IPC분류정보
국가/구분 |
United States(US) Patent
등록
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국제특허분류(IPC7판) |
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출원번호 |
US-0777820
(2004-02-12)
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등록번호 |
US-7468432
(2008-12-23)
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발명자
/ 주소 |
- Collins,Douglas A.
- Hogenkamp,Henricus P. C.
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출원인 / 주소 |
- Mayo Foundation for Medical Education and Research
- Regents of the University of Minnesota
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대리인 / 주소 |
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인용정보 |
피인용 횟수 :
2 인용 특허 :
101 |
초록
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The invention provides cobalamin compounds linked to a neutron capture therapy target (e.g. Boron-10 or Gadolinium-157), and optionally linked to a detectable moiety, as well as pharmaceutical compositions comprising the compounds, and methods for using the compounds in medical diagnosis and therapy
The invention provides cobalamin compounds linked to a neutron capture therapy target (e.g. Boron-10 or Gadolinium-157), and optionally linked to a detectable moiety, as well as pharmaceutical compositions comprising the compounds, and methods for using the compounds in medical diagnosis and therapy.
대표청구항
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What is claimed is: 1. A method of treating a tumor in a mammal comprising: a) administering to the mammal an effective amount of a compound of formula I linked to a molecule comprising B-10 wherein X is CN, OH, CH3, adenosyl, or a molecule comprising B-10; or a pharmaceutically acceptable salt
What is claimed is: 1. A method of treating a tumor in a mammal comprising: a) administering to the mammal an effective amount of a compound of formula I linked to a molecule comprising B-10 wherein X is CN, OH, CH3, adenosyl, or a molecule comprising B-10; or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable vehicle; and b) administering neutron capture therapy comprising subjecting said mammal to thermal neutron irradiation at the site of said tumor for a time and under conditions effective to treat said tumor. 2. A method for imaging a tumor in a mammal comprising: a) administering to the mammal a detectable amount of a compound of formula I linked to a molecule comprising B-10 wherein X is CN, OH, CH3, adenosyl, or a molecule comprising B-10; or a phannaceutically acceptable salt thereof; and b) detecting the presence of the compound. 3. The method of claim 2, further comprising treating the tumor with neutron capture therapy. 4. The method of claim 1, wherein the molecule comprising B-10 is directly linked to the 6-position of the compound of formula I or is directly linked to the b, d, or e-carboxamide group of the compound of formula I. 5. The method of claim 1, wherein the molecule comprising B-10 is linked by a linker to the 6-position of the compound of formula I or is linked by a linker to the a, b, d, or e-carboxamide group of the compound of formula I. 6. The method of claim 1, wherein the molecule comprising B-10 is linked to the b-carboxamide group of the compound of formula I. 7. The method of claim 1, wherein the molecule comprising B-10 is linked to the d-carboxamide group of the compound of formula I. 8. The method of claim 1, wherein the molecule comprising B-10 is linked to the e-carboxaniide group of the compound of formula I. 9. The method of claim 1, wherein the molecule comprising B-10 is linked to the b-caxboxamide group and a second molecule comprising B-10 is linked to the d-carboxamide group of the compound of formula I. 10. The method of claim 1, wherein the molecule comprising B-10 is linked to the 6-position of the compound of formula I. 11. The method of claim 1, wherein the molecule comprising B-10 contains 1 to about 20 boron atoms, inclusive. 12. The method of claim 1, wherein the molecule comprising B-10 is an amino acid, a carbohydrate, a nucleoside, or a carborane. 13. The method of claim 1, wherein the molecule comprising B-10 is o-carborane, m-carborane, or p-carborane. 14. The method of claim 1, wherein the molecule comprising B-10 is o-carborane. 15. The method of claim 5, wherein the linker is of the formula W-A-Q wherein A is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8) cycloalkyl, or (C6-C10)aryl, wherein W and Q are each independently--N(R)C(═O)--,--C(═O)N(R)--,--OC(═O)--,--C(═O)O--,--O--,--S--,--S(O)--,--S(O)2--,--N(R)--,--C(═O)--, or a direct bond; wherein each R is independently H or (C1-C6) alkyl. 16. The method of claim 15, wherein W is NH2 or COOH and Q is NH2 or COOH. 17. The method of claim 15, wherein A is (C1-C6)alkyl. 18. The method of claim 5, wherein the linker is about 5 angstroms to about 50 angstroms, inclusive. 19. The method of claim 5, wherein the linker comprises a therapeutic radionuclide or a diagnostic radionucide. 20. The method of claim 19, wherein the therapeutic radionuclide is a metallic radionuclide. 21. The method of claim 19, wherein the diagnostic radionuclide is a metallic radionuclide. 22. The method of claim 19, wherein the diagnostic radionuclide is a non-metallic radionuclide. 23. The method of claim 5, wherein the linker is a divalent radical comprising a peptide. 24. The method of claim 5, wherein the linker is a divalent radical comprising an amino acid. 25. The method of claim 5, wherein the linker is poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly-L-lysine-L-phenylalanine, poly-L-lysine or poly-L-lysine-L-tyrosine. 26. The method of claim 1, wherein the compound of formula I is further linked to a linker comprising a detectable radionuclide or a therapeutic radionuclide. 27. The method of claim 1, wherein the compound of formula I is further linked to a detectable radionuclide. 28. The method of claim 27, wherein the detectable radionuclide is a non-metallic radionuclide. 29. The method of claim 28, wherein the non-metallic radionuclide is Carbon-11, Fluorine-18, Bromme-76, Iodine-123, or Iodine-124. 