1-hydroxycycloalkanecarboxamide derivatives
View Patent ↗α-Hydroxycycloalkanecarboxamide derivatives of formula (I) or a pharmaceutically acceptable salt thereof, wherein formula (a) is a single or double bond; R 1 , R 2 and R 3 are each independently selected from H, halogen and OH; or R 1 and R 2 attached to the same carbon atom together represent oxo; R 4 is H or methyl; R 5 is Cl or I 2 ; R 6 is selected from —CO 2 —C 1-4 alkyl, —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, 2-methyltetrazol-5-yl, 5-methyl-1,2,4-oxadiazol-3-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 5-halomethyl-1,2,4-oxadiazol-3-yl, 3-halomethyl-1,2,4-oxadiazol-5-yl, tetrazol-5-yl, 5-halomethyl-1,2,3-triazolyl, and 5-methyl-1,2,3-triazolyl; R 7 and R 8 are each independently Cl or I 2 ; and n is 0 or 1, are bradykinin B1 antagonists or inverse agonists useful in the treatment or prevention of symptoms such as pain and inflammation associated with the bradykinin B1 pathway.
1. A compound having the formula (I):
or a pharmaceutically acceptable salt thereof, wherein
is a single or double bond;
R 1 , R 2 , and R 3 are each independently selected from H, halogen and OH; or
R 1 and R 2 attached to the same carbon atom together represent oxo;
R 4 is H or methyl;
R 5 is Cl or F;
R 6 is selected from 2-methyltetrazol-5-yl, 5-methyl-1,2,4-oxadiazol-3-yl, 3-methy1,2,4-oxadiazol-5-yl, 5-halomethyl-1,2,4-oxadiazol-3-yl, 3-halomethyl-1,2,4-oxadiazol-5-yl, tetrazol-5-yl, 5-halomethyl-1,2,3-triazolyl, and 5-methyl-1,2,3-triazolyl;
R 7 and R 8 are each independently Cl or F; and
n is 0 or 1.
2. A compound of claim 1 wherein at least one of R 1 , R 2 , and R 3 is a fluorine atom.
3. A compound of claim 1 wherein n is 0.
4. A compound of claim 1 wherein n is 1.
5. A compound of claim 1 wherein R 6 is 2-methyl-tetrazol-5-yl.
6. pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
7. A compound of claim 1 selected from the group consisting of:
R1/R2
R 4
R 6
R 5
R 7
R 8
H/H
H
2-CH 3 -2H-tetrazol-5-yl
F
F
Cl
H/H
Me
5-CH 2 F-1,2,4-oxadiazole
F
F
Cl
H/H
Me
3-CH 3 -1,2,4-oxadiazole
F
Cl
Cl
H/H
Me
3-CH 3 -1,2,4-oxadiazole
F
Cl
F
H/H
Me
2-CH 3 -2H-tetrazol-5-yl
F
F
Cl
H/H
Me
2-CH 3 -2H-tetrazol-5-yl
F
F
F
H/H
Me
5-CH 3 -1,2,4-oxadiazole
Cl
F
Cl
H/H
Me
5-CH 3 -1,2,4-oxadiazole
F
Cl
Cl
H/H
Me
3-CH 3 -1,2,4-oxadiazole
F
F
Cl
H/H
Me
2-CH 3 -2H-tetrazol-5-yl
Cl
Cl
Cl
H/H
Me
2-CH 3 -2H-tetrazol-5-yl
F
Cl
Cl
H/H
Me
