Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease
First Claim
Patent Images
1. A compound of the Formula Ia:
-
LAa-Ww—
Yy-D)p
Ia or a pharmaceutically acceptable salt or solvate thereof wherein, L- is a Ligand unit;
-A- is a Stretcher unit;
a is 0 or 1;
each —
W—
is independently an Amino Acid unit;
—
Y—
is a Spacer unit;
w is an integer ranging from 0 to 12;
y is 0, 1 or 2;
p ranges from 1 to about 20; and
-D is a Drug unit of the formulawherein, independently at each location;
R2 is selected from —
H and —
C1-C8 alkyl;
R3 is selected from —
H, —
C1-C8 alkyl, —
C3-C8 carbocycle, —
O—
(C1-C8 alkyl), -aryl, —
C1-C8 alkyl-aryl, —
C1-C8 alkyl-(C3-C8 carbocycle), —
C3-C8 heterocycle and —
C1-C8 alkyl-(C3-C8 heterocycle);
R4 is selected from —
H, —
C1-C8 alkyl, —
C3-C8 carbocycle, —
O—
(C1-C8 alkyl), -aryl, —
C1-C8 alkyl-aryl, —
C1-C8 alkyl-(C3-C8 carbocycle), —
C3-C8 heterocycle and —
C1-C8 alkyl-(C3-C8 heterocycle) wherein R5 is selected from —
H and -methyl;
or R4 and R5 join, have the formula —
(CRaRb)n—
wherein Ra and Rb are independently selected from —
H, —
C1-C8 alkyl and —
C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;
R6 is selected from —
H and —
C1-C8 alkyl;
R7 is selected from —
H, —
C1-C8 alkyl, —
C3-C8 carbocycle, —
O—
(C1-C8 alkyl), -aryl, —
C1-C8 alkyl-aryl, —
C1-C8 alkyl-(C3-C8 carbocycle), —
C3-C8 heterocycle and —
C1-C8 alkyl-(C3-C8 heterocycle);
each R8 is independently selected from —
H, —
OH, —
C1-C8 alkyl, —
C3-C8 carbocycle and —
O—
(C1-C8 alkyl);
R9 is selected from —
H and —
C1-C8 alkyl;
R10 is selected fromZ is —
O—
, —
S—
, —
NH—
or —
N(R14)—
;
R11 is selected from —
H, —
OH, —
NH2, —
NHR14, —
R14)2, —
C1-C8 carbocycle, —
O—
(C1-C8 alkyl), -aryl, —
C1-C8 alkyl-aryl, —
C1-C8 alkyl-(C3-C8 carbocycle), —
C3-C8 heterocycle and —
C1-C8 alkyl-(C3-C8 heterocycle);
or R11 is an oxygen atom which forms a carbonyl unit (C═
O) with the carbon atom to which it is attached and a hydrogen atom on this carbon atom is replaced by one of the bonds in the (C═
O) double bond;
each R12 is independently selected from -aryl and —
C3-C8 heterocycle;
R13 is selected from —
H, —
OH, —
NH2, —
NHR14, —
N(R14)2, —
C1-C8 alkyl, —
C3-C8 carbocycle, —
O—
(C1-C8 alkyl), -aryl, —
C1-C8 alkyl-aryl, —
C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and —
C1-8 alkyl-(C3-C8 heterocycle); and
Each R14 is independently —
H or —
C1-C8 alkyl.
2 Assignments
0 Petitions
Accused Products
Abstract
Drug-Linker-Ligand Conjugates are disclosed in which a Drug is linked to a Ligand via a peptide-based Linker unit. In one embodiment, the Ligand is an Antibody. Drug-Linker compounds and Drug compounds are also disclosed. Methods for treating cancer, an autoimmune disease or an infectious disease using the compounds and compositions of the invention are also disclosed.
