Perfluoroalkyl-Containing Complexes, Process For Their Production As Well As Their Use

Abstract

The invention relates to the subjects that are characterized in the claims, namely perfluoroalkyl-containing metal complexes with nitrogen-containing radicals of general formula I, process for their production and their use in NMR and x-ray diagnosis, radiodiagnosis, and radiotherapy, as well as in MRT lymphography and in blood-pool imaging.

1 - 22 . (canceled) 
     
     
         23 . A perfluoroalkyl-containing complexes with a nitrogen-containing linker structure of formula I 
       
         
           
           
               
               
           
         
       
       in which
 R represents a monosaccharide or oligosaccharide radical that is bonded via the 1-OH,
 in which case Q is one of the following groups
 δ-CO—(CH 2 ) n″ -ε 
 δ-NH—(CH 2 ) n″ -ε 
 δ-(CH) m -ε 
 
 wherein 
 n″ is an integer from 1 and 5, and 
 m is an integer from 1 and 6, and 
 wherein δ indicates the binding site to linker L, and ε represents the binding site to radical R; 
 
 or 
 R is case Q has the meaning of a direct bond, means a polar radical that is selected from
 the complexes K of formulas II to V, wherein R 1  here means a hydrogen atom or a metal ion equivalent of the atomic numbers 20-29, 31-33, 37-39, 42-44, 49 or 57-83, 
 
 or
 a carbon chain with 1-30 C atoms that is bonded via —CO—, —NR 7 — or a direct bond to linker L,
 which can be straight or branched, saturated or unsaturated, and which 
 optionally is interrupted by 1-10 oxygen atoms, 1-5 —NHCO groups, 1-5 —CONH groups, 1-2 sulfur atoms, 1-5 —NH groups or 1-2 phenylene groups, which optionally can be substituted by 1-2—OH groups, 1-2 —NH 2  groups, 1-2 —COOH groups, or 1-2 —SO 3 H groups, and which 
 optionally is substituted by 1-10 —OH groups, 1-5 —COOH groups, 1-2 SO 3 H groups, 1-5 —NH 2  groups, or 1-5 C 1 -C 4 -alkoxy groups, 
 
 
 R 7  means H or C 1 -C 4 -alkyl, 
 R f  is a perfluorinated, straight-chain or branched carbon chain with the formula —C n F 2n E, in which E represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom, and n stands for the numbers 4-30, 
 K stands for a metal complex of formula II, 
 
       
         
           
           
               
               
           
         
       
       in which
 R 1  means a hydrogen atom or a metal ion equivalent of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83,
 provided that at least two R 1  stand for metal ion equivalents, 
 
 R 2  and R 3 , independently of one another, represent hydrogen, C 1 -C 7 -alkyl, benzyl, phenyl, —CH 2 OH or —CH 2 OCH 3 , and 
 U stands for —C 6 H 4 —O—CH 2 -ω-, —(CH 2 ) 1-5 -ω, a phenylene group, —CH 2 —NHCO—CH 2 —CH(CH 2 COOH)—C 6 H 4 -ω-, —C 6 H 4 —(OCH 2 CH 2 ) 0-1 —N(CH 2 COOH)—CH 2 -ω or a C 1 -C 12 -alkylene or —(CH 2 ) 7-12 —C 6 H 4 —O group that optionally is interrupted by one or more oxygen atoms, 1 to 3 —NHCO groups, or 1 to 3 —CONH groups and/or is substituted by 1 to 3 —(CH 2 ) 0-5 COOH groups, wherein ω stands for the binding site to —CO—, 
 or of formula III 
 
       
         
           
           
               
               
           
         
         in which R 1  has the above-mentioned meaning, R 4  represents hydrogen or a metal ion equivalent that is mentioned under R 1 , and U 1  represents —C 6 H 4 —O—CH 2 -ω- or a group —(CH 2 ) p —, wherein ω means the binding site to —CO— and p 1  is an integer between 1 and 4, 
         or of formula IV 
       
       
         
           
           
               
               
           
         
         in which R 1  and R 2  have the above-mentioned meaning 
         or of formula VA or VB 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         in which R 1  has the above-mentioned meaning, 
         or of formula VI 
       
       
         
           
           
               
               
           
         
         in which R 1  has the above-mentioned meaning, 
         or of formula VII 
       
       
         
           
           
               
               
           
         
         in which R 1  and U 1  have the above-mentioned meaning, whereby ω means the binding site to —CO—, 
         or of formula VIII 
       
       
         
           
           
               
               
