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US 6,685,914 B1Granted
Macrocyclic chelants for metallopharmaceuticals
AssigneeBristol-Myers Squibb Pharma Company
InventorShuang Liu
Life of this patent
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Abstract
This invention relates to macrocyclic chelants comprised of one or two heteroatom-containing bridges, compositions containing them and their use in medicine, particularly in diagnostic imaging and radiotherapy. This invention relates especially to the use of metal chelates of the macrocyclic chelants as metallopharmaceuticals in Magnetic Resonance Imaging (MRI) and radiopharmaceuticals. This invention also relates to macrocyclic chelants as bifunctional chelating agents (BFC's) for the labeling of biologically active targeting molecules such as proteins, peptides, peptidomimetics, and non-peptide receptor ligands, with metal ions and radioisotopes.
Claims34
A compound of formula (I):
- and pharmnaceutically acceptable salts thereof wherein:
- R1, R2, R3 and R4 are independently selected at each occurrence from the group:
- C1-C10 alkyl substituted with 0-5 R5, C2-C10 alkenyl substituted with 0-5 R5 and aryl substituted with 0-5 R5;
- R5 is independently elected at each occurrence from the group:
- H, C(═O)OR18, C1-C10 alkyl substituted with 0-5 R13, C2-C10 alkenyl substituted with 0-5 R13, aryl substituted with 0-5 R13 and heterocycle substituted with 0-5 R13;
- X is P(═O)R9;
- A is CH2;
- Q1, Q2, and Q3 are independently —(CR11R12)n—, wherein:
- n is 2-5;
- R9 is selected from the group:
- OR14, NR15R16 and CH2NR15R16;
- R11 and R12 are independently selected from the group:
- H, C1-C10 alkyl substituted with 0-5 R17, C2-C10 alkenyl substituted with 0-5 R17 and aryl substituted with 0-3 R17;
- R13 is independently selected at each occurrence from the group:
- H, OH, NHR18, C(═O)R18, OC(═O)R18, OC(═O)OR18, C(═O)OR18, C(═O)NR218, PO3R218, SR18, SOR18, SO2R18, NHC(═O)R18, NHC(═O)NHR18, CH2OR18, CH3 and NHC(═S)NHR18;
- R14, R15 and R16 are independently selected from the group:
- hydrogen, C1-C10 alkyl substituted with 0-5 R13, C2-C10 alkenyl substituted with 0-5 R13 and aryl substituted with 0-5 R13;
- or, alternatively, two R14 or R15 and R16 may be taken together to form a transannular bridge, said bridge selected from the group:
- C3-C10 alkyl substituted with 0-5 R13 and ortho-aryl substituted with 0-3 R13;
- R17 is independently selected at each occurrence from the group:
- H, OH, NHR18, C(═O)R18, OC(═O)R18, OC(═O)OR18, C(═O)OR18, C(═O)NR218, PO3R218, SR18, SOR18, SO2R18, NHC(═O)R18, NHC(═O)NHR18 and NHC(═S)NHR18;
- and
- R18 is independently selected at each occurrence from the group:
- H, C1-C6 alkyl, benzyl and phenyl.
