DINITROXIDE BIRADICAL COMPOUNDS AS POLARIZING AGENTS

Abstract

The present invention relates to novel organic dinitroxide biradical compounds and their use as polarizing agents, in particular, in the techniques of Nuclear Magnetic Resonance (NMR) of solids or liquid samples and medical imaging.

Claims

1. A compound of formula (I) ##STR00050## wherein X.sub.1 is O, C(R.sup.6R.sup.7), NR.sup.8, S; X.sub.2 is O, SO.sub.2, or —NR.sup.9, CH.sub.2; X.sub.3 is C or N with the proviso that when X.sub.3 is N, then R.sup.5 is not present in the molecule; R.sup.5, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are, independently, H; a substituted or unsubstituted, linear, branched or cyclic C.sub.1-6 aliphatic group; —(CH.sub.2).sub.n—COOH with n being an integer from 1 to 10, —OH, —NH.sub.2,—N.sub.3, —C≡CH, P(O)(OH).sub.2, P(O)(OR.sup.11).sub.2, P(O)R.sup.11.sub.2, SSO.sub.2Me, —(CH.sub.2—CH.sub.2—O).sub.3—CH.sub.3 or —(CH.sub.2—CH.sub.2—O).sub.m—H with m being an integer from 1 to 500, preferably from 1 to 100, more preferably from 1 to 10, or ##STR00051##  with p being an integer from 0 to 7 and q an integer from 1 to 500; Q.sub.1 is a cyclic or acyclic nitroxide radical, as represented below ##STR00052## wherein R.sup.1 and R.sup.2 are, independently, a substituted or unsubstituted, linear, branched or cyclic C.sub.1-6 aliphatic group; a substituted or unsubstituted linear, branched or cyclic hetero-aliphatic group comprising 5 carbon atoms and one heteroatom or heteroatomic group, respectively, selected from O,S, —NR.sup.10—, P(O)(OR.sup.11).sub.2 and P(O)(R.sup.11).sub.2; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl, or substituted or unsubstituted 2,2,7,7-tetramethyl isoindolinoxyl; substituted or unsubstituted 2,2,7,7-tetraethyl isoindolinoxyl; or R.sup.1 and R.sup.2 are joined, as indicated by ##STR00053##  to form together with the nitrogen atom to which they are bound a 5- to 8-membered heterocyclic ring and which may contain an additional heteroatom or heteroatomic group selected from P(O)(OR.sup.11).sub.2, P(O)(R.sup.11).sub.2, O, S, N.sup.+−O.sup.−, NH, N(C.sub.1-C.sub.6 alkyl) wherein the alkyl is straight, branched or cyclic, wherein the heterocyclic ring bears from one substituent to the maximum number of substituent on the carbon atoms and optionally contains one double bond; and with the proviso that the two groups R.sup.1 or R.sup.2 together do not contain more than one hydrogen alpha to the (N—O.) group; R.sup.10 is hydrogen, hydroxyl; substituted or unsubstituted linear, branched or cyclic C.sub.1-6 alkyl; C.sub.1-6 alkylcarbonyl; substituted or unsubstituted aryl sulfinyl; or substituted or unsubstituted aryl sulfonyl; R.sup.11 is linear or branched C.sub.1-18 alkyl, H or an alkali metal; and wherein the point of attachment of the X.sub.2 atom by a single bond, as indicated by ##STR00054##  is to a primary or secondary non-olefinic or aromatic carbon atom of either R.sup.1 or R.sup.2, or to a carbon atom of the 5- to 8-membered heterocyclic ring formed by the joining of R.sup.1 and R.sup.2; R.sup.3 or R.sup.4 is linked to the double bond C═X.sub.3 in the compound of formula (I) as represented above, wherein R.sup.3 and R.sup.4 are, independently, a substituted or unsubstituted, linear, branched or cyclic C.sub.1-6 aliphatic group; a substituted or unsubstituted linear, branched or cyclic hetero-aliphatic group comprising 5 carbon atoms and one heteroatom or heteroatomic group, respectively, selected from O,S, —NR.sup.10—, P(O)(OR.sup.11).sub.2 and P(O)(R.sup.11).sub.2; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl, or substituted or unsubstituted 2,2,7,7 -tetramethyl isoindolinoxyl; substituted or unsubstituted 2,2,7,7-tetraethyl isoindolinoxyl; or R.sup.3 and R.sup.4 are joined, through the double bond C═X.sub.3 to form together with the nitrogen atom to which they are bound a 5- to 8-membered heterocyclic ring and which may contain an additional heteroatom or heteroatomic group selected from P(O)(OR.sup.11).sub.2, P(O)(R.sup.11).sub.2, O, S, N.sup.±—O.sup.−, NH, N(C.sub.1-C.sub.6 alkyl) wherein the alkyl is straight, branched or cyclic, wherein the heterocyclic ring bears from one substituent to the maximum number of substituent on the carbon atoms and optionally contains one double bond; and with the proviso that the two groups R.sup.3 or R.sup.4 together do not contain more than one hydrogen alpha to the (N—O.) group; with the proviso that the compound of formula ##STR00055## is excluded.

