P-amidobenzylethers in drug delivery agents

• US 20030130189A1
• Filed: 09/23/2002
• Published: 07/10/2003
• Est. Priority Date: 09/24/2001
• Status: Active Grant

• Current Assignee: Seagen Inc.
• Original Assignee: Seattle Genetics Incorporated
• Inventors: Senter, Peter D., Toki, Brian E.
• Granted Patent: US 7,553,816 B2
• Time in Patent Office: Days
• US Class Current: 514/12
• 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

Abstract

Compounds of the formulas

LA_n-Z-X-W_wD and BZ-X-W_wD

wherein: D is a drug moiety; L is a ligand; B is a blocking group; A is an optional acyl unit; Z is an amino acid or a peptide; X is an aminobenzyl ether self-immolative spacer group; W is an optional second self-immolative group; n is an integer of 0 or 1; and w is an integer of 0 or 1, and compositions of said compounds with pharmaceutically acceptable carrier, diluent and/or excipient, and methods of delivery the drug D via the compounds.

Claims

1. A compound of the formula:

L

A_n-Z-X-W_w

D

wherein;

D is a drug moiety;

L is a ligand;

A is an optional acyl unit;

Z is an amino acid or a peptide;

X is an aminobenzyl ether self-immolative group;

W is an optional second self-immolative group;

n is an integer of 0 or 1; and

w is an integer of 0 or 1.

3. A compound of claim 1, represented by the following formula:

4. A compound of claim 1, represented by the following formula:

7. A compound of claim 3 wherein the O of —

O-D is bonded to a carbon that forms an aromatic ring of D.

9. A compound of claim 7 wherein the drug is 1,2,9,9a-tetra-hydro-cyclo-propa[c]benz[e]indol-4-one (CBI) conjugated to a minor groove binder.

10. A compound of claim 7 wherein the drug is cyclopropapyrroloindole (CPI) conjugated to a minor groove binder.

11. A compound of claim 7 wherein the drug is 1,2,9,9a-tetra-hydro-cyclo-propa[c]pyrido[3,2-e]indol-4-one (CPyI) conjugated to a minor groove binder.

12. A compound of claim 7 wherein the drug is selected from:

U-76,073;

seco-adozelesin;

bizelesin;

1,2,9,9a-tetra-hydro-cyclo-propa[c]benz[e]indol-4-one-trimethoxyindole (CBI-TMI);

duocarmycin C2;

duocarmycin B2;

seco-CC-1065;

pancratistatin;

caminomycin;

streptonigrin;

zorubicin;

elliptinium acetate;

mitoxantrone;

daunorubicin;

phenol mustard;

doxorubicin;

etoposide, combretastatin A-4, and 7-ethyl-10-hydroxycamptothecin (SN-38).

17. A compound of claim 3 wherein the O of —

O-D is bonded to an aliphatic carbon of D.

19. A compound of claim 17 in which the drug is auristatin E.

21. A compound of claim 3 wherein the H of H-O-D has a pKa of 16 or less.

23. A compound of claim 4 wherein T is NH or N(lower alkyl).

25. A compound of claim 4 wherein T is O or S.

27. A compound of claim 23 wherein the drug is selected from 5-amino-1,2,9,9a-tetra-hydro-cyclopropa[c]benz[e]indol-4-one (CBI) conjugated to a minor groove binder;

5-amino-cyclopropapyrroloindole (CPI) conjugated to a minor groove binder; and

5-amino-1,2,9,9a-tetra-hydro-cyclopropa[c]pyrido[3,2-e]indol-4-one (CPyI) conjugated to a minor groove binder.

29. A compound of claim 23 wherein the drug 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.

31. A compound of claim 25 wherein the drug is auristatin E.

33. A compound of claim 25 wherein the drug 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.

35. A compound of claim 25 wherein the drug is a sulfhydryl-containing moiety selected from the group consisting of esperamicin, 6-mercaptopurine, and derivatives thereof.

37. A compound of claim 3 wherein L is an immunoglobulin, or an antigen-binding fragment thereof.

38. A compound of claim 4 wherein L is an immunoglobulin, or an antigen-binding fragment thereof.

39. A compound of claim 37 wherein L is an mAb selected from the group consisting of BR96, L6, herceptin, rituxan, CD70, S2C6, AC10, and antigen-binding fragments thereof.

40. A compound of claim 38 wherein L is an mAb selected from the group consisting of BR96, L6, herceptin, rituxan, CD70, S2C6, AC 10, and antigen-binding fragments thereof.

41. A compound of claim 3 wherein L is 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, carbohydrates, lectins, and apoprotein from low-density lipoproteins.

42. A compound of claim 4 wherein L is 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, carbohydrates, lectins, and apoprotein from low-density lipoproteins.

