Inhibitors of short-chain dehydrogenase activity for modulating hematopoietic stem cells and hematopoiesis

Abstract

A method of modulating hematopoietic stem cells and hematopoiesis includes administering to a subject in need thereof a 15-PGDH inhibitor.

1 - 24 . (canceled) 
     
     
         25 : A method of increasing neutrophils in a subject in need thereof, the method comprising administering to the subject a 15-PGDH inhibitor. 
     
     
         26 : The method of  claim 25 , wherein the subject has or is at risk of at least one of neutropenia, thrombocytopenia, anemia, or cytopenia. 
     
     
         27 : The method of  claim 25 , wherein the subject has received a hematopoietic stem cell transplant, bone marrow transplant, chemotherapy, a myelosuppressive therapy, radiation therapy, immunosuppressive therapy, and/or viral therapy, and/or has a bone marrow disease, cancer, viral infection, aplastic anemia, myelodysplasia, and/or myelofibrosis. 
     
     
         28 : The method of  claim 25 , wherein the subject has undergone a bone marrow transplant and/or hematopoietic stem cell transplant. 
     
     
         29 : The method of  claim 25 , wherein the subject has undergone chemotherapy. 
     
     
         30 : The method of  claim 25 , wherein the subject has aplastic anemia. 
     
     
         31 : The method of  claim 25 , wherein the 15-PGDH inhibitor is administered in combination with an immunosuppressive therapy. 
     
     
         32 : The method of  claim 25 , wherein the 15-PGDH inhibitor is administered in combination with a reduced dose of an immunosuppressive therapy. 
     
     
         33 : The method of  claim 25 , wherein the 15-PGDH inhibitor has the following formula (V): 
       
         
           
           
               
               
           
         
         wherein n is 0-2 
         X 6  is independently is 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  alkaryl, C 6 -C 24  aralkyl, halo, —Si(C 1 -C 3  alkyl) 3 , hydroxyl, sulfhydryl, C 1 -C 24  alkoxy, C 2 -C 24  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 2 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 polycyclic 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 I), 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; 
         and pharmaceutically acceptable salts thereof. 
       
     
     
         34 : The method of  claim 25 , wherein the 15-PGDH inhibitor has the following formula (VI): 
       
         
           
           
               
               
           
         
         wherein n=0-2; 
         X 6  is N or CR c ; 
         R 1  is selected from the group consisting of branched or linear alkyl including —(CH 2 )n 1 CH 3  (n 1 =0-7), 
       
       
         
           
           
               
               
           
         
       
       wherein n 2 =0-6 and X is any of the following: CF y H z  (y+z=3), CCl y H z  (y+z=3), OH, OAc, OMe, R 71 , OR 72 , CN, N(R 73 ) 2 , 
       
         
           
           
               
               
           
         
       
       (n 3 =0-5, m=1-5), and 
       
         
           
           
               
               
           
         
       
       (n 4 =0-5).
 R 5  is selected from the group consisting of H, Cl, F, NH 2 , and N(R 76 ) 2 ; 
 R 6  and R 7  can each independently be one of the following: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         each R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , R 63 , R 64 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 , R 71 , R 72 , R 73 , R 74 , R 76 , and R c  are the same or different and are 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  alkaryl, C 6 -C 24  aralkyl, halo, —Si(C 1 -C 3  alkyl) 3 , hydroxyl, sulfhydryl, C 1 -C 24  alkoxy, C 2 -C 24  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, and combinations thereof, and pharmaceutically acceptable salts thereof. 
       
     
     
         35 : The method of  claim 25 , wherein the 15-PGDH inhibitor has the following formula following formula: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof. 
       
     
     
         36 : A method of increasing neutrophils in a subject treated with an immunosuppressive therapy, the method comprising administering to the subject treated with the immunosuppressive therapy a 15-PGDH inhibitor. 
     
     
         37 : The method of  claim 36 , wherein the subject has or is at risk of at least one of neutropenia, thrombocytopenia, anemia, or cytopenia. 
     
     
         38 : The method of  claim 36 , wherein the subject has received a hematopoietic stem cell transplant, bone marrow transplant, chemotherapy, a myelosuppressive therapy, radiation therapy, and/or viral therapy, and/or has a bone marrow disease, cancer, viral infection, aplastic anemia, myelodysplasia, and/or myelofibrosis. 
     
     
         39 : The method of  claim 36 , wherein the subject has undergone a bone marrow transplant and/or hematopoietic stem cell transplant. 
     
     
         40 : The method of  claim 36 , wherein the subject has or is at risk of at least one of neutropenia, thrombocytopenia, anemia, or cytopenia. 
     
     
         41 : The method of  claim 36 , wherein the 15-PGDH inhibitor has the following formula (V): 
       
         
           
           
               
               
           
         
         wherein n is 0-2 
         X 6  is independently is 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  alkaryl, C 6 -C 24  aralkyl, halo, —Si(C 1 -C 3  alkyl) 3 , hydroxyl, sulfhydryl, C 1 -C 24  alkoxy, C 2 -C 24  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 2 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 polycyclic 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 I), 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; 
         and pharmaceutically acceptable salts thereof. 
       
     
     
         42 : The method of  claim 36 , wherein the 15-PGDH inhibitor has the following formula (VI): 
       
         
           
           
               
               
           
         
         wherein n=0-2; 
         X 6  is N or CR c ; 
         R 1  is selected from the group consisting of branched or linear alkyl including —(CH 2 ) n1 CH 3  (n 1 =0-7), 
       
       
         
           
           
               
               
           
         
       
       wherein n 2 =0-6 and X is any of the following: CF y H z  (y+z=3), CCl y H z  (y+z=3), OH, OAc, OMe, R 71 , OR 72 , CN, N(R 73 ) 2 , 
       
         
           
           
               
               
           
         
       
       (n 3 =0-5, m=1-5), and 
       
         
           
           
               
               
           
         
       
       (n 4 =0-5).
 R 5  is selected from the group consisting of H, Cl, F, NH 2 , and N(R 76 ) 2 ; 
 R 6  and R 7  can each independently be one of the following: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         each R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , R 63 , R 64 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 , R 71 , R 72 , R 73 , R 74 , R 76 , and R c  are the same or different and are 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  alkaryl, C 6 -C 24  aralkyl, halo, —Si(C 1 -C 3  alkyl) 3 , hydroxyl, sulfhydryl, C 1 -C 24  alkoxy, C 2 -C 24  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, and combinations thereof, and pharmaceutically acceptable salts thereof. 
       
     
     
         43 : The method of  claim 36 , wherein the 15-PGDH inhibitor has the following formula following formula: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof.