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US 2003/0125338 A1Published application
Compounds, compositions and methods for modulating beta-amyloid production
AssigneeActive Pass Pharmaceuticals, Inc.
InventorsBruce P. Connop, Amelia Grant, Parimal S. Nathwani
Life of this patent
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Abstract
Methods and compositions useful in the treatment of amyloidosis and conditions and diseases associated therewith, such as Alzheimer's disease, are provided. The methods involve administering to a subject in need thereof a pharmaceutical composition including one or more agents that modulate PPARα and/or PPARδ activity, resulting in an inhibition of β-amyloid production and/or release from cells of the subject, particularly brain cells.
Claims48
A compound of the formula
- 64
- wherein, independently at each occurrence,
- R1 is an organic moiety having at least 4 carbons;
- Z is selected from —O—, —NH—NH—, and —N(R2)—;
- R2 is selected from hydrogen and C1-C30 organic moieties with the proviso that R1 and R2 can join together with the nitrogen to which they are both attached and form a heterocyclic moiety;
- R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy radicals;
- R5, R6, R7, R8 and R9 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, halogen, haloalkyl, haloalkenyl, cyano, nitro, —R10—N═N—O—R11, —OR12, —C(O)OR12, —N(R12)2, —C(O)N(R12)2, —N(R12)C(O)OR11, heterocyclyl and heterocyclylalkyl;
- R10 is a bond or a straight or branched alkylene or alkenylene chain;
- R11 is hydrogen, alkyl or aralkyl;
- and
- R12 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl and cycloalkylalkenyl;
- with the proviso that Z is not NR2 when R3 is Cl, R4 is H, R5 is H, R6 is H, R7 is H, R8 is methyl and R9 is methyl.
9 more elements
A compound of the formula
- 65
- wherein,
- R1 is a hydrophobic moiety selected from non-aromatic organic moieties having at least 10 carbon atoms and aromatic moieties having at least 6 carbons, and R2 is hydrogen;
- or
- each of R1 and R2 are selected from hydrophobic organic moieties having at least one carbon atom, with the proviso that R1 and R2 in total have at least six carbon atoms, and with the further proviso that R1 and R2 can join together with the nitrogen to which they are both bonded and form a heterocyclic moiety.
2 more elements
A compound that (1) is a PPARα agonist and/or a PPARδ agonist, and (2) regulates the production and/or release of β-amyloid in cells.
A method for modulating the production and/or release of β-amyloid in a cell, comprising treating said cell with a compound of the formula
- 71
- wherein, independently at each occurrence,
- R15 and R17 are each independently selected from the group consisting of hydrogen and lower alkyl radicals;
- R16 is selected from the group consisting of hydrogen, halogen and lower alkoxy radicals;
- W is selected from the group consisting of hydroxy, lower alkoxy, —OM and —(NH)pNH2 radicals, wherein p is 0 or 1, and M is an alkali metal cation, an alkaline earth metal cation or the ammonium ion;
- m is 0, 1, 2 or 3;
- Y is selected from the group consisting of an aryl radical of 6 to 10 carbon atoms;
- 72
- wherein
- R18 is hydrogen or lower alkyl radical;
- R19 is hydrogen, H2N—,
- 73
- phenyl, (lower)alkoxyphenyl, or di(lower)alkoxy-phenyl, providing that when R18 is hydrogen and R19 is hydrogen, phenyl, (lower)alkoxyphenyl or di(lower)alkoxyphenyl, R16 is halo or lower alkoxy,
- R20 is selected from the group consisting of a lower alkyl radical, a halo radical, an aryl radical of 6 to 10 carbon atoms and a haloaryl radical of 6 to 10 carbon atoms,
- R21 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy and halo radicals,
- R22 is selected from the group consisting of hydrogen and lower alkyl radicals, and
- E is selected from the group consisting of
- 74
- and
- 75
- wherein
- R23 is hydrogen or lower alkyl
- R24 is hydrogen or lower alkyl, and
- q is an integer from 0 to 3.
