Compositions and therapeutic methods for the treatment of complement-associated diseases
Inventors
Kulikowski, Ewelina B. • Gilham, Dean E. • Wasiak, Sylwia • Halliday, Christopher R. A. • Tsujikawa, Laura M.
Assignees
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Publication Number
US-10111885-B2
Publication Date
2018-10-30
Expiration Date
Abstract
The invention comprises methods of modulating the complement cascade in a mammal and for treating and/or preventing diseases and disorders associated with the complement pathway by administering a compound of Formula I or Formula II, such as, for example, 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one or a pharmaceutically acceptable salt thereof.
Core Innovation
The invention relates to complement-modulating therapeutic compounds represented by Formula I or Formula II, including stereoisomers, tautomers, pharmaceutically acceptable salts, hydrates, and related forms such as solvates, chelates, crystalline forms, polymorphs, pseudopolymorphs, amorphous forms, and non-covalent complexes. The disclosure also provides explicit Formula II compound set members, including structures identified in the text such as JQ1 and additional thieno/triazolodiazepine structures.
The invention addresses the treatment and/or prevention of complement-associated diseases by modulating the complement system in a mammal or subject in need thereof. The disclosure links complement cascade modulation to clinical and laboratory activity, and includes complement-relevant terms such as complement component references C3, C4, C5, C9 and complement-related factors MBL2, CD55, and CD59.
The document further describes administration of Formula I or Formula II compounds, including stereoisomers, tautomers, salts, and hydrates, for complement-associated diseases and disorders. These include paroxysmal nocturnal hemoglobinuria, familial CD59 deficiency, cold agglutinin disease, hereditary angioedema, hemolytic anemia, thrombocytopenia, and additional listed complement-associated conditions.
Claims Coverage
The independent claim set comprises two independent claims. Across these claims, the coverage is defined by a general method using Formula I with variable substituent constraints and a method using a specifically named compound that is consistent with Formula I.
Treating complement-associated disease by administering a Formula I complement modulator
A method for treating a complement-associated disease or disorder selected from paroxysmal nocturnal hemoglobinuria, familial CD59 deficiency, cold agglutinin disease, hereditary angioedema, hemolytic anemia, and thrombocytopenia by modulating the complement system in a subject in need thereof, comprising administering a therapeutically effective amount of at least one compound of Formula I or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein R1 and R3 are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen; R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, and hydrogen; R5 and R7 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen; R6 is selected from amino, amide, alkyl, hydrogen, hydroxyl, piperazinyl, and alkoxy, wherein the alkoxy is optionally substituted with one or more groups chosen from amide, amine, aryl, benzyloxy, carbamate, carboxy, heterocyclyl, hydroxyl, methoxy, and sulfonamide; and W is CH or N.
Treating complement-associated disease by administering a named complement modulator
A method for treating a complement-associated disease or disorder selected from paroxysmal nocturnal hemoglobinuria, familial CD59 deficiency, cold agglutinin disease, hereditary angioedema, hemolytic anemia, and thrombocytopenia by modulating the complement system in a subject in need thereof comprising administering a therapeutically effective amount of 2-{2-[(dimethylamino)methyl]-1H-indol-5-yl}-5,7-dimethoxy-3,4-dihydroquinazolin-4-one or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof.
Overall, the claims cover therapeutic methods that modulate the complement system by administering therapeutically effective amounts of either Formula I compounds with defined substituent-variable constraints or a specific named compound, with stereoisomer, tautomer, pharmaceutically acceptable salt, and hydrate coverage, for treating selected complement-associated diseases.
Stated Advantages
Treat and/or prevent complement-associated diseases by modulating the complement system.
Documented Applications
Therapeutically treating and/or preventing complement-associated diseases or disorders by administering Formula I or Formula II compounds, including stereoisomers, tautomers, salts, and hydrates, to a mammal in need thereof.
Use of complement modulation activity readouts, including reduction of complement component mRNA/protein and complement activity assays, with in vitro and clinical-sample activity reporting for a named compound.
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