Pyrazole derivatives as inhibitors of STAT3

Patent metadata

Field	Value
Publication number	US-9732038-B2
Application number	US-201314407781-A
Country	US
Kind code	B2
Filing date	Mar 14, 2013
Priority date	Jun 14, 2012
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

Abstract

Compositions that modulate the activity of signal transducer and activator of transcription-3 (STAT3) activity as well as their methods of use, such as treatment and imaging are provided. Compositions contain small molecules such as substituted pyrazoles and are useful in treatment of diseases related to the activity of STAT3 including, for example, cancer and other diseases.

First claim

What is claimed is:

1. A compound which is 3-[{2-[(7-{2-[((4-((5-(4-Bromophenyl)-1-(4-sulfamoylphenyl)-1H-pyrazol-3-yl)methyl)phenyl)aminocarbonyl)-methoxy]-acetylamino}-heptylaminocarbonyl)-methoxy]-acetyl}-(4-aminobenzyl)]-5-(4-bromophenyl)-1-(4-aminosulfonylphenyl)-1H-pyrazole having the following structure

or a pharmaceutically acceptable salt thereof.

2. A method of inhibiting activation of STAT3 in a cancer cell, wherein the cancer is selected from human colorectal carcinoma, lymphoma, leukemia, multiple myeloma, breast cancer, lung cancer, and brain cancer, the method comprising contacting the cell with a compound which is 3-[{2-[(7-{2-[((4-((5-(4-Bromophenyl)-1-(4-sulfamoylphenyl)-1H-pyrazol-3-yl)methyl)phenyl)aminocarbonyl)-methoxy]-acetylamino}-heptylaminocarbonyl)-methoxy]-acetyl}-(4-aminobenzyl)]-5-(4-bromophenyl)-1-(4-aminosulfonylphenyl)-1H-pyrazole having the following structure

or a pharmaceutically acceptable salt thereof.

3. A method for treating cancer, wherein the cancer is selected from breast cancer, lung cancer, lymphoma, leukemia, multiple myeloma, brain cancer, and human colorectal carcinoma, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound which is 3-[{2-[(7-{2-[((4-((5-(4-Bromophenyl)-1-(4-sulfamoylphenyl)-1H-pyrazol-3-yl)methyl)phenyl)aminocarbonyl)-methoxy]-acetylamino}-heptylaminocarbonyl)-methoxy]-acetyl}-(4-aminobenzyl)]-5-(4-bromophenyl)-1-(4-aminosulfonylphenyl)-1H-pyrazole having the following structure

or a pharmaceutically acceptable salt thereof.

4. The method of claim 3 , wherein the 3-[{2-[(7-{2-[((4-((5-(4-Bromophenyl)-1-(4-sulfamoylphenyl)-1H-pyrazol-3-yl)methyl)phenyl)aminocarbonyl)-methoxy]-acetylamino}-heptylaminocarbonyl)-methoxy]-acetyl}-(4-aminobenzyl)]-5-(4-bromophenyl)-1-(4-aminosulfonylphenyl)-1H-pyrazole is used in combination with an anti-cancer agent.

5. The method of claim 4 , wherein the anti-cancer agent is temozolomide.

6. The method of claim 4 , wherein the anti-cancer agent is an anti-cancer vaccine.

7. A method of initiating apoptosis in a cancer cell, wherein the cancer is selected from human colorectal carcinoma, lymphoma, leukemia, multiple myeloma, breast cancer, lung cancer, and brain cancer, the method comprising contacting the cell with a compound which is 3-[{2-[(7-{2-[((4-((5-(4-Bromophenyl)-1-(4-sulfamoylphenyl)-1H-pyrazol-3-yl)methyl)phenyl)aminocarbonyl)-methoxy]-acetylamino}-heptylaminocarbonyl)-methoxy]-acetyl}-(4-aminobenzyl)]-5-(4-bromophenyl)-1-(4-aminosulfonylphenyl)-1H-pyrazole having the following structure

or a pharmaceutically acceptable salt thereof.

8. The method of any one of claims 2 , 3 and 7 , wherein the brain cancer is human glioma.

9. The method of claim 8 , wherein the human glioma is glioblastoma.

10. The method of any one of claims 2 , 3 and 7 , wherein the brain cancer is medulloblastoma.

Assignees

• Mayo Foundation

Inventors

• Daniels David J
• Parney Ian F
• Peterson Timothy E

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D231/12 Primary

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• A61K31/495

  having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53}) · CPC title

• G01N33/5308

  for analytes not provided for elsewhere, e.g. nucleic acids, uric acid, worms, mites · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title