Granted Patent
B2
US 12,473,288 · App. 18/202,704 · Granted Nov 18, 2025
Treatment of neurodegenerative diseases through inhibiton of Hsp90
Inventors:
Gabriela Chiosis (New York, NY); Huazhong He (New York, NY); Danuta Zatorska (Ericeira, PT)
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Abstract
Treatment of neurodegenerative diseases is achieved using small molecule purine scaffold compounds that inhibit Hsp90 and that possess the ability to cross the blood-brain barrier or are otherwise delivered to the brain.
Claims (48)
1 . A method for treatment of a neurodegenerative disease, comprising administering to an individual in need of such treatment a therapeutically effective amount of a compound having the structure:
wherein
R is hydrogen, or a C 1 to C 10 alkyl, C 2 to C 10 alkenyl, C 2 to C 10 alkynyl, or C 2 to C 10 alkoxyalkyl group, optionally including heteroatoms;
Y 1 and Y 2 are independently C or N;
X 4 is hydrogen or halogen;
X 3 is CH 2 , CF 2 , S, SO, SO 2 , O, NH, or NR 2 , wherein R 2 is alkyl; and
X 2 is halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido, dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SO 2 -alkyl, COO-alkyl, NH 2 , OH, or CN; and
X 1 has the formula —X—Y—Z— wherein X, Y and Z are independently C, N, S or O, connected by single or double bonds and with appropriate hydrogen substitution to satisfy valence, or Y may be (CH 2 ) 2 , wherein one of X and Z is bonded at the 5-position of the aryl ring and the other is bonded to the 4-position; and
wherein the compound is optionally in the form of an acid addition salt; and
wherein the neurodegenerative disease is selected from the group consisting of complete androgen insensitivity syndrome (CAIS), spinal and bulbar muscular atrophy (SBMA or Kennedy's disease), Alzheimer's Disease (AD), sporadic frontotemporal dementia with parkinsonism (FTDP), familial FTDP-17 syndromes, Parkinson's disease, and Huntington disease.
2 . The method of claim 1 , wherein the compound and the mode of administration are selected such that the compound is delivered to the brain.
3 . The method of claim 1 , wherein at least one of X, Y and Z is a carbon atom.
4 . The method of claim 1 , wherein X 1 is —O—(CH 2 ) n —O—, wherein n is 1 or 2.
5 . The method of claim 1 , wherein X 2 is halogen.
6 . The method of claim 5 , wherein X 2 is Br or I.
7 . The method of claim 1 , wherein R is an alkyl group containing a nitrogen heteroatom.
8 . A method for treatment of a neurodegenerative disease, comprising administering to an individual in need of such treatment a therapeutically effective amount of a compound of formula:
wherein
X 4 is hydrogen or halogen;
X 6 is amino;
X 3 is C, O, N, or S with hydrogens as necessary to satisfy valence, or CF 2 , SO, SO 2 or NR 3 where R 3 is alkyl;
R 1 is hydrogen, a C 1 to C 10 alkyl, alkenyl, alkynyl, or an alkoxyalkyl group, optionally including heteroatoms;
R 2 is selected from the group consisting of
where the squiggly line represents the attachment point to X 3 ; and
X 2 is halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SO 2 -alkyl, COO-alkyl, NH 2 , OH, or CN;
wherein the compound is optionally in the form of an acid addition salt; and
wherein the neurodegenerative disease is selected from the group consisting of complete androgen insensitivity syndrome (CAIS), spinal and bulbar muscular atrophy (SBMA or Kennedy's disease), Alzheimer's Disease (AD), sporadic frontotemporal dementia with parkinsonism (FTDP), familial FTDP-17 syndromes, Parkinson's disease, and Huntington disease.
9 . The method of claim 8 , wherein the compound and the mode of administration are selected such that the compound is delivered to the brain.
10 . The method of claim 8 , wherein X 3 is S.
