First-in-class of shmt2 and mthfd2 inhibitors as antitumor agents
AssigneesDuquesne University of the Holy Spirit, Wayne State University
InventorsAleem Gangjee, Larry H. Matherly
Life of this patent
Estimating the term…
Abstract
A compound of the Formula I and optionally a pharmaceutically acceptable salt thereof is provided: Formula I, wherein, R is one selected from the group consisting of H and CH3; n is an integer ranging from 1 to 4; X is one selected from the group consisting of —CH2—, O, S, —NH—, —NHCHO—, —NHCOCH3—, and —NHCOCF3—; and Ar is one selected from the group consisting of (a) 1,4-phenyl, (b) 2′-fluoro-1,4-phenyl, and (c) 2,5-thienyl. Methods of treating a patient having cancer, targeting mitochondrial metabolism, and targeting SHMT2 and MTHFD2 using the compounds of this invention are disclosed.
Claims27
A compound of Formula I, and optionally a pharmaceutically acceptable salt thereof:
- Formula I,
- wherein,
- R is one selected from the group consisting of H and CH3;
- n is an integer ranging from 1 to 4;
- X is one selected from the group consisting of —CH2—, O, S, —NH—, —NHCHO—, —NHCOCH3—, and —NHCOCF3—;
- and Ar is one selected from the group consisting of (a) 1,4-phenyl, (b) 2′-fluoro-1,4-phenyl, and (c) 2,5-thienyl.
A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, and optionally a pharmaceutically acceptable salt thereof:
- Formula I,
- wherein,
- R is one selected from the group consisting of H and CH3;
- n is an integer ranging from 1 to 4;
- X is one selected from the group consisting of —CH2—, O, S, —NH—, —NHCHO—, —NHCOCH3—, and —NHCOCF3—;
- and Ar is one selected from the group consisting of (a) 1,4-phenyl, (b) 2′-fluoro-1,4-phenyl, and (c) 2,5-thienyl.
A compound of Formula II, and optionally a pharmaceutically acceptable salt thereof:
- Formula II,
- wherein,
- R is one selected from the group consisting of H and CH3;
- n is an integer ranging from 1 to 4;
- X is one selected from the group consisting of —CH2—, O, S, —NH—, —NHCHO—, —NHCOCH3—, and —NHCOCF3—.
A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula II, and optionally a pharmaceutically acceptable salt thereof:
- Formula II,
- wherein,
- R is one selected from the group consisting of H and CH3;
- n is an integer ranging from 1 to 4;
- X is one selected from the group consisting of —CH2—, O, S, —NH—, —NHCHO—, —NHCOCH3—, and —NHCOCF3—.
A compound of Formula III, and optionally a pharmaceutically acceptable salt thereof:
- Formula III,
- wherein,
- R is one selected from the group consisting of H and CH3;
- n is an integer ranging from 1 to 4;
- X is one selected from the group consisting of CH and N;
- Y is one selected from the group consisting of CH and N;
- and Z is one selected from the group consisting of —CH2—, O, S, —NH—, —NHCHO—, —NHCOCH3—, and —NHCOCF3—.
A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula III, and optionally a pharmaceutically acceptable salt thereof:
- Formula III,
- wherein,
- R is one selected from the group consisting of H and CH3;
- n is an integer ranging from 1 to 4;
- X is one selected from the group consisting of CH and N;
- Y is one selected from the group consisting of CH and N;
- and Z is one selected from the group consisting of —CH2—, O, S, —NH—, —NHCHO—, —NHCOCH3—, and —NHCOCF3—.
A method of treating a patient having cancer comprising administering a therapeutically effective amount of a compound of Formula I, and optionally a pharmaceutically acceptable salt thereof:
- Formula I,
- wherein,
- R is one selected from the group consisting of H and CH3;
- n is an integer ranging from 1 to 4;
- X is one selected from the group consisting of —CH2—, O, S, —NH—, —NHCHO—, —NHCOCH3—, and —NHCOCF3—;
- and Ar is one selected from the group consisting of (a) 1,4-phenyl, (b) 2′-fluoro-1,4-phenyl, and (c) 2,5-thienyl.
