°, 10.40° and 12.37° (2θ, ±0.1° using Cu-Kα1 radiation).
Crystalline modification type II XRD fingerprint
A crystalline modification type II compound of Chemical Formula 1 wherein angles of 2θ representing XRD peaks of the crystalline modification include 5.81°, 7.10°, 8.49°, 9.32°, 11.74°, 15.97° and 16.45° (2θ, ±0.1° using Cu-Kα1 radiation).
Crystalline modification type III XRD fingerprint
A crystalline modification type III compound of Chemical Formula 1 wherein angles of 2θ representing XRD peaks of the crystalline modification include 3.01°, 6.81°, 7.33° and 12.28° (2θ, ±0.1° using Cu-Kα1 radiation).
Crystalline modification type IV XRD fingerprint
A crystalline modification type IV compound of Chemical Formula 1 wherein angles of 2θ representing XRD peaks of the crystalline modification include 5.81°, 6.93°, 8.42°, 9.43° and 11.53° (2θ, ±0.1° using Cu-Kα1 radiation).
Crystalline modification type V XRD fingerprint
A crystalline modification type V compound of Chemical Formula 1 wherein angles of 2θ representing XRD peaks of the crystalline modification include 8.71°, 9.67°, 11.36° and 11.66° (2θ, ±0.1° using Cu-Kα1 radiation).
Crystalline modification type VI XRD fingerprint
A crystalline modification type VI compound of Chemical Formula 1 wherein angles of 2θ representing XRD peaks of the crystalline modification include 33.40°, 6.96°, 7.50°, 9.68° and 12.50° (2θ, ±0.1° using Cu-Kα1 radiation).
Crystalline modification type VII XRD fingerprint
A crystalline modification type VII compound of Chemical Formula 1 wherein angles of 2θ representing XRD peaks of the crystalline modification include 3.09°, 6.31° and 6.78° (2θ, ±0.1° using Cu-Kα1 radiation).
Claim coverage is provided for Chemical Formula 1 expressed as crystalline modification types I–VII, where each independent claim specifies a distinct XRD peak-angle set (2θ) for crystalline identity using Cu-Kα1 radiation and ±0.1° tolerance. The dependent claims further expand the XRD peak sets and include pharmaceutical composition aspects, while some dependents address preparation routes to specific crystalline modifications.
Stated Advantages
The crystalline modification types bind HGF.
The crystalline modification types inhibit c-Met kinase activity.
The crystalline modification types suppress c-Met-driven tumor cell proliferation.
The crystalline modification types suppress c-Met-driven tumor cell migration.
The crystalline modification types suppress c-Met-driven angiogenesis.
Documented Applications
Therapeutic use for hyper proliferative disorders, including cancer, by suppressing c-Met-driven tumor cell proliferation, migration, and angiogenesis through HGF binding and c-Met kinase inhibition.
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