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

Abstract

Provided, among other things, is a compound of the formula:

1 . A compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 Y is N;  
 Z is allyl, arylcarbonyl, amino or alkoxycarbonylalkyl, or Z is according to the formula —CH(R 4 )(CN), or Z is —CH 2 C(═O)R 5 , where R 5  is (a) a C 6 -C 10  aryl group, said aryl group optionally substituted by one or more alkyl, alkoxy, halo, dialkylamino, hydroxy, nitro or C 1 -C 2  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 can be 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 can be substituted by one or more alkyl or alkoxy groups,  
 R 1  and R 4  are independently hydrogen, alkyl or phenyl optionally substituted with one or more halogen, alkyl, di(lower alkyl)amino or alkoxy groups; and  
 R 2  and R 3  are:  
 1. independently selected from hydrogen, acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino, (C 1 -C 3 )alkylenedioxy, ally, amino, ω-alkylenesulfonic acid, carbamoyl, carboxy, carboxyalkyl, cycloalkyl, dialkylamino, halo, hydroxy, (C 2 -C 6 )hydroxyalkyl, mereapto, nitro, sulfamoyl, sulfonic acid, alkylsulfonyl, alkylsulfinyl, alkylthio, trifluoromethyl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, 4-[C 6  or C 10 ]arylpiperidin-1-yl, 4-[C 6  or C 10 ]arylpiperazin-1-yl, Ar {wherein, consistent with the rules of aromaticity, Ar is C 6  or C 10  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 can be 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, ArSO 2 —, ArSO—, ArS—, ArSO 2 NH—, ArNH, (N—Ar)(N-alkyl)N—, ArC(O), ArC(O)NH—, ArNH—C(O)—, and (N—Ar)(N-alkyl)N—C(O)—, or together R 1  and R 2  comprise methylenedioxy; or  
 2. together with their ring carbons form a C 6 - or C 10 -aromatic fused ring system; or  
 3. together with their ring carbons form a C 5 -C 7  fused cycloalkyl ring having up to two double bonds including the fused double bond of the -olium or -onium containing ring, which cycloalkyl. ring can be 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 may be optionally substituted with one or more 1-pyrrolidinyl-, 4-[C 6  or C 10 ]arylpiperazin-1-yl, 4-[C 6  or C 10 ]arylpiperidin-1-yl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, halo or (C 1 -C 3 )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 can be 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, (C 1 -C 3 )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, (C 2 -C 6 )hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic acid, 1-pyrrolidinyl, 4-[C 6  or C 10 ]arylpiperazin-1-yl, 4[C 6  or C 10 ]arylpiperidin-1-yl, 1  azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl; and  
 wherein heterocycles, except those of Ar, can be substituted with, in addition to any substitution 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.  
 
   
   
       2 . The compound of  claim 1 , wherein R 2  and R 3  are independently hydrogen, alkyl, lower alkyl or together form an alkylene bridge of 3-4 carbon atoms.  
   
   
       3 . The compound of  claim 1 , wherein R 1  is hydrogen.  
   
   
       4 . The compound of  claim 1 , wherein Z is arylcarbonyl, amino or alkoxycarbonylalkyl, or Z is according to the formula CH(R 4 )(CN), or Z is —CH 2 C(═O)R 5 , where R 5  is a C 6 -C 10  aryl group, said aryl group optionally substituted by one or more alkyl, alkoxy, halo, dialkylamino, hydroxy, nitro or C 1 -C 2  alkylenedioxy groups.  
   
   
       5 . The compound of  claim 1 , wherein Z is arylcarbonyl, amino or alkoxycarbonylalkyl, or Z is according to the formula CH(R 4 )(CN).  
   
   
       6 . The compound of  claim 1 , wherein said compound is 1-allyl-3-(2-cyanomethyl)-imnidazollum chloride.  
   
   
       7 . The compound of  claim 1 , wherein said compound is 1-(phenyl)-3-(2-cyanomethyl)-imidazolium chloride.  
   
   
       8 . The compound of  claim 1 , wherein said compound is 1-(4-acetylphenyl)-3-(2-cyanomethyl)-imidazolium chloride.  
   
   
       9 . The compound of  claim 1 , wherein said compound is 1-(4-methoxyphenyl)-3-(2-cyanomethyl)-imidazolium chloride.  
   
