Matriptase inhibitors and methods of use

• US 20040186060A1
• Filed: 12/18/2003
• Published: 09/23/2004
• Est. Priority Date: 12/23/2002
• Status: Active Grant

• Current Assignee: Dendreon Pharmaceuticals, Inc. (Ya Fei Yuan,)
• Original Assignee: Dendreon Corporation (Bausch Health Cos., Inc.)
• Inventors: Levy, Odile Esther, Komandla, Mallareddy, Moreno, Ofir, Duncan, David F., Semple, Joseph E., Tamiz, Amir P., Alfaro-Lopez, L. Josue
• Granted Patent: US 7,019,019 B2
• Time in Patent Office: Days
• US Class Current: 514/19
• CPC Class Codes: C07D 231/56 Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 333/38 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The present invention provides matriptase inhibitors and compositions thereof useful for treating cancer. Martripase is a trypsin-like serine protease active in the development of cancerous conditions, such as tumors and metastasis of cancer.

Claims

1. A compound of the formula

2. The compound of claim 1, wherein

3. The compound of claim 2, wherein said compound has the formula

4. The compound of claim 3, wherein said compound has the formula

5. The compound of claim 3, wherein R² is selected from an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl, an optionally substituted carbamoyl, an optionally substituted ureido, an optionally substituted heteroarylalkylsulfamoyl, an optionally substituted alkylsulfamoyl, an optionally substituted arylsulfamoyl, an optionally substituted heteroarylsulfamoyl, and hydroxy.

6. The compound of claim 3, wherein R² is an optionally substituted C₁-C₈ alkoxycarbonyl.

7. The compound of claim 2, wherein said compound has the formula

8. The compound of claim 7, wherein said compound has the formula

9. The compound of claim 7, wherein said compound has the formula

10. The compound of claim 2, wherein said compound has the formula

11. The compound of claim 2, wherein said compound has the formula

12. The compound of claim 2, wherein said compound has the formula

13. The compound of claim 1, wherein said compound has the formula

14. The compound of claim 13, wherein said compound has the formula

15. A pharmaceutical composition, said pharmaceutical composition comprising:

16. The composition of claim 15, wherein

17. The composition of claim 16, wherein said compound has the formula

18. The composition of claim 17, wherein said compound has the formula

19. The composition of claim 17, wherein R² is selected from an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl, an optionally substituted carbamoyl, an optionally substituted ureido, an optionally substituted heteroarylalkylsulfamoyl, an optionally substituted alkylsulfamoyl, an optionally substituted arylsulfamoyl, an optionally substituted heteroarylsulfamoyl, and hydroxy.

20. The composition of claim 17, wherein R² is an optionally substituted C₁-C₈ alkoxycarbonyl.

21. The composition of claim 16, wherein said compound has the formula

22. The composition of claim 21, wherein said compound has the formula

23. The composition of claim 21, wherein said compound has the formula

24. The composition of claim 16, wherein said compound has the formula

25. The composition of claim 16, wherein said compound has the formula

26. The composition of claim 16, wherein said compound has the formula

27. The composition of claim 15, wherein said compound has the formula

28. The composition of claim 27, wherein said compound has the formula

29. A method for treating a condition in a mammal by decreasing or inhibiting the serine protease activity of matriptase or MTSP1, said method comprising:

administering an effective amount of a compound of the formula;

30. The method of claim 29, wherein

31. The method of claim 30, wherein said compound has the formula

32. The method of claim 31, wherein said compound has the formula

33. The method of claim 31, wherein R² is selected from an optionally substituted C₁-C₈ alkylcarbamoyl, an optionally substituted C₁-C₈ alkoxycarbonylamino, an optionally substituted C₁-C₈ alkylsulfonylcarbamoyl, an optionally substituted aralkylsulfonylcarbamoyl, an optionally substituted carbamoyl, an optionally substituted ureido, an optionally substituted heteroarylalkylsulfamoyl, an optionally substituted alkylsulfamoyl, an optionally substituted arylsulfamoyl, an optionally substituted heteroarylsulfamoyl, and hydroxy.

34. The method of claim 31, wherein R² is an optionally substituted C₁-C₈ alkoxycarbonyl.

35. The method of claim 30, wherein said compound has the formula

36. The method of claim 35, wherein said compound has the formula

37. The method of claim 35, wherein said compound has the formula

38. The method of claim 30, wherein said compound has the formula

39. The method of claim 30, wherein said compound has the formula

40. The method of claim 30, wherein said compound has the formula

41. The method of claim 29, wherein said compound has the formula

42. The method of claim 41, wherein said compound has the formula