Selective ligands for tau aggregates
The invention provides compounds of formula (I) and compositions comprising compounds of formula (I). The invention further provides uses of the compounds of formula (I) and compositions comprising compounds of formula (I), including the use of such compounds for the detection of tau deposits, and the use of such compounds and compositions as diagnostic agents in the diagnosis or monitoring of the progression of a disease or disorder such as Alzheimer's disease or corticobasal degeneration, or for the prevention or treatment of a disease or disorder such as Alzheimer's disease or corticobasal degeneration.
1. A compound of formula (I) or a pharmaceutically acceptable salt, ester, amide or carbamate thereof, or a salt of such an ester, amide or carbamate,
wherein
W is S, O or Se;
X is N or N + —R 2 ;
Y is S or O;
Z is CH or N;
or Y is Se and Z is CH;
B is selected from the group consisting of:
each R 1 is independently selected from the group consisting of —O—C 1-6 alkyl, —O—monohaloC 1-6 alkyl, —O-dihaloC 1-6 alkyl, —O-trihaloC 1-6 alkyl, C 1-6 alkyl, monohaloC 1-6 alkyl, dihaloC 1-6 alkyl, trihaloC 1-6 alkyl, OH, F, Br, I, and CN;
R 2 is selected from the group consisting of C 1-6 alkyl, monohaloC 1-6 alkyl, dihaloC 1-6 alkyl, trihaloC 1-6 alkyl, and C(O)C 1-6 alkyl;
each R 3 is independently selected from the group consisting of —O—C 1-6 alkyl, —O-monohaloC 1-6 alkyl, —O-dihaloC 1-6 alkyl, —O-trihaloC 1-6 alkyl, —(CH 2 ) p —O—C 1-6 alkyl, —(CH 2 ) q —C(O)—C 1-6 alkyl, —(CH 2 ) r —C(O)—O—C 1-6 alkyl, —(CH 2 ) s —N(R 5 ) 2 , OH, F, Cl, Br, I, —CN, —C 1-6 alkyl, monohaloC 1-6 alkyl, dihaloC 1-6 alkyl, and trihaloC 1-6 alkyl;
R 4A and R 4B are independently selected from the group consisting of H, OH, F, Cl, Br, I, C 1-6 alkyl, monohaloC 1-6 alkyl, dihaloC 1-6 alkyl, trihaloC 1-6 alkyl, O—C 1-6 alkyl, —O-monohaloC 1-6 alkyl, —O-dihaloC 1-6 alkyl, and —O-trihaloC 1-6 alkyl;
each R 5 is independently selected from the group consisting of H and C 1-6 alkyl;
m is 0, 1, 2 or 3;n is 0, 1, 2 or 3;
p is 1, 2 or 3; q is 0, 1, or 2; r is 0, 1, or 2; and s is 0, 1, 2, or 3.
2. The compound of claim 1 , wherein the compound of formula (I) comprises one or more radioisotopes selected from the group consisting of tritium ( 3 H), carbon-11 ( 11 C), nitrogen-13 ( 13 N), oxygen-15 ( 15 O), fluorine-18 ( 18 F), iodine-120 120 (I), iodine-123 ( 123 I) and iodine-125 ( 125 I).
3. The compound as claimed in claim 1 , wherein Y is S and Z is CH or N; or Y is Se and Z is CH.
4. The compound as claimed in claim 1 , wherein R 4A and R 4B are H;
or wherein the compound of formula (I) is the compound of formula (Ib),
wherein R 4A is selected from the group consisting of H, OH, F, Cl, Br, I, C 1-6 alkyl, monohaloC 1-6 alkyl, dihaloC 1-6 alkyl, trihaloC 1-6 alkyl, O—C 1-6 alkyl, —O-monohaloC 1-6 alkyl, —O-dihaloC 1-6 alkyl, and —O-trihaloC 1-6 alkyl; or
wherein the compound of formula (I) is the compound of formula (Ic),
wherein R 4B is selected from the group consisting of H, OH, F, Cl, Br, I, C 1-6 alkyl, monohaloC 1-6 alkyl, dihaloC 1-6 alkyl, trihaloC 1-6 alkyl, O—C 1-6 alkyl, —O-monohaloC 1-6 alkyl, —O-dihaloC 1-6 alkyl, and —O-trihaloC 1-6 alkyl.
