Lysosomal enzyme-cleavable antitumor drug conjugates
First Claim
Patent Images
1. A compound of the Formula (I):
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in whichL is a ligand, wherein L is capable of specifically targeting a selected cell population;
A is a carboxylic acyl unit;
Y is an amino acid;
Z is an amino acid;
X and W are each a self-immolative spacer;
D is a drug moiety having pendant to the backbone thereof a chemically reactive functional group, said functional group selected from the group consisting of a primary or secondary amine, hydroxyl, sulflydryl, carboxyl, aldehyde and a ketone;
n is an integer of 0 or 1, with the proviso that n cannot be the integer 0 for both Xn and Wn; and
m is an integer of 1, 2, 3, 4, 5 or 6;
and wherein Y and Z comprise a protein peptide sequence which is selectively enzymatically cleavable by tumor associated proteases.
1 Assignment
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Accused Products
Abstract
The present invention relates to drug-ligand conjugates wherein the drug is linked to the ligand through a protein peptide linker and a connector, a process for the preparation of the conjugates, method of controlling the growth of undesirable cells, pharmaceutical compositions, and intermediates thereof.
615 Citations
258 Claims
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1. A compound of the Formula (I):
-
in which L is a ligand, wherein L is capable of specifically targeting a selected cell population;
A is a carboxylic acyl unit;
Y is an amino acid;
Z is an amino acid;
X and W are each a self-immolative spacer;
D is a drug moiety having pendant to the backbone thereof a chemically reactive functional group, said functional group selected from the group consisting of a primary or secondary amine, hydroxyl, sulflydryl, carboxyl, aldehyde and a ketone;
n is an integer of 0 or 1, with the proviso that n cannot be the integer 0 for both Xn and Wn; and
m is an integer of 1, 2, 3, 4, 5 or 6;
and wherein Y and Z comprise a protein peptide sequence which is selectively enzymatically cleavable by tumor associated proteases. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258)
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5. A compound of claim 1 in which the
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6. A compound of claim 1 in which the
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7. A compound of claim 2 in which Y is phenylalanine.
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8. A compound of claim 2 in which Y is valine.
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9. A compound of claim 3 in which Z is lysine.
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10. A compound of claim 3 in which Z is citrulline.
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11. The compound of claim 1 in which D is a cytotoxic drug.
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12. The compound of claim 2 in which D is a cytotoxic drug.
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13. The compound of claim 3 in which D is a cytotoxic drug.
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14. The compound of claim 4 in which D is a cytotoxic drug.
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15. The compound of claim 5 in which D is a cytotoxic drug.
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16. The compound of claim 6 in which D is a cytotoxic drug.
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17. A compound of claim 1 in which D is an amino containing drug moiety selected from the group consisting of mitomycin-C, mitomycin-A, daunorubicin, doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, aminopterin, actinomycin, bleomycin, 9-amino camptothecin, N8-acetyl spermidine, 1-(2 chloroethyl)-1,2-dimethanesulfonyl hydrazide, tallysomycin, and derivatives thereof.
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18. A compound of claim 2 in which D is an amino containing drug moiety selected from the group consisting of mitomycin-C, mitomycin-A, daunorubicin, doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, aminopterin, actinomycin, bleomycin, 9-amino camptothecin, N8-acetyl spermidine, 1-(2 chloroethyl)-1,2-dimethanesulfonyl hydrazide, tallysomycin, and derivatives thereof.
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19. A compound of claim 3 in which D is an amino containing drug moiety selected from the group consisting of mitomycin-C, mitomycin-A, daunorubicin, doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, aminopterin, actinomycin, bleomycin, 9-amino camptothecin, N8-acetyl spermidine, 1-(2 chloroethyl)-1,2-dimethanesulfonyl hydrazide, tallysomycin, and derivatives thereof.
