US2002160992A1PendingUtilityA1

Reversing advanced glycosylation cross-links using heterocyclic-substituted thiazolium salts

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Priority: Nov 10, 1998Filed: Oct 23, 2001Published: Oct 31, 2002
Est. expiryNov 10, 2018(expired)· nominal 20-yr term from priority
Inventors:Dilip WagleSheng FangTaikyun RhoJohn J. EganSara VasanPeter C. UlrichAnthony Cerami
A61P 3/10A61P 9/14A61P 27/02A61P 13/12A61P 17/00A61K 31/5355A61K 31/496C07D 277/44A61K 31/454C07D 277/22A61K 31/427A61K 31/4709A61K 31/4439A61K 31/541C07D 417/06A61K 31/55
50
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Claims

Abstract

The present invention relates to compositions and methods for reversing advanced glycosylation end product-mediated cross-linking and protein aging. Accordingly, compositions are described which comprise thiazolium compounds substituted with heterocyclic groups which are capable of reversing the formation of advanced glycosylation end product cross-links. Both industrial and therapeutic applications for the invention are disclosed, as food spoilage and animal protein aging can be treated. Such compounds have particular application in the treatment of protein aging such as is responsible for the complications of aging and diabetes.

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
         1 . A composition for reversing pre-formed advanced glycosylation crosslinks comprising an effective amount of a compound of the structural formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  and R 2  are independently selected from the group consisting of hydrogen and an alkyl group optionally substituted by a hydroxy group;  
 Y is a group of the formula —CH 2 C(═O)R wherein R is a heterocyclic group other than alkylenedioxyaryl containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; said heterocyclic group optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, alkoxycarbonylalkyl, aryl, and aralkyl groups; and said one or more substituents optionally substituted by one or more alkyl or alkoxy groups;  
 or a group of the formula —CH 2 C(═O)—NHR′ wherein R′ is a heterocyclic group containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; said heterocyclic group optionally substituted by one or more alkoxycarbonylalkyl groups; and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion; and a carrier therefor.  
 
     
     
         2 . The composition of  claim 1  wherein Y is a group of the formula —CH 2 C(═O)R wherein R is a heterocyclic group other than alkylenedioxyaryl containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; said heterocyclic group optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, alkoxycarbonylalkyl, aryl, and aralkyl groups; and said one or more substituents optionally substituted by one or more alkyl or alkoxy groups; and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.  
     
     
         3 . The composition of  claim 2  wherein Y is selected from the group consisting of 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]; 3-(2-(4-morpholinyl)-2-oxoethyl); 3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]; 3-(2-(1-piperidinyl)-2-oxoethyl); 3-(2-(2-furanyl)-2-oxoethyl; 3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl]; 3-(2-(1-pyrrolidinyl)-2-oxoethyl; 3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]; 3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl; 3-(2-(2-thienyl)-2-oxoethyl); 3-(2-(2-thienyl)-2-oxoethyl); 3-(2-(4-thiomorpholinyl)-2-oxoethyl); 3-(2-(hexahydro-1-azepinyl)-2-oxoethyl); 3-[2-(4-[2-methoxyphenyl]-1-piperazinyl)-2-oxoethyl; 3-(2-(octahydro-1-azocinyl)-2-oxoethyl); 3-(2-(2-pyridinyl)-2-oxoethyl; 3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]; 3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl; 3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]; and 3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl].  
     
     
         4 . The composition of  claim 3  wherein said compound is 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-thiazolium bromide; 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)-thiazolium bromide; 3-(2-(4-morpholinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-(2(1-piperidinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-(2-(2-furanyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-(2-(1-pyrrolidinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-(2-(2-thienyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-(2-(2-thienyl)-2-oxoethyl)-4-methyl-5-hydroxyethylthiazolium bromide; 3-(2-(4-thiomorpholinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-(2-(hexahydro-1-azepinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-[2-(4-[2-methoxyphenyl]-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-(2-(octahydro-1-azocinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-(2-(2-pyridinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; or another biologically acceptable salt thereof.  
     
     
         5 . The composition of  claim 1  wherein said compound has the formula wherein Y is a group of the formula —CH 2 C(═O)—NHR′ wherein R′ is a heterocyclic group containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; said heterocyclic group optionally substituted by one or more alkoxycarbonylalkyl groups; and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.  
     
     
         6 . The composition of  claim 5  wherein said compound is 3-[2-[4-(2-ethoxy-2-oxoethyl)-2-thiazolyl]amino-2-oxoethyl]-4,5-dimethylthiazolium chloride or another biologically acceptable salt thereof.  
     
