Treprostinil derivative compounds and methods of using same
Inventors
BECKER, Cyrus K. • Venkatraman, Meenakshi S. • Zhang, Xiaoming
Assignees
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Publication Number
US-11339139-B2
Publication Date
2022-05-24
Expiration Date
Abstract
Compounds represented by formulae I, II, III, and IV including pro-drugs for treprostinil and prostacyclin analogs. Uses include treatment of pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH). The structures of the compounds can be adapted to the particular application for a suitable treatment dosage. Transdermal applications can be used.
Core Innovation
The invention relates to treprostinil derivative and prodrug compounds represented by Formula I, together with related Formulae II to IV. The compounds include variants in which R20 to R36 are independently H or deuterium, and Z is selected from OH, OR11, N(R11)R12, SR11 or P1. The disclosed scope also includes enantiomers, pharmaceutically acceptable salts, and polymorphs for the represented compounds.
A central structural feature is that R1 and R2 are independently H or P2, and at least one of R1 and R2 is P2. P2 is defined as C(=O)R14, where R14 is alkyl or substituted alkyl, with stated provisos restricting the identity of the alkyl for R14 and excluding certain substituted alkyl and alkoxy combinations. Additional provisos further narrow P1 and P2 through parameterized structural options and ring-forming alternatives.
The document characterizes these compounds and variants as providing improved systemic availability and transdermal delivery for therapy in pulmonary hypertension and pulmonary arterial hypertension. It further describes optional use in a patch formulation and includes formulation and stability assay discussion, as well as compound examples and analytical data.
Claims Coverage
The claim coverage centers on a Formula (I) compound defined by a constrained substituent framework with deuterium allowed, a Z group selected from specified functionalities including P1, and a specific linkage in which R1 and R2 include P2 defined as C(=O)R14 under stated provisos; the claimed scope also explicitly includes enantiomers, pharmaceutically acceptable salts, and polymorphs. The claim family also includes pulmonary hypertension treatment and a pharmaceutical composition including at least one solvent.
Treprostinil derivative/prodrug defined by Formula I with deuterium variants
A compound represented by Formula (I) wherein R20 to R36 are independently H or deuterium, and Z is selected from OH, OR11, N(R11)R12, SR11 or P1.
Prodrug linkage via R1/R2 where at least one is P2 as C(=O)R14
R1 and R2 are independently H or P2, wherein at least one of R1 and R2 is P2 and P2 is C(=O)R14, with R14 being alkyl or substituted alkyl and stated provisos excluding certain methyl and certain substituted alkoxy-substituted alkyl groups.
Allowed prodrug-forming substituent sets for P1 and Z
Z is selected from OH, OR11, N(R11)R12, SR11 or P1, where R11 and R12 are defined across alkyl, substituted alkyl, cycloalkyl, haloalkyl, heteroalkyl, aryl and heteroaryl classes, and P1 is selected from defined structural groups with m being 1, 2, 3 or 4 and optional ring-forming alternatives incorporating N, O and S atoms.
Pharmaceutically acceptable salt, enantiomer, or polymorph coverage of the Formula I compounds
The compound is further defined to include an enantiomer, a pharmaceutically acceptable salt, or a polymorph thereof.
Pulmonary hypertension treatment
A method for treating pulmonary hypertension in a subject by administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition including at least one solvent
A pharmaceutical composition includes at least one solvent.
The claims define treprostinil derivative and prodrug compounds by Formula (I) with deuterium variants, variable Z and P1/R11/R12 structures, and a key prodrug moiety where at least one of R1/R2 is P2 defined as C(=O)R14 with stated exclusions. The scope also includes enantiomers, pharmaceutically acceptable salts, polymorphs, pulmonary hypertension treatment, and compositions including at least one solvent.
Stated Advantages
Improved systemic availability.
Transdermal delivery.
Therapeutic use in pulmonary hypertension, including pulmonary arterial hypertension.
Documented Applications
Therapy for pulmonary hypertension, including pulmonary arterial hypertension, by administering a therapeutically effective amount of a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof.
Patch formulation.
Treating pulmonary hypertension in a subject by administering a therapeutically effective amount of a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof.
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