Compounds containing a vascular disrupting agent

1. A compound, or pharmaceutically acceptable salt thereof, comprising a vascular disrupting agent (VDA) selected from the group consisting of colchicine, azademethylcolchicine, azacolchicine, N-methyl desacetylcolchicine and desacetylcolchicine, associated with a matrix metalloproteinase (MMPI proteolytic cleavage site comprising the amino acid sequence -Arg-Ser-Cit-Gly-Hof-Tyr-Leu- (SEQ ID NO: 4).

2. A compound according to claim 1 wherein the compound is of formula (I)

X-Y  (I)

wherein

X is the VDA;

and Y is the MMP proteolytic cleavage site.

3. A compound according to claim 1 wherein the compound is of formula (II)

X-Y- c   (II)

wherein

X is the VDA;

Y is the MMP proteolytic cleavage site; and

c is a capping group.

4. A compound according to claim 1 wherein the compound is of formula (III)

X- a -Y  (III)

wherein

X is the VDA;

Y is the MMP proteolytic cleavage site; and

a is a linker directly or indirectly associated with X.

5. A compound according to claim 1 wherein the compound is of formula (IV)

X- a -Y- c   (IV)

wherein

X is the VDA;

a is a linker directly or indirectly associated with X;

Y is the MMP proteolytic cleavage site; and

c is a capping group.

6. A compound according to claim 1 wherein the compound is of formula (V)

X-Y- b - c   (V)

wherein

X is the VDA;

Y is the MMP proteolytic cleavage site;

b is a spacer group directly or indirectly linked to Y; and

c is a capping group.

7. A compound according to claim 1 wherein the compound is of formula (VI)

X- a -Y- b - c   (VI)

wherein

a is a linker directly or indirectly associated with X;

X is the VDA;

Y is the MMP proteolytic cleavage site;

b is a spacer group directly or indirectly linked to Y; and

c is a capping group.

8. A compound according to claim 1 , or pharmaceutically acceptable salt thereof, wherein the compound is of formula (VII)

X-Y-Z  (VII)

wherein

X is the VDA;

Y is the MMP proteolytic cleavage site; and

Z is an anti-cancer agent.

9. A process for preparing the compound of claim 2 , the process comprising the steps of

i) providing a solid support attached to X

ii) optionally attaching a linker a to the C or N terminal of X

iii) attaching amino acid residues step-wise to the C or N terminal of X, or the linker attached to X in (ii), to provide the peptide sequence Y containing the MMP proteolytic cleavage sequence;

iii) optionally attaching a capping group c to the respective C or N terminal of Y.

10. A compound, or pharmaceutically acceptable salt thereof, according to claim 1 for use in medicine.

11. A pharmaceutical formulation comprising a compound according to claim 1 and at least one additional pharmaceutically acceptable excipient, diluent or carrier.

12. A compound according to claim 1 , wherein the VDA is azademethylcolchicine.

13. A compound according to claim 3 , wherein X is azademethylcolchicine and c is a fluorescein.

14. The compound according to claim 3 , wherein c is selected from the group consisting of simple sugars, D-amino acids, proline imino acids, fluorescein, or fluorescein derivatives.

15. The compound according to claim 4 wherein the linker is a single amino acid or is an amino acid sequence.

16. The compound according to claim 6 wherein the spacer is selected from the group consisting of a single amino acid, amino acid sequence, and a succinyl group.

17. The compound according to claim 8 wherein Z is selected from the group consisting of a vascular disrupting agent, an antimetabolite, a cytotoxic agent, a biotoxin, radiotherapeutic, hormonal agent or any other natural products or agents known to induce a cytotoxic, cytostatic, anti-angiogenic or vascular disrupting effect.

18. The compound according to claim 17 wherein Z is a cytotoxic agent.

19. The compound according to claim 18 wherein the cytotoxic agent is doxorubicin.

20. A compound according to claim 1 wherein the compound is of formula (VIII)

X- a -Y-Z  (VIII)

wherein

a is a linker directly or indirectly associated with X;

X is the VDA;

Y is the MMP proteolytic cleavage site; and

Z is an anti-cancer agent.

21. A compound according to claim 1 wherein the compound is of formula (IX)

X- a -Y- b -Z  (IX)

wherein

a is a linker directly or indirectly associated with X;

X is the VDA;

Y is the MMP proteolytic cleavage site;

Z is an anti-cancer agent; and

b is a spacer group directly or indirectly linked to Y.