Compounds for the treatment of neurodegenerative diseases
Inventors
Griffioen, Gerard • VAN DOOREN, Tom • Rojas De La Parra, Verónica • Allasia, Sara • Marchand, Arnaud • Kilonda, Amuri • Chaltin, Patrick
Assignees
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Publication Number
US-9266832-B2
Publication Date
2016-02-23
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 characterised 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. The compounds have the formula (A1) wherein R1, R2, R4, R6, E, n, Y1, Y2, Y3, Y4, Y5, L, B, R8, and m are as defined in the claims.
Core Innovation
The invention provides compounds of formula (A1) and stereoisomers, enantiomers, tautomers, solvates, hydrates, salts, or prodrugs thereof. The compounds are defined by selections of structural variables including E, n, Y1–Y5, L, B, m, and multiple substituent sets, with permitted functional groups such as halogen, hydroxyl, alkoxy, thioether or thio groups, trifluoromethyl, trifluoromethoxy, nitro, cyano, carboxylic acid, carboxylates, esters, and various amide and sulfonyl-related groups, together with specified oxidation states for carbon or heteroatom centers.
The structural definition includes broad linker and ring options, with L selected from C1-6 alkylene, —O—, —NH—, —NR10—, C2-6 alkenylene, and C2-6 alkynylene, and B selected from aryl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocycle. The Y positions and Z, Z1, and Z2 positions are broadly variable, and R12 and R13 or R22 and R23 may be taken together to form a 4-, 5-, 6-, or 7-membered heterocycle or a non-aromatic heterocycle, as specified.
The invention addresses neurodegenerative disorders, including tauopathies associated with TAU protein dysfunction and tau aggregates, and α-synucleinopathies associated with α-synuclein polymer deposition. The document states a neuroprotective intent and describes that the disclosed compounds inhibit TAU-instigated cytotoxicity and are non-toxic to neural cells, and that the pharmaceutical embodiments are used as a medicine for prevention and treatment of the listed neurodegenerative disorders.
The document also describes a synthetic strategy for generating the compounds using intermediates of formulas I and II/IV/V/VI and a depicted intermediate VI, together with exemplar compounds Cpd001–Cpd024 shown structurally. The scheme describes condensation/coupling and optional functional group transformations to arrive at the compounds defined by formula (A1).
Claims Coverage
The consolidated independent claim coverage centers on clm-00001, a compound of formula (A1) or a stereoisomer, enantiomer, tautomer, solvate, hydrate, salt, or prodrug thereof. The claim defines broad structural-variable selections and oxidation-state rules, and dependent claims add pharmaceutical composition coverage, treatment of neurodegenerative disorders, and preparation-related claims.
Formula (A1) compound genus with stereoisomer, enantiomer, tautomer, solvate, hydrate, salt, and prodrug scope
A compound of formula (A1) or a stereoisomer, enantiomer, tautomer, solvate, hydrate, salt, or prodrug thereof, with E selected from CR3 and N, and the variables R1, R2, R3, R4, R5, R6, R8, Y1–Y5, L, B, m, n, Z, Z1, Z2, R10, R11, R12, R13, R20, R21, R22, and R23 defined by extensive structural selections.
Controlled heteroatom inclusion and oxidation-state constraints
Alkyl(ene), alkenyl(ene), and alkynyl(ene) and related aryl/heterocycle-derived moieties include no heteroatom or one or more heteroatoms selected from O, S and N, are unsubstituted or substituted with one or more Z, and carbon atoms or heteroatoms are unoxidized or oxidized to form C=O, C=S, N=O, N=S, S=O, or S(O)2 forms.
Linker and ring constraints using Y1–Y5, L, and B
n is selected from 1, 0, and 2, at least two of Y1, Y2, Y3, Y4 and Y5 are selected from CZ1, L is independently selected from C1-6 alkylene, —O—, —NH—, —NR10—, C2-6 alkenylene, and C2-6 alkynylene, and B represents a cyclic structure selected from aryl, cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocycle.
