초록

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

대표청구항 ▼

1. A method of increasing neutrophils in a subject in need thereof, the method comprising administering to the subject a 15-PGDH inhibitor, wherein the 15-PGDH inhibitor has the following formula (V): wherein n is 0-2X6 is independently N or CRc R1, R6, R7, and Rc are each independently selected fro

1. A method of increasing neutrophils in a subject in need thereof, the method comprising administering to the subject a 15-PGDH inhibitor, wherein the 15-PGDH inhibitor has the following formula (V): wherein n is 0-2X6 is independently N or CRc R1, R6, R7, and Rc are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, —Si(C1-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C4 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C6-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, phosphates, and phosphate esters, and wherein R6 and R7 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;U1 is N, C—R2, or C—NR3R4, wherein R2 is selected from the group consisting of a H, a lower alkyl group, O, (CH2)n1OR′ (wherein n1=1, 2, or 3), CF3, CH2—CH2X, O—CH2—CH2X, CH2—CH2—CH2X, O—CH2—CH2X, 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 R1 and R2 may be linked to form a cyclic or polycyclic ring, wherein R3 and R4 are the same or different and are each selected from the group consisting of H, a lower alkyl group, O, (CH2)n1OR′ (wherein n1=1, 2, or 3), CF3, CH2—CH2X, CH2—CH2—CH2X, (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 R3 or R4 may be absent;and pharmaceutically acceptable salts thereof. 2. The method of claim 1, further comprising administering in combination with the 15-PGDH inhibitor at least one hematopoietic cytokine or cell mobilization agent. 3. The method of claim 1, wherein the hematopoietic cytokine or cell mobilization agent comprises at least one of G-CSF or Plerixafor. 4. The method of claim 1, wherein the subject has or is at risk of at least one of neutropenia, thrombocytopenia, anemia, or cytopenia. 5. The method of claim 4, 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. 6. The method of claim 1, wherein the 15-PGDH inhibitor has the following formula (VI): wherein n=0-2;X6 is N or CRc;R1 is selected from the group consisting of branched or linear alkyl, —(CH2)n1CH3 (n1=0-7), wherein n2=0-6 and X is any of the following: CFyHz (y+z=3), CClyHz (y+z=3), OH, OAc, OMe, R71, OR72, CN, N(R73)2, (n3=0-5, m=1-5), and (n4=0-5); R5 is selected from the group consisting of H, Cl, F, NH2, and N(R76)2;R6 and R7 can each independently be one of the following: each R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R76, and Rc are the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, —Si(C1-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C6-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, phosphates, phosphate esters, and pharmaceutically acceptable salts thereof. 7. The method of claim 1, wherein the 15-PGDH inhibitor has the following formula following formula: or pharmaceutically acceptable salts thereof. 8. A method increasing numbers of and/or of mobilizing peripheral blood hematopoietic stem cells in a subject in need thereof, the method comprising administering to the subject a 15-PGDH inhibitor, wherein the 15-PGDH inhibitor has the following formula (V): wherein n is 0-2X6 is independently is N or CRc R1, R6, R7, and Rc are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, —Si(C1-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C6-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, phosphates, and phosphate esters, and wherein R6 and R7 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;U1 is N, C—R2, or C—NR3R4, wherein R2 is selected from the group consisting of a H, a lower alkyl group, O, (CH2)n1OR′ (wherein n1=1, 2, or 3), CF3, CH2—CH2X, O—CH2—CH2X, CH2—CH2—CH2X, O—CH2—CH2X, 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 R1 and R2 may be linked to form a cyclic or polycyclic ring, wherein R3 and R4 are the same or different and are each selected from the group consisting of H, a lower alkyl group, O, (CH2)n1OR′ (wherein n1=1, 2, or 3), CF3, CH2—CH2X, CH2—CH2—CH2X, (wherein X═H, F, Cl, Br, or I), CN, (C═O)—R′, (C═O)N(F)2, COOR′ (wherein R′ is H or a lower alkyl group), and R3 or R4 may be absent;and pharmaceutically acceptable salts thereof. 9. The method of claim 8, wherein the number of hematopoietic stem cells is increased in blood or bone marrow. 