Inhibitors of protein aggregation

A method of treatment of a synucleinopathy, which synucleinopathy results in a neurodegenerative disease state and/or clinical dementia,

• which method comprises orally administering to a subject a therapeutically effective amount of a diaminophenothiazine compound having the following formula:
• wherein each one of R1, R2, R4, R6, R8, and R9 is independently selected from:
• —H;
• —F;
• —Cl;
• —Br;
• —I;
• —OH;
• —OR;
• —SH;
• —SR;
• —NO2;
• —C(═O)R;
• —C(═O)OH;
• —C(═O)OR;
• —C(═O)NH2;
• —C(═O)NHR;
• —C(═O)NR2;
• —C(═O)NRN1RN2;
• —NH2;
• —NHR;
• —NR2;
• —NRN1RN2;
• —NHC(═O)H;
• —NRC(═O)H;
• —NHC(═O)R;
• —NRC(═O)R;
• and
• —R;
• wherein each R is independently selected from:
• unsubstituted aliphatic C1-6alkyl;
• substituted aliphatic C1-6alkyl;
• unsubstituted aliphatic C2-6alkenyl;
• substituted aliphatic C2-6alkenyl;
• unsubstituted C3-6cycloalkyl;
• substituted C3-6cycloalkyl;
• unsubstituted C6-10-carboaryl;
• substituted C6-10carboaryl;
• unsubstituted C5-10heteroaryl;
• substituted C5-10heteroaryl;
• and
• unsubstituted C6-10-carboaryl-C1-4alkyl;
• substituted C6-10-carboaryl-C1-4alkyl;
• wherein, in each group —NRN1RN2, independently, RN1 and RN2 taken together with the nitrogen atom to which they are attached form a ring having from 3 to 7 ring atoms;
• each one of R3NA and R3NB is independently selected from:
• —H;
• unsubstituted aliphatic C1-6alkyl;
• substituted aliphatic C1-6alkyl;
• unsubstituted aliphatic C2-6alkenyl;
• substituted aliphatic C2-6alkenyl;
• unsubstituted C3-6cycloalkyl;
• substituted C3-6cycloalkyl;
• unsubstituted C6-10-carboaryl;
• substituted C6-10-carboaryl;
• unsubstituted C5-10heteroaryl;
• substituted C5-10heteroaryl;
• and
• unsubstituted C6-10-carboaryl-C1-4alkyl;
• substituted C6-10-carboaryl-C1-4alkyl;
• or:
• R3NA and R3NB taken together with the nitrogen atom to which they are attached form a ring having from 3 to 7 ring atoms;
• and wherein the group —NR7NAR7NB is the same as the group —NR3NAR3NB:
• and wherein X is one or more anionic counter ions to achieve electrical neutrality;
• and pharmaceutically acceptable salts, mixed salts, and hydrates-thereof;
• wherein the therapeutically effective amount of a diaminophenothizine compound orally administered to the subject is selected from the group consisting of
• (i) a daily total dose of the diaminophenothizine compound orally administered to the subject of 200 mg-400 mg;
• (ii) a daily total dose of the diaminophenothizine compound orally administered to the subject of 100 mg-400 mg;
• (iii) in dosage units of about 10, 20, 30, 40, 50, 60, 80, 90, 100, 110, 120, or 130 mg three times a day;
• and
• (iv) in dosage units of about 10, 20, 30, 40, 50, 60, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg twice a day.