Hydrogen peroxide-activated compounds as selective anti-cancer therapeutics

Patent metadata

Field	Value
Publication number	US-10071954-B2
Application number	US-201515026442-A
Country	US
Kind code	B2
Filing date	Oct 2, 2015
Priority date	Oct 2, 2014
Publication date	Sep 11, 2018
Grant date	Sep 11, 2018

Abstract

Provided are compounds according to the following Formula I:

The Formula I compounds are activated in the presence of hydrogen peroxide and are therefore selective anti-cancer therapeutics for cancers associated with elevated reactive oxygen species (ROS). Also provided are methods and pharmaceutical compositions for treating cancers associated with increased ROS.

First claim

The invention claimed is:

1. A compound according to Formula I:

wherein:
R 1 is selected from the group consisting of OH and NHR 3 , wherein R 3 is selected from the group consisting of H and substituted or unsubstituted straight or branched C 1 -C 8 alkyl;
R 2 is selected from the group consisting of H, NHR 4 , C(═O)R 5 , and substituted or unsubstituted straight or branched C 1 -C 8 alkyl, wherein R 4 and R5 are each independently selected from the group consisting of H, substituted or unsubstituted straight or branched C 1 -C 8 alkyl, substituted or unsubstituted straight or branched C 2 -C 8 alkenyl, and substituted or unsubstituted straight or branched C 2 -C 8 alkynyl; and
A is selected from the group consisting of C and N.

2. The compound according to claim 1 , wherein R 1 is OH.

3. The compound according to claim 1 , where R 1 is NH 2 .

4. The compound according to claim 1 , wherein A is C and R 2 is H.

5. The compound according to claim 1 , wherein when A is N, then R 2 is C(═O)R 5 , wherein R 5 is selected from the group consisting of H and substituted or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, ethenyl, propenyl, ethynyl, and propynyl.

6. The compound according to claim 1 , wherein the cancer is associated with the production of elevated reactive oxygen species (ROS).

7. The compound according to claim 1 , wherein the compound is

8. A compound selected from the group consisting of:
2-(cyclohexylamino)-N-(2,5-dihydroxyphenyl)acetamide;
N-(5-amino-2-hydroxyphenyl)-2-(1-propioloylpiperidin-4-ylamino)acetamide; and
N-(5-amino-2-hydroxyphenyl)-2-(cyclohexylamino)acetamide.

9. A pharmaceutical composition comprising:
(a) a therapeutically effective amount of a compound according to claim 1 ; and
(b) a pharmaceutically-acceptable carrier.

10. A method of reducing proliferative capacity in a cell, the method comprising contacting the cell with an effective amount of a compound according to claim 1 .

11. The method according to claim 10 , wherein the cell is a mammalian cell.

12. The method according to claim 11 , wherein the cell is a cancer cell.

13. A method of treating acute myeloid leukemia comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 .

14. The method according to claim 13 , wherein the subject is a mammal.

15. The method according to claim 13 , further comprising administering to the subject one or more additional therapeutic agents.

16. The method according to claim 15 , wherein the one or more additional therapeutic agents are selected from the group consisting of cytarabine, doxorubicin, cisplatin, chlorambucil, cladribine, zosuquidar, gemtuzumab, arsenic trioxide, and sorafenib.

17. The method according to claim 16 , wherein the one or more additional therapeutic agents are selected from the group consisting of cytarabine and doxorubicin.

Assignees

• Univ Cincinnati

Inventors

• Merino Edward J
• Mulloy James
• Vadukoot Anish K
• Wunderlich Mark
• Abdulsalam Safnas F

Classifications

• C07D211/58

  attached in position 4 · CPC title

• A61K31/4468

  having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl · CPC title

• C07C233/26 Primary

  having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a saturated carbon skeleton containing rings · CPC title

• A61K31/7068

  having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid · CPC title

• A61K31/167 Primary

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