5-substituted-5-hydroxy-5-aryl-3-oxo-pentanoate derivatives and their enantiopure forms

Patent metadata

Field	Value
Publication number	US-10125074-B2
Application number	US-201615560868-A
Country	US
Kind code	B2
Filing date	Feb 1, 2016
Priority date	Mar 24, 2015
Publication date	Nov 13, 2018
Grant date	Nov 13, 2018

Abstract

The present invention relates to novel tertiary alcohol derivatives substituted with aryl and trifluoromethyl, and optical isomers thereof. In addition, the present invention also relates to methods for the preparation and use as enantiomer recognition agent thereof. The present invention provides pharmaceutical composition and use as therapeutically active substance thereof.

First claim

The invention claimed is:

1. A compound of formula I:

wherein
A is

B is aryl which is substituted with one or more groups selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy, hydroxy, cyano, and nitro, or is heteroaryl, which is unsubstitued or substituted with one or more groups selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy, hydroxy, cyano, and nitro;
R 1 and R 1′ may be the same or different and each is independently selected from the group consisting of C 1-7 -alkyl, halogen-C 1-7 -alkyl, and C 1-7 -alkyl substituted with one or more C 1-7 -alkoxy; or
R 1 and R 1′ may together form C 1-7 -alkylene;
R 2 is selected from the group consisting of C 1-7 -alkyl, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, C 3-7 -cycloalkyloxy, halogen-C 1-7 -alkoxy, C 1-7 -alkoxy substituted with one or more C 1-7 -alkyl, and hydroxy;
R 3 is selected from the group consisting of hydrogen, halogen, C 1-7 -alkyl, halogen-C 1-7 -alkyl, hydroxy-C 1-7 -alkyl, C 1-7 -alkoxy, and halogen-C 1-7 -alkoxy; and
n is 1, 2, 3, or 4;
or a salt thereof.

2. The compound of formula I or salt thereof according to claim 1 , wherein
B is aryl which is substituted with one or more groups selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, and halogen-C 1-7 -alkoxy, or
is heteroaryl which is unsubstitued or substituted with one or more groups selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, and halogen-C 1-7 -alkoxy.

3. The compound of formula I or salt thereof according to claim 1 , wherein
R 1 and R 1′ may be the same or different and each is independently selected from the group consisting of C 1-7 -alkyl, halogen-C 1-7 -alkyl and C 1-7 -alkyl substituted with one or more C 1-7 -alkoxy.

4. The compound of formula I or salt thereof according to claim 1 , wherein
R 2 is selected from the group consisting of C 1-7 -alkyl, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy, and C 1-7 -alkoxy substituted with one or more C 1-7 -alkyl.

5. The compound of formula I or salt thereof according to claim 1 , wherein
R 3 is selected from the group consisting of hydrogen, halogen and C 1-7 -alkyl.

