Compositions and methods for treating cns disorders

Abstract

The invention generally relates to thienopyridinone 5-HT 4 receptor modulators, and in particular the use of these compounds and their pharmaceutical compositions, e.g., in the treatment, modulation and/or prevention of physiological conditions associated with serotonin action, such as in treating Alzheimer's disease, cognition disorders, depression, and anxiety.

1 . A pharmaceutical composition comprising
 a first compound having the formula   
       
         
           
           
               
               
           
         
         
           wherein R 1  is (C 1 -C 8 ) branched or unbranched alkyl; a (C 1 -C 8 ) substituted or unsubstituted carbocyclic ring; branched or unbranched haloalkyl, a substituted or unsubstituted aryl or heteroaryl ring, or a substituted or unsubstituted (CH 2 ) p -aryl or (CH 2 ) p -heteroaryl ring, where p is 1, 2, 3, or 4; R 2  and R 3 , taken together, form a substituted or unsubstituted piperidine, pyrrolidine, azepane, aziridine, or azetidine ring; and n is 1, 2, 3, 4, 5 or 6; and pharmaceutically acceptable salts and/or esters thereof, the first compound being present in an amount which if administered alone does not substantially enhance memory; and 
         
         a second compound which is a cholinesterase or acetylcholinesterase inhibitor and is present in an amount which if administered alone does not substantially enhance memory. 
       
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein R 1  is a (C 1 -C 8 ) alkyl selected from the group consisting of methyl, ethyl, isopropyl, n-propyl, n-butyl or isobutyl; R 2  and R 3  taken together form a substituted or unsubstituted piperidine (N-containing six-membered cyclic ring); and n is 3. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the branched or unbranched haloalkyl group contains a halogen atom selected from the group consisting of F, Cl, Br, and I. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the first compound is 6,7-dihydro-4-hydroxy-7-isopropyl-6-oxo-N-(3-(piperidin-1-yl)propyl)thieno[2,3-b]pyridine-5-carboxamide or a pharmaceutically acceptable salt and/or ester thereof. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the amount of the first compound is sufficient to provide a dosage of less than about 0.25 mg/kg. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the amount of the first compound is sufficient to provide a dosage of between 0.01 and 0.25 mg/kg. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the second compound is selected from the group consisting of metrifonate, neostigmine, physostigmine, pyridostigmine, galantamine/galanthamine, donepezil, tacrine, ambenonium, demarcarium, edrophonium, rivastigmine, phenserine, mentane, and eptastigmine; or pharmaceutically acceptable salts and/or esters thereof. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the amount of the second compound is sufficient to provide a dosage of less than about 0.5 mg/kg. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the amount of the second compound is sufficient to provide a dosage of between 0.1 and 0.5 mg/kg. 
     
     
         10 . A method of treating Alzheimer's disease, a cognition disorder, or enhancing memory in a patient in need thereof, comprising administering to or diagnosing a patient in need thereof a therapy including a first compound having the formula 
       
         
           
           
               
               
           
         
         wherein R 1  is (C 1 -C 8 ) branched or unbranched alkyl; a (C 1 -C 8 ) substituted or unsubstituted carbocyclic ring; branched or unbranched haloalkyl, a substituted or unsubstituted aryl or heteroaryl ring, or a substituted or unsubstituted (CH 2 ) p -aryl or (CH 2 ) p -heteroaryl ring, where p is 1, 2, 3, or 4; R 2  and R 3 , taken together, form a substituted or unsubstituted piperidine, pyrrolidine, azepane, aziridine, or azetidine ring; and n is 1, 2, 3, 4, 5 or 6; and pharmaceutically acceptable salts and/or esters thereof, the first compound being present in an amount which if administered alone does not substantially enhance memory; and 
         a second compound which is a cholinesterase or acetylcholinesterase inhibitor and is present in an amount which if administered alone does not substantially enhance memory. 
       
     
     
         11 - 13 . (canceled) 
     
     
         14 . The method of  claim 10 , wherein the first and second compounds are administered together. 
     
     
         15 . The method of  claim 10 , wherein the first and second compounds are administered separately. 
     
     
         16 . The method of  claim 10 , wherein the amount of the first compound is sufficient to provide a dosage of less than about 0.25 mg/kg. 
     
     
         17 . The method of  claim 10 , wherein the amount of the first compound is sufficient to provide a dosage of between 0.01 and 0.25 mg/kg. 
     
     
         18 . The method of  claim 10 , wherein the amount of the second compound is sufficient to provide a dosage of less than about 0.5 mg/kg. 
     
     
         19 . The method of  claim 10 , wherein the amount of the second compound is sufficient to provide a dosage of between 0.1 and 0.5 mg/kg.