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20. A compound of claim 4 in which D is an amino containing drug moiety selected from the group consisting of mitomycin-C, mitomycin-A, daunorubicin, doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, aminopterin, actinomycin, bleomycin, 9-amino camptothecin, N8-acetyl spermidine, 1- (2 chloroethyl)-1,2-dimethanesulfonyl hydrazide, tallysomycin, and derivatives thereof.
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21. A compound of claim 5 in which D is an amino containing drug moiety selected from the group consisting of mitomycin-C, mitomycin-A, daunorubicin, doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, aminopterin, actinomycin, bleomycin, 9-amino camptothecin, N8-acetyl spermidine, 1-(2 chloroethyl)-1,2-dimethanesulfonyl hydrazide, tallysomycin, and derivatives thereof.
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22. A compound of claim 6 in which D is an amino containing drug moiety selected from the group consisting of mitomycin-C, mitomycin-A, daunorubicin, doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, aminopterin, actinomycin, bleomycin, 9-amino camptothecin, N8-acetyl spermidine, 1-(2 chloroethyl)-1,2-dimethanesulfonyl hydrazide, tallysomycin, and derivatives thereof.
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23. A compound of claim 17 in which D is doxorubicin.
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24. A compound of claim 18 in which D is doxorubicin.
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25. A compound of claim 19 in which D is doxorubicin.
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26. A compound of claim 20 in which D is doxorubicin.
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27. A compound of claim 21 in which D is doxorubicin.
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28. A compound of claim 22 in which D is doxorubicin.
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29. A compound of claim 17 in which D is mitomycin-C.
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30. A compound of claim 18 in which D is mitomycin-C.
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31. A compound of claim 19 in which D is mitomycin-C.
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32. A compound of claim 20 in which D is mitomycin-C.
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33. A compound of claim 21 in which D is mitomycin-C.
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34. A compound of claim 22 in which D is mitomycin-C.
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35. A compound of claim 17 in which D is mitomycin-A.
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36. A compound of claim 18 in which D is mitomycin-A.
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37. A compound of claim 19 in which D is mitomycin-A.
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38. A compound of claim 20 in which D is mitomycin-A.
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39. A compound of claim 21 in which D is mitomycin-A.
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40. A compound of claim 22 in which D is mitomycin-A.
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41. A compound of claim 17 in which D is tallysomycin.
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42. A compound of claim 18 in which D is tallysomycin.
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43. A compound of claim 19 in which D is tallysomycin.
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44. A compound of claim 20 in which D is tallysomycin.
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45. A compound of claim 21 in which D is tallysomycin.
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46. A compound of claim 22 in which D is tallysomycin.
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47. A compound of claim 17 in which D is N-(5,5-diacetoxypentyl)doxorubicin.
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48. A compound of claim 18 in which D is N-(5,5-diacetoxypentyl)doxorubicin.
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49. A compound of claim 19 in which D is N-(5,5-diacetoxypentyl)doxorubicin.
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50. A compound of claim 20 in which D is N-(5,5-diacetoxypentyl)doxorubicin.
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51. A compound of claim 21 in which D is N-(5,5-diacetoxypentyl)doxorubicin.
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52. A compound of claim 22 in which D is N-(5,5-diacetoxypentyl)doxorubicin.
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53. A compound of claim 1 in which D is a hydroxyl containing drug moiety selected from the group consisting of etoposide, camptothecin, taxol, esperamicin, 1,8-dihydroxy-bicyclo[7.3.1]trideca-4,9-diene-2,6-diyne-13-one, anguidine, doxorubicin, morpholino-doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, vincristine, vinblastine and derivatives thereof.
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54. A compound of claim 2 in which D is a hydroxyl containing drug moiety selected from the group consisting of etoposide, camptothecin, taxol, esperamicin, 1,8-dihydroxy-bicyclo[7.3.1]trideca-4,9-ene-2,6-diyne-13-one, anguidine, doxorubicin, morpholino-doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, vincristine, vinblastine and derivatives thereof.
