Compounds for inhibiting insulin secretion and methods related thereto

Abstract

Compounds, compositions and methods for altering insulin secretion, particularly in the context of treatment of subjects having, or suspected of being at risk for having, diabetes mellitus. The compounds have the following struture (I): including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein W 1 , W 2 , X, R 1 , R 2 , R 3 , R 4 , m and n are defined herein.

1 . A compound having the structure:  
     
       
         
         
             
             
         
       
     
     or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, wherein: 
 X is —S(O) q —, —O—, —N(R)— or —C(R)(R′)—;  
 m is 0 or 1;  
 n is 0, 1 or 2;  
 q is 0, 1 or 2;  
 W 1  and W 2  each represent an optional substituent, wherein W 1  and W 2  are the same or different and independently halogen, nitro, or lower alkyl;  
 R and R′ are the same or different and independently alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl,  
 or R and R′ taken together with the carbon atom to which they are bonded form a carbocycle, substituted carbocycle, heterocycle or substituted heterocycle;  
 R 1  is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl or substituted heteroaryl;  
 R 2  is hydrogen, nitro, —OR 2a , —C(═O)NR 2b R 2c , —CH 2 NR 2b R 2c , —CH 2 OR 2a , —NR 2b R 2c , —NHC(═O)R 2a , —NHC(═O)NR 2b R 2c  or —NHC(═NH)NR 2b R 2c ;  
 R 2a  is hydrogen, alkyl, substituted alkyl, arylalkyl, or substituted arylalkyl;  
 R 2b  and R 2c  are the same or different and independently hydrogen, alkyl, substituted alkyl, —SO 2 R 4 , —C(═NH)NH 2  or —C(═O)R 2d  where R 2d  is amino, alkyl, substituted alkyl, aryl or substituted aryl;  
 R 3  is hydroxy, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, —C(═O)N(R 3a )(R 3b ), —NHC(═O)N(R 3a )(R 3b ), —NHC(═S)N(R 3a )(R 3b ), —C(═O)OR 3c , —C(═O)R 3c , —NHC(═O)R 3d  or —NHSO 2 R 3d ;  
 R 3a  and R 3b  are the same or different and independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl,  
 or R 3a  and R 3b  taken together with the nitrogen atom to which they are attached form a heterocycle or substituted heterocycle;  
 R c  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;  
 R 3d  is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; and  
 R 4  is, at each occurrence, the same or different and independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl.  
 
   
   
       2 . The compound of  claim 1  wherein X is —S(O) q —.  
   
   
       3 . The compound of  claim 1  wherein X is —O—.  
   
   
       4 . The compound of  claim 1  wherein X is —N(R)—.  
   
   
       5 . The compound of  claim 1  wherein X is —C(R)(R′)—.  
   
   
       6 . The compound of  claim 1  wherein R 2  is hydrogen.  
   
   
       7 . The compound of  claim 1  wherein R 2  is —OR 2a .  
   
   
       8 . The compound of  claim 1  wherein R 2  is —C(═O)NR 2b R 2c .  
   
   
       9 . The compound of  claim 1  wherein R 2  is —CH 2 NR 2b R 2c .  
   
   
       10 . The compound of  claim 1  wherein R 2  is —CH 2 OR 2a .  
   
   
       11 . The compound of  claim 1  wherein R 2  is —NR 2b R 2c .  
   
   
       12 . The compound of  claim 11  wherein R 2b  and R 2c  are hydrogen.  
   
   
       13 . The compound of  claim 1  wherein R 2  is —NHC(═O)R 2a .  
   
   
       14 . The compound of  claim 1  wherein R 2  is —NHC(═O)NR 2b R 2c .  
   
   
       15 . The compound of  claim 1  wherein R 2  is —NHC(═NH)NR 2b R 2c .  
   
   
       16 . The compound of  claim 1  wherein R 1  is aryl or substituted aryl.  
   