2. The compound according to claim 1, wherein Q.sub.1 is a cyclic nitroxide radical, as represented below ##STR00056## wherein R.sup.1 and R.sup.2 are joined, as indicated by ##STR00057##  to form together with the nitrogen atom to which they are bound a 5- to 8-membered heterocyclic ring and which may contain an additional heteroatom or heteroatomic group selected from P(O)(OR.sup.11).sub.2, P(O)(R.sup.11).sub.2,O, S, N.sup.±−O.sup.−, NH, N(C.sub.1-C.sub.6 alkyl) wherein the alkyl is straight, branched or cyclic, wherein the heterocyclic ring bears from one substituent to the maximum number of substituent on the carbon atoms and optionally contains one double bond; and with the proviso that the two groups R.sup.1 or R.sup.2 together do not contain more than one hydrogen alpha to the (N—O.) group; and R.sup.11 is linear or branched C.sub.1-18 alkyl, H or an alkali metal.

3. The compound according to claim 1, wherein Q.sub.1 is, ##STR00058## with M being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K), rubidium (Rb) and cesium (Cs), ##STR00059##

4. The compound of formula (I) according to claim 1, wherein Q.sub.1 is an acyclic nitroxide radical, as represented below ##STR00060## wherein R.sup.1 and R.sup.2 are, independently, a substituted or unsubstituted, linear, branched or cyclic C.sub.1-6 aliphatic group; a substituted or unsubstituted linear, branched or cyclic hetero-aliphatic group comprising 5 carbon atoms and one heteroatom or heteroatomic group, respectively, selected from O,S, —NR.sup.10—, P(O)(OR.sup.11) and P(O)(R.sup.11); substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or substituted or unsubstituted 2,2,7,7-tetraethyl isoindolinoxyl; R.sup.10 is hydrogen, hydroxyl; substituted or unsubstituted linear, branched or cyclic C.sub.1-6 alkyl; C.sub.1-6 alkyl carbonyl; substituted or unsubstituted aryl sulfinyl; or substituted or unsubstituted aryl sulfonyl; R.sup.11 is linear or branched C.sub.1-18 alkyl, H or an alkali metal; with the proviso that the two groups R.sup.1 or R.sup.2 together do not contain more than one hydrogen alpha to the (N—O.) group.

5. The compound of formula (I) according to claim 1, wherein R.sup.3 and R.sup.4 are joined, through the double bond C═X.sub.3 to form together with the nitrogen atom to which they are bound a 5- to 8-membered heterocyclic ring and which may contain an additional heteroatom or heteroatomic group selected from P(O)(OR.sup.11).sub.2, P(O)(R.sup.11).sub.2, O, S, N±—O.sup.−, NH, N(C.sub.1-C.sub.6 alkyl) wherein the alkyl is straight, branched or cyclic, wherein the heterocyclic ring bears from one substituent to the maximum number of substituent on the carbon atoms and optionally contains one double bond; with X.sub.3 as defined in claim 1 and with the proviso that the two groups R.sup.3 or R.sup.4 together do not contain more than one hydrogen alpha to the (N—O.) group.

