US 10,117,850 B2 · Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases

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.

A method for the treatment of a neurodegenerative disorder in a subject, the method comprising administering to the subject an effective amount of a compound of formula (AA1) or a stereoisomer, enantiomer or tautomer thereof;

or of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of the compound of formula (AA1)
wherein,
a maximum of two dotted lines selected from the five dotted lines are a double bond;
E1 is independently selected from CR1;
and N;
E2 is independently selected from NR2;
and O;
E3 is independently selected from CR3;
and N;
Q is independently selected from NRb—C(O);
and C(O)NH;
Ra is hydrogen or taken together with Rb to form a substituted or unsubstituted 4, 5, 6, 7 or 8 membered ring containing one N atom;
Rb is hydrogen or taken together with Ra to form a substituted or unsubstituted 4, 5, 6, 7 or 8 membered ring containing one N atom;
each of R1, R3, R4, and R6 is independently selected from the group consisting of hydrogen;
halogen;
—OH;
—OR10;
—SH;
—SR10;
—S(O)R11;
—S(O)2R11;
—SO2NR12R13;
trifluoromethyl;
trifluoromethoxy;
nitro;
—NHC(O)R10;
—NHS(O)2R10;
—NHC(O)NR12R13;
—NR10C(O)R10;
—NR10S(O)2R10;
—NR10C(O)NR12R13;
—NR12R13;
-cyano;
—COOH;
—COOR10;
—C(O)NR12R13;
—C(O)R11;
alkyl;
alkenyl;
alkynyl;
aryl;
heterocycle;
arylalkylene;
arylalkenylene;
arylalkynylene;
heterocycle-alkylene;
heterocycle-alkenylene;
and heterocycle-alkynylene;
wherein the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, optionally includes one or more heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, the heteroatoms being selected from the group consisting of O, S and N;
wherein the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene can be unsubstituted or substituted with Z;
and
wherein a carbon atom or heteroatom of the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
R2 is selected from the group consisting of hydrogen;
alkyl;
alkenyl;
and alkynyl;
n is selected the group consisting of 0, 1, and 2;
B is cyclic structure selected from the group consisting of cycloalkyl;
cycloalkenyl;
cycloalkynyl;
aryl;
and heterocycle;
m is selected from the group consisting of 0;
1;
2;
3;
4 and 5;
R8 is independently selected from the group consisting of hydrogen;
halogen;
alkyl;
alkenyl;
alkynyl;
—OH;
—OR10;
—SH;
—SR10;
—S(O)R11;
—S(O)2R11;
—SO2NR12R13;
trifluoromethyl;
trifluoromethoxy;
nitro;
—NHC(O)R10;
—NHS(O)2R10;
—NHC(O)NR12R13;
—NR10C(O)R10;
—NR10S(O)2R10;
—NR10C(O)NR12R13;
—NR12R13;
-cyano;
—COOH;
—COOR10;
—C(O)NR12R13;
and —C(O)R11;
wherein the alkyl, alkenyl and alkynyl optionally includes one or more heteroatoms, the heteroatoms being selected from the group consisting of O, S and N;
wherein the alkyl, alkenyl and alkynyl can be unsubstituted or substituted with Z;
and
wherein a carbon atom or heteroatom of the alkyl, alkenyl and alkynyl, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
each R10 is independently selected from the group consisting of alkyl;
alkenyl;
alkynyl;
aryl;
heterocycle;
arylalkylene;
arylalkenylene;
arylalkynylene;
heterocycle-alkylene;
heterocycle-alkenylene and heterocycle-alkynylene;
wherein the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene optionally include one or more heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, the heteroatom selected from O, S and N;
and
wherein a carbon atom or heteroatom of the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
each R11 is independently selected from the group consisting of hydroxyl;
alkyl;
alkenyl;
alkynyl;
aryl;
heterocycle;
arylalkylene;
arylalkenylene;
arylalkynylene;
heterocycle-alkylene;
heterocycle-alkenylene and heterocycle-alkynylene;
wherein the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene optionally include one or more heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, the heteroatom selected from the group consisting of O, S and N;
and
wherein a carbon atom or heteroatom of the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
each R12 and R13 is independently selected from the group consisting of hydrogen;
alkyl;
alkenyl;
alkynyl;
aryl;
heterocycle;
arylalkylene;
arylalkenylene;
arylalkynylene;
heterocycle-alkylene;
heterocycle-alkenylene and heterocycle-alkynylene;
wherein the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene optionally include one or more heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, the heteroatom selected from the group consisting of O, S and N;
and
