# US 6,719,958 B1 · Polychelants, their complexes with metal ions, their preparation and their uses

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- Number: US 6,719,958 B1
- Document ID: US6719958B1
- Status: Granted
- Kind: B1
- Application number: 09/659,593
- Filed: 2000-09-11
- Granted: 2004-04-13
- Earliest claimed: 1996-03-08
- Assignees: Dibra S.p.A.
- Inventors: Luigia Gozzini; Federico Maisano; Marcella Murru
- Web page: https://patentgrep.com/patent/US6719958B1

## CPC

- A61K 51/0478: {complexes from non-cyclic ligands, e.g. EDTA, MAG3}
- A61K 49/06: Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K 49/085: {conjugated systems}
- A61K 49/122: {dimers of complexes or complex-forming compounds}
- A61K 49/124: {dendrimers, dendrons, hyperbranched compounds}
- A61K 49/14: Peptides, e.g. proteins
- A61K 49/146: {the peptide being a polyamino acid, e.g. poly-lysine}
- A61K 51/0482: {chelates from cyclic ligands, e.g. DOTA}
- A61K 51/088: {conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10)}
- C07C 229/16: to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
- C07C 229/76: Metal complexes of amino carboxylic acids
- C07D 257/02: not condensed with other rings
- A61K 2123/00: Preparations for testing in vivo
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

A new class of polychelants, their chelates with metal ions and their physiologically acceptable salts, useful, either as they are or in association or formulation with other components, for diagnostic imaging as general or specific contrast agents for specific tissues, organs or body compartments.

## Claims

### Claim 1

A compound of formula (I):
L[NH2]p[NHF]z[N[F]2]x (I),
in which
L is a polyaminic organic moiety;
F is a —CH2—T—K group, representing a chelant/chelate residue, where
T is a C2-C5 aliphatic chain, interrupted or not by one or more heteroatoms selected from O, N, S or by functional groups selected from carbonyl, thiocarbonyl, amide, ester, thiourea, thioamide groups, said chain being linked covalently to an atom of a residue K,
K is a tetraazacyclododecyl containing group, or one of its metal chelates, or one of its salts and where
the total number of the F groups is 3 to 2 m;
p is a number from 0 to m − 2, z is a number from 0 to m− 1, and x is a number from 1 to m,
where m is a number from 2 to 1000, m being the total number of the primary amino groups originally present on L and where
p+x+z=m, with the proviso that, when x=1, then z≠0, and in which the chelated metal ions are bi- or trivalent paramagnetic ions or radioisotopes.

### Claim 2

A compound of formula (I):
L[NH2]p[NHF]z[N[F]2]x (I),
in which:
L is selected from a group consisting of spermidine, norspermidine, spermine, 4,9-dioxadodecandiamine, 3,6-dioxaoctandiamine, an alkylenediamine, diethylenetriamine, triethylenetetramine, tris-(2-aminoethyl)amine, jeffamine, N-glucosamine, lysine and its derivatives, ornithine and diamino sugars;
F is a —CH2—T—K group, representing a chelant residue, where
T is a C2-C5 aliphatic chain, containing an amido or carbonylamino group, said chain being linked covalently to a nitrogen atom of a K residue,
K is a tetraazacyclododecyl containing group a tetraazacyclododecyl containing group, its derivatives, metal chelates or salts, in which
the metal ion chelates are selected from the bi- or trivalent ions of elements having atomic numbers between 20 and 31, or 39, 42, 43, 44, 49, or between 57 and 83 or the ions of the following radioisotopes 51Cr, 67Ga, 68Ga, 111In, 99mTc 40La, 175Yb, 153Sm, 166Ho, 90Y, 149Pm 177Lu 47Sc 142Pr, 159Gd and 212Bi and where
the total number of the F groups is 3 to 2 m;
p is a number from 0 to m − 2, z is a number from 0 to m − 1, and x is a number from 1 to m,
where m is a number from 2 to 1000, m being the total number of the primary amino groups originally present on L and where
p+x+z=m, with the proviso that, when x=1, then z≠0, and in which the chelated metal ions are bi- or trivalent paramagnetic ions or radioisotopes.

### Claim 3 (depends on 2)

A compound according to claim 2, in which the metal ions are selected from Mn(2+), Fe(3+), Gd(3+), Eu(3+), Dy(3+), In(3+) and 99mTe(3+).

### Claim 4 (depends on 2)

A compound according to claim 2, in which F is a chelant residue of formula:
in which T is as defined and
R is H or CH3 or CH2—O—Bz or
provided that only one of the R substituents is different from H, as well as their metal chelates, or their salts.

### Claim 5 (depends on 4)

A compound according to claim 4, in which F is a residue of formula (II) or (III)
or one of its salts.

### Claim 6 (depends on 5)

A compound according to claim 5, selected from the group consisting of:
where F is a chelant residue of formula (II)
or a chelate of formula (III)
or a salt thereof.

### Claim 7 (depends on 1)

A process for preparing a compound of claim 1 comprising reacting a chelant compound of formula (VI)
K—T—CHO (VI)
where K, T are as described above, or a chelate, or a salt thereof, with a polyamino compound of formula (VII)
L[NH2]m (VII)
where L and m are as described above, in a reaction medium, under conditions of reductive alkylation, provided that the aldehyde of formula (VI) is present in a 3 to 40 fold molar excess over the number m of primary amino groups, and the reaction is conducted in the presence of a reducing agent specific for the imine bond, but not for the aldehyde, said reducing agent being present in a 3-60 fold excess with respect to the total number of primary amino groups.

### Claim 8 (depends on 7)

The process according to claim 7, in which said reaction medium is selected from an aqueous buffer, at a pH from 5 to 10, a low molecular weight alcohol, an aprotic dipolar solvent, or mixtures thereof.

### Claim 9 (depends on 8)

The process according to claim 8, in which the reaction temperature is between −5 and 60° C. for a length of time of between 2 and 170 h.

### Claim 10 (depends on 7)

A process according to claim 7, in which:
a chelate of formula (VI), or one of its salts, is employed in a molar excess of about 10-35 fold with respect to the total number of amino groups;
the reaction medium is an aqueous buffer at a pH of 7-9, or methanol, or a mixture of the two;
the reducing agent is sodium cyanoborohydride;
the temperature is variable between 15-30° C.; and
the reaction time is between 10-72 h.

### Claim 11 (depends on 7)

A process according to claim 7, in which the reductive alkylation reaction occurs between a chelant of formula (VI) and the polyamino residue of formula (VII), followed by the subsequent formation of the corresponding metal complex and/or one of its salts.

### Claim 12 (depends on 1)

A pharmaceutical and/or diagnostic composition comprising as active ingredient at least one of the compound of claim 1, or one of its physiologically compatible salts, together with pharmaceutically acceptable carrier or diluent or excipient.

### Claim 13 (depends on 1)

A pharmaceutical composition for radiotherapy, comprising a compound of claim 1 together with pharmaceutically acceptable carrier, diluent and/or excipient.

### Claim 14 (depends on 1)

A contrastographic diagnostic composition for magnetic resonance imaging, comprising a compound of claim 1 together with pharmaceutically acceptable carriers diluent and/or excipient.

### Claim 15 (depends on 1)

A contrastographic diagnostic composition for scintigraphy, comprising a compound of claim 1 together with pharmaceutically acceptable carrier diluent and/or excipient.

### Claim 16 (depends on 1)

A method of radio therapy, NMR imaging or scintigraphy, comprising administering to a subject to be treated or imaged an effective amount of a compound of claim 1.