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55. A compound of claim 3 in which D is a hydroxyl containing drug moiety selected from the group consisting of etoposide, camptothecin, taxol, esperamicin, 1,8-dihydroxy-bicyclo[7.3.1]trideca-4,9-ene-2,6-diyne-13-one, anguidine, doxorubicin, morpholino-doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, vincristine, vinblastine and derivatives thereof.
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56. A compound of claim 4 in which D is a hydroxyl containing drug moiety selected from the group consisting of etoposide, camptothecin, taxol, esperamicin, 1,8-dihydroxy-bicyclo[7.3.1]trideca-4,9-ene-2,6-diyne-13-one, anguidine, doxorubicin, morpholino-doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, vincristine, vinblastine and derivatives thereof.
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57. A compound of claim 5 in which D is a hydroxyl containing drug moiety selected from the group consisting of etoposide, camptothecin, taxol, esperamicin, 1,8-dihydroxy-bicyclo[7.3.1]trideca-4,9-ene-2,6-diyne-13-one, anguidine, doxorubicin, morpholino-doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, vincristine, vinblastine and derivatives thereof.
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58. A compound of claim 6 in which D is a hydroxyl containing drug moiety selected from the group consisting of etoposide, camptothecin, taxol, esperamicin, 1,8-dihydroxy-bicyclo[7.3.1]trideca-4,9-ene-2,6-diyne-13-one, anguidine, doxorubicin, morpholino-doxorubicin, and derivatives thereof.
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59. A compound of claim 53 in which D is taxol.
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60. A compound of claim 54 in which D is taxol.
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61. A compound of claim 55 in which D is taxol.
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62. A compound of claim 56 in which D is taxol.
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63. A compound of claim 57 in which D is taxol.
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64. A compound of claim 58 in which D is taxol.
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65. A compound of claim 53 in which D is etoposide.
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66. A compound of claim 54 in which D is etoposide.
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67. A compound of claim 55 in which D is etoposide.
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68. A compound of claim 56 in which D is etoposide.
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69. A compound of claim 57 in which D is etoposide.
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70. A compound of claim 58 in which D is etoposide.
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71. A compound of claim 53 in which D is morpholino-doxorubicin.
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72. A compound of claim 54 in which D is morpholino-doxorubicin.
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73. A compound of claim 55 in which D is morpholino-doxorubicin.
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74. A compound of claim 56 in which D is morpholino-doxorubicin.
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75. A compound of claim 57 in which D is morpholino-doxorubicin.
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76. A compound of claim 58 in which D is morpholino-doxorubicin.
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77. A compound of claim 53 in which D is N-(5,5-diacetoxypentyl)doxorubicin.
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78. A compound of claim 54 in which D is N-(5,5-diacetoxypentyl)doxorubicin.
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79. A compound of claim 55 in which D is N-(5,5-diacetoxypentyl)doxorubicin.
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80. A compound of claim 56 in which D is N-(5,5-diacetoxypentyl)doxorubicin.
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81. A compound of claim 57 in which D is N-(5,5-diacetoxypentyl)doxorubicin.
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82. A compound of claim 58 in which D is N-(5,5-diacetoxypentyl)doxorubicin.
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83. A compound of claim 1 in which D is a sulfhydryl containing drug moiety selected from the group consisting of esperamicin, 6-mercaptopurine, or derivatives thereof.
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84. A compound of claim 2 in which D is a sulfhydryl containing drug moiety selected from the group consisting of esperamicin, 6-mercaptopurine, or derivatives thereof.
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85. A compound of claim 3 in which D is a sulfhydryl containing drug moiety selected from the group consisting of esperamicin, 6-mercaptopurine, or derivatives thereof.
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86. A compound of claim 4 in which D is a sulfhydryl containing drug moiety selected from the group consisting of esperamicin, 6-mercaptopurine, or derivatives thereof.
