IP Library › Granted Patent US 6,919,307

Granted Patent B2

US 6,919,307 · App. 10/138,935 · Granted Jul 19, 2005

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

Assignee: Praecis Pharmaceuticals, Inc.

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Quick Facts

Patent No.: US 6,919,307
App. No.: 10/138,935
Granted: Jul 19, 2005
Kind: B2

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Abstract

The present invention provides methods of treating a parasitic infection, a lymphoid malignancy or an autoimmune disorder in a subject by administering to the subject a therapeutically effective amount of an angiogenesis inhibitor compound comprising a MetAP-2 inhibitory core coupled to a peptide.

Claims (181)

1. A method of treating a subject having a lymphoid malignancy, 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. The method of claim 1 , wherein Z in said compound is Z is —C(O)— or C 1 -C 4 -alkylene-C(O)—.

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

4. The method of claim 2 , wherein Q in said compound is linear, branched or cyclic C 1 -C 6 -alkyl, phenyl or naphthyl.

5. The method of claim 4 , wherein Q in said compound is isopropyl, phenyl or cyclohexyl.

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

7. The method of claim 6 , wherein Z in said compound is C 1 -C 4 -alkylene-O— or C 1 -C 4 -alkylene-NH—.

8. The method of claim 7 , wherein Z in said compound is C 1 -C 2 -alkylene-O— or C 1 -C 2 -alkylene-NH.

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

10. The method of claim 9 , wherein Q in said compound is isopropyl, phenyl or cyclohexyl.

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

12. The method of claim 11 , wherein each R in said compound is, independently, hydrogen or linear or branched C 1 -C 4 -alkyl.

13. The method of claim 12 , wherein each R in said compound is, independently, hydrogen or methyl.

14. The method of claim 13 , wherein each R in said compound is hydrogen.

15. 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

16. The method of claim 15 , wherein R 1 in said compound is C 1 -C 4 -alkoxy.

17. The method of claim 16 , wherein R 1 in said compound is methoxy.

18. The method of claim 15 , wherein R 3 in said compound is hydrogen or C 1 -C 4 -alkyl.

19. The method of claim 18 , wherein R 3 in said compound is methyl.

20. The method of claim 15 , wherein D in said compound is linear, branched or cyclic C 1 -C 6 -alkyl; or aryl-C 1 -C 4 -alkyl.

21. 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 -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 method of claim 21 , wherein A in said compound is of the formula

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

24. The method of claim 23 , wherein P in said compound comprises an amino acid sequence which is a substrate for a matrix metalloprotease.

25. The method 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 method of claim 25 , wherein the matrix metalloprotease is MMP-2 or MMP-9.

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

28. The method of claim 27 , wherein P is Pro-Cha-Ala-Abu-Cys(Me)-His-Ala (SEQ ID NO:16).

29. A method of treating a subject having a lymphoid malignancy-comprising administering to the subject a therapeutically effective amount of a compound comprising the structure

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.

30. The method 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 method of claim 30 , wherein W in said compound is O; and P comprises 10 or fewer amino acid residues.

32. The method of claim 29 , wherein P in said compound comprises from 1 to about 20 amino acid residues.

33. The method of claim 32 , wherein P in said compound comprises an amino acid sequence which is a substrate for a matrix metalloprotease.

34. The method 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 method of claim wherein the matrix metalloprotease is MMP-2 or MMP-9.

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

37. The method of claim 36 , wherein P is -Pro-Cha-Ala-Abu-Cys(Me)-His-Ala (SEQ ID NO:16).

38. A method of treating a subject having a lymphoid malignancy, 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-pentanaic 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)-caxbamic 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-butyl)-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-butyl)-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-(3-methyl-butyl)-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-(3-methyl-butyl)-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-(3-methyl-butyl)-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-(3-methyl-butyl)-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-(3-methyl-butyl)-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-(3-methyl-butyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonyl}amino-3-methyl-butanol) ester;

(ID#34)-(2R-{(3R, 4S, 5S, 6R) 5-methoxy-4-[(2R, 3R)2-methyl-3-(3-(3-methyl-butyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonyl}amino-3-methyl-butanol) ester;

{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-propylcarbamol)-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-y1)-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.

39. A method of treating a subject having a lymphoid malignancy, comprising administering to the subject a therapeutically effective amount of a compound comprising the structure

40. The method of any one of claims 1 , 29 , 38 , 39 , wherein said lymphoid malignancy is a lymphoma.

41. The method of claim 40 wherein said lymphoma is a B cell lymphoma.

42. The method any one of claims 1 , 29 , 38 , 39 , wherein said lymphoid malignancy is leukemia.

43. A method of treating a subject having a parasitic infection, 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.

44. A method for treating a subject having a parasitic infection 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 a 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)—;

P is NHR or OR

or a pharmaceutically acceptable salt thereof.

45. The method of claim 44 , 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 .

46. The method of claim 45 , wherein Q is linear, branched or cyclic C 1 -C 6 -alkyl and P is NH 2 .

47. A method for treating a subject having a parasitic infection comprising administering to said subject a compound comprising the structure

48. A method of treating a subject having a parasitic infection, comprising administering to the subject a therapeutically effective amount of a compound comprising a structure selected from the group consisting of