Treprostinil derivatives and compositions and uses thereof
Inventors
Zhang, Xiaoming • Venkatraman, Meenakshi S. • BECKER, Cyrus K.
Assignees
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Publication Number
US-10759733-B2
Publication Date
2020-09-01
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 disclosure relates to treprostinil prodrug derivatives for increasing systemic availability of treprostinil and for treating conditions responsive to treprostinil, including pulmonary hypertension and pulmonary arterial hypertension (PAH). It addresses limitations of treprostinil free acid, including low oral bioavailability and short half-life, and notes irritation associated with inhaled dosing.
The disclosure presents chemical scaffold formulas for treprostinil derivatives as compounds of Formula (I) and Formula (II). In Formula (II), the fragment —O—Z—CO2H is defined as —O-heteroalkyl-CO2H, —O-cyclyl-CO2H, —O—CH2-cyclyl-CO2H, —O-cyclyl-CH2—CO2H, or —O—CH2-cyclyl-CH2—CO2H, where the cyclyl group is cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted.
The disclosure further constrains R7 and R8 to hydrogen, C1–C6 alkyl, or C3–C6 cycloalkyl, includes the case where R7 and R8 together form a C3–C6 cycloalkyl ring, and constrains n to an integer from 1 to 10. It also includes pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, and stereoisomers, and excludes a specified —O—Z—CO2H variant and sugar moieties.
In addition to the chemical structures, the disclosure describes topical administration, including transdermal delivery such as a transdermal patch. It also describes a kit comprising a Formula (II) compound and instructions for administering it to treat a medical condition responsive to treatment with treprostinil.
Claims Coverage
The consolidated content provides two independent claims: a transdermal patch containing a Formula (II) compound, and a kit comprising a Formula (II) compound with instructions to administer it for a treprostinil-responsive condition. Across both independent claims, the same Formula (II) structural constraints are central, including the permitted forms of the —O—Z—CO2H fragment, constraints on R7 and R8, the integer n range from 1 to 10, and the exclusion of sugar moieties.
Transdermal patch with formula (II) compound
A transdermal patch comprising a compound of Formula (II) wherein —O—Z—CO2H is —O-heteroalkyl-CO2H, —O-cyclyl-CO2H, —O—CH2-cyclyl-CO2H, —O-cyclyl-CH2—CO2H, or —O—CH2-cyclyl-CH2—CO2H, each optionally substituted; cyclyl is cycloalkyl, heterocyclyl, aryl, or heteroaryl; R7 and R8 are independently hydrogen, C1–C6 alkyl, or C3–C6 cycloalkyl, or together form a C3–C6 cycloalkyl ring; and n is an integer from 1 to 10.
Kit with formula (II) compound and instructions for treprostinil-responsive treatment
A kit comprising a compound of Formula (II) with the same —O—Z—CO2H structural options, cyclyl definition, R7/R8 constraints, and n range from 1 to 10, together with instructions for administering the compound to treat a medical condition responsive to treatment with treprostinil.
Both independent claims are grounded in the same Formula (II) treprostinil prodrug derivative scaffold with tightly defined —O—Z—CO2H options, R7/R8 constraints, and n from 1 to 10, while excluding a specified —O—Z—CO2H variant and sugar moieties. The main distinction is that one independent claim is directed to a transdermal patch containing the Formula (II) compound, and the other is directed to a kit containing the Formula (II) compound plus instructions to treat a treprostinil-responsive medical condition.
Stated Advantages
Increases systemic availability of treprostinil.
Treats conditions responsive to treprostinil, including pulmonary hypertension and pulmonary arterial hypertension (PAH).
Addresses limitations of treprostinil free acid, including low oral bioavailability and short half-life.
Avoids the irritation associated with inhaled dosing as described for treprostinil free acid.
Reduces reliance on clinician-administered parenteral routes as described for treprostinil in some contexts.
Documented Applications
Treatment of pulmonary hypertension and pulmonary arterial hypertension (PAH) responsive to treprostinil using treprostinil prodrug derivatives.
Use of Formula (II) compounds in a transdermal patch for topical/transdermal delivery.
Use of a kit including Formula (II) compound and instructions for administering to treat a medical condition responsive to treatment with treprostinil.
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