Heterocycle formation and explicit exclusions
R12 and R13 are not directly connected or are taken together to form a 4-, 5-, 6-, or 7-membered heterocycle, and R22 and R23 are not directly connected or are taken together to form a 4-, 5-, 6-, or 7-membered non-aromatic heterocycle; the claim excludes specified named compounds.
Pharmaceutical composition with excipients and therapeutically effective amount
A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of the compound defined in the earlier claims.
Method of treating neurodegenerative disorders by administration
A method of treating a neurodegenerative disorder in a subject by administering a compound or a pharmaceutical composition, where the treatment covers tauopathies and α-synucleinopathies and lists specific disorders including Alzheimer’s disease, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, parkinsonism, FTDP-17, Parkinson’s disease, diffuse Lewy body disease, and additional listed neurodegenerative conditions.
Preparation of compounds via reacting indolyl alkanamines with functionalized six-membered ring derivatives
A method of preparing the compounds described in the earlier claims by reacting substituted or unsubstituted (1H-indol-3-yl)alkanamines with a substituted or unsubstituted six-membered ring derivative having either an acid halide function or a carboxylic acid function, using a strong base or a peptide bond formation coupling agent in polar aprotic solvents, to obtain compounds including isomers, solvates, hydrates, salts, and prodrugs.
Leaving-group functionalization on a six-membered ring with nucleophile/catalyst step
A further method step in which a compound with a six-membered ring bearing a —CH2LG group is reacted with nucleophiles under strong base conditions or via derivatives using palladium or copper catalysts.
Derivative classes for the catalyst-mediated step
In the method step involving derivatives, the derivatives are chosen from boronic acid, stannane, and organozinc derivatives.
The claim set centers on compounds of formula (A1) with broadly defined variable substitution and oxidation-state constraints, supported by pharmaceutical composition coverage and methods of treating neurodegenerative disorders by administration. Additional dependent claims further cover preparation approaches that involve reacting indolyl alkanamines with functionalized six-membered ring derivatives, including a leaving-group —CH2LG related nucleophile step with optional palladium/copper catalyst involvement and specified derivative classes.
Stated Advantages
Solving problems related to drug properties such as physicochemical/ADME-Tox.
Efficient inhibition of tau aggregation–induced toxicity.
TAU-instigated cytotoxicity inhibitory biological properties.
Inhibits TAU-instigated cytotoxicity.
Non-toxic to neural cells.
Used for prevention and treatment of neurodegenerative disorders including tauopathies and α-synucleinopathies.
Improved lifespan/memory in TAU R406W transgenic mice.
Reduction of TAU phosphorylation.
Reduction of pathological aggregates.
Inhibition of α-synuclein aggregation in vitro.
Improved cytotoxicity readouts based on LDH release in engineered cell line evaluations.
Usable as a medicine, medicament, and for manufacture/administration contexts for prevention and treatment.
Documented Applications
Preventing or treating neurodegenerative disorders, including tauopathies and α-synucleinopathy.
As a medicine for prevention and treatment of neurodegenerative disorders, including tauopathies associated with TAU protein dysfunction/tau aggregates and α-synucleinopathies associated with α-synuclein polymer deposition.
Treatment in a subject of Alzheimer’s disease, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, parkinsonism including FTDP-17, Parkinson’s disease, diffuse Lewy body disease, and additional listed neurodegenerative conditions.
Manufacture of medicaments using the disclosed compounds and pharmaceutical compositions.
Biological evaluation in engineered neuroblastoma cell lines overexpressing TAU-P301L or α-synuclein WT, including LDH release cytotoxicity readouts.
In vivo testing in TAU R406W transgenic mice, assessing TAU phosphorylation reduction, improved lifespan/memory, and reduced pathological aggregates.
α-synuclein/PD-style modeling using paraquat and 6-hydroxydopamine paradigms, together with related assays.
In vitro α-synuclein aggregation inhibition assessment.
Exemplar chemical applications shown in Scheme 1 and described with example compounds Cpd001–Cpd024 and intermediate VI as part of the disclosed synthetic strategy.
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