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Claims for Patent: 4,647,447

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Claims for Patent: 4,647,447

Title: Diagnostic media
Abstract:A diagnostic medium contains at least one physiologically well tolerated complex salt comprising an anion of a complexing acid and one or more central ion or ions of an element with an atomic number of 21 to 29, 42, 44 or 57 to 83 and, optionally, one or more physiologically biocompatible cation or cations of an inorganic and/or organic base or amino acid, optionally, with additives customary in galenic formulations, dissolved or suspended in an aqueous medium.
Inventor(s): Gries; Heinz (Berlin, DE), Rosenberg; Douwe (Berlin, DE), Weinmann; Hanns-Joachim (Berlin, DE)
Assignee: Schering Aktiengesellschaft (Berlin and Bergkamen, DE)
Application Number:06/573,184
Patent Claims: 1. A method of performing an NMR diagnostic procedure in a patient in need of the same comprising administering to the patient an effective amount of an NMR diagnostic medium and then exposing the patient to an NMR measurement step to which the diagnostic medium is responsive thereby imaging at least a portion of the patient's body, wherein the diagnostic medium comprises a physiologically compatible salt of (a) an anion of a complexing acid and (b) at least one central ion of an element with an atomic number of 21 to 29, 42, 44 or 57 to 83 chelated therewith, wherein the salt is of the formula I or II ##STR8## or

wherein

X is --COOY, --PO.sub.3 HY or --CONHOY;

Y is a hydrogen atom, a metal ion equivalent or a physiologically biocompatible cation of an inorganic or organic base or amino acid;

A is --CHR.sub.2 --CHR.sub.3 --, --CH.sub.2 --CH.sub.2 --(ZCH.sub.2 --CH.sub.2).sub.m --, ##STR9## each R.sub.1 is a hydrogen atom or methyl; R.sub.2 and R.sub.3 together represent a trimethylene group or a tetramethylene group or individually are hydrogen, C.sub.1-8 -alkyl, phenyl or benzyl,

W is --NN--, --NHCOCH.sub.2 -- or --NHCS--;

m is the number 1, 2 or 3

Z is an oxygen atom, a sulfur atom, >NCH.sub.2 X, or >NCH.sub.2 CH.sub.2 OR.sub.4

R.sub.4 is C.sub.1-8 -alkyl

V is one of the X groups or is --CH.sub.2 OH, or --CONH(CH.sub.2).sub.n X,

n is a number from 1 to 12;

if R.sub.1, R.sub.2 and R.sub.3 are hydrogen atoms, both V's together are the group ##STR10## w is a number 1, 2 or 3; provided that at least two of the substituents Y are metal ion equivalents of an element with an atomic number of 21 to 29, 42, 44 or 57 to 83.

2. A method of claim 1 wherein the concentration of salt in the medium is 1 .mu.mole to 1 mole.

3. A method of claim 1 wherein the concentration of salt in the medium is 1 .mu.mole to 5 mmole.

4. A method of claim 1 wherein the concentration of salt in the medium is 250 mmole to 1 mole.

5. A method of claim 1 wherein the salt in the medium is the monosodium/mono-N-methylglucamine mixed salt of the gadolinium(III) complex of diethylenetriaminepentaacetic acid.

6. A method of claim 1 wherein the salt in the medium is the disodium salt of the gadolinium(III) complex of diethylenetriaminepentaacetic acid.

7. A method of claim 1 wherein the salt in the medium is the di-N-methylglucamine salt of the iron(III) complex of diethylenetriaminepentaacetic acid.

8. A method of claim 1 wherein the salt in the medium is the disodium salt of the iron (III) complex of diethylenetriaminepentaacetic acid.

9. A method of claim 1 wherein the salt in the medium is the disodium salt of the manganese(II) complex of diethylenetriaminepentaacetic acid.

10. A method of claim 1 wherein the salt in the medium is the di-N-methylglucamine salt of the bismuth(III) complex of diethylenetriaminepentaacetic acid.

11. A method of claim 1 wherein the salt in the medium is the di-N-methylglucamine salt of the manganese(II) complex of trans-1,2-cyclohexenediaminetetraacetic acid.