     
         7 . A pharmaceutical composition for administration to an animal to reverse pre-formed advanced glycosylation crosslinks within said animal, comprising a pharmaceutically effective amount of a compound selected from the group consisting of compounds of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  and R 2  are independently selected from the group consisting of hydrogen and a alkyl group optionally substituted by a hydroxy group;  
 Y is a group of the formula —CH 2 C(═O)R wherein R is a heterocyclic group other than alkylenedioxyaryl containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; said heterocyclic group optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo alkoxycarbonylalkyl, aryl, and aralkyl groups; and said one or more substituents optionally substituted by one or more alkyl or alkoxy groups;  
 or a group of the formula —CH 2 C(═O)—NHR′ wherein R′ is a heterocyclic group containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; said heterocyclic group optionally substituted by one or more alkoxycarbonylalkyl groups; and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion, and a carrier therefor.  
 
     
     
         8 . The composition of  claim 7  wherein Y is a group of the formula —CH 2 C(═O)R wherein R is a heterocyclic group other than alkylenedioxyaryl containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; said heterocyclic group optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, alkoxycarbonylalkyl, aryl, and aralkyl groups; and said one or more substituents optionally substituted by one or more alkyl or alkoxy groups; and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.  
     
     
         9 . The composition of  claim 8  wherein Y is selected from the group consisting of 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]; 3-(2-(4-morpholinyl)-2-oxoethyl); 3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]; 3-(2-(1-piperidinyl)-2-oxoethyl); 3-(2-(2-furanyl)-2-oxoethyl; 3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl]; 3-(2-(1-pyrrolidinyl)-2-oxoethyl; 3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]; 3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl; 3-(2-(2-thienyl)-2-oxoethyl); 3-(2-(2-thienyl)-2-oxoethyl); 3-(2-(4-thiomorpholinyl)-2-oxoethyl); 3-(2-(hexahydro-1-azepinyl)-2-oxoethyl); 3-[2-(4-[2-methoxyphenyl]-1-piperazinyl)-2-oxoethyl; 3-(2-(octahydro-1-azocinyl)-2-oxoethyl); 3-(2-(2-pyridinyl)-2-oxoethyl; 3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]; 3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl; 3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]; and 3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl].  
     
     
         10 . The composition of  claim 9  wherein said compound is 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-thiazolium bromide; 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)-thiazolium bromide; 3-(2-(4-morpholinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-(2-(1-piperidinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-(2-(2-furanyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-(2-(1-pyrrolidinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-(2-(2-thienyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-(2-(2-thienyl)-2-oxoethyl)-4-methyl-5-hydroxyethylthiazolium bromide; 3-(2-(4-thiomorpholinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-(2-(hexahydro-1-azepinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-[2-(4-[2-methoxyphenyl]-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-(2-(octahydro-1-azocinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-(2-(2-pyridinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; or another biologically acceptable salt thereof.  
     
     
         11 . The composition of  claim 7  wherein said compound has the formula wherein Y is group of the formula —CH 2 C(═O)—NHR′ and R′ is a heterocyclic group containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; said heterocyclic group optionally substituted by one or more alkoxycarbonylalkyl groups; and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.  
     
     
         12 . The composition of  claim 11  wherein said compound is 3-[2-[4-(2-ethoxy-2-oxoethyl)-2-thiazolyl]amino-2-oxoethyl]-4,5-dimethyl-thiazolium chloride or another biologically acceptable salt thereof.  
     
     
         13 . A method for reversing pre-formed advanced glycosylation crosslinks, comprising contacting the target protein with an effective amount of composition comprising a compound selected from the group consisting of compounds of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  and R 2  are independently selected from the group consisting of hydrogen and an alkyl group optionally substituted by a hydroxy group;  
 Y is a group of the formula —CH 2 C(═O)R wherein R is a heterocyclic group other than alkylenedioxyaryl containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; said heterocyclic group optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, alkoxycarbonylalkyl, aryl, and aralkyl groups; and said one or more substituents optionally substituted by one or more alkyl or alkoxy groups;  
 or a group of the formula —CH 2 C(═O)—NHR′ wherein R′ is a heterocyclic group containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; said heterocyclic group optionally substituted by one or more alkoxycarbonylalkyl groups; and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion; and a carrier therefor.  
 
     
     
         14 . The composition of  claim 13  wherein Y is a group of the formula —CH 2 C(═O)R wherein R is a heterocyclic group other than alkylenedioxyaryl containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; said heterocyclic group optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, alkoxycarbonylalkyl, aryl, and aralkyl groups; and said one or more substituents optionally substituted by one or more alkyl or alkoxy groups; and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.  
     