21 more elements
A radiopharmaceutical of formula (III):
- and pharmaceutically acceptable salts thereof, wherein:
- M is selected from the group:
- 64Cu, 67Cu, 67Ga, 68Ga, 99mTc, 111In, 90Y, 149Pr, 153Sm, 159Gd, 166Ho, 169Yb, 177Lu, 186Re and 188Re;
- R1, R2, R3 and R4 are independently selected at each occurrence from:
- C1-C10 alkyl substituted with 0-5 R5, C2-C10 alkenyl substituted with 0-5 R5 and aryl substituted with 0-5 R5;
- R5is independently elected at each occurrence from:
- H, C(═O)OR18, C(═O)OR23, C1-C10 alkyl substituted with 0-5 R13, C2-C10 alkenyl substituted with 0-5 R13, aryl substituted with 0-5 R13 and heterocycle substituted with 0-5 R13;
- X is P(═O)R9;
- A is CH2;
- Q1, Q2, and Q3 are independently —(CR11R12)n—, wherein:
- n is 2-5;
- R9 is selected from the group:
- OR14, NR15R16 and CH2NR15R16;
- R11 and R12 are independently selected from the group:
- H, C1-C10 alkyl substituted with 0-5 R17, C2-C10 alkenyl substituted with 0-5 R17 and aryl substituted with 0-3 R17;
- R13 is independently selected at each occurrence from the group:
- H, OH, OR23, NHR18, C(═O)R18, OC(═O)R18, OC(═O)OR18, OC(═O)OR23, C(═O)OR18, C(═O)OR23, C(═O)NR218, PO3R218, PO3R18R23, SR18, SR23, SOR18, SO2R218, SOR23, SO2R23, NHC(═O)R18, NHC(═O)NHR18, CH2OR18, CH2OR18, CH3 and NHC(═S)NHR18;
- R14, R15 and R16 are independently selected from the group:
- C1-C10 alkyl substituted with 0-5 R13, C2-C10 alkenyl substituted with 0-5 R13 and aryl substituted with 0-5 R13;
- or, alternatively, two R14 or R15 and R16 may be taken together to form a transannular bridge, said bridge selected from the group:
- C3-C10 alkyl substituted with 0-5 R13 and ortho-aryl substituted with 0-3 R13;
- R17 is independently selected at each occurrence from the group:
- H, OH, NHR18, C(═O)R18, OC(═O)R18, OC(═O)OR18, C(═O)OR18, C(═O)NR218, PO3R218, SR18, SOR18, SO2R18, NHC(═O)R18, NHC(═O)NHR18 and NHC(═S)NHR18;
- R18 is independently selected at each occurrence from the group:
- H, C1-C6 alkyl, benzyl and phenyl;
- and
- R23 is a bond to the metal M.
24 more elements
A MRI contrast agent of the formula (V):
- and pharmaceutically acceptable salts thereof, wherein:
- M is a paramagnetic metal ion of atomic number selected from the group:
- 21-29, 42-44 and 58-70;
- R1, R2, R3 and R4 are independently selected at each occurrence from:
- C1-C10 alkyl substituted with 0-5 R5, C2-C10 alkenyl substituted with 0-5 R5 and aryl substituted with 0-5 R5;
- R5is independently elected at each occurrence from:
- H, C(═O)OR18, C(═O)OR23, C1-C10 alkyl substituted with 0-5 R13, C2-C10 alkenyl substituted with 0-5 R13, aryl substituted with 0-5 R13 and heterocycle substituted with 0-5 R13;
- X is P(═O)R9;
- A is CH2;
- Q1, Q2 , and Q3 are independently —(CR11R12)n—, wherein:
- n is 2-5;
- R9 is selected from the group:
- OR14, NR15R16 and CH2NR15R16;
- R11 and R12 are independently selected from the group:
- H, C1-C10 alkyl substituted with 0-5 R 17,C2-C10 alkenyl substituted with 0-5 R17 and aryl substituted with 0-3 R17;
- R13 is independently selected at each occurrence from the group:
- H, OH, OR23, NHR18, C(═O)R18, OC(═O)R18, OC(═O)OR18, OC(═O)R23, C(═O)OR18, C(═O)OR23, C(═O)NR218, PO3R218, PO3R18R23, SR18, SR23, SOR18, SO2R18, SOR23, SO2R23, NHC(═O)R18, NHC(═O)NHR18, CH2OR18, CH2OR23, CH3 and NHC(═S)NHR18;
- R14, R15 and R16 are independently selected from the group:
- C1-C10 alkyl substituted with 0-5 R13, C2-C10 alkenyl substituted with 0-5 R13 and aryl substituted with 0-5 R13;
- or, alternatively, two R14 or R15 and R16 may be taken together to form a transannular bridge, said bridge selected from the group:
- C3-C10 alkyl substituted with 0-5 R13 and ortho-aryl substituted with 0-3 R13;
- R17 is independently selected at each occurrence from the group:
- H, OH, NHR18, C(═O)R18, OC(═O)R18, OC(═O)OR18, C(═O)OR18, C(═O)NR218, PO3R218, SR18, SOR18, SO2R18, NHC(═O)R18, NHC(═O)NHR18 and NHC(═S)NHR18;
- R18 is independently selected at each occurrence from the group:
- H, C1-C6 alkyl, benzyl and phenyl;
- and
- R23 is a bond to the metal M.
