Napthoquinone derivatives as inhibitors of tau aggregation for the treatment of alzheimer's and related neurodegenerative disorders
View Patent ↗Provided are napthoquinone-type compounds which can be used to modulate the aggregation of protein (e.g. tau) associated with neurodegenerative disease (e.g. Alzheimer's disease). Structure-function characteristics for oxidised and reduced napthoquinone-type compounds, such as menadione-related compounds, are disclosed. The invention further provides methods of treatment or prophylaxis of neurodegenerative diseases and/or clinical dementias based on the compounds.
1. A method of treatment of a neurodegenerative disease or clinical dementia, either being associated with tau protein aggregation, which method comprises administering to a subject a therapeutically effective amount of a compound, wherein the compound is selected from
a compound of formula II:
wherein
R 1A is —OMe, —OC(═O)Me, —COOH, —COOMe, —SO 3 H, —SO 3 M, or —SO 3 Me;
R 2A is —H, unsubstituted C 1-7 alkyl, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, C 1-7 aminoalkyl, C 1-7 carboxyalkyl, —OH, C 1-7 alkoxy, acyloxy, —COOH, ester, —SO 3 H, —SO 3 M, sulfonate, C 1-7 alkylsulfonate, or a short chain alkyl group;
R 3 , R 4 , R 5 , and R 6 are independently —H, —OH, C 1-7 alkyl, C 1-7 alkoxy or acyloxy; and,
M denotes a cation or cations of charge or cumulative charge to counter the charge on the —SO 3 — group;
or
a compound of formula III:
or a compound of formula IV:
wherein for formula III or IV:
either
(A) R 1A is unsubstituted C 1-7 alkyl, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, C 1-7 aminoalkyl, C 1-7 carboxyalkyl, —OH, C 1-7 alkoxy, acyloxy, —COOH, ester, —SO 3 H, —SO 3 M, sulfonate, C 1-7 alkylsulfonate, or a short chain alkyl group; and
R 2A is —H, unsubstituted C 1-7 alkyl, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, C 1-7 aminoalkyl, C 1-7 carboxyalkyl, —OH, C 1-7 alkoxy, acyloxy, —COOH, ester, —SO 3 H, —SO 3 M, sulfonate, C 1-7 alkylsulfonate, or a short chain alkyl group;
or
(B) R 1A is —H, unsubstituted C 1-7 alkyl, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, C 1-7 aminoalkyl, C 1-7 carboxyalkyl, —OH, C 1-7 alkoxy, acyloxy, —COOH, ester, —SO 3 H, —SO 3 M, sulfonate, C 1-7 alkylsulfonate, or a short chain alkyl group; and
R 2A is unsubstituted C 1-7 alkyl, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, C 1-7 aminoalkyl, C 1-7 carboxyalkyl, —OH, C 1-7 alkoxy, acyloxy, —COOH, ester, —SO 3 H, —SO 3 M, sulfonate, C 1-7 alkylsulfonate, or a short chain alkyl group;
R 1B , if present, is —H, unsubstituted C 1-7 alkyl, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, C 1-7 aminoalkyl, C 1-7 carboxyalkyl, —OH, C 1-7 alkoxy, acyloxy, —COOH, ester, —SO 3 H, —SO 3 M, sulfonate, C 1-7 alkylsulfonate, or a short chain alkyl group;
R 2B , if present, is —H, unsubstituted C 1-7 alkyl, C 1-7 haloalkyl, C 1-7 hydroxyalkyl, C 1-7 aminoalkyl, C 1-7 carboxyalkyl, —OH, C 1-7 alkoxy, acyloxy, —COOH, ester, —SO 3 H, —SO 3 M, sulfonate, C 1-7 alkylsulfonate, or a short chain alkyl group;
R 3 , R 4 , R 5 , and R 6 is independently —H, —OH, C 1-7 alkyl, C 1-7 alkoxy, or acyloxy; and,
R 7 and R 8 is independently —H, C 1-7 alkyl, acyl, —SO 3 H, —SO 3 M, or sulfonate;
M denotes a cation or cations of charge or cumulative charge to counter the charge on the —SO 3 group;
and a pharmaceutically acceptable salt thereof, or a therapeutic composition comprising the same, such as to inhibit the aggregation of the protein associated with said disease or dementia.
2. A method as claimed in claim 1 wherein the compound is used in combination with another treatment for said disease or dementia.
3. A method as claimed in claim 1 wherein the disease is selected from the list consisting of Familial Multiple System Tauopathy, Corticobasal Degeneration, Familial Gerstmann-Straussler-Scheinker Disease, Motor Neurone Disease; Lewy body disease; Pick's disease; Progressive Supranuclear Palsy; Alzheimer's disease.
4. The method as claimed in claim 1 wherein the compound is one according to formula IV.
5. The method as claimed in claim 4 wherein each of R 7 and R 8 is independently —H, -Me, -Et, —C(═O)Me, —C(═O)Et, —SO 3 H, —SO 3 M, —SO 3 Me, or —SO 3 Et.
6. The method as claimed in claim 5 wherein each of R 7 and R 8 is independently —H, -Me, —C(═O)Me, —SO 3 H, —SO 3 M, or —SO 3 Me.
