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Publication Number
US-12173021-B2
Publication Date
2024-12-24
Expiration Date
Abstract
Provided are novel prodrugs of treprostinil, as well as methods of making and methods of using these prodrugs.
Core Innovation
The invention relates to treprostinil prodrugs and treprostinil prodrugs/esters having a structural scope defined by a compound formula and pharmaceutically acceptable salts. The disclosed subject matter includes treprostinil hemi-succinate, treprostinil phosphonooxy ethyl ether, treprostinil cyclopentyl succinate, treprostinil side chain bi-piperidine carbamate, treprostinil cyclopentyl naproxen ester, treprostinil side chain isobutylphenylpropionic acid ester, treprostinil (6-methoxynaphthalen-2-yl)propanoic acid ester, treprostinil side chain L-valine ester, treprostinil side chain glycine ester, treprostinil L-alanine ester, treprostinil mono-PEG carbonate, and treprostinil di-PEG carbonate.
The disclosure also describes synthetic schemes and preparation of treprostinil derivatives and related intermediates, including ester, carbamate, carbonate, succinate-linked, phosphorus-containing, and second-drug-moiety embodiments. It reports characterization and purification information including NMR, LC-MS, IR, UPLC purity, HPLC purity, molecular formula and weight, and absence of free treprostinil.
The document further provides chemical-property characterization including in silico pKa and aqueous solubility at pH 7.0, together with stability data in plasma, liver microsome, hepatocyte, simulated intestinal fluid, and human skin homogenate for prodrugs LXX-LXXIII, including treprostinil formation over time. It also includes in vitro receptor activity summaries describing non-traditional dose-response and reduced or less active profiles at IP, EP1, EP2, and DP1 receptors using cAMP and calcium assays.
The content further states pharmaceutical compositions and therapeutic use for pulmonary hypertension and related disorders. It describes administration routes including oral, injection, and continuous subcutaneous administration, and reports improved stability, improved tolerance, reduced or no injection-site pain, delayed conversion until blood and/or liver, detectable treprostinil plasma levels for at least 24 hours, and conversion to a metabolic product consisting essentially of treprostinil.
Claims Coverage
The claim coverage centers on a compound having a specified formula, or a pharmaceutically acceptable salt thereof, and extends to pharmaceutical composition and therapeutic use for pulmonary hypertension. Across the independent-claim-related content, the inventive features also include conversion to a metabolic product consisting essentially of treprostinil, detectable treprostinil plasma levels for at least 24 hours, and continuous subcutaneous administration.
Specified compound formula or pharmaceutically acceptable salt
A compound having the following formula, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with effective amount and carrier
A pharmaceutical composition comprising an effective amount of the compound and a pharmaceutically acceptable carrier.
Treatment of pulmonary hypertension by administering the composition
A method for treating pulmonary hypertension by administering to a subject in need thereof the pharmaceutical composition.
Detectable treprostinil plasma levels for at least 24 hours
After administration, the subject has detectable treprostinil plasma levels for at least 24 hours.
Continuous subcutaneous administration
The method includes continuous subcutaneous administration as the form of administration.
Conversion to a metabolic product consisting essentially of treprostinil
After administration, the compound is converted into a metabolic product consisting essentially of treprostinil.
Overall, the claim coverage is directed to a specified-formula compound or salt, pharmaceutical compositions containing the compound, and methods for treating pulmonary hypertension by administering the composition. The claim set further includes detectable treprostinil plasma levels for at least 24 hours, conversion to a metabolic product consisting essentially of treprostinil, and continuous subcutaneous administration as related limitations.
Stated Advantages
Reduced or less active receptor profiles at IP, EP1, EP2, and DP1 receptors.
Reduced or no injection-site pain versus treprostinil.
Improved stability versus treprostinil.
Improved tolerance versus treprostinil.
Delays conversion until blood and/or liver.
Detectable treprostinil plasma levels for at least 24 hours.
High HPLC purity.
Absence of free treprostinil.
Documented Applications
Treating pulmonary hypertension by administering a pharmaceutical composition to a subject in need thereof.
Treatment contexts described as extending to congestive heart failure, peripheral vascular disease, Raynaud’s phenomenon, scleroderma, renal insufficiency, peripheral neuropathy, digital ulcers, intermittent claudication, ischemic limb disease, peripheral ischemic lesions, pulmonary fibrosis, and asthma.
Use for treating pulmonary hypertension, including WHO groups 1-5.
Site pain reduction.
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