24 more elements
A conjugate of the formula:
- Ch—Ln—W,
- and pharmaceutically acceptable salts thereof, wherein:
- Ch is a chelator of formula (VII):
- wherein:
- R1, R2, R3 and R4 are independently selected at each occurrence from the group:
- C1-C10 alkyl substituted with 0-5 R5, C2-C10 alkenyl substituted with 0-5 R5 and aryl substituted with 0-5 R5;
- R5 is independently elected at each occurrence from the group:
- H, C(═O)OR18, C1-C10 alkyl substituted with 0-5 R13, C2-C10 alkenyl substituted with 0-5 R13, aryl substituted with 0-5 R13 and heterocycle substituted with 0-5 R13;
- X is P(═O)R9;
- A is CH2;
- Q1, Q2, and Q3 are independently —(CR11R12)n—, wherein:
- n is 2-5;
- R9 is selected from the group:
- OR14, NR15R16 and CH2NR15R16;
- R11 and R12 are independently selected from the group:
- H, C1-C10 alkyl substituted with 0-5 R17, C2-C10 alkenyl substituted with 0-5 R17 and aryl substituted with 0-3 R17;
- R13 is independently selected at each occurrence from the group:
- H, OH, NHR18, C(═O)R18, OC(═O)R18, OC(═O)OR18, C(═O)OR18, C(═O)NR218, PO3R218, SR18, SOR18, SO2R18, NHC(═O)R18, NHC(═O)NHR18, CH2OR18, CH3, NHC(═S)NHR18 and a bond to Ln;
- R14, R15 and R16 are independently selected from the group:
- hydrogen, C1-C10 alkyl substituted with 0-5 R13, C2-C10 alkenyl substituted with 0-5 R13 and aryl substituted with 0-5 R13;
- or, alternatively, two R14 or R15 and R16 may be taken together to form a transannular bridge, said bridge selected from the group:
- C3-C10 alkyl substituted with 0-5 R13 and ortho-aryl substituted with 0-3 R13;
- R17 is independently selected at each occurrence from the group:
- H, OH, NHR18, C(═O)R18, OC(═O)R18, OC(═O)OR18, C(═O)OR18, C(═O)NR218, PO3R218, SR18, SOR18, SO2R18, NHC(═O)R18, NHC(═O)NHR18, NHC(═S)NHR18 and a bond to Ln;
- R18 is independently selected at each occurrence from the group:
- H, C1-C6 alkyl, benzyl, phenyl and a bond to Ln;
- Ln is a linking group of formula:
- L1−[Y1(CR19R20)f(Z1)f″Y2]f−L2,
- wherein:
- L1 is —[(CH2)gZ1]g′—(CR19R20)g″—;
- L2 is —(CR19R20)g″—[Z1(CH2)g]g′—;
- g is independently 0-10;
- g′ is independently 0-1;
- g″ is independently 0-10;
- f is independently 0-10;
- f′ is independently 0-10;
- f″ is independently 0-1;
- Y1 and Y2, at each occurrence, are independently selected from the group:
- a bond, O, NR20, C═O, C(═O)O, OC(═O)O, C(═O)NH—, C═NR20, S, SO, SO2, NHC(═O), (NH)2C(═O) and (NH)2C═S;
- R19 and R20 are independently selected at each occurrence from the group:
- H, C1-C10 alkyl substituted with 0-5 R21 and alkaryl wherein the aryl is substituted with 0-5 R21;
- R21 is independently selected at each occurrence from the group:
- NHR22, C(═O)R22, OC(═O)R22, OC(═O)OR22, C(═O)OR22, C(═O)NR222, —CN, SR22, SOR22, SO2R22, NHC(═O)R22, NHC(═O)NHR22, NHC(═S)NHR22 and a bond to W;
- R22 is independently selected at each occurrence from the group:
- H, C1-C6 alkyl, benzyl, phenyl and a bond to W;
- and
- W is a biologically active molecule selected from the group:
- IIb/IIIa receptor ligands, fibrin binding peptides, leukocyte binding peptides, chemotactic peptides, somatostatin analogs, selectin binding peptides, vitronectin receptor antagonists and tyrosine kinase inhibitors.
