Therapeutic agents and methods of use thereof for the modulation of angiogenesis
AssigneePraecis Pharmaceuticals, Inc.
InventorsGary L. Olson, Christopher Self, Lily Lee, Charles M. Cook, Jens 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.
Claims44
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 —NR2′R3′, wherein R2′ is alkyl or arylalkyl and R3′ 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.
A compound of the formula
- wherein
- W is O or NR;
- each R is, independently hydrogen or a C1-C4-alkyl;
- Q is hydrogen;
- R1 is hydroxy, C1-C4-alkoxy or halogen;
- Z is —C(O)— or C1-C4-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 —NR2′R3′, wherein R2′ is alkyl or arylalkyl and R3′ is hydrogen, alkyl, arylalkyl or acyl;
- or a pharmaceutically acceptable salt thereof.
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).
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 —NR2′R3′, wherein R2′ is hydrogen, alkyl or arylalkyl and R3′ 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.
Dependencies are inferred from the claim text.