Aminopyridinemethanol compounds and their use

Patent metadata

Field	Value
Publication number	US-11220482-B2
Application number	US-201816760766-A
Country	US
Kind code	B2
Filing date	Nov 2, 2018
Priority date	Nov 3, 2017
Publication date	Jan 11, 2022
Grant date	Jan 11, 2022

Abstract

The present invention is directed to novel compounds of Formula (I): pharmaceutically acceptable salts or solvates thereof, and their use, in particular in the treatment or prevention of malaria.

First claim

The invention claimed is:

1. A compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof,
wherein:
Y is formulae i or ii:

A is NR 1 R 2 wherein:
R 1 and R 2 are independently selected from the group consisting of:
a hydrogen atom;
a straight C1-C9 alkyl or haloalkyl group;
a straight or branched C1-C9 heteroalkyl group containing one or two heteroatoms, said group being optionally substituted by one or two groups independently selected from aryl, heteroaryl, cycloalkyl and metallocene;
a group of following formula:

 wherein n is an integer from 1 to 4 and R 5 and R 6 are independently aryl or heteroaryl groups,
a substituted or unsubstituted C3-C7 cycloalkyl group; and
an aryl group;

with the proviso that R 1 and R 2 are not both a hydrogen atom;
R 3 and R 4 are independently selected from the group consisting of a hydrogen atom and a C1-C9 alkyl group optionally containing a heteroatom, said group being optionally substituted by an aryl group or a cycloalkyl group; and

wherein the symbol

means that Y may be located at any free position of the pyridine ring;
with the proviso that the compound of Formula I is not one, more or all of the following,
2-(butylamino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethan-1-ol;
2-(dibutylamino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethan-1-ol;
2-(pentan-3-ylamino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethan-1-ol;
2-(di(pentan-3-yl)amino)-1-(2-trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethan-1-ol; and
2-(heptan-4-ylamino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-ylethan-1-ol.

2. The compound according to claim 1 , wherein R 3 and R 4 are hydrogen atoms.

3. The compound according to claim 1 , wherein R 2 is a hydrogen atom.

4. The compound according to claim 1 , wherein R 1 is selected from n-butyl, n-pentyl, n-hexyl, n-heptyl, 4,4,4-trifluoro-n-butyl, 6-fluoro-n-hexyl, 2-(benzhydrylamino)ethyl, 2-((di(pyridin-2-yl)methyl)amino)ethyl, (S)-1-methoxy-3-phenylpropan-2-yl, (S)-1-(cyclopropylmethoxy)-3-phenylpropan-2-yl, 2-(ferrocenylamino)ethyl, or 3-(4-benzhydrylpiperazin-1-yl)propyl and R 2 is a hydrogen atom.

5. The compound according to claim 1 , having formula II:

6. The compound according to claim 5 , having formula IIa:

7. The compound according to claim 5 , having formula IIb:

8. The compound according to claim 5 , wherein R 1 is selected from 4,4,4-trifluoro-n-butyl, 6-fluoro-n-hexyl, 2-(benzhydrylamino)ethyl, 2-((di(pyridin-2-yl)methyl)amino)ethyl, (S)-1-methoxy-3-phenylpropan-2-yl, 2-(ferrocenylamino)ethyl, 3-(4-benzhydrylpiperazin-1-yl)propyl, and (S)-1-(cyclopropylmethoxy)-3-phenylpropan-2-yl, and R 2 is a hydrogen atom.

9. The compound according to claim 1 , having formula III:

10. The compound according to claim 9 , having formula IIIa:

11. The compound according to claim 9 , having formula IIIb:

12. The compound according to claim 1 , selected from the group consisting of:
(S)-2-(n-pentylamino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethanol;
(R)-2-(n-pentylamino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethanol;
(S)-2-(n-hexylamino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethanol;
(R)-2-(n-hexylamino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethanol;
(S)-2-(n-heptylamino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethanol;
(R)-2-(n-heptylamino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethanol;
(S)-2-((2-(benzhydrylamino)ethyl)amino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethanol;
(R)-2-((2-(benzhydrylamino)ethyl)amino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethanol;
(S)-2-(((S)-1-methoxy-3-phenylpropan-2-yl)amino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethanol;
(R)-2-(((S)-1-methoxy-3-phenylpropan-2-yl)amino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethanol;
(S)-2-((2-(ferrocenylmethylamino)ethyl)amino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethanol;
(R)-2-((2-(ferrocenylmethylamino)ethyl)amino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethanol;
(S)-2-((3-(4-benzhydrylpiperazin-1-yl)propyl)amino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethanol;
(R)-2-((3-(4-benzhydrylpiperazin-1-yl)propyl)amino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethanol;
(S)-2-((4,4,4-trifluorobutyl)amino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethan-1-ol;
(R)-2-((4,4,4-trifluorobutyl)amino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethan-1-ol;
(S)-2-((6-fluorohexyl)amino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridine-4-yl)ethan-1-ol;
(R)-2-((6-fluorohexyl)amino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridine-4-yl)ethan-1-ol;
(S)-2-((2-((di(pyridine-2-yl)methyl)amino)ethyl)amino)-1-(2-(trifluoromethyl)-6-(4-(trifluoro methyl)phenyl)pyridin-4-yl)ethan-1-ol trifluoroacetic acid salt;
(R)-2-((2-((di(pyridine-2-yl)methyl)amino)ethyl)amino)-1-(2-(trifluoromethyl)-6-(4-(trifluoro methyl)phenyl)pyridin-4-yl)ethan-1-ol trifluoroacetic acid salt;
(S)-2-(((S)-1-(cyclopropylmethoxy)-3-phenylpropan-2-yl)amino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethan-1-ol;
(R)-2-(((S)-1-(cyclopropylmethoxy)-3-phenylpropan-2-yl)amino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-4-yl)ethan-1-ol;
(S)-2-(n-butylamino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)ethanol;
(R)-2-(n-butylamino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)ethanol;
(S)-2-(n-pentylamino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)ethanol;
(R)-2-(n-pentylamino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)ethanol;
(S)-2-(n-hexylamino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)ethanol;
(R)-2-(n-hexylamino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)ethanol;
(S)-2-(n-heptylamino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)ethanol;
(R)-2-(n-heptylamino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)ethanol;
(S)-2-((2-(benzhydrylamino)ethyl)amino)-1-(2-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)pyridi

Assignees

• Univ Amiens Picardie Jules Verne
• Centre Hospitalier Univ Damiens
• Centre National De La Rech Scientifique—Cnrs—
• Centre Nat Rech Scient

Inventors

• Sonnet Pascal
• Dassonville-Klimpt Alexandra
• Bentzinger Guillaume
• Mullie-Demailly Catherine
• Agnamey Patrice

Classifications

• A61P33/06

  Antimalarials · CPC title

• 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

• C07F17/02

  of metals of Groups 8, 9 or 10 of the Periodic Table · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D213/38 Primary

  having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom · CPC title