Novel compositions magnetic particles covered with gem-bisphosphonate derivatives

Abstract

The invention relates to a composition comprising acid magnetic particles (p) based on an iron compound, the acid magnetic particles (p) being complexed by one or more gem-bisphosphonate compounds, of formula I: X-L-CH(PO 3 H 2 ) 2   (I) in which: L represents an organic group connecting the X group to the gem-bisphosphonate group —CH(PO 3 H 2 ) 2 ; X represents a chemical group capable of reacting with a biovector; all or some of the X groups of the particles optionally being coupled to a biovector. The invention relates also to a process for the preparation of the compositions and their use, in particular as contrast products for Magnetic Resonance Imaging (MRI).

1 - 49 . (canceled) 
     
     
         50 . In a method of medical magnetic resonance imaging, for the diagnosis or monitoring of a patient condition, comprising administering a composition to a patient, the improvement wherein the composition comprises acid magnetic particles (p) based on an iron compound, the acid magnetic particles (p) being complexed by one or more gem-bisphosphonate compounds of formula I:
   X-L-CH(PO 3 H 2 ) 2    (I)   
       in which
 L represents an organic group connecting the X group to gem-bisphosphonate group —CH(PO 3 H 2 ) 2  and 
 X represents a chemical group capable of reacting with a biovector and all or some of the X groups of the particles optionally being coupled to a biovector. 
 
     
     
         51 . The method of  claim 50 , in which all or some of the X groups are coupled to a biovector. 
     
     
         52 . The method of  claim 50 , in which L is selected from the group consisting of aliphatic, alicyclic, aromatic, alicyclic-aliphatic, aromatic-aliphatic, and -L 1 -NHCO-L 2  where L 1  and L 2  are identical or different and individually represent an aliphatic, alicyclic, aromatic, alicyclic-aliphatic, or aromatic-aliphatic group, and wherein each of L, L 1 , and L 2  is optionally substituted by a methyl, hydroxyl, methoxy, acetoxy, or amido group or a chlorine, iodine, or bromine atom. 
     
     
         53 . The method of  claim 50 , in which L represents an optionally substituted phenylene group, and wherein the X and gem-bisphosphonate groups are in the ortho, meta, or para position. 
     
     
         54 . The method of  claim 50 , in which L represents an aliphatic group. 
     
     
         55 . The method of  claim 50 , in which L represents a group
   —(CH 2 ) p ,   
       where p is an integer from 1 to 5. 
     
     
         56 . The method of  claim 50  in which L represents
   L 1 -CONH-L 2 ,   
       where L 1  and L 2  are either identical or different and individually represent an aliphatic, alicyclic, aromatic, alicyclic-aliphatic or aromatic-aliphatic group, it being optionally possible for the groups to be substituted by methyl, hydroxyl, methoxy, acetoxy, amido group or a chlorine, iodine or bromine atom. 
     
     
         57 . The method of  claim 50 , in which L represents a group
   —(CH 2 ) m —CONH—(CH 2 ) n      
       where m and n individually represent an integer from 0 to 5. 
     
     
         58 . The method of  claim 50 , in which X is selected from the group consisting of —COOH, —NH 2 , —NCS, —NH—NH 2 , —CHO, maleimidyl, alkylpyrocarbonyl, acylazidyl, iminocarbonate, vinylsulfuryl, pyridyldisulfuryl, haloacetyl, dichlorotriazinyl, and halogen. 
     
     
         59 . The method of  claim 50 , in which X represents —COOH or —NH 2 . 
     
     
         60 . The method of  claim 50 , in which all or some of the compounds of formula (I) have the formula (Ia)
   HOOC—(CH 2 ) 2 —CH(PO 3 H 2 ) 2    (Ia).   
     
     
         61 . The method of  claim 50 , in which the particles (p) are, on average, complexed on at least 90% of their protonated sites by compounds of formula (I). 
     
     
         62 . The method of  claim 50 , in which the protonated sites are complexed by at least two gem-bisphosphonate compounds of formula (I) having a different structure. 
     
     
         63 . The method of  claim 50 , in which the protonated sites are complexed by at least two compounds of formula (I) having an identical structure. 
     
     
         64 . The method of  claim 50  in which all or some of the magnetic particles (p) are composed of iron hydroxide, iron hydroxide hydrate, ferrite, mixed iron oxides, or a mixture thereof. 
     
     
         65 . The composition of  claim 50 , in which all or some of the magnetic particles (p) are composed of a ferrite. 
     
