Ethynyl compounds, their preparation and their therapeutic use for the treatment of malaria

Patent metadata

Field	Value
Publication number	US-11078160-B2
Application number	US-201816628720-A
Country	US
Kind code	B2
Filing date	Jul 4, 2018
Priority date	Jul 4, 2017
Publication date	Aug 3, 2021
Grant date	Aug 3, 2021

Abstract

The present disclosure relates to compounds of formula (I) or a pharmaceutically acceptable salt thereof wherein R 1 means a fluorine atom or a perhalogeno linear alkyl radical containing 1, 2 or 3 carbon atoms; R 2 means a chlorine atom, a linear alkyl radical containing 1, 2 or 3 carbon atoms or a perhalogeno linear alkyl radical containing 1, 2 or 3 carbon atoms, and R means a hydrogen atom or a radical of formula (Ia). The present disclosure also relates to processes for their preparation as well their therapeutic uses, in particular such as for use in the treatment of malaria.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
R 1 is a fluorine atom or a perhalogeno linear alkyl radical containing 1, 2 or 3 carbon atoms,
R 2 is a chlorine atom; a linear alkyl radical containing 1, 2 or 3 carbon atoms optionally substituted with at least one fluorine atom; or a perhalogeno linear alkyl radical containing 1, 2 or 3 carbon atoms, and
R is a hydrogen atom or a radical of formula (Ia)

R 3 is a hydrogen atom; a hydroxyl radical; or a linear or branched alkyl radical containing 1, 2 or 3 carbon atoms,
and R 3 is in position 5 or in position 6 of said radical of formula (Ia),
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 1 is a fluorine atom or a trifluoromethyl radical.

3. The compound according to claim 1 , wherein R 2 is a chlorine atom, a methyl radical or a perhalogeno linear alkyl radical containing 1, 2 or 3 carbon atoms.

4. The compound according to claim 1 , wherein R is the radical of formula (Ia).

5. The compound according to claim 1 , wherein R is a radical of formula (Ia) and R 3 is in position 5 or 6 of said radical of formula (Ia).

6. The compound according to claim 1 , wherein R is the radical of formula (Ia) and R 3 is a hydrogen atom, a hydroxyl radical or a methyl radical.

7. The compound according to claim 5 , wherein R is the radical of formula (Ia) and R 3 is a hydroxyl radical in position 5 of said radical of formula (Ia).

8. The compound according to claim 5 , wherein R is the radical of formula (Ia) and R 3 is a linear or branched alkyl radical containing 1, 2 or 3 carbon atoms in position 6 of said radical of formula (Ia).

9. The compound according to claim 1 , wherein at least one of R 1 and R 2 is a perfluoromethyl radical.

10. The compound according to claim 1 , wherein both R 1 and R 2 are a perfluoromethyl radical.

11. The compound according to claim 1 , said compound being selected from:
5-((3-(carbamimidoylcarbamoyl)-5-(trifluoromethyl)phenyl)ethynyl)-N-(pyridin-2-yl)-2-(trifluoromethyl)benzamide,
5-((3-(carbamimidoylcarbamoyl)-5-(trifluoromethyl)phenyl)ethynyl)-N-(pyridin-2-yl)-2-(trifluoromethyl)benzamide,
5-((3-(carbamimidoylcarbamoyl)-5-(trifluoromethyl)phenyl)ethynyl)-N-(pyridin-2-yl)-2-(trifluoromethyl)benzamide,
5-((3-((diaminomethylene)carbamoyl)-5-(trifluoromethyl)phenyl)ethynyl)-2-methyl-N-(6-methylpyridin-2-yl)benzamide,
5-((3-(carbamimidoylcarbamoyl)-5-fluorophenyl)ethynyl)-N-(6-methylpyridin-2-yl)-2-(trifluoromethyl)benzamide,
5-((3-(carbamimidoylcarbamoyl)-5-trifluoromethyl)phenyl)ethynyl)-2-methyl-N-(pyridin-2-yl)benzamide,
5-((3-(carbamimidoylcarbamoyl)-5-(trifluoromethyl)phenyl)ethynyl)-N-(5-hydroxypyridin-2-yl)-2-(trifluoromethyl)benzamide,
5-((3-(carbamimidoylcarbamoyl)-5-(trifluoromethyl)phenyl)ethynyl)-2-chloro-N-(pyridin-2-yl)benzamide,
5-((3-(carbamimidoylcarbamoyl)-5-fluorophenyl)ethynyl)-N-(pyridin-2-yl)-2-(trifluoromethyl)benzamide,
N-carbamimidoyl-3-((3-carbamoyl-4-(trifluoromethyl)phenyl)ethynyl)-5-trifluoromethyl)benzamide, and
their pharmaceutically acceptable salts.

12. The compound according to claim 1 , said compound being selected from:
5-((3-(carbamimidoylcarbamoyl)-5-(trifluoromethyl)phenyl)ethynyl)-N-(pyridin-2-yl)-2-(trifluoromethyl)benzamide hydrochloride,
5-((3-(carbamimidoylcarbamoyl)-5-(trifluoromethyl)phenyl)ethynyl)-N-(pyridin-2-yl)-2-(trifluoromethyl)benzamide malonic acid,
5-((3-((diaminomethylene)carbamoyl)-5-(trifluoromethyl)phenyl)ethynyl)-2-methyl-N-(6-methylpyridin-2-yl)benzamide hydrochloride,
5-((3-(carbamimidoylcarbamoyl)-5-fluorophenyl)ethynyl)-N-(6-methylpyridin-2-yl)-2-(trifluoromethyl)benzamide hydrochloride,
5-((3-(carbamimidoylcarbamoyl)-5-trifluoromethyl)phenyl)ethynyl)-2-methyl-N-(pyridin-2-yl)benzamide hydrochloride,
5-((3-(carbamimidoylcarbamoyl)-5-(trifluoromethyl)phenyl)ethynyl)-N-(5-hydroxypyridin-2-yl)-2-(trifluoromethyl)benzamide hydrochloride,
5-((3-(carbamimidoylcarbamoyl)-5-(trifluoromethyl)phenyl)ethynyl)-2-chloro-N-(pyridin-2-yl)benzamide hydrochloride,
5-((3-(carbamimidoylcarbamoyl)-5-fluorophenyl)ethynyl)-N-(pyridin-2-yl)-2-(trifluoromethyl)benzamide hydrochloride, and
pharmaceutically acceptable salts thereof.

13. A composition comprising at least one compound according to claim 1 or a pharmaceutically acceptable salt thereof and of at least one other anti-malaria active principle different from said at least one compound.

14. A pharmaceutical composition comprising at least one compound according to claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, diluent or excipient thereof.

15. A method of treating malaria in a patient in need thereof that comprises administering of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a composition comprising said compound or pharmaceutically active salt to a patient having malaria.

Assignees

• Sanofi Sa

Inventors

• Pascal Cécile
• Pellet Alain
• Courtemanche Gilles
• Campbell Simon

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

• A61P33/06

  Antimalarials · CPC title

• A61K31/4402

  only substituted in position 2, e.g. pheniramine, bisacodyl · CPC title

• C07C279/22

  Y being a hydrogen or a carbon atom, e.g. benzoylguanidines · CPC title

• C07D213/75 Primary

  Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates · CPC title