289 Citations
119 Claims
-
1. A compound of the Formula Ia:
-
LAa-Ww—
Yy-D)p
Iaor a pharmaceutically acceptable salt or solvate thereof wherein, L- is a Ligand unit;
-A- is a Stretcher unit;
a is 0 or 1;
each —
W—
is independently an Amino Acid unit;
—
Y—
is a Spacer unit;
w is an integer ranging from 0 to 12;
y is 0, 1 or 2;
p ranges from 1 to about 20; and
-D is a Drug unit of the formula wherein, independently at each location;
R2 is selected from —
H and —
C1-C8 alkyl;
R3 is selected from —
H, —
C1-C8 alkyl, —
C3-C8 carbocycle, —
O—
(C1-C8 alkyl), -aryl, —
C1-C8 alkyl-aryl, —
C1-C8 alkyl-(C3-C8 carbocycle), —
C3-C8 heterocycle and —
C1-C8 alkyl-(C3-C8 heterocycle);
R4 is selected from —
H, —
C1-C8 alkyl, —
C3-C8 carbocycle, —
O—
(C1-C8 alkyl), -aryl, —
C1-C8 alkyl-aryl, —
C1-C8 alkyl-(C3-C8 carbocycle), —
C3-C8 heterocycle and —
C1-C8 alkyl-(C3-C8 heterocycle) wherein R5 is selected from —
H and -methyl;
or R4 and R5 join, have the formula —
(CRaRb)n—
wherein Ra and Rb are independently selected from —
H, —
C1-C8 alkyl and —
C3-C8 carbocycle and n is selected from 2, 3, 4, 5 and 6, and form a ring with the carbon atom to which they are attached;
R6 is selected from —
H and —
C1-C8 alkyl;
R7 is selected from —
H, —
C1-C8 alkyl, —
C3-C8 carbocycle, —
O—
(C1-C8 alkyl), -aryl, —
C1-C8 alkyl-aryl, —
C1-C8 alkyl-(C3-C8 carbocycle), —
C3-C8 heterocycle and —
C1-C8 alkyl-(C3-C8 heterocycle);
each R8 is independently selected from —
H, —
OH, —
C1-C8 alkyl, —
C3-C8 carbocycle and —
O—
(C1-C8 alkyl);
R9 is selected from —
H and —
C1-C8 alkyl;
R10 is selected from Z is —
O—
, —
S—
, —
NH—
or —
N(R14)—
;
R11 is selected from —
H, —
OH, —
NH2, —
NHR14, —
R14)2, —
C1-C8 carbocycle, —
O—
(C1-C8 alkyl), -aryl, —
C1-C8 alkyl-aryl, —
C1-C8 alkyl-(C3-C8 carbocycle), —
C3-C8 heterocycle and —
C1-C8 alkyl-(C3-C8 heterocycle);
or R11 is an oxygen atom which forms a carbonyl unit (C═
O) with the carbon atom to which it is attached and a hydrogen atom on this carbon atom is replaced by one of the bonds in the (C═
O) double bond;
each R12 is independently selected from -aryl and —
C3-C8 heterocycle;
R13 is selected from —
H, —
OH, —
NH2, —
NHR14, —
N(R14)2, —
C1-C8 alkyl, —
C3-C8 carbocycle, —
O—
(C1-C8 alkyl), -aryl, —
C1-C8 alkyl-aryl, —
C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and —
C1-8 alkyl-(C3-C8 heterocycle); and
Each R14 is independently —
H or —
C1-C8 alkyl.- View Dependent Claims (2, 7, 9, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 54, 56, 59, 63, 66, 77, 79, 100, 102, 104, 111, 112, 113, 114, 115, 116, 117, 118, 119)
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9. A compound or a pharmaceutically acceptable salt or solvate of the compound of claim 1 where -D is a Drug unit having the structure
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17. A compound or a pharmaceutically acceptable salt or solvate of the compound of claim 1 where the Ligand unit is an antibody unit.
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18. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 17 where the antibody unit is a monoclonal antibody unit.
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19. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 18 where the monoclonal antibody unit is cBR96, cAC10 or 1F6.
