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Details for Patent: 5,059,412

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Details for Patent: 5,059,412

Title: Macrocyclic aminophosphonic acid complexes for the treatment of calcific tumors
Abstract:Particle emitting radionuclides, e.g. Samarium-153, have been complexed with certain macrocyclic aminophosphonic acids wherein the nitrogen and phosphorus are interconnected by an alkylene group or substituted alkylene group. These complexes have been found useful in compositions and formulations for the therapeutic treatment of calcific tumors in animals.
Inventor(s): Simon; Jaime (Angleton, TX), Wilson; David A. (Richwood, TX), Garlich; Joseph R. (Lake Jackson, TX), Troutner; David E. (Columbia, MO)
Assignee: The Dow Chemical Company (Midland, MI)
Filing Date:Dec 19, 1988
Application Number:07/284,876
Claims:1. A composition suitable for administration to an animal having bone pain or having one or more calcific tumors comprising a complex which comprises a macrocyclic aminophosphonic acid or a physiologically acceptable salt thereof containing 1,4,7,10-tetraazacyclododecane as the macrocyclic moiety and wherein the nitrogen and phosphorous are interconnected by an alkylene or substituted alkylene radical of the formula ##STR5## wherein X and Y are independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, phosphonic, and hydrocarbon radicals having from 1-8 carbon atoms and physiologically acceptable salts of the acid radicals, and n is 1-3 with the proviso that when n>1, each X and Y may be the same as or different from the X and Y of any other carbon atom, and at least one radionuclide selected from the group consisting of Sm-153, Gd-159, Ho-166, Lu-177, and Yb-175 and wherein the resulting composition is therapeutically effective for the relief of bone pain or treatment of calcific tumors.

2. The composition of claim 1 wherein the radionuclide is Gd-159.

3. The composition of claim 1 wherein the radionuclide is Sm-153.

4. The composition of claim 1 wherein the radionuclide is Lu-177.

5. The composition of claim 1 wherein the radionuclide is Yb-175.

6. The composition of claim 1 wherein the radionuclide is Ho-166.

7. The composition of claim 1 wherein X and Y are hydrogen and n is 1.

8. The composition of claim 1 wherein the ligand to radionuclide molar ratio is at least about 1:1.

9. The composition of claim 1 wherein the macrocyclic aminophosphonic acid has the structure ##STR6## wherein substituents A, B, C, and D are independently ted from hydrogen, hydrocarbon radicals having from 1-8 carbon atoms, ##STR7## and physiologically acceptable salts of the acid radicals wherein X, Y, and n are as previously defined, X' and Y' are independently hydrogen, methyl, or ethyl radicals, n' is 2 or 3, with the proviso that at least two of said nitrogen substituents is a phosphoruscontaining group.

10. The composition of claim 9 wherein the radionuclide is Gd-159.

11. The composition of claim 9 wherein the radionuclide is Sm-153.

12. The composition of claim 9 wherein the radionuclide is Lu-177.

13. The composition of claim 9 wherein the radionuclide is Yb-175.

14. The composition of claim 9 wherein the radionuclide is Ho-166.

15. The composition of claim 9 wherein the macrocyclic aminophosphonic acid is 1,4,7,10-tetraazacyclododecanetetramethylenephosphonic acid or a physiologically acceptable salt.

