Emesis, dyspepsia, gastroparesis, constipation, gastroesophageal reflux, or post-operative ileus; cisapride analogs; side effect reduction of adverse events; (R)-quinuclidin-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)hexanoate or salts
Inventors
Irwin, Ian • Palme, Monica • Becker, Cyrus • Druzgala, Pascal
Assignees
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Publication Number
US-8138204-B2
Publication Date
2012-03-20
Expiration Date
Abstract
The subject invention provides stereoisomeric compounds of formula (X):wherein the variables are as defined herein, and compositions for the safe and effective treatment of various gastrointestinal disorders including, but not limited to, gastroparesis, gastroesophageal reflux and related conditions. The compounds of the subject invention are also useful in treating a variety of conditions involving the central nervous system.
Core Innovation
The invention relates to stereoisomerically defined ester compounds and stereoisomeric esterified cisapride analogs having a quinuclidinyl ester moiety or related ester-linked structure, including compounds with defined configurations such as (3R,4S,3′R), (3S,4R,3′R), (3R,4S,3′S), and (3S,4R,3′S). The bonds at positions 3 and 4 are cis relative to each other, and the compounds include specific allowed substituent definitions for R1, R2, R3, R4, R5, R9, R11, and R20, including aza-bicyclo heterocycle substituents. The stereochemical constraint and ester moiety define the invention.
The document explains that isolated stereoisomers show unexpected pharmacokinetic and pharmacodynamic differences. In particular, (3′R)-containing esters are described as rapidly hydrolyzed by esterases in human plasma, with enhanced susceptibility to serum/cytosolic esterases and avoidance of Phase I CYP450 involvement, while (3′S)-containing esters are described as more stable. The description also attributes reduced drug-drug interaction/toxicity risk and potential esterase-derived metabolite monitoring of clearance to the ester moiety.
The document further reports relative 5-HT4 receptor binding affinity rankings using Ki values, together with biological evaluation including 5-HT4 receptor affinity/partial agonism, prokinetic activity in dogs, CYP450-independent metabolism, and cardiac safety metrics. The cis relationship at positions 3 and 4 is linked to distinct esterase hydrolysis rates and distinct receptor affinity profiles for the resulting enantiomeric pairs, with (3′R) isomers suggested for short-duration or acute use and (3′S) isomers suggested for chronic treatment.
Claims Coverage
The independent claims cover two methods of treating gastrointestinal disorders responsive to a 5HT4 receptor agonist using stereochemically defined compounds with a fixed cis relationship between bonds at positions 3 and 4, together with constrained substituent options for R1, R2, R3, R4, R5, R9, R11, and R20. One independent claim additionally limits the treated disorder to a defined set of gastrointestinal disorders.
Cis stereochemistry-defined 5HT4 agonist for gastrointestinal disorder treatment
A method of treating a gastrointestinal disorder responsive to a 5HT4 receptor agonist by administering a therapeutically effective amount of a compound having bonds at positions 3 and 4 that are cis relative to each other, with R1 halogen, R2 amino/NH(C1-C4 alkyl)/N(C1-C4 alkyl)(C1-C4 alkyl), R3 OH/C1-C4 alkoxy, R4 H/methyl, and R5 defined as —O—C3-C8 cycloalkyl, —O-heterocycloalkyl, or heterocycloalkyl where the heterocycloalkyl is aza-bicyclo-octyl, aza-bicyclo-nonyl, aza-bicyclo-decyl, piperidinyl, piperazinyl, or pyrrolidinyl, with further allowed substitution patterns for these groups, and where R9, R11, and R20 are defined within the claim.
Selected gastrointestinal disorder treatment with cis stereochemistry-defined 5HT4 agonist compounds
A method of treating a gastrointestinal disorder selected from gastroesophageal reflux disease (GERD), emesis, dyspepsia, gastroparesis, constipation, intestinal pseudo-obstruction, post-operative ileus by administering a therapeutically effective amount of a compound having bonds at positions 3 and 4 cis relative to each other, with R1 halogen, R2 amino/NH(C1-C4 alkyl)/N(C1-C4 alkyl)(C1-C4 alkyl), R3 OH/C1-C4 alkoxy, R4 H/methyl, and R5 defined as —O—C3-C8 cycloalkyl, —O-heterocycloalkyl, or heterocycloalkyl where the heterocycloalkyl is aza-bicyclo-octyl, aza-bicyclo-nonyl, aza-bicyclo-decyl, piperidinyl, piperazinyl, or pyrrolidinyl, with further allowed substitution patterns, and where R9, R11, and R20 are defined within the claim.
Across the independent claims, the coverage centers on administering a cis-configured stereochemically defined ester compound framework for treating gastrointestinal disorders responsive to a 5HT4 receptor agonist, with R1/R2/R3/R4/R5/R9/R11/R20 constrained to enumerated classes and substitution patterns. One independent claim further limits the treated condition to a listed set of gastrointestinal disorders.
Stated Advantages
(3′R)-containing quinuclidinyl esters are rapidly hydrolyzed by esterases in human plasma, enabling short-duration action.
Enhanced susceptibility to serum/cytosolic esterases and avoidance of Phase I CYP450.
Reduced drug-drug interaction/toxicity risk.
Potential esterase-derived metabolite monitoring of clearance.
(3′R)-containing esters are stated to be suitable for IV use in premature newborn.
(3′S)-containing esters are described as more stable for chronic treatment.
Isoform-specific pharmacology based on (3′R) versus (3′S) stereoisomers, including suggested short-duration/acute versus chronic use.
Documented Applications
Treatment of a gastrointestinal disorder responsive to a 5HT4 receptor agonist.
Treatment of gastroesophageal reflux disease (GERD).
Treatment of emesis.
Treatment of dyspepsia.
Treatment of gastroparesis.
Treatment of constipation.
Treatment of intestinal pseudo-obstruction.
Treatment of post-operative ileus.
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