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US 2009/0156624 A1Published application
Methionine aminopeptidase-2 inhibitors and methods of use thereof
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 methods of parasitic infections, thymoma, and lymphoid malignancies in a subject by administering to the subject a therapeutically effective amount of one or more of the compounds of the invention.
Claims73
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)— 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.
15 more elements
A compound 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.
9 more elements
A compound of the formula
- wherein
- W is O or NR;
- each R is, independently hydrogen or a C1-C4-alkyl;
- Q is hydrogen;
- 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;
- 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.
12 more elements
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-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-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 (ID#31) (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;
- N-Carbamoyl (ID#30) (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;
- N-Carbamoyl (ID#32) (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;
- N-Carbamoyl (ID#40) (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 (ID#39) (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 (ID#26) (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 (ID#27) (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;
- (ID#24)-(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;
- (ID#36)-(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;
- (ID#37)-(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;
- (ID#38)-(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;
- (ID#34)-(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;
- {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-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.
33 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 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.
9 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, 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)— 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.
15 more elements
A method of treating a parasitic infection 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 parasitic infection in the subject.
9 more elements
A method of treating a thymoma 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 thymoma in the subject.
9 more elements
Dependencies are inferred from the claim text.