TRITYL-NITROXIDE MULTIRADICALS AS POLARIZING AGENTS FOR DYNMAIC NUCLEAR POLARIZATION

Abstract

The present invention relates to novel trityl-nitroxide radicals as polarizing agents for Dynamic Nuclear Polarization (DNP).

Claims

1. A compound of formula (I) ##STR00067## wherein n is 0 or 1; m is 1, 2 or 3; X.sub.1 and X.sub.2 are, independently, N, P; Q.sub.2 is ##STR00068## wherein X.sub.3 and X.sub.4 are joined, as indicated by to form together with the nitrogen atom to which they are bound a 5- to 8-membered heterocyclic ring, the heterocyclic ring being optionally substituted, and/or the heterocyclic ring optionally containing one or more carbon-carbon double bond, ##STR00069## is the point of attachment of the 5- to 8-membered heterocyclic ring, to the rest of the molecule; Q.sub.1 is selected from ##STR00070## wherein R.sub.19 to R.sub.30 are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms; M is a hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K), an ammonium group; preferably, M is a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K), an ammonium group; more preferably, M is a methyl group or an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); with the proviso that the compound of formula ##STR00071## is excluded.

2. The compound of formula (I) according to claim 1, wherein Q.sub.2 is selected from ##STR00072## wherein R.sub.1 to R.sub.18 are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms; or R.sub.1 to R.sub.9, R.sub.10, and R.sub.15 to R.sub.18, are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, and geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted 5- or 6-membered heterocyclic ring wherein at least one ring atom is oxygen; ##STR00073## is the point of attachment of the 5- to 6-membered heterocyclic ring to the rest of the molecule.

3. The compound of formula (I) according to claim 1, wherein Q.sub.2 is selected from ##STR00074## wherein R.sub.1 to R.sub.18 are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms; ##STR00075## is the point of attachment of the 5- to 6-membered heterocyclic ring to the rest of the molecule.

4. The compound of formula (I) according to claim 3, wherein R.sub.1 to R.sub.18 are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms.

5. The compound of formula (I) according to claim 1, wherein Q.sub.2 is selected from ##STR00076## wherein R.sub.1 to R.sub.9, R.sub.10, and R.sub.15 to R.sub.18, are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, and geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted 5- or 6-membered heterocyclic ring wherein at least one ring atom is oxygen; ##STR00077## is the point of attachment of the 5- to 6-membered heterocyclic ring to the rest of the molecule.

6. The compound of formula (I) according to claim 5, wherein R.sub.1 to R.sub.9, R.sub.10, and R.sub.15 to R.sub.18, are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms, and geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted 5- or 6-membered heterocyclic ring with one ring atom being oxygen.

7. The compound of formula (I) according to claim 1, wherein Q.sub.2 is selected from ##STR00078## wherein R.sub.1 to R.sub.7 and R.sub.10 to R.sub.16 are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms; or R.sub.1 to R.sub.7, R.sub.10, R.sub.15 and R.sub.16, are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, and geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted 5- or 6-membered heterocyclic ring wherein at least one ring atom is oxygen; ##STR00079## is the point of attachment of the 5-membered heterocyclic ring to the rest of the molecule.

8. The compound of formula (I) according to claim 1, wherein Q.sub.1 is selected from ##STR00080## wherein R.sub.19 to R.sub.30 are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms; M is a hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K), an ammonium group; ##STR00081## is the point of attachment of the (CO) group to the rest of the molecule.

9. The compound of formula (I) according to claim 1, wherein Q.sub.1 is selected from ##STR00082## wherein R.sub.19 to R.sub.30 are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms; M is a hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K), an ammonium group; ##STR00083## is the point of attachment of the (CO) group(s) to the rest of the molecule.

10. The compound of formula (I) according to claim 1, wherein Q.sub.1 is selected from ##STR00084## wherein M is an unsubstituted alkyl selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K), an ammonium group; ##STR00085## is the point of attachment of the (CO) group(s) to the rest of the molecule.

11. The compound of formula (I) according to claim 1, wherein X.sub.1 and X.sub.2 are N.

12. The compound of formula (I) according to claim 1, wherein it is selected from: ##STR00086## ##STR00087## ##STR00088## ##STR00089## ##STR00090##

13-14. (canceled)

15. A method for polarizing an analyte in a sample for Dynamic Nuclear Polarization comprising the steps of a) providing a sample comprising an analyte; b) contacting said sample with a compound of formula (I) according to claim 1 as polarizing agent (PA) that enables an optimal nuclear polarization of the analyte in a magnetic field; c) irradiating said sample with at least one radiation that causes electron spin flip, to enhance the performance of NMR detection or MRI performance; and d) optionally dissolving the sample and obtaining a hyperpolarized sample; said method optionally further comprises observing the NMR or MRI of the hyperpolarized sample.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0055] The invention is further described by the following drawings and examples which illustrate embodiments thereof. These examples and drawings should not in any way be interpreted as limiting the scope of the present invention.

[0056] FIG. 1 represents the Electron Paramagnetic Resonance (EPR) spectrum in ClCH.sub.2CH.sub.2Cl, 1.0 mM, of piperazine nitroxide 2 prepared according the synthetic protocol described in example 1.

[0057] FIG. 2a represents the EPR spectrum in ClCH.sub.2CH.sub.2Cl, 1.0 mM, of PyrroTriPol-OMe prepared according the synthetic protocol described in example 1.

[0058] FIG. 2b represents the HPLC chromatogram of PyrroTriPol-OMe.

[0059] FIG. 3a represents the EPR spectrum in H.sub.2O, 1.0 mM, of PyrroTriPol prepared in example 1.

[0060] FIG. 3b represents the HPLC chromatogram of PyrroTriPol.

[0061] FIG. 4 represents the EPR spectrum in ClCH.sub.2CH.sub.2Cl, 1.0 mM, of piperazine nitroxide 5 prepared according the synthetic protocol described in example 2.

[0062] FIG. 5a represents the EPR spectrum in ClCH.sub.2CH.sub.2Cl, 1.0 mM, of PyrroTriPol-H-OMe prepared according the synthetic protocol described in example 2.

[0063] FIG. 5b represents the HPLC chromatogram of PyrroTriPol-H-OMe.

[0064] FIG. 6a represents the EPR spectrum in H.sub.2O, 1.0 mM, of PyrroTriPol-H prepared in example 2.

[0065] FIG. 6b represents the HPLC chromatogram of PyrroTriPol-H.

[0066] FIG. 7a represents the EPR spectrum in ClCH.sub.2CH.sub.2Cl, 1.0 mM, of DiPyrroTriPol-OMe prepared according the synthetic protocol described in example 3.

[0067] FIG. 7b represents the HPLC chromatogram of DiPyrroTriPol-OMe.

[0068] FIG. 8a represents the EPR spectrum in ClCH.sub.2CH.sub.2Cl, 1.0 mM, of TriPyrroTriPol prepared according the synthetic protocol described in example 4.

[0069] FIG. 8b represents the HPLC chromatogram of TriPyrroTriPol.

[0070] FIG. 9a represents the EPR spectrum in ClCH.sub.2CH.sub.2Cl, 1.0 mM, of DiPyrroTriPol-H-OMe prepared according the synthetic protocol described in example 5.

[0071] FIG. 9b represents the HPLC chromatogram of DiPyrroTriPol-H-OMe.

[0072] FIG. 10a represents the EPR spectrum in ClCH.sub.2CH.sub.2Cl, 1.0 mM, of TriPyrroTriPol-H prepared in example 6.

[0073] FIG. 10b represents the HPLC chromatogram of TriPyrroTriPol-H.

[0074] FIG. 11 represents the chemical structures of (a) PyrroTriPol/TEMTriPol-I for aqueous solution, (b) PyrroTriPol-OMe/TEMTriPol-I-OMe for organic solutions and (c) the tri-radicals DiPyrroTriPol-OMe/DiTEMTriPol-I-OMe.

