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US 8,475,768 B2Granted
Paramagnetic chelates thereof and their use as contrast agents in magnetic resonance imaging (MRI)
AssigneeGe Healthcare Limited
InventorsOskar Axelsson, Harry John Wadsworth, Ian Martin Newington, Dennis O'Shea
Life of this patent
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Abstract
The present invention relates to chelators, in particular to chelators which are capable of forming complexes, i.e. paramagnetic chelates, with paramagnetic metal ions. The invention also relates to said paramagnetic chelates, said paramagnetic chelates linked to other molecules and their use as contrast agents in magnetic resonance imaging (MRI).
Claims23
Compound of formula (I):
- wherein
- R1 is H, NO2, NH2 or NHC(═O)R2, wherein R2 is C1-C6-alkyl, C6-C15-aryl, C7-C22-arylalkyl, O—C1-C6-alkyl, O—C7-C22-arylalkyl, (CH2)n—(C6H4)—NCS, (CH2)m—C≡CH or (CH2)m—N3 wherein n is 0 to 6 and m is 1 to 6;
- W and the bonds represented as dotted lines are present or absent and when present, W is N;
- and
- wherein when W is not present, R1 is NHC(O)R2, wherein R2 is C7-C22-arylalkyl, O—C1-C6-alkyl, O—C7-C22-arylalkyl, (CH2)n—(C6H4)—NCS, (CH2)m—C≡CH or (CH2)m—N3;
- X is a chelator moiety X consisting of a 6-membered aromatic or partially saturated ring system containing up to three heteroatoms selected from nitrogen and oxygen and having a hydroxyl group as a first substituent bound to a first atom in said ring system, and a hydroxyl group or an oxygen atom doubly bound to a second atom in said ring system wherein said first and second atom are adjacent atoms and wherein said first and second substituents are in ring positions such that X is capable of forming a complex with a paramagnetic metal ion;
- and wherein X is optionally substituted by up to three additional substituents, R, where each R is independently a hydrophilic group which renders the compound of formula (I) soluble in aqueous solutions.
4 more elements
Compound of formula (I):
- wherein
- R1 is NHC(═O)R2, wherein R2 is (CH2)n—(C6H4)—NCS, (CH2)m—C≡CH or (CH2)m—N3 wherein n is 0 to 6 and m is 1 to 6;
- W and the bonds represented as dotted lines are present or absent and when present, W is N;
- and
- X is a chelator moiety X consisting of a 6-membered aromatic or partially saturated ring system containing up to three heteroatoms selected from nitrogen and oxygen and having a hydroxyl group as a first substituent bound to a first atom in said ring system, and a hydroxyl group or an oxygen atom doubly bound to a second atom in said ring system wherein said first and second atom are adjacent atoms and wherein said first and second substituents are in ring positions such that X is capable of forming a complex with a paramagnetic metal ion;
- and wherein X is optionally substituted by up to three additional substituents, R, where each R is independently a hydrophilic group which renders the compound of formula (I) soluble in aqueous solutions.
3 more elements
Compound of formula (I):
- wherein
- R1 is NHC(═O)R2 and R2 is (CH2)n—(C6H4)—NCS and n is 0 to 6;
- W and the bonds represented as dotted lines are present or absent and when present, W is N;
- and
- X is a chelator moiety X consisting of a 6-membered aromatic or partially saturated ring system containing up to three heteroatoms selected from nitrogen and oxygen and having a hydroxyl group as a first substituent bound to a first atom in said ring system, and a hydroxyl group or an oxygen atom doubly bound to a second atom in said ring system wherein said first and second atom are adjacent atoms and wherein said first and second substituents are in ring positions such that X is capable of forming a complex with a paramagnetic metal ion;
- and wherein X is optionally substituted by up to three additional substituents, R, where each R is independently a hydrophilic group which renders the compound of formula (I) soluble in aqueous solutions;
- wherein said compound of formula (I) is linked to another molecule via the R1-group and said another molecule comprises an amino group and is selected from a polypeptide, a protein, an antibody, a natural or synthetic polymer and a dendrimer and wherein said compound of formula (I) is linked to said another molecule via a thiourea bond formed by a reaction of the R1-group of compound of formula (I) with said amino groups of said another molecule.
