Process for the preparation of hyperpolarized carboxylate compounds

Patent metadata

Field	Value
Publication number	US-10369236-B2
Application number	US-201415031860-A
Country	US
Kind code	B2
Filing date	Oct 27, 2014
Priority date	Oct 28, 2013
Publication date	Aug 6, 2019
Grant date	Aug 6, 2019

Abstract

The present invention relates to a process for the preparation of aqueous solutions of [1-13C]-hyperpolarized carboxylate containing molecules of diagnostic interest that comprises parahydrogenating with molecular parahydrogen unsaturated alkenyl or alkynyl esters of the concerned 13C-carboxylate molecules.

First claim

The invention claimed is:

1. A Para-Hydrogen Induced Polarization process for the preparation of an [1- 13 C]-hyperpolarized carboxylate containing molecule comprising hydrogenating with molecular para-hydrogen an unsaturated alkenyl or alkynyl ester of said carboxylate containing molecule of formula (II)
R—C*(O)—O—R′  (II)

in which:
C* denotes the naturally 13 C enriched or, optionally, 13 C labeled carboxylate carbon atom undergoing 13 C hyperpolarization;
R′ is an allyl of formula —CH 2 —CH═CH 2 or a propargyl residue of formula —CH 2 —C≡CH;
R is a C 1 -C 5 linear or branched alkyl chain, which is optionally interrupted by, or substituted with, one or more groups selected from the group consisting of carbonyl (—CO—), hydroxyl (—OH), amino (—NHR 1 ), halogen atom, halo-alkyl group, carbocyclic aliphatic moiety optionally substituted by one or more hydroxyl groups, and aromatic moiety optionally substituted by one or more hydroxyl groups; and
R 1 is H or an amino protecting group, or a physiologically acceptable salt thereof.

2. A process according to claim 1 , wherein R is selected from the group consisting of C 1 -C 5 alkyl, methylcarbonyl, hydroxyethyl, and aminoalkyl of formula R 2 —CH(NHR 1 )—, in which R 1 is H or an amino protecting group selected from the group consisting of trifluoroacetyl, acetyl, benzoyl, carbobenzoxy, and tert-butyl carbonate, and R 2 is H or C 1 -C 4 alkyl chain optionally substituted by a hydroxyl group, a phenyl ring, or a hydroxyphenyl ring.

3. A process according to claim 2 , wherein R is methyl.

4. A process according to claim 2 , wherein R is methylcarbonyl.

5. A process according to claim 2 , wherein R is an aminoalkyl of formula R 2 —CH(NHR 1 )—.

6. A process according to claim 2 , wherein R is a hydroxyethyl of formula CH 3 CH(OH)—.

7. A process according to claim 1 , comprising:
a) obtaining the unsaturated alkenyl or alkynyl ester of the carboxylate containing molecule of interest and reacting said unsaturated ester with the molecular para-hydrogen to produce a para-hydrogenated ester with an [1- 13 C]-carboxylate carbon atom and added polarized hydrogen;
b) inducing a polarization transfer from the added polarized hydrogen to the [1- 13 C]-carboxylate carbon atom of the para-hydrogenated ester to produce an [1- 13 C]-hyperpolarized ester; and
c) hydrolyzing the [1- 13 C]-hyperpolarized ester and collecting an aqueous solution of the [1- 13 C]-hyperpolarized carboxylate containing molecule, or of the corresponding [1- 13 C]-hyperpolarized carboxylic acid.

8. A process according to claim 7 , wherein the step a) comprises reacting the unsaturated ester with molecular para-hydrogen in an aqueous solvent, optionally including an amount from 10% to 30% of an organic solvent selected from short-chain alcohol or acetone, and in the presence of a water soluble hydrogenation catalyst.

