Pyrrolobenzodiazepines used to treat proliferative diseases

1. A Conjugate having formula IV:

L-(LU-D) p   (IV)

wherein L is a Ligand unit selected from an antibody, an antigen-binding fragment of an antibody or a Fc fusion protein,

LU is a Linker unit which is of formula 1a:

-A 1 -L 1 -,  (1a)

wherein:

-A 1 - is selected from the group consisting of:

wherein 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;

wherein 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

wherein 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;

L 1 is an amino acid sequence, and is cleavable by the action of an enzyme;

p is 1 to 20; and

D is a Drug unit of formula I:

wherein

R 2 is of formula III:

where A is a phenyl or a C 5-7 heteroaryl group,

X is selected from the group consisting of: O, S, C(═O), C(═O)O—, NH(C═O), NHNH, CONHNH,

 NR N , wherein R N is selected from the group consisting of H and C 1-4 alkyl, wherein * indicates the point of connection to Q 2 , wherein LU is connected to D via the X substituent of R 2 ;

and either:

(i) Q 1 is a single bond, and Q 2 is selected from a single bond and —Z—(CH 2 ) n —, where Z is selected from a single bond, O, S and NH and n is from 1 to 3; or

(ii) Q 1 is —CH═CH—, and Q 2 is a single bond;

R 12 is selected from:

(iia) C 1-5 saturated aliphatic alkyl;

(iib) C 3-6 saturated cycloalkyl;

 wherein each of R 21 , R 22 and R 23 are independently selected from H, C 1-3 saturated alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 12 group is no more than 5;

 wherein one of R 25a and R 25b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and

 where R 24 is selected from H, C 1-3 saturated alkyl, C 2-3 alkenyl, C 2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;

R 6 , R 7 , and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;

where R and R′ are independently selected from optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl, phenyl, naphthyl and C 5-20 heteroaryl groups;

either:

(a) R 10 is H, and R 11 is OH, OR A , where R A is 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;

R″ is a C 3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, and/or aromatic rings;

Y and Y′ are selected from O, S, or NH;

R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 respectively and R 10′ and R 11 ′ are the same as R 10 and R 11 , respectively, wherein if R 11 and R 11′ are SO Z M, M optionally represents a divalent pharmaceutically acceptable cation.

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 2 , wherein n is 5.

4. The Conjugate of claim 1 , wherein L 1 is selected from the group consisting of valine- alanine, valine-citrulline and phenyalanine-lysine.

5. The Conjugate according to claim 1 , wherein R 7 is selected from H, OH and OR.

6. The Conjugate according to claim 5 , wherein R 7 is a C 1-4 alkyloxy group.

7. The Conjugate according to claim 1 , wherein Y is O.

8. The Conjugate according to claim 1 , wherein R″ is C 3-7 alkylene.

9. The Conjugate according to claim 1 , wherein R 9 is H.

10. The Conjugate according to claim 1 , wherein R 6 is selected from H and halo.

11. The Conjugate according to claim 1 , wherein A is phenyl.

12. The Conjugate according to claim 1 , wherein X is selected from O, S, or NH.

13. The Conjugate according to claim 1 , wherein Q 1 is a single bond.

14. The Conjugate according to claim 13 , wherein Q 2 is a single bond.

15. The Conjugate according to claim 1 , wherein R 12 is methyl, ethyl or propyl.

16. The Conjugate according to claim 1 , wherein R 12 is cyclopropyl.

17. The Conjugate according to claim 1 , wherein R 12 is a group of formula:

wherein the total number of carbon atoms in the R 12 group is no more than 3.

18. The Conjugate according to claim 1 , wherein R 12 is the group:

19. The Conjugate according to claim 1 , wherein R 12 is a group of formula:

wherein R 24 is selected from H and methyl.