           
         
         in which R 1  has the above-mentioned meaning, 
         and U 2  represents a straight-chain or branched, saturated or unsaturated C 1 -C 20  alkylene group that optionally contains imino, phenylene, phenylenoxy, phenylenimino, amide, hydrazide, carbonyl, ester group(s), oxygen, sulfur and/or nitrogen atom(s) and that optionally is substituted by hydroxy, mercapto, oxo, thioxo, carboxy, carboxyalkyl, ester and/or amino group(s), 
         and free acid groups, optionally present in radical K, can optionally be present as salts of organic and/or inorganic bases or amino acids or amino acid amides, 
         and L represents a radical that is selected from radicals IXa) to IXc) below: 
       
       
         
           
           
               
               
           
         
         wherein n′ and m′, independently of one another, represent an integer between 0 and 4, and m′+n′≧1, and 
         R 8  and R 8′ , independently of one another, are either —H or —OH, wherein with m′+n′>1, each group —(CR 8 R 8′ )— can be the same or different, and 
         W is either a direct bond, —O— or a phenylene group, which optionally can be substituted by 1 to 4 hydroxy groups, 
         and q′ is 1, 2, 3 or 4, 
         wherein α means the binding site of L to complex K, β is the binding site of L to radical Q, and γ represents the binding site of L to radical X, 
         and 
         X stands for a group of formula (VI)
   ρ-Y—(CH 2 ) s -(G) t -(CH 2 ) s′ -ζ  (X) 
 
         wherein Y means a direct bond, a group —O— or a group NR 6 , 
         wherein R 6  stands for —H or a straight or branched, saturated or unsaturated C 1 -C 15  carbon chain, which can be interrupted by 1-4 O atoms, 1-3 —NHCO groups, 1-3 —CONH groups, 1-2 —SO 2  groups, 1-2 sulfur atoms, 1-3 —NH groups or 1-2 phenylene groups,
 which optionally can be substituted by 1-2 OH groups, 1-2 NH 2  groups, 1-2 —COOH groups or 1-2 —SO 3 H groups, 
 and which optionally is substituted by 1-10 OH groups, 1-5 —COOH groups, 1-2 —SO 3 H groups, 1-5 NH 2  groups, or 1-5 C 1 -C 4 -alkoxy groups, 
 
         and G means either —O— or —SO 2 —,
 s and s′, independently of one another, mean 1 or 2, 
 t means 0 or 1 and 
 ρ represents the binding site of X to L and ξ represents the binding site of X to R f . 
 
       
     
     
         24 . A metal complex according to  claim 23 , wherein the metal ion equivalent R 1  is an element of atomic numbers 21-29, 39, 42, 44 or 57-83. 
     
     
         25 . A metal complex according to  claim 23 , wherein the metal ion equivalent R 1  is an element of atomic numbers 27, 29, 31-33, 37-39, 43, 49, 62, 64, 70, 75 or 77. 
     
     
         26 . A metal complex according to  claim 23 , wherein R represents a monosaccharide radical with 5 to 6 C atoms or its deoxy compound. 
     
     
         27 . A metal complex according to  claim 23 , wherein R is one of the following radicals
 C(O)CH 2 O[(CH 2 ) 2 O] p R′   C(O)CH 2 OCH[CH 2 OCH(CH 2 OR′) 2 ] 2      C(O)CH 2 OCH 2 CH[CH 2 OCH(CH 2 OR′) 2 ] 2      R″N[(CH 2 ) 2 O] p R′   N{[(CH 2 ) 2 O] p R′} 2      R″NCH 2 CH(OH)CH 2 OH   N[CH 2 CH(OH)CH 2 OH] 2      R″NCH(CH 2 OH)CH(OH)CH 2 OH   N[CH(CH 2 OH)CH(OH)CH 2 OH] 2      R″NCH[CH 2 OCH(CH 2 OR′) 2 ] 2      R″NCH 2 CH[CH 2 OCH(CH 2 OR′) 2 ] 2      R″NCH 2 CH 2 OCH[CH 2 OCH(CH 2 OR′) 2 ] 2      R″NCH 2 CH 2 OCH 2 CH[CH 2 OCH(CH 2 OR′) 2 ] 2      N{CH[CH 2 OCH(CH 2 OR′) 2 ] 2 } 2      N{CH 2 CH[CH 2 OCH(CH 2 OR′) 2 ] 2 } 2      R″NCH 2 CH(OH)CH(OH)CH(OH)CH(OH)CH 2 OH   N[CH 2 CH(OH)CH(OH)CH(OH)CH(OH)CH 2 OH] 2      and a complex of formula (II),   
       wherein p is 1, 2, 3, 4, 5, 6, 7, 8 or 9. 
     
