Combination Therapies for the Treatment of Alzheimer's Disease and Related Disorders
The present invention relates to combination therapies for treating Alzheimer's disease or an amyloidosis-associated pathological condition comprising co-administering a therapeutically effective amount of a first compound, and a therapeutically effective amount of a second compound. In certain embodiments, the first compound or the second compound inhibits AB peptide polymerization; is an anti-inflammatory; improves cognitive function, mood, or social behavior; is associated with Tau or alpha-synuclein; or regulates amyloid peptide washout.
1 - 20 . (canceled)
21 . A method of treating a disease or condition in a subject in need thereof comprising co-administering a therapeutically effective amount of a first compound, and a therapeutically effective amount of a second compound, wherein the disease or condition is Alzheimer's disease, dementia, an amyloidosis-associated condition, or a head injury.
22 . A method of slowing the progression of a disease or condition in a subject in need thereof comprising co-administering a therapeutically effective amount of a first compound, and a therapeutically effective amount of a second compound, wherein the disease or condition is Alzheimer's disease, dementia, an amyloidosis-associated condition, or a head injury.
23 . The method of claim 21 , wherein the first compound and the second compound inhibit Aβ peptide polymerization.
24 . The method of claim 22 , wherein the first compound and the second compound inhibit Aβ peptide polymerization.
25 . The method of claim 23 , the compound inhibiting Aβ peptide polymerization is selected from the group consisting of formula I-IV:
wherein, independently for each occurrence,
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are hydrogen, halo, azido, alkyl, haloalkyl, perhaloalkyl, fluoroalkyl, perfluoroalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, amino, alkylamino, arylamino, acylamino, heteroarylamino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, oxycarbonyl, acyloxy, silyl, thioether, sulfo, sulfonate, sulfonyl, sulfonamido, formyl, cyano, isocyano, or —Y-(haloalkylene)-alkyl;
R 7 is hydrogen, halo, azido, alkyl, haloalkyl, perhaloalkyl, fluoroalkyl, perfluoroalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, amino, alkylamine, arylamino, acylamino, heteroarylamino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, oxycarbonyl, acyloxy, silyl, thioether, sulfo, sulfonate, sulfonyl, sulfonamide, formyl, cyano, isocyano, —Y-(haloalkylene)-alkyl, or —Y-(haloalkylene)-R;
R N is hydrogen, lower alkyl, or -(haloalkylene)-alkyl;
Y is a bond, N(R N ), O, or S; and
R is
provided that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , or R 10 is —Y-(haloalkylene)-alkyl;
or R N is -(haloalkylene)-alkyl.
26 . The method of claim 25 , the compound inhibiting Aβ peptide polymerization is
27 . The method of claim 25 , the compound inhibiting Aβ peptide polymerization is
28 . The method of claim 23 , the compound inhibiting Aβ peptide polymerization is selected from the group consisting of
29 . The method of claim 23 , the compound inhibiting Aβ peptide polymerization is a gamma secretase inhibitor, a metal ionophore, a statin or an endocannabinoid.
30 . The method of claim 24 , the compound inhibiting Aβ peptide polymerization is selected from the group consisting of formula I-IV:
wherein, independently for each occurrence,
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are hydrogen, halo, azido, alkyl, haloalkyl, perhaloalkyl, fluoroalkyl, perfluoroalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, amino, alkylamino, arylamino, acylamino, heteroarylamino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, oxycarbonyl, acyloxy, silyl, thioether, sulfo, sulfonate, sulfonyl, sulfonamido, formyl, cyano, isocyano, or —Y-(haloalkylene)-alkyl;
R 7 is hydrogen, halo, azido, alkyl, haloalkyl, perhaloalkyl, fluoroalkyl, perfluoroalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, amino, alkylamine, arylamino, acylamino, heteroarylamino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, oxycarbonyl, acyloxy, silyl, thioether, sulfo, sulfonate, sulfonyl, sulfonamide, formyl, cyano, isocyano, —Y-(haloalkylene)-alkyl, or —Y-(haloalkylene)-R;
R N is hydrogen, lower alkyl, or -(haloalkylene)-alkyl;
Y is a bond, N(R N ), O, or S; and
R is
provided that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , or R 10 is —Y-(haloalkylene)-alkyl;
or R N is -(haloalkylene)-alkyl.
31 . The method of claim 30 , the compound inhibiting Aβ peptide polymerization is
32 . The method of claim 30 , the compound inhibiting Aβ peptide polymerization is
33 . The method of claim 24 , the compound inhibiting Aβ peptide polymerization is selected from the group consisting of
34 . The method of claim 24 , the compound inhibiting Aβ peptide polymerization is a gamma secretase inhibitor, a metal ionophore, a statin or an endocannabinoid.