wherein a carbon atom or heteroatom of the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
or wherein R12 and R13 are taken together to form a 5-, 6-, or 7-membered unsubstituted or substituted heterocycle;
wherein L is:
(a) independently selected from the group consisting of —O—;
—NH—;
—NR10—;
C1-6alkylene;
C1-6alkenylene;
and C1-6alkynylene;
wherein a carbon atom or heteroatom of the C1-6alkylene, C1-6alkenylene or C1-6alkynylene, can be oxidized to form a C═S, N═O, N═S, S═O or S(O)2;
and wherein each of the C1-6alkylene, C1-6alkenylene or C1-6alkynylene optionally includes one or more heteroatoms, the heteroatoms being selected from the group consisting of S and N, and wherein each of the C1-6alkylene, C1-6alkenylene or C1-6alkynylene, can be unsubstituted or substituted;
R5 is selected from the group consisting of halogen;
—OH;
—OR10;
—SH;
—SR10;
—S(O)R11;
—S(O)2R11;
—SO2NR12R13;
trifluoromethyl;
trifluoromethoxy;
nitro;
—NHC(O)R10;
NHS(O)2R10;
—NHC(O)NR12R13;
—NR10C(O)R10;
—NR10S(O)2R10;
—NR10C(O)NR12R13;
—NR12R13;
-cyano;
—COOH;
—COOR10, —C(O)NR12R13;
—C(O)R11;
alkyl;
alkenyl;
alkynyl;
aryl;
heterocycle;
arylalkylene;
arylalkenylene;
arylalkynylene;
heterocycle-alkylene;
heterocycle-alkenylene;
and heterocycle-alkynylene;
wherein the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, optionally includes one or more heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, the heteroatoms being selected from the atoms O, S and N;
wherein the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene can be unsubstituted or substituted with Z;
and
wherein a carbon atom or heteroatom of the alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
and
each of X, Y, T, W and V form with the dotted lines one of the cycles having one of the structural formula (Ia), (IIa), (IIIa), (IVa), (Va), (VIIa), (VIIIa), (IXa), (Xa), (XIa), (XIIIa), (XIVa), (XVa), (XVIIa), (XVIIIa), (XIXa), (XXIa), (XXIIa), (XXIIIa) or (XXIVa),
or (b) a single bond;
and X, Y, T, W and V form with the dotted lines a cycle of formula (IIIa),
R5 is selected from the group consisting of halogen;
—OH;
—OR10;
—SH;
—SR10;
—S(O)R11;
—S(O)2R11;
—SO2NR12R13;
trifluoromethyl;
trifluoromethoxy;
nitro;
—NHC(O)R10;
—NHS(O)2R10;
—NHC(O)NR12R13;
—NR10C(O)R10;
—NR10S(O)2R10;
—NR10C(O)NR12R13;
—NR12R13;
-cyano;
—COOH;
—COOR10;
—C(O)NR12R13;
—C(O)R11;
alkenyl;
alkynyl;
aryl;
heterocycle;
arylalkylene;
arylalkenylene;
arylalkynylene;
heterocycle-alkylene;
heterocycle-alkenylene;
and heterocycle-alkynylene;
wherein the alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, optionally includes one or more heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, the heteroatoms being selected from the group consisting of O, S and N;
wherein the alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene can be unsubstituted or substituted with Z;
wherein a carbon atom or heteroatom of the alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)2;
wherein the left side of the formula (Ia), (IIa), (IIIa), (IVa), (Va), (VIIa), (VIIIa), (IXa), (Xa), (XIa), (XIIIa), (XIVa), (XVa), (XVIIa), (XVIIIa), (XIXa), (XXIa), (XXIIa), (XXIIIa), (XXIVa) is attached to Q and the right side thereof is attached to L;
wherein when X, Y, T, W, and V form with the dotted lines a cycle of formula (Ia), and E2 is NH, n is 1, E1 and E3 are CH and Ra, R4, and R6 are H, then Q is not —NH—CO— wherein the right side of —NH—CO— is attached to the cycle of formula (Ia);
each Z1 is independently selected from the group consisting of hydrogen;
alkyl;
and Z;
each Z is independently selected from the group consisting of halogen;
—OH;
—OR10;
—SH;
—SR10;
—S(O)R11;
—S(O)2R11;
—SO2NR12R13;
trifluoromethyl;
trifluoromethoxy;
nitro;
—NHC(O)R10;
—NHS(O)2R10;
—NHC(O)NR12R13;
—NR10C(O)R10;
—NR10S(O)2R10;
—NR10C(O)NR12R13;
—NR12R13;
-cyano;
—COOH;
—COOR10;
—C(O)NR12R13;
and —C(O)R11;
and
each R101 is independently selected from the group consisting of hydrogen and R11;
or a solvate, hydrate, salt or prodrug thereof;
and
wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, parkinsonism (linked to chromosome 17, FTDP-17), Parkinson's disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, and multiple system atrophy, with the proviso that said compound is not:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(4-ethylphenyl)-2-oxopyrrolidine-3-carboxamide.

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Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases

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Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases

Life of this patent

Abstract

Claims19