21 more elements
A method of treatment comprising modulating the production and/or release of β-amyloid in a human in need of said treatment, said method comprising administering to said human a compound of the formula
- 76
- wherein, independently at each occurrence,
- R15 and R17 are each independently selected from the group consisting of hydrogen and lower alkyl radicals;
- R16 is selected from the group consisting of hydrogen, halogen and lower alkoxy radicals;
- W is selected from the group consisting of hydroxy, lower alkoxy, —OM and —(NH)pNH2 radicals, wherein p is 0 or 1, and M is an alkali metal cation, an alkaline earth metal cation or the ammonium ion;
- m is 0, 1, 2 or 3;
- Y is selected from the group consisting of an aryl radical of 6 to 10 carbon atoms;
- 77
- wherein
- R18 is hydrogen or lower alkyl radical;
- R19 is hydrogen, H2N—,
- 78
- phenyl, (lower)alkoxyphenyl, or di(lower)alkoxy-phenyl, providing that when R18 is hydrogen and R19 is hydrogen, phenyl, (lower)alkoxyphenyl or di(lower)alkoxyphenyl, R16 is halo or lower alkoxy,
- R20 is selected from the group consisting of a lower alkyl radical, a halo radical, an aryl radical of 6 to 10 carbon atoms and a haloaryl radical of 6 to 10 carbon atoms,
- R21 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy and halo radicals,
- R22 is selected from the group consisting of hydrogen and lower alkyl radicals, and
- E is selected from the group consisting of
- 79
- and
- 80
- wherein
- R23 is hydrogen or lower alkyl,
- R24 is hydrogen or lower alkyl, and
- q is an integer from 0 to 3.
21 more elements
A method of treatment comprising modulating the production and/or release of β-amyloid in a human in need of said treatment, said method comprising administering to said human a compound of the formula
- 81
- wherein,
- R1 is selected from the group consisting of C1-C3 alkyl, hydrogen, metal cation and ammonium cation;
- R13 and R14 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, halogen, haloalkyl, haloalkenyl, cyano, nitro, —R10—N═N—O—R11, —OR12, —C(O)OR12, —N(R12)2, —C(O)N(R12)2, —N(R12)C(O)OR11, heterocyclyl and heterocyclylalkyl;
- R10 is a bond or a straight or branched alkylene or alkenylene chain;
- R11 is hydrogen, alkyl or aralkyl;
- and
- R12 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl and cycloalkylalkenyl;
- and
- n is 1, 2 or 3.
7 more elements
A method of treatment comprising modulating the production and/or release of β-amyloid in a non-human mammal in need of said treatment, said method comprising administering to said non-human mammal a compound of the formula
- 82
- wherein, independently at each occurrence,
- R15 and R17 are each independently selected from the group consisting of hydrogen and lower alkyl radicals;
- R16 is selected from the group consisting of hydrogen, halogen and lower alkoxy radicals;
- W is selected from the group consisting of hydroxy, lower alkoxy, —OM and —(NH)pNH2 radicals, wherein p is 0 or 1, and M is an alkali metal cation, an alkaline earth metal cation or the ammonium ion;
- m is 0, 1, 2 or 3;
- Y is selected from the group consisting of an aryl radical of 6 to 10 carbon atoms;
- 83
- wherein
- R18 is hydrogen or lower alkyl radical;
- R19 is hydrogen, H2N—,
- 84
- phenyl, (lower)alkoxyphenyl, or di(lower)alkoxy-phenyl, providing that when R18 is hydrogen and R19 is hydrogen, phenyl, (lower)alkoxyphenyl or di(lower)alkoxyphenyl, R16 is halo or lower alkoxy,
- R20 is selected from the group consisting of a lower alkyl radical, a halo radical, an aryl radical of 6 to 10 carbon atoms and a haloaryl radical of 6 to 10 carbon atoms,
- R21 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy and halo radicals,
- R22 is selected from the group consisting of hydrogen and lower alkyl radicals, and
- E is selected from the group consisting of
- 85
- and
- 86
- wherein
- R23 is hydrogen or lower alkyl,
- R24 is hydrogen or lower alkyl, and
- q is an integer from 0 to 3.
21 more elements
Dependencies are inferred from the claim text.