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Claims for Patent: 5,130,120

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Claims for Patent: 5,130,120

Title: Paramagnetic DTPA and EDTA alkoxyalkylamide complexes as MRI agents
Abstract:Novel magnetic resonance imaging agents and methods which utilize complexes of paramagnetic ions with alkoxyalkylamide derivatives of diethylenetriaminepentaacetic acid ("DTPA") or ethylenediaminetetraacetic acid ("EDTA"). These novel imaging agents are characterized by excellent NMR image-contrasting properties and by high solubilities in physiological solutions. The complexes are represented by the following formula: ##STR1## wherein A is --CH.sub.2 CH.sub.2 -- or ##STR2## and M.sup.+z is a paramagnetic ion of an element with an atomic number of 21-29, 42-44 or 58-70, and a valence, Z, of 2 or 3; the R groups may be the same or different and are selected from the group consisting of -O.sup..crclbar. and lower alkoxyalkylamino groups having from 2 to about 6 carbon atoms, wherein the number of R groups -O.sup..crclbar. equals Z and the remaining R groups are lower alkoxyalkylamino, equal to 4-Z when A is --CH.sub.2 CH.sub.2 --, or 5-Z when A ##STR3##
Inventor(s): Weber; Robert W. (Downingtown, PA)
Assignee: Mallinckrodt Medical, Inc. (St. Louis, MO)
Application Number:07/221,425
Patent Claims: 1. A complex having the following formula: ##STR7## wherein A is selected from the group consisting of --CH.sub.2 CH.sub.2 -- and ##STR8## wherein M.sup.+z is a paramagnetic ion of an element with an atomic number of 21-29, 42-44 or 58-70, and a valence, Z, of 2 or 3; the R groups may be the same or different and are selected from the group consisting of -O.sup..crclbar. and lower alkoxyalkylamino groups having from 2 to about 6 carbon atoms, the number of R groups -O.sup..crclbar. equals Z and the remaining R groups are lower alkoxyalkylamino, equal to 4- Z when A is --CH.sub.2 CH.sub.2 --, or 5 - Z when Z is ##STR9## .

2. The complex of claim 1, wherein A is ##STR10##

3. The complex of claim 1, wherein A is --CH.sub.2 CH.sub.2 --.

4. The complex of claim 2 or 3, wherein R is an alkoxyalkylamino, wherein the alkoxy portions contains 1 or 2 carbon atoms and the alkyl portion contains from about 2 to about 5 carbon atoms.

5. The complex of claim 2 or 3 wherein R is methoxyethylamino, methoxypropylamino, methoxybutylamino, methoxypentylamino, ethoxyethylamino, ethoxypropylamino or ethoxybutylamino.

6. The complex of claim 4, wherein M.sup.+z is chromium (III), manganese (II), manganese (III), iron (III), iron (II), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), terbium (III), dysprosium (III), holmium (III) or erbium (III).

7. The complex of claim 5, wherein M.sup.+z is gadolinium (III), terbium (III), dysprosium (III), holmium (III) or erbium (III).

8. The complex of claim 2, wherein R is methoxyethylamino and M.sup.+z is gadolinium (III).

9. A diagnositc composition suitable for enteral or parenteral administration to a warm-blooded animal, which comprises an NMR imaging-effective amount of a complex of a paramagnetic ion having the following formula: ##STR11## wherein A is selected from the group consisting of --CH.sub.2 CH.sub.2 -- and ##STR12## wherein M.sup.+z is a paramagnetic ion of an element with an atomic number of 21-29, 42-44 or 58-70, and a valence, Z, of 2 or 3; the R groups may be the same or different and are selected from the group consisting of --O.sup..crclbar. and lower alkoxyalkylamino groups having from 2 to about 6 carbon atoms, the number of R groups --O.sup..crclbar. equals Z and the remaining R groups are lower alkoxyalkylamino, equal to 4-Z when A is --CH.sub.2 CH.sub.2 --, or 5-Z when Z is ##STR13## and a pharmaceutically acceptable carrier.

10. The composition of claim 9, wherein A is ##STR14##

11. The composition of claim 9, wherein A is --CH.sub.2 CH.sub.2 --.

12. The composition of claim 10 or 11, which is suitable for parenteral administration, wherein R is an alkoxyalkylamino, in which the alkoxy portions contains 1 or 2 carbon atoms and the alkyl portion contains from about 2 to about 5 carbon atoms, and the complex is dissolved or suspended in a sterile aqueous pharmaceutically acceptable carrier at a concentration of from about 0.05 to 1.0M.

13. The composition of claim 12, wherein R is methoxypropylamino, methoxybutylamino, methoxyethylamino, ethoxyethylamino, methoxypentylamino, ethoxypropylamino or ethoxybutylamino, and wherein the concentration of the complex in the composition is from about 0.05 to about 1.0M.

14. The composition of claim 13, wherein M.sup.+z is chromium (III), manganese (II), manganese (III), iron (III), iron (II), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), terbium (III), dysprosium (III), holmium (III) or erbium (III).

15. The composition of claim 13, wherein M.sup.+z is gadolinium (III), terbium (III), dysprosium (III), holmium (III) or erbium (III).

