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-11046666-B2
Publication Date
2021-06-29
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-related chemical entities represented by Formula (I), including substituent definitions in which R20 through R36 are independently H or deuterium. Z is selected from —OH, —OR11, —N(R11)R12, —SR11, or P1, and R11 and R12 are defined by broad substituent classes.
Formula (I) further defines P1 and P2 as structural options parameterized by m being 1, 2, 3 or 4, with R14 and R15 selected from specified groups or taken together to form a 5- to 7-membered ring incorporating ring heteroatoms chosen from N, O and S, optionally substituted with halo, methyl and methoxy. Additional variables R16 and R17, and R18 and R19, are defined by hydrogen, alkyl, substituted alkyl, and optional ring-forming constraints.
The disclosure also covers related treprostinil derivatives extending the defined chemical space through Formula III and Formula IV, including specific sub-embodiments and at least one explicit example compound (Compound 59) within Formula III. Formula I compounds can include enantiomers, pharmaceutically acceptable salts, solvates and polymorphs, and a related variant Formula (IAA) with defined isotopic H/deuterium options and X defined as O or N-containing alternatives.
Claims Coverage
The independent claim coverage centers on a treprostinil-related compound of Formula (I) with extensive variable constraints, including isotopic selection (H or deuterium), Z selection, and P1/P2 structural options, and also covers salts, polymorphs, and stereoisomers. The merged content reflects the independent claim features repeated across the inputs.
Formula (I) compound with isotopic H or deuterium substitution
A compound represented by Formula (I) in which R20 through R36 are independently H or deuterium.
Z substituent selection including —OH, —OR11, —N(R11)R12, —SR11 or P1
In Formula (I), Z is —OH, —OR11, —N(R11)R12, —SR11 or P1.
P1 and P2 structural options with ring and substituent constraints
P1 and P2 are selected from defined structural options parameterized by m being 1, 2, 3 or 4, with R14 and R15 optionally forming a 5- to 7-membered ring incorporating ring heteroatoms chosen from N, O and S, and with substitution limits.
Additional constrained substituents R16/R17 and R18/R19
R16 and R17 are independently H or alkyl, or taken together optionally form a 3- to 6-membered ring, and R18 and R19 are independently hydrogen or alkyl with specified substituted-alkyl allowances.
Compounds further covered as salts, polymorphs, and stereoisomers
The compound of Formula (I) is also covered as a pharmaceutically acceptable salt, a polymorph or a stereoisomer thereof.
The claim coverage defines a Formula (I) treprostinil-related compound with explicit isotopic substitution at R20 through R36, selection of Z among specified functional groups or P1, detailed parameterized definitions for P1 and P2 including ring formation and heteroatom-incorporation constraints, additional constrained substituents, and coverage of pharmaceutically acceptable salts, polymorphs, and stereoisomers.
Stated Advantages
Improving bioavailability via transdermal delivery.
Improved systemic bioavailability compared with oral treprostinil via transdermal delivery, optionally patch.
Tailoring motifs for treatment or prophylaxis of pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH).
Better administration approach for treprostinil derivatives in pulmonary hypertension/pulmonary arterial hypertension contexts.
Documented Applications
Transdermal delivery via transdermal patch formulations for pharmaceutical compositions containing Formula I/II/III/IV compounds.
Treatment or prophylaxis of pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) using the disclosed compounds.
Pharmaceutical compositions for pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH).
Treatment of pulmonary hypertension by administering a compound of Formula (I) or a pharmaceutically acceptable salt to a subject via an administration route that includes transdermal delivery, optionally using a patch.
Treating pulmonary hypertension by administering to a subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt.
Pharmaceutical compositions and therapeutic use, including oral, parenteral, and topical formulations such as transdermal patches.
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