STAT3 dimerization inhibitors

Patent metadata

Field	Value
Publication number	US-10954258-B2
Application number	US-201916685461-A
Country	US
Kind code	B2
Filing date	Nov 15, 2019
Priority date	Oct 30, 2012
Publication date	Mar 23, 2021
Grant date	Mar 23, 2021

Abstract

The subject matter disclosed herein relates to compositions and methods of making and using the compositions. In a further aspect, the subject matter disclosed herein relates to inhibitors of STAT3 dimerization. Methods of making these compositions as well as compositions comprising these compositions are also disclosed. Also disclosed are methods of treating or preventing certain cancers by administering to an individual in need thereof and effective amount of the compounds disclosed herein. Still further, disclosed herein are methods of inhibiting STAT3 by contacting a cell with a compound or composition as disclosed herein.

First claim

What is claimed is:

1. A compound having Formula III:

wherein
R 1 is H, C 1 -C 10 alkyl, C(O)C 1 -C 10 alkyl, CO 2 C 1 -C 10 alkyl, benzyl, 4-piperidyl, 3-(4-pyridyl), pyridinyl, or

wherein R 4 is OH, Cl, F, Br, I, cyclohexyl, OC 1 -C 10 alkyl, C 1 -C 10 alkyl, C(O)C 1 -C 10 alkyl, CO 2 C 1 -C 10 alkyl, 4-piperidyl, 3-(4-pyridyl), morpholinyl, pyridinyl, OPh, PO(OEt) 2 , or PO(OH) 2 ;

R 2 is null, H, OH, Cl, F, Br, I, NH 3 , OC 1 -C 10 alkyl, cyclohexyl, C 1 -C 10 alkyl, C(O)C 1 -C 10 alkyl, CO 2 C 1 -C 10 alkyl, 4-piperidyl, 3-(4-pyridyl), morpholinyl, pyridinyl, phenyl, halogenated phenyl, PO(OEt) 2 , PO(OH) 2 or

wherein X is O, NH, S, or CH 2 , and R 5 is H, OH, Cl, F, Br, I, cyclohexyl, or C 1 -C 10 alkyl;

R 3 is H, OH, Cl, F, Br, I, OC 1 -C 10 alkyl, C 1 -C 10 alkyl, C(O)C 1 -C 10 alkyl, CO 2 C 1 -C 10 alkyl, NO 2 , NH 3 , or CN; and
R 6 is H, C 1 -C 10 alkyl, or a pharmaceutically acceptable counterion;
R 8 is H, C 1 -C 10 alkyl, C(O)C 1 -C 10 alkyl, CO 2 C 1 -C 10 alkyl, or benzyl;
each Y is, independent of the others, CH or N; and
Z is C or N;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the compound wherein is R 1 is H, C 1 -C 10 alkyl, C(O)C 1 -C 10 alkyl, CO 2 C 1 -C 10 alkyl, benzyl, 4-piperidyl, 3-(4-pyridyl), or pyridinyl.

3. The compound of claim 1 , wherein R 1 is

where each Y is CH, and R 4 is OH, Cl, F, Br, I, cyclohexyl, C 1 -C 10 alkyl, 4-piperidyl, 3-(4-pyridyl), morpholinyl, pyridinyl, or OPh.

4. The compound of claim 1 , wherein R 1 is

wherein each Y is CH, and R 4 is cyclohexyl, C 1 -C 10 alkyl, 4-piperidyl, 3-(4-pyridyl), morpholinyl, or pyridinyl.

5. The compound of claim 4 , wherein R 4 is cyclohexyl.

6. The compound of claim 1 , wherein R 2 is OH, Cl, F, Br, I, OCH 3 , C 1 -C 10 alkyl, 4-piperidyl, 3-(4-pyridyl), morpholinyl, phenyl, or pyridinyl.

7. The compound of claim 1 , wherein R 2 is

wherein each Y is CH, and R 5 is H, OH, Cl, F, Br, or I.

8. The compound of claim 7 , wherein X is 0.

9. The compound of claim 1 , wherein R 2 is OPh.

10. The compound of claim 1 , wherein R 3 is H or OCH 3 .

11. The compound of claim 1 , wherein R 8 is methyl or benzyl.

12. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

13. A method of reducing or inhibiting tumor growth in an individual with cancer, comprising: administering a therapeutically effective amount of the compound of claim 1 to the individual.

14. The method of claim 13 , wherein STAT3 is persistently tyrosine phosphorylated and constitutively activated in the cancer.

15. The method of claim 13 , wherein the cancer is pancreatic cancer, breast cancer, lung cancer, prostate cancer, ovarian cancer, colon cancer, gastric cancer, head and neck cancer, melanoma, leukemia, multiple myeloma or lymphoma.

16. A method of inhibiting STAT3-STAT3 dimerization and/or STAT3-EGFR binding in a cell, comprising: administering to the cell an effective amount of the compound of claim 1 to the cell.

Assignees

• H Lee Moffitt Cancer Ct & Res

Inventors

• Sebti Said M
• Lawrence Nicholas James
• Lawrence Harshani Rithma

Classifications

• A61K31/192

  having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid  {(cannabinoids A61K31/658)} · CPC title

• C07D213/16

  containing only one pyridine ring · CPC title

• C07F9/3882

  Arylalkanephosphonic acids (C07F9/3839 takes precedence) · CPC title

• C07F9/4056

  Esters of arylalkanephosphonic acids (C07F9/4025 takes precedence) · CPC title

• C07F9/4021

  Esters of aromatic acids (P-C aromatic linkage) · CPC title