2-(r2-thio)-10-[3-(4-r1-piperazin-1-yl) propyl]-10h-phenothiazine for treating a beta-amyloidopathy or an alpha-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 2-(R 2 -thio)-10-[3-(4-R 1 -piperazin-1-yl)propyl]-10H-phenothiazine useful for treating a β-amyloidopathy or an α-synucleinopathy accompanied by a cerebral protein deposit and a reduced activity of the cerebral ABCC1-transporter, according to the general formula I 
       
         
           
           
               
               
           
         
         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 
         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 . A 2-(R 2 -thio)-10-[3-(4-R 1 -piperazin-1-yl)propyl]-10H-phenothiazine according to  claim 1 , characterized in that wherein the halogen atom/the halogen atoms are selected from the group consisting of fluorine and chlorine. 
     
     
         3 . A 2-(R 2 -thio)-10-[3-(4-R 1 -piperazin-1-yl)propyl]-10H-phenothiazine according to  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 . A 2-(R 2 -thio)-10-[3-(4-R 1 -piperazin-1-yl)propyl]-10H-phenothiazine according to  claim 1 , wherein the residues R 3  and R 7  are hydrogen. 
     
     
         5 . A 2-(R 2 -thio)-10-[3-(4-R 1 -piperazin-1-yl)propyl]-10H-phenothiazine according to  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 . A composition comprising a 2-(R 2 -thio)-10-[3-(4-R 1 -piperazin-1-yl)propyl]-10H-phenothiazine according to  claim 1 , further comprising a further active substance. 
     
     
         7 . A composition according to  claim 6 , wherein a 1-benzohydrylpiperazine is a further active substance. 
     
     
         8 . A composition according to  claim 7 , wherein 1-benzohydryl-4-cinnamyl piperazine is the 1-benzohydrylpiperazine. 
     
     
         9 . A 2-(R 2 -thio)-10-[3-(4-R 1 -piperazin-1-yl)propyl]-10H-phenothiazines according to  claim 1 , wherein the β-amyloidopathy is Alzheimer's dementia. 
     
     
         10 . A 2-(R 2 -thio)-10-[3-(4-R 1 -piperazin-1-yl)propyl]-10H-phenothiazines according to  claim 1 , wherein the α-synucleinopathy is Parkinson's disease or Lewy body dementia. 
     
     
         11 . Method for the diagnosis or prediagnosis of a β-amyloidopathy or 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 to develop such an illness, wherein the proband has already taken substances transported by the cerebral ABCC1 transporter, comprising the following steps:
 a) determining a quantity of ingested substance in body fluid samples of the proband at a specific time point; 
 b) repeating the determination of step a) at at least one further later time point; 
 c) comparing the quantities determined in step a) and step b) with quantities which had been defined as characteristic at the same time points for probands who at the time of the sampling showed no clinical symptoms of a β-amyloidopathy or an α-synucleopathy. 
 
     
     
         12 . Method for the diagnosis or prediagnosis of a β-amyloidopathy or α-synucleopathy or for determining the risk of a proband to develop such a disease according to  claim 11 , wherein the body fluid samples of the proband are samples of at least one of blood plasma, blood serum, and cerebrospinal fluid. 
     
     
         13 . Method for the diagnosis or prediagnosis of a β-amyloidopathy or α-synucleopathy or for determining the risk of a proband to develop such a disease according to  claim 11 , wherein the β-amyloidopathy is an Alzheimer's dementia. 
     
     
         14 . Method for the diagnosis or prediagnosis of a β-amyloidopathy or α-synucleopathy or for determining the risk of a proband to develop such a disease according to  claim 11 , wherein the α-synucleopathy is Parkinson's disease or Lewy body dementia. 
     
     
         15 . Method for the diagnosis or prediagnosis of a β-amyloidopathy or an α-synucleopathy or for determining the risk of a proband to develop such a disease according to  claim 11 , wherein the substances transported via the cerebral ABCC1 transporter are selected from the group consisting of antibiotics, virostatics/antiviral medicaments, anti-allergics/antihistamines, cardio-vascular medicaments, antidepressants, antihyperuricemics, cytostatics, vitamins/vitamin analogues, antiphlogistics, anti-epileptics, hormones/hormone derivatives, leukotrienes, fluorescent samples, GSH-, sulfate, or glucuronide-coupled metabolites of natural substances (endogenously produced), toxins, and medicaments.