2-CH 3 -2H-tetrazol-5-yl
F
Cl
F
H/H
H
3-CH 3 -1,2,4-oxadiazole
F
Cl
Cl
H/H
H
5-CH 3 -1,2,4-oxadiazole
F
F
Cl
H/H
Me
5-CH 3 -1,2,4-oxadiazole
F
F
F
H/H
H
2-CH 3 -2H-tetrazol-5-yl
F
Cl
Cl
H/H
H
2-CH 3 -2H-tetrazol-5-yl
Cl
F
Cl
H/H
Me
2-CH 3 -2H-tetrazol-5-yl
Cl
F
H
H/H
H
3-CH 3 -1,2,4-oxadiazole
F
F
Cl
H/H
H
2-CH 3 -2H-tetrazol-5-yl
Cl
Cl
Cl
H/H
Me
2-CH 3 -2H-tetrazol-5-yl
Cl
F
F
H/H
Me
5-CH 3 -1,2,4-oxadiazole
F
Cl
F
H/H
Me
3-CH 3 -1,2,4-oxadiazole
Cl
Cl
F
H/H
H
2-CH 3 -2H-tetrazol-5-yl
F
F
F
H/H
H
5-CH 3 -1,2,4-oxadiazole
F
Cl
Cl
H/H
H
2-CH 3 -2H-tetrazol-5-yl
Cl
F
F
H/H
H
2-CH 3 -2H-tetrazol-5-yl
Cl
Cl
F
H/H
H
2-CH 3 -2H-tetrazol-5-yl
F
Cl
F
H/H
H
3-CH 3 -1,2,4-oxadiazole
F
F
F
2-F/H
Me
2-CH 3 -2H-tetrazol-5-yl
F
F
Cl
2-F/H
H
2-CH 3 -2H-tetrazol-5-yl
F
F
Cl
3-F/3-F
Me
2-CH 3 -2H-tetrazol-5-yl
F
F
Cl
3-F/3-F
H
2-CH 3 -2H-tetrazol-5-yl
F
F
Cl
3-F/3-F
Me
2H-tetrazol-5-yl
F
F
Cl
3-F/3-F
H
3-CH 3 -1,2,4-oxadiazole
F
F
Cl
3-F/3-F
H
5-CH 3 -1,2,4-oxadiazole
F
F
Cl
3-F/3-F
H
3-CH 3 -1,2,4-oxadiazole
Cl
F
Cl
3-F/3-F
H
2-CH 3 -2H-tetrazol-5-yl
Cl
F
Cl
3-F/3-F
H
2-CH 3 -2H-tetrazol-5-yl
F
Cl
Cl
3-F/3-F
H
3-CH 3 -1,2,4-oxadiazole
Cl
F
Cl
3-F/3-F
H
5-CH 3 -1,2,4-oxadiazole
Cl
F
Cl
3-F/3-F
Me
5-CH 2 F-1,2,3-triazole
F
F
Cl
3-F/3-F
H
2-CH 3 -2H-tetrazol-5-yl
Cl
Cl
Cl
3-OH/H
Me
2-CH 3 -2H-tetrazol-5-yl
F
F
Cl
oxo
Me
2-CH 3 -2H-tetrazol-5-yl
F
F
Cl
3-F/H
Me
2-CH 3 -2H-tetrazol-5-yl
F
F
Cl
2-OH/H
H
2-CH 3 -2H-tetrazol-5-yl
F
F
Cl
R1/R2
R 4
R 6
R 5
R 7
R 8
4-F/4-F
Me
2-CH 3 -2H-tetrazol-5-yl
F
F
Cl
4-F/4-F
H
2-CH 3 -2H-tetrazol-5-yl
F
F
Cl
4-F/4-F
H
2H-tetrazol-5-yl
F
F
Cl
4-F/4-F
Me
5-CH 3 -1,2,3-triazole
F
F
Cl
4-F/4-F
H
2-CH 3 -2H-tetrazol-5-yl
Cl
F
Cl
4-F/4-F
H
2-CH 3 -2H-tetrazol-5-yl
F
Cl
Cl
4-F/4-F
H
2-CH 3 -2H-tetrazol-5-yl
Cl
F
Cl
4-F/4-F
Me
5-CH 3 -1,2,4-oxadiazole
Cl
F
Cl
4-F/4-F
H
2-CH 3 -2H-tetrazol-5-yl
F
Cl
Cl
4-F/4-F
Me
5-CH 2 F-1,2,3-triazole
F
F
Cl
4-F/4-F
Me
5-CH 2 F-1,2,4-oxadiazole
F
F
Cl
4-F/4-F
H
2-CH 3 -2H-tetrazol-5-yl
Cl
Cl
Cl
4-F/4-F
H
2-CH 2 CHF 2 -2H-tetrazol-
F
F
Cl
5-yl
4-F/4-F
H
2-CHF 2 -2H-tetrazol-5-yl
F
F
Cl
N-((1R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)-4,4-difluoro-1-hydroxycyclohexanecarboxamide;
N-({5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}methyl)-4,4-difluoro-1-hydroxycyclohexanecarboxamide; and
N-((1R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)-4,4-difluoro-1,2-dihydroxycyclohexanecarboxamide;
or a pharmaceutically acceptable salt thereof.