6. The compound of formula I or salt thereof according to claim 1 , wherein
n is 1 or 2.

7. The compound of formula I according to claim 1 , which is selected from the group consisting of
5,5,5-trifluoro-4-hydroxy-1,1-dimethoxy-4-phenylpentan-2-one,
(R)-5,5,5-trifluoro-4-hydroxy-1,1-dimethoxy-4-phenylpentan-2-one,
(S)-5,5,5-trifluoro-4-hydroxy-1,1-dimethoxy-4-phenylpentan-2-one,
4-(4-chlorophenyl)-5,5,5-trifluoro-4-hydroxy-1,1-dimethoxypentan-2-one,
(R)-4-(4-chlorophenyl)-5,5,5-trifluoro-4-hydroxy-1,1-dimethoxypentan-2-one,
(S)-4-(4-chlorophenyl)-5,5,5-trifluoro-4-hydroxy-1,1-dimethoxypentan-2-one,
4-(4-bromophenyl)-5,5,5-trifluoro-4-hydroxy-1,1-dimethoxypentan-2-one,
(R)-4-(4-bromophenyl)-5,5,5-trifluoro-4-hydroxy-1,1-dimethoxypentan-2-one,
(S)-4-(4-bromophenyl)-5,5,5-trifluoro-4-hydroxy-1,1-dimethoxypentan-2-one,
5,5,5-trifluoro-4-hydroxy-1,1-dimethoxy-4-(4-(trifluoromethyl)phenyl)pentan-2-one,
(R)-5,5,5-trifluoro-4-hydroxy-1,1-dimethoxy-4-(4-(trifluoromethyl)phenyl)pentan-2-one,
(S)-5,5,5-trifluoro-4-hydroxy-1,1-dimethoxy-4-(4-(trifluoromethyl)phenyl)pentan-2-one,
5,5,5-trifluoro-4-hydroxy-1,1-dimethoxy-4-(p-tolyl)pentan-2-one,
(R)-5,5,5-trifluoro-4-hydroxy-1,1-dimethoxy-4-(p-tolyl)pentan-2-one,
(S)-5,5,5-trifluoro-4-hydroxy-1,1-dimethoxy-4-(p-tolyl)pentan-2-one,
5,5,5-trifluoro-4-hydroxy-1,1-dimethoxy-4-(4-methoxyphenyl)pentan-2-one,
(R)-5,5,5-trifluoro-4-hydroxy-1,1-dimethoxy-4-(4-methoxyphenyl)pentan-2-one,
(S)-5,5,5-trifluoro-4-hydroxy-1,1-dimethoxy-4-(4-methoxyphenyl)pentan-2-one,
5,5,5-trifluoro-4-hydroxy-1,1-dimethoxy-4-(thiophen-2-yl)pentan-2-one,
(R)-5,5,5-trifluoro-4-hydroxy-1,1-dimethoxy-4-(thiophen-2-yl)pentan-2-one,
(S)-5,5,5-trifluoro-4-hydroxy-1,1-dimethoxy-4-(thiophen-2-yl)pentan-2-one,
5,5,5-trifluoro-4-hydroxy-1,1-dimethoxy-4-(1H-pyrrol-2-yl)pentan-2-one,
(R)-5,5,5-trifluoro-4-hydroxy-1,1-dimethoxy-4-(1H-pyrrol-2-yl)pentan-2-one,
(S)-5,5,5-trifluoro-4-hydroxy-1,1-dimethoxy-4-(1H-pyrrol-2-yl)pentan-2-one,
ethyl 6,6,6-trifluoro-5-hydroxy-3-oxo-5-phenylhexanoate,
(R)-ethyl 6,6,6-trifluoro-5-hydroxy-3-oxo-5-phenylhexanoate,
(S)-ethyl 6,6,6-trifluoro-5-hydroxy-3-oxo-5-phenylhexanoate,
ethyl 6,6,6-trifluoro-5-hydroxy-2-methyl-3-oxo-5-phenylhexanoate,
(R)-ethyl 6,6,6-trifluoro-5-hydroxy-2-methyl-3-oxo-5-phenylhexanoate,
(S)-ethyl 6,6,6-trifluoro-5-hydroxy-2-methyl-3-oxo-5-phenylhexanoate,
ethyl 6,6,6-trifluoro-5-hydroxy-5-(4-methoxyphenyl)-3-oxohexanoate,
(R)-ethyl 6,6,6-trifluoro-5-hydroxy-5-(4-methoxyphenyl)-3-oxohexanoate,
(S)-ethyl 6,6,6-trifluoro-5-hydroxy-5-(4-methoxyphenyl)-3-oxohexanoate,
ethyl 5-(4-chlorophenyl)-6,6,6-trifluoro-5-hydroxy-3-oxohexanoate,
(R)-ethyl 5-(4-chlorophenyl)-6,6,6-trifluoro-5-hydroxy-3-oxohexanoate,
(S)-ethyl 5-(4-chlorophenyl)-6,6,6-trifluoro-5-hydroxy-3-oxohexanoate,
ethyl 6,6,6-trifluoro-5-hydroxy-3-oxo-5-(thiophen-2-yl)hexanoate,