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87. A compound of claim 5 in which D is a sulfhydryl containing drug moiety selected from the group consisting of esperamicin, 6-mercaptopurine, or derivatives thereof.
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88. A compound of claim 6 in which D is a sulfhydryl containing drug moiety selected from the group consisting of esperamicin, 6-mercaptopurine, or derivatives thereof.
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89. A compound of claim 1 in which D is a carboxyl containing drug moiety selected from the group consisting of methotrexate, camptothecin (ring-opened form of the lactone), butyric acid, retinoic acid, and derivatives thereof.
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90. A compound of claim 2 in which D is a carboxyl containing drug moiety selected from the group consisting of methotrexate, camptothecin (ring-opened form of the lactone), butyric acid, retinoic acid, and derivatives thereof.
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91. A compound of claim 3 in which D is a carboxyl containing drug moiety selected from the group consisting of methotrexate, camptothecin (ring-opened form of the lactone), butyric acid, retinoic acid, and derivatives thereof.
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92. A compound of claim 4 in which D is a carboxyl containing drug moiety selected from the group consisting of methotrexate, camptothecin (ring-opened form of the lactone), butyric acid, retinoic acid, and derivatives thereof.
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93. A compound of claim 5 in which D is a carboxyl containing drug moiety selected from the group consisting of methotrexate, camptothecin (ring-opened form of the lactone), butyric acid, retinoic acid, and derivatives thereof.
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94. A compound of claim 6 in which D is a carboxyl containing drug moiety selected from the group consisting of methotrexate, camptothecin (ring-opened form of the lactone), butyric acid, retinoic acid, and derivatives thereof.
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95. A compound of claim 89 in which D is camptothecin.
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96. A compound of claim 90 in which D is camptothecin.
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97. A compound of claim 91 in which D is camptothecin.
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98. A compound of claim 92 in which D is camptothecin.
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99. A compound of claim 93 in which D is camptothecin.
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100. A compound of claim 94 in which D is camptothecin.
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101. A compound of claim 1 in which D is an aldehyde containing drug.
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102. A compound of claim 2 in which D is an aldehyde containing drug.
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103. A compound of claim 3 in which D is an aldehyde containing drug.
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104. A compound of claim 4 in which D is an aldehyde containing drug.
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105. A compound of claim 5 in which D is an aldehyde containing drug.
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106. A compound of claim 6 in which D is an aldehyde containing drug.
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107. A compound of claim 101 in which D is an anthracycline.
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108. A compound of claim 102 in which D is an anthracycline.
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109. A compound of claim 103 in which D is an anthracycline.
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110. A compound of claim 104 which D is an anthracycline.
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111. A compound of claim 105 in which D is an anthracycline.
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112. A compound of claim 106 in which D is an anthracycline.
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113. A compound of claim 1 in which D is a ketone containing drug.
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114. A compound of claim 2 in which D is a ketone containing drug.
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115. A compound of claim 3 in which D is a ketone containing drug.
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116. A compound of claim 4 in which D is a ketone containing drug.
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117. A compound of claim 5 in which D is a ketone containing drug.
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118. A compound of claim 6 in which D is a ketone containing drug.
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119. A compound of claim 113 in which D is an anthracycline.
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120. A compound of claim 114 in which D is an anthracycline.
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121. A compound of claim 115 in which D is an anthracycline.
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122. A compound of claim 116 in which D is an anthracycline.
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123. A compound of claim 117 in which D is an anthracycline.
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124. A compound of claim 118 in which D is an anthracycline.
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125. A compound of claim 1 in which L is an immunoglobulin, or a fragment thereof.
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126. A compound of claim 2 in which L is an immunoglobulin, or a fragment thereof.
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127. A compound of claim 3 in which L is an immunoglobulin, or a fragment thereof.
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128. A compound of claim 4 in which L is an immunoglobulin, or a fragment thereof.
