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US 2026/0132160 A1Published application
Iron replacement treatments
AssigneeThe General Hospital Corporation
InventorsEric M. Gale, Artur Sargun, Jodie Babitt, Allison L. Fisher
Life of this patent
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Abstract
The present application provides compounds and methods for iron replacement therapy.
Claims150
A compound which is a Fe3+ complex of Formula (A-I):
- or a pharmaceutically acceptable salt thereof, wherein:
- indicates a coordinate bond;
- each L is independently a Fe3+ ligand;
- p is 0, 1 or 2;
- L1 is —C1-3 alkylene-, optionally substituted with R10;
- each R10 is independently —(C1-3 alkyl)qSO3RA, —(C1-3 alkyl)qSO2R8, —(C1-3 alkyl)qNHSO2R8, —(C1-3 alkyl)qCO2RA, —(C1-3 alkyl)qNRARB, —(C1-3 alkyl)q(C═O)NRARB, —(C1-3 alkyl)qOP(R8)O2RB, —(C1-3 alkyl)qOPO3RARB, —(C1-3 alkyl)qPO3RAR8, or —(C1-3 alkyl), (C═O)NHSO2R8;
- R1 is selected from C(O)O, P(O)(O)(ORB), and (C═O)NR10;
- each q is independently 0 or 1;
- each RA and RB are independently H or C1-3 alkyl;
- X2 is selected from N and C;
- X3 is selected from N and CR3;
- X4 is selected from N and CR4;
- X5 is selected from N and CR5;
- X6 is selected from N and CR6;
- provided that no more than two of X2, X3, X4, X3, and X6 are N;
- X2a is selected from N and C;
- X3a is selected from N and CR3a;
- X4a is selected from N and CR4a;
- X5a is selected from N and CR5a,
- X6a is selected from N and CR6a;
- provided that no more than two of X2a, X3a, X4a, X5a, and X6a are N;
- R3, R3a, R4, R4a, R5, R5a, R6, and R6a are each independently selected from H, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, —(C1-3 alkyl)qOH, —(C1-3 alkyl)qCN, and R10;
- each R8 is selected from C3-9 alkyl and —(C1-3 alkyl)qC6-10 aryl, wherein said C6-10 aryl is optionally substituted with 1, 2, or 3 substituents independently selected from R11;
- and
- each R11 is independently selected from C1-6 alkyl, C1-6 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, OH, CN, and C6-10 aryl, which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C1-6 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, OH, and CN;
- provided that if L1-R1 is CH2C(O)O or CH2CH2C(O)O, then R5 and R5a are not both S(O)2OH, methyl, halo, or tert-butyl.
23 more elements
A compound which is a Fe3+ complex of Formula (B-I):
- or a pharmaceutically acceptable salt thereof, wherein:
- indicates a coordinate bond;
- each L is independently a Fe3+ ligand;
- p is 0, 1 or 2;
- L1 is —C1-3 alkylene-, optionally substituted with R10;
- L2 is —C1-3 alkylene-, optionally substituted with R10;
- each R10 is independently —(C1-3 alkyl)qSO3RA, —(C1-3 alkyl)qSO2R8, —(C1-3 alkyl)qNHSO2R8, —(C1-3 alkyl)qCO2RA, —(C1-3 alkyl)qNRARB, —(C1-3 alkyl), (C═O)NRARB, —(C1-3 alkyl)qOP(R8)O2RB, —(C1-3 alkyl)qOPO3RARB, —(C1-3 alkyl)qPO3RAR8, or —(C1-3 alkyl), (C═O)NHSO2R8;
- R1 is selected from CO2RA, P(O)(ORA)(ORB), and (C═O)NRAR10;
- each RA and RB are independently H or C1-3 alkyl;
- X2 is selected from N and C;
- X3 is selected from N and CR3;
- X4 is selected from N and CR4;
- X5 is selected from N and CR5;
- X6 is selected from N and CR6;
- provided that no more than two of X2, X3, X4, X5, and X6 are N;
- R3, R4, R5, and R6 and are each independently selected from H, C1-3 alkyl, C1-3 alkoxy, C1.3 haloalkyl, C1-3 haloalkoxy, halo, —(C1-3 alkyl)qOH, —(C1-3 alkyl)qCN, and R10;
- each R8 is selected from C3.9 alkyl and —(C1-3 alkyl)qC6-10 aryl, wherein said C6-10 aryl is optionally substituted with 1, 2, or 3 substituents independently selected from R11;
- and
- each R11 is independently selected from C1-6 alkyl, C1-6 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, OH, CN, and C6-10 aryl, which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C1-6 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, OH, and CN.
