Benzamide or benzamine compounds useful as anticancer agents for the treatment of human cancers

Patent metadata

Field	Value
Publication number	US-11548894-B2
Application number	US-201816139865-A
Country	US
Kind code	B2
Filing date	Sep 24, 2018
Priority date	Jul 6, 2015
Publication date	Jan 10, 2023
Grant date	Jan 10, 2023

Abstract

The described invention provides small molecule anti-cancer compounds for treating tumors that respond to cholesterol biosynthesis inhibition. The compounds selectively inhibit the cholesterol biosynthetic pathway in tumor-derived cancer cells, but do not affect normally dividing cells.

First claim

What is claimed is:

1. A pharmaceutical composition comprising a small molecule anti-cancer compound of Formula I-f:

wherein:
X 1 is selected from the group consisting of H, F, CN, NH 2 , NO 2 , N 3 , and SO 2 Me;
n=1, 2, or 3;
L 2 is selected from the group consisting of S, O, NH, CHOH, C═O, —O(CH 2 )—, —S(CH 2 )—, —(CH 2 )O—, and —(CH 2 )S—;
R 1 is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxyalkyl, and acyloxyalkyl;
R 1 and R 2 may optionally form a ring, such that R 1 -R 2 consists of a three to six subunit chain comprising subunits independently selected from the group consisting of (CR 7 R 8 ), NR 9 , O, and S;
R 1 and R 3 may optionally form a ring, such that R 1 -R 3 comprises —(CR 10 R 11 ) m , where m=2, 3, 4 or 5;
R 2 is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxyalkyl, and acyloxyalkyl;
R 2 and R 4 may optionally form a ring, such that R 2 -R 4 consists of a one to four subunit chain comprising subunits independently selected from the group consisting of —(CR 12 R 13 ); R 2 may simultaneously form a ring with R 1 as described above;
R 3 is selected from the group consisting of H, D, F, Me, and Et;
R 4 is selected from the group consisting of H, Me, CD 3 , CF 3 , Et, i-Pr, cyclopropyl, and C 2 -C 6 alkynyl;
R 7 and R 8 are independently selected from the group consisting of H, D, F, Me, Et, OR, and NR 2 ; wherein R is selected from the group consisting of H, Me, and Et;
R 9 is selected from the group consisting of H, Me, Et, isopropyl, and cyclopropyl;
R 10 and R 11 are independently selected from the group consisting of H, D, F, Me, Et, OR, and NR 2 ; wherein R is selected from the group consisting of H, Me, and Et;
R 12 and R 13 are independently selected from the group consisting of H, D, F, Me, and Et; and
R 14 and R 15 can be attached at any available position on the aromatic ring and are selected from the group consisting of H, D, F, Cl, Br, CF 3 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, OR, NR 2 , NO 2 , N 3 , CN, CO 2 R, CO 2 NR 2 , SR, alkylacyl and arylacyl; wherein R is independently selected from the group consisting of H, Me, Et, isopropyl, cyclopropyl, propargyl, and acyl;
such that all possible stereoisomers, including optically active isomers, are included whenever stereogenic centers are present;
or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof,
wherein the pharmaceutical composition comprises a therapeutic amount of the compound and a pharmaceutically acceptable carrier.

2. A method of treating a cancer in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 1 , wherein the therapeutic amount is effective to inhibit tumor growth, inhibit tumor proliferation, induce cell death, or a combination thereof, wherein the cancer is treatable by inhibition of a cholesterol biosynthesis pathway.

3. The method according to claim 2 , wherein the therapeutic amount is effective to inhibit a cholesterol biosynthesis pathway.

4. The method according to claim 2 , wherein the therapeutic amount is effective to down-regulate SHREBP2 and its target genes.

Assignees

• Univ Texas

Inventors

• Debrabander Jef
• Parada Luis

Classifications

• C07D207/09

  Radicals substituted by nitrogen atoms, not forming part of a nitro radical · CPC title

• C07D213/16

  containing only one pyridine ring · CPC title

• C07D213/70

  Sulfur atoms · CPC title

• C07C205/61

  the carbon skeleton being further substituted by doubly-bound oxygen atoms · CPC title

• C07D209/48

  with oxygen atoms in positions 1 and 3, e.g. phthalimide · CPC title