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129. A compound of claim 5 in which L is an immunoglobulin, or a fragment thereof.
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130. A compound of claim 6 in which L is an immunoglobulin, or a fragment thereof.
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131. A compound of claim 125 in which L is an immunoglobulin selected from the group consisting of BR96, BR64, L6, a reduced BR96, a reduced BR64, a reduced L6, a chimeric BR96, a relaxed chimeric BR64, a chimeric L6, a reduced chimeric BR96, a reduced chimeric BR64, a reduced chimeric L6;
- and, a fragment thereof.
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132. A compound of claim 126 in which L is an immunoglobulin selected from the group consisting of BR96, BR64, L6, a reduced BR96, a reduced BR64, a reduced L6, a chimeric BR96, a relaxed chimeric BR64, a chimeric L6, a reduced chimeric BR96, a reduced chimeric BR64, a reduced chimeric L6;
- and, a fragment thereof.
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133. A compound of claim 127 in which L is an immunoglobulin selected from the group consisting of BR96, BR64, L6, a reduced BR96, a reduced BR64, a reduced L6, a chimeric BR96, a relaxed chimeric BR64, a chimeric L6, a reduced chimeric BR96, a reduced chimeric BR64, a reduced chimeric L6;
- and, a fragment thereof.
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134. A compound of claim 128 in which L is an immunoglobulin selected from the group consisting of BR96, BR64, L6, a reduced BR96, a reduced BR64, a reduced L6, a chimeric BR96, a relaxed chimeric BR64, a chimeric L6, a reduced chimeric BR96, a reduced chimeric BR64, a reduced chimeric L6;
- and, a fragment thereof.
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135. A compound of claim 129 in which L is an immunoglobulin selected from the group consisting of BR96, BR64, L6, a reduced BR96, a reduced BR64, a reduced L6, a chimeric BR96, a relaxed chimeric BR64, a chimeric L6, a reduced chimeric BR96, a reduced chimeric BR64, a reduced chimeric L6;
- and, a fragment thereof.
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136. A compound of claim 130 in which L is an immunoglobulin selected from the group consisting of BR96, BR64, L6, a reduced BR96, a reduced BR64, a reduced L6, a chimeric BR96, a relaxed chimeric BR64, a chimeric L6, a reduced chimeric BR96, a reduced chimeric BR64, a reduced chimeric L6;
- and, a fragment thereof.
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137. A compound of claim 131 in which L is a chimeric BR96, a reduced chimeric BR96;
- or a fragment thereof.
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138. A compound of claim 132 in which L is a chimeric BR96, a reduced chimeric BR96;
- or a fragment thereof.
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139. A compound of claim 133 in which L is a chimeric BR96, a reduced chimeric BR96;
- or a fragment thereof.
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140. A compound of claim 134 in which L is a chimeric BR96, a reduced chimeric BR96;
- or a fragment thereof.
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141. A compound of claim 135 in which L is a chimeric BR96, a reduced chimeric BR96;
- or a fragment thereof.
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142. A compound of claim 136 in which L is a chimeric BR96, a reduced chimeric BR96;
- or a fragment thereof.
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143. A compound of claim 1 in which L is a ligand selected from the group consisting of bombesin, EDG, transferrin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, TFG-α
- , TFG-β
, VGF, insulin and insulin-like growth factors I and II.
- , TFG-β
-
144. A compound of claim 2 in which L is a ligand selected from the group consisting of bombesin, EDG, transferrin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, TFG-α
- , TFG-β
, VGF, insulin and insulin-like growth factors I and II.
- , TFG-β
-
145. A compound of claim 3 in which L is a ligand selected from the group consisting of bombesin, EDG, transferrin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, TFG-α
- , TFG-β
, VGF, insulin and insulin-like growth factors I and II.
- , TFG-β
-
146. A compound of claim 4 in which L is a ligand selected from the group consisting of bombesin, EDG, transferrin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, TFG-α
- , TFG-β
, VGF, insulin and insulin-like growth factors I and II.
