Small molecule N-(alpha-peroxy) indole compounds and methods of use

Patent metadata

Field	Value
Publication number	US-10689341-B2
Application number	US-201716099853-A
Country	US
Kind code	B2
Filing date	May 10, 2017
Priority date	May 11, 2016
Publication date	Jun 23, 2020
Grant date	Jun 23, 2020

Abstract

The invention relates to novel N-(α-peroxy)indole compounds of Formula I and methods for use. (I) The N-(α-peroxy)indole compounds described herein are useful for treating or preventing parastic infections, bacterial infections, and cancer in subjects. The methods include administering an N-(α-peroxy)indole compound as described herein to a subject. Also described herein are methods for synthesizing N-(α-peroxy)indole compounds.

First claim

What is claimed is:

1. A compound of the following formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:
A 1 , A 2 , A 3 , and A 4 are each independently selected from CR and N, wherein each R is selected from the group consisting of hydrogen, halogen, cyano, trifluoromethyl, alkoxy, aryloxy, substituted or unsubstituted carbonyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl;
R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, trifluoromethyl, alkoxy, aryloxy, substituted or unsubstituted carbonyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl; and
R 7 , R 8 , and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl;
wherein R 5 and R 6 do not combine to form a cyclic compound.

2. The compound of claim 1 , wherein the compound has the following formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from hydrogen, halogen, cyano, trifluoromethyl, alkoxy, aryloxy, substituted or unsubstituted carbonyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl; and
R 7 , R 8 , and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl;
wherein R 5 and R 6 do not combine to form a cyclic compound.

3. The compound of claim 2 , wherein at least one of R 1 , R 3 , R 4 , R 6 , and R 8 is hydrogen.

4. The compound of claim 2 , wherein R 2 is hydrogen or alkoxy.

5. The compound of claim 2 , wherein R 5 or R 9 or R 7 is substituted or unsubstituted alkyl.

6. The compound of claim 2 , wherein R 7 is substituted or unsubstituted aryl.

7. The compound of claim 2 , wherein the compound has the following formula:

or a pharmaceutically acceptable salt or prodrug thereof.

8. The compound of claim 7 , wherein the compound is selected from the group consisting of:

9. The compound of claim 2 , wherein the compound is selected from the group consisting of:

10. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

11. The compound of claim 2 , wherein the compound has the following formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, halogen, cyano, trifluoromethyl, alkoxy, substituted or unsubstituted carbonyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.

12. A method of treating a parasitic infection, comprising:
administering to a subject in need thereof an effective amount of a compound having the structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:
A 1 , A 2 , A 3 , and A 4 are each independently selected from CR and N, wherein each R is selected from the group consisting of hydrogen, halogen, cyano, trifluoromethyl, alkoxy, aryloxy, substituted or unsubstituted carbonyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl;
R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, trifluoromethyl, alkoxy, aryloxy, substituted or unsubstituted carbonyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl; and
R 7 , R 8 , and R 9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl;
wherein R 5 and R 6 do not combine to form a cyclic compound.

13. The method of claim 12 , wherein the parasitic infection is a Plasmodium infection.

14. The method of claim 13 , wherein the Plasmodium infection is a Plasmodium falciparum infection.

15. The method of

Assignees

• Univ King Abdullah Sci & Tech

Inventors

• Wang Xinbo
• Lai Zhiping
• Pan Yupeng
• Huang Kuowei
• Wang Zhigang

Classifications

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C07D209/24

  with an alkyl or cycloalkyl radical attached to the ring nitrogen atom · CPC title

• C07D209/48

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

• C07D209/16

  Tryptamines · CPC title

• A61K31/4045

  Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin · CPC title