16 more elements
A compound which is a Fe3+ complex of Formula (C-I):
- or a pharmaceutically acceptable salt thereof, wherein:
- indicates a coordinate bond;
- each L is independently a Fe3+ ligand;
- p is 0, 1 or 2;
- L1 is —C1-3 alkylene-, or L1 is absent;
- R1 is selected from CO2RA, P(O)(ORA)(OR8), (C═O)NRAR10, SO3RA, SO2R8, NHSO2R8, NRARB, OP(R8)O2RB, OPO3RARB, and (C═O)NHSO2R8;
- each RA and RB are independently H or C1-3 alkyl;
- X2 is selected from N and C;
- X3 is selected from N and CR3;
- X4 is selected from N and CR4;
- X5 is selected from N and CR5;
- X6 is selected from N and CR6;
- provided that no more than two of X2, X3, X4, X5, and X6 are N;
- X2a is selected from N and C;
- X3a is selected from N and CR3a;
- X4a is selected from N and CR4a;
- X5a is selected from N and CR5a;
- X6a is selected from N and CR6a;
- provided that no more than two of X2a, X3a, X4a, X5a, and X6a are N;
- R3, R3a, R4, R4a, R5, R5a, R6, and R6a are each independently selected from H, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, —(C1-3 alkyl)qOH, —(C1-3 alkyl)qCN, —(C1-3 alkyl)qSO3RA, —(C1-3 alkyl)qSO2R8, —(C1-3 alkyl)qNHSO2R8, —(C1-3 alkyl)qCO2RA, —(C1-3 alkyl)qNRARB, —(C1-3 alkyl), (C═O)NRARB, —(C1-3 alkyl)qOP(R8)O2RB, —(C1-3 alkyl)qOPO3RARB, —(C1-3 alkyl)qPO3RAR8, and —(C1-3 alkyl)q(C═O)NHSO2R8;
- each q is independently 0 or 1;
- each R8 is selected from C3-9 alkyl and —(C1-3 alkyl)qC6-10 aryl, wherein said C6-10 aryl is optionally substituted with 1, 2, or 3 substituents independently selected from R11;
- and
- each R11 is independently selected from C1-6 alkyl, C1-6 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, OH, CN, and C6-10 aryl, which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C1-6 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, OH, and CN.
21 more elements
A compound which is a Fe3+ complex of Formula (D-I):
- or a pharmaceutically acceptable salt thereof, wherein:
- indicates a coordinate bond;
- each L is independently a Fe3+ ligand;
- p is 0, 1 or 2;
- L1 is —C1-3 alkylene-, or L1 is absent;
- L2 is —C1-3 alkylene-;
- R1 is selected from CO2RA, P(O)(ORA)(OR8), (C═O)NRAR10, SO3RA, SO2R8, NHSO2R8, NRARB, OP(R8)O2RB, OPO3RARB, and (C═O)NHSO2R8;
- R2 is selected from CO2RA, P(O)(ORA)(OR8), (C═O)NRAR10, SO3RA, SO2R8, NHSO2R8, NRARB, OP(R8)O2RB, OPO3RARB, and (C═O)NHSO2R8;
- each RA and RB are independently H or C1-3 alkyl;
- X2 is selected from N and C;
- X3 is selected from N and CR3;
- X4 is selected from N and CR4;
- X5 is selected from N and CR5;
- X6 is selected from N and CR6;
- provided that no more than two of X2, X3, X4, X5, and X6 are N;
- R3, R4, R5, and R6 and are each independently selected from H, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, —(C1-3 alkyl)qOH, —(C1-3 alkyl)qCN, —(C1-3 alkyl)qSO3RA, —(C1-3 alkyl)qSO2R8, —(C1-3 alkyl)qNHSO2R8, —(C1-3 alkyl)qCO2RA, —(C1-3 alkyl)qNRARB, —(C1-3 alkyl)q(C═O)NRARB, —(C1-3 alkyl)qOP(R8)O2RB, —(C1-3 alkyl)qOPO3RARB, —(C1-3 alkyl)qPO3RAR8, and —(C1-3 alkyl), (C═O)NHSO2R8;
- each R8 is selected from C3-9 alkyl and —(C1-3 alkyl)qC6-10 aryl, wherein said C6-10 aryl is optionally substituted with 1, 2, or 3 substituents independently selected from R11;
- and
- each R11 is independently selected from C1-6 alkyl, C1-6 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, OH, CN, and C6-10 aryl, which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C1-6 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, OH, and CN;