- , TFG-β
-
147. A compound of claim 5 in which L is a ligand selected from the group consisting of bombesin, EDG, transferrin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, TFG-α
- , TFG-β
, VGF, insulin and insulin-like growth factors I and II.
- , TFG-β
-
148. A compound of claim 6 in which L is a ligand selected from the group consisting of bombesin, EDG, transferrin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, TFG-α
- , TFG-β
, VGF, insulin and insulin-like growth factors I and II.
- , TFG-β
-
149. A compound of claim 1 in which L is a ligand selected from the group consisting of carbohydrates, lectins, and apoprotein from low density lipoproteins.
-
150. A compound of claim 2 in which L is a ligand selected from the group consisting of carbohydrates, lectins, and apoprotein from low density lipoproteins.
-
151. A compound of claim 3 in which L is a ligand selected from the group consisting of carbohydrates, lectins, and apoprotein from low density lipoproteins.
-
152. A compound of claim 4 in which L is a ligand selected from the group consisting of carbohydrates, lectins, and apoprotein from low density lipoproteins.
-
153. A compound of claim 5 in which L is a ligand selected from the group consisting of carbohydrates, lectins, and apoprotein from low density lipoproteins.
-
154. A compound of claim 6 in which L is a ligand selected from the group consisting of carbohydrates, lectins, and apoprotein from low density lipoproteins.
-
155. A compound of claim 1 in which X is the compound having the Formula
in which T is O, N, or S. -
156. A compound of claim 2 in which X is the compound having the Formula
in which T is O, N, or S. -
157. A compound of claim 3 in which X is the compound having the Formula
in which T is O, N, or S. -
158. A compound of claim 4 in which X is the compound having the Formula
in which T is O, N, or S. -
159. A compound of claim 5 in which X is the compound having the Formula
in which T is O, N, or S. -
160. A compound of claim 6 in which X is the compound having the Formula
in which T is O, N, or S. -
161. A compound of claim 155 in which X is p-aminobenzyl-carbamoyloxy.
-
162. A compound of claim 156 in which X is p-aminobenzyl-carbamoyloxy.
-
163. A compound of claim 157 in which X is p-aminobenzyl-carbamoyloxy.
-
164. A compound of claim 158 in which X is p-aminobenzyl-carbamoyloxy.
-
165. A compound of claim 159 in which X is p-aminobenzyl-carbamoyloxy.
-
166. A compound of claim 160 in which X is p-aminobenzyl-carbamoyloxy.
-
167. A compound of claim 1 in which X is the compound having the Formula
-
168. A compound of claim 2 in which X is the compound having the Formula
-
169. A compound of claim 3 in which X is the compound having the Formula
-
170. A compound of claim 4 in which X is the compound having the Formula
-
171. A compound of claim 5 in which X is the compound having the Formula
-
172. A compound of claim 6 in which X is the compound having the Formula
-
173. A compound of claim 167 in which X is γ
- -aminobutyric acid.
-
174. A compound of claim 168 in which X is γ
- -aminobutyric acid.
-
175. A compound of claim 169 in which X is γ
- -aminobutyric acid.
-
176. A compound of claim 170 in which X is γ
- -aminobutyric acid.
-
177. A compound of claim 171 in which X is γ
- -aminobutyric acid.
-
178. A compound of claim 172 in which X is γ
- -aminobutyric acid.
-
179. A compound of claim 167 in which X is α
- ,α
-dimethyl γ
-aminobutyric acid.
- ,α
-
180. A compound of claim 168 in which X is α
- ,α
-dimethyl γ
-aminobutyric acid.
- ,α
-
181. A compound of claim 169 in which X is α
- ,α
-dimethyl γ
-aminobutyric acid.
- ,α
-
182. A compound of claim 170 in which X is α
- ,α
-dimethyl γ
-aminobutyric acid.