   
       10 . The compound of  claim 1 , wherein said compound is 1-(4-methoxycarbonylphenyl-3-(2-cyanomethyl)-imidazolium chloride.  
   
   
       11 . The compound of  claim 1 , wherein said compound is 1,5-dicyclohexyl-3-(2-cyanomethyl)-imidazolium bromide.  
   
   
       12 . A method of (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 tis sue 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 to a subject an effective amount of one or more compounds of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 Y is N;  
 Z is allyl, arylcarbonyl, amino or alkoxycarbonylalkyl, or Z is according to the formula —CH(R 4 )(CN), or Z is —CH 2 C(═O)R 5 , where R 5  is (a) a C 6 -C 10  aryl group, said aryl group optionally substituted by one or more alkyl, alkoxy, halo, dialkylarnino, hydroxy, nitro or C 1 -C 2  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 can be 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 can be substituted by one or more alkyl or alkoxy groups,  
 R 1  and R 4  are independently hydrogen, alkyl or phenyl optionally substituted with one or more halogen, alkyl, di(lower alkyl)amino or alkoxy groups; and  
 R 2  and R 3  are:  
 1. independently selected from hydrogen, acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino, (C 1 -C 3 )alkylenedioxy, allyl, amino, ω-alkylenesulfonic acid, carbamoyl, carboxy, carboxyalkyl, cycloalkyl, dialkylamino, halo, hydroxy, (C 2 -C 6 )hydroxyalkyl, mereapto, nitro, sulfamoyl, sulfonic acid, alkylsulfonyl, alkylsulfinyl, alkylthio, trifluoromethyl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, 4-[C 6  or C 10 ]arylpiperidin-1-yl, 4-[C 6  or C 10 ]arylpiperazin-1-yl, Ar {wherein, consistent with the rules of aromaticity, Ar is C 6  or C 10  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 can be 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, ArSO 2 —, ArSO—, ArS—, ArSO 2 NH—, ArNH, (N—Ar)(N-alkyl)N—, ArC(O), ArC(O)NH—, ArNH—C(O)—, and (N—Ar)(N-alkyl)N—C(O)—, or together R 1  and R 2  comprise methylenedioxy; or  
 2. together with their ring carbons form a C 6 - or C 10 -aromatic fused ring system; or  
 3. together with their ring carbons form a C 5 -C 7  fused cycloalkyl ring having up to two double bonds including the fused double bond of the -olium or -onium containing ring, which cycloalkyl. ring can be 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 may be optionally substituted with one or more 1-pyrrolidinyl-, 4-[C 6  or C 10 ]arylpiperazin-1-yl, 4-[C 6  or C 10 ]arylpiperidin-1-yl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, halo or (C 1 -C 3 )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 can be 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, (C 1 -C 3 )alkylenedioxy alkylsulfonyl, alkylsulfinyl, co-alkylenesulfonic acid, alkylthio, allyl, amino, ArC(O)—, ArC(O)NH—, ArO—, Ar—, Ar-alkyl, carboxy, carboxyalkyl, cycloalkyl, dialkylamino, halo, trifluoromethyl, hydroxy, (C 2 -C 6 )hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic acid, 1-pyrrolidinyl, 4-[C 6  or C 10 ]arylpiperazin-1-yl, 4[C 6  or C 10 ]arylpiperidin-1-yl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl; and  
 wherein heterocycles, except those of Ar, can be substituted with, in addition to any substitution 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.  
 
   
   
       13 . The method of  claim 12 , wherein R 2  and R 3  are independently hydrogen, alkyl, lower alkyl or together form an alkylene bridge of 3-4 carbon atoms.  
   
   
       14 . The method of  claim 12 , wherein R 1  is hydrogen.  
   
   
       15 . The method of  claim 12 , wherein Z is arylcarbonyl, amino or alkoxycarbonylalkyl, or Z is according to the formula CH(R 4 )(CN), or Z is —CH 2 C(═O)R 5 , where R 5 is a C 6 -C 10  aryl group, said aryl group optionally substituted by one or more alkyl, alkoxy, halo, dialkylamino, hydroxy, nitro or C 1 -C 2  alkylenedioxy groups.  
   
   
       16 . The method of  claim 12 , wherein Z is arylcarbonyl, amino or alkoxycarbonylalkyl, or Z is according to the formula CH(R 4 )(CN).  
   