   
       17 . The compound of  claim 16  wherein W 1  is present at the 5-position and W 2  is not present.  
   
   
       18 . The compound of  claim 17  wherein W 1  is halogen.  
   
   
       19 . The compound of  claim 18  wherein W 1  is chloro.  
   
   
       20 . The compound of  claim 18  wherein X is S(O) q , q is 0, R 2  is —NR 2a R 2c , m is 0 and n is 1.  
   
   
       21 . The compound of  claim 18  wherein X is S(O) q , q is 0, R 2  is —NR 2a R 2c , m is 0 and n is 2.  
   
   
       22 . The compound of  claim 20  or  21  wherein R 3  is —C(═O)N(R 3a )(R 3b ).  
   
   
       23 . The compound of  claim 20  or  21  wherein R 3  is —C(═O)OR 3c .  
   
   
       24 . The compound of  claim 20  or  21  wherein R 3  is —C(═O)R 3c .  
   
   
       25 . The compound of  claim 20  or  21  wherein R 3  heterocycle or substituted heterocycle.  
   
   
       26 . The compound of  claim 20  or  21  wherein R 3  is NHC(═O)N(R 3a )(R 3b ).  
   
   
       27 . The compound of  claim 20  or  21  wherein R 3 —NHC(═S)N(R 3a )(R 3b ).  
   
   
       28 . The compound of  claim 20  or  21  wherein R 3  is —NHC(═O)R 3d .  
   
   
       29 . The compound of  claim 20  or  21  wherein R 3  is —NHSO 2 R 3d .  
   
   
       30 . The compound of  claim 1  wherein R 1  is alkyl or substituted alkyl.  
   
   
       31 . The compound of  claim 30  wherein W 1  is present at the 5-position and W 2  is not present.  
   
   
       32 . The compound of  claim 31  wherein W 1  is halogen.  
   
   
       33 . The compound of  claim 32  wherein W 1  is chloro.  
   
   
       34 . The compound of  claim 32  wherein X is S(O) q , q is 0, R 2  is —NR 2a R 2c , m is 0 and n is 1.  
   
   
       35 . The compound of  claim 32  wherein X is S(O) q , q is 0, R 2  is —NR 2a R 2c , m is 0 and n is 2.  
   
   
       36 . The compound of  claim 34  or  35  wherein R 3  is —C(═O)N(R 3a )(R 3b ).  
   
   
       37 . The compound of  claim 34  or  35  wherein R 3  is —C(═O)OR 3c .  
   
   
       38 . The compound of  claim 34  or  35  wherein R 3  is —C(═O)R 3c .  
   
   
       39 . The compound of  claim 34  or  35  wherein R 3  heterocycle or substituted heterocycle.  
   
   
       40 . The compound of  claim 34  or  35  wherein R 3  is NHC(═O)N(R 3a )(R 3b ).  
   
   
       41 . The compound of  claim 34  or  35  wherein R 3 —NHC(═S)N(R 3a )(R 3b ).  
   
   
       42 . The compound of  claim 34  or  35  wherein R 3  is —NHC(═O)R 3d .  
   
   
       43 . The compound of  claim 34  or  35  wherein R 3  is —NHSO 2 R 3d .  
   
   
       44 . A method for treating diabetes mellitus, comprising administering, to a subject having or suspected of being at risk for having diabetes mellitus, a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 1 .  
   
   
       45 . The method of  claim 44  wherein the diabetes mellitus is type 2 diabetes mellitus.  
   
   
       46 . The method of  claim 44  wherein the diabetes mellitus is maturity onset diabetes of the young.  
   
   
       47 . A method for enhancing insulin secretion, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 1 .  
   
   
       48 . A method for inhibiting a mitochondrial calcium/sodium antiporter, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 1 .  
   
   
       49 . The method of any one of claims  44 ,  47  or  48 , further comprising administration to the subject one or more agents that lower circulating glucose concentration.