Claims for Patent: 5,137,711

Summary for Patent: 5,137,711

Title:	Paramagnetic DTPA and EDTA alkoxyalkylamide complexes as MRI agents
Abstract:	Novel magnetic resonance imaging agents methods utilize complexes of paramagnetic ions with alkoxyalkylamide deriviatives of diethylenetriaminepentaacetic acid ("DTPA") or ethylenediaminetetyraacetic 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 number, Z, of 2 or 3; R.sup.1 is --O.sup.- or R.sup.3 --N--R.sup.2, R.sup.2 is --(CH.sub.2 CH.sub.2 O).sub.n --R.sup.4, n is 1-10, R.sup.4 is alkyl or aryl, R.sup.3 is H, R.sup.2, alkyl, hydroxy, alkoxy, cycloalkyl or aryl, wherein Z of the R.sup.1 groups are --O.sup.- and the remainder of the R.sup.1 groups are R.sup.2 -N--R.sup.3 groups.
Inventor(s):	Weber; Robert W. (Downingtown, PA), Periasamy; Muthunadar P. (Creve Coeur, MO)
Assignee:	Mallickrodt Medical, Inc. (St. Louis, MO)
Application Number:	07/377,491
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## and M.sup.+Z is a paramagentic ion of an element with an atomic number of 21-29, 42-44 or 58-70, and a valence number, Z, or 2 or 3; the R.sup.1 groups may be the same or different and are selected from the group consisting of --O.sup.- and ##STR9## wherein R.sup.2 is --(CH.sub.2 CH.sub.2 O).sub.n --R.sup.4 wherein n is 1-10 and R.sup.4 is alkyl having 1 to 8 carbon atoms or aryl, unsubstituted or substituted with hydroxy and R.sup.3 is H, R.sup.2, alkyl having from 1 to 8 carbon atoms, hydroxy, alkoxy having 1-8 carbon atoms, cycloalkyl with up to 10 carbon atoms or an aryl group which is optionally substituted with hydroxy, carboxyl, halogen, alkoxy having from 1 to 8 carbon atoms or alkyl having from 1 to 8 carbon atoms, wherein Z of the R.sup.1 groups are --O.sup.- and the remainder of the R.sup.1 groups are ##STR10## groups. 2. The complex of claim 1, wherein A is ##STR11## 3. The complex of claim 1, wherein A is --CH.sub.2 CH.sub.2 --. 4. The complex of claim 1 wherein n=1, 2 or 3 and R.sup.4 is alkyl having 1-5 carbon atoms. 5. The complex of claim 4 wherein R.sup.3 is H. 6. The complex of claim 1 wherein R.sup.3 is R.sup.2, alkyl having from 1-8 carbon atoms, hydroxy, alkoxy having from 1-8 carbon atoms. 7. The complex of claim 1, wherein M.sup.+Z is chromium (III), manganese (II), manganese (III), iron (III), iron (II), cobalt (II), nickel (II), copper (II), p-raseodymium (III), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), terbium (III), dysprosium (III), holmium (III) or erbium (III). 8. The complex of claim 1 or 6, wherein M.sup.+Z is gadolinium (II), terbium (III), dysprosium (III), holmium (III) or erbium (III). 9. The complex of claim 2, wherein R.sup.1 is methoxyethylamino and M.sup.+Z is gadolinium (III). 10. A diagnostic 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: ##STR12## wherein A is selected from the group consisting of --CH.sub.2 CH.sub.2 -- or ##STR13## 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.- and ##STR14## wherein R.sup.2 is --(CH.sub.2 CH.sub.2 O).sub.n --R.sup.4 wherein n is 1-10 and R.sup.4 is alkyl having 1 to 8 carbon atoms or aryl, unsubstituted or substituted with hydroxy and R.sup.3 is H, R.sup.2, alkyl having from 1 to 8 carbon atoms, hydroxy, alkoxy having 1 to 8 carbon atoms, cycloalkyl with up to 10 carbon atoms or aryl, unsubstituted or substituted with hydroxy, carboxyl, halogen, alkoxy having from 1 to 8 carbon atoms or alkyl having from 1 to 8 carbon atoms, wherein Z of the R.sup.1 groups are --O.sup.- and the remainder of the R.sup.1 groups are ##STR15## groups and a pharmaceutically acceptable carrier. 11. The composition of claim 10, wherein A is ##STR16## 12. The composition of claim 10, wherein A is --CH.sub.2 CH.sub.2 --. 13. The composition of claim 10 wherein n=1, 2 or 3 and R.sup.4 is alkyl having 1-5 carbon atoms. 14. The composition of claim 10 wherein R.sup.3 is hydrogen. 15. The composition of claim 10, wherein R.sup.3 is R.sup.2, alkyl having from 1-8 carbon atoms, hydroxy, or alkoxy from 1-8 carbon atoms. 16. The composition of claim 10, 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). 17. The composition of claim 16, wherein M.sup.+Z is gadolinium (III), terbium (III), dysprosium (III), (III) or erbium (III). 18. The composition of claim 17, wherein R.sup.1 is ethylamino and M.sup.+Z is gadolinium (III). 19. The composition of claim 10 which further contains a pharmaceutically acceptable buffer. 