- ,α
-
183. A compound of claim 171 in which X is α
- ,α
-dimethyl γ
-aminobutyric acid.
- ,α
-
184. A compound of claim 172 in which X is α
- ,α
-dimethyl γ
-aminobutyric acid.
- ,α
-
185. A compound of claim 167 in which X is β
- ,β
-dimethyl γ
-aminobutyric acid.
- ,β
-
186. A compound of claim 168 in which X is β
- ,β
-dimethyl γ
-aminobutyric acid.
- ,β
-
187. A compound of claim 169 in which X is β
- ,β
-dimethyl γ
-aminobutyric acid.
- ,β
-
188. A compound of claim 170 in which X is β
- ,β
-dimethyl γ
-aminobutyric acid.
- ,β
-
189. A compound of claim 171 in which X is β
- ,β
-dimethyl γ
-aminobutyric acid.
- ,β
-
190. A compound of claim 172 in which X is β
- ,β
-dimethyl γ
-aminobutyric acid.
- ,β
-
191. A compound of claim 1 in which X is the compound having the Formula
in which T is O, N, or S, R2 is H or C1-C5 alkyl. -
192. A compound of claim 2 in which X is the compound having the Formula
in which T is O, N, or S, R2 is H or C1-C5 alkyl. -
193. A compound of claim 3 in which X is the compound having the Formula
in which T is O, N, or S, R2 is H or C1-C5 alkyl. -
194. A compound of claim 4 in which X is the compound having the Formula
in which T is O, N, or S, R2 is H or C1-C5 alkyl. -
195. A compound of claim 5 in which X is the compound having the Formula
in which T is O, N, or S, R2 is H or C1-C5 alkyl. -
196. A compound of claim 6 in which X is the compound having the Formula
in which T is O, N, or S, R2 is H or C1-C5 alkyl. -
197. A compound of claim 1 in which W is
in which T is O, S or N. -
198. A compound of claim 2 in which W is
in which T is O, S or N. -
199. A compound of claim 3 in which W is
in which T is O, S or N. -
200. A compound of claim 4 in which W is
in which T is O, S or N. -
201. A compound of claim 5 in which W is
in which T is O, S or N. -
202. A compound of claim 6 in which W is
in which T is O, S or N. -
203. A compound of claim 1 in which A is
in which q is 1-10. -
204. A compound of claim 2 in which A is
in which q is 1-10. -
205. A compound of claim 3 in which A is
in which q is 1-10. -
206. A compound of claim 4 in which A is
in which q is 1-10. -
207. A compound of claim 5 in which A is
in which q is 1-10. -
208. A compound of claim 6 in which A is
in which q is 1-10. -
209. A compound of claim 1 in which A is 4-(N-succinimidomethyl)cyclohexane-1-carbonyl.
-
210. A compound of claim 2 in which A is 4-(N-succinimidomethyl)cyclohexane-1-carbonyl.
-
211. A compound of claim 3 in which A is 4-(N-succinimidomethyl)cyclohexane-1-carbonyl.
-
212. A compound of claim 4 in which A is 4-(N-succinimidomethyl)cyclohexane-1-carbonyl.
-
213. A compound of claim 5 in which A is 4-(N-succinimidomethyl)cyclohexane-1-carbonyl.
-
214. A compound of claim 6 in which A is 4-(N-succinimidomethyl)cyclohexane-1-carbonyl.
-
215. A compound of claim 1 in which A is m-succinimidobenzoyl.
-
216. A compound of claim 2 in which A is m-succinimidobenzoyl.
-
217. A compound of claim 3 in which A is m-succinimidobenzoyl.
-
218. A compound of claim 4 in which A is m-succinimidobenzoyl.
-
219. A compound of claim 5 in which A is m-succinimidobenzoyl.
