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

1. A pharmaceutical composition comprising 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;

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,

and a pharmaceutically acceptable carrier.

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

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

4. The pharmaceutical composition of claim 2 wherein Q is linear, branched or cyclic C 1 –C 6 -alkyl, phenyl or naphthyl.

5. The pharmaceutical composition of claim 4 wherein Q is isopropyl, phenyl or cyclohexyl.

6. The pharmaceutical composition of claim 1 wherein Z is C 1 –C 6 -alkylene-O— or C 1 –C 6 -alkylene-NR—.

7. The pharmaceutical composition of claim 6 wherein Z is C 1 –C 4 -alkylene-O— or C 1 –C 4 -alkylene-NH—.

8. The pharmaceutical composition of claim 7 wherein Z is C 1 –C 2 -alkylene-O— or C 1 –C 2 -alkylene-NH.

9. The pharmaceutical composition of claim 6 wherein Q is linear, branched or cyclic C 1 –C 6 -alkyl, phenyl or naphthyl.

10. The pharmaceutical composition of claim 9 wherein Q is isopropyl, phenyl or cyclohexyl.

11. The pharmaceutical composition of claim 1 wherein each R is, independently, hydrogen or linear, branched or cyclic C 1 –C 6 -alkyl.

12. The pharmaceutical composition of claim 11 wherein each R is, independently, hydrogen or linear or branched C 1 –C 4 -alkyl.

13. The pharmaceutical composition of claim 12 wherein each R is, independently, hydrogen or methyl.

14. The pharmaceutical composition of claim 13 wherein each R is hydrogen.

15. The pharmaceutical composition 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, cyclic C 1 –C 6 -alkyl, or branched alkyl or arylalkyl; or D is of the structure

16. The pharmaceutical composition of claim 15 wherein R 1 is C 1 –C 4 -alkoxy.

17. The pharmaceutical composition of claim 16 wherein R 1 is methoxy.

18. The pharmaceutical composition of claim 15 wherein R 3 is hydrogen or C 1 –C 4 -alkyl.

19. The pharmaceutical composition of claim 18 wherein R 3 is methyl.

20. The pharmaceutical composition of claim 15 wherein D is linear, branched or cyclic C 1 –C 6 -alkyl; or aryl-C 1 –C 4 -alkyl.

21. The pharmaceutical composition 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).

22. The pharmaceutical composition of claim 21 wherein A is of the formula

23. The pharmaceutical composition of claim 1 wherein P comprises from 1 to about 20 amino acid residues.

24. The pharmaceutical composition of claim 23 wherein P comprises an amino acid sequence which is a substrate for a matrix metalloprotease.

25. The pharmaceutical composition of claim 24 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.

26. The pharmaceutical composition of claim 25 wherein the matrix metalloprotease is MMP-2 or MMP-9.

27. The pharmaceutical composition of claim 26 wherein P comprises the sequence -Pro-Leu-Gly-Xaa-, wherein Xaa is a naturally occurring amino acid residue.

28. The pharmaceutical composition of claim 27 wherein P comprises the sequence Pro-Cha-Ala-Abu-Cys(Me)-His-Ala (SEQ ID NO:16).

29. A pharmaceutical composition comprising 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; linear, branched or cyclic C 1 –C 6 -alkyl; or aryl;

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

Z is —C(O)— or C 1 –C 4 -alkylene;

P is NHR, 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 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, Q is not hydrogen;

and a pharmaceutically acceptable carrier.

30. The pharmaceutical composition of claim 29 wherein

W is O or NH;

Z is alkylene-O or alkylene-NH;

Q is isopropyl;

R 1 is methoxy; and

P comprises from 1 to 15 amino acid residues.

31. The pharmaceutical composition of claim 30 wherein

W is O; and

P comprises 10 or fewer amino acid residues.

32. The pharmaceutical composition of claim 29 wherein P comprises from 1 to about 20 amino acid residues.

33. The pharmaceutical composition of claim 32 wherein P comprises an amino acid sequence which is a substrate for a matrix metalloprotease.

