2-(r2-thio)-10-[3-(4-r1-piperazin-1-yl)propyl]-10h-phenothiazines for treating a b-amyloidopathy or an a-synucleopathy, and method for the diagnosis or prediagnosis thereof

Abstract

The invention relates to 2-(R 2 -thio)-10-[3-(4-R 1 -piperazin-1-yl)propyl]- 10H-phenothiazine according to general formula I, for treating a β-amyloidopathy or an α-synucleinopathy accompanied by a cerebral protein deposit and a reduced activity of the cerebral ABCC1-transporter. The invention also relates to a method for the diagnosis or prediagnosis of a β-amyloidopathy or an α-synucleopathy accompanied by a cerebral protein deposit and a reduced activity of the cerebral ABCC1-transporter, or for determining the risk of a proband suffering from such an illness, the proband already having accumulated substances transported by the cerebral ABCC1 transporter.

1 . A method for treating a β-amyloidopathy or an α-synucleinopathy neurodegenerative disease, the method comprising:
 administering to a patient exhibiting a β-amyloidopathy or an α-synucleinopathy accompanied by a cerebral protein deposit and a reduced activity of the cerebral ABCC1-transporter a 2-(R 2 -thio)-10-[3-(4-R 1 -piperazin-1-yl)propyl]-10H-phenothiazine according to the general formula I, thereby activating the cerebral ABCC1-transporter of the patient; 
 
       
         
           
           
               
               
           
         
         wherein the residues 
         R 1  and R 2  are the same or different and each independently of one another is a C 1 -C 6  alkyl group, which independently of one another optionally comprises another substituent selected from the group consisting of alkyl, aryl, acyl, amino, nitro, sulfonyl, hydroxyl, alkoxy, aryloxy, arylthio, and alkylthio groups and halogen atoms, wherein the respective alkyl groups optionally comprise at least one further halogen atom and the residue; 
         R 3  is located at one of the positions 6-9 of the phenothiazine ring system and is a hydrogen atom or an alkyl, aryl, acyl, amino, nitro, sulfonyl, hydroxyl, alkoxy, aryloxy, arylthio, alkylthio group or a halogen atom, wherein the respective alkyl groups optionally comprise at least one further halogen atom or an NR 4 R 5  or OR 6  group, wherein R 4 , R 5 , and R 6  are the same or different and each independently of one another is selected from the group consisting of hydrogen and C 1 -C 3  alkyl groups and the residue; and 
         R 7  is located at one of the positions 1, 2, or 4 of the phenothiazine ring system and is a hydrogen atom or an alkyl, aryl, acyl, amino, nitro, sulfonyl, hydroxyl, alkoxy, aryloxy, arylthio, or alkylthio group or a halogen atom, wherein the respective alkyl groups optionally comprise at least one further halogen atom or an NR 8 R 9  or OR 10  group, wherein R 8 , R 9 , and R 10  are the same or different and each independently of one another is selected from the group consisting of hydrogen and C 1 -C 3  alkyl groups. 
       
     
     
         2 . The method of  claim 1 , wherein each halogen atom is selected from the group consisting of fluorine and chlorine. 
     
     
         3 . The method of  claim 1 , wherein R 1  and R 2  are the same or different and each independently of one another is a C 1 -C 3  alkyl group. 
     
     
         4 . The method of  claim 1 , wherein the residues R 3  and R 7  are hydrogen. 
     
     
         5 . The method of  claim 1 , wherein the residue R 1  is a methyl group, the residue R 2  is an ethyl group, and the residues R 3  and R 7  are hydrogen. 
     
     
         6 . The method of  claim 1 , further comprising: administering to the patient a further active substance along with the 2-(R 2 -thio)-10-[3-(4-R 1 -piperazin-1-yl)propyl]-10H-phenothiazine. 
     
     
         7 . The method of  claim 6 , wherein a 1-benzohydrylpiperazine is the further active substance. 
     
     
         8 . The method of  claim 7 , wherein 1-benzohydryl-4-cinnamyl piperazine is the 1-benzohydrylpiperazine. 
     
     
         9 . The method of  claim 1 , wherein the patient exhibits the β-amyloidopathy, and the β-amyloidopathy is Alzheimer's dementia. 
     
     
         10 . The method of  claim 1 , wherein the patient exhibits the α-synucleinopathy, and the α-synucleinopathy is Parkinson's disease or Lewy body dementia. 
     
     
         11 . The method of  claim 1 , comprising administering the 2-(R2-thio)-10-[3-(4-R1-piperazin-1-yl)propyl]-10H-phenothiazine to the patient prior to the patient exhibiting senile plaques.