4 more elements
Compound of formula (I):
- wherein
- R1 is NHC(═O)R2 and R2 is (CH2)m—C≡CH and m is 1 to 6;
- W and the bonds represented as dotted lines are present or absent and when present, W is N;
- and
- X is a chelator moiety X consisting of a 6-membered aromatic or partially saturated ring system containing up to three heteroatoms selected from nitrogen and oxygen and having a hydroxyl group as a first substituent bound to a first atom in said ring system, and a hydroxyl group or an oxygen atom doubly bound to a second atom in said ring system wherein said first and second atom are adjacent atoms and wherein said first and second substituents are in ring positions such that X is capable of forming a complex with a paramagnetic metal ion;
- and wherein X is optionally substituted by up to three additional substituents, R, where each R is independently a hydrophilic group which renders the compound of formula (I) soluble in aqueous solutions;
- wherein said compound of formula (I) is linked to another molecule via the R1-group and wherein said another molecule comprises an azido group and is selected from a polypeptide, a protein, an antibody, a natural or synthetic polymer and a dendrimer and wherein said compound of formula (I) is linked to said another molecule via a 1,2,3-triazole ring formed by a reaction of the R1-group of compound of formula (I) with said azido groups of said another molecule.
4 more elements
Compound of formula (I):
- wherein
- R1 is NHC(═O)R2 and R2 is (CH2)m—N3 and m is 1 to 6;
- W and the bonds represented as dotted lines are present or absent and when present, W is N;
- and
- X is a chelator moiety X consisting of a 6-membered aromatic or partially saturated ring system containing up to three heteroatoms selected from nitrogen and oxygen and having a hydroxyl group as a first substituent bound to a first atom in said ring system, and a hydroxyl group or an oxygen atom doubly bound to a second atom in said ring system wherein said first and second atom are adjacent atoms and wherein said first and second substituents are in ring positions such that X is capable of forming a complex with a paramagnetic metal ion;
- and wherein X is optionally substituted by up to three additional substituents, R, where each R is independently a hydrophilic group which renders the compound of formula (I) soluble in aqueous solutions;
- wherein said compound of formula (I) is linked to another molecule via the R1-group and wherein said another molecule comprises an ethynyl group and is selected from a polypeptide, a protein, an antibody, a natural or synthetic polymer and a dendrimer and wherein said compound of formula (I) is linked to said another molecule via a 1,2,3-triazole ring formed by a reaction of the R1-group of compound of formula (I) with said ethynyl groups of said another molecule.
4 more elements
Method for producing a compound of formula (I) wherein R1 is NHC(═O)R2 and R2 is (CH2)n—(C6H4)—NCS wherein n is 0 to 6 by
- a) reacting a compound of formula (IVa) or (IVb)
- with a compound of formula (V)
- XZ—C(═O)Y (V)
- wherein
- XZ is X as defined earlier and wherein the hydroxyl groups which are bound to X are protected;
- and
- Y is a leaving group;
- b) reducing the nitro group to obtain an amino group;
- c) reacting the product obtained with a compound of formula (IXA*)
- Y—C(═O)—(CH2)n—(C6H4)—NO2 (IXA*)
- wherein Y and n are as defined above;
- d) reducing the nitro group to an amino group;
- e) reacting the amino group with thiophosgene to give the isothiocyanate group —N═C═S;
- and
- removing the hydroxyl protecting groups of XZ.
12 more elements
Compound of formula (I):
- wherein
- R1 is NHC(═O)R2, wherein R2 is —(C6H4)—NCS;
- W is absent;
- and
- X is
2 more elements
Dependencies are inferred from the claim text.