Treprostinil derivatives and compositions and uses thereof
Inventors
Zhang, Xiaoming • Venkatraman, Meenakshi S. • BECKER, Cyrus K.
Assignees
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Publication Number
US-11034645-B2
Publication Date
2021-06-15
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 as compounds of Formula (I) and Formula (II), together with pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs, or stereoisomers thereof. The compounds are characterized by defined substituent patterns for R1 through R6, ring-forming possibilities, integer parameters j and m, and additional structural limitations, including provisos that both R1 and R2 are not hydrogen and that neither -OR1 nor -OR2 forms an acetate, a substituted cyclohexane-ester, or an ester with or of an amino acid, a peptide, or a protein.
The disclosure includes representative treprostinil derivative structures, including Compound Ia-1 to Ia-15, Compound Ib-1 to Ib-15, and Compounds II-1 through at least II-26, as well as specific selected compounds such as Compound II-4, II-5, II-7, II-9, II-13, and II-15. It also describes derivatized -OR1/-OR2 cases presented as Formula Ia, Formula Ib, and Formula Ic, along with stereochemical variants including racemic and (R)/(S) forms at stereocenters adjacent to oxygen and/or carboxyl groups.
The subject matter further relates to transdermal patch and kit use of these compounds for treprostinil-responsive treatment, and also to pharmaceutical compositions, topical compositions, and transdermal delivery systems. The disclosure mentions transdermal patch construction elements, stability assays, skin flux assay, and deuterated treprostinil isotopologues and deuterium enrichment.
Claims Coverage
The partial content includes two independent claim sets: a transdermal patch claim and a kit claim. Across these independent claims, the inventive features center on a defined treprostinil-derived Formula (I) compound with explicit structural provisos and its use in transdermal patch or kit form for a medical condition responsive to treprostinil.
Transdermal patch comprising a formula (I) treprostinil-derived compound with structural provisos
A transdermal patch comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof, with defined substituents R1 to R6, ring-forming options, and integer parameters j and m, subject to provisos that both R1 and R2 are not hydrogen and that neither -OR1 nor -OR2 forms an acetate, a substituted cyclohexane-ester, or an ester with or of an amino acid, a peptide, or a protein.
Kit comprising a formula (I) compound and instructions for treprostinil-responsive treatment
A kit comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph, or stereoisomer thereof, together with instructions for administering the compound to treat a medical condition responsive to treatment with treprostinil, with the same R1/R2 provisos and exclusions for acetate, substituted cyclohexane-ester, and amino-acid/peptide/protein ester forms.
The independent claims cover a transdermal patch and a kit, each centered on a constrained Formula (I) treprostinil-derived compound and explicit exclusions on R1/R2-derived acetate, substituted cyclohexane-ester, and amino-acid/peptide/protein ester forms.
Stated Advantages
The compounds are intended to function as prodrugs of treprostinil.
The background states limitations of treprostinil, including poor oral bioavailability, a short half-life, and irritation with inhaled treprostinil use.
Documented Applications
Treat a medical condition responsive to treatment with treprostinil.
Transdermal patch embodiments and kit embodiments using Formula (I) treprostinil derivatives.
Transdermal delivery using transdermal patches for treprostinil-responsive medical conditions.
Pharmaceutical compositions and topical compositions.
Therapeutic use for pulmonary hypertension, including pulmonary arterial hypertension, and other treprostinil-responsive conditions including pulmonary fibrosis, interstitial lung disease, asthma, congestive heart failure, peripheral vascular disease, severe intermittent claudication, atherogenesis/atherosclerosis, ischemic lesions, Buerger’s disease, Raynaud’s phenomenon/disease, scleroderma/systemic sclerosis, critical limb ischemia, neuropathic foot ulcers, kidney malfunction/failure, immunosuppression, proliferative disorders (tumors/cancers), and pain.
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