Fluorine substituted cyclic amine compounds and preparation methods, pharmaceutical compositions, and uses thereof

Patent metadata

Field	Value
Publication number	US-9637454-B2
Application number	US-201314438457-A
Country	US
Kind code	B2
Filing date	Oct 17, 2013
Priority date	Oct 26, 2012
Publication date	May 2, 2017
Grant date	May 2, 2017

Abstract

The present invention relates to the field of pharmaceutical chemistry and pharmacotherapeutics, and in particular to compounds of general formula I, racemates, R-isomers, S-isomers, and pharmaceutically acceptable salts thereof and their mixtures, and the preparation methods thereof and a pharmaceutical composition containing the compounds and uses thereof as an acetylcholine esterase inhibitor.

First claim

We claim:

1. A fluoro-substituted cyclic amine compound as shown in general formula I, or a racemate, a R-isomer, a S-isomer, a pharmaceutically acceptable salt thereof or a mixture thereof:

wherein
m is 1;
n is 0;
X is (CH 2 ) p or CO, wherein p is an integer of 0-3;
R 1 is a substituted or unsubstituted C 3 -C 10 cycloalkyl or a substituted C 6 -C 12 aryl, wherein the substituent(s) of R 1 is 1, 2, 3, 4 or 5 same or different substituents independently selected from the group consisting of a halogen, a C 1 -C 6 alkyl, a halogen substituted C 1 -C 6 alkyl, a C 1 -C 6 alkoxy, a C 1 -C 6 alkoxycarbonyl, a halogen substituted C 1 -C 6 alkoxy, a C 2 -C 6 alkenyl, a C 2 -C 6 alkynyl, a C 3 -C 8 cycloalkyl, a cyano, a nitro, an amino, a hydroxyl, a hydroxymethyl, a carboxyl, a mercapto, a sulfonyl, a C 6 -C 10 aryl and a 3-12 membered heterocyclic radical; or two adjacent substituents of the C 6 -C 12 aryl and carbon atom(s) of adjacent aromatic ring together form a C 3 -C 7 cycloalkyl, a C 3 -C 7 cycloalkenyl or a 3-7 membered heterocyclic radical; and each heterocyclic radical independently contains 1-4 heteroatoms selected from the group consisting of O, S and N; provided that when the C 6 -C 12 aryl is substituted with one halogen, then the halogen is F;
each of R 2 and R 3 is independently selected from the group consisting of a hydrogen, a carboxyl, a C 1 -C 4 alkoxycarbonyl and a C 1 -C 4 alkyl; or R 2 and R 3 together form a C 1 -C 4 alkylidene;
R 4 is 1-4 same or different substituents selected from the group consisting of a hydrogen, a halogen, a C 1 -C 6 alkyl, a halogen substituted C 1 -C 6 alkyl, a C 1 -C 6 alkoxy, a halogen substituted C 1 -C 6 alkoxy, a C 2 -C 6 alkenyl, a C 2 -C 6 alkynyl, a cyano, a nitro, an amino, a hydroxyl, a hydroxymethyl, a carboxyl, a mercapto, a sulfonyl, —O[(CH 2 ) q O] r R 5 , a phenyl and a 3-12 membered heterocyclic radical; wherein the heterocyclic radical contains 1-3 heteroatoms selected from the group consisting of O, S and N; R 5 is selected from the group consisting of a hydrogen, a halogen, a C 1 -C 6 alkyl, a halogen substituted C 1 -C 6 alkyl, a C 2 -C 6 alkenyl, a C 2 -C 6 alkynyl and a hydroxymethyl; q is 1, 2, 3 or 4; and r is 1, 2, 3 or 4; and
said halogen is F, Cl, Br or I.

2. The fluoro-substituted cyclic amine compound according to claim 1 , or the racemate, R-isomer, S-isomer, pharmaceutically acceptable salt thereof or mixture thereof, wherein,
X is (CH 2 ) p , p is 1 or 2;
R 1 is a substituted or unsubstituted C 3 -C 8 cycloalkyl or a substituted C 6 -C 12 aryl, wherein the substituent(s) of R 1 is 1-5 same or different substituents independently selected from the group consisting of a halogen, a C 1 -C 6 alkyl, a halogen substituted C 1 -C 6 alkyl, a C 1 -C 6 alkoxy, a C 1 -C 6 alkoxycarbonyl, a halogen substituted C 1 -C 6 alkoxy, a C 2 -C 6 alkenyl, a C 2 -C 6 alkynyl, a C 3 -C 8 cycloalkyl, a cyano, a nitro, an amino, a hydroxyl, a hydroxymethyl, a carboxyl, a mercapto, a sulfonyl, a phenyl, a naphthyl and 3-12 membered heterocyclic radical; or two adjacent substituents of the C 6 -C 12 aryl and carbon atom(s) of adjacent aromatic ring together form a 3-7 membered heterocyclic radical, wherein the heterocyclic radical contains 1-3 oxygen atoms; provided that when the C 6 -C 12 aryl is substituted with one halogen, then the halogen is F;
each of R 2 and R 3 is independently selected from the group consisting of a hydrogen, a carboxyl, a methoxycarbonyl, an ethoxycarbonyl, a propoxycarbonyl, a methyl, an ethyl, a propyl, an isopropyl, a butyl and a 2-methylpropyl; or R 2 and R 3 together form a methylene, an ethylene or a propylene;
R 4 is 1-3 same or different substituents selected from the group consisting of a hydrogen, a halogen, a C 1 -C 6 alkyl, a halogen substituted C 1 -C 6 alkyl, a C 1 -C 6 alkoxy, a halogen substituted C 1 -C 6 alkoxy, a C 2 -C 6 alkenyl, a C 2 -C 6 alkynyl, a cyano, a nitro, an amino, a hydroxyl, a carboxyl and —O[(CH 2 ) q O] r R 5 ; R 5 is selected from the group consisting of a hydrogen, a halogen, a C 1 -C 6 alkyl and a halogen substituted C 1 -C 6 alkyl; q is 1, 2 or 3; and r is 1, 2 or 3.

