# US 8,540,966 B2 · Contrast agents endowed with high relaxivity

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- Number: US 8,540,966 B2
- Document ID: US8540966B2
- Status: Granted
- Kind: B2
- Application number: 11/630,600
- Filed: 2005-06-28
- Published: 2011-10-20
- Granted: 2013-09-24
- Earliest claimed: 2004-07-02
- Assignees: Bracco Imaging S.P.A.
- Applicants: Silvio Aime; Matteo Galli; Luciano Lattuada; Pierfrancesco Morosini; Fulvio Uggeri; Kondareddiar Ramalingam
- Inventors: Silvio Aime; Matteo Galli; Luciano Lattuada; Pierfrancesco Morosini; Fulvio Uggeri; Kondareddiar Ramalingam
- Web page: https://patentgrep.com/patent/US8540966B2

## CPC

- C07H 15/26: Acyclic or carbocyclic radicals, substituted by hetero rings
- A61K 49/085: {conjugated systems}
- A61K 49/124: {dendrimers, dendrons, hyperbranched compounds}
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 237/08: having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07D 243/08: not condensed with other rings
- C07D 243/10: condensed with carbocyclic rings or ring systems
- C07F 9/3808: {Acyclic saturated acids which can have further substituents on alkyl}
- C07F 9/4006: {Esters of acyclic acids which can have further substituents on alkyl}
- C07F 9/5728: {condensed with carbocyclic rings or carbocyclic ring systems}
- C07H 17/02: Heterocyclic radicals containing only nitrogen as ring hetero atoms
- Y10T 436/24: Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION

## Abstract

The present invention relates to a novel class of paramagnetic ion-based contrast agents of formula (I), wherein a chelating backbone moiety is highly functionalized by the presence of one or more polyhydroxylated chain, that show a pharmacokinetic profile analogous to that of the commonly used T1-general extravascular agents (NSA) but are further characterized by a higher relaxivity.

## Claims

### Claim 1

A compound of formula (III)
wherein:
R is, independently, H or a C2-C70 aminopolyol moiety comprising a straight or branched alkyl chain substituted by from 2 to 30 hydroxyl groups, said chain being optionally interrupted by one or more groups selected from —O—, —NH—, —N<, —CO—, —CONH—, —NHCO—, —CON< or >NCO—; and optionally substituted by one or more C4-C10 cyclic units;
L is, independently, a direct bond or a divalent straight or branched linker moiety between R and the rest of the molecule, comprising at most 20 carbon atoms;
together with the corresponding protonated forms of the carboxy (—COOH) groups; or a physiologically acceptable salt of such ligand;
with the proviso that at least one of the R groups is other than H.

### Claim 2 (depends on 1)

A compound according to claim 1 of formula
wherein R and L are as defined in claim 1, together with the corresponding protonated forms of the carboxy (—COOH) groups.

### Claim 3 (depends on 2, 10)

A compound according to claim 2
wherein:
1a) L1 is a direct bond, L2 is —CH2CO—, R1 is H, and R2 is group A2;
2a) L1 is a direct bond, L2 is —CH2CO—, R1 is H, and R2 is group B1;
3a) L1 is a direct bond, L2 is —CH2CO—, R1 is H, and R2 is group B2;
4a) L1 is —CH2CH2CO—, L2 is a direct bond, R1 is group B1, and R2 is H;
5a) L1 is —CH2CH2CO—, L2 is a direct bond, R1 is group B2, and R2 is H;
6a) L1 is —CH2CH2CO—, L2 is a direct bond, R1 is group G3, and R2 is H;
7a) L1 is —CH2CH2CO—, L2 is —CH2CO—, R1 is group B1, and R2 is group B1;
8a) L1 is —CH2CH2CO—, L2 is —CH2CO—, R1 is group G3, and R2 is group G3;
9a) L1 is —CH2CO—, L2 is a direct bond, R1 is group B1, and R2 is H;
10a) L1 is —CH2CO—, L2 is a direct bond, R1 is group B2, and R2 is H;
11a) L1 is —CH2CH2CO—, L2 is —CH2CO—, R1 is group B2, and R2 is group B2;
12a) L1 is a direct bond, L2 is —CH2CO—, R1 is H, and R2 is group C1;
13a) L1 is —CH2CH2CO—, L2 is a direct bond, R1 is group B2, and R2 is H;
14a) L1 is a direct bond, L2 is —CH2CO—, R1 is H, and R2 is group G7;
15a) L1 is —CH2CH2CO—, L2 is a direct bond, R1 is group C1, and R2 is H;
and wherein any group A, B, C, G is as defined in claim 10; and the physiologically acceptable salts thereof.

### Claim 4 (depends on 1, 2)

A compound according to any one of claims 1 or 2 wherein L represents a direct bond or a linker comprising at most 15 carbon atoms.

