Targeted pyrrolobenzodiazapine conjugates

Patent metadata

Field	Value
Publication number	US-9242013-B2
Application number	US-201113641219-A
Country	US
Kind code	B2
Filing date	Apr 15, 2011
Priority date	Apr 15, 2010
Publication date	Jan 26, 2016
Grant date	Jan 26, 2016

Abstract

Provided are Conjugate comprising PBDs conjugated to a targeting agent and methods of using such PBDs.

First claim

The invention claimed is:

1. A conjugate having formula I:
L-(LU-D) p   (I)

or a pharmaceutically acceptable salt thereof;
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 wherein the Drug unit is a PBD dimer having the following formula II:

wherein:
R 2 is of formula III:

wherein A is a C 5-7 aryl group, X is connected to the Linker unit and is selected from the group consisting of —O—, —S—, —C(O)O—, —C(O)—, —NH(C═O)—, and —N(R N )—, wherein R N is selected from the group consisting of H, C 1-4 alkyl and (C 2 H 4 O) m CH 3 , where m is 1 to 3, and either:
(i) Q 1 is a single bond, and Q 2 is selected from the group consisting of a single bond and —Z—(CH 2 ) n —, wherein Z is selected from the group consisting of 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 a C 5-10 aryl group optionally substituted by one or more substituents selected from the group consisting of halo, nitro, cyano, C 1-7 alkoxy, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene;
R 6 and R 9 are independently selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;
R 7 is selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NHRR′, nitro, Me 3 Sn and halo;
wherein R and R′ are independently selected from the group consisting of optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl, and C 5-20 aryl groups;
either:
(a) R 10 is H, and R 11 is OH, OR A , wherein R A is C 1-4 alkyl, or
(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, wherein z is 2;
R″ is a C 3-12 alkylene group, which chain is optionally interrupted by one or more heteroatoms selected from the group consisting of O, S, and NH, or an aromatic ring;
Y and Y′ are selected from the group consisting of O, S, and 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 , and each M is a monovalent pharmaceutically acceptable cation or both M groups together are a divalent pharmaceutically acceptable cation;
wherein C 3-20 heterocyclyl is a monovalent moiety obtained by removing a hydrogen atom of a heterocyclic compound which has 3 to 20 ring atoms, of which 1 to 10 are heteroatoms selected from the group consisting of N, O and S; and
wherein C 3-7 heterocyclyl is a monovalent moiety obtained by removing a hydrogen atom of a heterocyclic compound which has 3 to 7 ring atoms, of which 1 to 4 are heteroatoms selected from the group consisting of N, O and S.

2. The conjugate according to claim 1 , wherein R 7 is selected from the group consisting of H, OH and OR.

3. The conjugate according to claim 2 , wherein R 7 is a C 1-4 alkyloxy group.

4. The conjugate according to claim 2 , wherein Y and Y′ are O.

5. The conjugate according to claim 4 , wherein R″ is C 3-7 alkylene.

6. The conjugate according to claim 5 , wherein R 9 is H.

7. The conjugate according to claim 6 , wherein R 6 is selected from the group consisting of H and halo.

8. The conjugate according to claim 1 , wherein A is phenyl, X is selected from the group consisting of —O—, —S—, and —NH—, and Q 1 is a single bond.

9. The conjugate according to claim 8 , wherein X is NH.

10. The conjugate according to claim 9 , wherein Q 1 is a single bond and Q 2 is a single bond.

11. The conjugate according to claim 1 , wherein R 12 is a C 5-7 aryl group optionally substituted by one or more substituents selected from the group consisting of halo, nitro, cyano, C 1-7 alkoxy, C 5-20 aryloxy, C 3-20 heterocyclyoxy, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene wherein the C 1-7 alkoxy group is optionally substituted by an amino group, and if the C 3-7 heterocyclyl group is a C 6 nitrogen containing heterocyclyl group, it is optionally substituted by a C 1-4 alkyl group.

12. The conjugate according to claim 11 , wherein the C 5-7 aryl group is an optionally substituted phenyl group.

13. The conjugate according to claim 12 , wherein R 12 bears one to three substituent groups.

14. The conjugate according to claim 1 , wherein R 10 and R 11 form a nitrogen-carbon double bond.

15. The conjugate according to claim 1 , wherein R 6′ , R 7′ , R 9′ , and Y′ are the same as R 6 , R 7 , R 9 , and Y respectively.

16. The conjugate of claim 1 , wherein A 1 is:

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.

17. The conjugate of claim 16 , wherein n is 5.

18. The conjugate of claim 1 , wherein L 1 is a dipeptide.

19. The conjugate of claim 18 , wherein L 1 is selected from the group consisting of valine-alanine, valine-citrulline and phenylalanine-lysine.

20. The conjugate of claim 1 wherein D has the formula:

wherein the wavy line of D indicates covalent attachment to LU.

21. The conjugate of claim 1 wherein LU-D has the formula:

wherein the wavy line of LU-D indicates covalent attachment to the antibody.

22. The conjugate of claim 21 wherein the Ligand unit is an antibody or antigen binding fragment thereof that specifically binds to a target antigen on the surface of a target cell.

23. The conjugate of claim 22 wherein the antibody is a monoclonal antibody.

24. The conjugate of claim 22 wherein the connection between the antibody or antigen binding fragment thereof and the Linker is formed between a thiol group of a cysteine residue

Assignees

• Howard Philip Wilson
• Jeffrey Scott
• Burke Patrick
• Senter Peter
• Seattle Genetics Inc
• Medimmune Ltd

Inventors

• Howard Philip Wilson
• Jeffrey Scott
• Burke Patrick
• Senter Peter

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/02

  Immunomodulators · CPC title