Treprostinil derivatives and compositions and uses thereof
Inventors
Zhang, Xiaoming • Venkatraman, Meenakshi S. • BECKER, Cyrus K.
Assignees
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Publication Number
US-10988435-B2
Publication Date
2021-04-27
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 treprostinil derivatives defined by Formula (I) and Formula (II) with broad substituent definitions and variable constraints. The compounds are described as prodrugs intended to improve systemic availability of treprostinil and to release treprostinil in vivo, with utility in treating pulmonary hypertension, including pulmonary arterial hypertension.
The invention also relates to methods of promoting vasodilation and/or 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 by administering a therapeutically effective amount of a treprostinil-derived compound of Formula (I) or Formula (II). The compounds are described with variable substituent definitions and allowed structural options, together with pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs and stereoisomers.
Formula (I) defines compounds using substituent variables including R1, R2, R3, R6, R9, R10, j, t, m, and k, with the proviso that R1 and R2 are not both hydrogen and with restrictions on the allowable forms of the substituents. Formula (II) embodiments are defined by ring A selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and u as an integer from 0 to 9, together with stereochemical options and representative compound variants.
Claims Coverage
The consolidated claims coverage includes three independent method claims. Across them, the covered methods administer a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer, for multiple vascular and cellular therapeutic effects, with structural limits on Formula (I) and Formula (II) compounds.
Therapeutic method using Formula (I) compounds
Administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (I), wherein both R1 and R2 are not hydrogen, with defined substituent variables including R3, R6, R9, R10, j, and t.
Therapeutic method using Formula (II) compounds
Administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (II), wherein ring A is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and u is an integer from 0 to 9.
Formula (II) treprostinil derivative method for specified therapeutic effects
Administering to a subject in need of treatment a therapeutically effective amount of a Formula (II) treprostinil derivative, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer, to promote vasodilation, inhibit platelet activation or aggregation, inhibit thrombus formation, stimulate thrombolysis, inhibit atherogenesis, inhibit cell proliferation, promote endothelial cell membrane remodeling, reduce inflammation, or provide cytoprotection.
The covered inventive concept is therapeutic administration of treprostinil derivative compounds defined by Formula (I) or Formula (II) for vascular and cellular effects. The Formula (I) claim is distinguished by detailed substituent and integer restrictions, while the Formula (II) claims are distinguished by ring A selection, the u range, and the specified therapeutic effect categories.
Stated Advantages
Improved systemic availability of treprostinil.
Addressing poor oral bioavailability and short systemic half-life of treprostinil.
Reducing inhalation irritation by using prodrug derivatives.
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.
Reduced side effects.
Documented Applications
Treating pulmonary hypertension, including pulmonary arterial hypertension.
A method for promoting vasodilation and other cardiovascular or vascular effects by administering a therapeutically effective amount of a Formula (I) or Formula (II) compound to a subject in need of treatment.
Pharmaceutical composition and transdermal delivery formulations, including transdermal patch formulations.
Biological stability and permeability evaluation using human liver microsomal stability assay, human plasma stability assay, human skin homogenate stability assay, and a skin permeability assay using human cadaver epidermis.
Biological assay characterization using LC-MS/MS and reporting intrinsic clearance (CLint) and half-life (t1/2), plus Franz diffusion cell skin permeability testing with cumulative permeability at 72 h.
Administration routes explicitly described include subcutaneous, intravenous, transdermal, oral inhalation, oral administration, and parenteral administration.
Disease-treatment methods for treprostinil-responsive conditions, notably pulmonary hypertension and pulmonary arterial hypertension.
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