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 .- 112 . (canceled) 
     
     
         113 . A method for treating a subject suffering from presenile dementia, senile dementia, Huntington's disease, tardive dyskinesia, hyperkinesia, mania, Tourette syndrome, Alzheimer's disease, dementia with Lewy bodies or frontotemporal dementia, comprising:
 administering to said subject at least one muscarinic agonist, wherein said at least one muscarinic agonist 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,   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, fesoterodine fumarate, methantheline bromide and combinations thereof.   
     
     
         114 . The method according to  claim 113 , wherein the muscarinic agonist is a compound of Formula X, XA or XB, or a stereoisomer thereof or a pharmaceutically acceptable salt of said compound or stereoisomer, 
       
         
           
           
               
               
           
         
       
       wherein
 X is O or S; 
 R 1  is NH 2 , or methyl, optionally substituted with 1-3 deuterium atoms; or, when X is S, R 1  can also be H; 
 m is 1 or 2; and 
 wherein one or more hydrogens in the compounds of Formula X, XA and XB may be replaced with deuterium. 
 
     
     
         115 . The method according to  claim 114 , wherein X is O and m is 1. 
     
     
         116 . The method according to  claim 115 , wherein R 1  is methyl. 
     
     
         117 . The method according to  claim 113 , wherein the method is for treating a subject suffering from Alzheimer's disease. 
     
     
         118 . The method according to  claim 114 , wherein the method is for treating a subject suffering from Alzheimer's disease. 
     
     
         119 . The method according to  claim 115 , wherein the method is for treating a subject suffering from Alzheimer's disease. 
     
     
         120 . The method according to  claim 116 , wherein the method is for treating a subject suffering from Alzheimer's disease. 
     
     
         121 . A method for treating a subject suffering from presenile dementia, senile dementia, Huntington's disease, tardive dyskinesia, hyperkinesia, mania, Tourette syndrome, Alzheimer's disease, dementia with Lewy bodies or frontotemporal dementia, comprising:
 administering to said subject at least one muscarinic agonist, wherein said at least one muscarinic agonist 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,   wherein the muscarinic agonist is a compound of Formula X, XA or XB, or a stereoisomer thereof or a pharmaceutically acceptable salt of said compound or stereoisomer,   
       
         
           
           
               
               
           
         
       
       wherein
 X is O or S; 
 R 1  is NH 2 , or methyl, optionally substituted with 1-3 deuterium atoms; or, when X is S, R 1  can also be H; 
 m is 1 or 2; and 
 wherein one or more hydrogens in the compounds of Formula X, XA and XB may be replaced with deuterium. 
 
     
     
         122 . The method according to  claim 121 , wherein X is O and m is 1. 
     
     
         123 . The method according to  claim 122 , wherein R 1  is methyl. 
     
     
         124 . The method according to  claim 121 , wherein the method is for treating a subject suffering from Alzheimer's disease. 
     
     
         125 . The method according to  claim 122 , wherein the method is for treating a subject suffering from Alzheimer's disease. 
     
     
         125 . The method according to  claim 123 , wherein the method is for treating a subject suffering from Alzheimer's disease. 
     
     
         126 . The method according to  claim 121 , 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, methantheline bromide and combinations thereof. 
     
     
         127 . The method according to  claim 122 , 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, methantheline bromide and combinations thereof. 
     
     
         128 . The method according to  claim 123 , 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, methantheline bromide and combinations thereof. 
     
     
         129 . The method according to  claim 124 , 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, methantheline bromide and combinations thereof. 
     
     
         130 . The method according to  claim 125 , 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, methantheline bromide and combinations thereof.