Compounds and Compositions for Cognition-Enhancement, Methods of Making, and Methods of Treating

Abstract

Disclosed are muscarinic agonist compounds including oxadiazole derivatives, compositions and preparations thereof. Also disclosed are methods of synthesizing such oxadiazole compounds. Further disclosed are methods for treating a subject with said muscarinic agonists or a pharmaceutically suitable form thereof to enhance cognitive function.

1 - 30 . (canceled) 
     
     
         31 . A method comprising administering an effective amount of a compound or composition of a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of —CR 2 R 3 R 4 , 
 
       
         
           
           
               
               
           
         
         R 2 , R 3  and R 4  are independently selected from D or F; and 
         R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  are independently selected from H, D, F or a methyl group; 
         provided that not more than one of R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  is a methyl group; 
       
       and pharmaceutically acceptable salts or stereoisomers thereof to a subject in need thereof. 
     
     
         32 . The method of  claim 31 , wherein the subject is suffering from presenile dementia, senile dementia, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, and Tourette syndrome or Alzheimer's disease. 
     
     
         33 .- 50 . (canceled) 
     
     
         51 . A method of enhancing cognition and/or memory in a subject comprising administering to a subject an effective amount of a compound or composition of  claim 31 . 
     
     
         52 . The method of  claim 51 , wherein the subject is a human who is suffering from Alzheimer's disease. 
     
     
         53 . A method of treating a cognitive disorder in a subject comprising administering to a subject an effective amount of a compound or composition of  claim 31 ,
 wherein said subject is suffering from a cognitive disorder selected from the group consisting of cognitive impairment, Mild Cognitive Impairment, frontotemporal dementia, dementia with Lewy bodies, presenile dementia, senile dementia, Down's syndrome, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, and Tourette syndrome or Alzheimer's disease.   
     
     
         54 . The method of  claim 53 , wherein the subject is a human who is suffering from Alzheimer's disease. 
     
     
         55 . A method stimulating muscarinic receptors in the brain of a subject comprising administering to a subject an effective amount of a compound or composition of  claim 31 . 
     
     
         56 .- 59 . (canceled) 
     
     
         60 . A method of treating psychosis in a subject, comprising administering to a subject suffering from psychosis, a therapeutically effective amount of a compound of a compound or composition of  claim 31 . 
     
     
         61 . The method of  claim 60 , wherein the psychosis accompanies or results from schizophrenia. 
     
     
         62 . The method of  claim 60 , wherein the psychosis accompanies or results from Alzheimer's disease. 
     
     
         63 . A method reduce the level of API in a subject, comprising administering to a subject in need of said reducing an amount of a compound of a compound or composition according to  claim 31 . 
     
     
         64 . The method of  claim 63 , wherein the subject suffers from Alzheimer's disease. 
     
     
         65 . The method of  claim 64 , wherein the level of Aβ is reduced in neurons expressing muscarinic M1 receptors. 
     
     
         66 . A method of treating a subject having a neurological condition comprising a deficit in cholinergic activity, the method comprising administering to said subject an effective amount of a compound or composition according to  claim 31  to cause at least one biological activity in said subject selected from the group consisting of inhibiting glycogen synthetase 3β activity, increasing protein kinase C activity, increasing levels of inositol phosphates, increasing levels of sAPPα, reducing the level of Aβ, and inhibiting apoptosis in neurons expressing M1 muscarinic receptors. 
     
     
         67 . The method of  claim 66 , wherein the subject suffers from Alzheimer's disease. 
     
     
         68 . The method according to  claim 67 , wherein the compound or composition is administered to the subject for at least a month. 
     
     
         69 .- 85 . (canceled) 
     
     
         86 . A method for treating a subject with a cognitive disorder comprising:
 administering to said subject a at least one muscarinic agonists, wherein said at least one muscarinic agonists is an M1 or M1/M4 selective muscarinic agonist and wherein the amount of M1 or M1/M4 selective muscarinic agonist is sufficient to achieve in the blood stream of the subject, in the absence of a muscarinic antagonist, a concentration sufficient to cause the subject to experience at least one moderate cholinergic side effect selected from the group consisting of diaphoresis, hypersalivation, flushing, gastro-intestinal tract upsets, increased stomach acid, nausea, vomiting and diarrhea, breathing difficulties, tachycardia, dizziness, syncope, headache, convulsions, somnolence and combinations thereof, and   administering to said subject at least one muscarinic antagonist, wherein the amount of said at least one muscarinic antagonist is sufficient to achieve in the blood stream of said subject a concentration of said at least one muscarinic antagonist sufficient to cause the subject to experience at most only mild or moderate cholinergic side effects during at least a portion of the time that the antagonist is present in the blood stream.   
     
     
         87 . The method of  claim 86 , wherein the subject experiences at most only mild cholinergic side effects during at least a portion of the time that the antagonist is present in the blood stream. 
     
     
         88 .- 91 . (canceled) 
     
     
         92 . The method of  claim 86 , wherein said at least one muscarinic antagonist is selected from the group consisting of N-methylatropine nitrate, flavoxate hydrochloride, N-methylscopolamine hydrochloride, glycopyrrolate bromide, darifenacin hydrobromide, solifenacin succinate, propantheline bromide, trospium chloride, tolterodine tartrate, fesotcrodine fumarate, methantheline bromide and combinations thereof. 
     
     
         93 - 109 . (canceled) 
     
     
         110 . The method according to  claim 92 , wherein the muscarinic antagonist is fesoterodine or a salt thereof. 
     
     
         111 . The method according to  claim 110 , wherein the muscarinic antagonist is fesoterodine fumarate. 
     
     
         12 . The method according to  claim 110 , wherein the muscarinic antagonist is a chloride salt of fesoterodine.