-
220. A compound of claim 6 in which A is m-succinimidobenzoyl.
-
221. A compound of claim 1 in which A is 4-(p-succinimidophenyl)butyryl.
-
222. A compound of claim 2 in which A is 4-(p-succinimidophenyl)butyryl.
-
223. A compound of claim 3 in which A is 4-(p-succinimidophenyl)butyryl.
-
224. A compound of claim 4 in which A is 4-(p-succinimidophenyl)butyryl.
-
225. A compound of claim 5 in which A is 4-(p-succinimidophenyl)butyryl.
-
226. A compound of claim 6 in which A is 4-(p-succinimidophenyl)butyryl.
-
227. A compound of claim 1 in which A is 4-(2-acetamido)benzoyl.
-
228. A compound of claim 2 in which A is 4-(2-acetamido)benzoyl.
-
229. A compound of claim 3 in which A is 4-(2-acetamido)benzoyl.
-
230. A compound of claim 4 in which A is 4-(2-acetamido)benzoyl.
-
231. A compound of claim 5 in which A is 4-(2-acetamido)benzoyl.
-
232. A compound of claim 6 in which A is 4-(2-acetamido)benzoyl.
-
233. A compound of claim 1 in which A is 3-thiopropionyl.
-
234. A compound of claim 2 in which A is 3-thiopropionyl.
-
235. A compound of claim 3 in which A is 3-thiopropionyl.
-
236. A compound of claim 4 in which A is 3-thiopropionyl.
-
237. A compound of claim 5 in which A is 3-thiopropionyl.
-
238. A compound of claim 6 in which A is 3-thiopropionyl.
-
239. A compound of claim 1 in which A is 4-(1-thioethyl)-benzoyl.
-
240. A compound of claim 2 in which A is 4-(1-thioethyl)-benzoyl.
-
241. A compound of claim 3 in which A is 4-(1-thioethyl)-benzoyl.
-
242. A compound of claim 4 in which A is 4-(1-thioethyl)-benzoyl.
-
243. A compound of claim 5 in which A is 4-(1-thioethyl)-benzoyl.
-
244. A compound of claim 6 in which A is 4-(1-thioethyl)-benzoyl.
-
245. A compound of claim 1 in which A is 6-(3-thiopropionylamido)-hexanoyl.
-
246. A compound of claim 2 in which A is 6-(3-thiopropionylamido)-hexanoyl.
-
247. A compound of claim 3 in which A is 6-(3-thiopropionylamido)-hexanoyl.
-
248. A compound of claim 4 in which A is 6-(3-thiopropionylamido)-hexanoyl.
-
249. A compound of claim 5 in which A is 6-(3-thiopropionylamido)-hexanoyl.
-
250. A compound of claim 6 in which A is 6-(3-thiopropionylamido)-hexanoyl.
-
251. A compound of claim 1 which is BR96-succinimidocaproyl-phenylalanine-lysine-p-aminobenzyl-carbamoyloxy-doxrubicin.
-
252. A compound of claim 1 which is BR96-succinimidocaproyl-valine-lysine-p-aminobenzyl-carbamoyloxy-doxorubicin.
-
253. A compound of claim 1 which is BR96-succinimidocaproyl-valine-citrulline-p-aminobenzyl-carbamoyloxy-doxorubicin.
-
254. A compound of claim 1 which is BR96-succinimidocaproyl-phenylalanine-lysine-p-aminobenzyl-carbamoyloxy-2′
- -taxol.
-
255. A compound of claim 1 which is BR96-succinimidocaproyl-phenylalanine-lysine-p-aminobenzyl-carbamoyloxy-7-taxol.
-
256. A compound of claim 1 which is BR96-succinimidocaproyl-phenylalanine-lysine-p-aminobenzyl-carbamoyloxy-mitomycin-C.
-
257. A compound of claim 1 which is BR96-succinimidocaproyl-phenylalanine-lysine-gamma-aminobutyric acid-mitomycin-C.
-
258. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
-
Specification