7. The method as claimed in claim 5 wherein each of R 7 and R 8 is —H.
8. The method as claimed in claim 1 wherein the compound has the formula II:
9. The method as claimed in claim 1 wherein the compound has the formula III:
10. A method as claimed in claim 9 wherein R 1B and R 2B are both —H:
11. The method as claimed in claim 9 wherein R 2A and R 2B are both —H:
12. The method as claimed in claim 1 wherein the short chain alkyl group in R 2A is one of the following groups, where n is 0, 1, or 2:
13. The method as claimed in claim 1 wherein for each of R 1A , R 2A , and R 1B and R 2B if present:
unsubstituted C 1-7 -alkyl is selected from -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu; and -tBu;
C 1-7 -alkoxy is selected from —OMe, —OEt, —O(nPr), —O(iPr), —O(nBu), —O(sBu), —O(iBu), and —O(tBu);
acyloxy is selected from —OC(═O)Me, —OC(═O)Et, —OC(═O)(nPr), —OC(═O)(iPr), —OC(═O)(nBu), —OC(═O)(sBu), —OC(═O)(iBu), and —O(C═O)(tBu);
ester is selected from —C(═O)OMe, —C(═O)OEt, —C═O)O(nPr), —C(═O)O(iPr), —C(═O)O(nBu), —C(═O)O(sBu), —C(═O)O(iBu), and —C(═O)O(tBu);
C 1-7 alkylsulfonate is selected from —SO 3 Me, —SO 3 Et, —SO 3 (nPr), —SO 3 (iPr), —SO 3 (nBu), —SO 3 (sBu), —SO 3 (iBu), and —SO 3 (tBu),
short chain alkyl group is CH 2 CH═C(CH 3 ) 2 , and
wherein if the compound is a compound of formula II, then: R 1A is: —OMe, —OC(═O)Me, —COOMe, —SO 3 H, —SO 3 M, or —SO 3 Me.
14. The method as claimed in claim 13
wherein for each of R 1A , R 2A , and R 1B and R 2B if present,
unsubstituted C 1-7 -alkyl is selected from -Me and -Et,
C 1-7 -alkoxy is selected from —OMe and —OEt, acyloxy is selected from —OC(═O)Me and —OC(═O)Et,
C 1-7 alkylsulfonate is selected from —SO 3 Me or —SO 3 Et,
short chain alkyl group is CH 2 CH═C(CH 3 ) 2 ,
wherein, if the compound is a compound of formula II, then: R 1A is: —OMe, —OC(═O)Me, —COOMe, —SO 3 H, —SO 3 M, or —SO 3 Me.
15. A method as claimed in claim 14 wherein each of R 1A , R 2A , and R 1B and R 2B if present,
unsubstituted C 1-7 -alkyl -Me,
C 1-7 -alkoxy —OMe,
acyloxy is —OC(═O)Me, and
C 1-7 alkylsulfonate is —SO 3 Me,
short chain alkyl group is CH 2 CH═C(CH 3 ) 2 ,
wherein, if the compound is a compound of formula II, then: R 1A is: —OMe, —OC(═O)Me, —COOMe, —SO 3 H, —SO M, or —SO 3 Me.
16. A method as claimed in claim 1 wherein each of R 3 , R 4 , R 5 , and R 6 is independently: —H, —OH, -Me, -Et, —OMe, —OEt, —OC(═O)Me, or —OC(═O)Et.
17. A method as claimed in claim 1 wherein each of R 3 , R 4 , R 5 , and R 6 is independently: —H, —OH, -Me, —OMe, or —OC(═O)Me.
18. A method as claimed in claim 17 wherein each of R 3 , R 4 , R 5 , and R 6 is independently: —H or —OH.
19. A method as claimed in claim 18 wherein each of R 4 , R 5 , and R 6 is —H.
20. A method as claimed in claim 1 wherein R 3 is —H.
21. A method as claimed in claim 1 wherein R 3 is —OH.
22. A method as claimed in claim 8 wherein R 1A is —SO 3 H or —SO 3 M, and each of R 2A , R 3 , R 4 , R 5 , and R 6 is —H.
23. A method as claimed in claim 8 wherein R 1A is —OMe, and each of R 2A , R 3 , R 4 , R 5 , and R 6 is —H.
24. A method as claimed in claim 8 wherein R 1A is —COOH; each R 2A , R 3 , R 4 , R 5 , R 6 is —H; and R 7 R 8 are —OH.
25. A method as claimed in claim 8 , wherein R 1a is methyl; each of R 2A , R 3 , R 4 , R 5 , R 6 is —H; and R 7 and R 8 are —C(═O)Me.
26. A method as claimed in claim 8 , wherein R 1A is methyl; each of R 2A , R 3 , R 4 , R 4 , R 5 , R 6 , is —H; and R 7 and R 8 are both either —SO 3 H or —SO 3 M.
27. A method as claimed in claim 8 , wherein R 1A and R 2A are methyl; each of R 3 , R 4 , R 5 , R 6 is —H; and R 7 and R 8 are —C(═O)Me.
28. A method as claimed in claim 1 wherein M is selected from the group consisting of: Na + and K + .
29. The method of claim 1 , wherein the compound is selected from the following compounds and pharmaceutically acceptable salts thereof: