Therapeutic agents and methods of use thereof for the modulation of angiogenesis

1. A method of treating a subject having an autoimmune disorder selected from the group consisting of lupus erythematosus, multiple sclerosis, myasthenia gravis, vasculitis, and diabetes mellitus, comprising administering to the subject a therapeutically effective amount of a compound comprising the structure of Formula XV,

wherein

A is a MetAP-2 inhibitory core;

W is O or NR;

each R is, independently, hydrogen or alkyl;

Z is —C(O)— or -alkylene-C(O)—;

P is NHR, OR or a peptide consisting of one to about one hundred amino acid residues connected at the N-terminus to Z;

Q is hydrogen, linear, branched or cyclic alkyl or aryl, provided that when P is —OR, Q is not hydrogen; or

Z is -alkylene-O— or alkylene-N(R)—;

P is hydrogen or a peptide consisting of from one to about one hundred amino acid residues connected to Z at the carboxyl terminus;

Q is hydrogen, linear, branched or cyclic alkyl or aryl, provided that when P is hydrogen, Q is not hydrogen;

and pharmaceutically acceptable salts thereof.

2. A method for treating a subject having an autoimmune disorder selected from the group consisting of lupus erythematosus, multiple sclerosis, myasthenia gravis, vasculitis, and diabetes mellitus comprising administering to said subject a compound comprising the formula

wherein

W is O or NR;

each R is, independently, hydrogen or —C 1 –C 4 -alkyl;

Q is hydrogen; linear, branched or cyclic C 1 –C 6 -alkyl; or aryl;

R 1 is hydroxyl, C 1 –C 4 -alkoxy or halogen;

Z is —C(O)— or C 1 –C 4 -alkylene

P is NHR or OR, or a peptide comprising 1 to 100 amino acid residues attached to Z at the N-terminus; or

Z is alkylene-O or alkylene-NR; and

P is hydrogen or a peptide comprising 1 to 100 amino acid residues attached to Z at the C-terminus;

or a pharmaceutically acceptable salt thereof; provided that when P is hydrogen, NHR or OR, O is not hydrogen.

3. The method of claim 2 , wherein

W is O;

R 1 is methoxy;

each R is hydrogen or methyl;

Q is linear, branched or cyclic alkyl or aryl; and

P is NH 2 or OCH 3 .

4. The method of claim 3 wherein Q is linear, branched or cyclic C 1 –C 6 -alkyl and P is NH 2 .

5. A method for treating a subject having an autoimmune disorder selected from the group consisting of lupus erythematosus, multiple sclerosis, myasthenia gravis, vasculitis, and diabetes mellitus, comprising administering to said subject a compound comprising the structure

6. A method of treating a subject having an autoimmune disorder selected from the group consisting of lupus erythematosus, multiple sclerosis, myasthenia gravis, vasculitis, and diabetes mellitus, comprising administering to the subject a therapeutically effective amount of a compound comprising a structure selected from the group consisting of

{(3R, 4S, 5S, 6R)-5-Methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonylamino}-3-methyl-butyric acid methyl ester;

2-{(3R, 4S, 5S, 6R)-5-Methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonylamino}-3-methyl-butyric acid methyl ester;

2-{(3R, 4S, 5S, 6R)-5-Methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonylamino}-4-methyl-pentanoic acid methyl ester;

{(3R, 4S, 5S, 6R)-5-Methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonylamino}-phenyl-acetic acid methyl ester;

(1-Carbamoyl-2-methyl-propyl)-carbamic acid-(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

(1-Carbamoyl-2-methyl-propyl)-carbamic acid-(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-butyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

(1-Hydroxymethyl-2-methyl-propyl)-carbamic acid-(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

2-{(3R, 4S, 5S, 6R)-5-Methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonylamino}-3,3-dimethyl-butyric acid methyl ester;

Cyclohexyl-2-{(3R, 4S, 5S, 6R)-5-Methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonylamino}-acetic acid methyl ester;

2-{(3R, 4S, 5S, 6R)-5-Methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonylamino}-3-methyl-pentanoic acid methyl ester;

[1-(1-Carbamoyl-2-hydroxy-ethylcarbamoyl)-2-methyl-propyl]-carbamic acid-(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R, 3R)-2-methyl-3 (3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

2-(3-{(3R, 4S, 5S, 6R)-5-Methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl}-ureido)-3-methyl-butyramide;

