Compounds, Methods and Formulations for the Oral Delivery of a Glucagon-Like Peptide (Glp)-1 Compound or a Melanocortin-4 Receptor (Mc4) Agonist Peptide

Abstract

The present invention relates to novel compounds, methods, and formulations useful for the oral delivery of a GLP-1 compound or an MC4 agonist peptide.

1 . A compound of formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  and R 2  are each independently H, OH, cyano, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , halo or NR 4 R 4 ′;  
 R 3  is H, C 1 -C 6  alkyl;  
 X is a 5-membered aromatic heterocycle that is optionally substituted with C 1 -C 4  alkyl; wherein said heterocycle contains at least two or three heteroatoms selected from N, S and O wherein at least one heteroatom must be N;  
 Y is S, CR 5 ═N or N═CR 5 ;  
 n is 2, 3, 4, 5, 6 or 7;  
 R 4  is H, COR 6 , SO 2 R 7 , or C 1 -C 6  alkyl;  
 R 4 ′ is H or C 1 -C 6  alkyl;  
 R 5  is H or forms a bond with X;  
 R 6  is H or C 1 -C 6  alkyl; and  
 R 7  is H or C 1 -C 6  alkyl;  
 or a pharmaceutical salt thereof; wherein said compound of formula I is not:  
                     
 
   
   
       2 . The compound of  claim 1  wherein R 1  and R 2  are each independently H, OH, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , halo or NR 4 R 4 ′ and wherein X is not substituted with C 1 -C 4  alkyl.  
   
   
       3 . The compound of  claim 1  or  2  wherein R 3  is H.  
   
   
       4 . The compound of any one of claims  1 - 3  wherein X is  
     
       
         
         
             
             
         
       
     
     R 3  is H and the (CH 2 ) n CO 2 R 3  moiety is attached at position number 2; or a pharmaceutical salt thereof.  
   
   
       5 . The compound of any one of claims  1 - 3  wherein X is  
     
       
         
         
             
             
         
       
     
     R 3  is H and the (CH 2 ) n CO 2 R 3  moiety is attached at position number 5; or a pharmaceutical salt thereof.  
   
   
       6 . A compound which is  
     
       
         
         
             
             
         
       
     
     or a pharmaceutical salt thereof.  
   
   
       7 . A compound which is  
     
       
         
         
             
             
         
       
     
     or a pharmaceutical salt thereof.  
   
   
       8 . A compound which is  
     
       
         
         
             
             
         
       
     
     or a pharmaceutical salt thereof.  
   
   
       9 . A compound which is  
     
       
         
         
             
             
         
       
     
     or a pharmaceutical salt thereof.  
   
   
       10 . A compound which is  
     
       
         
         
             
             
         
       
     
     or a pharmaceutical salt thereof.  
   
   
       11 . A compound which is  
     
       
         
         
             
             
         
       
     
     or a pharmaceutical salt thereof.  
   
   
       12 . A pharmaceutical composition comprising: 
 a) a compound of  claim 1  or a pharmaceutical salt thereof; and    b) a GLP-I compound.    
   
   
       13 . The composition of  claim 12  wherein the GLP-1 compound is Val 8 -Glu 22 -GLP-1(7-37)OH.  
   
   
       14 . A pharmaceutical composition comprising: 
 a) a compound of  claim 1  or a pharmaceutical salt thereof; and    b) an MC4 agonist peptide.    
   
   
       15 . (canceled)