11 . The method of claim 8 , wherein X 3 is CH 2 .
12 . The method of claim 8 , wherein X 2 is I.
13 . The method of claim 8 , wherein R 1 is an alkyl group containing a nitrogen heteroatom.
14 . The method of claim 8 , wherein R 1 is selected from the group consisting of 3-isopropylaminopropyl, 3-(isopropyl(methylamino)propyl, 3-(isopropyl(ethylamino)propyl, 3-((2-hydroxyethyl)(isopropyl)amino)propyl, 3-(methyl(prop-2-ynyl)amino)propyl, 3-(allyl(methylamino)propyl, 3-(ethyl(methylamino)propyl, 3-(cyclopropyl(propyl)amino)propyl, 3-(cyclohexyl(2-hydroxyethyl)amino)propyl, 3-(2-methylaziridin-1-yl)propyl, 3-(piperidin-1-yl)propyl, 3-(4-(2-hydroxyethyl) piperazin-1-yl)propyl, 3-morpholinopropyl, 3-(trimethylammonio)propyl, 2-(isopropylamino)ethyl, 2-(isobutylamino)ethyl, 2-(neopentylamino)ethyl, 2-(cyclopropylmethylamino)ethyl, 2-(ethyl(methyl)amino)ethyl, 2-(isobutyl(methyl)amino)ethyl, and 2-(methyl(prop-2-ynyl)amino)ethyl.
15 . A method for treatment of a neurodegenerative disease, comprising administering to an individual in need of such treatment a therapeutically effective amount of a compound of formula:
wherein
X 4 is hydrogen or halogen;
X 6 is amino;
X 3 is C, O, N, or S with hydrogens as necessary to satisfy valence, or CF 2 , SO, SO 2 or NR 3 where R 3 is alkyl;
R 1 is hydrogen, a C 1 to C 10 alkyl, alkenyl, alkynyl, or an alkoxyalkyl group, optionally including heteroatoms;
R 2 is
where the squiggly line represents the attachment point to X 3 ; and
X 2 is ethylene;
wherein the compound is optionally in the form of an acid addition salt; and
wherein the neurodegenerative disease is selected from the group consisting of complete androgen insensitivity syndrome (CAIS), spinal and bulbar muscular atrophy (SBMA or Kennedy's disease), Alzheimer's Disease (AD), sporadic frontotemporal dementia with parkinsonism (FTDP), familial FTDP-17 syndromes, Parkinson's disease, and Huntington disease.
16 . The method of claim 15 , wherein X 3 is S.
17 . The method of claim 15 , wherein X 3 is CH 2 .
18 . The method of claim 15 , wherein R 1 is an alkyl group containing a nitrogen heteroatom.
19 . The method of claim 15 , wherein R 1 is selected from the group consisting of 3-isopropylaminopropyl, 3-(isopropyl(methylamino)propyl, 3-(isopropyl(ethylamino)propyl, 3-((2-hydroxyethyl)(isopropyl)amino)propyl, 3-(methyl(prop-2-ynyl)amino)propyl, 3-(allyl(methylamino)propyl, 3-(ethyl(methylamino)propyl, 3-(cyclopropyl(propyl)amino)propyl, 3-(cyclohexyl(2-hydroxyethyl)amino)propyl, 3-(2-methylaziridin-1-yl)propyl, 3-(piperidin-1-yl)propyl, 3-(4-(2-hydroxyethyl) piperazin-1-yl)propyl, 3-morpholinopropyl, 3-(trimethylammonio)propyl, 2-(isopropylamino)ethyl, 2-(isobutylamino)ethyl, 2-(neopentylamino)ethyl, 2-(cyclopropylmethylamino)ethyl, 2-(ethyl(methyl)amino)ethyl, 2-(isobutyl(methyl)amino)ethyl, or 2-(methyl(prop-2-ynyl)amino)ethyl.
Continuity (6)
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