12. A method of claim 1 wherein the salt in the medium is the disodium salt of the ytterbium(III) complex of diethylenetriaminepentaacetic acid.

13. A method of claim 1 wherein the salt in the medium is the N-methylglucamine salt of the gadolinium(III) complex of 1,4,7,10-tetraazacyclododecanetetraacetic acid.

14. A method of claim 1 wherein the salt in the medium is the disodium salt of the manganese(II) complex of trans-1,2-cyclohenediaminetetraacetic acid.

15. A method of claim 1 wherein the salt in the medium is the disodium salt of the bismuth(III) complex of diethylenetriaminepentaacetic acid.

16. A method of claim 1 wherein the salt in the medium is the di-N-methyglucamine salt of the gadolinium(III) complex of 13,23-dioxo-15,18,21-tris-(carboxymethyl)-12,15,18,21,24-pentaazapentatria contanedioic acid.

17. A method of claim 1 wherein the salt in the medium is the sodium salt of the gadolinium(III) complex of 1,4,7,10-tetraazacyclododecanetetraacetic acid.

18. A method of claim 1 wherein the salt in the medium comprises liposomes charged with the gladolinium(III) complex of diethylenetriaminepentaacetic acid.

19. A method of claim 1 wherein the salt in the medium is the disodium salt of the holmium(III) complex of diethylenetriaminepentaacetic acid.

20. A method of claim 1 wherein the salt in the medium is the disodium salt of the lanthanum(III) complex of diethylenetriaminepentaacetic acid.

21. A method of claim 1 wherein the salt in the medium is the disodium salt of the di-N-methylglucamine salt of the ytterbium(III) complex of diethylenetriaminepentaacetic acid.

22. A method of claim 1 wherein the salt in the medium is the disodium salt of the sumarium(III) complex of diethylenetriaminepentaacetic acid.

23. A method of claim 1 wherein the salt in the medium is the disodium salt of the gadolinium(III) complex of 13,23-dioxo-15,18,21-tris-(carboxymethyl)-12,15,18,21,24-pentaazapentatria contanedioic acid.

24. In a method of imaging body tissue in a patient, comprising subjecting the patient to NMR tomography, the improvement comprising, prior to performing the NMR tomography, administering to the patient an effective amount of a pharmaceutical agent for affecting the relaxation times of atoms in body tissues undergoing NMR diagnosis, whereby image contrast is enhanced, said agent comprising an amount, effective to affect such relaxation times, of a paramagnetic, physiologically compatible salt of a physiologically compatible chelate complex of an ion of a lanthanide element of atomic numbers 57-70, or of a transition metal of atomic numbers 21-29, 42, or 44; and a pharmaceutically acceptable carrier.

25. A method of claim 24 wherein the concentration of said salt in the agent is 1 .mu.mole to 1 mole.

26. In a method of imaging body tissue in a patient, comprising subjecting the patient to NMR tomography, the improvement comprising, prior to performing the NMR tomography, administering to the patient an effective amount of a pharmaceutical agent for affecting the relaxation times of atoms in body tissues undergoing NMR diagnosis whereby image contrast is enhanced, said agent comprising an amount effective to affect such relaxation times of a paramagnetic, physiologically compatible salt of a complex of an ion and a ligand; and

a pharmaceutically acceptable carrier;

wherein the complexed ion is an ion of a lanthanide element of atomic numbers 57-70, or of a transition metal of atomic numbers 21-29, 42, or 44;

and wherein the ligand is that of a complexing agent which

(a) is an aminopolycarboxylic acid which is nitrilotriacetic acid, N-hydroxyethyl-N,N',N'-ethylenediaminetriacetic acid, N,N,N',N",N"-diethylenetriaminepentaacetic acid or N-hydroxyethyliminodiacetic acid;

(b) of the formula ##STR11## wherein R.sub.1 and R.sub.1 ' are identical or different and each is hydrogen or alkyl of 1-4 carbon atoms and p is an integer of 0-4; or

(c) an aminopolycarboxylic acid of the formula ##STR12## wherein m is an integer of 1 to 4,

n is an integer of 0 to 2, and

R.sub.5 is C.sub.4-12 -alkyl, C.sub.4-12 -alkenyl, C.sub.4-12 -cycloalkyl, C.sub.4-12 -cycloalkenyl, C.sub.7-12 -hydrocarbon aralkyl, C.sub.8-12 -hydrocarbon alkenyl, C.sub.6-12 -hydrocarbon aryl or --CH.sub.2 COOH.

