Treprostinil derivatives and compositions and uses thereof
Inventors
Zhang, Xiaoming • Venkatraman, Meenakshi S. • BECKER, Cyrus K.
Assignees
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Publication Number
US-11866402-B2
Publication Date
2024-01-09
Expiration Date
Abstract
The present disclosure provides treprostinil derivatives that can act as prodrugs of treprostinil. The treprostinil derivatives can be used to treat any conditions responsive to treatment with treprostinil, including pulmonary hypertension, such as pulmonary arterial hypertension.
Core Innovation
The invention relates to a method of promoting vasodilation and achieving multiple therapeutic outcomes by administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (II). The method encompasses inhibiting platelet activation or aggregation, inhibiting thrombus formation, stimulating thrombolysis, inhibiting atherogenesis, inhibiting cell proliferation, promoting endothelial cell membrane remodeling, reducing inflammation, and providing cytoprotection.
The administered compound is defined by structural moieties of Formula (II), including a specified O-Z-CO2H unit. The unit is limited to -O-heteroalkyl-CO2H, -O-cyclyl-CO2H, -O-CH2-cyclyl-CO2H, -O-cyclyl-CH2-CO2H, or -O-CH2-cyclyl-CH2-CO2H, with each option optionally substituted, and cyclyl is restricted to cycloalkyl, heterocyclyl, aryl, or heteroaryl.
The structural definition further constrains R7 and R8 and the spacer length n. R7 and R8 in each occurrence independently are hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl, or R7 and R8 together define that the carbon atom to which they are connected forms a C3-C6 cycloalkyl ring, while n is an integer from 1 to 10. The method includes a proviso that O-Z-CO2H is not present and does not contain a sugar moiety.
Claims Coverage
The claim set includes one independent method claim centered on administering a compound of Formula (II) to achieve multiple vascular and cellular therapeutic outcomes. The inventive features include the Formula (II) structural provisos for the O-Z-CO2H moiety, the R7/R8 and n constraints, and the exclusion of a sugar-containing variant; dependent claims further specify administration formats.
Method for achieving vascular and cellular therapeutic outcomes with Formula (II) compound
A method comprising administering to a subject a therapeutically effective amount of a compound of Formula (II) to promote vasodilation and provide one or more of: inhibiting platelet activation or aggregation, inhibiting thrombus formation, stimulating thrombolysis, inhibiting atherogenesis, inhibiting cell proliferation, promoting endothelial cell membrane remodeling, reducing inflammation, or providing cytoprotection, with the O-Z-CO2H unit limited to the specified alternatives and with the provisos that O-Z-CO2H is not present and that it does not contain a sugar moiety.
Defined O-Z-CO2H moiety with cyclyl, R7/R8, and n constraints
The O-Z-CO2H unit is limited to -O-heteroalkyl-CO2H, -O-cyclyl-CO2H, -O-CH2-cyclyl-CO2H, -O-cyclyl-CH2-CO2H, or -O-CH2-cyclyl-CH2-CO2H, where cyclyl is cycloalkyl, heterocyclyl, aryl, or heteroaryl; R7 and R8 are hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, or together form a C3-C6 cycloalkyl ring; and n ranges from 1 to 10.
Overall claim coverage centers on administering Formula (II) compounds to achieve the enumerated vascular and cellular therapeutic outcomes, while constraining the O-Z-CO2H alternatives, R7/R8, and n, and expressly excluding the sugar moiety-containing variant.
Stated Advantages
Promotes vasodilation.
Inhibits platelet activation or aggregation.
Inhibits thrombus formation.
Stimulates thrombolysis.
Inhibits atherogenesis.
Inhibits cell proliferation.
Promotes endothelial cell membrane remodeling.
Reduces inflammation.
Provides cytoprotection.
Longer half-life for deuterated treprostinil isotopologues.
Lower dose for deuterated treprostinil isotopologues.
Reduced side effects for deuterated treprostinil isotopologues.
Documented Applications
Used to treat a subject in need of treatment to achieve one or more of the listed vascular and biological outcomes, including promoting vasodilation, inhibiting platelet activation or aggregation and thrombus formation, stimulating thrombolysis, inhibiting atherogenesis and cell proliferation, promoting endothelial cell membrane remodeling, reducing inflammation, and providing cytoprotection.
Therapeutic use for prostacyclin/treprostinil-responsive conditions, including pulmonary hypertension (including PAH).
The method is specified as being practiced by administering the compound orally.
A dependent embodiment specifies administering the compound using a transdermal patch.
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