Diphenyl substituted alkanes as flap inhibitors
View Patent ↗The instant invention provides compounds of formula I which are 5-lipoxygenase activating protein inhibitors. Compounds of formula I are useful as anti-atherosclerotic, anti-asthmatic, anti-allergic, anti-inflammatory and cytoprotective agents.
1. A compound represented by structural formula I
the pyridyl-N-oxide analog of formula I, or a pharmaceutically acceptable salt thereof wherein:
R 1 is
R 2 is selected from the group consisting of (a) —C 1-6 alkyl optionally substituted with 1-3 of fluoro, (b) —C 3-6 cycloalkyl and
n is an integer selected from 0, 1, 2 and 3;
R 3 is selected from the group consisting of —H, —F, —OH, —CH 3 and —CF 3 ;
R 4 is selected from the group consisting of —H and —C 1-4 alkyl;
R 5 is selected from the group consisting of —H and —CH 3 ; and
R 7 is selected from the group consisting of —H, —C 1-6 alkyl optionally substituted with 1-3 fluoro, —C 3-6 cycloalkyl optionally substituted with 1-3 fluoro, —COC 1-6 alkyl and —COC 3-6 cycloalkyl;
R 8 is selected from the group consisting of —H, —C 1-6 alkyl optionally substituted with 1-3 fluoro, and —C 3-6 cycloalkyl optionally substituted with 1-3 fluoro; and
R 9 is selected from the group consisting of —CH 3 and —F.
2. The compound of claim 1 wherein:
R 1 is
R 2 is selected from the group consisting of (a) —C 1-6 alkyl optionally substituted with 1-3 fluoro, (b) —C 3-6 cycloalkyl and
n is an integer selected from 0, 1, 2 and 3;
R 3 is selected from the group consisting of —H, —F, —OH, —CH 3 and —CF 3 ;
R 4 is selected from the group consisting of —H and —C 1-4 alkyl; and
R 5 is selected from the group consisting of —H and —CH 3 .
3. The compound of claim 2 wherein R 2 is —C 1-6 alkyl optionally substituted with 1-3 fluoro.
4. The compound of claim 2 wherein R 2 is selected from —C 3-6 cycloalkyl and
5. The compound of claim 3 wherein R 3 is selected from —H, —OH and methyl.
6. The compound of claim 5 wherein R 4 is selected from —H, methyl and ethyl.
7. The compound of claim 1 selected from the group consisting of those of the following structural formula wherein R 2 , R 3 , R 4 and R 5 are defined as follows:
R 2
R 3
R 4
R 5
t-Bu
H
H
H
Me
H
H
H
Et
H
H
H
Pr
H
H
H
i-Pr
H
H
H
Cyclopropyl
H
H
H
Cyclobutyl
H
H
H
Cyclopentyl
H
H
H
Cyclohexyl
H
H
H
H
H
H
H
H
H
Me
Me
H
H
Et
Me
H
H
i-Pr
Me
H
H
t-Bu
Me
H
H
Cyclopropyl
Me
H
H
Cyclobutyl
Me
H
H
Me
H
H
Me
H
H
t-Bu
H
Et
H
i-Pr
H
Et
H
Cyclopropyl
H
Et
H
Cyclobutyl
H
Et
H
H
Et
H
H
Et
H
i-Pr
Me
Et
H
t-Bu
Me
Et
H
i-Pr
H
Me
H
t-Bu
H
Me
H
Cyclopropyl
H
Me
H
Cyclobutyl
H
Me
H
H
Me
H
H
Me
H
i-Pr
Me
Me
H
t-Bu
Me
Me
H
t-Bu
H
Me
Me
i-Pr
H
Me
Me
t-Bu
H
Me
Me
Cyclopropyl
H
Me
Me
Cyclobutyl
H
Me
Me
H
Me
Me
H
Me
Me
t-Bu
Me
Me
Me
the pyridyl-N-oxide analogs thereof, or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 selected from the group consisting of:
5-(4-{2,2-dimethyl-1-[4-(pyridin-2-ylmethoxy)phenyl]propyl}phenyl)-1,3,4-oxadiazol-2-amine;
5-(4-{cyclopropyl[4-(pyridin-2-ylmethoxy)phenyl]methyl}phenyl)-1,3,4-oxadiazol-2-amine;
5-(4-{cyclobutyl[4-(pyridin-2-ylmethoxy)phenyl]methyl}phenyl)-1,3,4-oxadiazol-2-amine;
5-(4-{(1-methylcyclopropyl)[4-(pyridin-2-ylmethoxy)phenyl]methyl}phenyl)-1,3,4-oxadiazol-2-amine;
5-(4-{(1-methylcyclobutyl)[4-(pyridin-2-ylmethoxy)phenyl]methyl}phenyl)-1,3,4-oxadiazol-2-amine;
5-(4-{1,2-dimethyl-1-[4-(pyridin-2-ylmethoxy)phenyl]propyl}phenyl)-1,3,4-oxadiazol-2-amine;
5-(4-{2,2-dimethyl-1-[4-(1-pyridin-2-ylpropoxy)phenyl]propyl}phenyl)-1,3,4-oxadiazol-2-amine;
5-(4-{2,2-dimethyl-1-[4-(1-methyl-1-pyridin-2-ylethoxy)phenyl]propyl}phenyl)-1,3,4-oxadiazol-2-amine; and
the pyridyl-N-oxide analogs thereof; or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.