Therapeutic agents and methods of use thereof for the modulation of angiogenesis
AssigneePraecis Pharmaceuticals, Inc.
InventorsGary L. Olson, Christopher Self, Lily Lee, Charles Michael Cook, Jens J. Birktoft
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Abstract
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.
Claims52
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 a linear, branched or cyclic alkyl or aryl;
- 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 a linear, branched or cyclic alkyl or aryl;
- and pharmaceutically acceptable salts thereof.
A compound of the formula
- wherein
- W is O or NR;
- each R is, independently hydrogen or a C1-C4-alkyl;
- Q is a linear, branched or cyclic C1-C6-alkyl;
- or aryl;
- R1 is hydroxy, C1-C4-alkoxy or halogen;
- Z is —C(O)— or C1-C4-alkylene-C(O)—;
- 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.
An angiogenesis inhibitor 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-6yloxycarbonylamino}-3-methyl-butyric acid methyl ester;
- 2-{(3R, 4S, 5S, 6R)-5-Methoxy4-[(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;
- N-Carbamoyl-GlyProLeuGlyMetTrpAlaGly-NH2-(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;
- N-Carbamoyl-GlyProLeuSar-OH-(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;
- H-MetTrpAla-(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
- H-MetGly-(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.
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;
- 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 angiogenic disease in the subject.
A compound of the formula
- wherein
- W is O;
- each R is, independently hydrogen;
- Q is a linear, branched or cyclic C1-C6-alkyl;
- or aryl;
- R1 is C1-alkoxy;
- Z is —C(O);
- P is NHR;
- or a pharmaceutically acceptable salt thereof.
An angiogenesis inhibitor compound comprising the structure
- or a pharmaceutically acceptable salt thereof.
An angiogenesis inhibitor 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, or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.