[1,10]-phenanthroline derivatives for the treatment of neurodegenerative or haematological diseases

Abstract

The present invention relates to a new family of [1,10]-phenantroline derivatives of formula (I), which are useful for the treatment or prophylaxis of a neurodegenerative or hematological disease or condition, their use as a medicament, especially for treating a neurodegenerative or hematological disease or condition, and a pharmaceutical composition comprising the compounds.

What is claimed is: 
     
         1 . A method of treating or preventing a neurodegenerative or hematological disease or condition, which method comprises administering to a patient a therapeutically effective amount, for such treatment or prevention, of at least one compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from —S—R 3 , —O—R 4  and halogen; 
         R 7  is selected from —CH═N—OR 8  or —CHO; 
         R 3  and R 4  are independently selected from the group consisting of C 1 -C 6  alkyl, C 6 -C 15  aryl and heteroaryl, each of which is optionally substituted by C 1 -C 6  alkyl, C 6 -C 15  aryl, halogen, —(C═O)NR 5 R 6 , —(C═O)OR 5 , C 1 -C 6  alkoxy and/or —NR 5 R 6 , 
         R 5  and R 6  being independently selected from hydrogen and C 1 -C 6  alkyl, 
         R 8  is selected from hydrogen and C 1 -C 6  alkyl; 
         or a salt or solvate or stereoisomer or tautomer thereof. 
       
     
     
         2 . The method according to  claim 1 , wherein:
 R 1  is selected from —S—R 3 , —O—R 4  and halogen;   R 7  is selected from —CH═N—OR 8  or —CHO;   R 3  and R 4  are independently a C 1 -C 6  alkyl, each of which is optionally substituted by C 1 -C 6  alkoxy and/or —NR 5 R 6 ;   R 5  and R 6  are independently selected from hydrogen and C 1 -C 6  alkyl; and   R 8  is selected from hydrogen and C 1 -C 6  alkyl.   
     
     
         3 . The method according to  claim 1 , wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis (ALS), schizophrenia, Huntington's Disease, brain injuries, stroke, ischemia, multiple sclerosis, epilepsy, Friedreich's Ataxia, spongiform encephalopathies, amyloidosis, vascular dementia, tauopathies, progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobular degeneration, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, Pick's disease, frontotemporal dementia, AIDS associated dementia, multiple sclerosis, mood disorders, depression, schizophrenia, and bipolar disorders. 
     
     
         4 . The method according to  claim 1 , wherein the hematological disease is selected from the group consisting of thalassaemia, anaemia, aplastic anaemia, Diamond-Blackfan anemia, sickle cell disease, hematologic disorders requiring periodic red cell transfusions, myelodysplastic syndrome, iron-induced cardiac dysfunction, iron-induced heart failure, and diabetes. 
     
     
         5 . The method according to  claim 2 , wherein the hematological disease is selected from the group consisting of thalassaemia, anaemia, aplastic anaemia, Diamond-Blackfan anemia, sickle cell disease, hematologic disorders requiring periodic red cell transfusions, myelodysplastic syndrome, iron-induced cardiac dysfunction, iron-induced heart failure, and diabetes. 
     
     
         6 . The method according to  claim 1 , wherein R 7  is —CH═N—OR 8 . 
     
     
         7 . The method according to  claim 5 , wherein R 8  is hydrogen. 
     
     
         8 . The method according to  claim 1 , wherein R 1  is —S—R 3 . 
     
     
         9 . The method according to  claim 8 , wherein R 3  is selected from methyl, ethyl, propyl, isopropyl and heteroaryl, said heteroaryl being optionally substituted by C 1 -C 6  alkyl, C 6 -C 15  aryl, halogen, —(C═O)NR 5 R 6 , —(C═O)OR 5 , C 1 -C 6  alkoxy and/or —NR 5 R 6 . 
     
     
         10 . The method according to  claim 9 , wherein the heteroaryl group is substituted by C 1 -C 3  alkyl. 
     