16. The composition of claim 15, wherein R is methoxyethylamino and M.sup.+z is gadolinium (III).

17. The composition of claim 13, which further contains a pharmaceutically acceptable buffer.

18. The composition of claim 12, which further contains a pharmaceutically acceptable electrolyte.

19. The composition of claim 11, which further comprises a stoichiometric excess of a complexing agent of the formula ##STR15## wherein A and R are as defined as in claim 11.

20. The composition of claim 19, wherein said excess complexing agent is complexed with a physiologically acceptable, non-toxic cation.

21. The composition of claim 20, wherein said excess complexing agent is employed in an amount ranging from about 0.1 to about 15 mole % excess, relative to the paramagnetic ion, and is complexed with a cation selected from the group consisting of calcium ions, magnesium ions, copper ions and zinc ions.

22. The composition of claim 21, wherein said excess complexing agent is complexed with calcium ions.

23. A method of performing an NMR diagnostic procedure, which comprises administering to a warm-blooded animal an effective amount of a complex of the formula ##STR16## wherein A is selected from the group consisting of ##STR17## wherein M.sup.+z is a paramagnetic ion of an element with an atomic number of 21-29, 42-44 or 58-70, and a valence, Z, of 2 or 3; the R groups may be the same or different and are selected from the group consisting of --O.sup..crclbar. and lower alkoxyalkylamino groups having from 2 to about 6 carbon atoms, wherein the number of R groups --O.sup..crclbar. equals Z and the remaining R groups are lower alkoxyalkylamino, equal to 4-Z when A is --CH.sub.2 CH.sub.2 --, or 5-Z when A is ##STR18## and then exposing the animal to an NMR imaging procedure, thereby imaging at least a portion of the body of the warm-blooded anmial.

24. The method of claim 23, wherein A is ##STR19##

25. The method of claim 23, wherein A is -CH.sub.2 CH.sub.2 --.

26. The method of claim 24 or 25, wherein the complex is administered parenterally and wherein R is an alkoxyalkylamino, in which the alkoxy portions contains 1 or 2 carbon atoms and the alkyl portion contains from about 2 to about 5 carbon atoms, and the complex is dissolved or suspended in a sterile aqueous pharmaceutically acceptable carrier at a concentration of from about 0.05 to 1.0M.

27. The method of claim 26, wherein R is methoxypropylamino, methoxybutylamino, methoxyethylamino, ethoxyethylamino, methoxypentylamino, ethoxypropylamino or ethoxybutylamino, and wherein the concentration of the complex in the pharmaceutically acceptable carrier is from about 0.05 to about 1.0M.

28. The method of claim 27, wherein M.sup.+z is chromium (III), manganese (II), manganese (III), iron (III), iron (II), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), terbium (III), dysprosium (III), holmium (III) or erbium (III).

29. The method of claim 27, wherein M.sup.+z is gadolinium (III), terbium (III), dysprosium (III), holmium (III) or erbium (III).

30. The method of claim 27, wherein R is methoxyethylamino and M.sup.+z is gadolinium (III).

31. The method of claim 27, wherein the pharmaceutically acceptable carrier contains a pharmaceutically acceptable buffer.

32. The method of claim 27, wherein the pharmaceutically acceptable carrier contains a pharmaceutically acceptable electrolyte.

33. The method of claim 27, wherein the pharmaceutically acceptable carrier contains a stoichiometric excess of a complexing agent of the formula ##STR20## wherein A and R are as defined as in claim 27.

34. The method of claim 33, wherein said excess complexing agent is complexed with a physiologically acceptable, non-toxic cation.

35. The method of claim 34, wherein said excess complexing agent is employed in an amount ranging from about 0.1 to about 15 mole % excess, relative to the paramagnetic ion, and is complexed with a cation selected from the group consisting of calcium ions, magnesium ions, copper ions and zinc ions.

36. The method of claim 35, wherein said excess complexing agent is complexed with calcium ions.

37. A complexing agent of the formula: ##STR21## wherein A is selected from the group consisting of --CH.sub.2 CH.sub.2 -- and ##STR22## wherein the complexing agent has a valence, Z, of 2 or 3; the R groups may be the same or different and are selected from the group consisting of --O.sup..crclbar. and lower alkoxyalkylamino groups having from 3 to about 6 carbon atoms, wherein the number R groups --O.sup..crclbar. equals Z and the remaining R groups are lower alkoxyalkylamino, equal to 4-Z when A is --CH.sub.2 CH.sub.2 --, or 5-Z when Z is ##STR23##

38. The complexing agent of claim 37, wherein A is ##STR24##

39. The complexing agent of claim 37, wherein A is --CH.sub.2 CH.sub.2 --.

40. The complexing agent of claim 38 or 39, wherein R is an alkoxyalkylamino, in which the alkoxy portions contains 1 or 2 carbon atoms and the alkyl portion contains from about 2 to about 5 carbon atoms.

41. The complexing agent of claim 40, wherein R is methoxyethylamino, methoxypropylamino, methoxybutylamino, methoxypentylamino, ethoxyethylamino, ethoxypropylamino or ethoxybutylamino.
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