20. The composition of claim 10, which further contains a pharmaceutically acceptable electrolyte. 21. The composition of claim 10, which further comprises a complexing agent of the formula ##STR17## wherein A and R.sup.1 are as defined as in claim 10, and said complexing agent is complexed with one or more physiologically acceptable, non-toxic cations. 22. The composition of claim 21, wherein said complexing agent is employed in an amount ranging from about 0.1 to about 15 mole % of the paramagnetic ion containing complex, and is complexed with one or more cations selected from the group consisting of sodium ions, calcium ions, magnesium ions, copper ions, zinc ions and mixtures thereto. 23. The composition of claim 21, wherein said complexing agent is complexed with calcium ions. 24. 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 ##STR18## wherein A is selected from the group consisting of --CH.sub.2 CH.sub.2 -- and ##STR19## 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.sup.1 groups may be the same or different and are selected from the group consisting of --O.sup.- and ##STR20## wherein R.sup.2 is --(CH.sub.2 CH.sub.2 O).sub.n --R.sup.4 wherein n is 1-10 and R.sup.4 is alkyl having 1 to 8 carbon atoms or an aryl group optionally substituted with hydroxy and R.sup.3 is H, R.sup.2, alkyl having from 1 to 8 carbon atoms, hydroxy, alkoxy having 1-8 carbon atoms, cycloalkyl with up to 10 carbon atoms or an aryl group optionally substituted with hydroxy, carboxyl, halogen, alkoxy having from 1 to 8 carbon atoms or alkyl having from 1 to 8 carbon atoms, wherein Z of the R.sup.1 groups are --O.sup.- and the remainder of the R.sup.1 groups are ##STR21## groups and then exposing the animal to an NMR imaging procedure, thereby imaging at least a portion of the body of the warm-blooded animal. 25. The method of claim 24 wherein A is ##STR22## 26. The method of claim 24, wherein A is --CH.sub.2 CH.sub.2 --. 27. The method of claim 24 wherein n=1, 2, or 3 and R.sup.4 is alkyl having 1-5 carbon atoms. 28. The method of claim 24 wherein R.sup.3 is H. 29. The method of claim 24, where R.sup.3 is R.sup.2, alkyl having from 1-8 carbon atoms, hydroxy, or alkoxy having from 1-8 carbon atoms. 30. The method of claim 24, 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). 31. The method of claim 30, wherein M.sup.+Z is gadolinium (III), terbium (III), dysprosium (III), holmium (III) or erbium (III). 32. The method of claim 31, wherein R.sup.1 is methoxyethylamino and M.sup.+Z is gadolinium (III). 33. The method of claim 28, wherein the pharmaceutically acceptable carrier contains a pharmaceutically acceptable buffer. 34. The method of claim 34, wherein the pharmaceutically acceptable carrier contains a pharmaceutically acceptable electrolyte. 35. The method of claim 24, wherein the pharmaceutically acceptable carrier contains a complexing agent of the formula ##STR23## wherein A and R.sup.1 are as defined as in claim 28, and said complexing agent is complexed with one or more physiologically acceptable, non-toxic cations. 36. The method of claim 35, wherein said complexing agent is employed in an amount ranging from about 0.1 to about 15 mole % of the paramagnetic ion-containing complex and is complexed with one or more cation selected from the group consisting of sodium ions, calcium ions, magnesium ions, copper ions, zinc ions, and mixtures thereof. 37. The method of claim 36, wherein said complexing agent is complexed with calcium ions. 38. A complexing agent of the formula: ##STR24## wherein A is selected from the group consisting of --CH.sub.2 CH.sub.2 -- and ##STR25## where the R.sup.1 groups may be the same or different and are selected from the group consisting of --O.sup.- and ##STR26## wherein R.sup.2 is --(CH.sub.2 CH.sub.2 O).sub.n --R.sup.4 wherein n is 1-10 and R.sup.4 is alkyl having 1 to 8 carbon atoms or aryl, unsubstituted or substituted with hydroxy and R.sup.3 is H, R.sup.2, alkyl having from 1 to 8 carbon atoms, hydroxy, alkoxy having 1-8 carbon atoms, cycloalkyl with up to 10 carbon atoms or an aryl, group which is optionally substituted with hydroxy, carboxyl, halogen, alkoxy having from 1 to 8 carbon atoms or alkyl having from 1 to 8 carbon atoms, wherein 2 or 3 of the R.sup.1 groups are --O.sup.- and the remainder of the R.sup.1 groups are ##STR27## groups. 