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 method of treating a patient in need of therapy for an amyloidosis comprising administering to the patient a therapeutically effective amount of a nitrogen-containing heteroaryl compound of the formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         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 wherein 
         A represents a group of formula (V) below 
       
       
         
           
           
               
               
           
         
         wherein 
         R 9  represents a 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. 
       
     
     
         20 . A method according to  claim 19  wherein the nitrogen-containing heteroaryl compound is of the formula (VII) 
       
         
           
           
               
               
           
         
         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 (V): 
       
       
         
           
           
               
               
           
         
         where 
         R 9  represents a 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 method according to  claim 19 , wherein R 1  and R 2  are each independently a hydrogen atom or C 1-2  alkyl group. 
     
     
         22 . A method according to  claim 19 , wherein R 1  and R 2  are hydrogen atoms. 
     
     
         23 . A method according to  claim 19 , wherein A is a group of formula (V) where R 9  is a C 1-5  alkyl, C 1-4  alkoxy or a C 1-4  alkylthio group. 
     
     
         24 . A method according to  claim 19 , wherein A is a group of formula (V) where R 9  is a C 2-4  alkyl or a butoxy group. 
     
     
         25 . A method according to  claim 19 , wherein A is a group of formula (V) where R 9  is a C 2-4  alkyl group. 
     
     
         26 . A method according to  claim 19 , wherein 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. 
     
     
         27 . A method according to  claim 19 , wherein 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. 
     
     
         28 . A method according to  claim 19 , wherein the nitrogen-containing heteroaryl derivative is selected from any of the following, or pharmacologically permitted salts thereof:
 6-ethyl-N,N′-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine,   N,N′-bis(3-hydroxyphenyl)-6-propyl-1,3,5-triazine-2,4-diamine,   6-isobutyl-N,N′-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine,   6-s-butyl-N,N′-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine,   6-t-butyl-N,N′-bis(3-hydroxyphenyl)-1,3,5-triazine-2,4-diamine, and   6-ethyl-N,N′-bis(3-hydroxy-4-methylphenyl)-1,3,5-triazine-2,4-diamine.   
     
     
         29 . A method according to  claim 19  wherein the amyloidosis is selected from the group consisting of Alzheimer's disease, type 2 diabetes, immunoglobulinic amyloidosis, reactive amyloidosis, dialysis related amyloidosis, 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. 
     
     
         30 . A method according to  claim 19  wherein the amyloidosis is Alzheimer's disease.