Therapeutic use of diaminophenothiazines

Abstract

Described are methods and materials for use in the treatment or prophylaxis of diseases, for example cognitive disorders, using diaminophenothiazines. In particular it relates to treatments having optimised pharmacokinetic properties, and dosage forms are intended to improve the relative cognitive or CNS benefits of the diaminophenothiazines, for instance compared to haematological effects.

1 . A method of treatment or prophylaxis of a cognitive or CNS disorder in a patient, wherein said disorder is one which is susceptible to treatment by a 3,7-diaminophenothiazine (DAPTZ) compound,
 which method comprises orally administering to said patient a dosage unit containing said DAPTZ compound in oxidised form as active ingredient,   wherein said dosage unit releases at least 50% of said active ingredient within 30 minutes under standard US/EU Pharmacopoeia dissolution conditions.   
     
     
         2 . A method as claimed in  claim 1  wherein the dosage unit comprises less than 70 mg. 
     
     
         3 . A method as claimed in  claim 1  wherein the cognitive or CNS disorder is a tauopathy. 
     
     
         4 . A method as claimed in  claim 1  wherein the cognitive or CNS disorder is selected from Alzheimer's disease, Pick's disease, Progressive Supranuclear Palsy (PSP), fronto-temporal dementia, parkinsonism linked to chromosome 17, disinhibition-dementia-parkinsonism-amyotrophy complex, pallido-ponto-nigral degeneration, Guam-ALS syndrome; pallido-nigro-luysian degeneration, cortico-basal degeneration. 
     
     
         5 . A method as claimed in  claim 1  wherein the cognitive or CNS disorder is mild cognitive impairment. 
     
     
         6 . A method as claimed in  claim 1  wherein the cognitive or CNS disorder is a synucleinopathy, which is optionally Parkinson's Disease, dementia with Lewy bodies, multiple system atrophy, drug-induced parkinsonism, or pure autonomic failure (PAF). 
     
     
         7 . A method as claimed in  claim 1  wherein the patient is one known or believed to be suffering from a haemoglobinopathy which is optionally Sickle-cell disease, thalassemia, methaemoglobinemia; an anemia which is optionally a haemolytic anemia; a haematological malignancy which is optionally lymphoma, myeloma, plasmacytoma or leukemia, a coagulopathy which is optionally hemophilia. 
     
     
         8 . A method as claimed in  claim 1  wherein the dosage unit is provided as a pharmaceutical composition comprising the DAPTZ compound and a pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         9 . A method as claimed in  claim 1  wherein the pharmaceutical composition is for a combination therapy and comprises in addition to the DAPTZ compound a further active ingredient selected from: a cholinesterase inhibitor; an NMDA receptor antagonist; a muscarinic receptor agonist; an inhibitor of conversion of amyloid precursor protein to beta-amyloid. 
     
     
         10 . A method as claimed in  claim 1  wherein said DAPTZ compound is selected from compounds of the following formulae and pharmaceutically acceptable salts, mixed salts, solvates, and hydrates thereof: 
       
         
           
           
               
               
           
         
         wherein each one of R 1 , R 2 , R 4 , R 6 , R 8 , and R 9  is independently selected from: —H; —F; —Cl; —Br; —I; —OH; —OR; —SH; —SR; —NO 2 ; —C(═O)R; —C(═O)OH; —C(═O)OR; —C(═O)NH 2 ; —C(═O)NHR; —C(═O)NR 2 ; —C(═O)NR N1 R N2 ; —NH 2 ; —NHR; —NR 2 ; —NR N1 R N2 ; —NHC(═O)H; —NRC(═O)H; —NHC(═O)R; —NRC(═O)R;
 —R; 
 
         wherein each R is independently selected from:
 unsubstituted aliphatic C 1-6 alkyl; substituted aliphatic C 1-6 alkyl; 
 unsubstituted aliphatic C 2-6 alkenyl; substituted aliphatic C 2-6 alkenyl; 
 unsubstituted C 3-6 cycloalkyl; substituted C 3-6 cycloalkyl; 
 unsubstituted C 6-10 carboaryl; substituted C 6-10 carboaryl; 
 unsubstituted C 5-10 heteroaryl; substituted C 5-10 heteroaryl; 
 unsubstituted C 6-10 carboaryl-C 1-4 alkyl; substituted C 6-10 carboaryl-C 1-4 alkyl; 
 
         wherein, in each group —NR N1 R N2 , independently, R N1  and R N2  taken together with the nitrogen atom to which they are attached form a ring having from 3 to 7 ring atoms; 
         and wherein, in each group —NR 3NA R 3NA , if present: 
         each one of R 3NA  and R 3NB  is independently selected from: —H;
 unsubstituted aliphatic C 1-6 alkyl; substituted aliphatic C 1-6 alkyl; 
 unsubstituted aliphatic C 2-6 alkenyl; substituted aliphatic C 2-6 alkenyl; 
 unsubstituted C 3-6 cycloalkyl; substituted C 3-6 cycloalkyl; 
 unsubstituted C 6-10 carboaryl; substituted C 6-10 carboaryl; 
 unsubstituted C 5-10 heteroaryl; substituted C 5-10 heteroaryl; 
 unsubstituted C 6-10 carboaryl-C 1-4 alkyl; substituted C 6-10 carboaryl-C 1-4 alkyl; 
 
