Quinazolinone-based oncogenic-ras-selective lethal compounds and their use
AssigneeThe Trustees of Columbia University in the City of New York
InventorsBrent R Stockwell, Matthew Welsch, Wan Seok Yang
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Abstract
The present invention provides, inter alia, compounds having the structure (1) compositions containing such compounds are also provided. Methods for using such compounds or compositions for treating or ameliorating the effects of a cancer having a cell that harbors an oncogenic RAS mutation, for modulating a lipoxygenase in a ferroptosis cell death pathway, and for depleting reduced glutathione (GSH) in a cell harboring an oncogenic RAS mutation are further provided.
Claims36
A compound having the structure (1):
- wherein
- R1 is selected from the group consisting of H, C1-4 alkyl, C1-4 alkoxy, hydroxy, and halogen;
- R2 is selected from the group consisting of H, C1-4 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, C3-8 heterocycloalkyl, aryl, heteroaryl, C1-4 aralkyl;
- R3 is selected from the group consisting of nothing, C1-4 alkyl, C1-4 alkoxy, carbonyl, C3-8 cycloalkyl, and C3-8 heterocycloalkyl;
- X is selected from the group consisting of C, N, and O;
- and
- n is an integer from 0-6,
- with the proviso that when X is C, n=0, and R3 is nothing, R1 cannot be H when R2 is CH3,
- or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
A compound having the structure (30):
- or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
A composition comprising a pharmaceutically acceptable carrier and a compound having the structure (1):
- wherein
- R1 is selected from the group consisting of H, C1-4 alkyl, C1-4 alkoxy, hydroxy, and halogen;
- R2 is selected from the group consisting of H, C1-4 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, C3-8 heterocycloalkyl, aryl, heteroaryl, C1-4 aralkyl;
- R3 is selected from the group consisting of nothing, C1-4 alkyl, C1-4 alkoxy, carbonyl, C3-8 cycloalkyl, and C3-8 heterocycloalkyl;
- X is selected from the group consisting of C, N, and O;
- and
- n is an integer from 0-6,
- with the proviso that when X is C, n=0, and R3 is nothing, R1 cannot be H when R2 is CH3,
- or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
A composition comprising a pharmaceutically acceptable carrier and a compound having the structure (30):
- or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
A method for treating or ameliorating the effects of a cancer comprising a cell that harbors an oncogenic RAS mutation, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a pharmaceutically acceptable carrier and a compound having the structure (30):
- or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
A method for modulating a lipoxygenase in a ferroptosis cell death pathway comprising administering to a cell an effective amount of a compound having the structure (1):
- wherein
- R1 is selected from the group consisting of H, C1-4 alkyl, C1-4 alkoxy, hydroxy, and halogen;
- R2 is selected from the group consisting of H, C1-4 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, C3-8 heterocycloalkyl, aryl, heteroaryl, C1-4 aralkyl;
- R3 is selected from the group consisting of nothing, C1-4 alkyl, C1-4 alkoxy, carbonyl, C3-8 cycloalkyl, and C3-8 heterocycloalkyl;
- X is selected from the group consisting of C, N, and O;
- and
- n is an integer from 0-6,
- with the proviso that when X is C, n=0, and R3 is nothing, R1 cannot be H when R2 is CH3,
- or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
A method for depleting reduced glutathione (GSH) in a cell harboring an oncogenic RAS mutation comprising administering to the cell an effective amount of a compound having the structure (1):
- wherein
- R1 is selected from the group consisting of H, C1-4 alkyl, C1-4 alkoxy, hydroxy, and halogen;
- R2 is selected from the group consisting of H, C1-4 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, C3-8 heterocycloalkyl, aryl, heteroaryl, C1-4 aralkyl;
- R3 is selected from the group consisting of nothing, C1-4 alkyl, C1-4 alkoxy, carbonyl, C3-8 cycloalkyl, and C3-8 heterocycloalkyl;
- X is selected from the group consisting of C, N, and O;
- and
- n is an integer from 0-6,
- with the proviso that when X is C, n=0, and R3 is nothing, R1 cannot be H when R2 is CH3,
- or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
A compound having the structure (100):
- wherein
- R1 is selected from the group consisting of H, C1-4 alkyl, C1-4 alkoxy, hydroxy, and halogen;
- R2 is selected from the group consisting of H, C1-4 alkyl, C1-4 alkoxy, C3-8 cycloalkyl, C3-8 heterocycloalkyl, aryl, heteroaryl, C1-4 aralkyl;
- R3 is selected from the group consisting of nothing, H, C1-4 alkyl, C1-4 alkoxy, carbonyl, C3-8 cycloalkyl, and C3-8 heterocycloalkyl;
- R4 and R5 are independently selected from the group consisting of H, C3-8 cycloalkyl, and C3-8 heterocycloalkyl;
- R6 is selected from the group consisting of H, —NH2, C1-4 alkyl, C1-4 alkoxy, carbonyl, aryl, heteraryl, C3-8 cycloalkyl, and C3-8 heterocycloalkyl;
- X is selected from the group consisting of C, N, and O;
- and
- n is an integer from 0-6,
- with the proviso that when X is C, n=0, and R3 is nothing, R1 cannot be H when R2 is CH3,
- or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
A method for treating or ameliorating the effects of a cancer comprising a cell that harbors an oncogenic RAS mutation, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of:
- or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
A method for modulating a lipoxygenase in a ferroptosis cell death pathway comprising administering to a cell an effective amount of a compound selected from the group consisting of:
- or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
A method for depleting reduced glutathione (GSH) in a cell harboring an oncogenic RAS mutation comprising administering to the cell an effective amount of a compound selected from the group consisting of:
- or an N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.