### Claim 5 (depends on 4)

A compound according to claim 4 wherein L represents a direct bond or a linker of formula
wherein
n and n′ are, independently, 0 or an integer from 1 to 4,
p, q and s are, independently, 0 or 1.

### Claim 6 (depends on 5)

A compound according to claim 5 wherein L represents a direct bond or a linker of formula
wherein n, q and s are as defined in claim 5.

### Claim 7 (depends on 1, 2)

A compound according to any one of claims 1 or 2 wherein, within the meanings for R, any C4-C10 cyclic unit is, independently, a carbocyclic or heterocyclic ring optionally substituted by one or more groups selected from hydroxy, hydroxymethyl and amino.

### Claim 8 (depends on 7)

A compound according to claim 7 wherein the carbocyclic or heterocyclic ring is selected from

### Claim 9 (depends on 1, 2)

A compound according to any one of claims 1 or 2 wherein each R is, independently, H or is selected from:
—NH—(CH2)0-2—C[(CH2)1-2—O-Q]3;
—NH—(CH2)1-2—CON[(CH2)1-3—CONH—C[(CH2)1-2—O-Q]3]2;
—N[(CH2)1-4—NHCO—(CHOH)4—CH2OH]2;
—NH—(CH2)0-2—C[(CH2)1-4—NHCO—(CHOH)4—CH2OH]3;
—N[(CH2)1-4—N[(CH2)1-4—COY]2]2;
—NH—C[(CH2)1-4—COY]3;
—NH—C[(CH2)1-2—O—(CH2)1-3—COY]3;
—NH—CH(COY)[(CH2)1-2—COY];
—NH—(CH2)1-2—CH[(CH2)1-2—O—(CH2)0-2—C(R1)(CH2OH)2]2;
—NH—(CH2)1-2—CH[(CH2)1-2—O—(CH2)1-2—CH[(CH2)1-2—O—cont. —(CH2)0-2—C(R1)(CH2OH)2]2]2;
—NH—(CH2)1-2—CH[(CH2)1-2—O—(CH2)1-2—CH[(CH2)1-2—O—cont. —(CH2)1-2—CH[(CH2)1-2—O—(CH2)0-2—C(R1)(CH2OH)2]2]2]2;
wherein
Q is a group of formula
R1 is H or methyl; and
Y is selected, independently, from

### Claim 10 (depends on 9)

A compound according to claim 9 wherein each R, independently, is H or is selected from the group of formula: A1 to A2, B1 to B3, G1 to G11, C1 to C11, D1 to D11, E1 to E11 and F1 to F11
wherein Y is
C1
D1
C2
D2
C3
D3
C4
D4
C5
D5
C6
D6
C7
D7
C8
D8
C9
D9
C10
D10
C11
D11
wherein Y is
E1
F1
E2
F2
E3
F3
E4
F4
E5
F5
E6
F6
E7
F7
E8
F8
E9
F9
E10
F10
E11
F11

### Claim 11 (depends on 1, 2)

A compound according to any one of claims 1 or 2 and any physiologically acceptable salt thereof, as a chelated complex with a bivalent or trivalent paramagnetic metal ion selected from Fe(2+), Fe(3+), Cu(2+), Cr(3+), Eu(3+), Dy(3+), La(3+), Yb(3+), Mn(2+), Mn(3+) and Gd(3+).

### Claim 12 (depends on 11)

A compound according to claim 11 wherein the paramagnetic metal ion is Gd(3+).

### Claim 13 (depends on 11)

A chelated complex of a compound according to claim 11, for diagnostic use.

### Claim 14 (depends on 11)

A pharmaceutical composition for diagnostic use comprising an effective amount of a chelated complex of a compound according to claim 11, together with optional carriers, diluents and excipients.

### Claim 15 (depends on 14)

A pharmaceutical composition according to claim 14 comprising a Gd chelated complex of a compound of formula (III).

### Claim 16 (depends on 14)

A method of imaging a human or animal body organ or tissue by use of MRI, said method comprising administering a pharmaceutical composition of claim 14 to the human or animal body, and imaging said human or animal body by use of MRI.

### Claim 17 (depends on 1, 2)

A compound according to any one of claims 1 or 2, wherein the physiologically acceptable salt is an acid or basic addition salt selected from: alkali or alkaline-earth metals such as potassium, sodium, calcium or magnesium; organic bases such as ethanolamine, diethanolamine, morpholine, glucamine, N-methylglucamine, and N,N-dimethylglucamine; anions of inorganic or organic acids such as chloride, bromide, iodide, sulfate, acetate, succinate, citrate, fumarate, maleate, oxalate; and cations and anions of amino acids such as taurine, glycine, lysine, arginine, ornithine or of aspartic and glutamic acid.