Carbamoyl Esters That Inhibit Cholinesterase And Release Pharmacologically Active Agents

Abstract

Carbamoyl esters inhibit cholinesterase activity and, upon hydrolysis release a pharmacologically active agent. In one embodiment, the carbamoyl ester has the following structure: wherein A is selected from the group consisting of an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl and a substituted heteroaryl. The carbamoyl esters are employed in methods to treat an individual. The pharmacologically active agent obtained by hydrolysis of the carbamoyl esters can treat, for example, a nervous system condition, a cholinergic deficiency and conditions or diseases associated with a deficiency in a pharmacologically active agent, such as acetylcholine.

1 . A compound that inhibits a cholinesterase, comprising an amine group that, upon hydrolysis, becomes at least a component of a pharmacologically active agent, wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of a hydrogen, an unsubstituted alkyl, a substituted alkyl, an unsubstituted aralkyl, a substituted aralkyl, an unsubstituted heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroaralkyl, a substituted heteroaralkyl, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted cycloalkyl, a substituted cycloalkyl, an unsubstituted heterocycloalkyl and a substituted heterocycloalkyl; 
 R 2  is selected from the group consisting of a hydrogen, an unsubstituted alkyl, a substituted alkyl, an unsubstituted aralkyl, a substituted aralkyl, an unsubstituted heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroaralkyl, a substituted heteroaralkyl, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted cycloalkyl, a substituted cycloalkyl, an unsubstituted heterocycloalkyl and a substituted heterocycloalkyl; 
 R 3  is selected from the group consisting of a hydrogen, an unsubstituted alkyl, a substituted alkyl, an unsubstituted aralkyl, a substituted aralkyl, an unsubstituted heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroaralkyl, a substituted heteroaralkyl, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted cycloalkyl, a substituted cycloalkyl, an unsubstituted heterocycloalkyl and a substituted heterocycloalkyl; 
 R 4  is selected from the group consisting of a hydrogen, an unsubstituted alkyl, a substituted alkyl, an unsubstituted aralkyl, a substituted aralkyl, an unsubstituted heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroaralkyl, a substituted heteroaralkyl, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted cycloalkyl, a substituted cycloalkyl, an unsubstituted heterocycloalkyl and a substituted heterocycloalkyl; and 
 R 5  is selected from the group consisting of a hydrogen, an unsubstituted alkyl, a substituted alkyl, an unsubstituted aralkyl, a substituted aralkyl, an unsubstituted heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroaralkyl, a substituted heteroaralkyl, an unsubstituted aryl, a substituted aryl, an unsubstituted heteroaryl, a substituted heteroaryl, an unsubstituted cycloalkyl, a substituted cycloalkyl, an unsubstituted heterocycloalkyl and a substituted heterocycloalkyl. 
 
     
     
         2 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein the pharmacologically active agent is an amphetamine compound. 
     
     
         5 . The compound of  claim 1 , wherein the pharmacologically active agent is at least one member selected from the group consisting of a cholinergic agent, an adrenergic agent, a noradrenergic agent, a dopaminergic agent, a serotonergic agent, a glutamatergic agent, a GABAergic agent, a histaminergic agent, a mono-amine oxidase inhibitor, a calcium channel blocker, a nootropic, a trace amine receptor modulator, and non-steroidal anti-inflammatory drugs. 
     
     
         6 . The compound of  claim 1 , wherein the pharmacologically active agent is selected from desipramine, fluoxetine, fluvoxamine, protripyline, amoxapine, paroxetine, dorzolamide, riluzole, baclofen, methylphenidate, sertraline, dopamine, amantadine, memantine, glutamic acid, glycine, alpha-methylhistamine, D-cycloserine, dobutamine, lamotrigine, levodopa, nimodipine, nomifensine, pramipexole, aspartic acid, l-cysteinesulfinic acid, glutamic acid, D-serine, brimonidine, and pergolide. 
     
     
         7 . The compound of  claim 1 , wherein R 3 , R 4 , and R 5  are unsubstituted alkyl. 
     
     
         8 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of H, substituted alkyl, and unsubstituted alkyl. 
     
     
         9 . The compound of  claim 1 , wherein R 2  is an unsubstituted aralkyl group, wherein said aralkyl group is an aryl substituent linked by a branched alkyl group having 3 carbon atoms and wherein said aryl substituent is phenyl. 
     
     
         10 . A pharmaceutical composition comprising the compound of  claim 1 , wherein the compound is administered as an admixture with conventional excipients selected from pharmaceutically or physiologically, acceptable organic, and inorganic carrier substances suitable for enteral or parenteral application. 
     
     
         11 . Use of a compound of  claim 1  for treatment of an individual having at least one condition selected from a central nervous system condition, a peripheral nervous system condition, and an autonomic nervous system condition. 
     
     
         12 . The compound of  claim 11 , wherein the central nervous system condition is at least one condition selected from the group consisting of Parkinson's disease, a memory impairment and a cognitive impairment, wherein preferably the memory impairment is in a human associated with at least one condition selected from the group consisting of Alzheimer's disease, age-associated memory loss, an impairment in memory consolidation, an impairment in short term memory, mild cognitive impairment and multiple sclerosis. 
     
     
         13 . Use of a compound of  claim 1  for treatment of a cholinergic deficiency in an individual, wherein the compound inhibits a cholinesterase thereby treating the cholinergic deficiency in the individual. 
     
     
         14 . The compound of  claim 13 , wherein the cholinergic deficiency in the individual is Alzheimer's disease. 
     
     
         15 . The compound of  claim 11 , wherein the individual is a human.