         or: R 3NA  and R 3NB  taken together with the nitrogen atom to which they are attached form a ring having from 3 to 7 ring atoms; 
         and wherein, in each group ═NR 3NC , if present, R 3NC  is independently selected from:
 —H; 
 unsubstituted aliphatic C 1-6 alkyl; substituted aliphatic C 1-6 alkyl; 
 unsubstituted aliphatic C 2-6 alkenyl; substituted aliphatic C 2-6 alkenyl; 
 unsubstituted C 3-6 cycloalkyl; substituted C 3-6 cycloalkyl; 
 unsubstituted C 6-10 carboaryl; substituted C 6-10 carboaryl; 
 unsubstituted C 5-10 heteroaryl; substituted C 5-10 heteroaryl; 
 unsubstituted C 6-10 carboaryl-C 1-4 alkyl; substituted C 6-10 carboaryl-C 1-4 alkyl; 
 
         and wherein, in each group —NR 7NA R 7NA , if present: 
         each one of R 7NA  and R 7NB  is independently selected from:
 —H; 
 unsubstituted aliphatic C 1-6 alkyl; substituted aliphatic C 1-6 alkyl; 
 unsubstituted aliphatic C 2-6 alkenyl; substituted aliphatic C 2-6 alkenyl; 
 unsubstituted C 3-6 cycloalkyl; substituted C 3-6 cycloalkyl; 
 unsubstituted C 6-10 carboaryl; substituted C 6-10 carboaryl; 
 unsubstituted C 5-10 heteroaryl; substituted C 5-10 heteroaryl; 
 unsubstituted C 6-10 carboaryl-C 1-4 alkyl; substituted C 6-10 carboaryl-C 1-4 alkyl; 
 
         or: R 7NA  and R 7NB  taken together with the nitrogen atom to which they are attached form a ring having from 3 to 7 ring atoms; 
         and wherein, in each group ═NR 7NC , if present, R 7NC  is independently selected from:
 —H; 
 unsubstituted aliphatic C 1-6 alkyl; substituted aliphatic C 1-6 alkyl; 
 unsubstituted aliphatic C 2-6 alkenyl; substituted aliphatic C 2-6 alkenyl; 
 unsubstituted C 3-6 cycloalkyl; substituted C 3-6 cycloalkyl; 
 unsubstituted C 6-10 carboaryl; substituted C 6-10 carboaryl; 
 unsubstituted C 5-10 heteroaryl; substituted C 5-10 heteroaryl; 
 unsubstituted C 6-10 carboaryl-C 1-4 alkyl; substituted C 6-10 carboaryl-C 1-4 alkyl; 
 
         and wherein X − , if present, is one or more anionic counter ions to achieve electrical neutrality. 
       
     
     
         11 . A method as claimed in  claim 10 , wherein each one of R 1 , R 2 , R 4 , R 6 , R 8 , and R 9  is independently selected from:
 —H;   —F; —Cl; —Br; —I;   —OH; —OR;   —C(═O)OH; —C(═O)OR;   —R.   
     
     
         12 . A method as claimed in  claim 10 , wherein each R is independently selected from:
 unsubstituted aliphatic C 1-6 alkyl; substituted aliphatic C 1-6 alkyl;   unsubstituted aliphatic C 2-6 alkenyl; substituted aliphatic C 2-6 alkenyl;   unsubstituted C 3-6 cycloalkyl; substituted C 3-6 cycloalkyl.   
     
     
         13 . A method as claimed in  claim 10 , wherein substituents on R, if present, are independently selected from:
 —F; —Cl; —Br; —I;   —OH; —OR;   —C(═O)OH; —C(═O)OR′;   —R′.   
     
     
         14 . A method as claimed in  claim 13 , wherein each R′ is independently selected from:
 unsubstituted aliphatic C 1-6 alkyl; 
 unsubstituted aliphatic C 2-6 alkenyl; 
 unsubstituted C 3-6 cycloalkyl; 
 unsubstituted C 6-10 carboaryl; 
 unsubstituted C 5-10 heteroaryl; 
 unsubstituted C 6-10 carboaryl-C 1-4 alkyl. 
 
     
     
         15 . A method as claimed in  claim 10 , wherein each one of R 1 , R 2 , R 4 , R 6 , R 8 , and R 9  is independently selected from: —H, -Me, -Et, -nPr, and -iPr. 
     
     
         16 . A method as claimed in  claim 15  wherein each one of R 1 , R 2 , R 4 , R 6 , R 8 , and R 9  is independently selected from: —H and -Me. 
     
     
         17 . A method as claimed in  claim 10 , wherein, in each group —NR 3NA R 3NB  and —NR 7NA R 7NB , if present, each one of R 3NA  and R 3NB  and —NR 7NA  and R 7NB , is independently selected from: —H, -Me, -Et, -nPr, and -iPr. 
     
     
         18 . A method as claimed in  claim 10 , wherein, in each group ═NR 3NC  and in each group ═NR 7NC , if present, ═R 3NC  and ═NR 7NC  are independently selected from: —H, -Me, -Et, -nPr, and -iPr. 
     
     
         19 . A method as claimed in  claim 10 , wherein R N10 , if present, is independently selected from: —H, -Me, and -Et. 
     
     
         20 . A method as claimed in  claim 10 , wherein X − , if present, is one or more anionic counter ions to achieve electrical neutrality, optionally selected from Cl − , Br − , I − , or NO 3   − . 
     
     
         21 . A method as claimed in  claim 1 , wherein the DAPTZ compound is selected from the following compound, and pharmaceutically acceptable salts, mixed salts, hydrates, and solvates thereof: 
       
         
           
           
               
               
           
         
       
     
     
         22 . A method as claimed in  claim 7  wherein the patient is over 70 years and is subject to an age-related anemic condition which is optionally myeloid dysplasia.