5. The compound as claimed in claim 1 , wherein W is S or O.
6. The compound as claimed in claim 1 , wherein X is N + —R 2 .
7. The compound as claimed in claim 1 , wherein m is 0 or 1.
8. The compound as claimed in claim 1 , wherein each R 3 is independently selected from the group consisting of O—C 1-4 alkyl, —O-monofluoroC 1-4 alkyl, —O-difluoroC 1-4 alkyl, —O-trifluoroC 1-4 alkyl, —(CH 2 ) p —O—C 1-4 alkyl, —(CH 2 ) q —C(O)—C 1-4 alkyl, —(CH 2 ) r —C(O)—O—C 1-4 alkyl, —N(R 5 ) 2 , F, Cl, Br, I, and —CN; p is 1; q is 0 or 1; r is 0 or 1; and each R 5 is independently selected from the group consisting of H and C 1-4 alkyl.
9. The compound as claimed in claim 1 , wherein the compound is selected from the group consisting of:
and where appropriate with a suitable counter-ion;
or a pharmaceutically acceptable salt, ester, amide or carbamate thereof, or a salt of such an ester, amide or carbamate; and
wherein the compound of may optionally comprise one or more radioisotopes selected from tritium ( 3 H), carbon-11 ( 11 C) nitrogen-13 ( 13 N), oxygen-15 ( 15 O), fluorine-18 ( 18 F), iodine-120 ( 120 I) iodine-123 ( 123 I) and iodine-125 ( 125 I).
10. A pharmaceutical or diagnostic composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide or carbamate thereof, or a salt of such an ester, amide or carbamate,
wherein
W is S, O or Se;
X is N or N + —R 2 ;
Y is S or O;
Z is CH or N;
or Y is Se and Z is CH;
B is selected from the group consisting of:
each R 1 is independently selected from the group consisting of —O—C 1-6 alkyl, —O-monohaloC 1-6 alkyl, —O-trihaloC 1-6 alkyl, C 1-6 alkyl, monohaloC 1-6 alkyl, dihaloC 1-6 alkyl, trihaloC 1-6 alkyl, OH, F, Br, I, and CN;
R 2 is selected from the group consisting of C 1-6 alkyl, monohaloC 1-6 alkyl, dihaloC 1-6 alkyl, trihaloC 1-6 alkyl, and C(O)C 1-6 alkyl;
each R 3 is independently selected from the group consisting of —O—C 1-6 alkyl, —O-monohaloC 1-6 alkyl, —O-trihaloC 1-6 alkyl, —(CH 2 ) p —O—C 1-6 alkyl, —(CH 2 ) q —C(O)—C 1-6 alkyl, —(CH 2 ) r —C(O)—O—C 1-6 alkyl, —(CH 2 ) s —N(R 5 ) 2 , OH, F, Cl, Br, I, —CN, —C 1-6 alkyl, monohaloC 1-6 alkyl, dihaloC 1-6 alkyl, and trihaloC 1-6 alkyl;
R 4A and R 4B are independently selected from the group consisting of H, OH, F, Cl, Br, I, C 1-6 alkyl, monohaloC 1-6 alkyl, dihaloC 1-6 alkyl, trihaloC 1-6 alkyl, O—C 1-6 alkyl, —O-monohaloC 1-6 alkyl, —O-dihaloC 1-6 alkyl, and —O-trihaloC 1-6 alkyl;
each R 5 is independently selected from the group consisting of H and C 1-6 alkyl;
m is 0, 1, 2 or 3; n is 0, 1, 2 or 3;
p is 1, 2 or 3, q is 0, 1, or 2; r is 0, 1, or 2; and s is 0, 1, 2 or 3;
together with a pharmaceutically suitable carrier.