34. The pharmaceutical composition of claim 33 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.

35. The pharmaceutical composition of claim 34 wherein the matrix metalloprotease is MMP-2 or MMP-9.

36. The pharmaceutical composition of claim 35 wherein P comprises the sequence -Pro-Leu-Gly-Xaa-, wherein Xaa is a naturally occurring amino acid residue.

37. The pharmaceutical composition of claim 36 wherein P comprises the a sequence Pro-Cha-Ala-Abu-Cys-(Me)-His-Ala (SEQ ID NO:16).

38. A pharmaceutical composition comprising a compound 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-butyric acid;

(ID#31) N-Carbamoyl (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;

(ID#30) N-Carbamoyl (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;

(ID#32) N-Carbamoyl (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;

(ID#40) N-Carbamoyl (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;

(ID#39)N-Carbamoyl (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;

(ID#26)N-Carbamoyl (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;

(ID#27)N-Carbamoyl (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;

(ID#24)-(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;

(ID#36)-(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;

(ID#37)-(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;

(ID#38)-(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; and

(ID#34)-(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;

and a pharmaceutically acceptable carrier.

39. A method of treating an angiogenic-disease in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the compound of Formula I and a pharmaceutically acceptable carrier,

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 a pharmaceutically acceptable salt thereof,

thereby treating the disease in the subject.

40. The method of claim 39 , wherein said angiogenic disease is an autoimmune disease.

41. The method of claim 40 , wherein said autoimmune disease is rheumatoid arthritis.

42. The method of claim 39 , wherein said angiogenic disease is cancer.

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

44. The method of claim 39 , wherein the pharmaceutical composition is administered to the subject intravenously.

45. The method of claim 39 , wherein the pharmaceutical composition is administered to the subject intramuscularly.

46. The method of claim 39 , wherein the pharmaceutical composition is administered to the subject orally.

47. The method of claim 39 , wherein the compound of Formula I is 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-butyric acid;

(ID#31) N-Carbamoyl (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;

(ID#30) N-Carbamoyl (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;

(ID#32) N-Carbamoyl (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;

(ID#40) N-Carbamoyl (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;

(ID#39)N-Carbamoyl (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;

(ID#26) N-Carbamoyl (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;

(ID#27) N-Carbamoyl (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;

(ID#24)-(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;

(ID#36)-(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;

(ID#37)-(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;

(ID#38)-(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; and

(ID#34)-(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.

48. A pharmaceutical composition comprising a compound of the structure

and a pharmaceutically acceptable carrier, wherein

W is O;

each R 1 is, independently hydrogen;

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

R 1 is C 1 -alkoxy;

Z is —C(O);

P is NHR;

or a pharmaceutically acceptable salt thereof.

49. A pharmaceutical composition comprising a compound of

the following structure and a pharmaceutically acceptable carrier.

50. A pharmaceutical composition comprising a compound of the structure (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, and a pharmaceutically acceptable carrier.

51. The pharmaceutical composition of claim 1 formulated as a controlled release composition.

52. The composition of claim 51 wherein said controlled release formulation is a microcapsule.

53. The pharmaceutical composition of claim 50 formulated as a controlled release composition.

54. The composition of claim 53 wherein said controlled release formulation is a microcapsule.

55. The pharmaceutical composition of claim 1 , further comprising a supplementary pharmaceutically active compound.

56. The pharmaceutical composition of claim 55 , wherein said supplementary pharmaceutically active compound is selected from the group consisting of Taxol, Paclitaxel, Actinomycin D, an antidiabetic agent, Tolbutamide, heparin, and a sulfated cyclodextrin.

57. A method for treating an angiogenic disease in a subject comprising administering to said subject a compound comprising the structure (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.

58. The method of claim 57 , wherein said compound is administered as a controlled release formulation.

59. The method of claim 39 wherein the compound of Formula I is of the structure