Medicinal compositions improving brain function and method for improving brain function

Abstract

An alkyl ether derivative represented by the formula: wherein R 1 , R 2 , R 3 , R 4 , m and n are as defined in the specification, or salts thereof exhibits synergistically improved anti-hypoxic activity when combined with a compound having an acetylcholine esterase inhibitory activity. Therefore, the combination according to the present invention is useful as a method for improving cerebral function. Further, a pharmaceutical composition containing the compound relating to the combination according to the present invention is useful for treatment and prevention of dysfunction of cerebral acetylcholine neurons in the sequelae of cerebrovascular dementia, senile dementia, Alzheimer's disease and ischemic cerebral lesion and in the cerebral apoplexy or the memory impairment caused by selective neuronal death.

1. A pharmaceutical composition comprising the following ingredients (A) and (B):
 Ingredient (A): An alkyl ether derivative represented by the following formula:   
       
         
           
           
               
               
           
         
         wherein R 1  represents a benzothienyl group which may be substituted with a group selected from a halogen atom, an alkyl group, and a phenyl group; R 2  represents a hydrogen atom; R 3  and R 4 , each represents an alkyl group, or R 3  and R 4 , taken conjointly with the nitrogen atom to which R 3  and R 4  are linked, form an azetidine ring; m represents 1; and n represents 2 to 3; or a salt thereof, 
         Ingredient (B): A compound selected from the group consisting of Donepezil and Tacrine. 
       
     
     
       2. A method of preparing a medicament comprising combining the following ingredients (A) and (B),
 Ingredient (A): An alkyl ether derivative represented by the following formula:   
       
         
           
           
               
               
           
         
         wherein R 1  represents a benzothienyl group which may be substituted with a group selected from a halogen atom, an alkyl group, and a phenyl group; R 2  represents a hydrogen atom; R 3  and R 4 , each represents an alkyl group, or R 3  and R 4 , taken conjointly with the nitrogen atom to which R 3  and R 4  are linked, form an azetidine ring; m represents; and n represents 2 to 3; or a salt thereof, 
         Ingredient (B): A compound selected from the group consisting of Donepezil and Tacrine. 
       
     
     
       3. A pharmaceutical composition as claimed in  claim 1  wherein the pharmaceutical composition is administered to a patient to treat Alzheimer's disease. 
     
     
       4. A method of treating Alzheimer's disease comprising administering the pharmaceutical composition of  claim 1  to a patient in need thereof. 
     
     
       5. The pharmaceutical composition as claimed in claim  1  9, wherein said ingredient (A) is 1-[3-(2-(1-benzothiophen-5-yl)ethoxy)propyl]-3-azetidinol.or 1-[3-(2-(1-benzothiophen-5-yl)ethoxy)propyl]-3-azetidinol or a salt thereof. 
     
     
       6. The pharmaceutical composition as claimed in claim  1  9, wherein said ingredient (A) is 1-[3-(2-(1-benzothiophen-5-yl)ethoxy)propyl]-3-azetidinol.maleate 1-[3-(2-(1-benzothiophen-5-yl)ethoxy)propyl]-3-azetidinol maleate. 
     
     
       7. The method as claimed in claim  2  10, wherein said ingredient (A) is 1-[3-(2-(1-benzothiophen-5-yl)ethoxy)propyl]-3-azetidinol.or 1-[3-(2-(1-benzothiophen-5-yl)ethoxy)propyl]-3-azetidinol or a salt thereof. 
     
     
       8. The method as claimed in claim  2  10, wherein said ingredient (A) is 1-[3-(2-(1-benzothiophen-5-yl)ethoxy)propyl]-3-azetidinolmaleate 1-[3-(2-(1-benzothiophen-5-yl)ethoxy)propyl]-3-azetidinol maleate. 
     
     
       9. A pharmaceutical composition comprising the following ingredients (A) and (B):
 Ingredient (A): An alkyl ether derivative represented by the following formula:   
       
         
           
           
               
               
           
         
          wherein R 1  represents a benzothienyl group which may be substituted with a group selected from a halogen atom, an alkyl group, and a phenyl group; R 2  represents a hydrogen atom; R 3  and R 4 , taken conjointly with the nitrogen atom to which R 3  and R 4  are linked, form an azetidine ring which may be substituted by a hydroxyl group; m represents 1; and n represents 2 to 3; or a salt thereof, 
         Ingredient (B): A compound selected from the group consisting of Donepezil and Tacrine. 
       
     
     
       10. A method of preparing a medicament comprising combining the following ingredients (A) and (B),
 Ingredient (A): An alkyl ether derivative represented by the following formula:   
       
         
           
           
               
               
           
         
          wherein R 1  represents a benzothienyl group which may be substituted with a group selected from a halogen atom, an alkyl group, and a phenyl group; R 2  represents a hydrogen atom; R 3  and R 4 , taken conjointly with the nitrogen atom to which R 3  and R 4  are linked, form an azetidine ring which may be substituted by a hydroxyl group; m represents 1; and n represents 2 to 3; or a salt thereof, 
         Ingredient (B): A compound selected from the group consisting of Donepezil and Tacrine. 
       
     
     
       11. A pharmaceutical composition as claimed in claim 9, wherein the pharmaceutical composition is administered to a patient to treat Alzheimer's disease. 
     
     
       12. A method of treating Alzheimer's disease comprising administering the pharmaceutical composition of claim 9 to a patient in need thereof.