Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases
Inventors
Griffioen, Gerard • VAN DOOREN, Tom • ROJAS DE LA PARRA, Veronica • Marchand, Arnaud • Allasia, Sara • Kilonda, Amuri • Chaltin, Patrick
Assignees
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Publication Number
US-9434722-B2
Publication Date
2016-09-06
Expiration Date
Abstract
This invention provides novel compounds and the novel compounds for use as a medicine, more in particular for the prevention or treatment of neurodegenerative disorders, more specifically certain neurological disorders, such as disorders collectively known as tauopathies, and disorders characterized by cytotoxic α-synuclein amyloidogenesis. The present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such neurodegenerative disorders. The present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds.
Core Innovation
The invention relates to compounds of formula (AA1) and formula (A1), including stereoisomers, enantiomers, tautomers, solvates, hydrates, salts, and prodrugs. The structures are defined by a maximum of two dotted lines selected from five dotted lines being a double bond, together with defined selections for E1, E2, E3, Q, Ra, Rb, R2, B, m, R5, R8, and linker L, and with Ra and Rb optionally forming a substituted or unsubstituted 4, 5, 6, 7 or 8 membered ring containing one N atom.
The compounds further include extensive substituent and oxidation options, with variable groups such as R1, R3, R4, R6, R10, R11, R12, and R13 selected from broad sets including halogen, hydroxyl, alkyl, alkenyl, alkynyl, aryl, heterocycle, and carbonyl-, sulfoxide-, sulfone-, amide-, and cyano-related groups, and with optional heteroatoms O, S, and N in certain moieties. The definitions also allow carbon atoms or heteroatoms of specified moieties to be oxidized to form C=O, C=S, N=O, N=S, S=O, or S(O)2 motifs, and in some cases permit optional substitution with Z.
The structural framework is further defined by cycle formation through X, Y, T, W, and V with the dotted lines to produce one of the listed structural formulas, including (Ia), (IIa), (IIIa), (IVa), (Va), (VIIa), (VIIIa), (IXa), (Xa), (XIa), (XIIIa), (XIVa), (XVa), (XVIIa), (XVIIIa), (XIXa), (XXIa), (XXIIa), (XXIIIa), or (XXIVa). The disclosures include explicit provisos excluding a named compound and, in one stated case, requiring that Q is not —NH—CO— under a specified cycle-forming condition.
Claims Coverage
The provided claim set includes three independent claims: one compound claim for formula (AA1), one pharmaceutical composition claim, and one compound claim for formula (A1). Across the independent claims, the coverage is centered on formula-defined compound genera with capped dotted-line double bonds, extensive substituent and ring-forming rules, cycle-forming constraints, and explicit exclusions of a named compound.
Compound of formula (AA1) with capped dotted-line double bonds
A compound of formula (AA1) or a stereoisomer, enantiomer or tautomer thereof, wherein a maximum of two dotted lines selected from the five dotted lines are a double bond, with E1 independently selected from CR1 and N, E2 independently selected from NR2 and O, E3 independently selected from CR3 and N, Q independently selected from NRb—C(O) and C(O)NH, and Ra and Rb each hydrogen or taken together to form a substituted or unsubstituted 4, 5, 6, 7 or 8 membered ring containing one N atom.
Extensive substituent and oxidation rules
R1, R3, R4, R6, R5, R8, R10, R11, R12, and R13 are independently selected from defined substituent sets, including halogen, —OH, —OR10, —SH, —SR10, —S(O)R11, —S(O)2R11, —SO2NR12R13, trifluoromethyl, trifluoromethoxy, nitro, cyano, carboxyl, carbonyl-related groups, alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene, and heterocycle-alkynylene, with optional heteroatoms O, S, and N and optional oxidation to C=O, C=S, N=O, N=S, S=O, or S(O)2.
Cycle formation by X, Y, T, W and V with defined structural formulas
Each of X, Y, T, W and V forms with the dotted lines one of the cycles having one of the structural formulas (Ia), (IIa), (IIIa), (IVa), (Va), (VIIa), (VIIIa), (IXa), (Xa), (XIa), (XIIIa), (XIVa), (XVa), (XVIIa), (XVIIIa), (XIXa), (XXIa), (XXIIa), (XXIIIa), or (XXIVa), with explicit provisos including a condition under which Q is not —NH—CO—.
Pharmaceutical composition including excipients and a therapeutically effective amount
A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of a compound according to formula (AA1) or a stereoisomer, enantiomer or tautomer thereof, with the same structural constraints applied to the embedded compound definition.
Compound of formula (A1) with capped dotted-line double bonds
A compound according to formula (A1) or a stereoisomer, enantiomer or tautomer thereof, wherein a maximum of two dotted lines selected from the five dotted lines are a double bond, with R1, R3, R4, and R6 selected from defined substituent groups, R2 selected from hydrogen, alkyl, alkenyl, and alkynyl, n selected from 0, 1, and 2, B selected from cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and heterocycle, m selected from 0 to 5, and R8 selected from a defined set.
Linker L and cycle-forming constraints
L is independently selected from —O—, —NH—, —NR10—, C1-6 alkylene, C1-6 alkenylene, and C1-6 alkynylene, with optional oxidation and optional heteroatom inclusion, and X, Y, T, W and V form with the dotted lines one of the cycles having one of the listed structural formulas, together with an explicit exclusion of a named compound.
The independent claim coverage is directed to formula-defined compound genera and one corresponding pharmaceutical composition, with a cap on dotted-line double bonds, broad but enumerated substituent and linker options, ring-forming rules for Ra and Rb, cycle-forming rules for X, Y, T, W and V, and explicit exclusions of a named compound.
Stated Advantages
Provides use as medicines.
Provides prevention/treatment of neurodegenerative disorders, including tauopathies and cytotoxic α-synuclein amyloidogenesis.
Provides prevention/treatment of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS).
Includes pharmaceutical compositions with pharmaceutically acceptable excipients and a therapeutically effective amount.
Inhibition of cytotoxicity.
An inhibitory effect on TAU-instigated cytotoxicity.
Inhibition of α-synuclein amyloidogenesis/α-synucleopathy as framed in connection with neurodegenerative disorders.
Documented Applications
Use as medicines.
Prevention/treatment of neurodegenerative disorders, including tauopathies and cytotoxic α-synuclein amyloidogenesis.
Prevention/treatment of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS).
Prevention and/or treatment of neurodegenerative disorders, including tauopathies and cytotoxic α-synuclein amyloidogenesis.
Prevention/treatment of neurodegenerative disorders including Alzheimer’s disease, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, Parkinson’s disease, parkinsonism (FTDP-17), diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, and multiple system atrophy.
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