9H-fluorene derivatives or their pharmaceutically acceptable salts

Patent metadata

Field	Value
Publication number	US-12492163-B2
Application number	US-202117907152-A
Country	US
Kind code	B2
Filing date	May 20, 2021
Priority date	May 20, 2020
Publication date	Dec 9, 2025
Grant date	Dec 9, 2025

Abstract

A group of novel 9H-fluorene derivatives suitable for the preparation of active substances for the treatment of Alzheimer's disease, in particular as multifunctional inhibitors of the BuChE and BACE1 enzymes and beta-amyloid aggregation.

First claim

The invention claimed is:

1 . A compound of formula I:

where:
n is an integer with value 0 or 1,
m is an integer with value 0 or 1,
R 1 is H or CH 3 ,
R 2 is H or CH 3 ,
R 3 is H, CH 3 , CF 3 , tert-butyl, cyclopropyl, cyclohexyl or:

 group, where R 4 is: H, 2-, 3- or 4-OCH 3 , 2-, 3- or 4-CF 3 , 2-, 3- or 4-isopropyl, or tert-butyl,
or a pharmaceutically acceptable salt thereof.

2 . The compound according to claim 1 , that is a compound of formula II:

where
R 1 , R 2 and R 3 are defined in claim 1 .

3 . The compound according to claim 1 , selected from the group consisting of:
(2R,3S)-3-((9H-fluoren-9-yl)amino)-1-(benzylamino)-4-phenylbutan-2-ol, (2S,3S)-3-((9H-fluoren-9-yl)amino)-1-(benzylamino)-4-phenylbutan-2-ol, (2R,3S)-3-((9H-fluoren-9-yl)amino)-1-((3-(tert-butyl)benzyl)amino)-4-phenylbutan-2-ol, (2R,3S)-3-((9H-fluoren-9-yl)amino)-1-((3-isopropylbenzyl)amino)-4-phenylbutan-2-ol, (2S,3S)-3-((9H-fluoren-9-yl)amino)-1-((4-(tert-butyl)benzyl)amino)-4-phenylbutan-2-ol, (2S,3S)-3-((9H-fluoren-9-yl)amino)-1-((3-methoxybenzyl)amino)-4-phenylbutan-2-ol, (2S,3S)-3-((9H-fluoren-9-yl)amino)-1-((2-methoxybenzyl)amino)-4-phenylbutan-2-ol, (2R,3S)-3-((9H-fluoren-9-yl)amino)-4-phenyl-1-((3-(trifluoromethyl)benzyl)amino)-butan-2-ol, (2R,3S)-3-((9H-fluoren-9-yl)amino)-4-phenyl-1-(((S)-1-phenylethyl)amino) butan-2-ol, (2R,3S)-3-((9H-fluoren-9-yl)amino)-4-phenyl-1-((2-phenylpropan-2-yl)amino) butan-2-ol, (2S,3S)-3-((9H-fluoren-9-yl)amino)-1-((cyclohexylmethyl)amino)-4-phenylbutan-2-ol, (2S,3S)-3-((9H-fluoren-9-yl)amino)-1-(tert-butylamino)-4-phenylbutan-2-ol, (2R,3S)-3-((9H-fluoren-9-yl)amino)-1-(neopentylamino)-4-phenylbutan-2-ol, (2R,3S)-3-((9H-fluoren-9-yl)amino)-4-phenyl-1-((2,2,2-trifluoroethyl)amino) butan-2-ol, (2S,3S)-3-((9H-fluoren-9-yl)amino)-1-((cyclopropylmethyl)amino)-4-phenylbutan-2-ol, (2R,3S)-3-((9H-fluoren-9-yl)amino)-1-((cyclopropylmethyl)amino)-4-phenylbutan-2-ol, N-((2S,3S)-4-(benzylamino)-3-hydroxy-1-phenylbutan-2-yl)-2-(9H-fluoren-9-yl) acetamide, N-((2S,3S)-4-((4-(tert-butyl)benzyl)amino)-3-hydroxy-1-phenylbutan-2-yl)-9H-fluorene-9-carboxamide, N-((2S,3S)-4-((4-(tert-butyl)benzyl)amino)-3-hydroxy-1-phenylbutan-2-yl)-2-(9H-fluoren-9-yl) acetamide, 2-(9H-fluoren-9-yl)-N-((2S,3S)-3-hydroxy-4-((2-methoxybenzyl)amino)-1-phenylbutan-2-yl) acetamide, 2-(9H-fluoren-9-yl)-N-((2S,3R)-3-hydroxy-1-phenyl-4-((3-(trifluoromethyl)benzyl)-amino) butan-2-yl) acetamide, N-((2S,3R)-3-hydroxy-1-phenyl-4-(((S)-1-phenylethyl)amino) butan-2-yl)-9H-fluorene-9-carboxamide, 2-(9H-fluoren-9-yl)-N-((2S,3R)-3-hydroxy-1-phenyl-4-(((S)-1-phenylethyl)amino) butan-2-yl) acetamide, N-((2S,3R)-3-hydroxy-1-phenyl-4-((2-phenylpropan-2-yl)amino) butan-2-yl)-9H-fluorene-9-carboxamide, 2-(9H-fluoren-9-yl)-N-((2S,3R)-3-hydroxy-1-phenyl-4-((2-phenylpropan-2-yl)amino)-butan-2-yl) acetamide, N-((2S,3R)-3-hydroxy-4-(neopentylamino)-1-phenylbutan-2-yl)-9H-fluorene-9-carboxamide, 2-(9H-fluoren-9-yl)-N-((2S,3R)-3-hydroxy-4-(neopentylamino)-1-phenylbutan-2-yl) acetamide and N-((2S,3R)-4-((cyclopropylmethyl)amino)-3-hydroxy-1-phenylbutan-2-yl)-2-(9H-fluoren-9-yl) acetamide.

4 . A method comprising administering the compound of claim 1 to a human subject.

5 . A method comprising administering the compound of claim 1 to a person with Alzheimer's disease.

6 . A method comprising administering the compound of claim 3 to a human subject.

7 . A method comprising administering the compound of claim 3 to a person with Alzheimer's disease.

8 . A method for simultaneously inhibiting butyrylcholinesterase and β-secretase comprising administering the compound of claim 1 to a human subject.

Assignees

• Univ Jagiellonski

Inventors

• Panek Dawid
• Malawska Barbara
• Pasieka Anna
• Jonczyk Jakub
• Wieckowska Anna
• Godyn Justyna
• Szalaj Natalia
• Bajda Marek
• Salat Kinga

Classifications

• C07C233/40

  having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07C2603/18

  Fluorenes; Hydrogenated fluorenes · CPC title

• C07C233/62

  having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups · CPC title

• C07C233/11

  with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings · CPC title