Progesterone analogs and uses related thereto
Inventors
Guthrie, David B. • Lockwood, Mark A. • Liotta, Dennis C. • Natchus, Michael G. • Stein, Donald G. • Sayeed, Iqbal
Assignees
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Publication Number
US-12459970-B2
Publication Date
2025-11-04
Expiration Date
Abstract
This disclosure relates to progesterone derivatives and uses related thereto. In certain embodiments, the disclosure relates to compounds disclosed herein and uses for managing inflammation resulting from traumatic brain injury or stroke.
Core Innovation
The invention relates to progesterone-derivative oxime/oxime-ester scaffold compounds according to Formula I and related sub-formulas, including C-20 oxime conjugates and C-3 oxime series variants, as well as pharmaceutically acceptable salts, prodrugs, esters, and pharmaceutical compositions containing the compounds and a pharmaceutically acceptable excipient. The disclosure centers on oxime/ester conjugates and steroid-oxime derivatives, including steroid-derived cyclopenta[a]phenanthrene-3-one oxime/oxyimino ether derivatives, designed to provide improved aqueous solubility compared with progesterone, while maintaining neuroactive prodrug features associated with oxime release and/or progesterone release.
The invention provides compounds selected from the group consisting of the disclosed compounds or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the compound and a pharmaceutically acceptable excipient. The compounds are presented in connection with chemical structures including stereochemistry, salt forms, hydrochloride/iodide salt forms, quaternized iodide salts, and characterization including hydrolytic or chemical stability half-lives.
The disclosure addresses reducing symptoms or delaying progression of inflammation, stroke, or traumatic brain injury in a subject by administering a pharmaceutical composition comprising the compound, and also provides methods for reducing symptoms or delaying progression of a neurodegenerative disease in a subject and for supporting a hormonal condition in a subject. The disclosure connects therapeutic use to hydrolytic behavior and degradation products, including hydrolysis behavior in plasma and in liver microsomes, with formation of free oximes and assessment of conversion related to progesterone.
Claims Coverage
The independent claims cover a compound, a pharmaceutical composition, and therapeutic methods for inflammation, stroke, traumatic brain injury, neurodegenerative disease, and hormonal condition support. Across the independent claims, the core coverage centers on using the same compound group, or pharmaceutically acceptable salt thereof, in specified therapeutic method contexts.
Progesterone-derivative compound selection
A compound selected from the group consisting of the disclosed compounds or a pharmaceutically acceptable salt thereof, including steroid-oxime derivatives and steroid-derived cyclopenta[a]phenanthrene-3-one oxime/oxyimino ether derivatives.
Pharmaceutical composition with excipient
A pharmaceutical composition comprising the compound selected from the group consisting of the disclosed compounds or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.
Combination composition with a second active therapeutic agent
The pharmaceutical composition further includes a second active therapeutic agent.
Reducing inflammation, stroke, or traumatic brain injury symptoms
A method for reducing symptoms or delaying progression of inflammation, stroke, or traumatic brain injury in a subject by administering a pharmaceutical composition comprising a compound selected from the group consisting of the disclosed compounds or a pharmaceutically acceptable salt thereof.
Reducing neurodegenerative disease symptoms or progression
A method for reducing the symptoms or delaying progression of a neurodegenerative disease in a subject by administering a pharmaceutical composition comprising a compound selected from the group consisting of the disclosed compounds or a pharmaceutically acceptable salt thereof.
Supporting a hormonal condition
A method for supporting a hormonal condition in a subject by administering a pharmaceutical composition comprising a compound selected from the group consisting of the disclosed compounds or a pharmaceutically acceptable salt thereof.
Timed administration within 24 hours for stroke or traumatic brain injury
The method where administering occurs within 24 hours after the stroke or within 24 hours after the traumatic brain injury.
Overall, the claim set is centered on administering the disclosed progesterone-derivative oxime/oxime-ester scaffold compounds, or salts, as standalone compound selection, in pharmaceutical compositions, and in therapeutic methods for neuroinflammation, stroke, traumatic brain injury, neurodegenerative disease, and hormonal condition support, with certain dependent claims further specifying second-active-agent combinations and timing.
Stated Advantages
Improved aqueous solubility for the C-20 oxime conjugates.
Hydrolysis to release free oximes and/or progesterone.
Reduction of glutamate-induced neuronal cell death for at least some compounds.
Comparable cerebral edema reduction to progesterone in rat cortical contusion.
Freely administered C-3 oxime is intrinsically active in edema reduction after cortical impact.
Pharmacokinetic differences between i.v. and i.m. routes are described, including detection of free oximes and avoidance of conversion to progesterone via liver hydrolysis for i.m. administration.
Reducing symptoms.
Delaying progression of inflammation, stroke, traumatic brain injury, and neurodegenerative disease.
Supporting a hormonal condition.
Documented Applications
Reducing symptoms or delaying progression of inflammation, stroke, or traumatic brain injury in a subject.
Reducing symptoms or delaying progression of a neurodegenerative disease in a subject, including amyotrophic lateral sclerosis, Parkinson’s disease, multiple sclerosis, catamenial epilepsy, diabetic neuropathy, inflammatory disorders, hemorrhagic shock, Niemann-Pick disorder, cerebral palsy, congenital heart disorders, and spinal cord trauma.
Supporting a hormonal condition in a subject, including pregnancy, pregnancy resulting from in vitro fertilization, assisted reproductive technology, persistent anovulatory bleeding, inadequate progesterone production, and endometrial hyperplasia.
In vivo and in vitro experimental characterization, including hydrolysis behavior in rat plasma and human plasma, and hydrolysis behavior in human liver microsomes with formation of free oximes and assessment of progesterone conversion.
In vivo/protocol descriptions for cerebral edema in a traumatic brain injury context and for rat pharmacokinetic studies using formulations and dosing routes, with LC/MS/MS and PK analysis.
In vitro and in vivo assays to evaluate anti-inflammatory and immunosuppressive effects after traumatic CNS injury.
Immunosuppression explicitly described as treatment for organ transplant, including immunosuppression with a second immunosuppressive agent.
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