45 more elements
A radiopharmaceutical of the formula:
- M—Ch—Ln—W,
- and pharmaceutically acceptable salts thereof, wherein,
- M is selected from the group 64Cu 67Cu 67Ga, 68Ga, 99mTc, 111In, 90Y, 149Pr, 153Sm, 159Gd, 166Ho, 169Yb, 177Lu, 186Re and 188Re;
- Ch is a chelator of formula (IX):
- wherein:
- R1, R2, R3 and R4 are independently selected at each occurrence from the group:
- C1-C10 alkyl substituted with 0-5 R5, C2-C10 alkenyl substituted with 0-5 R5 and aryl substituted with 0-5 R5;
- R5 is independently elected at each occurrence from the group:
- H, C(═O)OR18, C(═O)OR23, C1-C10 alkyl substituted with 0-5 R13, C2-C10 alkenyl substituted with 0-5 R13, aryl substituted with 0-5 R13 and heterocycle substituted with 0-5 R13;
- X is P(═O)R9;
- A is CH2;
- Q1, Q2, and Q3 are independently —(CR11R12)n—, wherein:
- n is 2-5;
- R9 is selected from the group:
- OR14, NR15R16 and CH2NR15R16;
- R11 and R12 are independently selected from the group:
- H, C1-C10 alkyl substituted with 0-5 R17, C2-C10 alkenyl substituted with 0-5 R17 and aryl substituted with 0-3 R17;
- R13 is independently selected at each occurrence from the group:
- H, OH, OR23, NHR18, C(═O)R18, OC(═O)OR23, OC(═O)R18, C(═O)OR23, OC(═O)OR18, C(═O)OR18, C(═O)NR218, PO3R218, PO3R18R23, SR18, SR23, SOR18, SO2R18, SOR23, SO2R23, NHC(═O)R18, NHC(═O)NHR18, CH2OR18, CH2OR23, CH3, NHC(═S)NHR18 and a bond to Ln;
- R14, R15 and R16 are independently selected from the group:
- C1-C10 alkyl substituted with 0-5 R13, C2-C10 alkenyl substituted with 0-5 R13 and aryl substituted with 0-5 R13;
- or, alternatively, two R14 or R15 and R16 may be taken together to form a transannular bridge, said bridge selected from the group:
- C3-C10 alkyl substituted with 0-5 R13 and ortho-aryl substituted with 0-3 R13;
- R17 is independently selected at each occurrence from the group:
- H, OH, NHR18, C(═O)R18, OC(═O)R18, OC(═O)OR18, C(═O)OR18, C(═O)NR218, PO3R218, SR18, SOR18, SO2R18, NHC(═O)R18, NHC(═O)NHR18, NHC(═S)NHR18 and a bond to Ln;
- R18 is independently selected at each occurrence from the group:
- H, C1-C6 alkyl, benzyl, phenyl and a bond to Ln;
- R23 is a bond to the metal M;
- Ln is a linking group of formula:
- L1—[Y1(CR19R20)f(Z1)f″Y2]f′—L2,
- wherein:
- L1 is —[(CH2)gZ1]g′—(CR19R20)g″—;
- L2 is —(CR19R20)g″—[Z1(CH2)g]g′—;
- g is independently 0-10;
- g′ is independently 0-1;
- g″ is independently 0-10;
- f is independently 0-10;
- f′ is independently 0-10;
- f″ is independently 0-1;
- Y1 and Y2, at each occurrence, are independently selected from the group:
- a bond, O, NR20, C═O, C(═O)O, OC(═O)O, C(═O)NH—, C=NR20, S, SO, SO2, NHC(═O), (NH)2C(═O) and (NH)2C═S;
- R19 and R20 are independently selected at each occurrence from the group:
- H, C1-C10 alkyl substituted with 0-5 R21 and alkaryl wherein the aryl is substituted with 0-5 R21;
- R21 is independently selected at each occurrence from the group:
- NHR22, C(═O)R22, OC(═O)R22, OC(═O)OR22, C(═O)OR22, C(═O)NR222, —CN, SR22, SOR22, SO2R22, NHC(═O)R22, NHC(═O)NHR22, NHC(═S)NHR22 and a bond to W;
- R22 is independently selected at each occurrence from the group:
- H, C1-C6 alkyl, benzyl, phenyl and a bond to W;
- and
- W is a biologically active molecule selected from the group:
- IIb/IIIa receptor ligands, fibrin binding peptides, leukocyte binding peptides, chemotactic peptides, somatostatin analogs, selectin binding peptides, vitronectin receptor antagonists and tyrosine kinase inhibitors.