39. The complexing agent of claim 38, wherein A is ##STR28## 40. The complexing agent of claim 38, wherein A is --CH.sub.2 CH.sub.2 --. 41. A complexing agent of the formula: ##STR29## wherein A is selected from the group consisting of --CH.sub.2 CH.sub.2 -- and ##STR30## wherein the R.sup.1 groups may be the same or different and are selected from the group consisting of --O.sup.- and an alkoxyalkyl amino group in which the alkoxy portion contains 1 or 2 carbon atoms, and the alkyl portion contains from 1 to 2 carbon atoms and the alkyl portion contains from about 2 to about 5 carbon atoms, wherein 2 or 3 of the R.sup.1 groups are --O.sup.- and the remainder of the R.sup.1 groups are as otherwise defined. 42. A complexing agent of the formula: ##STR31## wherein A is selected from the group consisting of --CH.sub.2 CH.sub.2 -- and ##STR32## wherein the R.sup.1 groups may be the same or different and are selected from the group consisting of --O.sup.-, methoxyethylamino, methoxypropylamino, methoxybutylamino, methoxypentylamino, ethoxypropylamino and ethoxybutylamino, wherein 2 or 3 of the R.sup.1 groups are --O.sup.- and the remainder of the R.sup.1 groups are as otherwise defined. 43. The complexing agent of claim 38 , wherein n=1, 2 or 3 and R.sup.4 is alkyl group having 1-5 carbon atoms. 44. The complexing agent of claim 38, wherein R.sup.3 is H. 45. The complexing agent of claim 38, wherein R.sup.3 is R.sup.2, alkyl having from 1-8 carbon atoms, hydroxy, or an alkoxy group having from 1-8 carbon atoms. 46. The complexing agent of claim 43 wherein R.sup.3 is an aryl group optionally substituted with hydroxy, carboxyl, halogen, alkoxy having from 1 to 8 carbon atoms or alkyl having from 1 to 8 carbon atoms. 47. A complex having the following formula: ##STR33## wherein A is selected from the group consisting of --CH.sub.2 CH.sub.2 -- and ##STR34## 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 number, Z, or 2 or 3; the R.sup.1 groups may be the same or different and are selected from the group consisting of --O.sup.- and an alkoxyalkyl amino group wherein the alkoxy portion contains 1 or 2 carbon atoms and the alkyl portion contains from about 2 to about 5 carbon atoms, wherein Z of the R.sup.1 groups are --O.sup.- and the remainder of the R.sup.1 groups are as otherwise defined. 48. A complex having the following formula: ##STR35## wherein A is selected from the group consisting of --CH.sub.2 CH.sub.2 -- and ##STR36## 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 number, Z, of 2 or 3; the R.sup.1 groups may be the same or different and are selected from the group consisting of --O.sup.-, methoxyethylamino, methoxypropylamino, methoxybutylamino, methoxypentylamino, ethoxyethylamino, ethoxypropylamino and ethoxybutylamino, wherein Z of the R.sup.1 groups are --O.sup.- and the remainder of the R.sup.1 groups are as otherwise defined. 49. A diagnostic composition suitable for 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: ##STR37## wherein A is selected from the group consisting of --CH.sub.2 CH.sub.2 -- or ##STR38## 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 number, Z, or 2 or 3; R.sup.1 groups may be the same or different and are selected from the group consisting of --O.sup.-, and an alkoxyalkyl amino group in which the alkoxy portion contains 1 or 2 carbon atoms and the alkyl portion contains from about 2 to about 5 carbon atoms, wherein Z of the R.sup.1 groups are --O.sup.- and the remainder of the R.sup.1 groups are as otherwise defined, and the complex is dissolved or suspended in a sterile aqueous pharmaceutically acceptable carrier at a concentration of from about 0.05 to 1.0 M. 50. A diagnostic 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: ##STR39## wherein A is selected from the group consisting of --CH.sub.2 CH.sub.2 -- or ##STR40## 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 number, Z, of 2 or 3; the R.sup.1 groups may be the same or different and are selected from the group consisting of --O.sup.-, methoxyethylamino, methoxypropylamino, methoxybutylamino, methoxypentylamino, ethoxyethylamino, ethoxypropylamino and ethoxybutylamino, wherein Z of the R.sup.1 groups are --O.sup.