Acetylcholinesterase dual inhibitors

Abstract

The invention provides compounds of formula: which have a tacrine moiety connected to an heterocyclic moiety through a linker. Through careful selection of the substituents and the linker, the activity and selectivity towards acetylcholinesterase can be modulated. The compounds show potent AChE inhibition activities together with modifications in the β-amyloid aggregation properties by binding simultaneously to the catalytic and peripheral AChE sites. They are useful in the treatment of AChE mediated diseases, such as the Alzheimer's disease.

1 . A method of treatment of a patient with an AChE-mediated disease, which comprises administration of an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         A, B are independently selected from CH and N; 
         D is selected from CH, O, S and N; 
         provided that at least one of A, B or D is an heteroatom; 
         when D is CH or N, then Z is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy; 
         when D is O or S, then Z is absent; 
         each L is independently selected from —CR a R b —, —CR a ═, —CO—, —O—, —S— and —NR a —; 
         k, m, n, q, x and w are each an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, with the proviso that k+m+n+q+x+w is at least 4; 
         R 1  to R 6  are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, —COR a , —C(O)OR a , —C(O)NR a R b , —C═NR a , —CN, —OR a , —OC(O)R a , —S(O) t —R a , —NR a R b , —NR a C(O)R b , —NO 2 , —N═CR a R b  and halogen; 
         R a  and R b  are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy and halogen; with the proviso that they are not halogen when linked to a N; 
         t is 0, 1 or 2; 
         or a tautomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof. 
       
     
     
         2 . The method of  claim 1 , for the treatment of a condition selected from the group consisting of cognitive disorders such as senile dementia, cerebrovascular dementia, mild recognition impairment, attention deficit disorder, and/or neurodegenerative dementing disease with aberrant protein aggregations such as specially Alzheimers's disease or condition, or prion disease as Creutzfeld-Jacob disease or Gerstmann-Straussler-Scheinher disease, or Parkinson's disease or condition, or Polyglutamine disease, or tauopathies such as Pick's disease, frontotemporal dementia, supranuclear progressive palsy, or familial amyotrophic lateral sclerosis or systemic amyloidosis or condition. 
     
     
         3 . A method according to  claim 2 , for the treatment of Alzheimers's disease. 
     
     
         4 . A method of biological assay which employs as reactive a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         A, B are independently selected from CH and N; 
         D is selected from CH, O, S and N; 
         provided that at least one of A, B or D is an heteroatom; 
         when D is CH or N, then Z is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy; 
         when D is O or S, then Z is absent; 
         each L is independently selected from —CR a R b —, —CR a ═, —CO—, —O—, —S— and —NR a —; 
         k, m, n, q, x and w are each an integer independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, with the proviso that k+m+n+q+x+w is at least 4; 
         R 1  to R 6  are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, —COR a , —C(O)OR a , —C(O)NR a R b , —C═NR a , —CN, —OR a , —OC(O)R a , —S(O) t —R a , —NR a R b , —NR a C(O)R b , —NO 2 , —N═CR a R b  and halogen; 
         R a  and R b  are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy and halogen; with the proviso that they are not halogen when linked to a N; 
         t is 0, 1 or 2; 
         or a tautomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof.