Methods of treating neurodegenerative disease with substituted n-hexanoic-l-tyrosine-l-isoleucine-(6)-aminohexanoic amide analogues
AssigneeAthira Pharma, Inc.
InventorsLeen H. Kawas, Jasbir Singh, Lansing Joseph Stewart, William R. Baker
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Abstract
The present technology relates to compounds, kits, compositions, and methods useful for the treatment of numerous pathologies including dementia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and other neurodegenerative diseases, spinal cord injury, traumatic brain injury, diabetes and metabolic syndrome, defective wound healing, and/or sensorineural hearing and vision loss.
Claims57
A method for treating a neurogenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I):
- or a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the tautomer, wherein:
- n is 1, 2, 3, 4, 5, 6, 7, 8, or 9;
- m is 0, 1, 2, 3, or 4;
- R1 is C1-C12 alkyl or C1-C12 substituted alkyl;
- R2 is selected from
- each Y is independently —Z—(CH2)q—W—Rb;
- q is 0-4;
- Z and W are independently selected from CH2, NRc, and Rb,
- or Z and W are taken together to form a C3-C8 heterocycloalkyl;
- each Rc is independently hydrogen or C1-C4 alkyl;
- each Rb is independently selected from hydrogen, C1-C12 alkyl, C1-C12 substituted alkyl, C3-C8 heterocycloalkyl, and C3-C8 substituted heterocycloalkyl;
- r is 0-5;
- U is heterocycloalkyl;
- R3 and R4 are independently hydrogen or C1-C12 alkyl,
- or R3 and R4 are taken together to form a spirocyclic ring system;
- R5 is hydrogen;
- and
- each R6 is independently selected from hydrogen, deuterium, CH3, F, 19F, and 18F;
- wherein each heterocyclic ring contains up to four heteroatoms selected from O, N, and S;
- with the proviso that when both Z and W are heteroatoms, the value of q cannot be 1.
A method for treating a neurogenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II):
- or a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the tautomer, wherein:
- n is 3, 4, 5, 6, 7, 8, or 9;
- m is 0, 1, 2, 3, or 4;
- R1 is selected from C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, and C2-C12 substituted alkynyl;
- R2 is selected from hydrogen,
- each Y is independently —Z—(CH2)q—W—Rb,
- or —C(═O)—Y forms an amide bond through a nitrogen atom on Y, and Y is selected from glycine, sarcosine, N,N-dimethylglycine, alanine, valine, leucine, isoleucine, lysine, ornithine, arginine, serine, and threonine;
- q is 0-4;
- each Z and W is independently selected from CH2, O, S, NRc, and Rb,
- or Z and W are taken together to form a C3-C8 heterocycloalkyl or C4-C10 heteroaryl or bicyclic ring system in which one of the rings is a C4-C10 heteroaryl;
- each Rc is independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl;
- each Rb is independently selected from hydrogen, C1-C12 alkyl, C1-C12 substituted alkyl, C3-C8 cycloalkyl, C3-C8 substituted cycloalkyl, C3-C8 heterocycloalkyl, and C3-C8 substituted heterocycloalkyl;
- U is selected from pyridine, 1,4-dihydropyridine, N-alkyl-1,4-dihydropyridine, and C-imidazole, or U is aryl, heteroaryl or heterocycloalkyl;
- R3 and R4 are independently selected from hydrogen, C1-C12 alkyl, C1-C12 substituted alkyl, C2-C12 alkenyl, C2-C12 substituted alkenyl, C2-C12 alkynyl, and C2-C12 substituted alkynyl,
- or R3 and R4 are taken together to form a fused bicyclic ring system or a spirocyclic ring system;
- and
- each R6 is independently selected from hydrogen, deuterium, CH3, F, 19F, and 18F;
- wherein each heterocyclic and heteroaryl ring contains up to four heteroatoms selected from O, N, and S;
- with the proviso that when both Z and W are heteroatoms, the value of q cannot be 1;
- and with the proviso that when R2 is hydrogen, at least one of the R3 or R4 groups is not hydrogen.
A method for treating a neurogenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound selected from:
- or a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the tautomer.
Dependencies are inferred from the claim text.