Boron-containing small molecules as antiprotozoal agents

Patent metadata

Field	Value
Publication number	US-9815857-B2
Application number	US-201715439634-A
Country	US
Kind code	B2
Filing date	Feb 22, 2017
Priority date	Feb 1, 2013
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

Abstract

This invention provides, among other things, novel compounds useful for treating protozoal infections, pharmaceutical compositions containing such compounds, as well as combinations of these compounds with at least one additional therapeutically effective agent.

First claim

What is claimed is:

1. A compound selected from the group consisting of:
2-Chloro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-pyrrolidin-1-yl-benzamide,
2-Chloro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-(3-methyl-pyrazol-1-yl)-benzamide,
2-Chloro-4-(4-chloro-pyrazol-1-yl)-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide,
2-Chloro-4-(3-chloro-pyrrolo[2,3-b]pyridin-1-yl)-N-(1-hydroxy-1,3-dihydro-benzo [c][1,2]oxaborol-6-yl)-benzamide,
2-Chloro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-(4-methylpiperazin-1-yl)benzamide hydrochloride,
2-Chloro-N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-morpholin-4-yl-benzamide,
6-Azetidin-1-yl-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-trifluoromethyl-nicotinamide,
6-Azetidin-1-yl-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-nicotinamide,
2-Chloro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-pyrrolidin-1-yl-benzamide,
N-(1-Hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-pyrrolidin-1-yl -2-trifluoromethyl-benzamide,
2-Chloro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-(2-oxo -pyrrolidin-1-yl)-benzamide,
N-(1-Hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-(2-oxo -pyrrolidin-1-yl)-2-trifluoromethyl-benzamide,
N-(1-Hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-pyrazol-1-yl-2-trifluoromethyl-benzamide,
N-(1-Hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-6-pyrazol-1-yl-4-trifluoromethyl-nicotinamide,
2-Chloro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-(3-methyl-pyrazol-1-yl)-benzamide,
2-Chloro-4-(4-chloro-pyrazol-1-yl)-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo [c][1,2]oxaborol-6-yl)-benzamide,
2-Chloro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-imidazol-1-yl-benzamide,
N-(1-Hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-6-imidazol-1-yl-2-trifluoromethyl-nicotinamide,
N-(1-Hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-6-imidazol-1-yl-4-trifluoromethyl-nicotinamide,
2-Chloro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-[1,2,4]triazol-1-yl-benzamide,
2-Chloro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-(4H -1,2,4-triazol-4-yl)benzamide,
2-Chloro-4-(3-chloro-pyrrolo[2,3-b]pyridin-1-yl)-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-benzamide,
2-Chloro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-piperidin-1-yl-benzamide,
2-Chloro-4-(4,4-dimethyl-piperidin-1-yl)-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro -benzo[c][1,2]oxaborol-6-yl)-benzamide,
2-Chloro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-4-(4-methylpiperazin-1-yl)benzamide hydrochloride,
N-(1-Hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-morpholin-4-yl -2-trifluoromethyl-benzamide,
N-(1-Hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-6-morpholin-4-yl -4-trifluoromethyl-nicotinamide,
N-(1-Hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-6-morpholin-4-yl -2-trifluoromethyl-nicotinamide,
N-(1-Hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-(6-oxo-6H -pyridazin-1-yl)-2-trifluoromethyl-benzamide, and
2-Chloro-4-(3-chloro-pyrrolo[2,3-b]pyridin-1-yl)-N-(1-hydroxy-3,4-dihydro-1H benzo[c][1,2]oxaborinin-7-yl)-benzamide or a salt thereof.

2. A combination comprising the compound of claim 1 , together with at least one other therapeutically active agent.

3. A pharmaceutical formulation comprising:
a) the compound of claim 1 , or a pharmaceutically acceptable salt thereof; and
b) a pharmaceutically acceptable excipient.

4. The pharmaceutical formulation of claim 3 , wherein the pharmaceutical formulation is a unit dosage form.

5. A method of killing and/or preventing the growth of a protozoa, comprising: contacting the protozoa with an effective amount of the compound of claim 1 , thereby killing and/or preventing the growth of the protozoa.

6. The method of claim 5 , wherein the protozoa is a trypanosomatid.

7. The method of claim 5 , wherein the protozoa is Trypanosoma congolense.

8. A method of treating protozoa-associated disease in an animal, comprising: administering to the animal a therapeutically effective amount of the compound of claim 1 , thereby treating the protozoa-associated disease.

9. The method of claim 8 , wherein the disease is African animal trypanosomiasis.

10. The method of claim 8 , wherein the animal is a cow or a bull.

Assignees

• Anacor Pharmaceuticals Inc

Inventors

• Akama Tsutomu
• Easom Eric
• Freund Yvonne
• Plattner Jacob J
• Sligar Jessica
• Chen Daitao
• Freeman Jennifer
• Perales Joe

Classifications

• C07F5/025 Primary

  Boronic and borinic acid compounds · CPC title

• A61K31/69

  Boron compounds · CPC title

• A61P33/02

  Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis · CPC title