Treprostinil derivatives and compositions and uses thereof
Inventors
Zhang, Xiaoming • Venkatraman, Meenakshi S. • BECKER, Cyrus K.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11407707-B2
Publication Date
2022-08-09
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 compounds of Formula (I) and treprostinil derivatives having specified substituent definitions, ring-formation constraints, and indices j and m. The compounds are presented as pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, or stereoisomers, and the disclosure includes Formula (II) derivatives incorporating the moiety —O—Z—CO2H.
The substituent framework constrains R1 and R2 so that both R1 and R2 are not hydrogen, and defines optional substitution patterns for R3, R4, R5, R6, R9, R10, R12, and R13 together with rules for when attached atoms form heterocyclic or heteroaryl rings. Further restrictions limit n, p, and q, and define Z as heteroalkyl or cycloalkyl options, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl variants, with explicit exclusions of acetate, substituted cyclohexane-ester, and amino acid, peptide, or protein ester forms.
The therapeutic use described comprises administering a therapeutically effective amount of a compound of Formula (I) for promoting vasodilation, 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. The treprostinil derivatives are also described as prodrugs intended to increase systemic availability and as compounds for treprostinil-responsive conditions, including pulmonary hypertension such as PAH.
Claims Coverage
The provided material identifies one independent therapeutic method claim and dependent claims that narrow the structural subset, administration route, and selected exemplified forms. The inventive coverage centers on administering a Formula (I) compound with detailed substituent and ring constraints, indices j and m, and multiple provisos excluding specific ester forms, with one independent claim directed to treprostinil-responsive therapeutic use.
Therapeutic method using Formula (I) compounds
A method of promoting vasodilation, 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, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (I).
Structural limitations on Formula (I)
Formula (I) is defined by substituent constraints for R1 through R13, ring-formation constraints, and integers j and m, with further restrictions including that both R1 and R2 are not hydrogen.
Excluded ester forms
The claims exclude compounds where neither —OR1 nor —OR2 forms an acetate, neither —OR1 nor —OR2 forms a substituted cyclohexane-ester, and neither —OR1 nor —OR2 forms an ester with or of an amino acid (protected or unprotected), a peptide, or a protein.
Dependent claim narrowing of delivery and compound selection
Dependent claims further narrow the method by specifying parenteral, transdermal, or oral inhalation administration and by selecting specified Formula (I) compounds or pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, or stereoisomers.
Treprostinil derivative moiety —O—Z—CO2H
A treprostinil derivative in which a substituent moiety of the form —O—Z—CO2H is connected to treprostinil, including heteroalkyl-CO2H and cycloalkyl-CO2H forms.
The claim coverage centers on administering a therapeutically effective amount of a structurally defined Formula (I) compound for the stated therapeutic effects, while excluding specific acetate, substituted cyclohexane-ester, and amino-acid/peptide/protein ester forms. Dependent claims further narrow the scope through delivery route, selected exemplified or pharmaceutically acceptable forms, and treprostinil-derivative moieties.
Stated Advantages
Promoting vasodilation.
Inhibiting platelet activation or aggregation.
Inhibiting thrombus formation.
Stimulating thrombolysis.
Inhibiting atherogenesis.
Inhibiting cell proliferation.
Promoting endothelial cell membrane remodeling.
Reducing inflammation.
Providing cytoprotection.
Improved systemic availability relative to poor oral bioavailability.
Documented Applications
Therapeutic treatment of a subject in need of treatment by administering a therapeutically effective amount of a Formula (I) compound to achieve the stated vasodilatory, antiplatelet, antithrombotic, thrombolytic, anti-atherogenic, anti-proliferative, anti-inflammatory, and cytoprotective effects.
Treatment of treprostinil-responsive conditions, including pulmonary hypertension such as PAH.
Treatment of pulmonary fibrosis, peripheral ischemic lesions, critical limb ischemia, diabetic neuropathic foot ulcer, atherogenesis, congestive heart failure, tumors, cancers, and pain.
Pharmaceutical composition embodiments.
Transdermal patch configurations.
Transdermal administration via a transdermal patch.
Interested in licensing this patent?