16. The composition of claim 15 wherein the radionuclide is Gd-159.

17. The composition of claim 15 wherein the radionuclide is Sm-153.

18. The composition of claim 15 wherein the radionuclide is Yb-175.

19. The composition of claim 15 wherein the radionuclide is Lu-177.

20. The composition of claim 15 wherein the radionuclide is Ho-166.

21. The composition of claim 15 wherein the ligand to radionuclide molar ratio is about 1:1 to about 3:1.

22. The composition of claim 15 wherein the ligand to radionuclide molar ratio is about 1:1 to about 1.5:1.

23. A sterile composition suitable for administration to an animal having bone pain or having one or more calcific tumors comprising at least one radionuclide selected from the group consisting of Samarium-153, Gadolinium-159, Holmium-166, Ytterbium-175, and Lutetium-177 complexed with at least one macrocyclic aminophosphonic acid or a physiologically acceptable salt thereof, containing the 1,4,7,10-tetraazacyclododecane moiety wherein the nitrogen and phosphorus are interconnected by an alkylene or substituted alkylene radical of the formula ##STR8## wherein X and Y are independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, phosphonic, and hydrocarbon a radicals having from 1-8 carbon atoms and physiologically acceptable salts of the acid radicals, and n is 1-3 with the proviso that when n>1, each X and Y may be the same as or different from the X and Y of any other carbon atom; and wherein the radionuclide in dosage form is present in an amount containing at least 0.02 mCi per kilogram of body weight of said animal.

24. The composition of claim 23 wherein the ligand to radionuclide molar ratio is at least about 1:1.

25. The composition of claim 23 wherein the macrocyclic aminophosphonic acid is 1,4,7,10-tetraazacyclododecanetetramethylenephosphonic acid or a physiologically acceptable salt thereof.

26. The composition of claim 23 wherein the radionuclide is Sm-153.

27. The composition of claim 23 wherein the radionuclide is Ho-166.

28. The composition of claim 23 wherein the radionuclide is Gd-159.

29. The composition of claim 23 wherein the radionuclide is Yb-175.

30. The composition of claim 23 wherein the raionuclide is Lu-177.

31. The composition of claim 25 wherein the ligand to radionuclide molar ratio is about 1:1 to about 3:1.

32. The composition of claim 25 wherein the ligand to radionuclide molar ratio is about 1:1 to about 1.5:1.

33. A pharmaceutical formulation comprising the composition of claim 1 and a pharmaceutically acceptable carrier.

34. The formulation of claim 33 wherein the radionuclide is Gd-159.

35. The formulation of claim 33 wherein the radionuclide is Sm-153.

36. The formulation of claim 33 wherein the radionuclide is Lu-177.

37. The formulation of claim 33 wherein the radionuclide is Yb-175.

38. The formulation of claim 33 wherein the radionuclide is Ho-166.

39. A pharmaceutical formulation comprising the composition of claim 9 and a pharmaceutically acceptable carrier.

40. The formulation of claim 39 wherein the radionuclide is Gd-159.

41. The formulation of claim 39 wherein the radionuclide is Sm-153.

42. The formulation of claim 39 wherein the radionuclide is Lu-177.

43. The formulation of claim 39 wherein the radionuclide is Yb-175.

44. The formulation of claim 39 wherein the radionuclide is Ho-166.

45. A pharmaceutical formulation comprising the composition of claim 15 and a pharmaceutically acceptable carrier.

46. The formulation of claim 45 wherein the radionuclide is Gd-159.

47. The formulation of claim 45 wherein the radionuclide is Sm-153.

48. The formulation of claim 45 wherein the radionuclide is Lu-177.

49. The formulation of claim 45 wherein the radionuclide is Yb-175.

50. The formulation of claim 45 wherein the radionuclide is Ho-166.

51. A pharmaceutical formulation comprising the composition of claim 23 and a pharmaceutically acceptable carrier.

52. The formulation of claim 51 wherein the radionuclide is Gd-159.

53. The formulation of claim 51 wherein the radionuclide is Sm-153.

54. The formulation of claim 51 wherein the radionuclide is Lu-177.

55. The formulation of claim 51 wherein the radionuclide is Yb-175.

56. The formulation of claim 51 wherein the radionuclide is Ho-166.

57. A method for the therapeutic treatment of an animal having one or more calcific tumors which comprises administering to said animal a therapeutically effective amount of at least one composition comprising a complex which comprises at least one macrocyclic aminophosphonic acid or a physiologically acceptable salt thereof containing 1,4,7,10-tetraazacyclododecane as the macrocyclic moiety and wherein the nitrogen and phosphorous are interconnected by an alkylene or substituted alkylene radical of the formula ##STR9## wherein X and Y are independently selected from the group consisting of hydrogen, hydroxyl, carboxyl, phosphonic, and hydrocarbon radicals having from 1-8 carbon atoms and physiologically acceptable salts of the acid radicals, and n is 1-3 with the proviso that when n>1, each X and Y may be the same as or different from the X and Y of any other carbon atom, and at least one radionuclide selected from the group consisting of Sm-153, Gd-159, Ho-166, Lu-177 and Yb-175.

