Compositions and methods for treating inflammatory bowel disease using a combination therapy of small molecule inhibitors of c-c chemokine receptor type 9 (ccr9) and anti-alpha4beta7 integrin blocking antibodies

Abstract

Provided herein are compositions, methods and kits for treating inflammatory bowel disease (IBD) such as Crohn's disease and ulcerative colitis in a mammal in need thereof. The method include administering to a subject with IBD a combination therapy containing a therapeutically effective amount of a chemokine receptor 9 (CCR9) inhibitor compound and a therapeutically effective amount of an anti-α4β7 integrin antibody such as vedolizumab. Also provided herein is a kit containing the CCR9 inhibitor compound and anti-α4β7 integrin antibody.

What is claimed is: 
     
         1 . A kit for treating or reducing the development of inflammatory bowel disease in a mammal, said kit comprising:
 (i) a therapeutically effective amount of a CCR9 chemokine receptor inhibitor
 or a pharmaceutically acceptable salt thereof; 
   (ii) a therapeutically effective amount of an anti-α4β7 integrin blocking antibody; and   (iii) instructions for effective administration.   
     
     
         2 . The kit of  claim 1 , wherein the inflammatory bowel disease is Crohn's disease (CD) or ulcerative colitis (UC). 
     
     
         3 . The kit of  claim 1 , wherein the anti-α4β7 integrin blocking antibody is vedolizumab. 
     
     
         4 . The kit of  claim 1 , wherein the CCR9 chemokine receptor inhibitor is a compound having formula (I) or a salt thereof: 
       
         
           
           
               
               
           
         
       
       where
 R 1  is selected from the group consisting of substituted or unsubstituted C 2-8  alkyl, substituted or unsubstituted C 1-8  alkoxy, substituted or unsubstituted C 1-8  alkylamino, and substituted or unsubstituted C 3-10 heterocyclyl, and; 
 R 2  is H, F, Cl, or substituted or unsubstituted C 1-8  alkoxy; or 
 R 1  and R 2  together with the carbon atoms to which they are attached form a non-aromatic carbocyclic ring or a heterocyclic ring; 
 R 3  is H, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 1-8  alkoxy, or halo; 
 R 4  is H or F; 
 R 5  is H, F, Cl, or —CH 3 ; 
 R 6  is H, halo, —CN, —CO 2 R a , —CONH 2 , —NH 2 , substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 1-8  alkoxy, or substituted or unsubstituted C 1-8  aminoalkyl; 
 R a  is H or substituted or unsubstituted C 1-8  alkyl; 
 where R 5  and R 6  may together form a carbocyclic ring; 
 L is a bond, —CH 2 —, or —CH(CH 3 )—; 
 each of A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8  are independently selected from the group consisting of N, N—O, and —CR 8 —; where at least one and not more than two of A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8  are N or N—O; 
 R 8  is each independently selected from the group consisting of H, halo, —CN, —OH, oxo, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 1-8  alkoxy, and —NR 20 R 21 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; and 
 R 20  and R 21  are each independently H, or substituted or unsubstituted C 1-8  alkyl. 
 
     
     
         5 . The kit of  claim 4 , where one of A 1  or A 2  is N or N—O, and the remaining of A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8  are —CR 8 —, where each R 8  is selected independently. 
     
     
         6 . The kit of  claim 1 , wherein the CCR9 chemokine receptor inhibitor is a compound having formula (II) or a salt thereof: 
       
         
           
           
               
               
           
         
         where 
         R 1  is selected from the group consisting of substituted or unsubstituted C 2-8  alkyl, substituted or unsubstituted C 1-8 alkoxy, substituted or unsubstituted C 1-8  alkylamino, and substituted or unsubstituted C 3-10  heterocyclyl; 
         R 2  is H, F, Cl, or substituted or unsubstituted C 1-8  alkoxy; or 
         R 1  and R 2  together with the carbon atoms to which they are attached form a non-aromatic carbocyclic ring or a heterocyclic ring; 
         R 3  is H, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 1-8  alkoxy, or halo; 
         R 4  is H or F; 
         R 5  is H, F, Cl, or —CH 3 ; 
         R 6  is H, halo, —CN, —CO 2 R a , —CONH 2 , —NH 2 , substituted or unsubstituted C 1-8  aminoalkyl, substituted or unsubstituted C 1-8  alkyl, or substituted or unsubstituted C 1-8  alkoxy; 
         R a  is H or substituted or unsubstituted C 1-8  alkyl; 
         where R 5  and R 6  may together form a carbocyclic ring; 
         L is a bond, —CH 2 —, or —CH(CH 3 )—; and 
         Z is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         and N-oxides thereof; 
         where the Z group may be unsubstituted or substituted with 1 to 3 independently selected R 8  substituents; 
         each R 8  is independently selected from the group consisting of H, halo, —CN, —OH, oxo, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8  alkoxy, and —NR 20 R 21 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; and 
         R 20  and R 21  are each independently H, substituted or unsubstituted C 1-8  alkyl. 
       