27. A method of claim 26 wherein the administration is orally or intravasally and is performed about 15-60 minutes before performing the NMR tomography.

28. A method of claim 27 wherein the dosage of complex salt is 1-100 .mu.mol/kg intravenously.

29. A method of claim 26, wherein the pharmaceutical agent has a pH of 6.5-7.5.

30. A method of claim 26, wherein the pharmaceutical agent is blood isotonic.

31. A method of claim 26, wherein the pharmaceutical agent comprises the paramagnetic complex salt dissolved or suspended in water in a concentration of 5-250 mmol/l.

32. A method of claim 26, wherein in the pharmaceutical agent, the complex salt is a salt of the complexed ion with an inorganic or organic acid or base.

33. A method of claim 26, wherein in the pharmaceutical agent, the inorganic or organic acid or base is hydrochloric acid, sulfuric acid, acetic acid, citric acid, aspartic acid, glutamic acid, sodium hydroxide, glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, diethanolamine, morpholine, lysine, ornithine or arginine.

34. A method of claim 26, wherein in the pharmaceutical agent, the complexing agent is an aminopolycarboxylic acid which is nitrilotriacetic acid, N,N,N',N'-ethylenediaminetetraacetic acid, N-hydroxyethyl-N,N',N'-ethylenediaminetriacetic acid, N,N,N',N",N"-diethylenetriaminepentaacetic acid or N-hydroxyethyliminodiacetic acid.

35. A method of claim 26, wherein in the pharmaceutical agent, the complexing agent is of the formula ##STR13## wherein R.sub.1 and R.sub.1 ' are identical or different and each is hydrogen or alkyl of 1-4 carbon atoms and p is an integer of 0-4.

36. A method of claim 26, wherein in the pharmaceutical agent, the complexing agent is an aminopolycarboxylic acid of the formula ##STR14## wherein m is an integer of 1 to 4,

n is an integer of 0 to 2, and

R.sub.5 is C.sub.4-12 -alkyl, C.sub.4-12 -alkenyl, C.sub.4-12 -cycloalkyl, C.sub.4-12 -cycloalkenyl, C.sub.7-12 -hydrocarbon aralkyl, C.sub.8-12 -hydrocarbon alkenyl, C.sub.6-12 -hydrocarbon aryl or --CH.sub.2 COOH.

37. A method of claim 26, wherein in the pharmaceutical agent, the complexed ion is an ion of a lanthanide element of atomic numbers 57-70.

38. A method of claim 26, wherein in the pharmaceutical agent, the complexed ion is an ion of a transition metal of atomic numbers 21-29, 42, or 44.

39. A method of claim 34, wherein in the pharmaceutical agent, the complexed ion is an ion of a lanthanide element of atomic numbers 57-70.

40. A method of claim 34, wherein in the pharmaceutical agent, the complexed ion is an ion of a transition metal of atomic numbers 21-29, 42, or 44.

41. A method of claim 35, wherein in the pharmaceutical agent, the complexed ion is an ion of a lanthanide element of atomic numbers 57-70.

42. A method of claim 35, wherein in the pharmaceutical agent, the complexed ion is an ion of a transition metal of atomic numbers 21-29, 42, or 44.

43. A method of claim 36, wherein in the pharmaceutical agent, the complexed ion is an ion of a lanthanide element of atomic numbers 57-70.

44. A method of claim 36, wherein in the pharmaceutical agent, the complexed ion is an ion of a transition metal of atomic numbers 21-29, 42, or 44.

45. A method of claim 26, wherein in the pharmaceutical agent, the paramagnetic complex salt is the di-N-methylglucamine salt of the manganese(II) complex of ethylenediaminetetraacetic acid.

46. A method of claim 26, wherein in the pharmaceutical agent, the paramagnetic complex salt is the N-methylglucamine salt of the gadolinium(III) complex of ethylenediaminetetraacetic acid.