- and the remainder of the R.sup.1 groups are as otherwise defined ,and wherein the concentration of the complex in the composition is from about 0.05 to about 1.0 M. 51. A method of performing an NMR diagnostic procedure, which comprises parenterally administering to a warm-blooded animal an effective amount of a complex of the formula ##STR41## wherein A is selected from the group consisting of --CH.sub.2 CH.sub.2 -- and ##STR42## 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 number, Z, of 2 or 3; the R.sup.1 groups may be the same or different and are selected from the group consisting of --O.sup.- and an alkoxyalkyl amino group in which the alkoxy portion contains 1 or 2 carbon atoms and the alkyl portion contains from about 2 to about 5 carbon atoms, Z of the R.sup.1 groups are --O.sup.- and the remainder of the R.sup.1 groups are as otherwise defined, and the complex is dissolved or suspended in a sterile aqueous pharmaceutically acceptable carrier at a concentration of from about 0.05 to 1.0 M. 52. A method of performing an NMR diagnostic procedure, which comprises parenterally administering to a warm-blooded animal an effective amount of a complex of the formula: ##STR43## wherein A is selected from the group consisting of --CH.sub.2 CH.sub.2 -- and ##STR44## 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 number, Z, of 2 or 3; the R.sup.1 groups may be the same or different and are selected from the group consisting of --O.sup.-, methoxyethylamino, methoxypropylamino, methoxybutylamino, methoxypentylamino, ethoxyethylamino, ethoxypropylamino and ethoxybutylamino, Z of the R.sup.1 groups are--O.sup.- and the remainder of the R.sup.1 groups are as otherwise defined, and wherein the concentration of the complex in the pharmaceutically acceptable carrier is from about 0.05 to about 1.0 M. 53. A complex having the following formula: ##STR45## wherein A is selected from the group consisting of --CH.sub.2 CH.sub.2 -- and ##STR46## 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 number, Z, of 2 or 3; the R.sup.1 groups may be the same or different and are selected from the group consisting of --O.sup.- and ##STR47## wherein R.sup.2 is --(CH.sub.2 CH.sub.2 O).sub.n --R.sup.4 wherein n is 1-10 and R.sup.4 is alkyl having 1 to 8 carbon atoms or aryl, unsubstituted or substituted with hydroxy and R.sup.3 is H, wherein Z of the R.sup.1 groups are --O.sup.- and the remainder of the R.sup.1 groups are ##STR48## groups. 54. A diagnostic 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: ##STR49## wherein A is selected from the groups consisting of --CH.sub.2 CH.sub.2 -- or ##STR50## 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 number, Z, of 2 or 3; the R.sup.1 groups may be the same or different and are selected from the group consisting of --O.sup.- and ##STR51## wherein R.sup.2 is --(CH.sub.2 CH.sub.2 O).sub.n --R.sup.4 wherein n is 1-10 and R.sup.4 is alkyl having 1 to 8 carbon atoms or aryl, unsubstituted or substituted with hydroxy and R.sup.3 is H, wherein Z of the R.sup.1 groups are --O.sup.- and the remainder of the R.sup.1 groups are ##STR52## groups and a pharmaceutically acceptable carrier. 55. 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 ##STR53## wherein A is selected from the group consisting of --CH.sub.2 CH.sub.2 -- and ##STR54## 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 number, Z, or 2 or 3; the R.sup.1 groups may be the same or different and are selected from the group consisting of --O.sup.- and ##STR55## wherein R.sup.2 is --(CH.sub.2 CH.sub.2 O).sub.n --R.sup.4 wherein n is 1-10 and R.sup.4 is alkyl having 1 to 8 carbon atoms or an aryl group optionally substituted with hydroxy and R.sup.3 is H, wherein Z of the R.sup.1 groups are --O.sup.- and the remainder of the R.sup.1 groups are ##STR56## groups and then exposing the animal to the NMR imaging procedure, thereby imaging at least a portion of the body of the warm-blooded animal. 56. A complexing agent of the formula: ##STR57## wherein A is selected from the group consisting of --CH.sub.2 CH.sub.2 -- and ##STR58## wherein the R.sup.1 groups may be the same or different and are selected from the group consisting of --O.sup.- and ##STR59## wherein R.sup.2 is --(CH.sub.2 CH.sub.2 O).sub.n --R.sup.4 wherein n is 1-10 and R.sup.4 is alkyl having 1 to 8 carbon atoms or aryl, unsubstituted or substituted with hydroxy and R.sup.3 is H, wherein the number of R.sup.1 groups --O.sup.- are 2 or 3 and the remainder of the R.sup.1 groups are ##STR60## groups.