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-11198673-B2
Publication Date
2021-12-14
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 a method of treating a subject to maintain an extracorporeal blood circuit by contacting the blood of the subject with a compound of Formula (II) or a pharmaceutically acceptable salt thereof. Formula (II) is defined by extensive structural constraints for R1, R2, R3, A, R4, R5, X, Y, R6, R7, q, and n, including allowed substituent classes, heteroaryl and heterocyclyl embodiments, and ring-forming combinations.
The disclosed framework specifies that A is a bond, C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene, and that X is selected from –C(O)O–, –OC(O)–, –C(O)S(O)2–, –S(O)2C(O)–, –C(O)N(R5)–, or –N(R5)C(O)–. R4 and Y are selected from cycloalkyl, aryl, heteroaryl, or heterocyclyl classes, with substitution limits that include 0-3 occurrences of –NH2 or R6, and R5 and R7 are independently H, C1-6 alkyl, aralkyl, or aryl with permitted substitution limits.
The disclosure further includes specific structural embodiments, subclass formulae, and exemplified compounds within the Formula (II) scope, including heteroaryl and heterocyclyl variants and additional substituted aryl or heteroaryl groups. The documents also describe compounds that inhibit Factor XIa and/or kallikrein, with therapeutic contexts that include thromboembolic disorders, angioedema including hereditary angioedema, and maintaining extracorporeal blood circuits.
Claims Coverage
The consolidated claim coverage centers on one independent method claim: contacting a subject’s blood with a Formula (II) compound or pharmaceutically acceptable salt to maintain an extracorporeal blood circuit. The independent scope is broad because of extensive substituent and ring-formation constraints in Formula (II), and the dependent claims add functional and subject-type limitations.
Maintaining an extracorporeal blood circuit by contacting blood with a Formula (II) compound
A method of treating a subject to maintain an extracorporeal blood circuit by contacting the blood of the subject with a compound of Formula (II) or a pharmaceutically acceptable salt thereof.
Formula (II) variable substituent and ring-formation constraints
Formula (II) is defined by the stated variable relationships for R1, R2, R3, A, R4, R5, X, Y, R6, R7, q, and n, including allowed substituent classes, heteroaryl or heterocyclyl options, and ring-forming rules.
Inhibiting blood coagulation
The method further includes inhibiting blood coagulation.
Human subject treatment
The method is performed on a human subject.
Mammal subject treatment
The method is performed on a mammal subject.
Specified Formula (II) compound embodiments
The method uses specified compound embodiments shown in the chemical structure images or a pharmaceutically acceptable salt thereof.
Overall, the claims focus on a treatment method that maintains an extracorporeal blood circuit by contacting blood with a Formula (II) compound or salt. Dependent claims narrow the method to inhibition of blood coagulation, human or mammal subjects, and specified compound embodiments within the Formula (II) framework.
Stated Advantages
Inhibiting blood coagulation.
Maintaining an extracorporeal blood circuit.
Improved bleeding profile versus thrombin/Factor Xa inhibitors.
Reduction of thrombosis risk by inhibiting Factor XIa and/or kallikrein.
Treating thromboembolic disorders associated with undesired thrombosis.
Treating angioedema, including hereditary angioedema (HAE).
Documented Applications
Maintaining an extracorporeal blood circuit by contacting the subject’s blood with a compound of Formula (II) or a pharmaceutically acceptable salt thereof.
Treating thrombotic and inflammation-related disorders by inhibiting Factor XIa and/or kallikrein.
Reducing stroke risk (ischemia/transient ischemic event).
Reducing systemic embolism.
Treating or preventing deep vein thrombosis.
Treating or preventing pulmonary embolism.
Treating angioedema, including hereditary angioedema (HAE).
Combination therapy and pharmaceutical composition use cases are discussed, including combinations with antithrombotic/anticoagulant and other agents.
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