A method of treating a patient having cancer comprising administering a therapeutically effective amount of a compound of Formula II, and optionally a pharmaceutically acceptable salt thereof:
- Formula II,
- wherein,
- R is one selected from the group consisting of H and CH3;
- n is an integer ranging from 1 to 4;
- X is one selected from the group consisting of —CH2—, O, S, —NH—, —NHCHO—, —NHCOCH3—, and —NHCOCF3—.
A method of treating a patient having cancer comprising administering a therapeutically effective amount of a compound of Formula III, and optionally a pharmaceutically acceptable salt thereof:
- Formula III,
- wherein,
- R is one selected from the group consisting of H and CH3;
- n is an integer ranging from 1 to 4;
- X is one selected from the group consisting of CH and N;
- Y is one selected from the group consisting of CH and N;
- and Z is one selected from the group consisting of —CH2—, O, S, —NH—, —NHCHO—, —NHCOCH3—, and —NHCOCF3—.
A method of targeting mitochondrial metabolism comprising administering to a cancer patient an effective amount of at least one compound selected from the group of Formula I, and optionally a pharmaceutically acceptable salt thereof, of Formula II, and optionally a pharmaceutically acceptable salt thereof, and of Formula III, and optionally a pharmaceutically acceptable salt thereof:
- Formula I,
- wherein,
- R is one selected from the group consisting of H and CH3;
- n is an integer ranging from 1 to 4;
- X is one selected from the group consisting of —CH2—, O, S, —NH—, —NHCHO—, —NHCOCH3—, and —NHCOCF3—;
- and Ar is one selected from the group consisting of (a) 1,4-phenyl, (b) 2′-fluoro-1,4-phenyl, and (c) 2,5-thienyl;
- and
- Formula II,
- wherein,
- R is one selected from the group consisting of H and CH3;
- n is an integer ranging from 1 to 4;
- X is one selected from the group consisting of —CH2—, O, S, —NH—, —NHCHO—, —NHCOCH3—, and —NHCOCF3—;
- and
- Formula III, wherein
- R is one selected from the group consisting of H and CH3;
- n is an integer ranging from 1 to 4;
- X is one selected from the group consisting of CH and N;
- Y is one selected from the group consisting of CH and N;
- and Z is one selected from the group consisting of —CH2—, O, S, —NH—, —NHCHO—, —NHCOCH3—, and —NHCOCF3—.
A method of targeting SHMT2 and MTHFD2 comprising administering to a cancer patient an effective amount of at least one compound selected from the group of Formula I, and optionally a pharmaceutically acceptable salt thereof, of Formula II, and optionally a pharmaceutically acceptable salt thereof, and of Formula III, and optionally a pharmaceutically acceptable salt thereof:
- Formula I,
- wherein,
- R is one selected from the group consisting of H and CH3;
- n is an integer ranging from 1 to 4;
- X is one selected from the group consisting of —CH2—, O, S, —NH—, —NHCHO—, —NHCOCH3—, and —NHCOCF3—;
- and Ar is one selected from the group consisting of (a) 1,4-phenyl, (b) 2′-fluoro-1,4-phenyl, and (c) 2,5-thienyl;
- and
- Formula II,
- wherein,
- R is one selected from the group consisting of H and CH3;
- n is an integer ranging from 1 to 4;
- X is one selected from the group consisting of —CH2—, O, S, —NH—, —NHCHO—, —NHCOCH3—, and —NHCOCF3—;
- and
- Formula III, wherein
- R is one selected from the group consisting of H and CH3;
- n is an integer ranging from 1 to 4;
- X is one selected from the group consisting of CH and N;
- Y is one selected from the group consisting of CH and N;
- and Z is one selected from the group consisting of —CH2—, O, S, —NH—, —NHCHO—, —NHCOCH3—, and —NHCOCF3—.
Dependencies are inferred from the claim text.