Contrast agents

Patent metadata

Field	Value
Publication number	US-11007283-B2
Application number	US-201716092905-A
Country	US
Kind code	B2
Filing date	Apr 5, 2017
Priority date	Apr 13, 2016
Publication date	May 18, 2021
Grant date	May 18, 2021

Abstract

The present invention relates to new class of functionalized polyazamacrocycles including at least one phosphonic or phosphinic group linked to a nitrogen atom of the macrocyclic cage, and capable of chelating paramagnetic metal ions, their chelated complexes with metal ions and the use thereof as contrast agents, particularly suitable for Magnetic Resonance Imaging (MRI) analysis.

First claim

The invention claimed is:

1. A compound of formula (I),

where:
R 1 , R 2 and R 3 independently of one another are H or a C 1 -C 3 alkyl optionally substituted by a C 1 -C 3 alkoxy or C 1 -C 3 hydroxyalkoxy group, or by a phenyl ring;
Y 1 , Y 2 and Y 3 independently of one another are a group of formula —PO(OR′) 2 , —PO(R 4 )(OR′), or —COOR′, with the proviso that at least one of them is —PO(OR′) 2 or —PO(R 4 )(OR′);
in which:
R′ independently of one another is H or C 1 -C 5 alkyl;
R 4 is an aryl or a cycloalkyl ring, or a C 1 -C 5 alkyl which is optionally substituted by an aryl or cycloalkyl ring;

L is a direct bond; and
Z is selected from the group consisting of: a substituted phenyl and a C 1 -C 6 alkyl comprising a substituent group selected from the groups of formula —NHSO 2 R 5 , —NHC(O)NHR 6 , —NHC(O)OR 7 and —NR 8 R 9
where:
R 5 is a phenyl or cycloalkyl ring;
R 6 is C 1 -C 5 alkyl, optionally substituted with a phenyl or a cycloalkyl ring; or a phenyl or cycloalkyl ring;
R 7 is C 1 -C 5 alkyl interrupted by one or more oxygen atoms and optionally substituted by a phenyl or a cycloalkyl ring; or a phenyl or cycloalkyl ring;
R 8 is a phenyl or cycloalkyl ring; or a C 1 -C 5 alkyl substituted by a phenyl or cycloalkyl ring;
R 9 is H, or a group of formula —(CH 2 ) n PO(OR′) 2 or —(CH 2 ) n PO(R 4 )(OR′); or individual diastereoisomers, their racemic mixtures, geometric isomers, or solved enantiomers of the same, or a physiologically acceptable salt thereof.

2. A compound according to claim 1 in which Z is a substituted phenyl, having the formula (III)

in which Q is a substituent group selected from the group consisting of: hydroxyl, —NH 2 , C 1 -C 3 alkoxy, C 1 -C 3 hydroxyalkyl, and carboxyl.

3. A compound according to claim 1 in which Z is a C 1 -C 6 alkyl comprising a substituent group selected from the groups of formula —NHSO 2 R 5 , —NHC(O)NHR 6 , —NHC(O)OR 7 and —NR 8 R 9 .

4. A compound according to claim 3 having the formula (V)

in which R 5 is as defined in claim 1 ;
or the formula (VI)

in which R 6 is a C 1 -C 3 alkyl optionally substituted by a phenyl or a cyclohexyl ring, or is a phenyl or cyclohexylalkyl ring;
or the formula (VII)

in which R 7 is a C 1 -C 5 alkyl interrupted by one or more oxygen atom(s) and optionally substituted by a phenyl or a cyclohexyl ring, or is a phenyl or cyclohexylalkyl ring;
or the formula (VIII)

in which:
R 8 is a phenyl or cycloalkyl ring; or is a C 1 -C 3 alkyl substituted by a phenyl or cyclohexyl ring;
R 9 is a hydrogen atom, or a group selected from the groups of formula —(CH 2 ) n PO(OR′) 2 and —(CH 2 ) n PO(R 4 )(OR′) in which n, R′ and R 4 are as defined in claim 1 .

5. A compound according to claim 1 in which in the formula (I) one of Y 1 , Y 2 and Y 3 is a carboxyl of formula —COOR′ and the other two, independently from one another, are selected from —PO(OR′) 2 and —PO(R 4 )(OR′).

6. A compound according to claim 1 in which in the formula (I) one of Y 1 , Y 2 and Y 3 is selected from —PO(OR′) 2 and —PO(R 4 ) (OR′) and the remaining two are carboxyls of formula —COOR′.

7. A compound according to claim 1 in which in the formula (I) R′ is H.

8. A compound of formula (I) according to claim 1 selected from the group consisting of:

or a physiologically acceptable salt thereof.

9. A paramagnetic complex of the compound of formula (I) according to claim 1 with a paramagnetic metal ion selected from the group consisting of Fe(2+), Fe(3+), Cu(2+), Cr(3+), Gd(3+), Eu(3+), Dy(3+), La(3+), Yb(3+) and Mn(2+), or a physiologically acceptable salt thereof.

10. A compound of formula (I) according to claim 1 , wherein the physiologically acceptable salt is with a cation of (i) an inorganic base selected from an alkali metal and alkaline-earth metal selected from potassium, sodium, calcium and magnesium, or of (ii) an organic base selected from ethanolamine, diethanolamine, morpholine, glucamine, N-methylglucamine, and N,N-dimethylglucamine or of (iii) an amino acid selected from lysine, arginine and ornithine or with (iv) an anion of a halo acid, as well as of (v) other suitable ions selected from acetate, succinate, citrate, fumarate, maleate and oxalate.

11. A pharmaceutical composition comprising the paramagnetic complex, or a pharmaceutical salt thereof, as defined in claim 9 in combination with a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

12. A process for the preparation of a compound of formula (I) as defined in claim 1 comprising the following main steps:
a) Obtaining a macrocyclic substrate 1 in a protected form;
b) Obtaining an alkylating molecule 2, in which any optional functional group(s) not involved with the coupling reaction with the substrate 1 is protected;
c) Coupling the protected substrate 1 with the alkylating molecule 2, to give the desired compound of formula (I) in a protected form or, alternatively, an intermediate thereof 3;
d) Optionally converting the intermediate obtained at the step c) of the process in the protected compound of formula (I);
e) Removing any protecting group and isolating the chelating ligand of formula (I); and
f) Complexing the obtained ligand with a paramagnetic metal ion and isolating the chelate complex, or the salt thereof.

13. A method for the in vivo imaging a human or animal body organ or tissue by use of the MRI technique that comprises the steps of:
a) administering the pharmaceutical composition according to claim 11 to a human or animal, positioning the human or animal in a MRI imaging system,
b) submitting the human or animal to a radiation frequency selected to excite the non-zero proton spin nuclei of the active paramagnetic substrate; and
c) recording a MR signal from said excited nuclei.

14. A method for the in vitro (ex vivo) imaging of a biological sample from a patient, by use of the MRI technique, that comprises contacting an effective amount of the paramagnetic complex or a physiologically acceptable salt thereof as defined in claim 9 with the biological sample and then obtaining MRI signals from said sample by use of the MRI.

15. A compound according to claim 1 in which in the formula (I) R 1 , R 2 and R 3 are H.

Assignees

• Bracco Imaging Spa

Inventors

• Lattuada Luciano
• Napolitano Roberta
• Boi Valeria
• Visigalli Massimo
• Aime Silvio
• Giovenzana Giovanni Battista
• Fringuello Mingo Alberto

Classifications

• C07D257/02

  not condensed with other rings · CPC title

• C07F9/6524

  having four or more nitrogen atoms as the only ring hetero atoms · CPC title

• G01R33/5601

  involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K49/106 Primary

  the complex-forming compound being cyclic, e.g. DOTA · CPC title