Neurosteroid compounds and methods for their preparation and use in treating central nervous system disorders
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Publication Number
US-12509487-B2
Publication Date
2025-12-30
Expiration Date
Abstract
Described herein is the chemical structure of neurosteroid derivative compounds, methods of synthesizing the derivatives, and their uses in treating disorders, including those of the central nervous system. These compounds are readily synthesized and have improved pharmaceutical properties, including water solubility, compared to known neurosteroids.
Core Innovation
The invention relates to neurosteroid derivative compounds having a general Formula (A), including enantiomers and diastereoisomers, and including pharmaceutically acceptable salts, hydrates, and solvates. The compounds are defined with substituent groups such as R1, R2, R3, R5, R11, R18, and R19, and a Z group that includes hydroxyl group formulas (ia)/(ib) and an isooxazole-containing group through formulas (iia)/(iib). The description further links these derivatives to ganaxolone (GX) and illustrates specific derivative embodiments, including ganaxolone-derived prodrugs and 17-isooxazole neurosteroid derivatives.
The disclosed compounds include 21-OH GX succinate sodium, UCI-50027 phosphate disodium, UCI-50027 methylphosphite disodium, UCI-50027 diisopropyl carbonate, and related derivative and salt forms, including malic acid, piperidine diol, citrate salt forms, carbamate derivatives, lysine, valine, succinate, carbamate, citric acid, phosphate, phosphite, and related salt forms. The disclosed subject matter also provides general isoxazole formulas identified as (iia) and (iib), and describes synthesis of ganaxolone-derived oxime and cyclization to an isoxazole, together with conversion of an aldehyde to an oxime and subsequent functionalization to UCI-50027.
The invention is directed to therapeutic use of these neurosteroid derivative compounds for central nervous system (CNS) disorders, including epilepsy, seizure, status epilepticus, and chemical neurotoxicity. The material further reports preclinical efficacy versus ganaxolone across seizure and status epilepticus models, mechanistic support using patch-clamp findings on GABA-A receptor modulation including extrasynaptic tonic currents and δ-subunit selectivity, and pharmacokinetic conversion, bioavailability improvements, and reported solubility and stability data.
Additional described preclinical outcomes include neuroprotection statements and model-based efficacy statements for organophosphate and nerve agent models. The material further includes characterization of key intermediates and final products, with analytical data such as NMR, MS, UV, HPLC purity, and solubility and stability in PBS at defined pH for UCI-50027 and related salts.
Claims Coverage
The independent claim coverage centers on a compound selected from a defined group, or a pharmaceutically acceptable salt thereof. Across the disclosed items, the inventive features are narrowed to specific named UCI-50027-related derivatives and salt forms, and extended to pharmaceutical compositions comprising the selected compound and a pharmaceutically acceptable carrier. Four specifically named compound variants are identified across the items.
Selected compound group comprising neurosteroid derivatives or pharmaceutically acceptable salts
A compound selected from the group consisting of a defined group, or a pharmaceutically acceptable salt thereof.
UCI-50027 methylphosphite disodium derivative
The compound is UCI-50027 methylphosphite disodium or a pharmaceutically acceptable salt thereof.
UCI-50027 phosphate disodium or diisopropyl carbonate derivative
The compound is UCI-50027 phosphate disodium, a pharmaceutically acceptable salt thereof, or UCI-50027 diisopropyl carbonate, a pharmaceutically acceptable salt thereof.
21-OH GX malic acid derivative
The compound is 21-OH GX malic acid or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising a compound of the selected-compound claim and a pharmaceutically acceptable carrier.
Pharmaceutical composition carrier selected from specified types
The pharmaceutically acceptable carrier is selected from cream, gel, liposome, nanoparticle, ointment, polymeric micelle, protein, or a microsphere.
Overall, the claims coverage centers on a selected neurosteroid derivative compound group, including specified phosphate, phosphite, bis-sodium and other named salt forms, and extends to pharmaceutical compositions comprising the selected compound with specified carrier types.
Stated Advantages
Improved solubility for bis-sodium phosphate/phosphite salts, supported by comparative solubility and stability tables.
Pharmacokinetic conversion and bioavailability improvements associated with prodrug forms.
Neuroprotection statements in organophosphate and nerve agent models.
Solubility and bioavailability motivations are stated for the neurosteroid derivative compounds.
Documented Applications
Therapeutic use for central nervous system (CNS) disorders, including epilepsy, seizure, status epilepticus, and chemical neurotoxicity.
Preclinical efficacy support in seizure and status epilepticus models, including EEG after discharges and neurosteroid derivative efficacy relative to ganaxolone.
Preclinical support in organophosphate and nerve agent models.
Pharmaceutical compositions comprising a compound of the selected group together with a pharmaceutically acceptable carrier.
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