Pyrrolobenzodiazepines used to treat proliferative diseases

Patent metadata

Field	Value
Publication number	US-9732084-B2
Application number	US-201314072904-A
Country	US
Kind code	B2
Filing date	Nov 6, 2013
Priority date	Apr 15, 2010
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

Abstract

Pyrrolobenzodiazepine dimers having a C2-C3 double bond and an aryl group at the C2 position on one monomer unit, and a C2-C3 double bond and either a conjugated double or triple bond at the C2 position or an alkyl group at the C2 position on the other monomer unit, and conjugates of these compounds.

First claim

The invention claimed is:

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.

Assignees

• Medimmune Ltd
• Seattle Genetics Inc

Inventors

• Howard Philip Wilson
• Masterson Luke
• Tiberghien Arnaud
• Jeffrey Scott
• Burke Patrick
• Senter Peter

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/02

  specific for leukemia · CPC title