Modified forms of pharmacologically active agents and uses therefor

Abstract

In accordance with the present invention, there are provided modified forms of nonsteroidal anti-inflamamatory drugs (NSAIDs). Modified NSAIDs according to the invention provide a new class of anti-inflammatory agent which provide the therapeutic benefits of NSAIDs while causing a much lower incidence of side-effects then typically observed with such agents.

What is claimed is:  
     
         1 . A compound having the structure: 
       X—L—Z 
       wherein: 
 X=a non-steroidal anti-inflammatory drug (NSAID),  
 L=an optional linker/spacer,  
 Z=a sulfur-containing functional group.  
 
     
     
         2 . A compound according to  claim 1  wherein said NSAID is acetaminophen, aspirin, ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodolac, fenprofen calcium, flurobiprofen, indomethacin, ketoprofen, carprofen, indoprofen, ketorolac tromethamine, magnesium salicylate, meclofenamate sodium, mefenamic acid, oxaprozin, piroxicam, sodium salicylate, sulindac, tolmetin, meloxicam, nabumetone, naproxen, lomoxicam, nimesulide, indoprofen, remifenzone, salsalate, tiaprofenic acid, or flosulide.  
     
     
         3 . A compound according to  claim 2  wherein said NSAID is naproxen, aspirin, ibuprofen, flurbiprofen, indomethacin, ketoprofen, or carprofen.  
     
     
         4 . A compound according to  claim 1  wherein Z has the structure: 
       —Y—S(O) n —Y′—Q 
       wherein: 
 each of Y and Y′ are optionally present, and when present are independently —O—, —S— or —NR′—, wherein R′ is H or an optionally substituted hydrocarbyl moiety;  
 n is 1 or 2, and  
 Q is H, a metal cation or an optionally substituted hydrocarbyl moiety.  
 
     
     
         5 . A compound according to  claim 1  wherein the sulfur-containing functional group is sulfonate, reverse sulfonate, sulfonamide, reverse sulfonamide, sulfone, sulfoxide, sulfinate, or reverse sulfinate.  
     
     
         6 . A compound according to  claim 5  wherein the sulfur-containing functional group is sulfonate or reverse sulfonate.  
     
     
         7 . A compound according to  claim 6  wherein the sulfur-containing functional group is a nitro, nitrate, nitrite, nitrosothiol, nitroglyceryl, S-nitrosocysteinyl, S-nitrosoglutathionyl, oxime or N-hydroxyguanidinyl substituted aromatic sulfonate.  
     
     
         8 . A compound according to  claim 7  wherein said aromatic sulfonate is tosylate or brosylate.  
     
     
         9 . A compound according to  claim 6  wherein the sulfur-containing functional group is a nitro, nitrate, nitrite, nitrosothiol, nitroglyceryl, S-nitrosocysteinyl, S-nitrosoglutathionyl, oxime or N-hydroxyguanidinyl substituted C1 to C10 alkyl sulfonate.  
     
     
         10 . A compound according to  claim 9  wherein the alkyl sulfonate is mesylate or triflate.  
     
     
         11 . A compound according to  claim 5  wherein the sulfur-containing functional group is a sulfone.  
     
     
         12 . A compound according to  claim 11  wherein the sulfur-containing functional group is a nitro, nitrate, nitrite, nitrosothiol, nitroglyceryl, S-nitrosocysteinyl, S-nitrosoglutathionyl, oxime or N-hydroxyguanidinyl substituted C 1  to C 10  alkyl sulfone.  
     
     
         13 . A compound according to  claim 12  wherein said sulfone is methyl sulfone, ethyl sulfone.  
     
     
         14 . A compound according to  claim 11  wherein the sulfur-containing functional group is a nitro, nitrate, nitrite, nitrosothiol, nitroglyceryl, S-nitrosocysteinyl, S-nitrosoglutathionyl, oxime or N-hydroxyguanidinyl substituted aromatic sulfone.  
     
     
         15 . A compound according to  claim 14  wherein the sulfur-containing functional group is a p-substituted aromatic sulfone.  
     
     
         16 . A compound according to  claim 5  wherein the sulfur-containing functional group is a sulfonamide or reverse sulfonamide.  
     
     
         17 . A compound according to  claim 16  wherein the sulfur-containing functional group is a nitro, nitrate, nitrite, nitrosothiol, nitroglyceryl, S-nitrosocysteinyl, S-nitrosoglutathionyl, oxime or N-hydroxyguanidinyl substituted C 1  to C 10  alkyl sulfonamide.  
     
     
         18 . A compound according to  claim 17  wherein the sulfur-containing functional group is methyl sulfonamide.  
     
