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US 7,084,108 B2Granted
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 Birktoft, Barry Morgan, Christopher C. Arico-Muendel
Life of this patent
Estimating the term…
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.
Claims27
A compound of Formula I,
- wherein
- A is a Met-AP2 inhibitory core;
- W is O or NR2;
- R1 and R2 are each, independently, hydrogen or alkyl;
- X is alkylene or substituted alkylene;
- n is 0 or 1;
- R3 and R4 are each, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- or R3 and R4, together with the carbon atom to which they are attached, form a carbocyclic or heterocyclic group;
- or R3 and R4 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 OR5 or N(R6)R7, wherein
- R5, R6 and R7 are each, independently, hydrogen, alkyl, substituted alkyl, azacycloalkyl or substituted azacycloalkyl;
- or R6 and R7, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic ring structure;
- or
- Z is —O—, —NR8—, alkylene-O— or alkylene-NR8—, where R8 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 —NR2R3, wherein R2, is hydrogen, alkyl or arylalkyl and R3, is hydrogen, alkyl, arylalkyl or acyl.
17 more elements
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.
7 more elements
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 NR2;
- R1 and R2 are each, independently, hydrogen or alkyl;
- X is alkylene or substituted alkylene;
- n is 0 or 1;
- R3 and R4 are each, independently, substituted alkyl, substituted aryl or substituted or unsubstituted heteroaryl;
- or R3 and R4, together with the carbon atom to which they are attached, form a carbocyclic or heterocyclic group;
- or R3 and R4 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 OR5 or N(R6)R7, wherein
- R5, R6 and R7 are each, independently, hydrogen, alkyl, substituted alkyl, azacycloalkyl or substituted azacycloalkyl;
- or R6 and R7, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic ring structure;
- or
- Z is —O—, —NR8—, alkylene-O— or alkylene-NR8—, where R8 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 —NR2R3, wherein R2, is hydrogen, alkyl or arylalkyl and R3, is hydrogen, alkyl, arylalkyl or acyl.
17 more elements
Dependencies are inferred from the claim text.