Small molecule inhibitors of mcl-1 and uses thereof

Patent metadata

Field	Value
Publication number	US-2016304485-A1
Application number	US-201615134098-A
Country	US
Kind code	A1
Filing date	Apr 20, 2016
Priority date	Apr 20, 2015
Publication date	Oct 20, 2016
Grant date	—

Abstract

This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of small-molecules having benzoic acid structure which function as inhibitors of Mcl-1 protein, and their use as therapeutics for the treatment of cancer and other diseases.

First claim

What is claimed is:

1 . A compound having Formula I:

including pharmaceutically acceptable salts, solvates, and/or prodrugs thereof; wherein R1, R2, R3, R4, X or Y, independently include any chemical moiety that permits the resulting compound to bind with an Mcl-1 protein.

2 . The compound of claim 1 , wherein R1, R2, R3, R4, X or Y, independently include any chemical moiety that permits the resulting compound to bind the BH3 binding pocket of an Mcl-1 protein.

3 . The compound of claim 1 , wherein X-R1 is a substituted or non-substituted moiety comprising H, C, N, O, and/or S.

4 . The compound of claim 1 , wherein X is absent or is selected from the group consisting of:

5 . The compound of claim 4 , wherein R1 is selected from the group consisting of from

6 . The compound of claim 1 , wherein R2 is a substituted or non-substituted moiety comprising H, C, N, O, and/or S.

7 . The compound of claim 1 , wherein R2 is selected from the group consisting of H,

8 . The compound of claim 1 , wherein Y-R3 is selected from the group consisting of from

9 . The compound of claim 1 , wherein Y is selected from the group consisting of

10 . The compound of claim 1 , wherein R3 is selected from the group consisting of H,

11 . The compound of claim 1 , wherein R4 is an acid moiety, an ester moiety, and/or a carboxylic bioisostere moiety.

12 . The compound of claim 1 , wherein R4 is selected from the group consisting of H, CH 3 , OH, OCH 3 , OCH 2 CH 3 , COOH, COOCH 3 , COOCH 2 CH 3

(wherein X, Y, Z are independently N, C or CO),

13 . The compound of claim 1 , wherein said compound is selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.

14 . The compound of claim 1 , wherein the compound is comprised within a pharmaceutical composition.

15 . A method of treating, ameliorating, or preventing a hyperproliferative disease in a patient comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of claim 14 ,
wherein said hyperproliferative disease is cancer, wherein said cancer is head and neck cancers, colon cancer, lung cancer, ovarian cancer, prostate cancer, multiple myeloma, acute myeloid leukemia, melanoma, breast cancer, and/or pancreatic cancer, wherein said patient is a human patient.

16 . The method of claim 15 further comprising administering to said patient one or more anticancer agents,
wherein said anticancer agent one or more of a chemotherapeutic agent, and radiation therapy.

17 . The method of claim 15 , wherein said compound is capable of one or more of binding with a Mcl-1 protein and/or binding the BH3 groove within Mcl-1,
wherein said binding results in inhibited Mcl-1 protein activity.

18 . A kit comprising a compound of claim 1 and instructions for administering said compound to a patient having a hyperproliferative disease,
wherein said hyperproliferative disease is cancer, wherein said cancer is head and neck cancers, colon cancer, lung cancer, ovarian cancer, prostate cancer, multiple myeloma, acute myeloid leukemia, melanoma, breast cancer, and/or pancreatic cancer.

19 . The kit of claim 18 further comprising one or more anticancer agents.

20 . The kit of claim 19 , wherein said compound is to be administered together with one or more anticancer agents.

Assignees

• Univ Michigan Regents

Inventors

• Nikolovska-Coleska Zaneta
• Stuckey Jeanne A
• Mady Ahmed
• Miao Lei

Classifications

• C07C311/29

  having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• A61K31/18

  Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63) · CPC title

• C07C235/56

  having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• A61K31/167

  having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol · CPC title

• C07D295/26

  Sulfur atoms · CPC title