9. A process according to claim 8 , wherein the hydrogenation catalyst is selected from the group consisting of Rhodium complexes of formula [Rh(diphosphine)diene)] + [anion] − ; where the diphosphine is a chelating phosphine selected from the group consisting of (1,4-Bis(R 1 R 2 )ethane) and (1,4-Bis(R 1 R 2 )butane), in which R 1 and R 2 are each individually selected from the group consisting of DPPETS, DPPBTS, DAPBTS, sulfonated CHIRAPHOS, and sulfonated BINAP; and where the diene is selected from the group consisting of 1,5-cyclooctadiene and norbornadiene.

10. A process according to claim 7 , wherein step a) comprises reacting the unsaturated ester with molecular para-hydrogen in an organic solvent, or a suitable mixture of organic solvents, and in the presence of a hydrogenation catalyst soluble in the organic solvent and insoluble in an aqueous solvent.

11. A process according to claim 10 , wherein the hydrogenation catalyst is selected from the group consisting of Rhodium complexes of formula [Rh(diphosphine)diene)] + [anion] − , where the diphosphine is selected from the group consisting of 1,4-Bis(diphenylphosphino)butane; 1,2-Bis(diphenylphosphino)ethane; 2,2′-Bis(diphenylphosphino)-1,1′-binaftyl; 2,3-diphenylphosphinobutane; 1,4-Bis(diphenylphosphino)-1,4-bisdeoxy-2,3-O-isopropyliden-L-treitol; and 1,2-Bis[(2-methoxyphenyl)(phenilphosphino)]ethane; and where the diene is selected from the group consisting of 1,5-cyclooctadiene and norbornadiene.

12. A process according to claim 10 , wherein the organic solvent is an organochlorinated solvent selected from the group consisting of chloroform, dichloromethane, carbon tetrachloride and mixtures thereof, and mixtures of these solvents with an amount from 10% to 30% of a short-chain alcohol or acetone, and wherein the hydrogenation catalyst is [Rh(COD)dppb][BF 4 ] where COD is cyclo-1,5-octadiene and dppb is 1,4-bis(diphenylphosphino)butane).

13. A process according to claim 7 , wherein the step b) is carried out by applying a field cycling procedure to the para-hydrogenated ester obtained at step a) of the process to give the corresponding [1- 13 C]-hyperpolarized ester.

14. A process according to claim 10 , wherein the step c) is carried out by diluting the organic solution of the [1- 13 C]-hyperpolarized ester obtained at step b) with an aqueous solution promoting the hydrolysis of the ester to the corresponding water soluble [1- 13 C]-hyperpolarized carboxylate containing molecule, or the corresponding carboxylic acid, and then collecting, by phase transfer extraction, the aqueous solution of the [1- 13 C]-hyperpolarized compound of interest, which is ready for use in an in vivo application.

15. A process according to claim 8 , wherein the step c) of the process is carried out by adding to the aqueous solution of the [1- 13 C]-hyperpolarized ester obtained at step b) a base promoting its hydrolysis, to give the aqueous solution of the [1- 13 C]-hyperpolarized carboxylate containing molecule of interest.

16. A process according to claim 15 , further comprising a step d) removing the hydrogenation catalyst and the optional organic solvent from the obtained aqueous solution, to give the aqueous solution of the [1- 13 C]-hyperpolarized carboxylate containing molecule of interest ready for use in an in vivo application.

17. A method of using the unsaturated alkenyl or alkynyl ester of formula (II), as defined in claim 1 , as a suitable hydrogenable substrate precursor for the preparation of the [1- 13 C]-hyperpolarized carboxylate containing molecule of diagnostic interest for an MR application by use of PHIP technique.

18. A process according to claim 1 , wherein R ′is a propargyl residue of formula —CH 2 C≡CH.

19. A process according to claim 1 , wherein the [1- 13 C]-hyperpolarized carboxylate containing molecule is pyruvate.

Assignees

• Bracco Imaging Spa

Inventors

• Aime Silvio
• Boi Tommaso
• Cerutti Erika
• Reineri Francesca

Classifications

• A61K49/06

  Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations · CPC title

• C07C227/20

  by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates · CPC title

• C07C51/412

  by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part · CPC title

• B01J2531/822

  Rhodium · CPC title

• C07C69/68

  Lactic acid esters · CPC title