[0075] FIG. 12 represents the experimental performance of (a) 10 mM PyrroTriPol and TEMTriPol-I in glycerol-d.sub.8/D.sub.2O/H.sub.2O (60:30:10; v/v/v) containing 0.25 M of U-.sup.13C, .sup.15N-proline, (b) 16 mM PyrroTriPol-OMe and TEMTriPol-1-OMe in TCE and (c) 11 mM DiPyrroTriPol-OMe and DiTEMTriPol-1-OMe in 1,1,2,2-Tetrachloroethane with the addition of hexagonal Boron Nitride powder, at 9.4, 8 kHz MAS (3.2 mm rotor) and 110 K.

DETAILED DESCRIPTION OF THE INVENTION

[0076] The present invention is a compound of formula (I)

##STR00008## [0077] wherein [0078] n is 0 or 1; [0079] m is 1, 2 or 3; [0080] X.sub.1 and X.sub.2 are, independently, N, P; [0081] Q.sub.2 is

##STR00009## [0082] wherein [0083] X.sub.3 and X.sub.4 are joined, as indicated by [0084] to form together with the nitrogen atom to which they are bound a 5- to 8-membered heterocyclic ring, preferably a 5- or 6-membered heterocyclic ring, more preferably a 5-membered heterocyclic ring, [0085] the heterocyclic ring being optionally substituted, and/or [0086] the heterocyclic ring optionally containing one or more carbon-carbon double bond;

##STR00010## [0087] is the point of attachment of the 5- to 8-membered heterocyclic ring, preferably the 5- or 6-membered heterocyclic ring, more preferably the 5-membered heterocyclic ring, to the rest of the molecule; [0088] Q.sub.1 is selected from

##STR00011## [0089] wherein [0090] R.sub.19 to R.sub.30 are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms; [0091] M is a hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K), an ammonium group; preferably, M is a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K), an ammonium group; more preferably, M is a methyl group or an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0092] with the proviso that the compound of formula

##STR00012## [0093] is excluded.

[0094] In the compounds of formula (I), the bridge/linker presented here as a saturated 6-membered ring containing heteroatoms in positions 1 and 4 (i.e. X.sub.1 and X.sub.2) provides stiffness and reduces flexibility. It also provides a good distance range between the Q.sub.1 and Q.sub.2 radical centers, which promotes an efficient and fast transfer of polarization.

[0095] The compounds of formula (I) generate scalable synthesis of efficient trityl-nitroxides for aqueous and organic solvents with high .sub.on/off amplification factors, minimized depolarization effects and fast nuclear polarization buildups.

[0096] As used herein, and unless otherwise indicated, the term alkyl means a saturated, linear, branched hydrocarbon having 1 to 10 carbon atoms, for example, 1 to 6 atoms. Examples of alkyls include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, and their branched isomers such as isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, isobutyl, t-butyl, isopentyl, neopentyl.

[0097] As used herein, and unless otherwise indicated, the term cycloalkyl means a saturated cyclic hydrocarbon having 3 to 10 carbon atoms, for example, 3 to 6 carbon atoms. Examples of cyclic alkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl.

[0098] An alkyl, may it be linear or branched, can be unsubstituted or substituted with one or more suitable substituents selected among halogen atoms such as fluorine, chlorine, bromine, iodine; hydroxyl; alkoxy; alkyl; cycloalkyl; alkylhalides; nitro (NO.sub.2); nitrile (CN); aryl; CO-aryl; CO-alkyl; CO-cycloalkyl; CO-alkoxy; CO.sub.2H; CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, an alkyl having 1 to 6 carbon atoms; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); with alkyl as defined above and hydroxyl, alkylhalides, alkoxy and aryl as defined hereinafter.

[0099] A cycloalkyl, can be unsubstituted or substituted with one or more suitable substituents selected among halogen atoms such as fluorine, chlorine, bromine, iodine; hydroxyl; alkoxy; alkyl; cycloalkyl; alkylhalides; nitro (NO.sub.2); nitrile (CN); aryl; CO-aryl; CO-alkyl; CO-cycloalkyl; CO-alkoxy; CO.sub.2H; CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, an alkyl having 1 to 6 carbon atoms; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); with alkyl as defined above and hydroxyl, alkylhalides, alkoxy and aryl as defined hereinafter.

[0100] As used herein, and unless otherwise indicated, the term alkyl halide refers to an alkyl or a cycloalkyl as described above, in which at least one hydrogen atom is substituted by a halogen atom selected from fluorine, chlorine, bromine and iodine. Non-limiting examples of alkyl halides are methyl fluoride, methyl chloride, methyl bromide, methyl iodide, ethyl fluoride, ethyl chloride, ethyl bromide, methyl difluoride, methyl dichloride, methyl chlorofluoride, methyl bromochlorofluoride, 2-chloropropyl, fluorocyclopentyl, (dibromomethyl) cyclohexyl, 2-iodo-2-methyl propyl, 2,4-dibromopentyl, methyl trifluoride, methyl trichloride, methyl tribromide, methyl triiodide.

[0101] As used herein, and unless otherwise indicated, ammonium group means a cation of formula (NH.sub.4).sup.+.

[0102] As used herein, and unless otherwise indicated, the term alkoxy means an alkyl or a cycloalkyl as defined above, linked to another group via an oxygen atom (i.e. O-(cyclo)alkyl).

[0103] As used herein, and unless otherwise indicated, the term hydroxyl means OH.

[0104] As used herein, and unless otherwise indicated, the term halogen or halide employed or in combination with other terms means fluorine, chlorine, bromine, iodine.

[0105] The term heterocyclic ring, as used herein, refers to a non aromatic, partially unsaturated or fully saturated, 5-, 6-, 7- or 8-membered ring, for example 5- to 8-membered ring, or 5- to 6-membered ring wherein at least one ring atom is a heteroatom selected from oxygen, sulfur, and nitrogen. The remaining atoms of the heterocyclic ring are carbon atoms.

[0106] The heterocyclic ring may be partially unsaturated meaning that it may contain one or more unsaturated carbon-carbon bond. Preferably the unsaturated carbon-carbon bond is a carbon-carbon double bond (CC). In some embodiments the heterocyclic ring contains one or more carbon-carbon double bonds. In some embodiments, the heterocyclic ring contains one carbon-carbon double bond.

[0107] In embodiments where the nitrogen atom present in the heterocyclic ring is a nitrogen bearing a substituent R.sub.x to form

##STR00013##

R.sub.x can be hydrogen, hydroxyl, a substituted or unsubstituted linear, branched alkyl, a cycloalkyl as defined above, with

##STR00014##

representing the points of attachment of nitrogen to the other members of the ring. The heterocyclic ring is joined to the rest of the molecule via any of the carbon ring atoms.

[0108] Substituents on carbon atoms of the heterocyclic rings include alkyl; cycloalkyl; halogen atoms such as fluorine, chlorine, bromine, iodine; alkyl halide; alkoxy; hydroxyl; aryl; nitro (NO.sub.2); nitrile (CN); CO-aryl; CO-alkyl; CO-cycloalkyl; CO-alkoxy; CO.sub.2H; CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, an alkyl having 1 to 6 carbon atoms; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); with hydroxyl, alkyl, cycloalkyl, alkyl halide, alkoxy, and aryl as defined herein.

[0109] As used herein, and unless otherwise indicated, the term aryl refers to an aromatic hydrocarbon having up to 14 carbon atoms, for example, 6 to 14 carbon atoms, which can be a single ring (monocyclic) or multiple rings (bicyclic, up to three rings) fused together or linked covalently. Any suitable ring position of the aryl moiety can be covalently linked to the defined chemical structure. Examples of aryl include, but are not limited, to phenyl, 1-naphtyl, 2-naphtyl, dihydronaphtyl, tetrahydronaphtyl, biphenyl, anthryl, phenanthryl. An aryl can be unsubstituted substituted with one or more suitable substituents including halogen atoms such as fluorine, chlorine, bromine, iodine; hydroxyl; alkyl; cycloalkyl; alkyl halide; alkoxy; aryl; nitro (NO.sub.2); nitrile (CN); CO-aryl; CO-alkyl; CO-cycloalkyl; CO-alkoxy; CO.sub.2H; CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being independently an alkyl having 1 to 6 carbon atoms; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); with hydroxyl, alkyl, cycloalkyl, alkyl halide, alkoxy, and aryl as defined herein.