6. The compound of formula (I) according to claim 1, wherein R.sup.3 and R.sup.4 are joined and form together with the nitrogen atom to which they are bound a 5-membered heterocyclic ring selected from ##STR00061## wherein M is an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K), rubidium (Rb) and cesium (Cs). Preferably, M is lithium (Li), sodium (Na) or potassium (K).

7. The compound of formula (I) according to claim 1, wherein X.sub.2 is O or —NR.sup.9 wherein R.sup.9 is H; a substituted or unsubstituted, linear, branched or cyclic C.sub.1-6 alkyl group; —(CH.sub.2).sub.n—COOH with n being an integer from 1 to 10, —(CH.sub.2—CH.sub.2—O).—CH.sub.3 or —(CH.sub.2—CH.sub.2—O).sub.m—H with m being an integer from 1 to 500, preferably from 1 to 100, more preferably from 1 to

10.

8. The compound of formula (I) according to claim 1, wherein X.sub.2 is O or —NR.sup.9 wherein R.sup.9 is H, a linear or branched C.sub.1-6 alkyl, —(CH.sub.2—CH.sub.2—O).sub.m—CH.sub.3 with m being 1 to 10.

9. The compound of formula (I) according to claim 1, wherein it is represented as below ##STR00062## with X.sub.2 as defined in any one of the preceding claims; with the proviso that the compound of formula ##STR00063## is excluded.

10. The compound of formula (I) according to claim 1, wherein it is represented as below: ##STR00064##

11. The compound of formula (I) according to claim 1, wherein it is represented as below: ##STR00065##

12. Use of at least one compound of formula (I) according to claim 1 as a polarizing agent.

13. The use of at least one compound of formula (I) according to claim 1 in the techniques of structural biology, Nuclear Magnetic Resonance (NMR) of solids or applied to liquid samples, particle physics, and medical imaging.

14. A method for polarizing a compound in a sample for Dynamic Nuclear Polarization comprising contacting said sample with at least one compound of formula (I) according to claim 1.

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

Description

FIGURES

[0169] FIG. 1 represents the EPR spectrum of Compound 3, in CH.sub.2Cl.sub.2 (1 mM) at 25° C.

[0170] FIG. 2 represents the .sup.1H-NMR of Compound 3 in CDCl.sub.3.

[0171] FIG. 3 represents the HPLC chromatogram of Compound 3.

[0172] FIG. 4 represents the EPR spectrum of Compound 5, in CH.sub.2Cl.sub.2 (1 mM) at 25° C.

[0173] FIG. 5 represents the .sup.1H-NMR of Compound 5 in CDCI.sub.3.

[0174] FIG. 6 represents the HPLC chromatogram of Compound 5.

[0175] FIG. 7 represents the EPR spectrum of Compound 7, in CH.sub.2Cl.sub.2 (1 mM) at 25° C.

[0176] FIG. 8 represents the .sup.1H-NMR of Compound 7 in CDC.sub.3.

[0177] FIG. 9 represents the HPLC chromatogram of Compound 7.

[0178] FIG. 10 represents the .sup.1H-NMR of Compound 9 in D.sub.2O.

[0179] FIG. 11 represents the EPR spectrum of Compound 10, in water (1 mM) at 25° C.

[0180] FIG. 12 represents the .sup.1H-NMR of Compound 10, in D.sub.2O.

[0181] FIG. 13 represents the HPLC chromatogram of Compound 10.

[0182] FIG. 14 represents the .sup.1H-NMR of Compound 13 in CDCl.sub.3.

[0183] FIG. 15 represents the EPR spectrum of Compound 14, in water (1 mM) at 25° C.

[0184] FIG. 16 represents the .sup.1H-NMR of Compound 14 in in D.sub.2O.

