PYRROLOBENZODIAZEPINES AND CONJUGATES THEREOF

• US 20150344482A1
• Filed: 12/20/2013
• Published: 12/03/2015
• Est. Priority Date: 12/21/2012
• Status: Active Grant

• Current Assignee: MedImmune Ltd. (Astrazeneca PLC)
• Original Assignee: Spirogen SARL
• Inventors: HOWARD, Philip Wilson
• Granted Patent: US 9,562,049 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/5517 condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• 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: A61P 35/02 specific for leukemia
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

A compound with the formula I:

and salts and solvates thereof.

Claims

1-81. -81. (canceled)

82. A compound with the formula I:

83. A compound according to claim 82, wherein R⁷ is a C_1-4 alkyloxy group.

84. A compound according to claim 82, wherein Y is O, and R″

is C_3-7 alkylene.

85. A compound according to claim 82, wherein R⁶ and R⁹ are H.

86. A compound according to claim 82, wherein there is a double bond between C2′

and C3′

, and R¹² is;

(a) a C_5-7 aryl group, which may bear one to three substituent groups selected from methoxy, ethoxy, fluoro, chloro, cyano, bis-oxy-methylene, methyl-piperazinyl, morpholino and methylthiophenyl;

or

(b) methyl, ethyl or propyl;

or

(c) cyclopropyl;

(d) a group of formula;

87. A compound according to claim 82, wherein there is a single bond between C2′

and C3′

, R¹² is

88. A compound according to claim 82, wherein there is a double bond between C2 and C3, and R² is

(a) a C_5-7 aryl group, which may bears one to three substituent groups selected from methoxy, ethoxy, fluoro, chloro, cyano, bis-oxy-methylene, methyl-piperazinyl, morpholino and methyl-thiophenyl;

or

(b) methyl, ethyl or propyl;

or

(c) cyclopropyl;

or

(d) a group of formula;

89. A compound according to claim 82, wherein there is a single bond between C2 and C3, R² is

90. A compound according to claim 82, wherein R²⁰ is H or Me and R^21a and R^21b are both H.

91. A compound according to claim 82, wherein R²⁰ is H or Me and R^21a and R^21b together form ═

O.

92. A compound according to claim 90, wherein R²⁰ is H.

93. A compound according to claim 82, wherein R^11b is OH.

94. A compound according to claim 82, wherein R^11b is OR^A.

95. A compound according to claim 82, wherein R^11b is SO_zM.

96. A compound according to claim 95, wherein M is Na⁺ and z is 3.

97. The use of a compound according to claim 82 in the manufacture of a medicament for treating a proliferative disease.

98. A compound according to claim 82 for use in the treatment of a proliferative disease.

99. A conjugate comprising a compound of formula I according to claim 82, or a pharmaceutically acceptable salt or solvate thereof, linked to a targeting agent.

100. A conjugate of formula IV:

L-(R^L′

-D)_p 

 

(IV)

or a pharmaceutically acceptable salt or solvate thereof, wherein L is a Ligand unit, R^L′

is a Linker unit and D is of formula II;

101. The conjugate according to claim 100, wherein L-R^L′

is a group;

102. The conjugate according to claim 101, wherein C(═

O)O and L² together form the group;

103. The conjugate according to claim 101, wherein A is:

104. The conjugate according to claim 99, wherein the cell binding agent of R¹⁰ is an antibody or an active fragment thereof.

105. The conjugate according to claim 104, wherein the antibody or antibody fragment is an antibody or antibody fragment for a tumour-associated antigen.

106. A compound of formula A: