Cyanomethyl substituted thiazoliums and imidazoliums and treatments of disorders associated with protein aging

A compound of the formula:

• wherein:
• Y is N;
• Z is an alkyl group of 1 to 7 carbon atoms, arylcarbonyl, amino or (lower)alkoxycarbonyl(lower)alkyl, or Z is according to the formula -CH(R4)(CN), or Z is -CH2C(═O)R5, where R5 is (a) a C6-C10 aryl group, said aryl group optionally substituted by one or more lower alkyl, lower alkoxy, halo, di(lower)alkylamino, hydroxy, nitro or C1-C2 alkylenedioxy groups or (b) heterocyclic group containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur wherein the heterocyclic group is optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, alkoxycarbonylalkyl, aryl, and aralkyl group, and the one or more substituents are optionally substituted by one or more alkyl or alkoxy groups,
• R1 and R4 are independently hydrogen, lower alkyl or phenyl optionally substituted with one or more halogen, lower alkyl, di(lower alkyl)amino or alkoxy groups;
• R2 and R3 are independently hydrogen, lower alkyl, or together form an alkylene bridge of 3-4 carbon atoms;
• and
• X− is a biologically or pharmaceutically acceptable anion.

A method of, in an animal, (i) improving the elasticity or reducing wrinkles of a skin, treating (ii) diabetes or treating, inhibiting the (iii) discoloration of teeth, or ameliorating one or more of the following conditions:

• (iv) adverse sequelae of diabetes, (v) kidney damage, (vi) damage to blood vasculature, (vii) hypertension, (viii) retinopathy, (ix) damage to lens proteins, (x) cataracts, (xi) peripheral neuropathy, (xii) osteoarthritis, or (xiii) damage to cardiovascular tissue due to heart failure, (xiv) improving myocardial elasticity, (xv) preventing damage to tissues in the intraperitoneal cavity caused by contact with elevated levels of reducing sugars, or (xvi) treating or ameliorating one of the conditions described above, the method comprising administering an effective amount of one or more compounds of the formula:
• wherein
• Y is N or
• Z is absent when Y is S and, if present, Z is an alkyl group of 1 to 7 carbon atoms, vinyl, allyl, arylcarbonyl, amino or alkoxycarbonylalkyl, or Z is according to the formula -CH(R4)(CN), or Z is -CH2C(═O)R5, where R5 is (a) a C6-C10 aryl group, said aryl group optionally substituted by one or more alkyl, alkoxy, halo, dialkylamino, hydroxy, nitro or C1-C2 alkylenedioxy groups or (b) heterocyclic group containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur wherein the heterocyclic group is optionallysubstituted by one or more substituents selected from the group consisting of alkyl, oxo, alkoxycarbonylalkyl, aryl, and aralkyl group, and the one or more substituents are optionally substituted by one or more alkyl or alkoxy groups,
• R1 and R4 are independently hydrogen, alkyl or phenyl optionally substituted with one or more halogen, alkyl, di(lower alkyl)amino or alkoxy groups;
• and
• R2 and R3 are:
• 1. independently selected from hydrogen, acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylarnino, (C1-C3)alkylenedioxy, allyl, amino, ωalkylenesulfonic acid, carbamoyl, carboxy, carboxyalkyl, cycloalkyl, dialkylamino, halo, hydroxy, (C2-C6)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic acid, alkylsulfonyl, alkylsulfinyl, alkylthio, trifluoromethyl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl,4-[C6 or C10]arylpiperidin-1-yl, 4-[C6 or C10]arylpiperazin-1-yl, Ar {wherein, consistent with the rules of aromaticity, Ar is C6 or C10 aryl or a 5-or 6-membered heteroaryl ring, wherein 6-membered heteroaryl ring contains one to three atoms of N, and the 5-membered heteroaryl ring contains from one to three atoms of N or one atom of O or S and zero to two atoms of N, each heteroaryl ring is optionally fused to a benzene, pyridine, pyrimidine, pyridazine, pyrazine, or (1,2,3)triazine (wherein the ring fusion is at a carbon—carbon double bond of Ar)}, Ar-alkyl, Ar-O, ArSO2-, ArSO-, ArS-, ArSO2NH-, ArNH, (N-Ar)(N-alkyl)N-, ArC(O)-, ArC(O)NH-, ArNH-C(O)-, and (N-Ar)(N-alkyl)N-C(O)-, or together R1 and R2 comprise methylenedioxy;
• or
• 2. together with their ring carbons form a C6-C10-aromatic fused ring system;
• or
• 3. together with their ring carbons form a C5-C7 fused cycloalkyl ring having up to two double bonds including the fused double bond of the -olium or -onium containing ring, which cycloalkyl ring is optionally substituted by one or more of the group consisting of alkyl, alkoxycarbonyl, amino, aminocarbonyl, carboxy, fluoro, or oxo substituents;
• or
• 4. together with their ring carbons form a 5- or 6-membered heteroaryl ring, wherein the 6-membered heteroaryl ring contains one to three atoms of N, and the 5-membered heteroaryl ring contains from one to three atoms of N or one atom of O or S and zero to two atoms of N, each heteroaryl ring is optionally substituted with one or more 1-pyrrolidinyl-, 4-[C6 or C10]arylpiperazin-1-yl, 4-[C6 or C10]arylpiperidin-1-yl, azetidin-1yI, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, halo or (C1-C3)alkylenedioxy groups;
• or
• 5. together with their ring carbons form a five to eight membered heterocycle, wherein the heterocycle consists of ring atoms selected from the group consisting of carbon, nitrogen, and S(O), where n═0, 1, or 2;
• and
• X is a biologically or pharmaceutically acceptable anion,
• wherein aryl or Ar is optionally substituted with, in addition to any substitutions specifically noted, one or more substituents selected from the group consisting of acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino, (C1-C3)alkylenedioxy, alkylsulfonyl, alkylsulfinyl, ω-alkylenesulfonic acid, alkylthio. allyl, amino, ArC(O)-, ArC(O)NH-, ArO-, Ar-, Ar-alkyl-, carboxy, carboxyalkyl, cycloalkyl, dialkylamino, halo, trifluoromethyl, hydroxy, (C2-C6)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic acid, 1-pyrrolidinyl, 4-[C6 or C10]arylpiperazin-1-yl-, 4-[C6 or C10]arylpiperidin-1-yl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, and piperidin-1-yl;
• and
• wherein heterocycles, except those of Ar, are optionally substituted with, in addition to any substitutions specifically noted, acylamino, alkanoyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, amino, ArC(O)-, ArO-, Ar-, carboxy, dialkylamino, fluoro, fluoroalkyl, difluoroalkyl, hydroxy, mercapto, sulfamoyl, or trifluoromethyl.

