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 muscarinic 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 (3-5C)heteroarylene group containing 1 or 2 heteroatoms selected independently from oxygen, nitrogen, and sulfur; wherein the heteroarylene group is 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)alkyl, 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 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; q is 0, 1, or 2; and the —CONR 7 R 8 group is in the para position.
9. The compound of claim 1 , wherein R 4 is hydrogen or methyl.
10. The compound of claim 1 , wherein R 8 is hydrogen.
11. The compound of claim 10 , wherein R 7 is hydrogen.
12. A compound selected from:
biphenyl-2-yl-carbamic acid 1- {2-[5-(4-carbamoylpiperidin-l-ylmethyl)thiophen-2- ylcarbamoyl]ethyl}piperidin-4-y1 ester; or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 .
14. The compound of claim 1 , wherein Ar 1 is selected from divalent species of pyrrole, imidazole, thiazole, oxazole, furan, thiophene, pyrazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, and pyrimidine, where the point of attachment is at any available carbon or nitrogen ring atom.
15. The compound of claim 14 , wherein Ar 1 is selected from 2,5-furylene, 2,4-thienylene, 2,5-thienylene, 2,5-pyridylene, 2,6-yridylene, and 2,5-pyrrolylene.
16. The compound of claim 14 , wherein Ar 1 is selected from 3-fluoro-2,5-thienylene, 3-chloro-2,5-thienylene, 3-methyl-2,5-thienylene, 3-methoxy-2,5-thienylene, and 3-methoxy-6-chloro-2,5-pyridylene.