Compositions and methods of treatment of cancer

• US 8,349,853 B2
• Filed: 09/05/2002
• Issued: 01/08/2013
• Est. Priority Date: 09/05/2001
• Status: Expired due to Term

• Current Assignee: Minerva Biotechnologies Corporation
• Original Assignee: Minerva Biotechnologies Corporation
• Inventors: Bamdad, Cynthia C.
• Primary Examiner(s): Ward, Paul V.
• Application Number:
  US10/237,150
• Publication Number:
  US 20030130293A1
• Time in Patent Office: 3,778 Days
• Field of Search: 514/266.3, 514/266.31, 544/287, 544/290
• US Class Current: 514/266.31
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/475 having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine vincamine A61K31/4375
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

This invention generally relates to compositions and methods for cancer treatment and, in particular, to compositions able to interact (e.g., bind to) with MUC1 growth factor receptor or its ligands, and methods for treating the same. The invention also relates to assays or use of such compositions for the treatment of patients susceptible to or exhibiting symptoms characteristic of cancer or tumorigenesis. Other compositions of the present invention useful for the treatment or prevention of cancer or tumorigenesis include homologs, analogs, derivatives, enantiomers or functional equivalents. The present compositions can also be packaged in kits in some cases.

Claims

1. A method of reducing proliferation of tumor cells that express cleaved form of MUC1 in which MGFR region is accessible to ligand interaction, by contacting the cells with an effective amount of a compound, which has the structure:

2. The method according to claim 1, wherein R¹ is H or substituted or unsubstituted or branched or straight-chain alkyl.

3. The method according to 2, wherein R¹ is ethyl.

4. The method according to claim 1, wherein R¹ comprises a cyclic group, multicyclic group or a fusedcyclic group;

an alkylcyclic group, an alkylmulticyclic group or an alkylfusedcyclic group;

heterocyclic group, multiheterocyclic group or a fusedheterocyclic group;

or a alkylheterocyclic group, a alkylheteromulticyclic group or an alkyl fusedheterocyclic group.

5. The method according to claim 4, wherein R¹ is substituted or unsubstituted benzyl, substituted or unsubstituted arylmethyl, or substituted or unsubstituted heteroarylmethyl.

6. The method according to claim 4, wherein R¹ is an alkylaryl.

7. The method according to claim 6, wherein R¹ is substituted or unsubstituted benzyl.

8. The method according to claim 7, wherein the substituent is independently selected from H, lower alkyl, lower alkoxy, and halogens.

9. The method according to claim 4, wherein R¹ is an aromatic group.

10. The method according to claim 9, wherein R¹ is a substituted or unsubstituted naphthyl group or substituted or unsubstituted phenyl group.

11. The method according to claim 10, wherein the substituent is independently selected from H, lower alkyl, lower alkoxy, and halogens.

12. The method according to claim 11, wherein the substituent is independently selected from H, methyl, ethyl, methoxy, ethoxy, Br, Cl, and F.

13. The method according to claim 1, wherein R² is branched or straight-chain lower alkyl.

14. The method according to claim 13, wherein R² is methyl.

15. The method according to claim 13, wherein R² is ethyl.

16. The method according to claim 13, wherein R² is isopropyl.

17. The method according to claim 1, wherein R³ is straight-chain or branched, substituted or unsubstituted alkyl, alkyl hydroxyl, alkyl amino, alkyl aryl, or alkyl heteroaryl.

18. The method according to claim 17, wherein R³ is aminopropyl or dimethyl aminopropyl.

19. The method according to claim 17, wherein R³ is methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, pentyl, iso-pentyl, hexyl, 2-(N,N-dimethyl amino ethyl), 2-phenylethyl, or 2-methyl furanyl.

20. The method according to claim 1, wherein R⁴ is straight-chain or branched, substituted or unsubstituted alkyl having 1-13 carbon atoms.

21. The method according to claim 20, wherein R⁴ is halogenated alkyl.

22. The method according to claim 21, wherein R⁴ is dichloromethyl.

23. The method according to claim 20, wherein R⁴ is 2,4,4-trimethylpentyl, or C₁₃H₂₇.

24. The method according to claim 1, wherein R⁴ comprises a non-aromatic, bicyclic ring.

25. The method according to claim 24, wherein R⁴ comprises adamantane.

26. The method according to claim 1, wherein R⁴ comprises a substituted or unsubstituted aromatic, heteroaromatic, or fused heteroaromatic group.

27. The method according to claim 26, wherein R⁴ comprises a substituted or unsubstituted phenyl, naphthyl, heteroaryl or diphenylmethyl, each of which is optionally substituted.

28. The method according to claim 27, wherein the substituent is selected from alkyl, alkoxy and halogen.

29. The method according to claim 28, wherein the substituent is selected from methyl, ethyl, methoxy, ethoxy, Br, Cl and F.

30. The method according to claim 27, wherein R⁴ is benzodioxolane.

31. The method according to claim 26, wherein R⁴ is a substituted or unsubstituted heteroarylmethyl, bicyclic heteroaryl, -alkylaryl, -alkylheteroaryl, branched-alkylaryl, or branched alkylheteroaryl.

32. The method according to claim 31, wherein R⁴ is a substituted or unsubstituted 1-phenyl-1-alkyl, or 1-phenyl-1-branched alkyl.

33. The method according to claim 31, wherein R⁴ is 1-phenyl-1-propyl.

34. The method according to claim 1, wherein R⁴ comprises substituted or unsubstituted nitrogen atom.

35. The method according to claim 34, wherein R⁴ is —

NH-alkyl, —

NH-benzyl, —

NH-aryl, —

NH-alkylaryl, —

NH-non-aromatic cyclic group, or —

NH-fusedaryl.

36. The method according to claim 35, wherein R⁴ is —

NH-phenyl, —

NH-phenyl substituted with lower alkyls and/or halogens, or —

NH-naphthyl.

37. The method according to claim 34, wherein R⁴ is substituted or unsubstituted NH-benzyl.

38. The method according to claim 1, wherein A¹, A², and A⁴ are H and A³ is Cl, and R¹ is benzyl, R² is isopropyl, R³ is aminopropyl and R⁴ is 4-methylphenyl.

39. The method according to claim 1, wherein A¹, A², and A⁴ are H and A³ is Cl, and R¹ is benzyl, R² is ethyl, R³ is dimethyl aminopropyl and R⁴ is 4-bromophenyl.

40. The method according to claim 1, wherein the tumor cells are colon cancer cells.

41. A method of reducing proliferation of tumor cells that express cleaved form of MUC1 in which MGFR region is accessible to ligand interaction comprising:

(i) assaying tumor cells for the presence of the cleaved form of MUC1 in which MGFR region is accessible to ligand interaction; and

(ii) if the tumor cells are positive for the presence of the cleaved form of MUC1 in which MGFR region is accessible to ligand interaction, contacting the cells with an effective amount of a compound, which has the structure;