A method of, in an animal, (i) improving the elasticity or reducing wrinkles of a skin, treating (ii) diabetes or treating, inhibiting the (iii) discoloration of teeth, or ameliorating one or more of the following conditions:

• (iv) adverse sequelae of diabetes, (v) kidney damage, (vi) damage to blood vasculature, (vii) hypertension, (viii) retinopathy, (ix) damage to lens proteins, (x) cataracts, (xi) peripheral neuropathy, (xii) osteoarthritis, or (xiii) damage to cardiovascular tissue due to heart failure, (xiv) improving myocardial elasticity, (xv) preventing damage to tissues in the intraperitoneal cavity caused by contact with elevated levels of reducing sugars. or (xvi) treating or ameliorating one of the conditions described above, the method comprising administering an effective amount of one or more compounds of the formula:
• wherein:
• Y is N or
• Z is absent when Y is S and, if present, Z is an alkyl group of 1 to 7 carbon atoms, arylcarbonyl, amino or (lower)alkoxycarbonyl(lower)alkyl, or Z is according to the formula -CH(R4)(CN), or Z is -CH2C(0)R5, where R5 is (a) a C6-C10 aryl group, said aryl group optionally substituted by one or more lower alkyl, lower alkoxy, halo, di(lower)alkylamino, hydroxy, nitro or C1-C2 alkylenedioxy groups or (b) heterocyclic group containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur wherein the heterocyclic group is optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, alkoxycarbonylalkyl, aryl, and aralkyl group, and the one or more substituents is optionally substituted by one or more alkyl or alkoxy groups,
• R1 and R4 are independently hydrogen, lower alkyl or phenyl optionally substituted with one or more halogen, lower alkyl, di(lower alkyl)amino or alkoxy groups;
• R2 and R3 are independently hydrogen, lower alkyl, or together form an alkylene bridge of 3-4 carbon atoms;
• and
• X is a biologically or pharmaceutically acceptable anion.