[0185] FIG. 17 represents the HPLC chromatogram of Compound 14.

EXAMPLES

1/Synthesis of the AsymPol Biradical Family

[0186] Chemicals were purchased primarily from the Sigma-Aldrich Chemical Company and Acros and were used without further purification. Dichloromethane, acetonitrile and pyridine were freshly distilled over calcium hydride before use; triethylamine was purchased anhydrous and stored over potassium hydroxide pellets. Thin layer chromatography (TLC) was performed on glass backed TLC plates with extra hard layer (Kieselgel 60 F.sub.254, 250 μm, Silicycle) and compounds were visualized by UV light. Silica gel (230-400 mesh, 60 Å) was purchased from Silicycle, and used for flash chromatography. .sup.1H and .sup.13C NMR spectra were recorded at the frequencies stated, using deuterated solvents as internal standards. 400 MHz spectra were recorded on a Bruker Advance 400 spectrometer. Residual proton signals from the deuterated solvents were used as references [D.sub.2O (4.81 ppm), <d.sub.6-DMSO (2.50 ppm), chloroform (7.26 ppm), <d.sub.4-MeOH (4.84 and 3.31 ppm)] for .sup.1H spectra. The residual .sup.13C signals from the deuterated solvents being used as references [J6-DMSO (39.7 ppm), chloroform (77.0 ppm), <d.sub.4-MeOH (49.05 ppm)] for .sup.13C spectra. All coupling constants were measured in Hertz. All moisture sensitive reactions were carried out in oven-dried glassware using nitrogen or argon from standard BOC industrial cylinders, dried through an activated silica column. Molecular mass of the new organic compounds was determined by HR-ESI/ESI-MS (Bruker, MicroTof-Q). Purity of 3, 5, 10 and 14 were analysed on GL Sciences Inertsustain C18 4.6×150 mm analytical column with UV detection at 254 nm on Beckman Coulter Gold HPLC system. Analytical HPLC run (Flow rate=1 mL/min): Solvent A, 0.1% TFA in water; Solvent B, MeOH; 8 min linear gradient from 0% to 100% B, 2 min linear gradient from 100% to 0% B (initial conditions; 100% A).

##STR00043##

[0187] Compound 3: To a solution of 2 (K. Oyaizu, T. Kawamoto, T. Suga and H. Nishide, Macromolecules, 2010, 43, 10382-10389) (0.032 g, 0.175 mmol) in CH.sub.2Cl.sub.2 (4 mL) was added DCC (0.039 g, 0.192 mmol), HOBt (0.053 g, 0.35 mmol) and triethyl amine (0.073 mL, 0.525 mmol) under an inert atmosphere of argon. After stirring for 15 minutes, 1 (G. M. Rosen, J. Med. Chem., 1974, 17, 358-360) (0.03 g, 0.175 mmol) was added. The resulting solution was stirred for 12 hours at 25° C., diluted with CH.sub.2Cl.sub.2 (10 mL) and washed successively with sat. aqueous solution of NaHCO.sub.3 (10 mL) and brine (10 mL). The organic layer was concentrated in vacuo and the crude product was purified by flash column chromatography (silica) using a gradient elution (EtOAc: petroleum ether; 0: 100 to 30:70) to give 3 (0.049 g, 83% yield) as a yellow solid.

[0188] TLC (Silica gel, 10% MeOH in CH.sub.2Cl.sub.2), R.sub.f(1)=0.2, R.sub.f(2)=0.8, R.sub.f(3)=0.9, PMA active.

[0189] (Silica gel, 2.5% MeOH in CH.sub.2Cl.sub.2), R.sub.f(3)=0.3

[0190] .sup.1H-NMR (CDCl.sub.3): Compound 3 is a nitroxide biradical and hence, shows broadening of peaks. Therefore, integration of the NMR peaks in NMR spectra was not performed.

[0191] LCMS: calculated for C.sub.18H.sub.31N.sub.3O.sub.3: 337.2365, found 339.2520 (M+2H) .sup.2+.