[0110] Non-limiting examples of substituted aryl can be tolyl, methoxyphenyl, dimethoxy phenyl, trimethoxyphenyl, fluorophenyl, difluorophenyl, methyltrifluoride phenyl, nitrophenyl, methylnitrophenyl, methoxynitrophenyl, dimethoxynitrophenyl chloronitrophenyl, nitrilphenyl, tolylnitrophenyl, methoxynapthtyl, CO-phenyl.

[0111] As used herein, and unless otherwise indicated, the term optional and optionally means that what the term refers to is not compulsory.

[0112] When a chemical group (i.e. a heterocyclic ring) is said to be optionally substituted, it means that the substitution of that group is not compulsory and the group may or may not be substituted. Both embodiments are englobed by this expression.

[0113] When a chemical group (i.e. a heterocyclic ring) is said to optionally contain one or more carbon-carbon double bond, it means that the presence of one or more double bonds is not compulsory and that said chemical group may or may not contain one or more carbon-carbon double bonds. Both embodiments are englobed by this expression.

[0114] When a method comprises an optional step, it means that said step is not compulsory and may or may not take place. Both embodiments are englobed by this expression.

[0115] In a first embodiment of the invention, in the compound of formula (I), Q.sub.2 is selected from

##STR00015##

wherein [0116] R.sub.1 to R.sub.18 are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms; or [0117] R.sub.1 to R.sub.9, R.sub.10, and R.sub.15 to R.sub.18, are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, and geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted 5- or 6-membered heterocyclic ring wherein at least one ring atom is oxygen.

##STR00016##

is the point of attachment of the 5- to 6-membered heterocyclic ring to the rest of the molecule.

[0118] In this first embodiment, n=1, m, X.sub.1, X.sub.2 and Q.sub.1 are as described above.

[0119] In a second embodiment of the invention, in the compound of formula (I), Q.sub.2 is selected from

##STR00017##

wherein R.sub.1 to R.sub.18 are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms.

##STR00018##

is the point of attachment of the 5- to 6-membered heterocyclic ring to the rest of the molecule.

[0120] In this second embodiment, n=1, m, X.sub.1, X.sub.2 and Q.sub.1 are as described above.

[0121] Preferably, R.sub.1 to R.sub.18 are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms.

[0122] More preferably, R.sub.1 to R.sub.18 are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms.

[0123] In a third embodiment of the invention, Q.sub.2 is selected from

##STR00019##

wherein [0124] R.sub.1 to R.sub.9, R.sub.10, and R.sub.15 to R.sub.18, are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, and geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted 5- or 6-membered heterocyclic ring wherein at least one ring atom is oxygen.

[0125] In this third embodiment, n=1, m, X.sub.1, X.sub.2 and Q.sub.1 are as described above.

##STR00020##

is the point of attachment of the 5- to 6-membered heterocyclic ring to the rest of the molecule.

[0126] In a variant embodiment, [0127] R.sub.1 to R.sub.9, R.sub.10, and R.sub.15 to R.sub.18, are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, and geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted 5- or 6-membered heterocyclic ring wherein at least one ring atom is oxygen.

[0128] In another variant embodiment, R.sub.1 to R.sub.9, R.sub.10, and R.sub.15 to R.sub.18, are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms, and [0129] geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound, a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted 5- or 6-membered heterocyclic ring with one ring atom being oxygen.

[0130] When geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound a substituted cycloalkyl having 3 to 6 carbon atoms, a substituted 5- or 6-membered heterocyclic ring with one ring atom being oxygen, said cycloalkyl and said heterocyclic ring are preferably substituted with one or more suitable substituents including [0131] halogen atoms such as fluorine, chlorine, bromine, iodine; [0132] hydroxyl; [0133] unsubstituted alkyl having 1 to 6 carbon atoms; [0134] substituted alkyl having 1 to 6 carbon atoms, the substitution including CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, an alkyl having 1 to 6 carbon atoms; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0135] cycloalkyl; [0136] alkyl halide; [0137] alkoxy; [0138] aryl; [0139] nitro (NO.sub.2); [0140] nitrile (CN); [0141] CO-aryl; [0142] CO-alkyl; [0143] CO-cycloalkyl; [0144] CO-alkoxy; [0145] CO.sub.2H; [0146] CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0147] NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being independently an alkyl having 1 to 6 carbon atoms; [0148] OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K);
with hydroxyl, alkyl, cycloalkyl, alkyl halide, alkoxy, and aryl as defined herein.

[0149] In a fourth embodiment of the invention, Q.sub.2 is selected from

##STR00021## ##STR00022##

with R.sub.31 to R.sub.36, independently, representing [0150] a hydrogen; [0151] a hydroxyl; [0152] an alkoxy with the alkyl being, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0153] an unsubstituted alkyl selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0154] a substituted alkyl selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers, the substitution including CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0155] an unsubstituted phenyl; [0156] a substituted phenyl, the substitution including a halogen atom in the group consisting of fluorine, chlorine, bromine, iodine; CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0157] CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0158] NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0159] OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K).

[0160] In this fourth embodiment, n=1, m, X.sub.1, X.sub.2 and Q.sub.1 are as described above.

##STR00023##

is the point of attachment of the 5- to 6-membered heterocyclic ring to the rest of the molecule.

[0161] In a fifth embodiment of the invention, Q.sub.2 is selected from

##STR00024##

wherein [0162] R.sub.1 to R.sub.7 and R.sub.10 to R.sub.16 are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms; or [0163] R.sub.1 to R.sub.7, R.sub.10, R.sub.15 and R.sub.16, are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, and [0164] geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted 5- or 6-membered heterocyclic ring wherein at least one ring atom is oxygen.

[0165] In a variant embodiment, [0166] R.sub.1 to R.sub.7 and R.sub.10 to R.sub.16 are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms; or [0167] R.sub.1 to R.sub.7, R.sub.10, R.sub.15 and R.sub.16, are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, and [0168] geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted 5- or 6-membered heterocyclic ring wherein at least one ring atom is oxygen.

[0169] In another variant embodiment, R.sub.1 to R.sub.7, R.sub.10, R.sub.15 and R.sub.16, are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms, and [0170] geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound, a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted 5- or 6-membered heterocyclic ring with one ring atom being oxygen.

[0171] When geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound a substituted cycloalkyl having 3 to 6 carbon atoms, a substituted 5- or 6-membered heterocyclic ring with one ring atom being oxygen, said cycloalkyl and said heterocyclic ring are preferably substituted with one or more suitable substituents including [0172] halogen atoms such as fluorine, chlorine, bromine, iodine; [0173] hydroxyl; [0174] unsubstituted alkyl having 1 to 6 carbon atoms; [0175] substituted alkyl having 1 to 6 carbon atoms, the substitution including CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, an alkyl having 1 to 6 carbon atoms; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0176] cycloalkyl; [0177] alkyl halide; [0178] alkoxy; [0179] aryl; [0180] nitro (NO.sub.2); [0181] nitrile (CN); [0182] CO-aryl; [0183] CO-alkyl; [0184] CO-cycloalkyl; [0185] CO-alkoxy; [0186] CO.sub.2H; [0187] CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0188] NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being independently an alkyl having 1 to 6 carbon atoms; [0189] OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0190] with hydroxyl, alkyl, cycloalkyl, alkyl halide, alkoxy, and aryl as defined herein

##STR00025##

is the point of attachment of the 5-membered heterocyclic ring to the rest of the molecule.

