Preparation of (R,R)-fenoterol and (R,R)-or (R,S)-fenoterol analogues and their use in treating congestive heart failure
Inventors
Wainer, Irving W. • Zhu, Weizhong • Chakir, Khalid • Xiao, Rui Ping • Abernethy, Darrell R. • Beigi, Farideh M.
Assignees
National Institutes of Health NIH • US Department of Health and Human Services
Publication Number
US-8703826-B2
Publication Date
2014-04-22
Expiration Date
2027-08-10
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Abstract
This disclosure concerns the discovery of (R,R)- and (R,S)-fenoterol analogues which are highly effective at binding β2-adrenergic receptors. Exemplary chemical structures for these analogues are provided. Also provided are pharmaceutical compositions including the disclosed (R,R)-fenoterol and fenoterol analogues, and methods of using such compounds and compositions for the treatment of cardiac disorders such as congestive heart failure and pulmonary disorders such as asthma or chronic obstructive pulmonary disease.
Core Innovation
This disclosure concerns the discovery and preparation of (R,R)-fenoterol and (R,R)- or (R,S)-fenoterol analogues that are highly effective at binding β2-adrenergic receptors. Exemplary chemical structures for these analogues are provided, along with pharmaceutical compositions including these compounds. Methods of using the disclosed compounds and compositions for the treatment of cardiac disorders such as congestive heart failure, and pulmonary disorders such as asthma or chronic obstructive pulmonary disease are also described.
Fenoterol is a β2-adrenergic receptor agonist traditionally used to treat pulmonary disorders like asthma and exists in distinct stereoisomeric forms, with only one (the (R,R)-isomer) responsible for generating bronchodilation. The commercially available fenoterol is a racemic mixture of (R,R)- and (S,S)-isomers. The inactive enantiomer, (S,S)-fenoterol, may cause adverse side effects or tolerance often associated with β2-adrenergic receptor agonist treatment.
The problem solved by the present invention is providing fenoterol compositions effective for treating disorders such as asthma, chronic obstructive pulmonary disease, or congestive heart failure, but with reduced side effects such as hypersensitivity and drug resistance (tolerance). Purification and use of optically pure (R,R)-fenoterol or synthesized (R,R)- or (R,S)-fenoterol analogues reduce undesirable side-effects caused by physiologically less active stereoisomers.
Claims Coverage
The patent includes at least one independent claim directed to compounds having a specified chemical formula and pharmaceutical compositions comprising such compounds. The claims cover stereoisomeric (R,R)- and (R,S)-fenoterol analogues with defined substituents and optically pure forms.
Compounds having a specified chemical formula
The patent claims compounds represented by a general formula where substituents R1-R3, R4, R5, and groups X, Y1-Y3 are defined as hydrogen, acyl, alkoxy carbonyl, amino carbonyl, or related groups, exemplifying (R,R)- and (R,S)-fenoterol analogues.
Compounds with stereoisomeric configurations
Claims include the compound as (R,R)-compound or (R,S)-compound forms, defining the stereochemical configuration of the fenoterol analogues as part of the invention.
Pharmaceutical compositions containing claimed compounds
Pharmaceutical compositions comprising the claimed compounds and at least one pharmaceutically acceptable carrier are claimed, including those where R4 is methyl, R1-R3 are hydrogen, and the compound is optically pure.
The claims cover inventive fenoterol analogues defined by detailed chemical structures and stereochemistry, and pharmaceutical compositions comprising these compounds, emphasizing the optically pure (R,R)- and (R,S)-stereoisomers with specific substituents.
Stated Advantages
Fenoterol analogues have an equal or higher efficacy for β2-adrenergic receptor binding than racemic fenoterol with the ability to reduce adverse effects such as hypersensitivity and drug tolerance.
Use of purified optically active (R,R)-fenoterol and (R,S)-fenoterol analogues reduces side effects and adverse responses associated with inactive stereoisomers.
Certain fenoterol analogues show higher systemic exposure and longer clearance times than (R,R)-fenoterol, potentially producing longer-acting drugs.
Documented Applications
Treatment of cardiac disorders such as congestive heart failure by administering therapeutically effective doses of (R,R)-fenoterol or fenoterol analogues.
Treatment of pulmonary disorders including asthma and chronic obstructive pulmonary disease using therapeutically effective doses of the disclosed (R,R)- and (R,S)-fenoterol analogues.
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