47 more elements
A MRI contrast agent of the formula:
- M—Ch—Ln—W,
- and pharmaceutically acceptable salt thereof, wherein:
- M is a paramagnetic metal ion of atomic number selected from the group:
- 21-29, 42-44 and 58-70;
- Ch is a chelator of formula (XI):
- wherein:
- R1, R2, R3 and R4 are independently selected at each occurrence from the group:
- C1-C10 alkyl substituted with 0-5 R5, C2-C10 alkenyl substituted with 0-5 R5 and aryl substituted with 0-5 R5;
- R5 is independently elected at each occurrence from the group:
- H, C(═O)OR18, C(═O)OR23, C1-C10 alkyl substituted with 0-5 R13, C2-C10 alkenyl substituted with 0-5 R13, aryl substituted with 0-5 R13 and heterocycle substituted with 0-5 R13;
- X is P(═O)R9;
- A is CH2;
- Q1, Q2, and Q3 are independently —(CR11R12)n—, wherein:
- n is 2-5;
- R9 is selected from the group:
- OR14, NR15R16 and CH2NR15R16;
- R11 and R12 are independently selected from the group:
- H, C1-C10 alkyl substituted with 0-5 R17, C2-C10 alkenyl substituted with 0-5 R17 and aryl substituted with 0-3 R17;
- R13 is independently selected at each occurrence from the group:
- H, OH, OR23, NHR18, C(═O)R18, OC(═O)R18, OC(═O)OR18, OC(═O)OR23, C(═O)OR18, C(═O)OR23, C(═O)NR218, PO3R218, PO3R18R23, SR18, SR23, SO18R, SO2R18, SOR23, SO2R23, NHC(═O)R18, NHC(═O)NHR18, CH2OR18, CH2OR23, CH3, NHC(═S)NHR18 and a bond to Ln;
- R14, R15 and R16 are independently selected from the group:
- C1-C10 alkyl substituted with 0-5 R13, C2-C10 alkenyl substituted with 0-5 R13 and aryl substituted with 0-5 R13;
- or, alternatively, two R14 or R15 and R16 may be taken together to form a transannular bridge, said bridge selected from the group:
- C3-C10 alkyl substituted with 0-5 R13 and ortho-aryl substituted with 0-3 R13;
- R17 is independently selected at each occurrence from the group:
- H, OH, NHR18, C(═O)R18, OC(═O)R18, OC(═O)OR18, C(═O)OR18, C(═O)NR218, PO3R218, SR18, SOR18, SO2R18, NHC(═O)R18, NHC(═O)NHR18, NHC(═S)NHR18 and a bond to Ln;
- R18 is independently selected at each occurrence from the group:
- H, C1-C6 alkyl, benzyl, phenyl and a bond to Ln;
- R23 is a bond to the metal M;
- Ln is a linking group of formula:
- L1—[Y1(CR19R20)f(Z1)f″Y2]f′—L2,
- wherein:
- L1 is —[(CH2)gZ1]g′—(CR19R20)g″—;
- L2 is —(CR19R20)g″—[Z1(CH2)g]g′—;
- g is independently 0-10;
- g′ is independently 0-1;
- g″ is independently 0-10;
- f is independently 0-10;
- f′ is independently 0-10;
- f″ is independently 0-1;
- Y1 and Y2, at each occurrence, are independently selected from the group:
- a bond, O, NR20, C═O, C(═O)O, OC(═O)O, C(═O)NH—, C=NR20, S, SO, SO2, NHC(═O), (NH)2C(═O) and (NH)2C═S;
- R19 and R20 are independently selected at each occurrence from:
- H, C1-C10 alkyl substituted with 0-5 R21 and alkaryl wherein the aryl is substituted with 0-5 R21;
- R21 independently selected at each occurrence from the group:
- NHR 22, C(═O)R22 OC(═O)R , OC(═O)OR , C(═O)OR, C(═O)NR222, —CN, SR22, SOR, SO2R22, NHC(═O)R22, NHC(═O)NHR22, NHC(═S)NHR22 and a bond to W;
- R22 is independently selected at each occurrence from the group:
- H, C1-C6 alkyl, benzyl, !r;80 phenyl and a bond to W;
- and
- W is a biologically active molecule selected from the group:
- IIb/IIIa receptor ligands, fibrin binding peptides, leukocyte binding peptides, chemotactic peptides, somatostatin analogs, selectin binding peptides, vitronectin receptor antagonists and tyrosine kinase inhibitors.
48 more elements
Dependencies are inferred from the claim text.