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.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein
 X 1  is O, C(R 6 R 7 ), NR 8 , S; 
 X 2  is O, SO 2 , or —NR 9 , CH 2 ; 
 X 3  is C or N with the proviso that when X 3  is N, then R 5  is not present in the molecule; 
 R 5 , R 6 , R 7 , R 8  and R 9  are, independently, H; a substituted or unsubstituted, linear, branched or cyclic C 1-6  aliphatic group; —(CH 2 ) n —COOH with n being an integer from 1 to 10, —OH, —NH 2 ,—N 3 , —C≡CH, P(O)(OH) 2 , P(O)(OR 11 ) 2 , P(O)R 11   2 , SSO 2 Me, —(CH 2 —CH 2 —O) 3 —CH 3  or —(CH 2 —CH 2 —O) m —H with m being an integer from 1 to 500, preferably from 1 to 100, more preferably from 1 to 10, or 
 
       
       
         
           
           
               
               
           
         
          with p being an integer from 0 to 7 and q an integer from 1 to 500;
 Q 1  is a cyclic or acyclic nitroxide radical, as represented below 
 
       
       
         
           
           
               
               
           
         
         wherein
 R 1  and R 2  are, independently, a substituted or unsubstituted, linear, branched or cyclic C 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 10 —, P(O)(OR 11 ) 2  and P(O)(R 11 ) 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 1  and R 2  are joined, as indicated by 
 
       
       
         
           
           
               
               
           
         
         
            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 11 ) 2 , P(O)(R 11 ) 2 , O, S, N + −O − , NH, N(C 1 -C 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 1  or R 2  together do not contain more than one hydrogen alpha to the (N—O.) group; 
 
           R 10  is hydrogen, hydroxyl; substituted or unsubstituted linear, branched or cyclic C 1-6  alkyl; C 1-6  alkylcarbonyl; substituted or unsubstituted aryl sulfinyl; or substituted or unsubstituted aryl sulfonyl; 
           R 11  is linear or branched C 1-18  alkyl, H or an alkali metal; and
 wherein the point of attachment of the X 2  atom by a single bond, as indicated by 
 
         
       
       
         
           
           
               
               
           
         
         
           
              is to a primary or secondary non-olefinic or aromatic carbon atom of either R 1  or R 2 , or to a carbon atom of the 5- to 8-membered heterocyclic ring formed by the joining of R 1  and R 2 ; 
           
         
         R 3  or R 4  is linked to the double bond C═X 3  in the compound of formula (I) as represented above, wherein R 3  and R 4  are, independently, a substituted or unsubstituted, linear, branched or cyclic C 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 10 —, P(O)(OR 11 ) 2  and P(O)(R 11 ) 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 3  and R 4  are joined, through the double bond C═X 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 11 ) 2 , P(O)(R 11 ) 2 , O, S, N ± —O − , NH, N(C 1 -C 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 3  or R 4  together do not contain more than one hydrogen alpha to the (N—O.) group; 
 with the proviso that the compound of formula 
 
       
       
         
           
           
               
               
           
         
       
       is excluded. 
     
     
         2 . The compound according to  claim 1 , wherein Q 1  is a cyclic nitroxide radical, as represented below 
       
         
           
           
               
               
           
         
         wherein
 R 1  and R 2  are joined, as indicated by 
 
       
       
         
           
           
               
               
           
         
         
            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 11 ) 2 , P(O)(R 11 ) 2 ,O, S, N ± −O − , NH, N(C 1 -C 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 1  or R 2  together do not contain more than one hydrogen alpha to the (N—O.) group; and 
 
           R 11  is linear or branched C 1-18  alkyl, H or an alkali metal. 
         
       
     
     
         3 . The compound according to  claim 1 , wherein Q 1  is, 
       
         
           
           
               
               
           
         
         with M being an alkali metal selected in the group consisting of lithium (Li), sodium (Na), potassium (K), rubidium (Rb) and cesium (Cs), 
       
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of formula (I) according to  claim 1 , wherein Q 1  is an acyclic nitroxide radical, as represented below 
       
         
           
           
               
               
           
         
         wherein
 R 1  and R 2  are, independently, a substituted or unsubstituted, linear, branched or cyclic C 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 10 —, P(O)(OR 11 ) and P(O)(R 11 ); substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; 
 or substituted or unsubstituted 2,2,7,7-tetraethyl isoindolinoxyl; 
 R 10  is hydrogen, hydroxyl; substituted or unsubstituted linear, branched or cyclic C 1-6  alkyl; C 1-6  alkyl carbonyl; substituted or unsubstituted aryl sulfinyl; or substituted or unsubstituted aryl sulfonyl; 
 R 11  is linear or branched C 1-18  alkyl, H or an alkali metal; 
 
         with the proviso that the two groups R 1  or R 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 3  and R 4  are joined, through the double bond C═X 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 11 ) 2 , P(O)(R 11 ) 2 , O, S, N±—O − , NH, N(C 1 -C 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 3  as defined in  claim 1  and with the proviso that the two groups R 3  or R 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 3  and R 4  are joined and form together with the nitrogen atom to which they are bound a 5-membered heterocyclic ring selected from 
       
         
           
           
               
               
           
         
         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 2  is O or —NR 9  wherein R 9  is H; a substituted or unsubstituted, linear, branched or cyclic C 1-6  alkyl group; —(CH 2 ) n —COOH with n being an integer from 1 to 10, —(CH 2 —CH 2 —O).—CH 3  or —(CH 2 —CH 2 —O) 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 2  is O or —NR 9  wherein R 9  is H, a linear or branched C 1-6  alkyl, —(CH 2 —CH 2 —O) m —CH 3  with m being 1 to 10. 
     
     
         9 . The compound of formula (I) according to  claim 1 , wherein it is represented as below 
       
         
           
           
               
               
           
         
         with X 2  as defined in any one of the preceding claims; 
         with the proviso that the compound of formula 
       
       
         
           
           
               
               
           
         
         is excluded. 
       
     
     
         10 . The compound of formula (I) according to  claim 1 , wherein it is represented as below: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of formula (I) according to  claim 1 , wherein it is represented as below: 
       
         
           
           
               
               
           
         
       
     
     
         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.