43. A compound of claim 3 wherein L is selected from the group consisting of poly(ethylene glycol);

poly(propylene glycol);

(hydroxypropyl)methacrylamide;

chitins;

dextrans;

styrene-co-maleic acid/anhydride, polyglutamic acid and polylysine.

44. A compound of claim 4 wherein L is selected from the group consisting of poly(ethylene glycol);

poly(propylene glycol);

(hydroxypropyl)methacrylamide;

chitins;

dextrans;

styrene-co-maleic acid/anhydride, polyglutamic acid and polylysine.

45. A compound of claim 3 wherein m is 0.

46. A compound of claim 4 wherein m is 0.

49. A compound of claim 3 wherein m is 1 and the substituent is an electron-withdrawing group selected from F, Cl, Br, CN, CF₃, CONH₂, CHO, CO₂CH₃, COCH₃, NHCOCH₃, NO₂, and sulfonyl groups.

50. A compound of claim 4 wherein m is 1 and the substituent is an electron-withdrawing group selected from F, Cl, Br, CN, CF₃, CONH₂, CHO, CO₂CH₃, COCH₃, NHCOCH₃, NO₂, and sulfonyl groups.

53. A compound of claim 3 wherein Z is a dipeptide or a tripeptide.

54. A compound of claim 4 wherein Z is a dipeptide or a tripeptide.

57. A compound of claim 3 wherein Z is valine-citrulline.

58. A compound of claim 4 wherein Z is valine-citrulline.

61. A compound of claim 3 wherein Z is phenylalanine-lysine.

62. A compound of claim 4 wherein Z is phenylalanine-lysine.

65. A compound of claim 3 wherein

66. A compound of claim 4 wherein

69. A compound of claim 3 wherein n is 1.

70. A compound of claim 4 wherein n is 1.

71. A compound of claim 69 wherein A is

72. A compound of claim 70 wherein A is

73. A compound of claim 71 where q=5.

74. A compound of claim 72 where q=5.

77. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

79. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 3 and a pharmaceutically acceptable carrier, diluent or excipient.

80. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 4 and a pharmaceutically acceptable carrier, diluent or excipient.

83. A method of reducing cellular proliferation, the method comprising contacting a cell with an anti-proliferative amount of a compound of claim 1.

84. A method of treating cancer in a mammal, the method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.

85. A method for the treatment of a disease in which intracellular enzymes are released or are made accessible by cell damage which comprises administering to a host in need of said treatment an effective amount of a compound of claim 1.

86. A method for the treatment of an undesirable biological condition comprising administering to a subject having the undesirable condition, an amount of a compound of claim 1 effective to mitigate the biological condition.

91. A method of reducing cellular proliferation, the method comprising contacting a cell with an anti-proliferative amount of a compound of claim 3.

92. A method of treating cancer in a mammal, the method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 3.

93. A method for the treatment of a disease in which intracellular enzymes are released or are made accessible by cell damage which comprises administering to a host in need of said treatment an effective amount of a compound of claim 3.

94. A method for the treatment of an undesirable biological condition comprising administering to a subject having the undesirable condition, an amount of a compound of claim 3 effective to mitigate the biological condition.

95. A method of reducing cellular proliferation, the method comprising contacting a cell with an anti-proliferative amount of a compound of claim 4.

96. A method of treating cancer in a mammal, the method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 4.

97. A method for the treatment of a disease in which intracellular enzymes are released or are made accessible by cell damage which comprises administering to a host in need of said treatment an effective amount of a compound of claim 4.

98. A method for the treatment of an undesirable biological condition comprising administering to a subject having the undesirable condition, an amount of a compound of claim 4 effective to mitigate the biological condition.

2. A compound of the formula:

B

Z-X-W_w

D

wherein;

D is a drug moiety;

B is a blocking group;

Z is an amino acid or a peptide;

X is an aminobenzyl ether self-immolative group;

W is an optional second self-immolative group; and

w is an integer of 0 or 1.

5. A compound of claim 2, represented by the following formula:

6. A compound of claim 2, represented by the following formula

8. A compound of claim 5 wherein the O of —

O-D is bonded to a carbon that forms an aromatic ring of D.

13. A compound of claim 8 wherein the drug is 1,2,9,9a-tetra-hydro-cyclo-propa[c]benz[e]indol-4-one (CBI) conjugated to a minor groove binder.

14. A compound of claim 8 wherein the drug is cyclopropapyrroloindole (CPI) conjugated to a minor groove binder.

15. A compound of claim 8 wherein the drug is 1,2,9,9a-tetra-hydro-cyclo-propa[c]pyrido[3,2-e]indol-4-one (CPyI) conjugated to a minor groove binder.