58. The method of claim 57 wherein the radionuclide is Gd-159.

59. The method of claim 57 wherein the radionuclide is Sm-153.

60. The method of claim 57 wherein the radionuclide is Lu-177.

61. The method of claim 57 wherein the radionuclide is Yb-175.

62. The method of claim 57 wherein the radionuclide is Ho-166.

63. The method of claim 57 wherein X and Y are hydrogen and n is 1.

64. The method of claim 57 wherein the macrocyclic aminophosphonic acid has the structure ##STR10## wherein substituents A, B, C, and D are independently selected from hydrogen, hydrocarbon radicals having from 1-8 carbon atoms, ##STR11## and physiologically acceptable salts of the acid radicals wherein X, Y, and n are as previously defined, X' and Y' are independently hydrogen, methyl, or ethyl radicals, n' is 2 or 3, with the proviso that at least two of said nitrogen substituents is a phosphorus containing group.

65. The method of claim 64 wherein the radionuclide is Gd-159.

66. The method of claim 64 wherein the radionuclide is Sm-153.

67. The method of claim 64 wherein the radionuclide is Lu-177.

68. The method of claim 64 wherein the radionuclide is Ho-166.

69. The method of claim 64 wherein the radionuclide is Yb-175.

70. The method of claim 64 wherein the macrocyclic aminophosphonic acid is 1,4,7,10-tetraazacyclododecanetetramethylenephosphonic acid or a physiologically acceptable salt.

71. The method of claim 70 wherein the radionuclide is Gd-159.

72. The method of claim 70 wherein the radionuclide is Sm-153.

73. The method of claim 70 wherein the radionuclide is Yb-175.

74. The method of claim 70 wherein the radionuclide is Lu-177.

75. The method of claim 70 wherein the radionuclide is Ho-166.

76. The method of claim 70 wherein the animal is a human.

77. A method for the therapeutic treatment of an animal having bone pain which comprises administering to said animal a therapeutically effective amount of at least one composition comprising a complex which comprises at least one macrocyclic aminophosphonic acid or a physiologically acceptable salt thereof containing 1,4,7,10-tetraazacyclododecane as the macrocyclic moiety and wherein the nitrogen and phosphorous are interconnected by an alkylene or substituted alkylene radical of the formula ##STR12## wherein X and Y are independently selected from the group consisiting of hydrogen, hydroxyl, carboxyl, phosphonic, and hydrocarbon radicals having from 1-8 carbon atoms and physiologically acceptable salts of the acid radicals, and n is 1-3 with the proviso that when n>1, each X and Y may be the same as or different from the X and Y of any other carbon atom, and at least one radionuclide selected from the group consisting of Sm-153, Gd-159, Ho-166, Lu-177, and Yb-175.

78. The method of claim 77 wherein the radionuclide is Gd-159.

79. The method of claim 77 wherein the radionuclide is Sm-153.

80. The method of claim 77 wherein the radionuclide is Lu-177.

81. The method of claim 77 wherein the radionuclide is Ho-166.

82. The method of claim 77 wherein the radionuclide is Yb-175.

83. The method of claim 77 wherein the macrocyclic aminophosphonic acid is 1,4,7,10-tetraazacyclododecanetetramethylenephosphonic acid or a physiologically acceptable salt.

84. The method of claim 83 wherein the radionuclide is Gd-159.

85. The method of claim 83 wherein the radionuclide is Sm-153.

86. The method of claim 83 wherein the radionuclide is Yb-175.

87. The method of claim 83 wherein the radionuclide is Lu-177.

88. The method of claim 83 wherein the radionuclide is Ho-166.
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