Preventives or remedies for alzheimer's disease, or amyloid protein fibril-formation inhibitors, which include a nitrogen-containing heteroaryl compound

Abstract

The present invention relates to preventives or remedies for Alzheimer's disease, or to amyloid protein fibril-formation inhibitors, which include as an active ingredient a compound of general formula (I) below or a pharmacologically permitted salt thereof; and also to nitrogen-containing heteroaryl derivatives having specific substituents, or pharmacologically permitted salts thereof, which are valuable as preventives or remedies for Alzheimer's disease, or as amyloid protein fibril-formation inhibitors: (where, R 1 and R 2 are H or alkyl; Z 1 and Z 2 are H, alkyl, alkoxy, haloalkyl or halogeno; Z 3 is alkoxy, SH, alkylthio, NH 2 , mono- or di-alkylamino, OH or halogeno; Z 4 and Z 5 are H or halogeno; and A is 4,6-pyrimidine-1,3-diyl, 1,3,5-triazine-2,6-diyl, etc).

1 - 18 . (canceled) 
   
   
       19 . A pharmaceutical composition which contains, as an active ingredient, at least one nitrogen-containing heteroaryl compound represented by the following general formula (I) 
     
       
         
         
             
             
         
       
     
     [where
 R 1  and R 2  each independently represent a hydrogen atom or a C 1-6  alkyl group, 
 Z 1  and Z 2  each independently represent a hydrogen atom, C 1-6  alkyl group, C 1-6  alkoxy group, halo-C 1-6  alkyl group or halogen atom, 
 Z 3  represents a C 1-6  alkoxy group, mercapto group, C 1-6  alkylthio group, amino group, mono- or di-C 1-6 alkylamino group, hydroxy group or halogen atom, 
 Z 4  and Z 5  each independently represent a hydrogen atom or halogen atom, and 
 A represents a group of formula (II) or (III) below 
 
     
       
         
         
             
             
         
       
     
     (where
 R 3  represents a hydrogen atom, C 1-6  alkyl group, C 1-6  alkoxy group, mercapto group, C 1-6  alkylthio group, amino group, mono- or di-C 1-6  alkylamino group or hydroxy group, 
 R 4  represents a hydrogen atom or nitro group, 
 R 5  represents a hydrogen atom or C 1-6  alkyl group, 
 R 6  represents a hydrogen atom, C 1-6  alkyl group, C 1-6  alkoxy group, mercapto group, C 1-6  alkylthio group, amino group, mono- or di-C 1-16  alkylamino group or hydroxy group or pharmacologically permitted salt thereof. 
 
   
   
       20 . A nitrogen-containing heteroaryl derivative represented by the formula (VI) 
     
       
         
         
             
             
         
       
       [where R 1  and R 2  each independently represent a hydrogen atom or C 1-6  alkyl group, 
       Z 1  and Z 2  each independently represent a hydrogen atom, C 1-6  alkyl group, C 1-6  alkoxy group, halogen atom or halo-C 1-6  alkyl group, 
       Z 4  and Z 5  each independently represent a hydrogen atom or halogen atom, and 
       A represents a group of formula (II) to (Vl) below 
     
     
       
         
         
             
             
         
       
     
     (where
 R 3  represents a hydrogen atom, C 1-6  alkyl group, C 1-6  alkoxy group, mercapto group, C 1-6  alkylthio group, amino group, mono- or di-C 1-6  alkylamino group or hydroxy group, 
 R 4  represents a hydrogen atom or nitro group, 
 R 5  represents a hydrogen atom or C 1-6  alkyl group, 
 R 6  represents a hydrogen atom, C 1-6  alkyl group, C 1-6  alkoxy group, mercapto group, C 1-6  alkylthio group, amino group, mono- or di-C 1-6  alkylamino group or hydroxy group or pharmacologically permitted salt thereof. 
 
   
   
       21 . A nitrogen-containing heteroaryl derivative or pharmacologically permitted salt thereof according to  claim 20 , where R 1  and R 2  are each independently a hydrogen atom or C 1-2  alkyl group. 
   
   
       22 . A nitrogen-containing heteroaryl derivative or pharmacologically permitted salt thereof according to  claim 20 , where R 1  and R 2  are hydrogen atoms. 
   
   
       23 . A nitrogen-containing heteroaryl derivative or pharmacologically permitted salt thereof according to  claim 20 , where A is a group of formula (II) (where R 3  is a hydrogen atom, C 1-5  alkyl, C 1-3  alkylthio or mono- or di-C 1-3  alkylamino group, and R 4  is a hydrogen atom or nitro group) or a group of formula (III) (where R 5  and R 6  are each independently a hydrogen atom or C 1-2  alkyl group). 
   
   
       24 . A nitrogen-containing heteroaryl derivative or pharmacologically permitted salt thereof according to  claim 20 , where A is a group of formula (II) (where R 3  is a hydrogen atom, C 1-5  alkyl, C 1-3  alkylthio or mono- or di-C 1-3  alkylamino group, and R 4  is a hydrogen atom or nitro group) or a group of formula (III) (where R 5  is a hydrogen atom and R 6  is a methyl or ethyl group). 
   
   
       25 . A nitrogen-containing heteroaryl derivative or pharmacologically permitted salt thereof according to  claim 20 , where A is a group of formula (II) (where R 3  is a hydrogen atom, C 1-4  alkyl or amino group, and R 4  is a hydrogen atom or nitro group). 
   
