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Publication Number
US-10869933-B2
Publication Date
2020-12-22
Expiration Date
Abstract
The invention relates to (among other things) oligomer-phenothiazine conjugates and related compounds. A conjugate of the invention, when administered by any of a number of administration routes, exhibits advantages over un-conjugated phenothiazine compounds.
Core Innovation
The invention relates to oligomer–phenothiazine conjugates in which a phenothiazine residue is covalently attached via a stable or degradable linker to a water-soluble, non-peptidic oligomer. The non-peptidic oligomer is a poly(ethylene oxide) polymer (POLY), including PEG oligomers, and the conjugates are defined by structural variables including R1–R4, a spacer moiety X, and an integer n representing oligomer length.
The disclosed conjugates include phenothiazine residues such as promethazine, mequitazine, promizin(e), and thiazinamium methylsulfate. The phenothiazine residue is covalently connected through the spacer/linkage moiety X to the POLY polymer, including definitions and options for PEG oligomer structure and end groups.
Discrete oligomer conjugates are described as having altered biological distribution characteristics relative to the non-conjugated phenothiazine. A stated rationale is that discrete oligomer conjugates reduce blood-brain barrier (BBB) penetration while maintaining gastro-intestinal (GI) crossing and bioactivity/bioavailability.
Examples include PEGylated promethazine, including mPEG-N-promethazine and mPEG-O-promethazine, with PEG-size-dependent variants such as mPEG3/5/7/9-N-promethazine and mPEG3/5/7/9-O-promethazine. Analytical characterization, physicochemical evaluation including pKa and LogP, and in vitro receptor binding are described to show reduced affinity across histamine receptors (H1–H4) and muscarinic acetylcholine receptors (M1–M5).
Claims Coverage
The provided independent claim is directed to a method of treating multiple conditions by administering a therapeutically effective amount of a specified compound formula containing a poly(ethylene oxide) polymer (POLY) moiety, variable substituents R1–R4, a spacer moiety X, and an integer n for oligomer length.
Treating allergic reactions, anaphylaxis, motion sickness, nausea, or visceral pain with a POLY-containing compound
Administering to a subject in need thereof a therapeutically effective amount of a compound having the formula with R1, R2, R3, and R4, n being an integer equal to or greater than one, X being a spacer moiety, and POLY being a poly(ethylene oxide) polymer.
Variable substituents defining R1–R4 and optional heterocycle
Selecting R1, R2, R3, and R4 independently from hydrogen, unsubstituted alkyl, and substituted alkyl; or having R3 and R4 together form a heterocycle with the nitrogen.
POLY and spacer moiety incorporated into the compound formula
Including a spacer moiety X in the compound formula and incorporating POLY as a poly(ethylene oxide) polymer with integer n indicating an oligomer length of at least one.
Across the independent claim, the coverage is anchored on administering a therapeutically effective amount of a compound formula that combines a poly(ethylene oxide) polymer (POLY) with defined variable substituents (R1–R4), a spacer moiety (X), and an oligomer-length integer (n). Dependent claims further narrow treatment delivery by specifying administration routes, dosage ranges, dosing schedules, and constraining POLY structure and the spacer moiety X.
Stated Advantages
Reduces blood-brain barrier (BBB) penetration while maintaining gastro-intestinal (GI) crossing and bioactivity/bioavailability.
PEG-promethazine conjugates reduce visceral pain in an acetic-acid writhing analgesic assay.
PEG-promethazine conjugates show decreased BBB/CNS penetration versus promethazine, as indicated by brain:plasma ratios.
PEG-promethazine conjugates retain primarily H1 histamine receptor binding while showing PEG-size-dependent reduced affinity and loss of measurable binding at many other histamine and muscarinic receptor subtypes.
Documented Applications
Treatment of allergic reactions.
Treatment of anaphylaxis.
Treatment of motion sickness.
Treatment of nausea.
Treatment of visceral pain.
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