Lipoxygenase inhibitors

Patent metadata

Field	Value
Publication number	US-10646471-B2
Application number	US-201615380548-A
Country	US
Kind code	B2
Filing date	Dec 15, 2016
Priority date	Apr 1, 2011
Publication date	May 12, 2020
Grant date	May 12, 2020

Abstract

The disclosure provides bisindole suitable for inhibiting lipoxygenases or Aβ-formation, and treating associated diseases, such as Alzheimer's disease. The bisindoles are indolo[2,3-b]carbazole derivatives, and may be administered to a patient as part of a pharmaceutical formulation.

First claim

What is claimed is:

1. A method of inhibiting a lipoxygenase selected from the group consisting of: 5-lipoxygenase, 12-lipoxygenase, 15-lipoxygenase, and a combination thereof in cells determined to be in need thereof, comprising contacting the cells with a bisindole of a formula selected from:

or a salt thereof.

2. The method of claim 1 wherein the cells are isolated human cells in vitro.

3. The method of claim 1 wherein the cells are in situ as part of a person and the cells are contacted by the bisindole for treating a neurodegenerative disease selected from Alzheimer's disease, dementia and amyloid beta (Aβ) associated disease.

4. A method of treating a person for a neurodegenerative disease selected from Alzheimer's disease, dementia and amyloid beta (Aβ) associated disease by inhibiting lipoxygenase activity, comprising-inhibiting lipoxygenase in cells of the person, the lipoxygenase selected from the group consisting of: 5-lipoxygenase, 12-lipoxygenase, 15-lipoxygenase, and a combination thereof, by contacting the cells with a composition comprising a bisindole of a formula selected from:

or a salt thereof.

5. The method of claim 1 , wherein the bisindole inhibits the lipoxygenase by not less than fifty percent and up to ninety-eight percent.

6. A method of inhibiting a lipoxygenase selected from the group consisting of: 5-lipoxygenase, 12-lipoxygenase, 15-lipoxygenase, and a combination thereof in cells determined to be in need thereof, comprising contacting the cells with a bisindole of formula (I):

wherein:
R 1 , R 3 , R 4 , R 5 , R 7 , and R 8 are hydrogen;
R 2 and R 6 are fluorine;
R 9 are substituents independently selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 5 -C 10 aryl, C 6 -C 10 alkaryl, C 6 -C 10 aralkyl, halo, hydroxyl, sulfhydryl, C 1 -C 10 alkoxy, C 2 -C 10 alkenyloxy, C 2 -C 10 alkynyloxy, C 5 -C 10 aryloxy, C 2 -C 10 alkoxycarbonyl, C 6 -C 10 aryloxycarbonyl, C 2 -C 10 alkylcarbonyl, C 6 -C 10 arylcarbonyl, halocarbonyl, C 2 -C 10 alkylcarbonato, C 6 -C 10 arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C 1 -C 10 alkyl)-substituted carbamoyl, di-(C 1 -C 10 alkyl)-substituted carbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, di-(C 1 -C 10 )-alkoxyboryl, isothiocyanato, azido, amino, mono- and di-(C 1 -C 10 alkyl)-substituted amino, mono- and di-(C 5 -C 10 aryl)-substituted amino, C 2 -C 10 alkylamido, imino, alkylimino, nitro, sulfo, sulfonato, C 1 -C 10 alkylsulfanyl, C 1 -C 10 alkylsulfinyl, C 1 -C 10 alkylsulfonyl, C 5 -C 10 arylsulfonyl and combinations thereof; and
R 11 and R 12 are hydrogen or methyl; and
R 10 is:

or a salt of the bisindole.

7. The method of claim 6 , wherein the bisindole is:

or a salt of the bisindole.

8. The method of claim 6 , wherein:
R 1 , R 3 , R 4 , R 5 , R 7 , R 8 , R 11 , R 12 are hydrogen;
R 2 and R 6 are fluorine; and
R 10 is:

9. The method of claim 1 , wherein contacting the cells with the bisindole of the formula includes administering to a person an effective amount of the bisindole and, thereby, inhibiting the lipoxygenase selected from the group consisting of: 5-lipoxygenase, 12- lipoxygenase, 15-lipoxygenase, and a combination thereof, in the cells of the person responsive to the bisindole, wherein the effective amount is not less than 0.001 milligram (mg)/kilogram (kg)/day and not more than 100 mg/kg/day of the bisindole.

10. The method of claim 4 , wherein the bisindole is:

or a salt of the bisindole.

11. The method of claim 4 , wherein contacting the cells with the composition includes administering to the person an effective amount of the composition, and thereby inhibiting the lipoxygenase selected from the group consisting of 5-lipoxygenase, 12-lipoxygenase, 15-lipoxygenase, and a combination thereof in cells of the person, and wherein the effective amount is not less than 0.1 milligram (mg)/kilogram (kg)/day and not more than 50 mg/kg/day of the bisindole.

12. The method of claim 4 , wherein contacting the cells with the composition includes administering to the person an effective amount of the composition, and thereby inhibiting the lipoxygenase selected from the group consisting of 5-lipoxygenase, 12-lipoxygenase, 15-lipoxygenase, and a combination thereof and amyloid beta in cells of the person.

13. The method of claim 4 , wherein the bisindole is selected from:

Assignees

• Stanford Res Inst Int

Inventors

• Jong Ling

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61K31/4196

  1,2,4-Triazoles · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• G01N2500/04

  Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A) · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title