Huperzine A derivatives, their preparation and their use

Abstract

The present invention relates to novel huperzine A derivatives of formula (II), wherein Y is or R″ and Y together form ═CH; R is (C 1 -C 5 ) alkyl, wherein n is 0 or 1, X is H, (C 1 -C 5 ) alkyl; (C 1 -C 5 ) alkyloxy; nitro, halogen, carboxy, alkyloxycarbonyl, hydroxymethyl, hydroxy, amino substituted by bis-(C 1 -C 5 ) alkyl; —(CH 2 ) m COOZ, wherein m=0-5, Z is H or (C 1 -C 5 ) alkyl; —CH═CH—G, wherein G is phenyl, furanyl, carboxy, alkyloxycarbonyl; and dihydro- or tetrahydro-pyridyl substituted by (C 1 -C 5 ) alkyl at the nitrogen atom; R′ is H, (C 1 -C 5 ) alkyl, pyridoyl, benzoyl substituted by (C 1 -C 5 ) alkyloxy; R″ is H or (C 1 -C 5 ) alkyl; processes for their use as acetylcholinesterase inhibitor.

We claim:  
     
       1. A huperzine A compound having tile following structural formula                    
       wherein Y and —R″ together form═CH, R is                    
       X is hydrogen, C 1 -C 5  lower alkyloxy, nitro, halogen, hydroxymethyl, hydroxy, amino substituted by two C 1 -C 5  lower alkyls or —CH═CH—G group, is phenyl or furanyl and R′ is hydrogen. 
     
     
       2. A method of treating myasthenia  amyasthenia by inhibiting cholinesterase comprising administering a huperzine A compound according to claim  1   10 to a patient in need of such treatment in an amount effective to inhibit cholinesterase. 
     
     
       3. A method of treating dysmnesia, caused by a failure in central cholinergic system by inhibiting cholinesterase comprising administering a huperzine A compound according to claim  1   10 to a patient in need of such treatment in an amount effective to inhibit cholinesterase. 
     
     
       4. A method of inhibiting cholinesterase comprising administering a huperzine A compound according to claim  1   10 in an amount effective to inhibit cholinesterase to a patient in need of such treatment. 
     
     
       5. A method of inhibiting cholinesterase according to  claim 4 , wherein said cholinesterase is an acetylcholinesterase. 
     
     
       6. A method of inhibiting cholinesterase according to  claim 4 , wherein the cholinesterase is butyrylcholinesterase. 
     
     
       7. A method of improving memory impairment comprising administering a huperzine A compound according to claim  1   10 in an amount effective to improve mnemory imnpairmientmemory impairment to a patient in need of such treatment. 
     
     
       8. A compound according to claim  1   10 , wherein R″ and Y are ═CH, prepared by a process of condensing huperzine A and the corresponding substituted aldehyde in an anhydrous solvent. 
     
     
       9. A method of inhibiting cholinesterase according to  claim 4 , wherein said huperzine A compound exhibits weaker inhibition effect on butyrylcholinesterase than huperzine A. 
     
     
       10. A huperzine A compound of the formula                    
       
         wherein  
       
       
         Y and —R″ together form a ═CH group;  
       
       
         R is  
         
           
           
               
               
           
         
       
       
         wherein X is selected from the group consisting of hydrogen, C 
         1 
         -C 
         5  
         lower alkoxy, nitro, halogen, hydroxymethyl, hydroxy, amino substituted by two C 
         1 
         -C 
         5  
         lower alkyls and —CH═CH—G,  
       
       
         wherein G is phenyl or furanyl; and  
       
       
         R′ is hydrogen.  
       
     
     
       11. A huperzine A compound of the formula                    
       
         wherein  
       
       
         Y and —R″ together form ═CH;  
       
       
         R is selected from the group consisting of:  
         
           
           
               
               
           
         
       
       
         and R′ is hydrogen.  
       
     
     
       12. A huperzine A compound of the formula                    
       
         wherein  
       
       
         Y and —R″ together form ═CH; and  
       
       
         R is  
         
           
           
               
               
           
         
       
     
     
       13. A huperzine A compound of the formula                    
       
         wherein  
       
       
         Y and —R″ together form ═CH; and  
       
       
         R is  
         
           
           
               
               
           
         
       
       
         wherein each X is independently selected from the group consisting of hydrogen, methoxy, nitro, halogen, hydroxymethyl, and hydroxy;  
       
       
         and R′ is H.  
       
     
     
       14. A method of treating amyasthenia by inhibiting cholinesterase comprising administering a huperzine A compound according to  claim 11  to a patient in need of such treatment in an amount effective to inhibit cholinesterase.  
     
     
       15. A method of treating amyasthenia by inhibiting cholinesterase comprising administering a huperzine A compound according to  claim 12  to a patient in need of such treatment in an amount effective to inhibit cholinesterase.  
     
     
       16. A method of treating amyasthenia by inhibiting cholinesterase comprising administering a huperzine A compound according to  claim 13  to a patient in need of such treatment in an amount effective to inhibit cholinesterase.  
     
     
       17. A method of treating dysmnesia caused by a failure in central cholinergic system by inhibiting cholinesterase comprising administering a huperzine A compound according to  claim 11  to a patient in need of such treatment in an amount effective to inhibit cholinesterase.  
     
     
       18. A method of treatment dysmnesia caused by a failure in central cholinergic system by inhibiting cholinesterase comprising administering a huperzine A compound according to  claim 12  to a patient in need of such treatment in an amount effective to inhibit cholinesterase.  
     
     
       19. A method of treating dysmnesia caused by a failure in central cholinergic system by inhibiting cholinesterase comprising administering a huperzine A compound according to  claim 13  to a patient in need of such treatment in an amount effective to inhibit cholinesterase.  
     
     
       20. A method of inhibiting cholinesterase comprising administering a huperzine A compound according to  claim 11  in an amount effective to inhibit colinesterase to a patient in need of such treatment.  
     
     
       21. A method of inhibiting cholinesterase comprising administering a huperzine A compound according to  claim 12  in an amount effective to inhibit colinesterase to a patient in need of such treatment.  
     
     
       22. A method of inhibiting cholinesterase comprising administering a huperzine A compound according to  claim 13  in an amount effective to inhibit colinesterase to a patient in need of such treatment.  
     
     
       23. A method of improving memory impairment comprising administering a huperzine A compound according to  claim 11  in an amount effective to improve memory impairment to a patient in need of such treatment.  
     
     
       24. A method of improving memory impairment comprising administering a huperzine A compound according to  claim 12  in an amount effective to improve memory impairment to a patient in need of such treatment.  
     
     
       25. A method of improving memory impairment comprising administering a huperzine A compound according to  claim 13  in an amount effective to improve memory impairment to a patient in need of such treatment.