Lysosomal enzyme-cleavable antitumor drug conjugates

• US 6,214,345 B1
• Filed: 05/14/1993
• Issued: 04/10/2001
• Est. Priority Date: 05/14/1993
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Firestone, Raymond Armand, Dubowchik, Gene Michael
• Primary Examiner(s): Achutamurthy, Ponnathapura
• Application Number:
  US08/062,366
• Time in Patent Office: 2,888 Days
• Field of Search: 530/391.7, 530/391.9, 530/351, 424/178.1, 424/179.1, 424/181.1, 424/184.1
• US Class Current: 424/178.1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/68 the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
• CPC Class Codes: A61K 47/6809 Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
• CPC Class Codes: A61K 47/6889 Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 5/0205 containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
• CPC Class Codes: C07K 5/021 containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
• CPC Class Codes: C07K 5/06034 the side chain containing 2 to 4 carbon atoms
• CPC Class Codes: C07K 5/06078 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/0812 and aromatic or cycloaliphatic

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.

Claims

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.

2. A compound of claim 1 in which Y is an amino acid selected from the group consisting of alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan and proline.

3. A compound of claim 1 in which Z an amino acid selected from the group consisting of lysine, lysine protected with acetyl or formyl, arginine, arginine protected with tosyl or nitro groups, histidine, ornithine, ornithine protected with acetyl or formyl, and citrulline.

4. A compound of claim 1 in which the

5. A compound of claim 1 in which the

6. A compound of claim 1 in which the

7. A compound of claim 2 in which Y is phenylalanine.

8. A compound of claim 2 in which Y is valine.

9. A compound of claim 3 in which Z is lysine.

10. A compound of claim 3 in which Z is citrulline.

11. The compound of claim 1 in which D is a cytotoxic drug.

12. The compound of claim 2 in which D is a cytotoxic drug.

13. The compound of claim 3 in which D is a cytotoxic drug.

14. The compound of claim 4 in which D is a cytotoxic drug.

15. The compound of claim 5 in which D is a cytotoxic drug.

16. The compound of claim 6 in which D is a cytotoxic drug.

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.

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.

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.

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.

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.

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.

23. A compound of claim 17 in which D is doxorubicin.

24. A compound of claim 18 in which D is doxorubicin.

25. A compound of claim 19 in which D is doxorubicin.

26. A compound of claim 20 in which D is doxorubicin.

27. A compound of claim 21 in which D is doxorubicin.

28. A compound of claim 22 in which D is doxorubicin.

29. A compound of claim 17 in which D is mitomycin-C.

30. A compound of claim 18 in which D is mitomycin-C.

31. A compound of claim 19 in which D is mitomycin-C.

32. A compound of claim 20 in which D is mitomycin-C.

33. A compound of claim 21 in which D is mitomycin-C.

34. A compound of claim 22 in which D is mitomycin-C.

35. A compound of claim 17 in which D is mitomycin-A.

36. A compound of claim 18 in which D is mitomycin-A.

37. A compound of claim 19 in which D is mitomycin-A.

38. A compound of claim 20 in which D is mitomycin-A.

39. A compound of claim 21 in which D is mitomycin-A.

40. A compound of claim 22 in which D is mitomycin-A.

41. A compound of claim 17 in which D is tallysomycin.

42. A compound of claim 18 in which D is tallysomycin.

43. A compound of claim 19 in which D is tallysomycin.

44. A compound of claim 20 in which D is tallysomycin.

45. A compound of claim 21 in which D is tallysomycin.

46. A compound of claim 22 in which D is tallysomycin.

47. A compound of claim 17 in which D is N-(5,5-diacetoxypentyl)doxorubicin.

48. A compound of claim 18 in which D is N-(5,5-diacetoxypentyl)doxorubicin.

49. A compound of claim 19 in which D is N-(5,5-diacetoxypentyl)doxorubicin.

50. A compound of claim 20 in which D is N-(5,5-diacetoxypentyl)doxorubicin.

51. A compound of claim 21 in which D is N-(5,5-diacetoxypentyl)doxorubicin.

52. A compound of claim 22 in which D is N-(5,5-diacetoxypentyl)doxorubicin.

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.

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.

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.

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.

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.

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.

