Peptide analogues and uses thereof

• US 20040002479A1
• Filed: 03/12/2003
• Published: 01/01/2004
• Est. Priority Date: 03/12/2002
• Status: Abandoned Application

• Current Assignee: Ariad Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: Ariad Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Sawyer, Tomi K., Wang, Yihan, Berstein, David L.
• Application Number:
  US10/386,649
• Publication Number:
  US 20040002479A1
• Time in Patent Office: Days
• US Class Current: 514/79
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/663 Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• CPC Class Codes: C07F 9/3821 substituted by B, Si, P or a metal C07F9/3839 takes precedence
• CPC Class Codes: C07F 9/3834 Aromatic acids (P-C aromatic linkage)
• CPC Class Codes: C07F 9/650952 having the nitrogen atoms in the positions 1 and 4
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N

Abstract

This invention relates to compounds of the general formula:

in which R^A, R^B, R^C, R^D, R^G and Z are as defined herein, and to their preparation and use.

Claims

1. A compound having the structure (I):

2. The compound of claim 1, wherein R^C is a benzyl moiety optionally substituted with one or more occurrences of R^C and R^E and the compound has the structure:

3. The compound of claim 1, wherein ZR^B is —

CH₂CH(CH₃)(CH₃) and the compound has the structure;

4. The compound of claim 1, wherein R^D is an aryl moiety optionally substituted with one or more occurrences of R^F and R³, and the compound has the structure:

5. The compound of claim 1, wherein WR^A is B(OH)₂ and the compound has the structure:

6. The compound of claim 1, wherein R^D is an aryl moiety optionally substituted with one or more occurrences of R^F and R³, and R^C is a benzyl moiety optionally substituted with one or more occurrences of R^E and R³, and the compound has the structure:

7. The compound of claim 1, wherein R^D is an aryl moiety optionally substituted with one or more occurrences of R^F and R³, and R^C is a benzyl moiety optionally substituted with one or more occurrences of R^E and R³, ZR^B is isobutyl, and the compound has the structure:

8. The compound of any one of claims 1-7, wherein only one of R^A, R^B, R^C, R^D, R^E or R^F comprises or is substituted with a phosphorus-containing moiety.

9. The compound of any one of claims 1-7, wherein two or more of R^A, R^B, R^C, R^D, R^E or R^F comprise or are substituted with a phosphorus-containing moiety.

10. The compound of any one of claims 1-7, wherein one or more occurrences of R^A, R^B, R^C, R^D, R^E or R^F comprises or is substituted with a phosphorus-containing moiety of Series I:

11. The compound of any one of claims 1-7, wherein one or more occurrences of R^A, R^B, R^C, R^D, R³ or R^F comprises or is substituted with a phosphorus-containing moiety of Series Ia:

12. The compound of claim 11, wherein Y is O.

13. The compound of any one of claims 1-7, wherein one or more occurrences of R^A, R^B, R^C, R^D, R^E or R^F comprises or is substituted with a phosphorus-containing moiety of Series Ib:

14. The compound of claim 13, wherein Y is O.

15. The compound of any one of claims 1, 2, 3, 4, 6 or 7 wherein W is a covalent bond and R^A is B(OH)₂.

16. The compound of any one of claims 1, 2, 3, 4, 6 or 7, wherein W is a lower alkyl moiety and R^A is a phosphorus-containing moiety.

17. The compound of claims 1, 2, 4, 5, or 6, wherein ZR^B is a linear or branched, cyclic or acyclic, substituted or unsubstituted alkyl moiety.

18. The compound of any one of claims 1, 2, 4, 5, or 6, wherein ZR^B is, —

CH₂(cyclopentyl), —

CH₂(cyclohexyl), —

CH₃, —

CH₂CH₃, —

CH₂CH₂CH₃, —

CH₂CH₂CH₂CH₃, or —

CH₂CH(CH₃)(CH₃).

19. The compound of any one of claims 1, 2, 4, 5, or 6, wherein Z is a lower alkyl moiety and R^B is a phosphorus-containing moiety.

20. The compound of any one of claims 1, 3, 4 or 5, wherein R^C is a substituted or unsubstituted aryl, alkylaryl, heteroaryl, or alkylheteroaryl moiety.

21. The compound of any one of claims 1, 2, 3, or 5, wherein R^D is a substituted or unsubstituted aryl, alkylaryl, heteroaryl, or alkylheteroaryl moiety.

22. The compound of any one of claims 1-5, wherein either or both of R^C and R^D comprise any one of the following structures:

23. The compound of any one of claims 1-5, wherein either or both of R^C and R^D comprise any one of the following structures:

24. The compound of any one of claims 1, 3, 4, or 5, wherein R^C comprises any one of the following structures:

25. The compound of any one of claims 1-3 or 5, wherein R^D comprises any one of the following structures:

26. The compound of any one of claims 1-7, wherein one or more occurrences of R^A, R^B, R^C, R^D, R^E or R^F comprise or are substituted with a phosphorus-containing moiety having the structure:

27. The compound of any one of claims 1-7, wherein one or more occurrences of R^A, R^B, R^C, R^D, R^E or R^F comprise or are substituted with a phosphorus-containing moiety having the structure:

28. The compound of any one of claims 1-7, wherein one or more occurrences of R^A, R^B, R^C, R^D, R^E or R^F comprise or are substituted with a phosphorus-containing moiety having the structure:

29. The compound of any one of claims 1-7, wherein one or more occurrences of R^A, R^B, R^C, R^D, R^E or R^F comprise or are substituted with a phosphorus-containing moiety having the structure:

30. The compound of any one of claims 1-7, wherein one or more occurrences of R^A, R^B, R^C, R^D, R^E or R^F comprise or are substituted with a phosphorus-containing moiety having the structure:

31. The compound of any one of claims 1-7, wherein one or more occurrences of R^A, R^B, R^C, R^D, R^E or R^F comprise or are substituted with a phosphorus-containing moiety having the structure:

32. The compound of any one of claims 1-7, wherein one or more occurrences of R^A, R^B, R^C, R^D, R^E or R^F comprise or are substituted with a phosphorus-containing moiety having the structure:

33. The compound of any one of claims 1-7, wherein one or more occurrences of R^A, R^B, R^C, R^D, R^E or R^F comprise or are substituted with a phosphorus-containing moiety having the structure:

34. The compound of any one of claims 1-7, wherein one or more occurrences of R^A, R^B, R^C, R^D, R^E or R^F comprise or are substituted with a phosphorus-containing moiety having the structure:

35. The compound of any one of claims 1-7, wherein R^G is hydrogen.

36. The compound of any one of claims 1-7, wherein R^G is lower alkyl.

37. The compound of any one of claims 2, 4, 6 or 7, wherein R³ is hydrogen.

38. The compound of any one of claims 1-6, wherein ZR^B and R^C may each independently be hydrogen, C_1-8 alkyl, C_3-10 alkyl, C_6-10 aryl or —

CH₂R^H, wherein R^H, for each occurrence, is independently one of C_6-10 aryl, C_6-10aryl(C_1-6)alkyl, C_1-6alkyl(C_6-10)aryl, C_3-10cycloalkyl, C_1-8alkoxy, or C_1-8alkylthio, where the ring portion of any of the foregoing aryl, aralkyl, or alkaryl groups of ZR^B, R^C or R^H can optionally be substituted by one or two substituents independently selected from the group consisting of C_1-6alkyl, C_3-8cycloalkyl, C_1-6alkyl(C_3-8)cycloalkyl, C_2-8alkenyl, C_2-8alkynyl, cyano, amino, C_1-6alkylamino, di(C_1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C_1-6)alkoxy, trifluoromethyl, halogen, C_1-6alkoxy, C_6-10aryl, C_6-10aryl(C_1-6)alkyl, C_6-10aryl(C_1-6)alkoxy, hydroxy, C_1-6alkylthio, C_1-6alkylsulfinyl, C_1-6alkylsulfonyl, C_6-10arylthio, C_6-10arylsulfinyl, C_6-10arylsulfonyl, C_6-10aryl, C_1-6alkyl(C_6-10)aryl, and halo(C_6-10)aryl.

47. A pharmaceutical composition comprising any one of the compounds of claims 1-7, or 39-46, or a pharmaceutically acceptable derivative thereof;

and

a pharmaceutically acceptable carrier or diluent,

said composition optionally further comprising an additional therapeutic agent.

48. The composition of claim 47, wherein the composition further comprises an additional therapeutic agent and the therapeutic agent is an anticancer agent, or an approved agent for the treatment of osteoporosis.

39. A compound having the structure:

40. The compound of claim 39, wherein each occurrence of m is O and V and U are each N and the compound has the structure:

41. A compound having the structure:

42. The compound of claim 41, wherein each occurrence of m is O and V and U are each N and the compound has the structure:

43. A compound having the structure:

44. The compound of claim 43, wherein each occurrence of m is O, V and U are each N and the compound has the structure:

45. A compound having the structure:

46. The compound of claim 45, wherein each occurrence of m is O, V and U are each N, and the compound has the structure:

49. A method for treating a bone-related disorder comprising administering a therapeutically effective amount of any one of compounds 1-7, or 39-46, or a pharmaceutically acceptable derivative thereof, to a subject in need thereof,

and optionally further comprising administering an additional therapeutic agent.

50. A method for treating cancer comprising administering a therapeutically effective amount of any one of compounds 1-7, or 39-46, or a pharmaceutically acceptable derivative thereof, to a subject in need thereof,

and optionally further comprising administering an additional therapeutic agent.

51. A method for inhibiting cell adhesion in a mammal comprising administering an effective amount of any one of compounds 1-7, or 39-46, or a pharmaceutically acceptable derivative thereof, to a subject in need thereof.

52. A method for inhibiting HIV infection comprising administering an effective amount of any one of compounds 1-7, or 39-46, or a pharmaceutically acceptable derivative thereof, to a subject in need thereof.

53. A method for inhibiting cyclic degradation in a cell comprising contacting a cell with an effective amount of any one of compounds 1-7, or 39-46, or a pharmaceutically acceptable derivative thereof.

54. A method for treating an inflammatory disorder comprising administering a therapeutically effective amount of any one of compounds 1-7, or 39-46, or a pharmaceutically acceptable derivative thereof, to a subject in need thereof,

and optionally further comprising administering an additional therapeutic agent.

55. A method reducing the activity of NF-kB in a cell comprising contacting a cell with an effective amount of any one of compounds 1-7, or 39-46, or a pharmaceutically acceptable derivative thereof.