   
       26 . A nitrogen-containing heteroaryl derivative or pharmacologically permitted salt thereof according to  claim 20 , where A is a group of formula (II) (where R 3  is an ethyl, propyl, isopropyl or amino group and R 4  is a hydrogen atom, or R 3  is a hydrogen atom and R 4  is a nitro group). 
   
   
       27 . A nitrogen-containing heteroaryl derivatives or pharmacologically permitted salts thereof according to  claim 20 , where Z 1  and Z 2  are each independently a hydrogen atom or para-position fluorine atom, chlorine atom or C 1-2  alkyl group, the hydroxy group on the phenyl ring to which Z 1  is bonded is in the meta-position, and Z 4  and Z 5  are hydrogen atoms. 
   
   
       28 . A nitrogen-containing heteroaryl derivative or pharmacologically permitted salt thereof according to  claim 20 , where Z 1  and Z 2  are each independently a hydrogen atom or para-position fluorine atom, chlorine atom or C 1-2  alkyl group, the hydroxy group on the phenyl ring to which Z 1  is bonded is in the meta-position, and Z 4  and Z 5  are hydrogen atoms. 
   
   
       29 . A nitrogen-containing heteroaryl derivative or pharmacologically permitted salt thereof according to  claim 20 , where Z 1  and Z 2  are hydrogen atoms or para-position methyl groups, the hydroxy group on the phenyl ring to which Z 1  is bonded is in the meta-position, and Z 4  and Z 5  are hydrogen atoms. 
   
   
       30 . A pyrimidine derivative of the formula (VIII), or pharmacologically permitted salt thereof, 
     
       
         
         
             
             
         
       
     
     (where
 R 1  and R 2  respectively and independently represent a hydrogen atom or C 1-6  alkyl group, 
 R 3  represents a hydrogen atom, C 1-6  alkyl group, C 1-6  alkoxy group, mercapto group, C 1-6  alkylthio group, amino group, mono- or di-C 1-6  alkylamino group or hydroxy group, and 
 Z 6  represents a C 1-6  alkoxy group or a halogen atom). 
 
   
   
       31 . A pyrimidine derivative or pharmacologically permitted salt thereof according to  claim 30 , where R 1  and R 2  are hydrogen atoms, R 3  is a hydrogen atom or C 1-4  alkyl group, and Z 6  is a methoxy group, ethoxy group or chlorine atom. 
   
   
       32 . A nitrogen-containing heteroaryl derivative according to  claim 20  which is selected from the group consisting of: 
     N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine, 
     2-methyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine, 
     2-ethyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine, 
     2-propyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine, 
     2-isopropyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine, 
     2-butyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine, 
     2-amino-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine, 
     N,N′-bis(3-hydroxyphenyl)-5-nitropyrimidine-4,6-diamine, 
     N,N′-bis(3-hydroxyphenyl)pyrimidine-2,4-diamine,
 or a pharmacologically permitted salts thereof. 
 
   
   
       33 . A nitrogen-containing heteroaryl derivative according to  claim 20  which is
 2-methyl-N,N′-bis(3-hydroxyphenyl)pyrimidine-4,6-diamine or a pharmacologically permitted salt thereof.   
   
   
       34 . A pharmaceutical composition according to  claim 19  which contains, as an active ingredient, a nitrogen-containing heteroaryl derivative as defined above, or pharmacologically permitted salt thereof. 
   
   
       35 . A method of treating a patient in need of therapy for an amyloidosis comprising administering to the patient a therapeutically effective amount of a composition which contains as an active ingredient at least one nitrogen-containing heteroaryl compound of formula (I) 
     
       
         
         
             
             
         
       
     
     [where
 R 1  and R 2  each independently represent a hydrogen atom or a C 1-6  alkyl group, 
 Z 1  and Z 2  each independently represent a hydrogen atom, C 1-6  alkyl group, C 1-6  alkoxy group, halo-C 1-6  alkyl group or halogen atom, 
 Z 3  represents a C 1-6  alkoxy group, mercapto group, C 1-6  alkylthio group, amino group, mono- or di-C 1-6  alkylamino group, hydroxy group or halogen atom, 
 Z 4  and Z 5  each independently represent a hydrogen atom or a halogen atom, and 
 A represents a group of formula (II) to (VI) below 
 
     
       
         
         
             
             
         
       
     
     (where
 R 3  represents a hydrogen atom, C 1-6  alkyl group, C 1-6  alkoxy group, mercapto group, C 1-6  alkylthio group, amino group, mono- or di-C 1-6  alkylamino group or hydroxy group, 
 R 4  represents a hydrogen atom or nitro group, 
 R 5  represents a hydrogen atom or C 1-6  alkyl group, 
 R 6  represents a hydrogen atom, C 1-6  alkyl group, C 1-6  alkoxy group, mercapto group, C 1-6  alkylthio group, amino group, mono- or di-C 1-6  alkylamino group or hydroxy group or pharmacologically permitted salt thereof. 
 
   
   
       36 . A method as claimed in  claim 35  wherein the nitrogen-containing heteroaryl derivative is as defined above. 
   
   
       37 . A method as claimed in  claim 35  wherein the amyloidosis is selected from the group consisting of Alzheimer's disease, type 2 diabetes, immunoglobulinic amyloidosis, reactive amyloidosis, familial amyloidosis, dialysis related amyoidosis, senile amyloidosis, cerebrovascular amyloidosis, hereditary cerebral haemorrhage with amyloidosis, Creutzfeldt-Jacob disease, bovine spongiform encephalitis(BSE), scrapie, medullary carcinoma of the thyroid, insulinoma, localized atrial amyloid, amyloidosis cutis, localized nodular amyloidosis and familial amyloidosis.