47. A method of claim 26, wherein in the pharmaceutical agent, the paramagnetic complex salt is the di-N-methylglucamine salt of the gadolinium(III) complex of diethylenetriaminepentaacetic acid.

48. A method of claim 26, wherein in the pharmaceutical agent, the paramagnetic complex salt is the di-N-methylglucamine salt of the dysprosium(III) complex of diethylenetriaminepentaacetic acid.

49. A method of claim 26, wherein in the pharmaceutical agent, the paramagnetic complex salt is the di-N-methylgucamine salt of the holmium(III) complex of diethylenetriaminepentaacetic acid.

50. A method of claim 26, wherein in the pharmaceutical agent, the paramagnetic complex salt is the disodium salt of the manganese(II) complex of ethylenediaminetetraacetic acid.

51. A method of claim 26, wherein in the pharmaceutical agent, the paramagnetic complex salt is the complex

52. A method of claim 26, wherein in the pharmaceutical agent, the paramagnetic complex salt is the N-methylglucamine salt of the gladolinium(III) complex of diethylenetriaminepentaacetic acid.

53. A method of claim 26, wherein in the pharmaceutical agent, the paramagnetic complex salt is the copper(II) chloride complex of 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane.

54. A method of claim 26 wherein in the pharmaceutical agent, the paramagnetic complex salt is the N-methylglucamine salt of the iron(II) complex of ethane-1-hydroxy-1,1-diphosphonic acid.

55. A method of claim 26, wherein in the pharmaceutical agent, the paramagnetic complex salt is the di-lysine salt of the gadolinium(III) complex of diethylenetriaminepentaacetic acid.

56. A method of claim 26, wherein in the pharmaceutical agent, the paramagnetic complex salt is the dimorpholine salt of the manganese(II) complex of ethylendediaminetetraacetic acid.

57. A method of claim 26, wherein in the pharmaceutical agent, the paramagnetic complex salt is the tri-diethanolamine salt of the manganese(II) complex of diethylenetriaminepentaacetic acid.

58. A method of claim 26, wherein in the pharmaceutical agent, the paramagnetic complex salt is the tri-N-methylglucamine salt of the manganese(II) complex of diethylenetriaminepentaacetic acid.

59. A method of claim 26, wherein in the pharmaceutical agent, the paramagnetic complex salt is the N-methylglucamine salt of the dysprosium(III) complex of ethylenediaminetetraacetic acid.

60. A method of claim 26, wherein in the pharmaceutical agent, the complex ion is gadolinium(III).

61. A method of claim 60, wherein in the pharmaceutical agent, the ligand is N,N,N',N",N"-diethylenetriaminepentaacetic acid.

62. A method of claim 61, wherein, in the pharmaceutical agent, the complex salt is a salt of the complexed ion with the cation of an inorganic base which is sodium or an organic base which is N-methylglucamine.

63. A method of claim 62, wherein in the pharmaceutical agent, said base is inorganic.

64. A method of claim 26, wherein in the pharmaceutical agent, the ligand is N,N,N',N",N"-diethylenetriaminepentaacetic acid.

65. In a method of imaging body tissue in a patient, comprising subjecting the patient to NMR tomography, the improvement comprising, prior to performing the NMR tomography, administering to the patient an effective amount of a pharmaceutical agent for affecting the relaxation times of atoms in body tissues undergoing NMR diagnosis, whereby image contrast is enhanced, said agent comprising an amount, effective to affect such relaxation times, of a paramagnetic, physiologically compatible salt of a complex of an ion and, as a ligand, an acyclic or cyclic complexing agent containing organic nitrogen, phosphorus, oxygen or sulfur, the complexed ion being an ion of a lanthanide element of atomic numbers 57-70, or of a transition metal of atomic numbers 21-29, 42, or 44; and a pharmaceutically acceptable carrier.

66. The method of claim 65 wherein the salt is the di-N-methylglucamine salt of the nickel (II) complex of ethylenediaminetetraacetic acid.

67. A method of claim 65 wherein the salt is the diethanolamine salt of the cobalt (II) complex of ethylenediaminetetraacetic acid.

68. A method of claim 65 wherein the salt is the di-diethanolamine salt of the copper (II) complex of ethylenediaminetetraacetic acid.
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