##STR00044##

[0192] Compound 5: To a solution of 2 (K. Oyaizu, T. Kawamoto, T. Suga and H. Nishide, Macromolecules, 2010, 43, 10382-10389) (0.03 g, 0.162 mmol) in CH.sub.2Cl.sub.2 (4 mL) was added DCC (0.037 g, 0.18 mmol), HOBt (0.049 g, 0.32 mmol) and triethyl amine (0.07 mL, 0.495 mmol) under an inert atmosphere of argon. After stirring for 15 minutes, 4 (G. M. Rosen, J. Med. Chem., 1974, 17, 358-360) (0.03 g, 0.162 mmol) was added. The resulting solution was stirred for 12 hours at 25° C., diluted with CH.sub.2Cl.sub.2 (10 mL) and washed successively with sat. aqueous solution of NaHCO.sub.3 (10 mL) and brine (10 mL). The organic layer was concentrated in vacuo and the crude product which was purified by flash column chromatography (silica) using a gradient elution (EtOAc: petroleum ether; 0:100 to 35:65) to give 5 (0.051 g, 91% yield) as a yellow solid.

[0193] TLC (Silica gel, 40% EtOAc in pet ether), R.sub.f(2)=0.3, R.sub.f(5)=0.2, PMA active.

[0194] .sup.1H-NMR (CDCl.sub.3): Compound 5 is a nitroxide biradical and hence, shows broadening of peaks. Therefore, integration of the NMR peaks in NMR spectra was not performed.

[0195] LCMS: calculated for C.sub.19H.sub.33N.sub.3O.sub.3: 351.2522, found 353.2673 (M+2H).sup.2+.

##STR00045##

[0196] Compound 7: To a solution of 2 (K. Oyaizu, T. Kawamoto, T. Suga and H. Nishide, Macromolecules, 2010, 43, 10382-10389) (0.06 g, 0.326 mmol) in THF (6 mL) was added DCC (0.087 g, 0.423 mmol), HOBt (0.057 g, 0.423 mmol) and DMAP (0.23 g, 0.195 mmol) under an inert atmosphere of argon. After stirring for 15 minutes, 6 (0.068 g, 0.390 mmol) was added. The resulting solution was stirred for 12 hours at 25° C. Solvent was removed under vacuo. The residue was diluted with CH.sub.2Cl.sub.2 (10 mL) and washed successively with sat. aqueous solution of NaHCO.sub.3 (10 mL) and brine (10 mL). The organic layer was concentrated in vacuo and the crude product which was purified by flash column chromatography (silica) using a gradient elution (EtOAc: petroleum ether; 0: 100 to 20:80) to give 7 (0.048 g, 43% yield) as a yellow solid.

[0197] TLC (Silica gel, 20% EtOAc in pet ether), R.sub.f(2)=0.3, R.sub.f(7)=0.2, PMA active.

[0198] .sup.1H-NMR (CDCl.sub.3): Compound 7 is a nitroxide biradical and hence, shows broadening of peaks. Therefore, integration of the NMR peaks in NMR spectra was not performed.

[0199] HRMS: calculated for C.sub.18H.sub.30N.sub.2O.sub.4: 338.4480, found 361.2096 (M+Na).sup.+.

##STR00046##

[0200] Compound 9: To a solution of 2 (K. Oyaizu, T. Kawamoto, T. Suga and H. Nishide, Macromolecules, 2010, 43, 10382-10389) (0.005 g, 0.029 mmol) in CH.sub.2Cl.sub.2 (3 mL) was added DCC (0.006 g, 0.32 mmol), HOBt (0.009 g, 0.059 mmol) and triethylamine (0.013 mL, 0.088 mmol) under an inert atmosphere of argon. After stirring for 15 minutes, 8 (A. P. Jagtap, M. A. Geiger, D. Stoppler, M. Orwick-Rydmark, H. Oschkinat and S. T. Sigurdsson, Chem. Commun., 2016, 52, 7020-7023) (0.015 g, 0.029 mmol) was added. The resulting solution was stirred for 12 hours at 25° C. The reaction mixture was diluted with CH.sub.2Cl.sub.2 (10 mL) and washed successively with sat. aqueous solution of NaHCO.sub.3 (10 mL) and brine (10 mL). The organic layer was concentrated in vacuo and the crude product which was purified by flash column chromatography (silica) using a gradient elution (EtOAc: petroleum ether; 0:100 to 30:70) to give 9 (0.011 g, 58% yield) as a yellow solid.

