Heteroaryl amines as novel acetylcholinesterase inhibitors

Abstract

Compounds of the formula wherein ring A, ring B, ring D, R 2 , R 3 , R 4 , R 5 , R 6 ,R 11 , R 12 , R 13 , E, G, X and P are as defined below. The compounds of formula I are cholinesterase inhibitors and are useful in enhancing memory in patients suffering from dementia and Alzheimer's disease.

1 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein one of R 2 , R 3  and the side chain containing  
       
         
           
           
               
               
           
         
       
       may optionally be attached to the carbon atom designated by an asterisk in ring B rather than to a member of ring A; 
 ring A is benzo, thieno, pyrido, pyrazino, pyrimido, furano, seleno, pyrrolo, thiazolo, or imidazolo;  
 R 1  is phenyl, phenyl-(C 1 -C 6 )alkyl, cinnamyl or heteroarylmethyl, wherein the heteroaryl moiety of said heteroarylmethyl is selected from imidazolo, thiazolo, thieno, pyrido and isoxazolo, and wherein said phenyl and said heteroaryl moiety may optionally be substituted with one or two substituents independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and halo;  
 R 2  and R 3  are independently selected from hydrogen, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl optionally substituted with from one to three fluorine atoms, benzyloxy, hydroxy, phenyl, benzyl, halo, nitro, cyano, COOR 4 , CONHR 4 , NR 4 R 5 , NR 4 COR 5 , or SO p CH 2 -phenyl wherein p is 0, 1 or 2;  
 or R 2  and R 3  are attached to adjacent carbon atoms and form, together with the carbons to which they are attached, a five or six membered ring wherein each atom of the ring is carbon, nitrogen or oxygen (e.g., a methylenedioxy, ethylenedioxy or lactam ring);  
 R 4  and R 5  are independently selected from hydrogen and (C 1 -C 6 )alkyl, or R 4  and R 5 , when part of said NR 4 R 5 , optionally form, together with the nitrogen to which they are attached, a ring containing four to eight members wherein one atom of the ring is nitrogen and the others are carbon, oxygen or nitrogen, or R 4  and R 5 , when part of said NR 4 COR 5 , optionally form, together with the nitrogen and carbon to which they are attached, a four to eight membered lactam ring;  
 X is nitrogen or CH;  
 Y is oxygen, sulfur or NR 6 ;  
 R 6  is hydrogen, (C 1 -C 6 )alkyl, CO(C 1 -C 6 )alkyl or SO 2 —, phenyl, wherein the phenyl moiety of said SO 2 -phenyl may optionally be substituted with from one to five substituents independently selected from (C 1 -C 4 ) alkyl;  
 n is an integer from 1 to 4;  
 each q is independently 1 or 2; and  
 Z is oxygen or sulfur;  
 with the proviso that any CH q  group wherein q is 1 must be attached to one and only one other CH q  group wherein q is 1;  
 or a pharmaceutically acceptable salt of such compound.  
 
     
     
         2 . A compound according to  claim 1 , having the formula  
       
         
           
           
               
               
           
         
       
       wherein X is CH, CCH 3  or N; Y is NH, NCH 3 , NCH 2 CH 3 , S, O or NSO 2 C 6 H 5 ; R 2  and R 3  are independently selected from the group consisting of (C 1 -C 4 )alkyl, chloro, fluoro, methoxy, amino and  
       
         
           
           
               
               
           
         
       
       or R 2  and R 3 , together with the carbons to which they are attached, form a γ-lactam ring; and R 1  is benzyl, methoxybenzyl, fluorobenzyl or a group of the formula  
       
         
           
           
               
               
           
         
       
       wherein W is hydrogen, (C 1 -C 6 )alkyl, phenyl or benzyl.  
     
     
         3 . A compound according to  claim 2 , wherein X is CH, CCH 3  or N; Y is NH, NCH 3 , sulfur or oxygen; R 2  and R 3  are independently selected from the group consisting of (C 1 -C 4 )alkyl, chloro, fluoro, methoxy, amino and  
       
         
           
           
               
               
           
         
       
       and R 1  is benzyl.  
     
     
         4 . A compound according to  claim 3 , wherein R 2  and R 3  are independently selected from the group consisting of (C 1 -C 4 )alkyl, chloro, amino and  
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound according to  claim 1 , selected from the group consisting of: 
 1-(2-methyl-1H-benzimidazol-5-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone hydrochloride;    1-(2-phenyl-1H-benzimidazol-5-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone hydrochloride;    1-(1-ethyl-2-methyl-1H-benzimidazol-5-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone hydrochloride;    1-(2-methyl-6-benzothiazolyl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone hydrochloride;    1-(2-methyl-6-benzothiazolyl)-3-[1-((2-methyl-4-thiazolyl)methyl)-4-piperidinyl]-1-propanone;    1-(5-methyl-benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;    1-(6-methyl-benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;    1-(3,5-dimethyl-benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;    1-(benzo[b]thien-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;    1-(benzofuran-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;    1-(1-phenylsulfonyl-6-methyl-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;    1-(6-methyl-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;    1-(1-phenylsulfonyl-5-amino-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone;    1-(5-amino-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone; and    1-(5-acetylamino-indol-2-yl)-3-[1-(phenylmethyl)-4-piperidinyl]-1-propanone.    
     
     
         6 . A pharmaceutical composition for enhancing memory or treating or preventing Alzheimer's disease comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         7 . A pharmaceutical composition for inhibiting cholinesterase in a mammal, comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         8 . A method of inhibiting cholinesterase in a mammal, comprising administering to a mammal a cholinesterase inhibiting amount of a compound according to  claim 1 .  
     
     
         9 . A method of enhancing memory or treating or preventing Alzheimer's disease, comprising administering to a patient a memory enhancing effective amount of a compound according to claim  1 .