     
         11 . The method according to  claim 1 , wherein R 1  is —O—R 4 . 
     
     
         12 . The method according to  claim 11 , wherein R 4  is selected from methyl, ethyl, and ethyl substituted by an amine of formula —NR 5 R 6  or methoxy, wherein each of R 5  and R 6  is independently selected from hydrogen and C 1 -C 6  alkyl. 
     
     
         13 . The method according to  claim 12 , wherein the amine is primary or tertiary. 
     
     
         14 . The method according to  claim 13 , wherein the tertiary amine is diethyl-amine. 
     
     
         15 . The method according to  claim 1 , wherein the double bond of the oxime group —CH═NOR 8  presents an E conformation. 
     
     
         16 . The method according to  claim 1 , wherein R 1  is chloro. 
     
     
         17 . The method according to  claim 1 , wherein R 3  is a C 1 -C 3  alkyl group substituted by —(C═O)NR 5 R 6  or —(C═O)OR 5 . 
     
     
         18 . The method according to  claim 1 , wherein R 7  is —CH═N—OR 8  and R 1  is —S—R 3  or —O—R 4 . 
     
     
         19 . The method according to  claim 1 , wherein the compound of formula (I) is selected from the following compounds:
 4-Methoxy-[1,10]phenanthroline-2-carbaldehyde oxime   4-Chloro-[1,10]phenanthroline-2-carbaldehyde oxime   4-Chloro-[1,10]phenanthroline-2-carbaldehyde   4-Methylsulfanyl-[1,10]phenanthroline-2-carbaldehyde oxime   4-Propylsulfanyl-[1,10]phenanthroline-2-carbaldehyde oxime   4-Ethoxy-[1,10]phenanthroline-2-carbaldehyde oxime   4-Isopropylsulfanyl-[1,10]phenanthroline-2-carbaldehyde oxime   4-(2-Methoxy-ethoxy)-[1,10]phenanthroline-2-carbaldehyde oxime   4-(2-Amino-ethoxy)-[1,10]phenanthroline-2-carbaldehyde oxime   4-(2-Diethylamino-ethoxy)-[1,10]phenanthroline-2-carbaldehyde oxime   4-(2-Methoxy-ethylsulfanyl)-[1,10]phenanthroline-2-carbaldehyde oxime   2-[2-(Hydroxyimino-methyl)-[1,10]phenanthrolin-4-ylsulfanyl]-N,N-dimethyl-acetamide   4-(2,2,2-Trifluoro-ethylsulfanyl)-[1,10]phenanthroline-2-carbaldehyde oxime   [2-(Hydroxyimino-methyl)-[1,10]phenanthrolin-4-ylsulfanyl]-acetic acid methyl ester   4-(Thiazol-2-ylsulfanyl)-[1,10]phenanthroline-2-carbaldehyde oxime   [2-(Hydroxyimino-methyl)-[1,10]phenanthrolin-4-ylsulfanyl]-acetic acid   4-(5-Methyl-thiazol-2-ylsulfanyl)-[1,10]phenanthroline-2-carbaldehyde oxime   4-(5-Methyl-[1,3,4]thiadiazol-2-ylsulfanyl)-[1,10]phenanthroline-2-carbaldehyde oxime   4-([1,3,4]Thiadiazol-2-ylsulfanyl)-[1,10]phenanthroline-2-carbaldehyde oxime   4-Methylsulfanyl-[1,10]phenanthroline-2-carbaldehyde   4-Propylsulfanyl-[1,10]phenanthroline-2-carbaldehyde   4-Propylsulfanyl-[1,10]phenanthroline-2-carbaldehyde oxime   4-Ethoxy-[1,10]phenanthroline-2-carbaldehyde   4-Isopropylsulfanyl-[1,10]phenanthroline-2-carbaldehyde   4-(2-Methoxy-ethoxy)-[1,10]phenanthroline-2-carbaldehyde   4-(2-Diethylamino-ethoxy)-[1,10]phenanthroline-2-carbaldehyde   or salts, solvates, stereoisomers or tautomers thereof.