     
         19 . A compound according to  claim 16  wherein the sulfur-containing functional group is a nitro, nitrate, nitrite, nitrosothiol, nitroglyceryl, S-nitrosocysteinyl, S-nitrosoglutathionyl, oxime or N-hydroxyguanidinyl substituted aromatic sulfonamide.  
     
     
         20 . A compound according to  claim 19  wherein the sulfur-containing functional group is toluene sulfonamide.  
     
     
         21 . A compound according to  claim 5  wherein the sulfur-containing functional group is a sulfinate or reverse sulfinate.  
     
     
         22 . A compound according to  claim 1  wherein L, when present, has the structure: 
       W—R— 
       wherein: 
 R is optional, and when present is alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene, heterocyclic, substituted heterocyclic, oxyalkylene, substituted oxyalkylene, alkenylene, substituted alkenylene, arylene, substituted arylene, alkarylene, substituted alkarylene, aralkylene or substituted aralkylene, and  
 W is ester, reverse ester, thioester, reverse thioester, amide, reverse amide, phosphate, phosphonate, imine or enamine.  
 
     
     
         23 . A formulation comprising a compound according to  claim 1  in a pharmaceutically acceptable carrier therefor.  
     
     
         24 . A formulation according to  claim 23  wherein said pharmaceutically acceptable carrier is a solid, solution, emulsion, dispersion, micelle or liposome.  
     
     
         25 . A formulation according to  claim 23  wherein said pharmaceutically acceptable carrier further comprises an enteric coating.  
     
     
         26 . A method for the alleviation of side effects induced by the administration of a non-steroidal anti-inflammatory drug (NSAID) to a subject, said method comprising chemically modifying said NSAID prior to administration to a subject, wherein said NSAID is chemically modified by covalent attachment thereto of a sulfur-containing functional group.  
     
     
         27 . A method for alleviating the systemic toxicity of a non-steroidal anti-inflammatory drug (NSAID), said method comprising chemically modifying said NSAID prior to administration to a subject, wherein said NSAID is chemically modified by covalent attachment thereto of a sulfur-containing functional group.  
     
     
         28 . A method for reducing the maximum concentration in plasma achieved upon administration of a non-steroidal anti-inflammatory drug (NSAID), said method comprising modifying the NSAID by covalent attachment thereto of a sulfur-containing functional group.  
     
     
         29 . A method for the controlled release in vivo of a non-steroidal anti-inflammatory drug (NSAID), said method comprising chemically modifying the NSAID by the covalent attachment thereto of a sulfur-containing functional group.  
     
     
         30 . A method for the treatment of a subject afflicted with a pathological condition, said method comprising administering to said subject a therapeutically effective amount of a chemically modified non-steroidal anti-inflammatory drug (NSAID), wherein the NSAID is effective for treatment of said condition, and wherein the modified NSAID is prepared by covalent attachment thereto of a sulfur-containing functional group.  
     
     
         31 . In a method for the administration of a non-steroidal anti-inflammatory drug (NSAID) to a subject for the treatment of a pathological condition, the improvement comprising directly or indirectly covalently attaching said NSAID to a sulfur-containing functional group prior to administration thereof to said subject.  
     
     
         32 . A method for the preparation of a modified non-steroidal anti-inflammatory drug (NSAID) having reduced propensity to induce side effects, said method comprising modifying the NSAID by directly or indirectly covalently attaching said NSAID to a sulfur-containing functional group prior to administration thereof to said subject.  
     
     
         33 . In the treatment of a subject suffering from a pathological condition by administration thereto of a non-steroidal anti-inflammatory drug (NSAID), the improvement comprising covalently attaching said NSAID to a sulfur-containing functional group prior to administration thereof to said subject.  
     
     
         34 . A method for the preparation of a protected form of a non-steroidal anti-inflammatory drug (NSAID), said method comprising directly or indirectly covalently attaching a sulfur-containing functional group to said NSAID.  
     
     
         35 . A method for reducing the side effects induced by administration of a non-steroidal anti-inflammatory drug (NSAID) to a subject, said method comprising directly or indirectly covalently attaching a sulfur-containing functional group to said NSAID prior to administration to said subject.  
     
     
         36 . A method for enhancing the effectiveness of a non-steroidal anti-inflammatory drug (NSAID), said method comprising directly or indirectly covalently attaching a sulfur-containing functional group to said NSAID.  
     
     
         37 . A method for the prevention or treatment of an inflammatory or infectious disease in a subject in need thereof, said method comprising administering to said subject an amount of the compound of  claim 1  effective to alleviate said condition.