Stereoisomeric compounds and methods for the treatment of gastrointestinal and central nervous system disorders
Inventors
Irwin, Ian • Palme, Monica • Becker, Cyrus
Assignees
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Publication Number
US-7176218-B2
Publication Date
2007-02-13
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 isolated ester prodrugs of cisapride and stereoisomeric esterified cisapride analogs. The compounds are defined by specific (3,4,3′) stereochemistry in an ester moiety, including an acid 1-aza-bicyclo[2.2.2]oct-3-yl ester structure connected to a cisapride-derived acid, and pharmaceutically acceptable salts thereof.
A stated problem is that cisapride is associated with adverse effects mediated through CYP450 oxidative metabolism. The disclosure addresses this by esterifying cisapride analogs so that Phase I breakdown and oxidative pathways are avoided in favor of esterase-mediated breakdown, with the ester group acted on by serum esterases, cytosolic esterases, and esterases in human plasma to generate metabolic breakdown products.
The document further associates stereochemical configuration with distinct esterase metabolism and pharmacology. The (3′R) versus (3′S) quinuclidinol configuration is described as producing different rates of esterase metabolism, with (3′R) isomers rapidly hydrolyzed and (3′S) isomers much more slowly metabolized, and different 5-HT4 receptor binding affinities are described, with Ki ranking used to distinguish binding strength and stereoisomeric excess targets specified.
Claims Coverage
The independent claims are directed to 4 specific stereochemically defined cisapride ester prodrug compounds and pharmaceutically acceptable salts thereof. Across the independent claims, the inventive features focus on stereochemically defined esterified cisapride analogs, including the ester prodrug compound selections and, in dependent claims, pharmaceutical compositions and stereoisomeric-excess thresholds.
Stereochemically defined (3R,4S,3′R) ester prodrug compound
A compound selected from (3R,4S,3′R)-6-[4-(4-Amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester and pharmaceutically acceptable salts thereof.
Stereochemically defined (3S,4R,3′R) ester prodrug compound
A compound selected from (3S,4R,3′R)-6-[4-(4-Amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester and pharmaceutically acceptable salts thereof.
Stereochemically defined (3R,4S,3′S) ester prodrug compound
A compound selected from (3R,4S,3′S)-6-[4-(4-Amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester and pharmaceutically acceptable salts thereof.
Stereochemically defined (3S,4R,3′S) ester prodrug compound
A compound selected from (3S,4R,3′S)-6-[4-(4-Amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester and pharmaceutically acceptable salts thereof.
Claim coverage centers on the identity of the stereochemically defined cisapride ester prodrug compounds and pharmaceutically acceptable salts. Dependent refinements include pharmaceutical compositions with pharmaceutically acceptable excipients, adjuvants, carriers, or solvents and stereoisomeric excess of at least about 90%, with preferred ranges up to at least about 99%, as well as selection of a dihydrochloride salt form.
Stated Advantages
Reduced adverse effects versus cisapride by avoiding CYP450-mediated oxidative metabolism via esterase-mediated breakdown.
Storage stability.
Shorter physiological half-life.
The (3′R) isomers are rapidly hydrolyzed by esterases in human plasma, associated with short-acting behavior.
The (3′S) isomers are much more slowly metabolized, associated with longer-acting/chronic use.
Ability to monitor clearance using esterase-generated metabolites in urine or serum.
Different therapeutic use based on stereoisomer-specific properties, including different 5-HT4 receptor binding affinities (Ki ranking).
Documented Applications
Treatment or therapeutic utility for gastrointestinal disorders including gastroesophageal reflux disease (GERD), gastroparesis, dyspepsia, constipation, post-operative ileus, intestinal pseudo-obstruction, and emesis.
Treatment or therapeutic utility for central nervous system (CNS) disorders.
Use context for ATI-7505/ATI-7500 in relation to 5-HT4 binding potency and partial agonism, and evaluation of gastric emptying and motor activity in dogs.
Biological characterization of the stereoisomerically defined ester prodrugs, including esterase-mediated behavior in human plasma and stereoisomer-dependent 5-HT4 receptor binding affinities.
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