(R)-ethyl 6,6,6-trifluoro-5-hydroxy-3-oxo-5-(thiophen-2-yl)hexanoate,
(S)-ethyl 6,6,6-trifluoro-5-hydroxy-3-oxo-5-(thiophen-2-yl)hexanoate,
ethyl 6,6,6-trifluoro-5-hydroxy-5-(4-methoxyphenyl)-2-methyl-3-oxohexanoate,
(R)-ethyl 6,6,6-trifluoro-5-hydroxy-5-(4-methoxyphenyl)-2-methyl-3-oxohexanoate,
(S)-ethyl 6,6,6-trifluoro-5-hydroxy-5-(4-methoxyphenyl)-2-methyl-3-oxohexanoate,
ethyl 5-(4-chlorophenyl)-6,6,6-trifluoro-5-hydroxy-2-methyl-3-oxohexanoate,
(R)-ethyl 5-(4-chlorophenyl)-6,6,6-trifluoro-5-hydroxy-2-methyl-3-oxohexanoate,
(S)-ethyl 5-(4-chlorophenyl)-6,6,6-trifluoro-5-hydroxy-2-methyl-3-oxohexanoate,
ethyl 6,6,6-trifluoro-5-hydroxy-2-methyl-3-oxo-5-(thiophen-2-yl)hexanoate,
(R)-ethyl 6,6,6-trifluoro-5-hydroxy-2-methyl-3-oxo-5-(thiophen-2-yl)hexanoate,
(S)-ethyl 6,6,6-trifluoro-5-hydroxy-2-methyl-3-oxo-5-(thiophen-2-yl)hexanoate,
(R)-ethyl 6,6,6-trifluoro-5-hydroxy-5-phenyl-3-(((R)-1-phenylethyl)amino)hex-2-enoate,
(S)-ethyl 6,6,6-trifluoro-5-hydroxy-3-(((R)-1-phenylethyl)amino)-5-(thiophen-2-yl)hex-2-enoate,
3-(3,3,3-trifluoro-2-hydroxy-2-phenylpropyl)cyclohex-2-enone,
(R)-3-(3,3,3-trifluoro-2-hydroxy-2-phenyl propyl)cyclohex-2-enone,
(S)-3-(3,3,3-trifluoro-2-hydroxy-2-phenyl propyl)cyclohex-2-enone,
3-(3,3,3-trifluoro-2-hydroxy-2-(p-tolyl)propyl)cyclohex-2-enone,
(R)-3-(3,3,3-trifluoro-2-hydroxy-2-(p-tolyl)propyl)cyclohex-2-enone,
(S)-3-(3,3,3-trifluoro-2-hydroxy-2-(p-tolyl)propyl)cyclohex-2-enone,
3-(3,3,3-trifluoro-2-hydroxy-2-(4-methoxyphenyl)propyl)cyclohex-2-enone,
(R)-3-(3,3,3-trifluoro-2-hydroxy-2-(4-methoxyphenyl)propyl)cyclohex-2-enone,
(S)-3-(3,3,3-trifluoro-2-hydroxy-2-(4-methoxyphenyl)propyl)cyclohex-2-enone,
3-(2-(4-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropyl)cyclohex-2-enone,
(R)-3-(2-(4-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropyl)cyclohex-2-enone,
(S)-3-(2-(4-chlorophenyl)-3,3,3-trifluoro-2-hydroxypropyl)cyclohex-2-enone,
3-(2-(4-bromophenyl)-3,3,3-trifluoro-2-hydroxypropyl)cyclohex-2-enone,
(R)-3-(2-(4-bromophenyl)-3,3,3-trifluoro-2-hydroxypropyl)cyclohex-2-enone,
(S)-3-(2-(4-bromophenyl)-3,3,3-trifluoro-2-hydroxypropyl)cyclohex-2-enone,
3-(3,3,3-trifluoro-2-hydroxy-2-(4-(trifluoromethyl)phenyl)propyl)cyclohex-2-enone,
(R)-3-(3,3,3-trifluoro-2-hydroxy-2-(4-(trifluoromethyl)phenyl)propy

Assignees

• Okinawa Inst Science & Tech School Corp

Inventors

• Tanaka Fujie
• Zhang Dongxin

Classifications

• C07C227/42

  Crystallisation · CPC title

• C07C2601/10

  the ring being unsaturated · CPC title

• C07C49/753 Primary

  containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups · CPC title

• C07C49/255

  containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups · CPC title

• C07D333/22

  Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom · CPC title