Preparation of (R,R)-fenoterol and (R,R)- or (R,S)-fenoterol analogues and their use in treating congestive heart failure
Inventors
Wainer, Irving William • Zhu, Weizhong • Chakir, Khalid • Xiao, Rui-Ping • Abernethy, Darrell R. • Beigi Abhari, Farideh M.
Assignees
US Department of Health and Human Services
Publication Number
US-9908841-B2
Publication Date
2018-03-06
Expiration Date
2027-08-10
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Abstract
This disclosure concerns the discovery of (R,R)- and (R,S)-fenoterol analogs which are highly effective at binding β2-adrenergic receptors. Exemplary chemical structures for these analogs are provided. Also provided are pharmaceutical compositions including the disclosed (R,R)-fenoterol and fenoterol analogs, 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 of (R,R)- and (R,S)-fenoterol analogs which are highly effective at binding β2-adrenergic receptors. Exemplary chemical structures for these analogs are provided, along with pharmaceutical compositions comprising the disclosed (R,R)-fenoterol and fenoterol analogs, 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.
Fenoterol is a β2-adrenergic receptor agonist traditionally used to treat pulmonary disorders. It exists as stereoisomers including (R,R), (R,S), (S,R), and (S,S) forms, with commercial fenoterol being a racemic mixture of (R,R) and (S,S). Pharmacological studies show that the (R,R)-isomer is primarily responsible for bronchodilation, while the inactive (S,S)-isomer may cause adverse effects like hypersensitivity and drug tolerance.
The invention aims to provide fenoterol compositions effective for treating disorders such as asthma, chronic obstructive pulmonary disease, or congestive heart failure but having reduced side effects. Substantially purified (R,R)-fenoterol or (R,R)- or (R,S)-fenoterol analogues are expected to reduce side effects caused by physiologically less active forms of the drug by removing the inactive enantiomers that cause adverse effects.
Claims Coverage
The patent contains one independent composition claim and one independent pharmaceutical composition claim, both directed to compounds and compositions featuring specific fenoterol analog structures and stereochemistry.
Compound having specific fenoterol analogue structure
A compound having a defined general formula with substituents R1-R3, R4, R5, X, Y, R6, R7 and R8, where R5 is a napthyl derivative, and the compound is characterized by the stereochemistry being (R,R) or (R,S).
Pharmaceutical composition comprising the defined fenoterol compound
A pharmaceutical composition comprising the compound of the defined structure and stereochemistry and at least one pharmaceutically acceptable carrier, with the same provisions on R5, R4, and stereochemistry as the compound claim.
The claims cover fenoterol analog compounds and pharmaceutical compositions thereof, specifically those with defined structural components and (R,R) or (R,S) stereochemistry, particularly including napthyl derivatives and lower alkyl substituents.
Stated Advantages
Use of substantially purified (R,R)-fenoterol or (R,R)- or (R,S)-fenoterol analogues is expected to reduce side effects such as hypersensitivity and drug resistance (tolerance) observed with racemic fenoterol.
The disclosed fenoterol analogues have comparable or greater efficacy at β2-adrenergic receptor binding, potentially allowing lower doses and thereby minimizing adverse effects.
Certain fenoterol analogues have longer systemic exposure and slower clearance rates than (R,R)-fenoterol, suggesting possible longer-acting therapeutic effects.
Documented Applications
Treatment of cardiac disorders such as congestive heart failure by administering therapeutically effective amounts of (R,R)-fenoterol or fenoterol analogues.
Treatment of pulmonary disorders such as asthma or chronic obstructive pulmonary disease using therapeutically effective doses of the disclosed fenoterol analogues.
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