[0191] In this fifth embodiment, n=1, m, X.sub.1, X.sub.2 are as described above and [0192] Q.sub.1 is as described above with M being a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K), an ammonium group. Preferably, M is a methyl group or an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K).

[0193] As already mentioned above, the compounds of formula (I), the bridge/linker presented here as a saturated 6-membered ring containing heteroatoms in positions 1 and 4 (i.e. X.sub.1 and X.sub.2) provides stiffness and reduces flexibility. It also provides a good distance range between the Q.sub.1 and Q.sub.2 radical centers, which promotes an efficient and fast transfer of polarization. Moreover, the stiffness and the coupling between the two electron spins from Q.sub.1 and Q.sub.2 (called dipolar coupling and/or J-exchange interaction) is particularly favorable for high-field applications when Q.sub.2 is a 5-membered heterocyclic ring, possibly bearing a double bound in conjugation to the CO group from the linker. This is the case when Q.sub.2 corresponds to a pyrrolinoxyl radical, for example.

[0194] The sixth embodiment of the invention corresponds to the fifth embodiment where Q.sub.1 is as described above with M being a hydrogen.

[0195] In a seventh embodiment of the invention, Q.sub.2 is selected from

##STR00026##

with R.sub.31 to R.sub.34, independently, representing [0196] a hydrogen; [0197] a hydroxyl; [0198] an alkoxy with the alkyl being, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0199] an unsubstituted alkyl selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0200] a substituted alkyl selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers, the substitution including a halogen atom selected in the group consisting of fluorine, chlorine, bromine, iodine; CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0201] an unsubstituted phenyl; [0202] a substituted phenyl, the substitution including a halogen atom selected in the group consisting of fluorine, chlorine, bromine, iodine; CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0203] CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0204] NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0205] OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K).

[0206] In this seventh embodiment, n=1, m, X.sub.1, X.sub.2 are as described above and Q.sub.1 is as described above with M being a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K), an ammonium group. More preferably, M is a methyl group, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K)

##STR00027##

is the point of attachment of the 5-membered heterocyclic ring to the rest of the molecule.

[0207] The eighth embodiment of the invention corresponds to the seventh embodiment where Q.sub.1 is as described above with M being a hydrogen.

[0208] In a ninth embodiment of the invention, Q.sub.2 is selected from

##STR00028## [0209] wherein [0210] R.sub.1 to R.sub.4, R.sub.7 and R.sub.11 to R.sub.15, are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, or [0211] R.sub.1 to R.sub.4, R.sub.7 and R.sub.15 are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, and [0212] geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted 5- or 6-membered heterocyclic ring wherein at least one ring atom is oxygen.

[0213] In a variant embodiment, [0214] R.sub.1 to R.sub.4, R.sub.7 and R.sub.15, are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, and [0215] geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted 5- or 6-membered heterocyclic ring wherein at least one ring atom is oxygen.

[0216] In another variant embodiment, [0217] R.sub.1 to R.sub.4, R.sub.7 and R.sub.15, are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms, and [0218] geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound, a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted 5- or 6-membered heterocyclic ring with one ring atom being oxygen.

[0219] When geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound a substituted cycloalkyl having 3 to 6 carbon atoms, a substituted 5- or 6-membered heterocyclic ring with one ring atom being oxygen, said cycloalkyl and said heterocyclic ring are preferably substituted with one or more suitable substituents including. [0220] a halogen atom selected in the group consisting of fluorine, chlorine, bromine, iodine; [0221] a hydroxyl; [0222] an alkoxy with the alkyl being, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0223] an unsubstituted alkyl selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0224] a substituted alkyl selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers, the substitution including a halogen atom selected in the group consisting of fluorine, chlorine, bromine, iodine; CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0225] an unsubstituted phenyl; [0226] a substituted phenyl, the substitution including a halogen atom selected in the group consisting of fluorine, chlorine, bromine, iodine; CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0227] CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K);. [0228] NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0229] OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K). [0230] an unsubstituted cycloalkyl selected in the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; [0231] a substituted cycloalkyl selected in the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the substitution including a halogen atom selected in the group consisting of fluorine, chlorine, bromine, iodine; CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0232] nitro (NO.sub.2); [0233] nitrile (CN); [0234] CO-alkyl with alkyl being methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0235] CO-phenyl; [0236] CO-cycloalkyl with cycloalkyl being cyclopropyl, cyclobutyl, cyclopentyle, cyclohexyl; [0237] CO-alkoxy with alkyl being methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0238] CO.sub.2H; [0239] CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0240] NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being independently an alkyl having 1 to 6 carbon atoms; [0241] OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K).

[0242] In this ninth embodiment, n=1, m, X.sub.1, X.sub.2 are as described above Q.sub.1 is as described above with M a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K), an ammonium group. Preferably, M is a methyl group or an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K)

##STR00029##

is the point of attachment of the 5-membered heterocyclic ring to the rest of the molecule.

[0243] The tenth embodiment of the invention corresponds to the ninth embodiment where Q.sub.1 is as described above with M being a hydrogen.

[0244] In an eleventh embodiment of the invention, Q.sub.2 is selected from

##STR00030##

with R.sub.33 and R.sub.34, independently, representing [0245] a hydrogen; [0246] a hydroxyl; [0247] an alkoxy with the alkyl being, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0248] an unsubstituted alkyl selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0249] a substituted alkyl selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers, the substitution including a halogen atom selected in the group consisting of fluorine, chlorine, bromine, iodine; CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0250] an unsubstituted phenyl; [0251] a substituted phenyl, the substitution including a halogen atom selected in the group consisting of fluorine, chlorine, bromine, iodine; CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0252] CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0253] NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0254] OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of Lithium (Li), sodium (Na), potassium (K).

##STR00031##

is the point of attachment of the 5-membered heterocyclic ring to the rest of the molecule.

[0255] In this eleventh embodiment, n=1, m, X.sub.1, X.sub.2 are as described above and Q.sub.1 is as described above with M is a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K), an ammonium group. Preferably, M is a methyl group, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K).

[0256] The twelfth embodiment of the invention corresponds to the eleventh embodiment where Q.sub.1 is as described above with M being a hydrogen.

[0257] In a thirteenth embodiment of the invention, Q.sub.2 is selected from

##STR00032##

wherein [0258] R.sub.1 to R.sub.7 and R.sub.10 to R.sub.16 are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms; or [0259] R.sub.1 to R.sub.7, R.sub.10, R.sub.15 and R.sub.16, are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, and [0260] geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted 5- or 6-membered heterocyclic ring wherein at least one ring atom is oxygen.

[0261] In a variant embodiment, [0262] R.sub.1 to R.sub.4, R.sub.7 and R.sub.15, are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, and [0263] geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted 5- or 6-membered heterocyclic ring wherein at least one ring atom is oxygen.

[0264] In another variant embodiment, [0265] R.sub.1 to R.sub.4, R.sub.7 and R.sub.15, are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms, and [0266] geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound, a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted 5- or 6-membered heterocyclic ring with one ring atom being oxygen.