11. A method for detecting tau deposits comprising using a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide or carbamate thereof, or a salt of such an ester, amide or carbamate,
wherein:
W is S, O or Se;
X is N or N + —R 2 ;
Y is S or O;
Z is CH or N;
or Y is Se and Z is CH;
B is selected from the group consisting of:
each R 1 is independently selected from the group consisting of —O—C 1-6 alkyl, —O-monohaloC 1-6 alkyl, —O-trihaloC 1-6 alkyl, C 1-6 alkyl, monohaloC 1-6 alkyl, dihaloC 1-6 alkyl, trihaloC 1-6 alkyl, OH, F, Cl, Br, I, and CN;
R 2 is selected from the group consisting of C 1-6 alkyl, monohaloC 1-6 alkyl, dihaloC 1-6 alkyl, trihaloC 1-6 alkyl, and C(O)C 1-6 alkyl;
each R 3 is independently selected from the group consisting of —O—C 1-6 alkyl, —O-monohaloC 1-6 alkyl, —O-trihaloC 1-6 alkyl, —(CH 2 ) p —O—C 1-6 alkyl, —(CH 2 ) q —C(O)—C 1-6 alkyl, —(CH 2 ) r —C(O)—O—C 1-6 alkyl, —(CH 2 ) s —N(R 5 ) 2 , OH, F, Cl, Br, I, —CN, —C 1-6 alkyl, monohaloC 1-6 alkyl, dihaloC 1-6 alkyl, and trihaloC 1-6 alkyl;
R 4A and R 4B are independently selected from the group consisting of H, OH, F, Cl, Br, I, C 1-6 alkyl, monohaloC 1-6 alkyl, dihaloC 1-6 alkyl, trihaloC 1-6 alkyl, O—C 1-6 alkyl, —O-monohaloC 1-6 alkyl, —O-dihaloC 1-6 alkyl, and —O-trihaloC 1-6 alkyl;
each R 5 is independently selected from the group consisting of H and C 1-6 alkyl;
m is 0, 1, 2 or 3; n is 0, 1, 2 or 3;
p is 1, 2 or 3; q is 0, 1, or 2; r is 0, 1, or 2; and s is 0, 1, 2 or 3.
12. A method of treatment or monitoring the progression of a tauopathy in a subject, wherein the method comprises administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt, ester, amide or carbamate thereof, or a salt of such an ester, amide or carbamate,
wherein
W is S, O or Se;
X is N or N + —R 2 ;
Y is S or O;
Z is CH or N;
or Y is Se and Z is CH;
B is selected from the group consisting of:
each R 1 is independently selected from the group consisting of —O—C 1-6 alkyl, —O-monohaloC 1-6 alkyl, —O-trihaloC 1-6 alkyl, C 1-6 alkyl, monohaloC 1-6 alkyl, dihaloC 1-6 alkyl, trihaloC 1-6 alkyl, OH, F, Cl, Br, I, and CN;
R 2 is selected from the group consisting of C 1-6 alkyl, monohaloC 1-6 alkyl, dihaloC 1-6 alkyl, trihaloC 1-6 alkyl, and C(O)C 1-6 alkyl;
each R 3 is independently selected from the group consisting of —O—C 1-6 alkyl, —O-monohaloC 1-6 alkyl, —O-trihaloC 1-6 alkyl, —(CH 2 ) p —O—C 1-6 alkyl, —(CH 2 ) q —C(O)—C 1-6 alkyl, —(CH 2 ) r —C(O)—O—C 1-6 alkyl, —(CH 2 ) s —N(R 5 ) 2 , OH, F, Cl, Br, I, —CN, —C 1-6 alkyl, monohaloC 1-6 alkyl, dihaloC 1-6 alkyl, and trihaloC 1-6 alkyl;
R 4A and R 4B are independently selected from the group consisting of H, OH, F, Cl, Br, I, C 1-6 alkyl, monohaloC 1-6 alkyl, dihaloC 1-6 alkyl, trihaloC 1-6 alkyl, O—C 1-6 alkyl, —O-monohaloC 1-6 alkyl, —O-dihaloC 1-6 alkyl, and —O-trihaloC 1-6 alkyl;
each R 5 is independently selected from the group consisting of H and C 1-6 alkyl;
m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; and
p is 1, 2 or 3; q is 0, 1, or 2; r is 0, 1, or 2; and s is 0, 1, 2 or 3;
wherein the tauopathy is selected from the group consisting of: Alzheimer's disease, corticobasal degeneration, Pick's disease, progressive supranuclear palsy, Parkinson's disease, argyrophilic grain disease, frontotemporal dementia and Parkinsonism linked to chromosome 17, Guadeloupean parkinsonism, globular glial tauopathies, ageing-related tau astrogliopathy, Parkinsonism-dementia complex of Guam, myotonic dystrophy, Down's syndrome, British dementia, familial Danish dementia, Lewy body disorders, and Prion disease.