3,7-diamino-10H-phenothiazine salts and their use
View Patent ↗This invention pertains generally to the field of phenothiazine compounds, and more particularly to certain stably reduced phenothiazine compounds, specifically, certain 3,7 diamino-10H-phenothiazine (DAPTZ) compounds of the following formula wherein: each of R 1 and R 9 is independently selected from: —H; C 1-4 alkyl; C 2-4 alkenyl; and halogenated C 1-4 alkyl; each of R 3NA and R 3NB is independently selected from: —H; C 1-4 alkyl; C 2-4 alkenyl; and halogenated C 1-4 alkyl; each of R 7NA and R 7NB is independently selected from: —H; C 1-4 alkyl; C 2-4 alkenyl; and halogenated C 1-4 alkyl; each of HX 1 and HX 2 is independently a protic acid; and pharmaceutically acceptable salts, solvates, and hydrates thereof. These compounds are useful as drugs, for example, in the treatment of tauopathies, such as Alzheimer's disease, and also as prodrugs for the corresponding oxidized thioninium drugs (for example, methythioninium chloride, MTC).
1. A compound selected from compounds of the following formula and pharmaceutically acceptable salts thereof:
wherein:
each of R 1 and R 9 is independently selected from: —H, C 1-4 alkyl, C 2-4 -alkenyl, and halogenated C 1-4 alkyl;
each of R 3NA and R 3NB is independently selected from: —H, C 1-4 alkyl, C 2-4 alkenyl, and halogenated C 1-4 alkyl;
each of R 7NA and R 7NB is independently selected from: —H, C 1-4 alkyl, C 2-4 alkenyl, and halogenated C 1-4 alkyl;
each of HX 1 and HX 2 is independently a protic acid.
2. A compound according to claim 1 , wherein each of R 1 and R 9 is independently —H, -Me, -Et, or —CF 3 .
3. A compound according to claim 1 , wherein each of R 1 and R 9 is independently —H, -Me, or -Et.
4. A compound according to claim 1 , wherein R 1 and R 9 are the same.
5. A compound according to claim 1 , wherein each of R 1 and R 9 is independently —H.
6. A compound according to claim 1 , wherein each of R 3NA and R 3NB independently -Me, -Et, -nPr, -nBu, —CH 2 —CH═CH 2 , or —CF 3 .
7. A compound according to claim 1 , wherein R 3NA and R 3NB are the same.
8. A compound according to claim 1 , wherein each of R 7NA and R 7NB is independently -Me, -Et, -nPr, -nBu, —CH 2 —CH═CH 2 , or —CF 3 .
9. A compound according to claim 1 , wherein R 7NA and R 7NB are the same.
10. A compound according to claim 1 , with the proviso that: at least one of R 3NA and R 3NB and R 7NA and R 7NB is other than -Et.
11. A compound according to claim 1 , with the proviso that: if: each of R 1 and R 9 is —H;
then: R 3NA and R 3NB and R 7NA and R 7NB are not each -Et.
12. A compound according to claim 1 , wherein each of the groups —N(R 3NA )(R 3NB ) and —N(R 7NA )(R 7NB ) is independently selected from: —NMe 2 , —NEt 2 , —N(nPr) 2 , —N(Bu) 2 , —NMeEt, —NMe(nPr), and —N(CH 2 CH═CH 2 ) 2 .
13. A compound according to claim 1 , wherein the groups —N(R 3NA )(R 3NB ) and —N(R 7NA )(R 7NB ) are the same, and are selected from: —NMe 2 and —NEt 2 .
14. A compound according to claim 1 , wherein the groups —N(R 3NA )(R 3NB ) and —N(R 7NA )(R 7NB ) are the same.
15. A compound according to claim 1 , with the proviso that: each of the groups —N(R 3NA )(R 3NB ) and —N(R 7NA )(R 7NB ) is other than —NEt 2 .
16. A compound according to claim 1 , wherein the groups —N(R 3NA )(R 3NB ) and —N(R 7NA )(R 7NB ) are the same, and are selected from: —NMe 2 , —N(nPr) 2 , —N(Bu) 2 , —NMeEt, —NMe(nPr), and —N(CH 2 CH═CH 2 ) 2 .
17. A compound according to claim 1 , wherein each of the groups —N(R 3NA )(R 3NB ) and —N (R 7NA )(R 7NB ) is: —NMe 2 .
18. A compound according to claim 1 , wherein each of HX 1 and HX 2 is independently a monoprotic acid.
19. A compound according to claim 1 , wherein each of HX 1 and HX 2 is independently a hydrohalide acid.
20. A compound according to claim 1 , wherein each of HX 1 and HX 2 is independently selected from HCl, HBr, and Hl.
21. A compound according to claim 1 , wherein HX 1 and HX 2 are each HCl.
22. A compound according to claim 1 , wherein HX 1 and HX 2 are each HBr.
23. A compound according to claim 1 , selected from compounds of the following formula, and pharmaceutically acceptable salts thereof:
24. A compound according to claim 1 , selected from compounds of the following formula, and pharmaceutically acceptable salts thereof:
25. A compound according to claim 1 , in substantially purified form.
26. A compound according to claim 1 , wherein one or more of the carbon atoms of the compound is 11 C.
27. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier or diluent.
28. A method of preparing a pharmaceutical composition comprising admixing a compound according to claim 1 , and a pharmaceutically acceptable carrier or diluent.
29. A pharmaceutical composition comprising a compound of the following formula:
and a pharmaceutically acceptable carrier or diluent.
30. A pharmaceutical composition comprising a compound of the following formula:
and a pharmaceutically acceptable carrier or diluent.