[0267] When geminal R.sub.11 and R.sub.12, and geminal R.sub.13 and R.sub.14, are joined to form together with the carbon to which they are bound a substituted cycloalkyl having 3 to 6 carbon atoms, a substituted 5- or 6-membered heterocyclic ring with one ring atom being oxygen, said cycloalkyl and said heterocyclic ring are preferably substituted with one or more suitable substituents including [0268] a halogen atom selected in the group consisting of fluorine, chlorine, bromine, iodine; [0269] a hydroxyl; [0270] an alkoxy with the alkyl being, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0271] an unsubstituted alkyl selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0272] a substituted alkyl selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers, the substitution including a halogen atom selected in the group consisting of fluorine, chlorine, bromine, iodine; CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0273] an unsubstituted phenyl; [0274] a substituted phenyl, the substitution including a halogen atom selected in the group consisting of fluorine, chlorine, bromine, iodine; CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0275] CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0276] NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0277] OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K). [0278] an unsubstituted cycloalkyl selected in the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; [0279] a substituted cycloalkyl selected in the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the substitution including a halogen atom selected in the group consisting of fluorine, chlorine, bromine, iodine; CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0280] nitro (NO.sub.2); [0281] nitrile (CN); [0282] CO-alkyl with alkyl being methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0283] CO-phenyl; [0284] CO-cycloalkyl with cycloalkyl being cyclopropyl, cyclobutyl, cyclopentyle, cyclohexyl;

[0285] CO-alkoxy with alkyl being methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0286] CO.sub.2H; [0287] CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0288] NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being independently an alkyl having 1 to 6 carbon atoms; [0289] OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K)

##STR00033##

is the point of attachment of the 5-membered heterocyclic ring to the rest of the molecule.

[0290] In this eleventh embodiment, n=1, m, X.sub.1, X.sub.2 are as described above and Q.sub.1 is as described above with M a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K), an ammonium group. Preferably, M is a methyl group, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K).

[0291] The fourteenth embodiment of the invention corresponds to the thirteenth embodiment where Q.sub.1 is as described above with M being a hydrogen.

[0292] In a fifteenth embodiment of the invention, Q.sub.2 is selected from

##STR00034##

with R.sub.31 and R.sub.32, independently, representing [0293] a hydrogen; [0294] a hydroxyl; [0295] an alkoxy with the alkyl being, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0296] an unsubstituted alkyl selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0297] a substituted alkyl selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers, the substitution including a halogen atom selected in the group consisting of fluorine, chlorine, bromine, iodine; CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0298] an unsubstituted phenyl; [0299] a substituted phenyl, the substitution including a halogen atom selected in the group consisting of fluorine, chlorine, bromine, iodine; CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0300] CO.sub.2M.sub.a with M.sub.a being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K); [0301] NR.sub.aR.sub.bR.sub.c with R.sub.a, R.sub.b and R.sub.c being, independently, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers; [0302] OPO.sub.3(M.sub.b).sub.2 with M.sub.b being a hydrogen, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K).

[0303] In this thirteenth embodiment, n=1, m, X.sub.1, X.sub.2 are as described above Q.sub.1 is as described above with M a substituted or unsubstituted linear, branched alkyl having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 10 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K), an ammonium group. Preferably, M is a methyl group, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K).

##STR00035##

is the point of attachment of the 5-membered heterocyclic ring to the rest of the molecule.

[0304] The sixteenth embodiment of the invention corresponds to the fifteenth embodiment where Q.sub.1 is as described above with M being a hydrogen.

[0305] In a seventeenth embodiment of the invention, Q.sub.1 is selected from

##STR00036##

wherein [0306] R.sub.19 to R.sub.30 are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms; [0307] M is a hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, a substituted or unsubstituted aryl having 6 to 14 carbon atoms, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K), an ammonium group.

[0308] In this sixteenth embodiment, n=1, m, X.sub.1, X.sub.2 and Q.sub.2 are as described above.

##STR00037##

is the point of attachment of the (CO) group to the rest of the molecule.

[0309] In a eighteenth embodiment of the invention, Q.sub.1 is selected from

##STR00038##

wherein [0310] R.sub.19 to R.sub.30 are, independently, hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms; [0311] M is a hydrogen, a substituted or unsubstituted linear, branched alkyl having 1 to 6 carbon atoms, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K), an ammonium group.

[0312] In this seventeenth embodiment, n=1, m, X.sub.1, X.sub.2 and Q.sub.2 are as described above.

##STR00039##

is the point of attachment of the (CO) group(s) to the rest of the molecule.

[0313] In a ninteenth embodiment of the invention, Q.sub.1 is selected from

##STR00040##

wherein M is, an unsubstituted alkyl selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers, an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K), an ammonium group.

[0314] In this ninteenth embodiment, n=1, m, X.sub.1, X.sub.2 and Q.sub.2 are as described above.

##STR00041##

is the point of attachment of the (CO) group(s) to the rest of the molecule.

[0315] In all the embodiments disclosed herein, X.sub.1 and X.sub.2 are preferably N.

[0316] The twentieth embodiment of the invention corresponds to the nineteenth embodiment where Q.sub.1 is as described above with M being a hydrogen.

[0317] As already indicated, the compound of formula

##STR00042##

is not part of the invention and is excluded from all of the embodiments disclosed herein.

[0318] In an exemplary embodiment according to the invention, the compound of formula (I) is

##STR00043##

[0319] In an exemplary embodiment according to the invention, the compound of formula (I) is

##STR00044##

[0320] In an exemplary embodiment according to the invention, the compound of formula (I) is

##STR00045##

[0321] In an exemplary embodiment according to the invention, the compound of formula (I) is

##STR00046##

[0322] In an exemplary embodiment according to the invention, the compound of formula (I) is

##STR00047##

[0323] In an exemplary embodiment according to the invention, the compound of formula (I) is

##STR00048##

[0324] In an exemplary embodiment according to the invention, the compound of formula (I) is

##STR00049##

[0325] In an exemplary embodiment according to the invention, the compound of formula (I) is

##STR00050##

[0326] In an exemplary embodiment according to the invention, the compound of formula (I) is

##STR00051##

[0327] In an exemplary embodiment according to the invention, the compound of formula (I) is

##STR00052##

[0328] In an exemplary embodiment according to the invention, the compound of formula (I) is

##STR00053##

[0329] In an exemplary embodiment according to the invention, the compound of formula (I) is

##STR00054##

[0330] In an exemplary embodiment according to the invention, the compound of formula (I) is

##STR00055##

[0331] In an exemplary embodiment according to the invention, the compound of formula (I) is

##STR00056##

[0332] The nitroxide-carbon-based biradicals proposed up to now offer low to moderate performance at high field and fast MAS. More importantly, their widespread use has been so far limited since they suffer either from limited chemical stability (HyTEK) or they require a tedious synthesis. Both aspects have prevented the commercialization of these radicals so far.

[0333] The compounds of formula (I) address both problems of limited efficiency and stability of nitroxide-carbon-based biradicals. In addition, the synthetic route for these compounds is compatible with large scale synthesis and thus commercialization.

[0334] In order to illustrate the performance of the polarizing agent family disclosed in this application, the inventors describe herein the returned DNP efficiency for several members of this family (i.e. PyrroTriPol in FIG. 11a, PyrroTriPol-OMe in FIG. 11b, DiPyrroTriPol-OMe in FIG. 11c) and compare them to TEMTriPol-1 (FIG. 11a, G. Mathies et al., Angew. Chemie-Int. Ed., vol. 54, no. 40, pp. 11770-11774, 2015, doi: 10.1002/anie.201504292), TEMTriPol-OMe (FIG. 11b) and DiTEMTriPol-OMe (FIG. 11c). Note that the TEMTriPol-OMe biradical and the DiTEMTriPol-OMe triradical have never been reported so far and correspond to TEMTriPol derivatives that are soluble in organic solvent (e.g. 1,1,2,2-Tetrachloroethane, chloroform, etc.), as opposed to TEMTriPol-1 which is soluble in aqueous solution.

[0335] In [FIG. 12], the inventors report experimental data for 10 mM PyrroTriPol and TEMTriPol-I in glycerol-d.sub.8/D.sub.2O/H.sub.2O (60:30:10; v/v/v) containing 0.25 M of U-.sup.13C, .sup.15N-proline.