A solid pharmaceutical dosage form comprising a therapeutically effective amount of one or more active compounds and a pharmaceutically acceptable excipient, the active compounds of the formula:

• wherein:
• Y is N or S;
• Z is absent when Y is S and, if present, Z is an alkyl group of 1 to 7 carbon atoms, vinyl, allyl, arylcarbonyl, amino or alkoxycarbonylalkyl, or Z is according to the formula -CH(R4)(CN), or Z is -CH2C(═O)R5, where R5 is (a) a C6-C10 aryl group, said aryl group optionally substituted by one or more alkyl, alkoxy, halo, dialkylamino, hydroxy, nitro or C1-C2 alkylenedioxy groups or (b) heterocyclic group containing 4-10 ring members and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur wherein the heterocyclic group is optionallysubstituted by one or more substituents selected from the group consisting of alkyl, oxo, alkoxycarbonylalkyl, aryl, and aralkyl group, and the one or more substituents are optionally substituted by one or more alkyl or alkoxy groups,
• R1 and R4 are independently hydrogen, alkyl or phenyl optionally substituted with one or more halogen, alkyl, di(lower alkyl)amino or alkoxy groups;
• and
• R2 and R3 are:
• 1. independently selected from hydrogen, acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino, (C1-C3)alkylenedioxy, allyl, amino, ω-alkylenesulfonic acid, carbamoyl, carboxy, carboxyalkyl, cycloalkyl, dialkylamino, halo, hydroxy, (C2-C6)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic acid, alkylsulfonyl, alkylsulfinyl, alkylthio, trifluoromethyl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, 4-[C6 or C10]arylpiperidin-1-yl, 4-[C6 or C10]arylpiperazin-l-yl, Ar {wherein, consistent with the rules of aromaticity, Ar is C6 or C10 aryl or a 5- or 6-membered heteroaryl ring, wherein 6-membered heteroaryl ring contains one to three atoms of N, and the 5-membered heteroaryl ring contains from one to three atoms of N or one atom of O or S and zero to two atoms of N, each heteroaryl ring is optionally fused to a benzene, pyridine, pyrimidine, pyridazine, pyrazine, or (1,2,3)triazine (wherein the ring fusion is at a carbon—carbon double bond of Ar)}, Ar-alkyl, Ar-O, ArSO2-, ArSO-, ArS-, ArSO2NH-, ArNH, (N-Ar)(N-alkyl)N-, ArC(O)-, ArC(O)NH-, ArNH-C(O)-, and (N-Ar)(N-alkyl)N-C(O)-, or together R1 and R2 comprise methylenedioxy;
• or
• 2. together with their ring carbons form a C6- or C10- aromatic fused ring system;
• or
• 3. together with their ring carbons form a C5-C7 fused cycloalkyl ring having up to two double bonds including the fused double bond of the -olium or -onium containing ring, which cycloalkyl ring is optionally substituted by one or more of the group consisting of alkyl, alkoxycarbonyl, amino, aminocarbonyl, carboxy, fluoro, or oxo substituents;
• or
• 4. together with their ring carbons form a 5- or 6-membered heteroaryl ring, wherein the 6-membered heteroaryl ring contains one to three atoms of N, and the 5-membered heteroaryl ring contains from one to three atoms of N or one atom of O or S and zero to two atoms of N, each heteroaryl ring is optionally substituted with one or more 1-pyrrolidinyl-, 4-[C6 or C10]arylpiperazin-1-yl, 4-[C6 or C10]arylpiperidin-1-yl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, halo or (C1-C3)alkylenedioxy groups;
• or
• 5. together with their ring carbons form a five to eight membered heterocycle, wherein the heterocycle consists of ring atoms selected from the group consisting of carbon, nitrogen, and S(O)n, where n=0, 1, or 2;
• and
• X is a biologically or pharmaceutically acceptable anion,
• wherein aryl or Ar is optionally substituted with, in addition to any substitutions specifically noted, one or more sub stituents selected from the group consisting of acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino, (C1-C3)alkylenedioxy, alkylsulfonyl, alkylsulfinyl, ω-alkylenesulfonic acid, alkylthio, allyl, amino, ArC(O)-, ArC(O)NH-, ArO-, Ar-, Ar-alkyl-, carboxy, carboxyalkyl, cycloalkyl, dialkylamino, halo, trifluoromethyl, hydroxy, (C2-C6)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic acid, 1-pyrrolidinyl, 4-[C6 or C10]arylpiperazin-1-yl-, 4-[C6 or C10]arylpiperidin-1-yl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, and piperidin-1-yl;
• and
• wherein heterocycles, except those of Ar, are optionally substituted with, in addition to any substitutions specifically noted, acylamino, alkanoyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, amino, ArC(O)-, ArO-, Ar-, carboxy, dialkylamino, fluoro, fluoroalkyl, difluoroalkyl, hydroxy, mercapto, sulfamoyl, or trifluoromethyl.