     
         15 . The composition of  claim 14  wherein Y is selected from the group consisting of 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]; 3-(2-(4-morpholinyl)-2-oxoethyl); 3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]; 3-(2-(1-piperidinyl)-2-oxoethyl); 3-(2-(2-furanyl)-2-oxoethyl; 3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl]; 3-(2-(1-pyrrolidinyl)-2-oxoethyl; 3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]; 3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl; 3-(2-(2-thienyl)-2-oxoethyl); 3-(2-(2-thienyl)-2-oxoethyl); 3-(2-(4-thiomorpholinyl)-2-oxoethyl); 3-(2-(hexahydro-1-azepinyl)-2-oxoethyl); 3-[2-(4-[2-methoxyphenyl]-1-piperazinyl)-2-oxoethyl; 3-(2-(octahydro-1-azocinyl)-2-oxoethyl); 3-(2-(2-pyridinyl)-2-oxoethyl; 3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]; 3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl; 3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]; and 3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl].  
     
     
         16 . The composition of  claim 15  wherein said compound is 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-thiazolium bromide; 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)-thiazolium bromide; 3-(2-(4-morpholinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-(2-(1-piperidinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-(2-(2-furanyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-(2-(-1-pyrrolidinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-(2(2-thienyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-(2- (2-thienyl)-2-oxoethyl)-4-dimethyl-5-hydroxyethylthiazolium bromide; 3-(2-(4thiomorpholinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-(2-(hexahydro-1-azepinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-[2-(4-[2-methoxyphenyl]-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-(2-(octahydro-1-azocinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-(2-(2-pyridinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; or another biologically acceptable salt thereof.  
     
     
         17 . The composition of  claim 13  wherein said compound has the formula wherein Y is a group of the formula —CH 2 C(═O)—NHR′ wherein R′ is a heterocyclic group containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; said heterocyclic group optionally substituted by one or more alkoxycarbonylalkyl groups; and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.  
     
     
         18 . The composition of  claim 17  wherein said compound is 3-[2-[4-(2-ethoxy-2-oxoethyl)-2-thiazolyl]amino-2-oxoethyl]-4,5-dimethyl-thiazolium chloride or another biologically acceptable salt thereof.  
     
     
         19 . A method for treating an animal to reverse pre-formed advanced glycosylation crosslinks of a target protein within said animal, said method comprising administering an effective amount of a pharmaceutical composition, said pharmaceutical composition comprising a compound selected from the group consisting of compounds of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  and R 2  are independently selected from the group consisting of hydrogen and an alkyl group optionally substituted by a hydroxy group;  
 Y is a group of the formula —CH 2 C(═O)R wherein R is a heterocyclic group other than alkylenedioxyaryl containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; said heterocyclic group optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, alkoxycarbonylalkyl aryl, and aralkyl groups; and said one or more substituents optionally substituted by one or more alkyl or alkoxy groups;  
 or a group of the formula —CH 2 C(═O)—NHR′ wherein R′ is a heterocyclic group containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; said heterocyclic group optionally substituted by one or more alkoxycarbonylalkyl groups; and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion; and a carrier therefor.  
 
     
     
         20 . The composition of  claim 19  wherein Y is a group of the formula —CH 2 C(═O)R wherein R is a heterocyclic group other than alkylenedioxyaryl containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; said heterocyclic group optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, alkoxycarbonylalkyl, aryl, and aralkyl groups; and said one or more substituents optionally substituted by one or more alkyl or alkoxy groups; and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.  
     
     
         21 . The composition of  claim 20  wherein Y is selected from the group consisting of 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]; 3-(2-(4-morpholinyl)-2-oxoethyl); 3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]; 3-(2-(1-piperidinyl)-2-oxoethyl); 3-(2-(2-furanyl)-2-oxoethyl; 3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl]; 3-(2-(1-pyrrolidinyl)-2-oxoethyl; 3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]; 3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl; 3-(2-(2-thienyl)-2-oxoethyl); 3-(2-(2-thienyl)-2-oxoethyl); 3-(2-(4-thiomorpholinyl)-2-oxoethyl); 3-(2-(hexahydro-1-azepinyl)-2-oxoethyl); 3-[2-(4-[2-methoxyphenyl]-1-piperazinyl)-2-oxoethyl; 3-(2-(octahydro-1-azocinyl)-2-oxoethyl); 3-(2-(2-pyridinyl)-2-oxoethyl; 3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]; 3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl; 3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]; and 3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl].  
     
