Biphenyl compounds useful as muscarinic receptor antagonists

Patent metadata

Field	Value
Publication number	US-9283183-B2
Application number	US-201414539550-A
Country	US
Kind code	B2
Filing date	Nov 12, 2014
Priority date	Mar 11, 2004
Publication date	Mar 15, 2016
Grant date	Mar 15, 2016

Abstract

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.

First claim

What is claimed is:

1. A pharmaceutical composition comprising a pharmaceutically acceptable propellant and biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1 , wherein the composition further comprises an agent selected from β 2 adrenergic receptor agonists, steroidal anti-inflammatory agents, phosphodiesterase-4 inhibitors, and combinations thereof.

3. The pharmaceutical composition of claim 2 , wherein the composition comprises a β 2 adrenergic receptor agonist and a steroidal anti-inflammatory agent.

4. The pharmaceutical composition of claim 1 , wherein said biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]-methylamino}ethyl)piperidin-4-yl ester or pharmaceutically acceptable salt thereof is in solution.

5. The pharmaceutical composition of claim 1 , wherein said biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]-methylamino}ethyl)piperidin-4-yl ester or pharmaceutically acceptable salt thereof is in a suspension.

6. The pharmaceutical composition of claim 1 , wherein the propellant is a hydrofluoroalkane.

7. The pharmaceutical composition of claim 6 , wherein the hydrofluoroalkane is 1,1,1,2-tetrafluoroethane.

8. The pharmaceutical composition of claim 6 , wherein the hydrofluoroalkane is 1,1,1,2,3,3,3-heptafluoro-n-propane.

9. The pharmaceutical composition of claim 1 , wherein the composition further comprises a co-solvent selected from ethanol and pentane.

10. The pharmaceutical composition of claim 1 , wherein the composition further comprises a surfactant selected from the sorbitan trioleate, oleic acid, lecithin, and glycerin.

11. The pharmaceutical composition of claim 1 , comprising from about 0.01% to about 5% by weight of said biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester or pharmaceutically acceptable salt thereof; from about 0% to about 20% by weight ethanol; and from about 0% to about 5% by weight surfactant; with the remainder being a hydrofluoroalkane propellant.

12. The pharmaceutical composition of claim 1 , wherein said biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]-methylamino}ethyl)piperidin-4-yl ester or pharmaceutically acceptable salt thereof is micronized.

13. A pharmaceutical composition comprising 1,1,1,2-tetrafluoroethane and biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising 1,1,1,2,3,3,3-heptafluoro-n-propane and biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition of claim 2 , wherein the composition further comprises a β 2 adrenergic receptor agonist.

16. The pharmaceutical composition of claim 15 , wherein the β 2 adrenergic receptor agonist is formoterol or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition of claim 2 , wherein the composition further comprises a steroidal anti-inflammatory agent.

Assignees

• Mammen Mathai
• Ji Yuhua
• Mu Yongqi
• Husfeld Craig
• Li Li
• Theravance Biopharma R&D Ip Llc

Inventors

• Mammen Mathai
• Ji Yuhua
• Mu Yongqi
• Husfeld Craig
• Li Li

Classifications

• A61P9/06

  Antiarrhythmics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P1/06

  Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia · CPC title