[0201] TLC (Silica gel, 3% Me0H in CH.sub.2Cl.sub.2), R.sub.f(2)=0.3, R.sub.f(9)=0.6, PMA active.

[0202] .sup.1H-NMR (CDCl.sub.3): Compound 9 is a nitroxide biradical and hence, shows broadening of peaks. Therefore, integration of the NMR peaks in NMR spectra was not performed.

[0203] HRMS: calculated for C.sub.36H.sub.67N.sub.3O.sub.5Si.sub.2: 677.4619, found 700.4505 (M+Na).sup.+.

##STR00047##

[0204] Compound 10: TBAF (0.8 mL, 0.778 mmol, 1 M in THF) was added to a solution of 9 (0.088 g, 0.130 mmol) in anhydrous THF (4 mL). The resulting solution was heated at 60° C. for 12 hours, cooled down and the solvent removed in vacuo. The residue was dissolved in MeOH (4 mL) and DOWEX (0.50 g) and CaCO.sub.3 (0.165 g) were added. The resulting suspension was stirred at for 12 hours at 27° C. The reaction mixture was filtered through a bed of celite, the filtrate concentrated under vacuo and the crude product was purified by flash column chromatography (silica) using a gradient elution (MeOH: CH.sub.2Cl.sub.2; 0:100 to 10:90) to give 10 (0.034 g, 49% yield) as a yellow solid.

[0205] TLC (Silica gel, 10% MeOH in CH.sub.2Cl.sub.2), R.sub.f(12)=1, R.sub.f(10)=0.1, PMA active.

[0206] .sup.1H-NMR (D.sub.2O): Compound 10 is a nitroxide biradical and hence, shows broadening of peaks. Therefore, integration of the NMR peaks in NMR spectra was not performed.

[0207] HRMS: calculated for C.sub.24H.sub.39N.sub.3O.sub.5: 449.2890, found 472.2774 (M+Na).sup.+.

##STR00048##

[0208] Compound 13: To a solution of 10 (0.045 g, 0.10 mmol) in CH.sub.3CN (4 mL) was added 11 (0.058 g, 0.3 mmol) and 12 (0.053 g, 0.35 mmol) under an inert atmosphere of argon. After stirring for 2 hours at 27° C., tBuOOH (0.384 mL, 3.2 mmol, 75% in water) was added. The resulting solution was stirred for 30 minutes at 25° C. The solvent was removed under vacuo, the residue obtained was diluted with CH.sub.2Cl.sub.2 (10 mL) and washed successively with sat. aqueous solution of NaHCO.sub.3 (10 mL) and brine (10 mL). The organic layer was concentrated in vacuo and the crude product was purified by flash column chromatography (silica) using a gradient elution (MeOH: CH.sub.2C12; 0:100 to 3:97) to give 13 (0.028 g, 35% yield) as a yellow solid.

[0209] TLC (Silica gel, 10% MeOH in CH.sub.2Cl.sub.2), R.sub.f(10)=0.4, R.sub.f(13)=0.6, PMA active.

[0210] .sup.1H-NMR (CDCl.sub.3): Compound 13 is a nitroxide biradical and hence, shows broadening of peaks. Therefore, integration of the NMR peaks in NMR spectra was not performed.

[0211] .sup.31P-NMR (CDCl.sub.3): -3.74, -4.35

[0212] HRMS: calculated for C.sub.36H.sub.53N.sub.7O.sub.11P.sub.2: 821.3278, found 844.3172 (M+Na).