     
         28 . A metal complex according to  claim 23 , wherein K stands for a metal complex of formula II. 
     
     
         29 . A metal complex according to  claim 28 , wherein R 2  and R 3 , independently of one another, mean hydrogen or C 1 -C 4 -alkyl. 
     
     
         30 . A metal complex according to  claim 23 , wherein E means a fluorine atom in the formula —C n F 2n F. 
     
     
         31 . A metal complex according to  claim 23 , wherein L in formula I represents the lysine radical (Vc). 
     
     
         32 . A metal complex according to  claim 23 , wherein L in formula I represents a diamine radical (Va) or (Vb). 
     
     
         33 . A metal complex according to  claim 23 , wherein U represents —CH 2 — or —C 6 H 4 —O—CH 2 -ω in metal complex K, wherein ω stands for the binding site to —CO—. 
     
     
         34 . A method for NMR or x-ray diagnosis, comprising administering to a subject undergoing NM or x-ray diagnosis an effective amount of a contrast media comprising a metal complex according to  claim 24 . 
     
     
         35 . A method according to  claim 34 , which is for infarction or necrosis imaging. 
     
     
         36 . A method for radiodiagnosis or radiotherapy, comprising administering to a subject undergoing radiodiagnosis or radiotherapy an effective amount of a contrast media comprising a metal complex according to  claim 25 . 
     
     
         37 . A method for lymphography for diagnosis of changes in the lymphatic system, comprising administering to a subject undergoing lymphography for diagnosis of changes in the lymphatic system an effective amount of a contrast media comprising a metal complex according to  claim 25 . 
     
     
         38 . A method for the diagnosis of an inflammatory disease, comprising administering to a subject undergoing diagnosis of an inflammatory disease an effective amount of a contrast media comprising a metal complex according to  claim 24 . 
     
     
         39 . A method for visualizing arteriosclerotic plaque, comprising administering to a subject undergoing visualization of an arteriosclerotic plaque an effective amount of a contrast media comprising a metal complex according to  claim 24 . 
     
     
         40 . A method for diagnosis of a cardiovascular disease, comprising administering to a subject undergoing diagnosis of a cardiovascular disease an effective amount of a contrast media comprising a metal complex according to  claim 24 . 
     
     
         41 . A method for tumor imaging, comprising administering to a subject undergoing tumor imaging an effective amount of a contrast media comprising a metal complex according to  claim 24 . 
     
     
         42 . A method for blood-pool imaging, comprising administering to a subject undergoing blood-pool imaging an effective amount of a contrast media comprising a metal complex according to  claim 24 . 
     
     
         43 . A pharmaceutical composition comprising a metal complex according to  claim 23 , and a galenically acceptable additive or carrier. 
     
     
         44 . A process for preparing a perfluoroalkyl-containing complex with a nitrogen-containing linker structure of formula I 
       
         
           
           
               
               
           
         
         with K in the meaning of a metal complex of one of formulas II to IV comprising reacting a carboxylic acid of formula IIa 
       
       
         
           
           
               
               
           
         
         in which R 5  means a metal ion equivalent of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83 or a carboxyl protective group, and R 2 , R 3  and U have the above-mentioned meaning, 
       
       or a carboxylic acid of formula IIIa 
       
         
           
           
               
               
           
         
         in which R 4 , R 5  and U 1  have the above-mentioned meaning, or a carboxylic acid of formula IVa 
       
       
         
           
           
               
               
           
         
         in which R 5  and R 2  have the above-mentioned meaning, 
       
       or a carboxylic acid of formula Va or Vb 
       
         
           
           
               
               
           
         
         in which R 5  has the above-mentioned meaning, 
       
       or a carboxylic acid of formula VIa 
       
         
           
           
               
               
           
         
         in which R 5  has the above-mentioned meaning, 
       
       or a carboxylic acid of formula VIIa 
       
         
           
           
               
               
           
         
         in which R 5  and U 1  have the above-mentioned meanings, 
         or a carboxylic acid of formula VIIIa 
       
       
         
           
           
               
               
           
         
         in which R 5  has the above-mentioned meanings, 
         and U 2  is defined as above, 
       
       in optionally activated form with an amine of formula X 
       
         
           
           
               
               
           
         
         in which L, R, R f , Q and X have the meaning indicated above, in a coupling reaction and optionally subsequent cleavage of optionally present protective groups to form a metal complex of formula I 
         or 
         if R 5  has the meaning of a protective group, cleaving these protective groups and reacting with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83, 
       
       and then, optionally present acidic hydrogen atoms are substituted by cations of inorganic and/or organic bases, amino acids or amino acid amides.