   
       17 . The method of  claim 12 , wherein said compound is 1-allyl-3-(2-cyanomethyl)-imidazolium chloride.  
   
   
       18 . The method of  claim 12 , wherein said compound is 1-(phenyl)-3-(2-cyanomethyl)-imidazolium chloride.  
   
   
       19 . The method of  claim 12 , wherein said compound is 1-(4-acetylphenyl)-3-(2-cyanomethyl)-imidazolium chloride.  
   
   
       20 . The method of  claim 12 , wherein said compound is 1-(4-methoxyphenyl)-3-(2-cyanomethyl)-imidazolium chloride.  
   
   
       21 . The method of  claim 12 , wherein said compound is 1-(4-methoxycarbonylphenyl-3-(2-cyanomethyl)-imidazolium chloride.  
   
   
       22 . The method of  claim 12 , wherein said compound is 1,5-dicyclohexyl-3-(2-cyanomethyl)-imidazolium bromide.  
   
   
       23 . 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;  
 Z is allyl, arylcarbonyl, amino or alkoxycarbonylalkyl, or Z is according to the formula —CH(R 4 )(CN), or Z is —CH 2 C(═O)R 5 , where R 5  is (a) a C 6 -C 10  aryl group, said aryl group optionally substituted by one or more alkyl, alkoxy, halo, dialkylamino, hydroxy, nitro or C 1 -C 2  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 can be 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 can be substituted by one or more alkyl or alkoxy groups,  
 R 1  and R 4  are independently hydrogen, alkyl or phenyl optionally substituted with one or more halogen, alkyl, di(lower alkyl)amino or alkoxy groups; and  
 R 2  and R 3  are:  
 1. independently selected from hydrogen, acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino, (C 1 -C 3 )alkylenedioxy, allyl, amino, ω-alkylenesulfonic acid, carbamoyl, carboxy, carboxyalkyl, cycloalkyl, dialkylamino, halo, hydroxy, (C 2 -C 6 )hydroxyalkyl, mereapto, nitro, sulfamoyl, sulfonic acid, alkylsulfonyl, alkylsulfinyl, alkylthio, trifluoromethyl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, 4-[C 6  or C 10 ]arylpiperidin-1-yl, 4-[C 6  or C 10 ]arylpiperazin-1-yl, Ar {wherein, consistent with the rules of aromaticity, Ar is C 6  or C 10  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 can be 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, ArSO 2 —, ArSO—, ArS—, ArSO 2 NH—, ArNH, (N—Ar)(N-alkyl)N—, ArC(O), ArC(O)NH—, ArNH—C(O)—, and (N—Ar)(N-alkyl)N—C(O)—, or together R 1  and R 2  comprise methylenedioxy; or  
 2. together with their ring carbons form a C 6 - or C 10 -aromatic fused ring system; or  
 3. together with their ring carbons form a C 5 -C 7  fused cycloalkyl ring having up to two double bonds including the fused double bond of the -olium or -onium containing ring, which cycloalkyl. ring can be 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 may be optionally substituted with one or more 1-pyrrolidinyl-, 4-[C 6  or C 10 ]arylpiperazin-1-yl, 4-[C 6  or C 10 ]arylpiperidin-1-yl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, halo or (C 1 -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 can be 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, (C 1 -C 3 )alkylenedioxy alkylsulfonyl, alkylsulfinyl, co-alkylenesulfonic acid, alkylthio, allyl, amino, ArC(O)—, ArC(O)NH—, ArO—, Ar—, Ar-alkyl, carboxy, carboxyalkyl, cycloalkyl, dialkylamino, halo, trifluoromethyl, hydroxy, (C 2 -C 6 )hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic acid, 1-pyrrolidinyl, 4-[C 6  or C 10 ]arylpiperazin-1-yl, 4[C 6  or C 10 ]arylpiperidin-1-yl, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl; and  
 wherein heterocycles, except those of Ar, can be substituted with, in addition to any substitution 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.  
 
   
   
       24 . The solid pharmaceutical dosage form of  claim 23 , wherein the solid dosage form is a tablet, capsule or lozenge.  
   
   
       25 . The solid pharmaceutical dosage form of  claim 23 , wherein R 1  is hydrogen.