     
     
         7 . The kit of  claim 6 , wherein the inhibitor is a compound having formula (IIIa) or (IIIb) or a salt thereof: 
       
         
           
           
               
               
           
         
         where 
         R 1  is selected from the group consisting of substituted or unsubstituted C 2-8  alkyl, substituted or unsubstituted C 1-8  alkoxy, substituted or unsubstituted C 1-8  alkylamino, and substituted or unsubstituted C 3-10  heterocyclyl; 
         R 2  is H, F, Cl, or substituted or unsubstituted C 1-8  alkoxy; or 
         R 1  and R 2  together with the carbon atoms to which they are attached form a non-aromatic carbocyclic ring or a heterocyclic ring; 
         R 3  is H, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 1-8  alkoxy, or halo; 
         R 4  is H or F; 
         R 5  is H, F, Cl, or —CH 3 ; 
         R 6  is H, halo, —CN, —CO 2 R a , —CONH 2 , —NH 2 , substituted or unsubstituted C 1-8  aminoalkyl, substituted or unsubstituted C 1-8  alkyl, or substituted or unsubstituted C 1-8  alkoxy; 
         R a  is H or substituted or unsubstituted C 1-8  alkyl; 
         or where R 5  and R 6  together with the carbon atoms to which they are attached form a carbocyclic ring; 
         each R 8  is independently selected from the group consisting of H, halo, —CN, —OH, oxo, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 1-8  alkoxy, and —NR 20 R 21 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; 
         R 20  and R 21  are each independently H, or substituted or unsubstituted C 1-8  alkyl; and 
         n is 0, 1, 2 or 3. 
       
     
     
         8 . The kit of  claim 7 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . The kit of  claim 1 , wherein the CCR9 chemokine receptor inhibitor is 
       
         
           
           
               
               
           
         
       
     
     
         10 . The kit of  claim 1 , wherein the CCR9 chemokine receptor inhibitor and the anti-α4β7 integrin blocking antibody are formulated for sequential administration or concomitant administration. 
     
     
         11 . The kit of  claim 10 , wherein the CCR9 chemokine receptor inhibitor and the anti-α4β7 integrin blocking antibody are formulated for concomitant administration. 
     
     
         12 . A kit for treating or reducing the development of inflammatory bowel disease in a mammal, said kit comprising:
 (i) a therapeutically effective amount of vercirnon or a pharmaceutically acceptable salt thereof;   (ii) a therapeutically effective amount of an anti-α4β7 integrin blocking antibody; and   (iii) instructions for effective administration.   
     
     
         13 . The kit of  claim 12 , wherein the CCR9 chemokine receptor inhibitor and the anti-α4β7 integrin blocking antibody are formulated for sequential administration or concomitant administration. 
     
     
         14 . The kit of  claim 13 , wherein the CCR9 chemokine receptor inhibitor and the anti-α4β7 integrin blocking antibody are formulated for concomitant administration. 
     
     
         15 . The kit of  claim 12 , wherein the inflammatory bowel disease is Crohn's disease (CD) or ulcerative colitis (UC). 
     
     
         16 . The kit of  claim 12 , wherein the anti-α4β7 integrin blocking antibody is vedolizumab. 
     
     
         17 . A kit for treating or reducing the development of inflammatory bowel disease in a mammal, said kit comprising:
 (i) a therapeutically effective amount of a CCR9 chemokine receptor inhibitor or a pharmaceutically acceptable salt thereof;   (ii) a therapeutically effective amount of an anti-TNFα blocking antibody; and   (iii) instructions for effective administration.   
     
     
         18 . The kit of  claim 17 , wherein the inflammatory bowel disease is Crohn's disease (CD) or ulcerative colitis (UC). 
     
     
         19 . The kit of  claim 17 , wherein the anti-α4β7 integrin blocking antibody is vedolizumab. 
     
     
         20 . The kit of  claim 17 , wherein the CCR9 chemokine receptor inhibitor is