     
         22 . The composition of  claim 21  wherein said compound is 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-thiazolium bromide; 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)-thiazolium bromide; 3-(2-(4-morpholinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-(2-(1-piperidinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-(2-(2-furanyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl-]-4,5-dimethylthiazolium bromide; 3-(2-(1-pyrrolidinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-(2-(2-thienyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-(2-(2-thienyl)-2-oxoethyl)-4-methyl-5-hydroxyethylthiazolium bromide; 3-(2-(4-thiomorpholinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-(2-(hexahydro-1-azepinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-[2-(4-[2-methoxyphenyl]-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-(2-(octahydro-1-azocinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-(2-(2-pyridinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; or another biologically acceptable salt thereof.  
     
     
         23 . The composition of  claim 19  wherein said compound has the formula wherein Y is a group of the formula —CH 2 C(═O)—NHR′ wherein R′ is a heterocyclic group containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; said heterocyclic group optionally substituted by one or more alkoxycarbonylalkyl groups; and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.  
     
     
         24 . The composition of  claim 23  wherein said compound is 3-[2-[4-(2-ethoxy-2-oxoethyl)-2-thiazolyl]amino-2-oxoethyl]-4,5-dimethyl-thiazolium chloride or another biologically acceptable salt thereof.  
     
     
         25 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  and R 2  are independently selected from the group consisting of hydrogen and an alkyl group optionally substituted by a hydroxy group;  
 Y is a group of the formula —CH 2 C(═O)R wherein R is a heterocyclic group other than alkylenedioxyaryl containing 4-10 ring members and one heteroatom selected from the group consisting of nitrogen and sulfur, or 2-3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; said heterocyclic group optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, alkoxycarbonylalkyl, aryl, and aralkyl groups; and said one or more substituents optionally substituted by one or more alkyl or alkoxy groups;  
 or a group of the formula —CH 2 C(═O)—NHR′ wherein R′ is a heterocyclic group containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen. nitrogen, and sulfur; said heterocyclic group optionally substituted by one or more alkoxycarbonylalkyl groups;  
 and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.  
 
     
     
         26 . The compound of  claim 25  wherein said compound has the formula wherein Y is group of the formula —CH 2 C(═O)R wherein R is a heterocyclic group other than alkylenedioxyaryl containing 4-10 ring members and one heteroatom selected from the group consisting of nitrogen and sulfur, or 2-3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; said heterocyclic group optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, alkoxycarbonylalkyl, aryl, and aralkyl groups; and said one or more substituents optionally substituted by one or more alkyl or alkoxy groups; 
 and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.  
 
     
     
         27 . The composition of  claim 26  wherein Y is selected from the group consisting of3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]; 3-(2-(4-morpholinyl)-2-oxoethyl); 3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]; 3-(2-(1-piperidinyl)-2-oxoethyl); 3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl]; 3-(2-(1-pyrrolidinyl)-2-oxoethyl; 3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]; 3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl; 3-(2-(2-thienyl)-2-oxoethyl); 3-(2-(2-thienyl)-2-oxoethyl); 3-(2-(4-thiomorpholinyl)-2-oxoethyl); 3-(2-(hexahydro-1-azepinyl)-2-oxoethyl); 3-[2-(4-[2-methoxyphenyl]-1-piperazinyl)-2-oxoethyl; 3-(2-(octahydro-1-azocinyl)-2-oxoethyl); 3-(2-(2-pyridinyl)-2-oxoethyl; 3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]; 3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl; 3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]; and 3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl].  
     
     
         28 . The composition of  claim 27  wherein said compound is 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-thiazolium bromide; 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)-thiazolium bromide; 3-(2-(4-morpholinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-(2-(1-piperidinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-(2-(1-pyrrolidinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide; 3-(2-(2-thienyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-(2-(2-thienyl)-2-oxoethyl)-4-methyl-5-hydroxyethylthiazolium bromide; 3-(2-(4-thiomorpholinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-(2-(hexahydro-1-azepinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-[2-(4-[2-methoxyphenyl]-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-(2-(octahydro-1-azocinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-(2-(2-pyridinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; 3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium chloride; or another biologically acceptable salt thereof.  
     
     
         29 . The composition of  claim 25  wherein said compound has the formula wherein Y is group of the formula —CH 2 C(═O)—NHR′ and R′ is a heterocyclic group containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; said heterocyclic group optionally substituted by one or more alkoxycarbonylalkyl groups; 
 and X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion.  
 
     
     
         30 . The composition of  claim 29  wherein said compound is 3-[2-(2′-amino-5′-carboethoxymethylene-thiazolyl)-2-oxoethyl]-4,5-dimethyl-thiazolium chloride or another biologically acceptable salt thereof.

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