- provided that the compound is not any one of the following compounds:
17 more elements
A compound of Formula (A):
- or a salt thereof, wherein:
- L1 is —C1-3 alkylene-, optionally substituted with R10;
- each R10 is independently —(C1-3 alkyl)qSO3RA, —(C1-3 alkyl)qSO2R8, —(C1-3 alkyl)qNHSO2R8, —(C1-3 alkyl)qCO2RA, —(C1-3 alkyl)qNRARB, —(C1-3 alkyl), (C═O)NRARB, —(C1-3 alkyl)qOP(R8)O2RB, —(C1-3 alkyl)qOPO3RARB, —(C1-3 alkyl)qPO3RAR8, or —(C1-3 alkyl)q(C═O)NHSO2R8;
- R1 is selected from CO2RA, P(O)(ORA)(ORB), and (C═O)NRAR10;
- each q is independently 0 or 1;
- each RA and RB are independently H or C1-3 alkyl;
- X2 is selected from N and C;
- X3 is selected from N and CR3;
- X4 is selected from N and CR4;
- X5 is selected from N and CR5;
- X6 is selected from N and CR6;
- provided that no more than two of X2, X3, X4, X5, and X6 are N;
- X2a is selected from N and C;
- X3a is selected from N and CR3a, X4a is selected from N and CR4a, X5a is selected from N and CR5a;
- X6a is selected from N and CR6a;
- provided that no more than two of X2a, X3a, X4a, X5a, and X6a are N;
- R3, R3a, R4, R4a, R5, R5a, R6, and R6a are each independently selected from H, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, —(C1-3 alkyl)qOH, —(C1-3 alkyl)qCN, and R10;
- each R8 is selected from C3.9 alkyl and —(C1-3 alkyl)qC6-10 aryl, wherein said C6-10 aryl is optionally substituted with 1, 2, or 3 substituents independently selected from R11;
- and
- each R11 is independently selected from C1-6 alkyl, C1-6 alkoxy, C1-3 haloalkyl, C1.3 haloalkoxy, halo, OH, CN, and C6-10 aryl, which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C1-6 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, OH, and CN,
- provided that:
- (i) if L1R1 is CH2C(═O)ORA or CH(CH3)C(═O)ORA, then:
- X3 is different from X3a;
- or
- X4 is different from X4a;
- or
- X5 is different from X5a, or
- X6 is different from X6a;
- or
- X2 is N;
- or
- X2a is N;
- and
- (ii) the compound of Formula (A) is not any one of the following compounds:
31 more elements
A compound of Formula (B):
- or a salt thereof, wherein:
- L1 is —C1-3 alkylene-, optionally substituted with R10;
- L2 is —C1-3 alkylene-, optionally substituted with R10;
- each R10 is independently —(C1-3 alkyl)qSO3RA, —(C1-3 alkyl)qSO2R8, —(C1-3 alkyl)qNHSO2R8, —(C1-3 alkyl)qCO2RA, —(C1-3 alkyl)qNRARB, —(C1-3 alkyl), (C═O)NRARB, —(C1-3 alkyl)qOP(R8)O2RB, —(C1-3 alkyl)qOPO:
- RARB, —(C1-3 alkyl)qPO3RAR8, or —(C1-3 alkyl)q(C═O)NHSO2R8;
- R1 is selected from CO2RA, P(O)(ORA)(ORB), and (C═O)NRAR10;
- each q is independently 0 or 1;
- each RA and RB are independently H or C1-3 alkyl;
- X2 is selected from N and C;
- X3 is selected from N and CR3;
- X4 is selected from N and CR4;
- X5 is selected from N and CR5;
- X6 is selected from N and CR6;
- provided that no more than two of X2, X3, X4, X5, and X6 are N;
- R3, R4, R5, and R6 and are each independently selected from H, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, —(C1-3 alkyl)qOH, —(C1-3 alkyl)qCN, and R10;
- each R8 is selected from C3-9 alkyl and —(C1-3 alkyl)qC6-10 aryl, wherein said C6-10 aryl is optionally substituted with 1, 2, or 3 substituents independently selected from R11;
- and
- each R11 is independently selected from C1-6 alkyl, C1-6 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, OH, CN, and C6-10 aryl, which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C1-6 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, OH, and CN,
- provided that:
- (i) if R1 is P(OX(OH)(OH), then R5 is not C1-3 alkyl or halo;
- and
- (ii) the compound of Formula (A) is not any one of the following compounds:
19 more elements
A compound of Formula (C):
- or a salt thereof, wherein:
- L1 is —C1-3 alkylene-, or L1 is absent;
- R1 is selected from CO2RA, P(O)(ORA)(OR8), (C═O)NRAR10, SO3RA, SO2R8, NHSO2R8, NRARB, OP(R8)O2RB, OPO3RARB, and (C═O)NHSO2R8;
- each RA and RB are independently H or C1-3 alkyl;
- X2 is selected from N and C;
- X3 is selected from N and CR3;
- X4 is selected from N and CR4;
- X5 is selected from N and CR5;
- X6 is selected from N and CR6;
- provided that no more than two of X2, X3, X4, X5, and X6 are N;
- X2a is selected from N and C;
- X3a is selected from N and CR3a;
- X4a is selected from N and CR4a;
- X5a is selected from N and CR5a;
- X6a is selected from N and CR6a;
- provided that no more than two of X2a, X3a, X4a, X5a, and X6a are N;
- R3, R3a, R4, R4a, R5, R5a, R6, and R6a are each independently selected from H, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, —(C1-3 alkyl)qOH, —(C1-3 alkyl)qCN, —(C1-3 alkyl)qSO3RA, —(C1-3 alkyl)qSO2R8, —(C1-3 alkyl)qNHSO2R8, —(C1-3 alkyl)qCO2RA, —(C1-3 alkyl)qNRARB, —(C1-3 alkyl)q(C═O)NRARB, —(C1-3 alkyl)qOP(R8)O2RB, —(C1-3 alkyl)qOPO3RARB, —(C1-3 alkyl)qPO3RAR8, and —(C1-3 alkyl)q(C═O)NHSO2R8;
- each q is independently 0 or 1;
- each R8 is selected from C3-9 alkyl and —(C1-3 alkyl)qC6-10 aryl, wherein said C6-10 aryl is optionally substituted with 1, 2, or 3 substituents independently selected from R11;
- and
- each R11 is independently selected from C1-6 alkyl, C1-6 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, OH, CN, and C6-10 aryl, which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C1-6 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, OH, and CN.
18 more elements
A compound of Formula (D):
- or a salt thereof, wherein:
- L1 is —Cd alkylene-, or L1 is absent;
- L2 is —C1-3 alkylene-;
- R1 is selected from CO2RA, P(O)(ORA)(OR8), (C═O)NRAR10, SO3RA, SO2R8, NHSO2R8, NRARB, OP(R8)O2RB, OPO3RARB, and (C═O)NHSO2R8;
- R2 is selected from CO2RA, P(O)(ORA)(OR8), (C═O)NRAR10, SO3RA, SO2R8, NHSO2R8, NRARB, OP(R8)O2RB, OPO3RARB, and (C═O)NHSO2R8;
- provided that at least one of R1 and R2 is P(O)(ORA)(OR8);
- each RA and RB are independently H or C1-3 alkyl;
- X2 is selected from N and C;
- X3 is selected from N and CR3;
- X4 is selected from N and CR4;
- X5 is selected from N and CR5;
- X6 is selected from N and CR6;
- provided that no more than two of X2, X3, X4, X3, and X6 are N;
- R3, R4, R5, and R6 and are each independently selected from H, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, —(C1-3 alkyl)qOH, —(C1-3 alkyl)qCN, —(C1-3 alkyl)qSO3RA, —(C1-3 alkyl)qSO2R8, —(C1-3 alkyl)qNHSO2R8, —(C1-3 alkyl)qCO2RA, —(C1-3 alkyl)qNRARB, —(C1-3 alkyl)q(C═O)NRARB, —(C1-3 alkyl)qOP(R8)O2RB, —(C1-3 alkyl)qOPO3RARB, —(C1-3 alkyl)qPO3RAR8, and —(C1-3 alkyl)q(C═O)NHSO2R8;
- each R8 is selected from C3-9 alkyl and —(C1-3 alkyl)qC6-10 aryl, wherein said C6-10 aryl is optionally substituted with 1, 2, or 3 substituents independently selected from R11;
- and
- each R11 is independently selected from C1-6 alkyl, C1-6 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, OH, CN, and C6-10 aryl, which is optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, C1-6 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, halo, OH, and CN;
- provided that the compound of Formula (D) is not:
15 more elements
Dependencies are inferred from the claim text.