Biphenyl compounds useful as muscarinic receptor antagonists
This invention provides compounds of formula I: wherein a, b, c, d, m, n, p, s, t, W, Ar 1 , R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 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 pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound having the formula:
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 independently selected from halo, hydroxy, (1-4C)alkyl, and (1-4C)alkoxy;
t is 0, 1 or 2;
n is 0 or an integer from 1 to 3;
p is 0 or 1; and
R 7 and R 8 are independently hydrogen or (1-4C)alkyl;
wherein each alkyl 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 pharmaceutical composition of claim 1 , wherein m is 0, s is 0 and t is 1.
3. The pharmaceutical composition of claim 1 , wherein Ar 1 represents phen-1,3-ylene or phen-1,4-ylene, optionally substituted with one or two R 5 substituents.
4. The pharmaceutical composition of claim 1 , wherein R 4 is selected from hydrogen, methyl and ethyl.
5. The pharmaceutical composition of claim 1 , wherein R 7 is selected from hydrogen, methyl, ethyl, n-propyl and isopropyl; and R 8 is hydrogen.
6. The pharmaceutical composition of claim 1 , wherein R 7 and R 8 are ethyl.
7. The pharmaceutical composition of claim 1 , wherein a and b each represent 0; m is 0; s is 0; t is 1; Ar 1 represents phen-1,4-ylene optionally substituted with one or two R 5 substituents; n is 2 and the —CONR 7 R 8 group is in the para position; and R 8 is hydrogen.
8. The pharmaceutical composition of claim 7 , wherein R 5 is independently selected from halo, (1-4C)alkyl, and (1-4C)alkoxy, wherein each alkyl and alkoxy group is optionally substituted with from 1 to 3 fluoro substituents.
9. The pharmaceutical composition of claim 1 , wherein the compound is biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.
10. The pharmaceutical composition of claim 1 , which is suitable for administration by inhalation.
11. The pharmaceutical composition of claim 10 , which is in the form of an aerosol.
12. The pharmaceutical composition of claim 10 , which is in the form of a powder.
13. The pharmaceutical composition of claim 10 , which is in the form of a solution.
14. The pharmaceutical composition of claim 10 , wherein the compound is micronized.
15. The pharmaceutical composition of claim 14 , wherein the compound is combined with the carrier to form a suspension.
16. The pharmaceutical composition of claim 15 , wherein the carrier is an isotonic aqueous solution.
17. The pharmaceutical composition of claim 14 , wherein the compound is combined with the carrier to form a free flowing powder.
18. The pharmaceutical composition of claim 17 , wherein the carrier is lactose or starch.
19. The pharmaceutical composition of claim 10 , which further comprises a liquefied propellant.
20. The pharmaceutical composition of claim 10 , which is administered using a nebulizer inhaler.
21. The pharmaceutical composition of claim 10 , which is administered using a metered-dose inhaler.
22. The pharmaceutical composition of claim 10 , which is administered using a dry powder inhaler.