[0336] In addition, the inventors report experimental data for 16 mM PyrroTriPol-OMe and TEMTriPol-OMe in 1,1,2,2-Tetrachloroethane in [FIG. 12b], as well as for 11 mM DiPyrroTriPol-OMe and DiTEMTriPol-OMe in 1,1,2,2-Tetrachloroethane in [FIG. 12c]. The results reported in [FIG. 12] show that PyrroTriPol yields high DNP enhancement factor (.sub.on/off80) and short buildup time (Tb2 s) on a partially protonated aqueous matrix. More importantly, the returned sensitivity is 1.6 times higher with PyrroTriPol than with TEMTriPol-1, which is consistent with the fact that the DNP enhancement is higher while the DNP buildup time and depolarization effect are similar. This trend also holds true in the case of non-aqueous DNP matrix. Strikingly, PyrroTriPol-OMe returns a DNP enhancement factor of 120 with a buildup time of 0.8 seconds. This translates into an improvement in sensitivity by a factor of 2, compared to TEMTriPol-1-OMe.

[0337] As a complement, we also report in [FIG. 12c], the case of tri-radicals for both the TEMTriPol and PyrroTriPol family. The first thing to note is that, in the TEMTriPol case, the DNP performance decreases when adding a second nitroxide moiety. The DNP enhancement factor .sub.on/off is lowered from 73 for TEMTriPol-OMe to 20 for DiTEMTriPol-I-OMe. The inventors noted that this differs from the observation made by Yau et al. in JMR 244 (2014) 98-100. In this work, Yau et al. observed that, in the case of nitroxide based polarizing agents, tri-radicals returns higher sensitivity than bi- or tetra-radicals. This comparison also proves that the latter observation cannot be generalized as a rule to all polarizing agent structures. In the PyrroTriPol case, the inventors noted that the tri-radical version (DiPyrroTriPol-OMe) returns a similar sensitivity (slightly smaller) than the bi-radical case (PyrroTriPol-OMe).

[0338] Syntheses of particular compounds of formula (I) according to the invention are described in details in the examples.

[0339] A general method for the synthesis of the compounds of the invention can be obtained according to a one-step synthesis as described below.

[0340] The solvents used for the reaction may be the same or selected from diethylether, dimethylether, dioxane, dichloromethane, dichloroethane, acetonitrile, chloroform, dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofurane (THF) or toluene.

[0341] The reaction temperature can be between 20 and 50 C., preferably between 20 and 30 C.

[0342] The reaction time can be between 1 and 48 h, more preferably between 6 and 24 h.

[0343] The molar ratio between the trityl compound and the nitroxide radical can be between 1 and 6, in particular between 1 and 1.2.

[0344] The compounds of formula (I) can be isolated and purified, if necessary, by conventional separation/purification methods used in the synthetic organic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, various chromatographic techniques or the like.

[0345] The compounds of the invention are stable and are soluble either in aqueous or organic solvent.

[0346] Another object of the present invention relates to the use of a compound of formula (I) as a polarizing agent.

[0347] Another object of the invention is the use of a compound of formula (I) according to the invention as a PA for DNP in the context of structural biology, material sciences, Nuclear Magnetic Resonance of solids or applied to liquid samples, particle physics, and medical imaging. In particular, the compounds of formula (I) may be used as DNP agents for polarizing an NMR-active isotope of a nucleus in Nuclear Magnetic Resonance (NMR) spectroscopy. The term NMR spectroscopy, as used herein, encompasses Solid State NMR (SS-NMR) spectroscopy, liquid state NMR spectroscopy and Magnetic Resonance Imaging (MRI), in all of which the compounds of the invention may be used as DNP agents.

[0348] A nucleus having an NMR-active spin may be, for example: .sup.1H, .sup.2H, .sup.6Li, .sup.7Li, .sup.10B, .sup.11B, .sup.13C, .sup.14N, .sup.15N, .sup.17O, .sup.19F, .sup.23Na, .sup.25 Mg, .sup.27 Al, .sup.29Si, .sup.31P, .sup.33S, .sup.35Cl, .sup.37Cl, .sup.39K, .sup.41 K, .sup.43Ca, .sup.47Ti, .sup.49Ti, .sup.50V, .sup.51V, .sup.53Cr, .sup.77Se, .sup.89Y, .sup.117Sn, .sup.119Sn and .sup.199Hg.

[0349] A further object of the invention relates to a method for polarizing an analyte in a sample for Dynamic Nuclear Polarization comprising the steps of [0350] a) providing a sample comprising an analyte; [0351] b) contacting said sample with a compound of formula (I) as polarizing agent that enables an optimal nuclear polarization of the analyte in a magnetic field; [0352] c) irradiating said sample with at least one radiation that causes electron spin flip, to enhance the performance of NMR detection or MRI performance; and [0353] d) optionally dissolving the sample and obtaining a hyperpolarized sample.

[0354] Said method optionally further comprises observing the NMR or MRI of the hyperpolarized sample.

[0355] The irradiation is preferably a microwave irradiation. The frequency range of the microwave irradiation by which the polarization is transferred to an NMR-active nucleus is usually from 5 to 800 GHz.

[0356] The term analyte, as used herein, refers to a chemical or a biological entity, such as a solid inorganic, organic or metallo-organic material having a crystal lattice or an amorphous solid structure (e.g. zeolites, nanoparticles, mesoporous and porous materials, glasses, Metal Organic Frameworks (MOF), a molecular chemical or biochemical compound including polymeric compounds and macromolecular compounds (e.g. proteins, enzymes, DNA/RNA and a biological entity (e.g. a whole cell, a leaf, a virus particle, tissue or bone components or a whole body, having one or more NMR-active spins to be investigated by NMR spectroscopy)). The chemical or a biological entity may be isolated or in its natural environment. The analyte may be dissolved in aqueous medium, an organic solvent or solvent mixture or an aqueous/organic solvent mixture. The analyte may be present in the sample without a solvent.

[0357] The investigation by NMR spectroscopy may be structure determination, monitoring of reaction kinetics, flow imaging, etc.

[0358] The polarizing agent may be dissolved in the solvent(s) of the sample or may be introduced without a solvent chemically bound to the analyte, such as in doped polymers, materials functionalized with polarizing agents, or paramagnetic spin labels on biological samples.

[0359] The polarizing agent may also be dispersed in the analyte, for example by initially introducing the polarizing agent with a solvent and evaporating the solvent in a following step leaving the polarizing agent and analyte, or be introduced by wet impregnation. The polarizing agent may also be added during a synthetic preparation step.

[0360] The polarizing agent may be present in a solid state during the polarization time, such as in a frozen solution comprising a frozen solvent or solvent mixture containing the analyte or in a solid state.

[0361] The polarizing agent may be present in a liquid state or in a liquid solution during the polarization time.

[0362] A compound of formula (I) according to the invention, when used as a polarizing agent, is used at a concentration of 0.01 to 200 mM.

[0363] In solid state NMR experiments, the temperature of a sample including the polarizing agent is in the range of 1 to 300 K.

[0364] The invention will be further illustrated by the following figures and examples.

EXAMPLES

[0365] All commercially available reagents were purchased from Sigma-Aldrich, Inc. or Acros Organics and used without further purification. All moisture-and air-sensitive reactions were carried out in oven-dried glassware under an inert atmosphere of Ar. Thin-layer chromatography (TLC) was performed using glass plates pre-coated with silica gel (0.25 mm, F-25, Silicycle) and compounds were visualized under UV light. Column chromatography was performed using 230-400 mesh silica gel (Silicycle). Radicals show broadening and loss of NMR signals due to their paramagnetic nature and, therefore, those NMR spectra are not shown. EPR spectra were recorded on a MiniScope MS200 (Magnettech Germany) spectrometer. Mass spectrometric analyses of all organic compounds were performed on an ESI-HRMS (Bruker, MicrOTOF-Q) in a positive or negative ion mode.