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20. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 1 where —
- Yy—
is
- Yy—
-
21. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 1 where -A- is
-
22. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 1 where -A- is
-
23. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 1 where -A- is
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24. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 1 where -A- is
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25. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 1 where -A- is
-
26. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 1 where -A- is
-
27. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 21 where -A- is
-
28. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 22 where -A- is
-
29. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 24 where -A- is
-
30. The compound or a pharmaceutically acceptable salt or solvate of the compound of claim 1 where —
- Ww—
is -Phenylalanine-Lysine- or -valine-citrulline-, the amino terminus of —
Ww—
forming a bond with a Stretcher unit when a is 1 or with a Ligand unit if a is 0, and the C-terminus of —
Ww—
forming a bond with a Spacer unit when y is 1 or 2, and with a Drug unit when y is 0.
- Ww—
-
54. The compound of claim 1 having the structure
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56. The compound of claim 1 having the structure
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59. The compound of claim 1 having the structure
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63. The compound of claim 1 having the structure
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66. The compound of any one of claims 54, 56, 59 or 63 where p ranges from about 7 to about 9, from about 3 to about 5, or about 1 to about 3.
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77. The compound of claim 1 having the formula
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79. The compound of claim 1 having the formula
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100. The compound of claim 79 wherein L is rituximab.
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102. The compound of claim 77 or 79 wherein L is S2C6.
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104. The compound of claim 77 wherein L is rituximab.
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111. A composition comprising an effective amount of a compound or a pharmaceutically acceptable salt or solvate thereof of any one of claims 1, 44, 77, 79, 99, 100 or 104 and a pharmaceutically acceptable carrier or vehicle.
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112. A method for killing or inhibiting the multiplication of a tumor cell or cancer cell comprising administering to an animal in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt or solvate thereof of any one of claims 1, 44, 77, 79, 99, 100 or 104.
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113. A method for treating cancer, comprising administering to an animal in need thereof an effective amount of a compound or a pharmaceutically acceptable salt or solvate of the compound of any one of claims 1, 44, 77, 79, 99, 100 or 104.
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114. A method for treating an autoimmune disease, comprising administering to an animal in need thereof an effective amount of a compound or a pharmaceutically acceptable salt or solvate of the compound of any one of claims 1, 44, 77, 79, 99, 100 or 104.
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115. A method for treating an infectious disease, comprising administering to an animal in need thereof an effective amount of a compound or a pharmaceutically acceptable salt or solvate of the compound of any one of claims 1, 44, 77, 79, 99, 100 or 104.
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116. The method of claim 113 further comprising administering to the animal an effective amount of an anticancer agent.
-
117. The method of claim 114 further comprising administering to the animal an effective amount of an immunosuppressant agent.
-
118. The method of claim 115 further comprising administering to the animal an effective amount of an anti-infectious agent.
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119. The compound or a pharmaceutically acceptable salt or solvate thereof of any one of claims 1, 44, 77, 79, 99, 100 or 104, in an isolated or a purified form.
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3-6. -6. (canceled)
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8. (canceled)
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10-16. -16. (canceled)
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31-43. -43. (canceled)
- 44. A compound of the formula
-
47. (canceled)
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50-51. -51. (canceled)
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53. (canceled)
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55. (canceled)
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57-58. -58. (canceled)
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60-62. -62. (canceled)
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64-65. -65. (canceled)
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67-76. -76. (canceled)
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78. (canceled)
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80-99. -99. (canceled)
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101. (canceled)
-
103. (canceled)
-
105-110. -110. (canceled)
Specification
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- Resources
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Current AssigneeSeagen Inc.
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Original AssigneeSeattle Genetics Incorporated
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InventorsToki, Brian E, Doronina, Svetlana O, Senter, Peter D
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current514/2.400
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CPC Class CodesA61K 47/64 Drug-peptide, drug-protein ...A61K 47/642 the peptide or protein in t...A61K 47/6817 ToxinsA61K 47/6851 the antibody targeting a de...A61K 47/6867 the tumour determinant bein...A61P 31/00 Antiinfectives, i.e. antibi...A61P 35/00 Antineoplastic agentsA61P 37/00 Drugs for immunological or ...A61P 37/06 Immunosuppressants, e.g. dr...C07K 5/0205 containing the structure -N...