2-{(3R, 4S, 5S, 6R)-5-Methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonylamino}-3-methyl-butyro acid;

N-Carbamoyl-Gly-Arg-Gly-Asp-Ser-Pro-(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-butyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester (SEQ ID NO:31);

N-Carbamoyl-Gly-Arg-Gly-Asp-Tyr-(OMe)-Arg-Glu-(3R, 4S 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-butyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester (SEQ ID NO:30);

N-Carbamoyl-Gly-Arg-Gly-Asp-(3R, 4S, 5S, 6R)-5-methoxy-4-[2R,3R)-2-methyl-3-(3-methyl-butyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester (SEQ ID NO:32);

N-Carbamoyl-Gly-Arg-Gly-3-amino-3-pyridyl-propionic acid-(3R, 4S, 5S, 6R)-5-methoxv-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester (SEQ ID NO:40);

N-Carbamoyl-Gly-Pro-Leu-Gly-Met-Trp-Ala-Gly-(3R, 4S, 5S, 6R)-5-methoxy-4-[2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester (SEQ ID NO:39);

N-Carbamoyl-Gly-Pro-Leu-(Me)Gly-(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester (SEQ ID NO:26);

N-Carbamoyl-Gly-Pro-Leu-Gly-(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester (SEQ ID NO:27);

Ac-Pro-Leu-Gly-Met-Trp-Ala-(2R-{(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonyl}-amino-3-methyl-butanol) ester (SEQ ID NO:24);

Ac-Pro-Leu-Gly-Met-Gly-(2R-{(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonyl}-amino-3-methyl-butanol) ester (SEQ ID NO:36);

Met-Trp-Ala-(2R-{(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonyl}-amino-3-methyl-butanol) ester (SEQ ID NO:37);

Met-Gly-(2R-{(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonyl}-amino-3-methyl-butanol) ester (SEQ ID NO:38);

Ac-Pro-Leu-Gly-Met-Ala-(2R-{(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonyl}-amino-3-methyl-butanol) ester (SEQ ID NO:34);

{2-Methyl-1-[methyl-(1-methyl-piperidin-4-yl)-carbamoyl]-propyl}-carbamic acid 5-methoxy-4-[2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

[1-(2-Dimethylamino-ethylcarbamoyl)-2-methyl-propyl]-carbamic acid 5-methoxy-4-[2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

{1-[(2-Dimethylamino-ethyl)-methyl-carbamoyl]-2-methyl-propyl}-carbamic acid 5-methoxy-4-[2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

[1-(3-Dimethylamino-propylcarbamoyl)-2-methyl-propyl]-carbamic acid 5-methoxy-4-[2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

[1-(3-Dimethylamino-2,2-dimethyl-propylcarbamoyl)-2-methyl-propyl]-carbamic acid 5-methoxy-4-[2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

[2-Methyl-1-(4-methyl-piperazine-1-carbonyl)-propyl]-carbamic acid 5-methoxy-4-[2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

{2-Methyl-1-[2-(1-methyl-pyrrolidin-2-yl)-ethylcarbamoyl]-propyl}-carbamic acid 5-methoxy-4-[2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

[2-Methyl-1-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-propyl]-carbamic acid 5-methoxy-4-[2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester; and

[1-(4-Benzyl-piperazine-1-carbonyl)-2-methyl-propyl]-carbamic acid 5-methoxy-4-[2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester.

7. The method any one of claims 1 , 2 , 5 or 6 wherein said subject is human.

8. The method any one of claims 1 , 2 , 5 or 6 wherein said compound is administered to said subject using a pharmaceutically acceptable formulation.

9. The method any one of claims 1 , 2 , 5 or 6 wherein said compound is administered to the subject intravenously.

10. The method any one of claims 1 , 2 , 5 or 6 wherein said compound is administered to the subject intramuscularly.

11. The method any one of claims 1 , 2 , 5 or 6 wherein said compound is administered to the subject orally.

12. The method of claim 1 , wherein Z in said compound is Z is —C(O)— or C 1 –C 4 -alkylene-C(O)—.

13. The method of claim 12 , wherein Z in said compound is —C(O)— or C 1 –C 2 -alkylene-C(O)—.

14. The method of claim 12 , wherein Q in said compound is linear, branched or cyclic C 1 –C 6 -alkyl, phenyl or naphthyl.