16. A compound of claim 8 wherein the drug is selected from:

U-76,073;

seco-adozelesin;

bizelesin;

1,2,9,9a-tetra-hydro-cyclo-propa[c]benz[e]indol-4-one-trimethoxyindole (CBI-TMI);

duocarmycin C2;

duocarmycin B2;

seco-CC-1065;

pancratistatin;

caminomycin;

streptonigrin;

zorubicin;

elliptinium acetate;

mitoxantrone;

daunorubicin;

phenol mustard;

doxorubicin;

etoposide, combretastatin A-4, and 7-ethyl-10-hydroxycamptothecin (SN-38).

18. A compound of claim 5 wherein the O of —

O-D is bonded to an aliphatic carbon of D.

20. A compound of claim 18 in which the drug is auristatin E.

22. A compound of claim 5 wherein the H of H—

O-D has a pKa of 16 or less.

24. A compound of claim 6 wherein T is NH or N(lower alkyl).

26. A compound of claim 6 wherein T is O or S.

28. A compound of claim 24 wherein the drug is selected from 5-amino-1,2,9,9a-tetra-hydro-cyclopropa[c]benz[e]indol-4-one (CBI) conjugated to a minor groove binder. 5-amino-cyclopropapyrroloindole (CPI) conjugated to a minor groove binder;

and 5-amino-1,2,9,9a-tetra-hydro-cyclopropa[c]pyrido[3,2-e]indol-4-one (CPyI) conjugated to a minor groove binder.

30. A compound of claim 24 wherein the drug 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.

32. A compound of claim 26 wherein the drug is auristatin E.

34. A compound of claim 26 wherein the drug is a hydroxyl-containing 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.

36. A compound of claim 26 wherein the drug is a sulfhydryl-containing moiety selected from the group consisting of esperamicin, 6-mercaptopurine, and derivatives thereof.

47. A compound of claim 5 wherein m is 0.

48. A compound of claim 6 wherein m is 0.

51. A compound of claim 5 wherein m is 1 and the substituent is an electron-withdrawing group selected from F, Cl, Br, CN, CF₃, CONH₂, CHO, CO₂CH₃, COCH₃, NHCOCH₃, NO₂, and sulfonyl groups.

52. A compound of claim 6 wherein m is 1 and the substituent is an electron-withdrawing group selected from F, Cl, Br, CN, CF₃, CONH₂, CHO, CO₂CH₃, COCH₃, NHCOCH₃, NO₂, and sulfonyl groups.

55. A compound of claim 5 wherein Z is a dipeptide or a tripeptide.

56. A compound of claim 6 wherein Z is a dipeptide or a tripeptide.

59. A compound of claim 5 wherein Z is valine-citrulline.

60. A compound of claim 6 wherein Z is valine-citrulline.

63. A compound of claim 5 wherein Z is phenylalanine-lysine.

64. A compound of claim 6 wherein Z is phenylalanine-lysine.

67. A compound of claim 5 wherein

68. A compound of claim 6 wherein

75. A compound of claim 5 wherein B is a carbobenzoxy protecting group.

76. A compound of claim 6 wherein B is a carbobenzoxy protecting group.

78. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 2 and a pharmaceutically acceptable carrier, diluent or excipient.

81. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 5 and a pharmaceutically acceptable carrier, diluent or excipient.

82. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 6 and a pharmaceutically acceptable carrier, diluent or excipient.

87. A method of reducing cellular proliferation, the method comprising contacting a cell with an anti-proliferative amount of a compound of claim 2.

88. A method of treating cancer in a mammal, the method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 2.

89. A method for the treatment of a disease in which intracellular enzymes are released or are made accessible by cell damage which comprises administering to a host in need of said treatment an effective amount of a compound of claim 2.

90. A method for the treatment of an undesirable biological condition comprising administering to a subject having the undesirable condition, an amount of a compound of claim 2 effective to mitigate the biological condition.

99. A method of reducing cellular proliferation, the method comprising contacting a cell with an anti-proliferative amount of a compound of claim 5.

100. A method of treating cancer in a mammal, the method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 5.

101. A method for the treatment of a disease in which intracellular enzymes are released or are made accessible by cell damage which comprises administering to a host in need of said treatment an effective amount of a compound of claim 5.

102. A method for the treatment of an undesirable biological condition comprising administering to a subject having the undesirable condition, an amount of a compound of claim 5 effective to mitigate the biological condition.

103. A method of reducing cellular proliferation, the method comprising contacting a cell with an anti-proliferative amount of a compound of claim 6.

104. A method of treating cancer in a mammal, the method comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 6.

105. A method for the treatment of a disease in which intracellular enzymes are released or are made accessible by cell damage which comprises administering to a host in need of said treatment an effective amount of a compound of claim 6.

106. A method for the treatment of an undesirable biological condition comprising administering to a subject having the undesirable condition, an amount of a compound of claim 6 effective to mitigate the biological condition.