10. The method of claim 8, further comprising administering in combination with the 15-PGDH inhibitor at least one hematopoietic cytokine or cell mobilization agent. 11. The method of claim 10, wherein the hematopoietic cytokine or cell mobilization agent comprises at least one of G-CSF or Plerixafor. 12. The method of claim 8, wherein the subject has or is at risk of at least one of neutropenia, thrombocytopenia, anemia, or cytopenia. 13. The method of claim 12, wherein the subject has received a hematopoietic stem cell transplant, bone marrow transplant, chemotherapy, a myelosuppressive therapy, radiation therapy, viral therapy, and/or has a bone marrow disease, cancer, viral infection, aplastic anemia, myelodysplasia, and/or myelofibrosis. 14. The method of claim 8, wherein the 15-PGDH inhibitor has the following formula (VI): wherein n=0-2;X6 is N or CRc;R1 is selected from the group consisting of branched or linear alkyl —(CH2)n1CH3 (n1=0-7), wherein n2=0-6 and X is any of the following: CFyHz (y+z=3), CClyHz (y+z=3), OH, OAc, OMe, R71, OR72, CN, N(R73)2, (n3=0-5, m=1-5), and (n4=0-5); R5 is selected from the group consisting of H, Cl, F, NH2, and N(R76)2;R6 and R7 can each independently be one of the following: each R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R76, and Rc are the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, —Si(C1-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C6-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, phosphates, phosphate esters, and pharmaceutically acceptable salts thereof. 15. The method of claim 8, wherein the 15-PGDH inhibitor has the following formula following formula: or pharmaceutically acceptable salts thereof. 16. A method of treating at least one of neutropenia, thrombocytopenia, anemia, or cytopenia in a subject in need thereof, the method comprising: administering to the subject a 15-PGDH inhibitor, wherein the 15-PGDH inhibitor has the following formula (V): wherein n is 0-2X6 is independently is N or CRc R1, R6, R7, and Rc are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, —Si(C1-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C4 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C6-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, and phosphates, phosphate esters, and wherein R6 and R7 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;U1 is N, C—R2, or C—NR3R4, wherein R2 is selected from the group consisting of a H, a lower alkyl group, O, (CH2)n1OR′ (wherein n1=1, 2, or 3), CF3, CH2—CH2X, O—CH2—CH2X, CH2—CH2—CH2X, O—CH2—CH2X, 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 R1 and R2 may be linked to form a cyclic or polycyclic ring, wherein R3 and R4 are the same or different and are each selected from the group consisting of H, a lower alkyl group, O, (CH2)n1OR′ (wherein n1=1, 2, or 3), CF3, CH2—CH2X, CH2—CH2—CH2X, (wherein X═H, F, Cl, Br, or I), CN, (C═O)—R′, (C═O)N(F)2, COOR′ (wherein R′ is H or a lower alkyl group), and R3 or R4 may be absent;and pharmaceutically acceptable salts thereof. 17. The method of claim 16, further comprising administering in combination with the 15-PGDH inhibitor at least one hematopoietic cytokine or cell mobilization agent. 18. The method of claim 17, wherein the hematopoietic cytokine or cell mobilization agent comprises at least one of G-CSF or Plerixafor. 19. The method of claim 16, 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. 20. The method of claim 16, wherein the 15-PGDH inhibitor has the following formula (VI): wherein n=0-2;X6 is N or CRc;R1 is selected from the group consisting of branched or linear alkyl, —(CH2)n1CH3 (n1=0-7), wherein n2=0-6 and X is any of the following: CFyHz (y+z=3), CClyHz (y+z=3), OH, OAc, OMe, R71, OR72, CN, N(R73)2, (n3=0-5, m=1-5), and (n4=0-5); R5 is selected from the group consisting of H, Cl, F, NH2, and N(R76)2;R6 and R7 can each independently be one of the following: each R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63 R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R76, and Rc are the same or different and are independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C3-C20 aryl, heteroaryl, heterocycloalkenyl containing from 5-6 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, —Si(C1-C3 alkyl)3, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C6-C20 arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkylethers, phosphates, phosphate esters, and pharmaceutically acceptable salts thereof. 21. The method of claim 16, wherein the 15-PGDH inhibitor has the following formula following formula: or pharmaceutically acceptable salts thereof.