     
         66 . The method of  claim 50 , in which all or some of the magnetic particles (p) are composed of maghemite, magnetite, or a mixture thereof. 
     
     
         67 . The method of  claim 50 , in which the particles (p) are superparamagnetic. 
     
     
         68 . The method of  claim 50 , in which between 1 and 70% of the X groups of compounds of formula (I) are coupled to a biovector. 
     
     
         69 . The method of  claim 50 , in which the X groups of compounds of formula (I) are coupled to at least two different biovectors. 
     
     
         70 . The method of  claim 50 , in which the biovector is selected from proteins, optionally recombinant or mutated, glycoproteins, lectins, biotin, vitamins, phospholipids, folic acid derivatives, antibodies or antibody fragments, peptides and derivatives thereof, monosaccharides or polysaccharides, avidin, streptavidin, receptor substrates or inhibitors, steroids and analogs thereof, oligonucleotides, ribonucleic acid sequences, deoxyribonucleic acid sequences, hormones or hormone-like substances, amino acids and derivatives, organic molecules with pharmacological activity, amino alcohols, integrin-targeting agents and MMP-targeting agents. 
     
     
         71 . The method of  claim 50 , in which the biovector represents a peptide derivative. 
     
     
         72 . The method of  claim 50 , in which the biovector represents an antifolic or folic acid derivative. 
     
     
         73 . The method of  claim 50 , in which the biovector represents a phospholipid derivative. 
     
     
         74 . The method of  claim 50 , in which the biovector represents a phospholipid derivative selected from the group consisting of a phosphatidylserine derivative, phosphatidylethanolamine derivative, phosphatidylcholine derivative, phosphatidylinositol derivative, sphingomyelin derivative, or ceramide derivative. 
     
     
         75 . The method of  claim 50 , in which the biovector represents a protein, optionally recombinant or mutated. 
     
     
         76 . The method of  claim 50 , in which the biovector represents an antibody or an antibody fragment which is optionally functionalized. 
     
     
         77 . The method of  claim 50 , in which the biovector represents an optionally functionalized pharmacophore. 
     
     
         78 . The method of  claim 50 , in which the biovector is selected from the amino alcohols of formula (II) 
       
         
           
           
               
               
           
         
       
       in which R 1  and R 2  are identical or different and represent an aliphatic hydrocarbon chain comprising from 2 to 6 carbon atoms, preferably substituted by 6 to 10 hydroxyl groups, or else by 4 to 8 hydroxyl groups when R 1  and/or R 2  is interrupted by an oxygen atom. 
     
     
         79 . The method of  claim 50 , in which the biovector is selected from aminopolyethylene glycols. 
     
     
         80 . The method as claimed in  claim 78 , in which the biovector is selected from the amino alcohols of general formula (II) 
       
         
           
           
               
               
           
         
       
       in which R 1  represents a group —(CH 2 )—(CHOH) 4 —CH 2 OH or —(CH 2 )—CHOH—CH 2 OH and R 2  represents a group —CH 2 —(CHOH) 4 —CH 2 OH. 
     
     
         81 . The method of  claim 50 , in which the X groups form a covalent bond with the biovector, of type —CONH—, —COO—, —NHCO—, —OCO, —NH—CS—NH—, —C—S—, —N—NH—CO—, —CO—NH—N—, —CH 2 —NH—, —N—CH 2 —, —N—CS—N—, —CO—CH 2 —S—, —N—CO—CH 2 —S—, —N—CO—CH 2 —CH 2 —S, —CH═NH—NH—, —NH—NH═CH—, —CH═N—O— or —O—N═CH—, and also the formulae below 
       
         
           
           
               
               
           
         
       
     
     
         82 . The method of  claim 50 , in which the particles complexed and coupled to the biovector have an overall hydrodynamic diameter of between 5 nm and 200 nm. 
     
     
         83 . The method of  claim 50 , in which the concentration of the particles (p) in the composition is between 2 μmol L −1  and 4 mol L −1 , expressed as total number of moles of metal ions. 
     
     
         84 . The method of  claim 50 , wherein the composition further comprises one or more pharmaceutically acceptable vehicles and/or additives. 
     
     
         85 . The method of  claim 50 , wherein the composition is sterile. 
     
     
         86 . The method of  claim 50 , for the diagnosis or monitoring of a pathology selected from the group consisting of cardiovascular disease, cancer, inflammatory disease, and degenerative disease.