##STR00049##

[0213] Compound 14: To a solution of 13 (0.045 g, 0.0739 mmol) in H.sub.2O (2 mL) was added triethylamine (0.3 mL, 2.143 mmol). The resulting solution was stirred for 12 hours at 60° C. The solvent was removed in vacuo. The residue was diluted with H.sub.2O (2 mL) and KOH (0.018 g, 0.325 mmol) was added. The resulting solution was stirred for 12 hours at 60 ° C. The solvent was removed in vacuo to give 14 (0.038 g, 68%>yield) as a yellow solid.

[0214] TLC (Silica gel, 10% MeOH in CH.sub.2Cl.sub.2), R.sub.f(13)=0.6, R.sub.f(14)=O,PMA active.

[0215] .sup.1H-NMR (D20): Compound 14 is a nitroxide biradical and hence, shows broadening of peaks. Therefore, integration of the NMR peaks in NMR spectra was not performed.

[0216] .sup.31P-NMR (D20): −3.23

[0217] HRMS: calculated for C.sub.24H.sub.41N.sub.3O.sub.11P.sub.2: 609.2216, found 630.1948 (M+Na−2H)

2/ Sensitivity of the Compounds According to the Invention Under DNP Conditions

[0218] The table below compares the sensitivity gain (ϵ.sub.B/√{square root over (T.sub.B.sup.T)}.sup.+ ) obtained with compound according to the invention, AsymPol, AsymPolPOK and AMUPol which is currently considered as one of the best performing polarizing agent for MAS-DNP experiments.

TABLE-US-00001 TABLE 1 Experimental parameters that characterize the DNP performance of AsymPol and AsymPolPOK, with a comparison to AMUPol. Buildup Time DNP sensitivity DNP gain T.sub.B .sup.εon/off ε.sub.B .Math. T.sub.B(MAS).sub.−1/2 ε.sub.B.sub.(MAS).sub.− Static MAS Static MAS 9.4 T AMUPol.sup.[a] 27 s.sup. −1/2 43 16.3 s 2.5 s 28 151 AsymPol.sup.[b] 39 s.sup. −1/2 30 1.0 s 0.6 s 11 32 AsymPolPOK.sup.[a] 68 s.sup. −1/2 83 3.5 s 1.5 s 25 105 .sup.[a]10 mM biradical in d.sub.8-glycerol/D.sub.2O/H.sub.20 (6:3:1; v:v) with 20 mM .sup.13C-urea, 10 kHz MAS rate, at 105K and 9.4 T. .sup.[b]same as [a] but 10 mM biradical in d.sub.6- DMSO/D.sub.2O/H.sub.2O(8:1:1; v:v). .sup.[c]same as [a] but at −130K and 8 kHz MAS rate using a 3.2 mm rotor.

[0219] It appears clearly from these results that the use of AsymPol biradicals provides a significant increase in DNP sensitivity compared to AMUPol. These results also illustrate the limits of relying solely on Bon Off to evaluate polarizing agent's efficiency.

3/ Characteristics of the Compounds According to the Invention

[0220] Table 2 compares certain characteristics of the known polarizing agents, i.e. TOTAPOL, AMUPol and TEKPol.

TABLE-US-00002 TABLE 2 AMUPol TEKPol (« b Turea » (« bTbK » Characteristics AsymPol TOTAPOL family) family) Spin interaction intense moderate moderate to moderate intense Relative rigid flexible rigid very rigid orientations of the g tensor Amplification important moderate important to important factor ε.sub.on/off (for very to very 10 mM biradicals) important important Depolarization weak moderate strong moderate strength (almost to strong absent Polarization speed very sast slow fast moderate Sensitivity gain very high moderate moderate to moderate to important important Efficiency at high good weak weak to weak MAS frequency moderate (>20 kHz)

[0221] The table above illustrates the reason for which the polarizing agents proposed up now offer modest performances (especially at high spinning frequencies).