3, 7-DIAMINO-10H-PHENOTHIAZINE SALTS AND THEIR USE

摘要

Described are methods of preparing reduced 3,7-diamino-10H-phenothiazine (DAPTZ) compounds of formula:;;wherein: R1 and R9 are independently selected from: —H; C1-4alkyl; C2-4alkenyl; and halogenated C1-4alkyl; each of R3NA and R3NB is independently selected from: —H; C1-4alkyl; C2-4alkenyl; and halogenated C1-4alkyl; each of R7NA and R7NB is independently selected from: —H; C1-4alkyl; C2-4alkenyl; and halogenated C1-4alkyl; each of HX1 and HX2 is independently a protic acid; and pharmaceutically acceptable salts, solvates, and hydrates thereof. These methods are particularly useful for producing stable reduced forms, and with high purity. The stability and purity are especially relevant for pharmaceutical compositions for the treatment of disease. The compounds are useful for treatment of e.g. tauopathies, such as Alzheimer's disease, and also as prodrugs for the corresponding oxidized thioninium drugs.

主权项

1. A method of preparing a 3,7-diamino-10H-phenothiazine (DAPTZ) compound of formula (1): wherein:
each of R1 and R9 is independently selected from: —H, C1-4alkyl, C2-4alkenyl, and halogenated C1-4alkyl;each of R3NA and R3NB is independently selected from: —H, C1-4alkyl, C2-4alkenyl, and halogenated C1-4alkyl;each of R7NA and R7NB is independently selected from: —H, C1-4alkyl, C2-4alkenyl, and halogenated C1-4alkyl; andeach of HX1 and HX2 is independently a protic acid; from a corresponding ring amine-protected compound of formula (2): wherein RProt is a protecting group; said method comprising:
ring amino deprotection (DP), wherein the protecting group RProt is removed from said corresponding ring amine-protected compound (2); andsalt formation (SF), wherein the resulting deprotected compound reacts with a protic acid to form a salt.