Therapeutic agents and methods of use thereof for the modulation of angiogenesis
The present invention provides angiogenesis inhibitor compounds comprising a MetAP-2 inhibitory core coupled to a peptide, as well as pharmaceutical compositions comprising the angiogenesis inhibitor compounds and a pharmaceutically acceptable carrier. The present invention also provides methods of treating an angiogenic disease, e.g., cancer, in a subject by administering to the subject a therapeutically effective amount of one or more of the angiogenesis inhibitor compounds of the invention.
1. A compound of Formula I,
wherein
A is a Met-AP2 inhibitory core;
W is O or NR 2 ;
R 1 and R 2 are each, independently, hydrogen or alkyl;
X is alkylene or substituted alkylene;
n is 0 or 1;
R 3 and R 4 are each, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or R 3 and R 4 , together with the carbon atom to which they are attached, form a carbocyclic or heterocyclic group; or R 3 and R 4 together form an alkylene group;
Z is —C(O)— alkylene or alkylene—C(O)—; and
P is a peptide comprising from 1 to about 100 amino acid residues attached at its amino terminus to Z or a group OR 5 or N(R 6 )R 7 , wherein
R 5 , R 6 and R 7 are each, independently, hydrogen, alkyl, substituted alkyl, azacycloalkyl or substituted azacycloalkyl; or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic ring structure; or
Z is —O—, —NR 8 —, alkylene-O— or alkylene-NR 8 —, where R 8 is hydrogen or alkyl; and
P is hydrogen, alkyl or a peptide consisting of from 1 to about 100 amino acid residues attached at its carboxy terminus to Z; 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.
2. The compound of claim 1 , wherein at least one of R 3 and R 4 is a substituted alkyl group.
3. The compound of claim 2 , wherein at least one of R 3 and R 4 is a substituted normal, branched or cyclic C 1 –C 6 alkyl group.
4. The compound of claim 3 , wherein at least one of R 3 and R 4 is a substituted normal or branched C 1 –C 4 alkyl group.
5. The compound of claim 1 , wherein one of R 3 and R 4 is a substituted aryl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group.
6. The compound of claim 5 , wherein one of R 3 and R 4 is selected from the group consisting of indolyl, imidazolyl, pyridyl, indolylmethyl, imidazolylmethyl and pyridylmethyl.
7. The compound of claim 1 , wherein n is 1 and X is C 1 –C 6 -alkylene.
8. The compound of claim 7 , wherein X is methylene or ethylene.
9. The compound of claim 1 , wherein Z is C 1 –C 6 -alkylene-C(O)—.
10. The compound of claim 9 , wherein Z is methylene-C(O)— or ethylene-C(O)—.
11. The compound of claim 1 , wherein at least one of R 6 and R 7 is alkyl, substituted alkyl, substituted or unsubstituted azacycloalkyl or substituted or unsubstituted azacycloalkyl.
12. The compound of claim 11 , wherein at least one of R 6 and R 7 is an azacycloalkyl group having an N-alkyl substituent.
13. The compound of claim 12 , wherein the N-alkyl substituent is a C 1 –C 4 -alkyl group.
14. The compound of claim 13 , wherein the N-alkyl substituent is a methyl group.
15. The compound of claim 1 , wherein R 6 and R 7 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted five or six-membered aza- or diazacycloalkyl group.
16. The compound of claim 15 , wherein R 6 and R 7 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted five or six-membered diazacycloalkyl group which includes an N-alkyl substituent.
17. The compound of claim 16 , wherein the N-alkyl substituent is a C 1 –C 4 -alkyl group.
18. The compound of claim 17 , wherein the N-alkyl substituent is a methyl group.
19. The compound of claim 1 , wherein P is NH 2 or one of the groups shown below:
20. An angiogenesis inhibitor compound selected from the group consisting of
{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-Dimethylamnino-2,2-dimethy-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.
21. 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 Met-AP2 inhibitory core;
W is O or NR 2 ;
R 1 and R 2 are each, independently, hydrogen or alkyl;
X is alkylene or substituted alkylene;
n is 0 or 1;
R 3 and R 4 are each, independently, substituted alkyl, substituted aryl or substituted or unsubstituted heteroaryl; or R 3 and R 4 , together with the carbon atom to which they are attached, form a carbocyclic or heterocyclic group; or R 3 and R 4 together form an alkylene group;
Z is —C(O)— or alkylene-C(O)—; and
P is a peptide comprising from 1 to about 100 amino acid residues attached at its amino terminus to Z or a group OR 5 or N(R 6 )R 7 , wherein
R 5 , R 6 and R 7 are each, independently, hydrogen, alkyl, substituted alkyl, azacycloalkyl or substituted azacycloalkyl; or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic ring structure; or
Z is —O—, —NR 8 —, alkylene-O— or alkylene-NR 8 —, where R 8 is hydrogen or alkyl; and
P is hydrogen, alkyl or a peptide consisting of from 1 to about 100 amino acid residues attached at its carboxy terminus to Z; 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.
22. The method of claim 21 , wherein said angiogenic disease is an autoimmune disease.
23. The method of claim 22 , wherein said autoimmune disease is rheumatoid arthritis.
24. The method of claim 21 , wherein said angiogenic disease is cancer.
25. The compound of claim 1 , wherein R 1 is a substituted or unsubstituted alkyl group.
26. The compound of claim 25 , wherein R 1 is a substituted or unsubstituted normal, branched or cyclic C 1 –C 6 alkyl group.
27. The compound of claim 26 , wherein R 1 is a normal or branched C 1 –C 4 alkyl group.