Pyrrolobenzodiazepines and targeted conjugates
View Patent ↗A compound, or a pharmaceutically acceptable salt or solvate thereof, or conjugates thereof, selected from the group consisting of formula wherein: (a) R 10 is H, and R 11 is OH, OR A , where R A is saturated C 1-4 alkyl; (b) R 10 and R 11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or (c) R 10 is H and R 11 is S0 2 M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation, or both M together are a divalent pharmaceutically acceptable cation.
1. A Conjugate having formula IV:
L-(LU-D) p (IV)
or a pharmaceutically acceptable salt thereof;
wherein L is a Ligand unit selected from an antibody and an antigen-binding fragment of an antibody,
LU is a Linker unit which is -A 1 -L 1 -, wherein A 1 is selected from the group consisting of:
where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, and n is 0 to 6;
where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, and n is 0 to 6;
where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, n is 0 or 1, and m is 0 to 30; and
where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, n is 0 or 1, and m is 0 to 30; and
L 1 comprises an amino acid sequence which is cleavable by the action of an enzyme,
p is 1 to 20; and
D is selected from the group consisting of:
where
(a) R 10 is H, and R 11 is OH, OR A , where R A is saturated C 1-4 alkyl;
(b) R 10 and R 11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or
(c) R 10 is H and R 11 is SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation, or both M together are a divalent pharmaceutically acceptable cation, and the asterisk indicates the point of attachment to the Linker Unit.
2. The Conjugate of claim 1 , wherein A 1 is:
where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, and n is 0 to 6.
3. The Conjugate of claim 1 , wherein L 1 which comprises an amino acid sequence, is a dipeptide selected from the group consisting of valine-alanine, valine-citrulline and phenyalanine-lysine.
4. A drug linker of formula V:
LU-D (V)
or a pharmaceutically acceptable salt thereof, wherein LU is a Linker unit which is G 1 -L 1 , wherein G 1 is selected from the group consisting of:
where the asterisk indicates the point of attachment to L 1 and n is 0 to 6;
where the asterisk indicates the point of attachment to L 1 and n is 0 to 6;
where the asterisk indicates the point of attachment to L 1 , n is 0 or 1, and m is 0 to 30; and
where the asterisk indicates the point of attachment to L 1 , n is 0 or 1, and m is 0 to 30;
L 1 comprises an amino acid sequence which is cleavable by the action of an enzyme, and D is selected from the group consisting of:
where
(a) R 10 is H, and R 11 is OH, OR A , where R A is saturated C 1-4 alkyl;
(b) R 10 and R 11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or
(c) R 10 is H and R 11 is SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation, or both M together are a divalent pharmaceutically acceptable cation, and the asterisk indicates the point of attachment to the Linker Unit.
5. A method of treating a proliferative disease comprising administering to a subject in need of treatment a therapeutically effective amount of a conjugate according to claim 1 , wherein the proliferative disease treated is kidney cancer.