15. The method of claim 14 , wherein Q in said compound is isopropyl, phenyl or cyclohexyl.

16. The method of claim 1 , wherein Z in said compound is C 1 –C 6 -alkylene-O— or C 1 –C 6 -alkylene-NR—.

17. The method of claim 16 , wherein Z in said compound is C 1 –C 4 -alkylene-O— or C 1 –C 4 -alkylene-NH—.

18. The method of claim 17 , wherein Z in said compound is C 1 –C 2 -alkylene-O— or C 1 –C 2 -alkylene-NH.

19. The method of claim 16 , wherein Q in said compound is linear, branched or cyclic C 1 –C 6 -alkyl , phenyl or naphthyl.

20. The method of claim 19 , wherein Q in said compound is isopropyl, phenyl or cyclohexyl.

21. The method of claim 1 , wherein each R in said compound is, independently, hydrogen or linear, branched or cyclic C 1 –C 6 -alkyl.

22. The method of claim 21 , wherein each R in said compound is, independently, hydrogen or linear or branched C 1 –C 4 -alkyl.

23. The method of claim 22 , wherein each R in said compound is, independently, hydrogen or methyl.

24. The method of claim 23 , wherein each R in said compound is hydrogen.

25. The method of claim 1 , wherein A in said compound is of Formula II,

wherein

R 1′ is hydrogen or alkoxy;

R 2′ is hydrogen or hydroxy;

R 3′ is hydrogen or alkyl; and

D is linear or branched alkyl or arylalkyl; or D is of the structure

26. The method of claim 25 , wherein R 1′ in said compound is C 1 –C 4 -alkoxy.

27. The method of claim 26 , wherein R 1′ in said compound is methoxy.

28. The method of claim 25 , wherein R 3′ in said compound is hydrogen or C 1 –C 4 -alkyl.

29. The method of claim 28 , wherein R 3′ in said compound is methyl.

30. The method of claim 25 , wherein D in said compound is linear, branched or cyclic C 1 –C 6 -alkyl; or aryl-C 1 –C 4 -alkyl.

31. The method of claim 1 , wherein A in said compound is selected from the group consisting of

wherein

p is an integer from 0 to 10;

R 1 ″ is hydrogen, —OH or C 1 –C 4 C-alkoxy;

X is a leaving group; and

R 2 ″ is H, OH, amino, C 1 -C 4 C-alkylamino or di(C 1 –C 4 -alkyl)amino.

32. The method of claim 31 , wherein A in said compound is of the formula

33. The method of claim 1 , wherein P in said compound comprises from 1 to about 20 amino acid residues.

34. The method of claim 33 , wherein P in said compound comprises an amino acid sequence which is a substrate for a matrix metalloprotease.

35. The method of claim 34 , wherein the matrix metalloprotease is selected from the group consisting of MMP-2, MMP-1, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13 and MMP-26.

36. The method of claim 35 , wherein the matrix metalloprotease is MMP-2 or MMP-9.

37. The method of claim 36 , wherein P in said compound comprises the sequence -Pro-Leu-Gly-Xaa-, wherein Xaa is a naturally occurring amino acid residue.

38. The method of claim 37 , wherein P is Pro-Cha-Ala-Abu-Cys(Me)-His-Ala (SEQ ID NO:16).

39. The method of claim 2 , wherein

W is O or NH;

Z is alkylene-O or allcylene-NH;

Q is isopropyl;

R 1 is methoxy; and

P comprises from 1 to 15 amino acid residues.

40. The method of claim 39 , wherein W in said compound is O; and P comprises 10 or fewer amino acid residues.

41. The method of claim 2 , wherein P in said compound comprises from 1 to about 20 amino acid residues.

42. The method of claim 41 , wherein P in said compound comprises an amino acid sequence which is a substrate for a matrix metalloprotease.

43. The method of claim 42 , wherein the matrix metalloprotease is selected from the group consisting of MMP-2, MMP-1, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13 and MMP-26.

44. The method of claim 43 , wherein the matrix metalloprotease is MMP-2 or MMP-9.

45. The method of claim 44 , wherein P in said compound comprises the sequence -Pro-Leu-Gly-Xaa-, wherein Xaa is a naturally occurring amino acid residue.

46. The method of claim 45 , wherein P is Pro-Cha-Ala-Abu-Cys(Me)-His-Ala (SEQ ID NO:16).