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Perfluoroalkyl-containing complexes with polar radicals, process for their production and their use

Imported: 24 Feb '17 | Published: 13 Jan '04

Johannes Platzek, Peter Mareski, Ulrich Niedballa, Bernd Raduechel, Hanns-Joachim Weinmann, Bernd Misselwitz

USPTO - Utility Patents

Abstract

Perfluoroalkyl-containing complexes with polar radicals of general formula I

(K)

1-G-(Z-R

f)

m(R)

p  (I)

in which R means the polar radical, R

f means a perfluorinated carbon chain, K is a metal complex, and Z represents a linker group,

are suitable for intravenous lymphography, for tumor diagnosis and for infarction and necrosis imaging.

Claims

1. Perfluoroalkyl-containing complexes with polar radicals of formula I

in which

in which

of fomuila III

in which R

1 has the above-mentioned meaning, R

4 is hydrogen or a metal ion equivalent that is mentioned under R

1, and U

1 represents —C

6H

4—O—CH

2--, whereby means the binding site to —CO—, or of formula IV

in which R

1 and R

2 have the above-mentioned meaning

or of formula V A of V B

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 has the above-mentioned meaning, and

whereby is the binding site of G to complex K, is the binding site of G to radical R and represents the binding site of G to radical Z,

2. Metal complexes according to claim 1, wherein metal ion equivalent R

1 in radical K is an element of atomic numbers 21-29, 39, 42, 44 or 57-83.

3. Metal complexes according to claim 1, wherein metal ion equivalent R

1 in radical K is an element of atomic numbers 27, 29, 31-33, 37-39, 43, 49, 62, 64, 70, 75 and 773.

4. Metal complexes according to claim 1, wherein K is a metal complex of formula II, III, VB or VII.

5. Metal complexes according to claim 1, wherein polar radical R has the meaning of complex K.

6. Metal complexes according to claim 5, wherein polar radical R is one of complexes K of formulas II, III, VA or VII.

7. Metal complexes according to claim 5, wherein R

1 is a metal ion equivalent of atomic numbers 20, 25 or 64.

8. Metal complexes according to claim 1, wherein polar radical R has one of the following meanings:

9. Metal complexes according to claim 1, wherein polar radical R is the folic acid radical.

10. Metal complexes according to claim 1, wherein G in formula I is a lysine radical (a) or (b).

11. Metal complexes according to claim 1, wherein U in metal complex K represents the group —CH

2— or —C

6H

4—O—CH

2-, whereby stands for the binding site to —CO—.

12. A method for the production of contrast media for use in NMR diagnosis or x-ray diagnosis, which comprises formulating a metal complex of claim 2 into a form suitable for NMR diagnosis or x-ray diagnosis.

13. A method for the production of contrast media for infarction or necrosis imaging, which comprises formulating a metal complex of claim 2 into a form suitable for infarction or necrosis imaging.

14. A method for the production of contrast media for use in radiodiagnosis or radiotherapy, which comprises formulating a metal complex of claim 3 into a form suitable for radiodiagnosis or radiotherapy.

15. A method for the production of contrast media for lymphography in the diagnosis of changes in the lymphatic system, which comprises formulating a metal complex of claim 2 into a form suitable for lympography.

16. A method for the production of contrast media for use in indirect lymphography, which comprises formulating a metal complex of claim 2 into a form suitable for indirect lympography.

17. A method for the production of contrast media for use in intravenous lymphography, which comprises formulating a metal complex of claim 2 into a form suitable for intravenous lympography.

18. A method for the production of contrast media for visualizing the vascular space, which comprises formulating a metal complex of claim 2 into a form suitable for visualizing the vascular space.

19. A method for the production of contrast media for tumor imaging, which comprises formulating a metal complex of claim 2 into a form suitable for tumor imaging.

20. A pharmaceutical composition comprising at least one physiologically compatible metal complex according to claim 1, optionally with the additives that are commonly used in galenicals.

21. Process for the production of perfluoroalkyl-containing complexes with polar radicals of formula I of claim 1:

in which K, G, R, Z, R

f, l, m and p have the meaning that is indicated in claim 1, which comprises reacting a carboxylic acid of formula IIa

in which R

5 is a metal ion eqiuvalent 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 abovementioned 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, optionally activated form, with an amine of formula VIII

in which G, R, Z, R

f, m and p have the indicated meaning, in a coupling reaction and optionally subsequently cleaving optionally present protective groups to provide a metal complex of formula I, or

22. Metal complexes according to claim 1, wherein polar radical R has one of the following meanings:

—C(O)CH

2O[(CH

2)

2O]

4—CH

3.

23. A metal complex according to claim 1, wherein metal ion equivalent R

1 is a gadolinium(III), terbium(III), dysprosium(III), holmium(III), erbium(III), iron(III) or manganese(II) ion.

24. A metal complex according to claim 1, wherein K is of formula II, III, VB or VII.

25. A metal complex according to claim 1, wherein R

2 and R

3, independently of one another, hydrogen or C

1-C

4 alkyl.

26. A metal complex according to claim 1, wherein R

2 is methyl and R

3 is hydrogen.

27. A metal complex according to claim 1, wherein Rf is —C

nF

2n+1, where n is a number from 4-15.

28. A metal complex according to claim 1, wherein Rf is —C

4F

9, —C

6F

13, —C

8F

17, C

12F

25 or —C

14F

29.

29. A composition of claim 20, wherein the composition contains 0.1 mol-2 mol/l of the metal complex.