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

1. A compound of Formula I,

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, wherein the N-terminus of the peptide is —NR 2′ R 3′ , wherein R 2′ is alkyl or arylalkyl and R 3′ is hydrogen, alkyl, arylalkyl or acyl;

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

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein Z is —C(O)— or C 1 -C 4 -alkylene-C(O)—.

3. The compound of claim 2 wherein Z is —C(O)— or C 1 -C 2 -alkylene-C(O)—.

4. The compound of claim 1 wherein Z is C 1 -C 6 -alkylene-O— or C 1 -C 6 -alkylene-NR—.

5. The compound of claim 4 wherein Z is C 1 -C 4 -alkylene-O— or C 1 -C 4 -alkylene-NH—.

6. The compound of claim 5 wherein Z is C 1 -C 2 -alkylene-O— or C 1 -C 2 -alkylene-NH.

7. The compound of claim 4 wherein Q is hydrogen, linear, branched or cyclic C 1 -C 6 -alkyl , phenyl or naphthyl, provided that when P is hydrogen or —OR, Q is not hydrogen.

8. The compound of claim 7 wherein Q is isopropyl, phenyl or cyclohexyl.

9. The compound of claim 1 wherein each R is, independently, hydrogen or linear, branched or cyclic C 1 -C 6 -alkyl.

10. The compound of claim 9 wherein each R is, independently, hydrogen or linear or branched C 1 -C 4 -alkyl.

11. The compound of claim 10 wherein each R is, independently, hydrogen or methyl.

12. The compound of claim 11 wherein each R is hydrogen.

13. The compound of claim 1 wherein A 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, branched or C 1 -C 6 cyclic alkyl or arylalkyl; or D is of the structure

14. The compound of claim 13 wherein R 1 is C 1 -C 4 -alkoxy.

15. The compound of claim 14 wherein R 1 is methoxy.

16. The compound of claim 13 wherein R 3 is hydrogen or C 1 -C 4 -alkyl.

17. The compound of claim 16 wherein R 3 is methyl.

18. The compound of claim 13 wherein D is linear, branched or cyclic C 1 -C 6 -alkyl; or aryl-C 1 -C 4 -alkyl.

19. The compound of claim 1 wherein A 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 -alkoxy;

X is a leaving group; and

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

20. The compound of claim 19 wherein A is of the formula

21. The compound of claim 1 wherein P comprises from 1 to about 20 amino acid residues.

22. The compound of claim 21 wherein P comprises an amino acid sequence which is a substrate for a matrix metalloprotease.

23. The compound of claim 22 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.

24. The compound of claim 23 wherein the matrix metalloprotease is MMP-2 or MMP-9.

25. The compound of claim 24 wherein P comprises the sequence -Pro-Leu-Gly-Xaa-, wherein Xaa is a naturally occurring amino acid residue.

26. The compound of claim 25 wherein P comprises a sequence selected from the group consisting of Pro-Cha-Gly-Cys(Me)-His (SEQ ID NO:2); Pro-Gln-Gly-Gle-Ala-Gly-Gln-D-Arg (SEQ ID NO :3); Pro-Gln-Gly-Ile-Ala-Gly-Trp (SEQ ID NO :4); Pro-Leu-Gly-Cys(Me)-His-Ala-D-Arg (SEQ ID NO :5); Pro-Leu-Gly-Met-Trp-Ser-Arg (SEQ ID NO :35); Pro-Leu-Gly-Leu-Trp-Ala-D-Arg (SEQ ID NO :6); Pro-Leu-Ala-Leu-Trp-Ala-Arg (SEQ ID NO:7); Pro-Leu-Ala-Leu-Trp-Ala-Arg (SEQ ID NO:8); Pro-Leu-Ala-Tyr-Trp-Ala-Arg (SEQ ID NO:9); Pro-Tyr-Ala-Tyr-Trp-Met-Arg (SEQ ID NO:10); Pro-Cha-Gly-Nva-His-Ala (SEQ ID NO:11); Pro-Leu-Ala-Nva (SEQ ID NO:12); Pro-Leu-Gly-Leu (SEQ ID NO:13); Pro-Leu-Gly-Ala (SEQ ID NO:14); Arg-Pro-Leu-Ala-Leu-Trp-Arg-Ser (SEQ ID NO:15); Pro-Cha-Ala-Abu-Cys(Me)-His-Ala (SEQ ID NO:16); Pro-Cha-Ala-Gly-Cys(Me)-His-Ala (SEQ ID NO:17); Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu (SEQ ID NO:18); Pro-Lys-Pro-Leu-Ala-Leu (SEQ ID NO:19); Arg-Pro-Lys-Pro-Tyr-Ala-Nva-Trp-Met (SEQ ID NO :20); Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg (SEQ ID NO :21); Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg (SEQ ID NO:22); and Arg-Pro-Lys-Pro-Leu-Ala-Nva-Trp (SEQ ID NO:23).

27. A compound of the formula

wherein

W is O or NR;

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

Q is hydrogen; R 1 is hydroxy, C 1 -C 4 -alkoxy or halogen;

Z is —C(O)— or C 1 -C 4 -alkylene-C(O)—;

P is 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 a peptide comprising 1 to 100 amino acid residues attached to Z at the C-terminus, wherein the N-terminus of the peptide is —NR 2′ R 3′ , wherein R 2′ is alkyl or arylalkyl and R 3′ is hydrogen, alkyl, arylalkyl or acyl;

or a pharmaceutically acceptable salt thereof.

