Therapeutic compounds and compositions
Inventors
Chrusciel, Robert A. • Gadwood, Robert C. • Hayward, Neil J. • Melnick, Michael J. • Navia, Manuel A. • Poel, Toni J. • Stassen, Frans L. • Stewart, Catherine A.
Assignees
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Publication Number
US-9994521-B2
Publication Date
2018-06-12
Expiration Date
Abstract
The present invention provides compounds and compositions that inhibit Factor XIa or kallikrein and methods of using these compounds and composition.
Core Innovation
The invention relates to compounds of formula (II) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the compounds of formula (II) or the pharmaceutically acceptable salts thereof. The disclosed embodiments define a broad chemical space with extensive substituent variables and ring/linker elements, including R1-R11, A, X, Y, q, and n, with specified options for substituents and ring-forming possibilities.
The compounds are described as Factor XIa-targeting inhibitors, and the disclosure also ties the chemistry to reducing the risk of deep vein thrombosis in a subject after an ischemic event and to inhibiting Factor XIa in a subject after ischemia. The document further presents specific compound structures and intermediate/final compounds as representative embodiments of the formula (II) framework.
The claims and embodiments cover administering an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof, optionally as part of a pharmaceutical composition. The therapeutic context is consistently directed to Factor XIa inhibition and deep vein thrombosis risk reduction in the specified subject populations.
Claims Coverage
The independent claims provide two therapeutic method scopes that each administer an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof, formulated as a pharmaceutical composition. Across the claims, the inventive coverage is defined by extensive structural substituent definitions for the formula (II) scaffold and by two biological objectives: deep vein thrombosis risk reduction and Factor XIa inhibition.
Reducing the risk of deep vein thrombosis by administering a formula (II) compound
A method of reducing the risk of deep vein thrombosis comprising administering to a subject that has suffered an ischemic event an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein the compound is defined by the structural variables including R1-R11, A, X, Y, q, and n.
Inhibiting Factor XIa by administering a formula (II) compound
A method of inhibiting Factor XIa in a subject comprising administering to the subject that has suffered ischemia an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein the compound is defined by the structural variables including R1-R11, A, X, Y, q, and n.
Both independent claims are directed to administering formula (II) compounds or pharmaceutically acceptable salts after ischemic events, with one claim focused on reducing the risk of deep vein thrombosis and the other focused on inhibiting Factor XIa. The claimed compounds are constrained by detailed variable definitions that specify the chemical architecture through R1-R11, A, X, Y, q, and n.
Stated Advantages
Reduces the risk of deep vein thrombosis.
Inhibits Factor XIa.
Reduces systemic embolism.
Treats deep vein thrombosis and pulmonary embolism.
Provides recurrence prophylaxis for deep vein thrombosis and pulmonary embolism.
Reduces stroke risk.
Inhibits kallikrein in hereditary angioedema.
Documented Applications
Reducing the risk of deep vein thrombosis in a subject that has suffered an ischemic event.
Inhibiting Factor XIa in a subject that has suffered ischemia.
Therapeutic scope for thrombosis and ischemia/ischemic events, and angioedema, framed as prothrombotic disorders.
Therapeutic scope directed to small-molecule inhibitors of Factor XIa and/or kallikrein for thrombosis/ischemia/angioedema.
Reducing systemic embolism, including administration to a mammal/human subject in the context of ischemic events/ischemia.
Treating deep vein thrombosis and pulmonary embolism, including recurrence prophylaxis and prophylactic/therapeutic methods.
Inhibiting kallikrein in hereditary angioedema.
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