3. The fluoro-substituted cyclic amine compound according to claim 2 , or the racemate, R-isomer, S-isomer, pharmaceutically acceptable salt thereof or mixture thereof, wherein
R 1 is a substituted phenyl, wherein the phenyl is substituted with 1-5 same or different substituents independently selected from the group consisting of a halogen, a C 1 -C 6 alkyl, a C 1 -C 6 alkoxy, a halogen substituted C 1 -C 6 alkoxy, a C 1 -C 6 alkoxycarbonyl, a C 2 -C 6 alkenyl, a C 2 -C 6 alkynyl, a cyano, a nitro, an amino, a hydroxyl, a hydroxymethyl, a trifluoromethyl, a trifluoromethoxy, a carboxyl, a mercapto, a sulfonyl and a phenyl, or two adjacent substituents of the phenyl and carbon atoms of adjacent benzene ring together form

provided that when the phenyl is substituted with one halogen, then the halogen is F;
R 4 is 1-2 same or different substituents selected from the group consisting of a hydrogen, a halogen, a C 1 -C 6 alkyl, a C 1 -C 6 alkoxy, a halogen substituted linear or branched C 1 -C 6 alkoxy, a hydroxyl and —O[CH 2 ) q O] r R 5 ; R 1 is selected from a C 1 -C 6 alkyl or a halogen substituted C 1 -C 6 alkyl; q is 1, 2 or 3; and r is 1, 2 or 3.

4. The fluoro-substituted cyclic amine compound according to claim 3 , or the racemate, R-isomer, S-isomer, pharmaceutically acceptable salt thereof or mixture thereof, wherein,
R 1 is a cyclobutyl, a cyclopentyl, a cyclohexyl, a cycloheptyl or a substituted phenyl, wherein the phenyl is substituted with 1-5 same or different substituents independently selected from the group consisting of a halogen, a nitro, a cyano, a trifluoromethyl, a tritluoroethyl, a trifluoropropyl, a trifluoromethoxy, a methyl, an ethyl, a propyl, an isopropyl, a butyl, a tert-butyl, a 2-methylpropyl, a phenyl, a methoxycarbonyl, an ethoxycarbonyl and a propoxycarbonyl, or two adjacent substituents of the phenyl and carbon atoms of adjacent benzene ring together form

provided that when the phenyl is substituted with one halogen then the halogen is F.

5. The fluoro-substituted cyclic amine compound according to claim 1 , being a compound of general formula (II), or a racemate, R-isomer, S-isomer, pharmaceutically acceptable salt thereof or mixture thereof:

wherein,
R 1 is

or a C3-C10 cycloalkyl, R 6 represents 1, 2, 3, 4 or 5 substituents, the substituent is independently selected from the group consisting of a halogen, a nitro, a cyano, a C1-C6 alkyl, a halogen substituted C 1 -C 6 alkyl, a C 1 -C 6 alkoxy, a halogen substituted C 1 -C 6 alkoxy, a phenyl and a C 1 -C 6 alkoxycarbonyl, or two adjacent R 6 and carbon atoms of adjacent benzene ring together form

provided that when R 1 is substituted with one R 6 and R 6 is halogen, then the halogen is F;
each of R 2 and R 3 is independently selected from the group consisting of a hydrogen, a carboxyl, a C 1 -C 4 alkoxycarbonyl and a C 1 -C 1 alkyl; or R 2

Assignees

• Shanghai Inst Materia Medica Cas
• Shanghai Inst Of Materia Madica Chinese Acad Of Sciences

Inventors

• Liu Hong
• Zhang Haiyan
• Zhou Yu
• Fu Yan
• Jiang Hualiang
• Tang Xican
• Chen Kaixian

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/08

  Antiepileptics; Anticonvulsants · 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

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title