Unique Dual-Action Therapeutics

Abstract

A new family of therapeutics which provides a controlled-release delivery platform for non-steroidal anti-inflammatory agents on an ester or an ester-carbonate backbone is disclosed herein. These agents are reversible inhibitors of acetylcholinesterase and are thus useful for clinical conditions benefiting from inflammation suppression and cholinergic intervention. These compounds are of the general formula wherein n=0, 1; X═C, Si, and N+ and NSAID=ibuprofen, naproxen, indomethacin and diclofenac. Other embodiments are also disclosed.

1 . A compound of Formula 1 
       
         
           
           
               
               
           
         
         wherein
 n is 0 or 1; 
 X is Si, C, or N + ; 
 wherein when X is C or N + , each R is alike or different and is hydrogen or (C 1 -C 6 ) alkyl; 
 when X is Si, each R is methyl; and 
 NSAID is a non-steroidal anti-inflammatory agent. 
 
       
     
     
         2 . The compound of  claim 1  wherein the NSAID is ibuprofen, naproxen, indomethacin, diclofenac. 
     
     
         3 . The compound of  claim 1  which is
 4-[{2-(4-isobutylphenyl)propanoyloxy}methyl]phenyl 3,3-dimethylbutyl carbonate, 
 4-[{2-(4-isobutylphenyl)propanoyloxy}methyl]phenyl 2-(trimethylsilyl)ethyl carbonate, 
 4-[{2-(2-Methoxynaphthalen-6-yl)propanoyloxy}methyl]phenyl 3,3-dimethylbutyl carbonate, 
 4-[{2-(2-Methoxynaphthalen-6-yl)propanoyloxy}methyl]phenyl 2-(trimethylsilyl)ethyl carbonate, 
 4-[{2-(2-Methoxynaphthalen-6-yl)propanoyloxy}methyl]phenyl 3-methylbutyl carbonate, 
 4-[[2-{1-(4′-Chlorobenzoyl)-2-methyl-5-methoxy-1H-indol-3-yl}ethanoyl]-methyl]phenyl 3,3-dimethylbutyl carbonate, 
 4-[[2-{1-(4′-chlorobenzoyl)-2-methyl-5-methoxy-1H-indol-3-yl}ethanoyl]-methyl]phenyl 2-(trimethylsilyl)ethyl carbonate, 
 [o-(2,6-dichloroanilino)phenyl]acetyl 3,3-dimethylbutyl carbonate, 
 [o-(2,6-dichloroanilino)phenyl]acetyl 2-(trimethylsilyl)ethyl carbonate, 
 4-[{2-(4-isobutylphenyl)propanoyloxy}methyl]phenyl 2-(trimethylammonium)ethyl carbonate iodide, 
 4-[{2-(2-methoxynaphthalen-6-yl)propanoyloxy}methyl]phenyl 2-(trimethylsilyl)ethyl carbonate, 
 4-[{2-(2,6-dichlorophenylamino)phenylethanoyl}methyl]phenyl 2-(trimethylsilyl)ethyl carbonate, 
 3,3-dimethylbutyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate, 
 (S)-3,3-dimethylbutyl 2-(6-methoxynaphthalen-2-yl)propanoate, 
 3,3-dimethylbutyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate, 
 3,3-dimethylbutyl 2-(4-isobutylphenyl)propanoate, 
 2-(trimethylsilyl)ethyl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate, 
 2-(trimethylsilyl)ethyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate, 
 (S)-2-(trimethylsilyl)ethyl 2-(6-methoxynaphthalen-2-yl)propanoate, 
 2-(trimethylsilyl)ethyl 2-(4-isobutylphenyl)propanoate, 
 2-[[2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetyl]oxy]-N,N,N-trimethyl-ethanaminium iodide, 
 2-[2-(6-methoxy-2-naphthalenyl)-1-oxopropoxy]-N,N,N-trimethyl-ethanaminium iodide, or 
 N,N,N-Trimethyl-2-[2-[4-(2-methylpropyl)phenyl]-1-oxopropoxy]-ethanaminium iodide. 
 
     
     
         4 . A process identified herein as Method A for production of compound of  claim 1  wherein n is 1 and X is Si or C comprising the coupling of the acid chloride of an 
       
         
           
           
               
               
           
         
         NSAID [NSAID-CO—Cl] to the carbonate of a 4-hydroxybenzyl phenol exemplified by  5  or  6  wherein these referenced carbonates were prepared for this purpose by linking the requisite chloroformate to 4-hydroxybenzaldehyde with subsequent formyl reduction. 
       
     
     
         5 . A. process identified herein as Method B for the production of the compound of  claim 1  wherein n is 1, X is Si or C comprising the direct coupling of the NSAID's 
       
         
           
           
               
               
           
         
       
       carboxylic acid moiety onto the benzyl alcohol carbonates (e.g. 5 or 6) by in situ activation of that —COOH by carbonyldiimidazole or carbodimides thus avoiding the intermediacy of an acid chloride. 
     
     
         6 . A process identified herein as Method C for production of the compound of  claim 1  wherein n is 1, X is Si or C comprising the direct coupling of the requisite NSAID carboxylic acid under Mitsunobu conditions to the —CH 2 OH of p-hydroxymethylphenol (4-hydroxybenzyl alcohol) and then reacting a chloroformate with the phenolic hydroxyl of the resulting adduct. 
     
     
         7 . A process identified herein as Method D for production of the compound of  claim 1  wherein n is 1, X is Si or C comprising the displacement of the chloro from Cl—CH 2 —C 6 H 4 —O—CO—O—CH 2 CH 2 —SiMe 3  by the carboxylic acid anion of an NSAID carboxylic acid generated in situ by a strong base in a non-polar, aprotic solvent 
     
     
         8 . A process identified herein as Method E for production of the compound of  claim 1  wherein n is 0, X is Si or C by the EDC-catalyzed, 4-(dimethylamino)pyridine-activated esterification of either 3,3-dimethyl-1-butanol on 2-(trimethylsilyl)ethanol with requisite NSAID acids as specifically exemplified by compounds 19-26. 
     
     
         9 . A process identified herein as Method F consisting of three steps for the production of the compound of  claim 1  wherein n is 0, X is N +  in which an NSAID is precondensed with 2-chloro-1-methyl-pyridinium iodide and the intermediate thereof intercepted by the lithium salt of N,N-dimethylaminoethanol and subsequently methylated to yield choline esters of NSAIDs as specifically exemplified by compounds 27-29. 
     
     
         10 . A pharmaceutical composition comprising a compound of  claim 1  in a pharmaceutically acceptable carrier. 
     
     
         11 . The pharmaceutical composition of  claim 10  wherein the composition is suitable for administration as a tablet or pill for oral administration, a solution or suspension for parental administration or ointment for topical application 
     
     
         12 . A method for treating a systemic or topical inflammatory or pro-inflammatory condition which comprises administering to the patient a pharmaceutically effective amount of the compound of  claim 1 . 
     
     
         13 . The method of  claim 12  wherein the systemic or topical inflammatory or pro-inflammatory condition is vesication, multiple sclerosis, Alzheimer's disease, depression, amyotrophic lateral sclerosis, dementia, Parkinson's disease, or other neurodegenerative states 
     
     
         14 . The method of  claim 12  wherein the compound is administered topically, parenterally or orally 
     
     
         15 . The method of  claim 12  wherein the compound is employed prophylactically to prevent vesication or inflammation subsequently to be effected by chemical agents known to produce such vesication or inflammation.