59. A compound of claim 53 in which D is taxol.

60. A compound of claim 54 in which D is taxol.

61. A compound of claim 55 in which D is taxol.

62. A compound of claim 56 in which D is taxol.

63. A compound of claim 57 in which D is taxol.

64. A compound of claim 58 in which D is taxol.

65. A compound of claim 53 in which D is etoposide.

66. A compound of claim 54 in which D is etoposide.

67. A compound of claim 55 in which D is etoposide.

68. A compound of claim 56 in which D is etoposide.

69. A compound of claim 57 in which D is etoposide.

70. A compound of claim 58 in which D is etoposide.

71. A compound of claim 53 in which D is morpholino-doxorubicin.

72. A compound of claim 54 in which D is morpholino-doxorubicin.

73. A compound of claim 55 in which D is morpholino-doxorubicin.

74. A compound of claim 56 in which D is morpholino-doxorubicin.

75. A compound of claim 57 in which D is morpholino-doxorubicin.

76. A compound of claim 58 in which D is morpholino-doxorubicin.

77. A compound of claim 53 in which D is N-(5,5-diacetoxypentyl)doxorubicin.

78. A compound of claim 54 in which D is N-(5,5-diacetoxypentyl)doxorubicin.

79. A compound of claim 55 in which D is N-(5,5-diacetoxypentyl)doxorubicin.

80. A compound of claim 56 in which D is N-(5,5-diacetoxypentyl)doxorubicin.

81. A compound of claim 57 in which D is N-(5,5-diacetoxypentyl)doxorubicin.

82. A compound of claim 58 in which D is N-(5,5-diacetoxypentyl)doxorubicin.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

95. A compound of claim 89 in which D is camptothecin.

96. A compound of claim 90 in which D is camptothecin.

97. A compound of claim 91 in which D is camptothecin.

98. A compound of claim 92 in which D is camptothecin.

99. A compound of claim 93 in which D is camptothecin.

100. A compound of claim 94 in which D is camptothecin.

101. A compound of claim 1 in which D is an aldehyde containing drug.

102. A compound of claim 2 in which D is an aldehyde containing drug.

103. A compound of claim 3 in which D is an aldehyde containing drug.

104. A compound of claim 4 in which D is an aldehyde containing drug.

105. A compound of claim 5 in which D is an aldehyde containing drug.

106. A compound of claim 6 in which D is an aldehyde containing drug.

107. A compound of claim 101 in which D is an anthracycline.

108. A compound of claim 102 in which D is an anthracycline.

109. A compound of claim 103 in which D is an anthracycline.

110. A compound of claim 104 which D is an anthracycline.

111. A compound of claim 105 in which D is an anthracycline.

112. A compound of claim 106 in which D is an anthracycline.

113. A compound of claim 1 in which D is a ketone containing drug.

114. A compound of claim 2 in which D is a ketone containing drug.

115. A compound of claim 3 in which D is a ketone containing drug.

116. A compound of claim 4 in which D is a ketone containing drug.

117. A compound of claim 5 in which D is a ketone containing drug.

118. A compound of claim 6 in which D is a ketone containing drug.

119. A compound of claim 113 in which D is an anthracycline.

120. A compound of claim 114 in which D is an anthracycline.

121. A compound of claim 115 in which D is an anthracycline.

122. A compound of claim 116 in which D is an anthracycline.

123. A compound of claim 117 in which D is an anthracycline.

124. A compound of claim 118 in which D is an anthracycline.

125. A compound of claim 1 in which L is an immunoglobulin, or a fragment thereof.

126. A compound of claim 2 in which L is an immunoglobulin, or a fragment thereof.

127. A compound of claim 3 in which L is an immunoglobulin, or a fragment thereof.

128. A compound of claim 4 in which L is an immunoglobulin, or a fragment thereof.

129. A compound of claim 5 in which L is an immunoglobulin, or a fragment thereof.

130. A compound of claim 6 in which L is an immunoglobulin, or a fragment thereof.

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.

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.

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.

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.

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.

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.

137. A compound of claim 131 in which L is a chimeric BR96, a reduced chimeric BR96;

or a fragment thereof.

138. A compound of claim 132 in which L is a chimeric BR96, a reduced chimeric BR96;

or a fragment thereof.

139. A compound of claim 133 in which L is a chimeric BR96, a reduced chimeric BR96;

or a fragment thereof.

140. A compound of claim 134 in which L is a chimeric BR96, a reduced chimeric BR96;

or a fragment thereof.

141. A compound of claim 135 in which L is a chimeric BR96, a reduced chimeric BR96;

or a fragment thereof.

142. A compound of claim 136 in which L is a chimeric BR96, a reduced chimeric BR96;

or a fragment thereof.

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.

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.

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.

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.

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.

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.

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.

180. A compound of claim 168 in which X is α

,α

-dimethyl γ

-aminobutyric acid.

181. A compound of claim 169 in which X is α

,α

-dimethyl γ

-aminobutyric acid.

182. A compound of claim 170 in which X is α

,α

-dimethyl γ

-aminobutyric acid.

183. A compound of claim 171 in which X is α

,α

-dimethyl γ

-aminobutyric acid.

184. A compound of claim 172 in which X is α

,α

-dimethyl γ

-aminobutyric acid.

185. A compound of claim 167 in which X is β

,β

-dimethyl γ

-aminobutyric acid.

186. A compound of claim 168 in which X is β

,β

-dimethyl γ

-aminobutyric acid.

187. A compound of claim 169 in which X is β

,β

-dimethyl γ

-aminobutyric acid.

188. A compound of claim 170 in which X is β

,β

-dimethyl γ

-aminobutyric acid.

189. A compound of claim 171 in which X is β

,β

-dimethyl γ

-aminobutyric acid.

190. A compound of claim 172 in which X is β

,β

-dimethyl γ

-aminobutyric acid.

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.