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

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:

• 6
• wherein
• R1 and R2 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 —CH2C(═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 —CH2C(═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.

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

• 7
• wherein
• R1 and R2 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 —CH2C(═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 —CH2C(═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.

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

• 8
• wherein
• R1 and R2 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 —CH2C(═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 —CH2C(═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.

A compound of the formula

• 9
• wherein
• R1 and R2 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 —CH2C(═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 —CH2C(═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.