Biphenyl compounds useful as muscarinic receptor antagonists
This invention provides compounds of formula I: wherein a, b, c, d, m, n, p, s, t, Ar 1 , R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and W are as defined in the specification. The compounds of formula I are mescaline receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat pulmonary disorders.
1. A compound of formula I:
wherein:
a is 0 or 1; R 1 is halo;
b is 0 or 1; R 2 is halo;
m is 0 or 1;
R 4 is selected from hydrogen; and (1-4C)alkyl;
s is 0, 1 or 2;
Ar 1 represents a phenylene group substituted with (R 5 ) q where q is 0 or an integer from 1 to 4 and each R 5 is selected independently from halo, hydroxy, (1-4C)allkyl and (1-4C)alkoxy;
t is 0, 1 or 2;
n is 2;
p is 0 or 1; and
R 7 and R 8 are independently hydrogen or (1-4C)alkyl;
wherein each alkyl and alkoxy group in R 5 , R 7 , and R 8 is optionally substituted with 1 to 5 fluoro substituents;
or a pharmaceutically acceptable salt or stereoisomer thereof.
2. The compound of claim 1 , wherein a and b each represent 0.
3. The compound of claim 1 , wherein m and s each represents 0, and t is 1.
4. The compound of claim 1 , wherein the —CONR 7 R 8 group is in the para position and p represents 0.
5. The compound of claim 1 , wherein Ar 1 represents phen-1,4-ylene and q is 0, 1. or 2.
6. The compound of claim 5 where q is 0.
7. The compound of claim 5 wherein q is 1 or 2 and R 5 is selected independently from hydroxy, halo, (1-4C)alkyl and (1-4C)alkoxy, wherein each alkyl and alkoxy group is optionally substituted with from 1 to 3 fluoro substituents.
8. The compound of claim 1 wherein a, b, m, p, and s each represent 0; t is 1; Ar 1 represents phen-1,4-ylene and q is 0, 1, or 2 and the —CONR 7 R 8 group is in the para position.
9. The compound of any one of claims 1 , 2 , or 3 to 8 , wherein R 4 is hydrogen or methyl.
10. The compound of any one of claims 1 , 2 , or 3 to 8 , wherein R 8 is hydrogen.
11. The compound of claim 10 , wherein R 7 is hydrogen.
12. A compound selected from:
biphenyl-2-ylcarbamic acid 1-{2-[4-(4-carbamoylpiperidin-1-ylmethyl)phenylcarbamoyl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[4-(4-carbamoylpiperidin-1-ylmethyl)-2-chloro-5-methoxyphenylcarbamoyl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[4-(4-carbamoylpiperidin-1-ylmethyl)-3-methoxyphenylcarbamoyl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[4-(4-carbanaoyl-piperidin-1-ylmethyl)-3-hydroxyphenylcarbamoyl]ethyl}piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)phenyl]methylcarbamoyl}ethyl)piperidin-4-yl ester;
biphenyl-2-ylcarbamic acid 1-{2-[4-(4-methylcarbainoylpiperidin-1-ylmethyl)phenylcarbamoyl]ethyl}piperidin-4-yl ester,
biphenyl-2-ylcarbamic acid 1-{2-[4-(4-ethylcarbamoylpiperidin-1-ylmethyl)phenylcarbamoyl]ethyl}piperidin-4-yl ester;
biphenyl-2-yl-carbamic acid 1{2-[4-(4-propylcarbamoylpiperidin-1-ylmethyl)phenylcarbamoyl]ethyl}piperidin-4-yl ester;
biphenyl-2-yl-carbamic acid 1-{2-[4-(4-isopropylcarbamoylpiperidin-1-ylmethyl)phenylcarbamoyl]ethyl}piperidin-4-yl ester; and
biphenyl-2-yl-carbamic acid 1-{2-[4-(4-carbamoylpiperidin-1-ylmethyl)-2-chlorophenylcarbamoyl]ethyl}piperidin-4-yl ester;
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 or 12 .