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Details for Patent: 5,300,279

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Details for Patent: 5,300,279

Title: Organic amine phosphonic acid complexes for the treatment of calcific tumors
Abstract:Particle-emitting radionuclides, e.g. Gd-159, Ho-166, Lu-177 and Yb-175, have been complexed with organic aminoalkylenephosphonic acids. These complexes have been found useful in compositions for the therapeutic treatment of calcific tumors or the relief of bone pain in animals.
Inventor(s): Simon; Jaime (Angleton, TX), Garlich; Joseph R. (Lake Jackson, TX), Goeckeler; William F. (Midland, MI), Wilson; Davis A. (Richwood, TX), Volkert; Wynn A. (Columbia, MO), Troutner; David E. (Phoenixville, PA)
Assignee: The Dow Chemical Company (Midland, MI)
Filing Date:Dec 19, 1990
Application Number:07/629,894
Claims:1. A therapeutically effective composition comprising (1) an aminophosphonic acid of the formula ##STR7## wherein substituents A, B, C, D, E and F are independently selected from hydrogen, methyl, ethyl, isopropyl, benzyl ##STR8## and physiologically acceptable salts of the acid radicals and wherein X' and Y' are independently hydrogen, methyl or ethyl radicals; n' is 2 or 3; and m and m' each is independently 0-10; with the proviso that at least one of said nitrogen substituents is the phosphorus-containing group of Formula (B); and wherein R is ##STR9## wherein X and Y are independently selected from 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 atoms; with the further proviso that when m or m'.gtoreq.1 the E and F substituents may be same as or different from any other substituent of any other nitrogen atom and each R can be the same as or different from any other R and (2) at least one radionuclide selected from G-159, Ho-166, Lu-177 and Yb-175.

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

3. The composition of claim 1 wherein the aminophosphonic acid has the formula ##STR10## wherein A, B and C are defined as in claim 1.

4. The composition of claim 3 wherein the aminophosphonic acid is nitrilotrimethylenephosphonic acid or a physiologically acceptable salt thereof and the radionuclide is Yb-175.

5. The composition of claim 1 wherein the aminophosphonic acid has the formula ##STR11## wherein m is zero and R is --CH.sub.2 CH.sub.2 -- and A, B, C, D, E, F and m' are defined as in claim 1.

6. The composition of claim 5 wherein X and Y are hydrogen; n is 1; and X' and Y' are each independently hydrogen, methyl or ethyl radicals.

7. The composition of claim 5 wherein the aminophosphonic acid is ethylenediaminetetramethylenephosphonic acid or a physiologically acceptable salt thereof.

8. The composition of claim 7 wherein the radionuclide is Ho-166.

9. The composition of claim 5 wherein at least one of the nitrogen substituents is ##STR12## wherein X', Y' and n' are defined as in claim 1.

10. The composition of claim 9 wherein the aminophosphonic acid is hydroxyethylethylenediaminetrimethylenephosphonic acid or a physiologically acceptable salt thereof.

11. The composition of claim 10 wherein the radionuclide is Ho-166.

12. The composition of claim 5 wherein the radionuclide is Ho-166 and the aminophosphonic acid is N-methylethylenediaminetrimethylenephosphonic acid, N-isopropylethylenediaminetrimethylenephosphonic acid, N-benzylethylenediaminetrimethylenephosphonic acid, or a physiologically acceptable salt thereof.

13. The composition of claim 1 wherein the aminophosphonic acid is ##STR13## wherein m is 1, m' is zero and R is --CH.sub.2 CH.sub.2 -- and A, B, C, D, E, and F are defined as in claim 1.

14. The composition of claim 13 wherein X and Y are each hydrogen; and n is 1; and X' and Y' are each independently hydrogen, methyl or ethyl radicals.

15. The composition of claim 13 wherein the aminophosphonic acid is diethylenetriaminepentamethylenephosphonic acid or a physiologically acceptable salt thereof.

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

17. The composition of claim 1 wherein the radionuclide is Yb-175 and the aminophosphonic acid is at least one of nitrilotrimethylenephosphonic acid, ethylenediaminetetramethylenephosphonic acid, hydroxyethylethylenediaminetrimethylenephosphonic acid, diethylenetriaminepentamethylenephosphonic acid, or a physiologically acceptable salt thereof.

18. The composition of claim 1 wherein the radionuclide is Ho-166 and the aminophosphonic acid is at least one of ethylenediaminetetramethylenephosphonic acid, hydroxyethylethylenediaminetrimethylenephosphonic acid, N-methylethylenediaminetrimethylenephosphonic acid, N-isopropylethylenediaminetrimethylenephosphonic acid, N-benzylethylenediaminetrimethylenephosphonic acid, or a physiologically acceptable salt thereof.

19. The composition of claim 1 wherein the radionuclide is Lu-177 and the aminophosphonic acid is at least one of ethylenediaminetetramethylenephosphonic acid, hydroxyethylethylenediaminetrimethylenephosphonic acid, or a physiologically acceptable salt thereof.

20. The composition of claim 1 wherein the radionuclide is Gd-159 and the aminophosphonic acid is at least one of ethylenediaminetetramethylenephosphonic acid, hydroxyethylethylenediaminetrimethylenephosphonic acid, or a physiologically acceptable salt thereof.