30. The method of claim 27, wherein the detectable radionuclide is directly linked to the compound of formula I. 31. The method of claim 27, wherein the detectable radionuclide is linked by a linker to the compound of formula I. 32. The method of claim 31, wherein the linker is of the formula W-A wherein A is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8) cycloalkyl, or (C6-C10)aryl, wherein W is--N(R)C(═O)--,--C(═O)N(R)--,--OC(═O)--,--C(═O)O--,--O--,--S--,--S(O)--,--S(O)2--,--N(R)--,--C(═O)--, or a direct bond; wherein each R is independently H or (C1-C6)alkyl; and wherein A is substituted with one or more non-metallic radionuclides. 33. The method of claim 31, wherein the linker is about 5 angstroms to about 50 angstroms, inclusive. 34. The method of claim 31, wherein the linker is a divalent peptide or amino acid. 35. The method of claim 31, wherein the linker is poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-omithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly-L-lysine-L-phenylalanine, poly-L-lysine, or poly-L-lysine-L-tyrosine. 36. The method of claim 31, wherein the linker is linked to the 6-position of the compound of formula I or is linked to the a, b, d or e-carboxamide group of the compound of formula I. 37. The method of claim 1, wherein the compound of formula I is present in a detectable amount, and wherein the method further comprises imaging the tumor and detecting the presence of the compound of formula I. 38. The method of claim 2, wherein the molecule comprising B-10 is directly linked to the 6-position of the compound of formula I or is directly linked to the b, d, or e-carboxamide group of the compound of formula I. 39. The method of claim 2, wherein the molecule comprising B-10 is linked by a linker to the 6-position of the compound of formula I or is linked by a linker to the a, b, d, or e-carboxaniide group of the compound of formula I. 40. The method of claim 2, wherein the molecule comprising B-10 is linked to the b-carboxamide group of the compound of formula I. 41. The method of claim 2, wherein the molecule comprising B-10 is linked to the d-carboxamide group of the compound of formula I. 42. The method of claim 2, wherein the molecule comprising B-10 is linked to the e-carboxamide group of the compound of formula I. 43. The method of claim 2, wherein the molecule comprising B-10 is linked to the b-carboxamide group and a second molecule comprising B-10 is linked to the d-carboxamide group of the compound of formula I. 44. The method of claim 2, wherein the molecule comprising B-10 is linked to the 6-position of the compound of formula I. 45. The method of claim 2, wherein the molecule comprising B-10 contains 1 to about 20 boron atoms, inclusive. 46. The method of claim 2, wherein the molecule comprising B-10 is an amino acid, a carbohydrate, a nucleoside, or a carborane. 47. The method of claim 2, wherein the molecule comprising B-10 is o-carborane, m-carborane, or p-carborane. 48. The method of claim 2, wherein the molecule comprising B-10 is o-carborane. 49. The method of claim 39, wherein the linker is of the formula W-A-Q wherein A is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8) cycloalkyl, or (C6-C10)aryl, wherein W and Q are each independently--N(R)C(═O)--,--C(═O)N(R)--,--OC(═O)--,--C(═O)O--,--O--,--S--,--S(O)--,--S(O)2--,--N(R)--,--C(═O)--, or a direct bond; wherein each R is independently H or (C1-C6) alkyl. 50. The method of claim 49, wherein W is NH2 or COOH and Q is NH2 or COOH. 51. The method of claim 49, wherein A is (C1-C6)alkyl. 52. The method of claim 39, wherein the linker is about 5 angstroms to about 50 angstroms, inclusive. 53. The method of claim 39, wherein the linker comprises a therapeutic radionuclide or a diagnostic radionucide. 54. The method of claim 53, wherein the therapeutic radionuclide is a metallic radionuclide. 55. The method of claim 53, wherein the diagnostic radionuclide is a metallic radionuclide. 56. The method of claim 53, wherein the diagnostic radionuclide is a non-metallic radionuclide. 57. The method of claim 39, wherein the linker is a divalent radical comprising a peptide. 58. The method of claim 39, wherein the linker is a divalent radical comprising an amino acid. 59. The method of claim 39, wherein the linker is poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly-L-lysine-L-phenylalanine, poly-L-lysine, or poly-L-lysine-L-tyrosine. 60. The method of claim 2, wherein the compound of formula I is further linked to a linker comprising a detectable radionuclide or a therapeutic radionucide. 61. The method of claim 2, wherein the compound of formula I is further linked to a detectable radionuclide. 62. The method of claim 61, wherein the detectable radionuclide is a non-metallic radionuclide. 63. The method of claim 62, wherein the non-metallic radionuclide is Carbon-11, Fluorine-18, Bromine-76, Iodine-123, or Iodine-124. 64. The method of claim 61, wherein the detectable radionuclide is directly linked to the compound of formula I. 65. The method of claim 61, wherein the detectable radionucide is linked by a linker to the compound of formula I. 66. The method of claim 65, wherein the linker is of the formula W-A wherein A is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8) cycloalkyl, or (C6-C10)aryl, wherein W is--N(R)C(═O)--,--C(═O)N(R)--,--OC(═O)--,--C(═O)O--,--O--,--S--,--S(O)--,--S(O)2--,--N(R)--,--C(═O)--, or a direct bond; wherein each R is independently H or (C1-C6)alkyl; and wherein A is substituted with one or more non-metallic radionuclides. 67. The method of claim 65, wherein the linker is about 5 angstroms to about 50 angstroms, inclusive. 68. The method of claim 65, wherein the linker is a divalent peptide or amino acid. 69. The method of claim 65, wherein the linker is poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-omithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly-L-lysine-L-phenylalanine, poly-L-lysine, or poly-L-lysine-L-tyrosine. 70. The method of claim 65, wherein the linker is linked to the 6-position of the compound of formula I or is linked to the a, b, d, or e-carboxamide group of the compound of formula I.
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