Heteroaromatic glucokinase activators

Abstract

2,3-Di-substituted N-heteroaromatic propionamides with said substitution at the 3-position being a substituted phenyl group and at the 2-position being a methyl cycloalkyl ring, said propionamides being glucokinase activators which increase insulin secretion in the treatment of type II diabetes.

1 . A compound comprising an amide of the formula:  
     
       
         
         
             
             
         
       
       wherein, the * indicates an asymmetric carbon atom,  
       R 1  and R 2  are independently hydrogen, halo, amino, hydroxyamino, cyano, nitro, lower alkyl, —OR 5 , —C(O)OR 6 , perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, lower alkoxy lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, lower alkyl sulfinyl, or sulfonamido; R 3  is cycloalkyl having from 3 to 7 carbon atoms or lower alkyl having from 2 to 4 carbon atoms;  
       R 4  is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amide group shown, which five- or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom; said mono-substituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of lower alkyl, halo, nitro, cyano, perfluoro-lower alkyl, oxo, —(CH 2 ) n —OR 7 , —(CH 2 ) n —C(O)—OR 7 , —(CH 2 ) n —C(O)—NH—R 7 , —C(O)C(O)—OR 7 , or —(CH 2 ) n —NHR 7 ; 
 n is 0, 1, 2, 3 or 4;  
 R 5  is hydrogen, lower alkyl, or perfluoro-lower alkyl; R 6  is lower alkyl; and R 7  is hydrogen or lower alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
   
   
       2 . The compound of  claim 1 , wherein the amide is the R configuration at the asymmetric carbon shown.  
   
   
       3 . The compound of  claim 1 , wherein R 3  is cycloalkyl having from 3 to 7 carbon atoms.  
   
   
       4 . The compound of  claim 3 , wherein R 3  is cyclopentyl.  
   
   
       5 . The compound of  claim 4  wherein R 4  is unsubstituted pyridine.  
   
   
       6 . The compound of  claim 5 , wherein one of R 1  and R 2  is halo and the other is lower alkyl sulfonyl.  
   
   
       7 . The compound of  claim 4  wherein R 4  is a pyridine ring mono-substituted with one of said substituents.  
   
   
       8 . The compound of  claim 7 , wherein said substituent is cyano.  
   
   
       9 . The compound of  claim 8 , wherein one of R 1  or R 2  is halo or perfluoro lower alkyl and the other is halo or lower alkyl thio.  
   
   
       10 . The compound of  claim 7 , wherein said substitutent is —(CH 2 ) n —C(O)—OR 7  wherein n and R 7  are as above.  
   
   
       11 . The compound of  claim 10 , wherein one of R 1  and R 2  is hydrogen or halo and the other is halo, amino, cyano, nitro or perfluoro-lower alkyl.  
   
   
       12 . The compound of  claim 11 , wherein said amide is 6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid.  
   
   
       13 . The compound of  claim 11 , wherein said amide is 6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester.  
   
   
       14 . The compound of  claim 11 , wherein said amide is 6-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester.  
   
   
       15 . The compound of  claim 11 , wherein said amide is 6-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-nicotinic acid methyl ester.  
   
   
       16 . The compound of  claim 11 , wherein said amide is 6-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester.  
   
   
       17 . The compound of  claim 11 , wherein said amide is 6-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid.  
   
   
       18 . The compound of  claim 11 , wherein said amide is 6-[2-(4-cyano-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester.  
   
   
       19 . The compound according to  claim 7 , wherein said substitutent is —(CH2)-nOR7 wherein n and R7 are as above.  
   
   
       20 . The compound according to  claim 19 , wherein one of R1 and R2 is lower alkyl sulfonyl or hydrogen and the other is lower alkyl sulfonyl.  
   
   
       21 . The compound of  claim 20 , wherein said amide is 3-cyclopentyl-N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-methanesulfonyl-phenyl)-propionamide.  
   
   
       22 . The compound of  claim 7 , wherein said substituent is halo or perfluoro-lower alkyl.  
   
   
       23 . The compound of  claim 22 , wherein one of R 1  and R 2  is halo or perfluoro-lower alkyl and the other is halo, nitro, lower alkyl sulfonyl, or lower alkyl thio.  
   
   
       24 . The compound of  claim 7 , wherein said substituent is nitro.  
   
   
       25 . The compound of  claim 24 , wherein one of R 1  and R 2  is halo or perfluoro-lower alkyl and the other is halo or lower alkyl thio.  
   
   
       26 . The compound of  claim 7 , wherein said substituent is lower alkyl.  
   
   
       27 . The compound of  claim 26 , wherein one of R 1  and R 2  is halo or hydrogen and the other of said R 1  and R 2  is halo, perfluoro-lower alkyl, lower alkyl sulfonyl, or perfluoro-lower alkyl sulfonyl.  
   
   
       28 . The compound of  claim 7 , wherein said substituent is —(CH 2 ) n —C(O)—NH—R 7  wherein n and R 7  are as above.  
   
   
       29 . The compound of  claim 28 , wherein one of R 1  and R 2  is halo or hydrogen and the other of said R 1  and R 2  is halo, or lower alkyl sulfonyl.