Claims for Patent: 8,927,486

Summary for Patent: 8,927,486

Title:	Compounds
Abstract:	The present invention relates to prodrugs of vascular disrupting agents comprising a vascular disrupting agent (VDA) associated with a matrix metalloproteinase (MMP) proteolytic cleavage site and to the use of such prodrugs in the targeted treatment of cancer.
Inventor(s):	Falconer; Robert (Nab Wood, GB), Gill; Jason (Rothwell Haigh, GB), Atkinson; Jennifer (Needingworth, GB), Loadman; Paul (Bradford, GB), Bibby; Michael (Eldwick, GB), Patterson; Laurence (Bingley, GB)
Assignee:	Incanthera Limited (Bradford, GB)
Application Number:	13/125,732
Patent Claims:	1. A compound, or pharmaceutically acceptable salt thereof, comprising a vascular disrupting agent (VDA) associated with a matrix metalloproteinase (MMP) proteolytic cleavage site, wherein the VDA is selected from the group consisting of azademethylcolchicine, colchicine, azacolchicine, N-methyl desacetylcolchicine, desacetylcolchicine, N-acetylcolchinol-O-phosphate, colchicinoids, combrestatins, phenstatin, podophyllotoxins, steganacins, amphethinile, stilbenes, flavonoids, vincristine, vinblastine, vinflunine, maytansinoids, phomopson A, rhizoxin, auristatin, and dolstatin, and the MMP proteolytic cleavage site comprises the amino acid sequence eu-P2'-Hof-Gly-Cit-Ser-Arg, wherein P2' is an amino acid selected from Asp, Ala, Ser, Asn, Pro, Leu, Arg and Thr. 2. The compound according to claim 1 wherein the compound is of formula (I) X--Y (I) wherein X is the VDA; and Y is the peptide comprising the MMP proteolytic cleavage site. 3. The compound according to claim 1 wherein the VDA is selected from azademethylcolchicine, colchicine, azacolchicine, N-methyl desacetylcolchicine, desacetylcolchicine. 4. The compound according to claim 2 wherein Y is a peptide sequence of between seven and ten amino acids. 5. The compound according to claim 1 wherein the amino acid at P2' is methylated. 6. The compound according to claim 2 wherein the compound is of formula (II) X--Y-c (II) wherein c is a capping group which prevents non-specific degradation of the peptide by enzymes other than MMPs. 7. The compound according to claim 6 wherein c is selected from the group consisting of fluorescein isothiocyanate and fluorescein. 8. The compound according to claim 6 wherein c is the formula (c).sub.n and wherein n is an integer between 1 and 5. 9. The compound according to claim 8 wherein c is a non-natural amino acid and n is 3. 10. The compound according to claim 2 wherein the compound is of formula (III) X-a-Y (III) wherein a is a linker directly or indirectly associated with X and wherein the linker is a single amino acid or amino acid sequence. 11. The compound according to claim 10 wherein the compound is of formula (IV) X-a-Y-c (IV) wherein c is a capping group which prevents non-specific degradation of the peptide by enzymes other than MMPs. 12. The compound according to claim 6 wherein the compound is of formula (V) X--Y-b-c (V) wherein b is a spacer group directly or indirectly linked to Y and wherein the spacer is selected from the group consisting of a single amino acid, amino acid sequence and a succinyl group. 13. The compound according to claim 11 wherein the compound is of formula (VI) X-a-Y-b-c (VI) wherein b is a spacer group directly or indirectly linked to Y and wherein the spacer is selected from the group consisting of a single amino acid, amino acid sequence and a succinyl group. 14. The compound as claimed in claim 2 wherein the compound is of formula (VII) X--Y--Z (VII) wherein Z is an anti-cancer agent selected from the group consisting of a VDA, an antimetabolite and a cytotoxic agent, wherein the VDA is selected from the group consisting of azademethylcolchicine, colchicine, azacolchicine, N-methyl desacetylcolchicine, desacetylcolchicine, N-acetylcolchinol-O phosphate, colchicinoids, combrestatins, phenstatin, podophyllotoxins, steganacins, amphethinile, stilbenes, flavonoids, vincristine, vinblastine, vinflunine, maytansinoids, phomopson A, rhizoxin, auristatin, and dolstatin, the antimetabolite is 5-fluorouracil, and the cytotoxic agent is selected from the group consisting of anthracycline and doxorubicin. 15. The compound according to claim 14 wherein Z is doxorubicin. 16. The compound according to claim 14 wherein X is selected from azademethylcolchicine, colchicine, azacolchicine, N-methyl desacetylcolchicine, desacetylcolchicine. 17. The compound according to claim 14 wherein X and Z are selected from azademethylcolchicine, colchicine, azacolchicine, N-methyl desacetylcolchicine, desacetylcolchicine. 18. A pharmaceutical formulation comprising a compound according to claim 1 and at least one additional pharmaceutically acceptable excipient, diluent or carrier. 19. The compound according to claim 3, wherein the VDA is azademethylcolchicine. 20. The compound according to claim 1, wherein a further anti-cancer agent is linked to the peptide comprising the MMP proteolytic cleavage site. 21. The compound according to claim 20, wherein the anti-cancer agent is selected from the group consisting of 5-fluorouracil, anthracycline, doxorubicin, vinca alkaloid, taxane, a cytotoxic nucleotide, a biotoxin, radiotherapeutic, hormonal agent, colchicine, azademethylcolchicine, N-methyl desacetylcolchicine or desacetylcolchicine. 22. The compound according to claim 21, wherein the anti-cancer agent is doxorubicin. 23. The compound according to claim 1 further comprising a capping group on the peptide comprising the MMP proteolytic cleavage site which prevents non-specific degradation of the peptide. 24. A pharmaceutical formulation comprising the compound according to claim 1 and another therapeutic agent wherein the another therapeutic agent is selected from the group consisting of cisplatin, carboplatin, cyclophosphamide, melphalan, carmustine, methotrexate, 5-fluorouracil, cytarabine, mercatopurine, daunorubicin, doxorubicin, epirubicin, vinblastine, vincristine, dactinomycin, mitomycin C, taxol, L-asparaginase, granulocyte colony stimulating factor (G-CSF), etoposide, colchicine, deferoxamine mesylate and camptothecin.

Details for Patent 8,927,486

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2028-10-22