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Publication Number
US-9844554-B2
Publication Date
2017-12-19
Expiration Date
Abstract
Provided herein are methods, compounds, compositions, and kits for the treatment of an enteric nervous system disorder. Such methods may comprise administering to a subject an effective amount of a phenothiazine compound, a peripherally restricted dopamine decarboxylase inhibitor, and/or a peripherally restricted dopamine D2 receptor antagonist that does not substantially inhibit hERG channels.
Core Innovation
The invention relates to phenothiazine-based compounds related to metopimazine, including metopimazine and metopimazine acid, metopimazine acid prodrugs and derivatives, and compounds defined by Formula I/II/III/IV, Formula V/VI/VII/VIII/IX/X/XI/XII, and related formulae. The description provides extensive substituent definitions and structural variability, including R1, R2, R3, L, R4, X', R5, R6, R7, R8, R14, and R15, and identifies metopimazine as a specific Formula III compound.
The invention further describes prodrug and ester families, including Formula V prodrugs, Formula VI prodrugs, Formula VII prodrugs, Formula VIII/IX ester prodrugs, Formula X ester prodrug, Formula XI amino acid prodrug, and Formula XII additional prodrug. It also includes phenyl/heteroaryl-containing thio-sulfonamide scaffold structures linked to a piperidine-containing ring, with alternative structural definitions across the stated formula sets.
The invention relates to treating enteric nervous system and gastrointestinal disorders by administering peripherally restricted dopamine D2 receptor antagonists and/or phenothiazine-containing compounds, including dopamine decarboxylase inhibitor co-administration. The disclosed approach is directed to reduce cardiac and extrapyramidal risks and to minimize hERG channel inhibition and drug-induced long QT risk, while certain prodrugs and esters are stated to increase lipophilicity, aqueous solubility, and/or bioavailability versus the parent metopimazine acid compound.
Claims Coverage
The provided independent claims cover chemical compound embodiments defined by formula and substituent scope, primarily centered on Formula V compounds, with additional independent coverage for Formula VII and Formula XI compounds. Across the excerpts, five inventive feature groupings are present, all defined by structural formula limitations and substituent constraints.
Formula V compound definition with variable X' , R5 and R6 substituent framework
A compound of Formula V, or a salt thereof, defined with X' as O or NH, R5 selected from C1-C10 alkyl, C1-C10 alkenyl, C1-C10 alkynyl, C4-C7 cycloalkyl, C3-C7 heterocycloalkyl, C6-C10 aryl, or C6-C10 heteroaryl, each optionally substituted, and R6 selected from —OR7, —SR7, —NR7R8, —COOR7, —CONR7R8, —OCOR7, —NR7—CO—R8, C1-C10 alkyl, C1-C10 alkenyl, C1-C10 alkynyl, C4-C7 cycloalkyl, C3-C7 heterocycloalkyl, C6-C10 aryl, or C6-C10 heteroaryl, with R7 and R8 independently selected from H and the same substitution classes listed for R5.
Formula VII compound definition with restricted X, R14 and R15
A compound of Formula VII, or a salt thereof, defined with X as O or NH, R14 as C1-C4 linear or branched alkyl, and R15 as C1-C6 linear or branched alkyl, phenyl, or C4-C7 cycloalkyl.
Formula XI compound definition
A compound of Formula XI, or a salt thereof, as defined by the Formula XI representation.
Formula V compound definition with restricted R5 substitution motif
A compound of Formula V, or a salt thereof, defined with X' as O or NH, R5 as C1-C10 alkyl substituted with one R6 group selected from —NR7R8, —CONR7R8, and —NR7—CO—R8, and R7 and R8 independently selected from H and C1-C10 alkyl, C1-C10 alkenyl, C1-C10 alkynyl, C4-C7 cycloalkyl, C3-C7 heterocycloalkyl, C6-C10 aryl, or C6-C10 heteroaryl.
Formula V compound definition with X' as O and unsubstituted R5
A compound of Formula V, or a salt thereof, defined with X' as O and R5 as unsubstituted C2-C10 alkyl, C1-C10 alkenyl, or C1-C10 alkynyl.
Across the provided independent claims, the structural scope centers on Formula V compounds with defined X' and variable or constrained R5/R6 substituent patterns, Formula VII compounds with X, R14, and R15 limitations, and Formula XI compounds, including salts. The Formula V variants emphasize either broad substitution classes or narrower R5 patterns with a single specified R6 group type.
Stated Advantages
Avoid adverse cardiac effects, including minimal hERG channel inhibition and drug-induced long QT risk.
Reduce central nervous system and extrapyramidal risks, including extrapyramidal side effects and tardive dyskinesia.
D2-selective binding and markedly lower hERG potency than domperidone.
Certain prodrugs and esters can increase lipophilicity versus the parent.
Certain prodrugs and esters can increase aqueous solubility versus the parent.
Certain prodrugs and esters can increase bioavailability versus the parent.
Reduced cardiac and extrapyramidal risks.
The peripherally restricted D2 receptor antagonist approach is intended to minimize hERG channel inhibition.
Documented Applications
Treating enteric nervous system and gastrointestinal disorders, including gastroparesis, irritable bowel syndrome, functional dyspepsia, nausea and vomiting, delayed gastric emptying, and gastrointestinal motility.
Use with dopamine decarboxylase inhibitors in combinations described as not crossing the blood-brain barrier, for the same ENS/GI disorder treatment context.
Kit composition and instructions including metopimazine-related formulas and a dopamine decarboxylase inhibitor for administration in the described treatment context.
Use in pharmaceutical compositions for enteric nervous system disorder with pharmaceutically acceptable carriers in dosage forms.
Use in oral dosage form, transdermal patch, and sublingual dosage form.
Use with peripherally restricted dopamine D2 antagonism and/or dopamine decarboxylase inhibitor activity, including carbidopa and related forms.
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