21. A composition comprising 1) a complex which comprises at least one radionuclide of Gd-159, Ho-166, Lu-177 or Yb-175 and at least one of an aminophosphonic acid, or a physiologically acceptable salt thereof, wherein the aminophosphonic acid is ethylenediaminetetramethylenephosphonic acid, diethylenetriaminepentamethylenephosphonic acid, hydroxyethylethylenediaminetrimethylenephosphonic acid, nitrilotrimethylenephosphonic acid, N-methylethylenediaminetrimethylenephosphonic acid, N-isopropylethylenediaminetrimethylenephosphonic acid, or N-benzylethylenediaminetrimethylenephosphonic acid, and 2) at least one of the above aminophosphonic acids, or a physiologically acceptable salt thereof, in excess of that required to make the complex, and wherein the resulting composition is therapeutically effective.

22. The composition of claim 21 wherein a physiologically acceptable liquid carrier is present.

23. The composition of claim 22 wherein the physiologically acceptable liquid carrier is water and the resulting solution is adjusted to have a pH of about 7 to about 8.

24. The composition of claim 21 wherein the radionuclide is Gd-159.

25. The composition of claim 24 wherein the aminophosphonic acid is ethylenediaminetetramethylenephosphonic acid, hydroxyethylethylenediaminetrimethylenephosphonic acid, or a physiologically acceptable salt thereof.

26. The composition of claim 21 wherein the radionuclide is Ho-166.

27. The composition of claim 26 wherein the aminophosphonic acid is ethylenediaminetetramethylenephosphonic acid, hydroxyethylethylenediaminetrimethylenephosphonic acid, N-methylethylenediaminetrimethylenephosphonic acid, N-isopropylethylenediaminetrimethylenephosphonic acid, N-benzylethylenediaminetrimethylenephosphonic acid, or a physiologically acceptable salt thereof.

28. The composition of claim 21 wherein the radionuclide is Lu-177.

29. The composition of claim 28 wherein the aminophosphonic acid is ethylenediaminetetramethylenephosphonic acid, hydroxyethylethylenediaminetrimethylenephosphonic acid, or a physiologically acceptable salt thereof.

30. The composition of claim 21 wherein the radionuclide is Yb-175.

31. The composition of claim 30 wherein the aminophosphonic acid is ethylenediaminetetramethylenephosphonic acid, hydroxyethylethylenediaminetrimethylenephosphonic acid, diethylenetriaminepentamethylenephosphonic acid, nitrilotrimethylenephosphonic acid, or a physiologically acceptable salt thereof.

32. A sterile composition suitable for administration to a mammal comprising 1) a complex which comprises at least one radionuclide of Gd-159, Ho-166, Lu-177 or Yb-175 and at least one of an aminophosphonic acid, or a physiologically acceptable salt thereof, wherein the aminophosphonic acid is ethylenediaminetetramethylenephosphonic acid, diethylenetriaminepentamethylenephosphonic acid, hydroxyethylethylenediaminetrimethylenephosphonic acid, nitrilotrimethylenephosphonic acid, N-methylethylenediaminetrimethylenephosphonic acid, N-isopropylethylenediaminetrimethylenephosphonic acid, or N-benzylethylenediaminetrimethylenephosphonic acid, and 2) at least one of the above aminophosphonic acids, or a physiologically acceptable salt thereof, in excess of that required to make the complex, and wherein the resulting composition is therapeutically effective 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 mammal.

33. The composition of claim 32 wherein a physiologically acceptable liquid carrier is present.

34. The composition of claim 33 wherein the physiologically acceptable liquid carrier is water and the resulting solution is adjusted to have a pH of about 7 to 8.

35. The composition of claim 32 wherein the radionuclide is Gd-159.

36. The composition of claim 35 wherein the aminophosphonic acid is ethylenediaminetetramethylenephosphonic acid, hydroxyethylethylenediaminetrimethylenephosphonic acid, or a physiologically acceptable salt thereof.

37. The composition of claim 32 wherein the radionuclide is Ho-166.

38. The composition of claim 37 wherein the aminophosphonic acid is ethylenediaminetetramethylenephosphonic acid, hydroxyethylethylenediaminetrimethylenephosphonic acid, N-methylethylenediaminetrimethylenephosphonic acid, N-isopropylethylenediaminetrimethylenephosphonic acid, N-benzylethylenediaminetrimethylenephosphonic acid, or a physiologically acceptable salt thereof.

39. The composition of claim 32 wherein the radionuclide is Lu-177.

40. The composition of claim 39 wherein the aminophosphonic acid is ethylenediaminetetramethylenephosphonic acid, hydroxyethylethylenediaminetrimethylenephosphonic acid, or a physiologically acceptable salt thereof.

41. The composition of claim 32 wherein the radionuclide is Yb-175.

42. The composition of claim 41 wherein the aminophosphonic acid is ethylenediaminetetramethylenephosphonic acid, hydroxyethylethylenediaminetrimethylenephosphonic acid, diethylenetriaminepentamethylenephosphonic acid, nitrilotrimethylenephosphonic acid, or a physiologically acceptable salt thereof.
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