Combinations of 15-pgdh inhibitors with corticosteroids and/or tnf inhibitors and uses thereof

Abstract

A method of treating intestinal, gastrointestinal, or bowel disorders in a subject in need thereof includes administering to the subject a therapeutically effective amount of 15-PGDH inhibitor alone or in combination with a corticosteroid and/or TNF alpha antagonist.

1 - 23  (canceled) 
     
     
         24 . A method of treating intestinal, gastrointestinal, or bowel disorders in a subject in need thereof, the method comprising administering to the subject a 15-PGDH inhibitor and a tumor necrosis factor α (TNFα) inhibitor in a therapeutically effective amount. 
     
     
         25 . The method of  claim 24 , wherein the disorder is inflammatory bowel disease. 
     
     
         26 . The method of  claim 24 , wherein the disorder is ulcerative colitis. 
     
     
         27 . The method of  claim 24 , wherein the disorder is Crohn's disease. 
     
     
         28 . The method of  claim 24 , wherein the disease is inflammatory bowel disease. 
     
     
         29 . The method of  claim 24 , wherein the 15-PGDH inhibitor is a compound having Formula (V): 
       
         
           
           
               
               
           
         
         wherein n is 0-2; 
         X 6  is independently N or CR c ; 
         R 1 , R 6 , R 7 , and R c  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 24  alkyl, C 2 -C 24  alkenyl, C 2 C 24  alkynyl, C 3 -C 20  aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C 6 -C 24  aralkyl, halo, -Si(C 1 -C 3 alkyl) 3 , hydroxyl, sulfhydryl, C 1 -C 24  alkoxy, C 2 -Cz 4  alkenyloxy, C 2 -C 24  alkynyloxy, C 5 -C 20  aryloxy, acyl, acyloxy, C 2 -C 24  alkoxycarbonyl, C 6 -C 20  aryloxycarbonyl, C 2 -C 24  alkylcarbonato, C 6 -C 20  arylcarbonato, carboxy, carboxylato, carbamoyl, C 1 -C 24  alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C 1 -C 24  alkyl amino, C 5 -C 20  aryl amino, C 2 -C 24  alkylamido, C 6 -C 20  arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C 1 -C 24  alkylsulfanyl, arylsulfanyl, C 1 -C 24  alkylsulfinyl, C 5 -C 20  arylsulfinyl, C 1 -C 24  alkylsulfonyl, C 5 -C 20  arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, phosphates, phosphate esters, groups incorporating amino acids or other moieties expected to bear positive or negative charge at physiological pH, combinations thereof, and wherein R 6  and R 7  may be linked to form a cyclic or polycyclic ring, wherein the ring is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl; 
         U 1  is N, C-R 2 , or C-NR 3 R 4 , wherein R 2  is selected from the group consisting of a H. a lower alkyl group, O, (CH 2 ) n1  OR (wherein n1═1, 2, or 3), CF 3 , CH 2 -CH 2 X, O-CH 2 -CH 2 X, CH 2 -CH 2 -CH 2 X, O-CH 2 -CH:X, X, (wherein X═H, F, Cl, Br, or I), CN, (C═O)-R, (C═O)N(R') 2 , O(CO)R', COOR' (wherein R′is H or a lower alkyl group), and wherein R 1  and R 2  may be linked to form a cyclic or polycyelie ring, wherein R 3  and R 4  are the same or different and are each selected from the group consisting of H, a lower alkyl group, O, (CH 2 ) n1 OR′ (wherein n1═1, 2, or 3), CF 3 , CH 2 - CH 2 X, CH 2 -CH 2 - CH 2 X, (wherein X═H, F, Cl, Br, or D), CN, (C═O)-R′, (C═O)N(R′) 2 , COOR′ (wherein R′ is H or a lower alkyl group), and R 3  or R 4  may be absent; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         30 . The method of  claim 24 , wherein the 15-PGDH inhibitor is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         31 . The method of  claim 24 , wherein the TNFα inhibitor is an anti-TNF alpha antibody. 
     
     
         32 . The method of  claim 31 , wherein the anti-TNF alpha antibody is infliximab, adalimumab certolizumab pegol, or golimumab. 
     
     
         33 . The method of  claim 24 , wherein the TNFα inhibitor is a receptor-construct fusion protein. 
     
     
         34 . The method of  claim 33 , wherein the receptor-construct fusion protein is etanercept. 
     
     
         35 . The method of  claim 24 , wherein the TNFα inhibitor is a small molecule. 
     
     
         36 . The method of  claim 35 , wherein the small molecule is pomalidomide, thalidomide, lenalidomide, or bupropion. 
     
     
         37 . The method of  claim 24 , wherein the 15-PGDH inhibitor and the TNFα inhibitor are provided in a pharmaceutical composition together.