[0366] Purification of PyrroTriPol and PyrroTriPol-H was performed on a preparative Agilent HPLC system using a GL Sciences Inertsustain C18 14250 mm column with UV detection at =254 nm with a flow rate of 10 mL/min using the following gradient: Solvent A, H.sub.2O; solvent B, CH.sub.3CN; 0-4 min isocratic 4% B, 4-20 min gradient 4-100% B, 20-21 min isocratic 100% B, 21-23 min 100-4% B. Purity of all biradicals was analyzed on an analytical Agilent HPLC system using a Pursuit 5 C18 4.6250 mm analytical column with UV detection at =254 nm with a flow rate of 1 mL/min using an isocratic run for PyrroTriPol-OMe, DiPyrroTriPol-OMe, TriPyrro TriPol, PyrroTriPol-H-OMe, DiPyrroTriPol-H-OMe and TriPyrroTriPol-H: 0-16 min 100%.

Example 1:

Synthesis of Piperazine Nitroxide 2

##STR00057##

[0367] To a solution of nitroxide 1 (doi: org/10.1016/j.saa.2008.07.045) (0.1 00 g, 0.54 mmol) in EtOAc (5.0 mL) was added N,N-dicyclohexylcarbodiimide or DCC (0.167 g, 0.81 mmol) and N-hydroxybenzotriazole or HOBt (0.124 g, 0.81 mmol) and the resulting solution was stirred at 22 C. for 5 min. and added dropwise to a solution of piperazine (0.140 g, 1.63 mmol) in EtOAc (10 mL) and Et.sub.3N (0.11 mL, 0.81 mmol). The reaction mixture was stirred at 22 C. for 12 h. The precipitate was filtered off, the solvent was removed in vacuo and the residue purified by column chromatography (CH.sub.2Cl.sub.2:MeOH, 9:1+0.1% Et.sub.3N) to yield piperazine nitroxide 2 (0.108 g, 0.43 mmol, 79%) as yellow solid.

[0368] TLC (Silica gel, CH.sub.2Cl.sub.2:MeOH 9:1), Rf (piperazine nitroxide 2)=0.1

[0369] ESI-HRMS: calcd. for C.sub.13H.sub.22N.sub.3O.sub.2 [M+H.sup.+] 253.1785, measured 253.1776 (m=0.0009, error =3.6 ppm).

[0370] EPR (ClCH.sub.2CH.sub.2Cl, 1.0 mM): EPR spectrum represented in [FIG. 1].

Synthesis of PyrroTriPol-OMe

##STR00058##

[0371] To a solution of trityl 3 (doi: 10.1055/s-0035-1561299) (0.030 g, 0.029 mmol) in DMF (2.0 mL) was added benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (0.020 g, 0.044 mmol), N-hydroxybenzotriazole (0.006 g, 0.044 mmol) and DIPEA (0.008 mL, 0.044 mmol) and the resulting solution was stirred at 22 C. for 5 min. Nitroxide 2 (0.008 g, 0.032 mmol) was added to the solution and the resulting reaction mixture was stirred at 22 C. for 12 h. Saturated aqueous NaHCO.sub.3 (10 mL) was added and the solution extracted with EtOAc (310 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, the solvent was removed in vacuo and the residue purified by flash column chromatography (petroleum ether:EtOAc, 6:4) to give PyrroTriPol-OMe (0.033 g,0.026 mmol, 88% yield) as a green solid.

[0372] TLC (Silica gel, pet. ether:EtOAc 1:1), Rf (PyrroTriPol-OMe)=0.4

[0373] ESI-HRMS: calcd. for C.sub.55H.sub.63N.sub.3O.sub.7S.sub.12 [M+Na.sup.+] 1284.1207, measured 1284.1164 (m=0.0043, error=3.3 ppm).

[0374] EPR (ClCH.sub.2CH.sub.2Cl, 1.0 mM): EPR spectrum represented in [FIG. 2a].

[0375] HPLC: HPLC chromatogram represented in [FIG. 2b].

Synthesis of PyrroTriPol

##STR00059##

[0376] To a solution of PyrroTriPol-OMe (0.015 g, 0.012 mmol) in MeOH (2.0 mL) was added NaOH (0.003 g, 0.072 mmol) and H.sub.2O (0.1 mL). The reaction mixture was stirred at 22 C. for 48 h. The solvent was removed in vacuo and the residue purified by C18-HPLC to afford PyrroTriPol (0.013 g, 0.010 mmol, 86% yield) as a green solid.

[0377] ESI-HRMS: calcd. for C.sub.53H.sub.59N.sub.3O.sub.7S.sub.12 [MH.sup.+] 1232.0929, measured 1232.0922 (m=0.0007, error=0.6 ppm).

[0378] EPR (H.sub.2O, 1.0 mM): EPR spectrum represented in [FIG. 3a].

[0379] HPLC: HPLC chromatogram represented in [FIG. 3b].

Example 2:

Synthesis of Piperazine Nitroxide 5

##STR00060##

[0380] To a solution of nitroxide 4 (doi: org/10.1039/C7CP07444A) (0.100 g, 0.54 mmol) in EtOAc (5.0 mL) was added N,N-dicyclohexylcarbodiimide or DCC (0.167 g, 0.81 mmol) and N-hydroxybenzotriazole or HOBt (0.124 g, 0.81 mmol) and the mixture stirred at 22 C. for 5 min. and added dropwise to a solution of piperazine (0.140 g, 1.63 mmol) in EtOAc (10 mL) and Et.sub.3N (0.11 mL, 0.81 mmol). The resulting mixture was stirred at 22 C. for 12 h. The precipitate was filtered off, the solvent was removed in vacuo and purified by column chromatography (CH.sub.2Cl.sub.2:MeOH, 9:1+0.1% Et.sub.3N) to yield piperazine nitroxide 2 (0.099 g, 0.39 mmol, 72%) as yellow solid.

[0381] TLC (Silica gel, CH.sub.2Cl.sub.2:MeOH 9:1), Rf (piperazine nitroxide 5)=0.1

[0382] ESI-HRMS: calcd. for C.sub.13H.sub.24N.sub.3O.sub.2 [M+Na.sup.+] 277.1761, measured 277.1760 (m=0.0001, error=0.4 ppm).

[0383] EPR (ClCH.sub.2CH.sub.2Cl, 1.0 mM): EPR spectrum represented in [FIG. 4].

Synthesis of PyrroTriPol-H-OMe

##STR00061##

[0384] To a solution of trityl 3 (doi: 10.1055/s-0035-1561299) (0.030 g, 0.029 mmol) in DMF (2.0 mL) was added benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (0.020 g, 0.044 mmol), N-hydroxybenzotriazole (0.006 g, 0.044 mmol) and DIPEA (0.008 mL, 0.044 mmol) and the resulting solution stirred at 22 C. for 5 min. Nitroxide 5 (0.008 g, 0.032 mmol) was added to the solution and the resulting reaction mixture was stirred at 22 C. for 12 h. Saturated aqueous NaHCO.sub.3 (10 mL) was added and the solution extracted with EtOAc (310 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, the solvent was removed in vacuo and the residue purified by flash column chromatography (petroleum ether:EtOAc, 6:4) to give PyrroTriPol-H-OMe (0.032 g, 0.025 mmol, 86% yield) as a green solid.

[0385] TLC (Silica gel, CH.sub.2Cl.sub.2:MeOH 9:1), Rf (PyrroTriPol-H-OMe)=0.4.

[0386] ESI-HRMS: calcd. for C.sub.55H.sub.65N.sub.3O.sub.7S.sub.12 [M+Na.sup.+] 1286.1363, measured 1286.1354 (m=0.0009, error=0.7 ppm).

[0387] EPR (ClCH.sub.2CH.sub.2Cl, 1.0 mM): EPR spectrum represented in [FIG. 5a].

[0388] HPLC: HPLC chromatogram represented in [FIG. 5b].