28. The compound of claim 27 wherein P comprises from 1 to about 20 amino acid residues.

29. The compound of claim 28 wherein P comprises an amino acid sequence which is a substrate for a matrix metalloprotease.

30. The compound of claim 29 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.

31. The compound of claim 30 wherein the matrix metalloprotease is MMP-2 or MMP-9.

32. The compound of claim 31 wherein P comprises the sequence -Pro-Leu-Gly-Xaa-, wherein Xaa is a naturally occurring amino acid residue.

33. The compound of claim 32 wherein P comprises a sequence selected from the group consisting of Pro-Cha-Gly-Cys(Me)-His (SEQ ID NO:2); Pro-Gln-Gly-Ile-Ala-Gly-Gln-D-Arg (SEQ ID NO :3); Pro-Gln-Gly-Ile-Ala-Gly-Trp (SEQ ID NO :4); Pro-Leu-Gly-Cys(Me)-His-Ala-D-Arg (SEQ ID NO :5); Pro-Leu-Gly-Met-Trp-Ser-Arg (SEQ ID NO :35); Pro-Leu-Gly-Leu-Trp-Ala-D-Arg (SEQ ID NO :6); Pro-Leu-Ala-Leu-Trp-Ala-Arg (SEQ ID NO:7); Pro-Leu-Ala-Leu-Trp-Ala-Arg (SEQ ID NO:8); Pro-Leu-Ala-Tyr-Trp-Ala-Arg (SEQ ID NO:9); Pro-Tyr-Ala-Tyr-Trp-Met-Arg (SEQ ID NO:10); Pro-Cha-Gly-Nva-His-Ala (SEQ ID NO:11); Pro-Leu-Ala-Nva (SEQ ID NO:12); Pro-Leu-Gly-Leu (SEQ ID NO:13); Pro-Leu-Gly-Ala (SEQ ID NO:14); Arg-Pro-Leu-Ala-Leu-Trp-Arg-Ser (SEQ ID NO:15); Pro-Cha-Ala-Abu-Cys(Me)-His-Ala (SEQ ID NO:16); Pro-Cha-Ala-Gly-Cys(Me)-His-Ala (SEQ ID NO:17); Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu (SEQ ID NO:18); Pro-Lys-Pro-Leu-Ala-Leu (SEQ ID NO:19); Arg-Pro-Lys-Pro-Tyr-Ala-Nva-Trp-Met (SEQ ID NO :20); Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg (SEQ ID NO :21); Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg (SEQ ID NO:22); and Arg-Pro-Lys-Pro-Leu-Ala-Nva-Trp (SEQ ID NO:23).

34. An angiogenesis inhibitor compound selected from the group consisting of

N-Carbamoyl-GlyArgGlyAspSerPro-(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-GlyArgGlyAspTyr(OMe)ArgGlu-(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-GlyArgGlyAsp-(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-GlyArgGly-(3-amino-3-pyridyl-propionic 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 (SEQ ID NO:40);

N-Carbamoyl-GlyProLeuGlyMetTrpAlaGly-(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-GlyProLeuGly-(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-ProLeuGlyMetTrpAla-(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-ProLeuGlyMetGly-(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); and

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

35. A method of treating an angiogenic disease in a subject, comprising administering to the subject a therapeutically effective amount of an angiogenesis inhibitor compound comprising the structure

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, wherein the N-terminus of the peptide is —NR 2′ R 3′ , wherein R 2′ is hydrogen, alkyl or arylalkyl and R 3′ is hydrogen, alkyl, arylalkyl or acyl;

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

or a pharmaceutically acceptable salt thereof.

36. The method of claim 35 , wherein said angiogenic disease is an autoimmune disease.

37. The method of claim 36 , wherein said autoimmune disease is rheumatoid arthritis.

38. The method of claim 35 , wherein said angiogenic disease is cancer.

39. The method of claim 35 , wherein said subject is a human.

40. The method of claim 35 , wherein said angiogenesis inhibitor compound is administered to said subject using a pharmaceutically acceptable formulation.

41. The method of claim 35 , wherein the angiogenesis inhibitor compound is administered to the subject intravenously.

42. The method of claim 35 , wherein the angiogenesis inhibitor compound is administered to the subject intramuscularly.

43. The method of claim 35 , wherein the angiogenesis inhibitor compound is administered to the subject orally.

44. The method of claim 35 , wherein the angiogenesis inhibitor compound is selected from the group consisting of

N-Carbamoyl-GlyArgGlyAspSerPro-(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-GlyArgGlyAspTyr(OMe)ArgGlu-(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-GlyArgGlyAsp-(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-GlyArgGly-(3-amino-3-pyridyl-propionic 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 (SEQ ID NO:40);

N-Carbamoyl-GlyProLeuGlyMetTrpAlaGly-(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-GlyProLeuGly-(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-ProLeuGlyMetTrpAla-(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-ProLeuGlyMetGly-(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); and

Ac-ProLeuGlyMetAla-(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).