Method for treating diabetic nephropathy

Abstract

Provided, among other things, is a method of treating or ameliorating or preventing an indication of the invention in an animal, including a human comprising administering an effective amount of a compound of the formula I:

1 . A method of treating or ameliorating diabetic nephropathy in an subject in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of the formula I: 
     
       
         
         
             
             
         
       
     
     wherein 
     R 1  and R 2  are
 (a) independently selected from hydrogen, acyloxyalkyl, alkenyl, alkyl, amino, (C 2 -C 6 )hydroxyalkyl, and Ar, wherein Ar is C 6  or C 10  aryl; or 
 (b) together with their ring carbons R 1  and R 2  form a C 6 - or C 10 -aromatic fused ring system; or 
 (c) together with their ring carbons R 1  and R 2  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; 
 
     Z is
 (a) hydrogen, or alkyl; or 
 (b) or a group of the formula —NR 3 R 4 ; wherein R 3  and R 4  are hydrogen; 
 
     Y is
 (a) amino, or 
 (b) a group of the formula —CH(R 5 )—R 6  wherein 
 
     R 5  is hydrogen or alkyl-; 
     R 6  is
 (a) hydrogen, alkyl, wherein alkyl is optionally substituted with alkoxycarbonyl, alkynyl, or Rs, wherein Rs is a C 6  or C 10  aryl or a heterocycle containing 4-10 ring atoms of which 1-3 are heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; or 
 (b) a group of the formula —W—R 7 , wherein R 7  is alkyl, alkoxy, hydroxy or Rs, wherein W is —C(═O)—; 
 (c) a group of the formula —CH(OH)Rs; or 
 (d) a group of the formula —W—N(R 9 )R 10 , wherein
 [a] R 9  is hydrogen and R 10  is alkyl or cycloalkyl, optionally substituted with (i) [C 6  or C 10 ]aryl, or (ii) 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, said heteroaryl ring can 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, and morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, halo or (C 1 -C 3 ) alkylenedioxy groups, or fused to a substituted phenyl or pyridine ring, wherein the ring fusion is at a carbon-carbon double bond of the heteroaryl ring, or (iii) a heterocycle containing 4-10 ring atoms of which 1-3 are heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; or 
 [b] R 9  is hydrogen and R 10  is Ar; or 
 [c] R 9  and R 10  are both alkyl groups; or 
 [d] R 9  and R 10  together with N form a heterocycle containing 4-10 ring atoms which can incorporate up to one additional heteroatom selected from the group of N, O or S in the ring, wherein the heterocycle is optionally substituted with (C 6 - or C 10 )aryl, (C 6 - or C 10 )arylalkyl, or 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 such heteroaryl can 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; or 
 [f] R 9  and R 10  are both hydrogen; 
 
 
     Q is S; 
     M is absent; 
     X is a pharmaceutically acceptable anion, or a pharmaceutically acceptable salt of the compound,
 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, (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, azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl; and 
 wherein heterocycle, except those of Ar, is 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; 
 
     and a pharmaceutically acceptable carrier, thereby treating or ameliorating said diabetic nephropathy. 
   
   
       2 . The method of  claim 1 , comprising administering a compound, wherein R 1  and R 2  are both alkyl. 
   
   
       3 . The method of  claim 2 , wherein alkyl is methyl. 
   
   
       4 . The method of  claim 1 , comprising administering a compound, wherein Z is hydrogen. 
   
   
       5 . The method of  claim 1 , comprising administering a compound, wherein Y is —CH 2 —C(═O)—Rs. 
   
   
       6 . The method of  claim 5 , comprising administering a compound, wherein Rs is C 6  aryl. 
   
   
       7 . The method of  claim 1 , wherein the compound is 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium salt. 
   
   
       8 . The method of  claim 7 , wherein the compound is 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium chloride. 
   
   
       9 . The method of  claim 7 , wherein the compound is 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium bromide. 
   
   
       10 . The method of  claim 1 , wherein the diabetic nephropathy is associated with diabetes. 
   
   
       11 . The method of  claim 1 , wherein the diabetic nephropathy is associated with albuminuria. 
   
   
       12 . The method of  claim 1 , wherein the treatment or amelioration of said diabetic nephropathy, breaks, reduces or inhibits the formation of advanced glycoslyation end products or advanced glycoslyation end product-mediated crosslinks. 
   
   
       13 . The method of  claim 1 , wherein said subject is a mammal. 
   
   
       14 . The method of  claim 13 , wherein said mammal is a human. 
   
   
       15 . The method of  claim 1 , wherein the pharmaceutical composition is administered via oral, parenteral, sublingual, buccal, rectal, nasal, inhalation, ocular, vaginal, topical, pulmonary, intramuscular, subcutaneous, intraperitoneal, intraarterial, intravenous or intrathecal routes. 
   
   
       16 . The method of  claim 15 , wherein the pharmaceutical composition is administered orally as a tablet, chewable tablet, capsule, or lozenge. 
   
   
       17 . The method of  claim 1 , wherein the therapeutically effective amount is from about 0.7 mg to about 280 mg daily. 
   
   
       18 . The method of  claim 1 , wherein the therapeutically effective amount is from about 0.5 mg to about 210 mg daily. 
   
   
       19 . The method of  claim 1 , wherein the therapeutically effective amount is 0.1 mg/kg to 4 mg/kg body weight daily. 
   
   
       20 . The method of  claim 19 , wherein the therapeutically effective amount is 1 mg/kg body weight daily.