Synthesis of PyrroTriPol-H

##STR00062##

[0389] To a solution of PyrroTriPol-H-OMe (0.015 g, 0.012 mmol) in MeOH (2.0 mL) was added (0.003 g, 0.072 mmol) and H.sub.2O (0.1 mL). The reaction mixture was stirred at 22 C. for 48 h. The solvent was removed in vacuo and the residue purified by C18-HPLC to afford PyrroTriPol-H (0.013 g, 0.010 mmol, 88% yield) as a green solid.

[0390] ESI-HRMS: calcd. for C.sub.53H.sub.60N.sub.3O.sub.7S.sub.12 [M+H.sup.+] 1234.1085, measured 1234.1034 (m=0.0051, error=4.1 ppm).

[0391] EPR (H.sub.2O, 1.0 mM): EPR spectrum represented in [FIG. 6a].

[0392] HPLC: HPLC chromatogram represented in [FIG. 6b].

Example 3:

Synthesis of DiPyrroTriPol-OMe

##STR00063##

[0393] To a solution of trityl 6 (doi: 10.1055/s-0035-1561299) (0.010 g, 0.010 mmol) in DMF (1.0 mL) was added benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate or BOP (0.013 g, 0.030 mmol), N-hydroxybenzotriazole or HOBt (0.004 g, 0.030 mmol) and DIPEA (0.011 mL, 0.060 mmol) and the resulting solution was stirred at 22 C. for 5 min. Nitroxide 2 as synthesized in example 1 (0.008 g, 0.030 mmol) was added and the resulting solution was stirred at 22 C. for 12 h. Saturated NaHCO.sub.3 (10 mL) was added and the solution extracted with EtOAc (310 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, the solvent was removed in vacuo and the residue purified by flash column chromatography (pet. ether:EtOAc, 3:7) to give DiPyrroTriPol-OMe (0.013 g,0.009 mmol, 88% yield) as a green solid.

[0394] TLC (Silica gel, pet. ether:EtOAc 3:7), Rf (DiPyrroTriPol-OMe)=0.4.

[0395] ESI-HRMS: calcd. for C.sub.67H.sub.81N.sub.6O.sub.8S.sub.12 [M+Na.sup.+] 1504.2657, measured 1504.2583 (m=0.0074, error=4.9 ppm).

[0396] EPR (ClCH.sub.2CH.sub.2Cl, 1.0 mM): EPR spectrum represented in [FIG. 7a].

[0397] HPLC: HPLC chromatogram represented in [FIG. 7b].

Example 4:

Synthesis of TriPyrroTriPol

##STR00064##

[0398] To a solution of Finland trityl (doi: 10.1055/s-0035-1561299) (0.010 g, 0.010 mmol) in DMF (1.0 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or BOP (0.020 g, 0.045 mmol), N-hydroxybenzotriazole or HOBt (0.006 g, 0.045 mmol) and DIPEA (0.016 mL, 0.090 mmol) and the resulting solution was stirred at 22 C. for 5 min. Nitroxide 2 as synthesized in example 1 (0.011 g, 0.045 mmol) was added and the resulting reaction solution was stirred at 22 C. for 12 h. Saturated NaHCO.sub.3 (10 mL) was added and the solution extracted with EtOAc (310 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, the solvent was removed in vacuo and the residue purified by flash column chromatography (pet. ether:EtOAc, 6:4) to give TriPyrroTriPol (0.013 g, 0.008 mmol, 76% yield) as a green solid.

[0399] TLC (Silica gel, EtOAc), Rf (TriPyrroTriPol)=0.4.

[0400] ESI-HRMS: calcd. for C.sub.79H.sub.99N.sub.9O.sub.9S.sub.12Na [M+Na+] 1726.4112, measured 1726.4120 (m=0.0008, error=0.5 ppm).

[0401] EPR (ClCH.sub.2CH.sub.2Cl, 1.0 mM): EPR spectrum represented in [FIG. 8a].

[0402] HPLC: HPLC chromatogram represented in [FIG. 8b].

Example 5:

Synthesis of DiPyrroTriPol-H-OMe

##STR00065##

[0403] To a solution of trityl 6 (doi: 10.1055/s-0035-1561299) (0.010 g, 0.010 mmol) in DMF (1.0 mL) was added benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate or BOP (0.013 g, 0.030 mmol), N-hydroxybenzotriazole or HOBt (0.004 g, 0.030 mmol) and DIPEA (0.011 mL, 0.060 mmol) and the resulting solution was stirred at 22 C. for 5 min. Nitroxide 5 prepared in example 2 (0.008 g, 0.030 mmol) was added and the resulting reaction solution was stirred at 22 C. for 12 h. Saturated NaHCO.sub.3 (10 mL) was added and the solution extracted with EtOAc (310 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, the solvent was removed in vacuo and the residue purified by flash column chromatography (pet. ether:EtOAc, 3:7) to give DiPyrroTriPol-H-OMe (0.008 g, 0.005 mmol, 54% yield) as a green solid.

[0404] TLC (Silica gel, pet. ether:EtOAc 3:7), Rf (DiPyrroTriPol-H-OMe)=0.4.

[0405] ESI-HRMS: calcd. for C.sub.67H.sub.85N.sub.6O.sub.8S.sub.12 [M+Na.sup.+] 1508.2970, measured 1508.2953 (m=0.0017, error=1.1 ppm).

[0406] EPR (ClCH.sub.2CH.sub.2Cl, 1.0 mM): EPR spectrum represented in [FIG. 9a].

[0407] HPLC: HPLC chromatogram represented in [FIG. 9b].

Example 6:

Synthesis of TriPyrroTriPol-H

##STR00066##

[0408] To a solution of Finland trityl (doi: 10.1055/s-0035-1561299) (0.010 g, 0.010 mmol) in DMF (1.0 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or BOP (0.020 g, 0.045 mmol), N-hydroxybenzotriazole or HOBt (0.006 g, 0.045 mmol) and DIPEA (0.016 mL, 0.090 mmol) and the resulting solution was stirred at 22 C. for 5 min. Nitroxide 5 prepared in example 2 (0.011 g, 0.045 mmol) was added and the resulting reaction solution was stirred at 22 C. for 12 h. Saturated NaHCO.sub.3 (10 mL) was added and the solution extracted with EtOAc (310 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, the solvent was removed in vacuo and the residue purified by flash column chromatography (EtOAc) to give TriPyrroTriPol-H (0.010 g, 0.006 mmol, 58% yield) as a green solid.

[0409] TLC (Silica gel, EtOAc), Rf (TriPyrroTriPol-H)=0.4.

[0410] ESI-HRMS: calcd. for C.sub.79H.sub.105N.sub.9O.sub.9S.sub.12 [M+Na.sup.+] 1732.4582, measured 1732.4589 (m=0.0007, error=0.4 ppm).

[0411] EPR (ClCH.sub.2CH.sub.2Cl, 1.0 mM): EPR spectrum represented in [FIG. 10a].

[0412] HPLC: HPLC chromatogram represented in [FIG. 10b].

[0413] The piperazine bridge, linked through amide bonds to trityl and nitroxide moieties as in the above synthesized compounds, increases the interaction between unpaired electrons (called dipolar coupling and exchange interaction) and constrains the relative orientation of the two paramagnetic centers (trityl and nitroxide) in the compounds.

[0414] The piperazine bridge/linker has a reduced flexibility and limits the number of accessible conformations of the compounds. This typically translates into a narrower distribution of dipolar couplings and J-exchange interactions. In addition, such a rigid bridge/linker also prevents the presence of conformations with too short nitroxide-trityl distances (unlike in the case of TEMTriPol-I), that typically yield a non-optimal DNP transfer.

[0415] The above synthesized compounds have been tested successfully. In addition to provide very good polarization transfer efficiency, compared to state-of-the-art polarizing agents, these compounds were still performing well in the fast spinning frequency regime (i.e. MAS frequency larger than 10 kHz) and at high magnetic field (i.e. about 5-21 T). In addition, the newly developed trityl-nitroxides possess an easy synthesis and purification to prepare larger quantities of persistent and efficient trityl-nitroxide biradicals for different solvents.