Biphenyl derivatives

• US 7,524,959 B2
• Filed: 10/18/2006
• Issued: 04/28/2009
• Est. Priority Date: 02/14/2003
• Status: Active Grant

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Theravance, Inc
• Inventors: Hughes, Adam, Mammen, Mathai, Chen, Yan
• Primary Examiner(s): SEAMAN, D MARGARET M
• Application Number:
  US11/582,885
• Publication Number:
  US 20070037984A1
• Time in Patent Office: 923 Days
• Field of Search: 514/314, 546/157
• US Class Current: 546/157
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/452 Piperidinium derivatives pancuronium A61K31/58
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 11/12 Mucolytics
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/40 Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 211/46 having a hydrogen atom as the second substituent in position 4
• CPC Class Codes: C07D 211/48 having an acyclic carbon atom attached in position 4
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 453/02 containing not further condensed quinuclidine ring systems
• CPC Class Codes: C07D 471/08 : Bridged systems
• CPC Class Codes: G01N 33/9433 : (Nor)adrenaline

Abstract

This invention provides biphenyl derivatives of formula I:

• • wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, W, a, b and c are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The biphenyl derivatives of this invention possess both β₂ adrenergic receptor agonist and muscarinic receptor antagonist activity and therefore, such biphenyl derivatives are useful for treating pulmonary disorders, such as chronic obstructive pulmonary disease and asthma.

Claims

1. A compound of the formula:

2. Biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1, 2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenyl-carbamoyl) ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2, wherein the compound is in the form of a pharmaceutically acceptable salt.

4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising:

(a) biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof;

(b) a steroidal anti-inflammatory agent; and

(c) a pharmaceutically acceptable carrier.

6. A pharmaceutical composition comprising an isotonic aqueous solution comprising from about 0.05 μ

g/mL to about 10 mg/mL of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising:

(a) biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenyl-carbamoyl) ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof; and

(b) a pharmaceutically acceptable carrier;

wherein the pharmaceutical composition is a dry powder.

8. The pharmaceutical composition of claim 7, wherein the carrier is lactose or starch.

9. A pharmaceutical composition comprising:

(a) micronized particles of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenylcarbamoyl) ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof; and

(b) dry lactose having a particle size between about 1 μ

m and about 100 μ

m.

10. A pharmaceutical composition comprising:

(a) biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenyl-carbamoyl) ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof; and

(b) a propellant.

11. The pharmaceutical composition of claim 10, wherein the propellant is a hydrofluoroalkane.

12. A method of treating a pulmonary disorder, the method comprising administering to a patient in need of treatment a therapeutically effective amount of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenylcarbamoyl)-ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.

13. A method of treating a pulmonary disorder, the method comprisingadministering to a patient in need of treatment a therapeutically effective amount of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenylcarbamoyl)-ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof;

and a therapeutically effective amount of a steroidal anti-inflammatory agent.

14. A method of treating chronic obstructive pulmonary disease, the method comprising administering to a patient in need of treatment a therapeutically effective amount of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenyl-carbamoyl) ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.

15. A method of treating asthma, the method comprising administering to a patient in need of treatment a therapeutically effective amount of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethylamino]methyl}-2-methylphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.

16. A method of producing bronchodilation in a patient, the method comprising administering to the patient a bronchodilation-producing amoun of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethylamino]methyl}-2-methylphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.

17. A method of antagonizing a muscarinic receptor in a biological system or sample having a muscarinic receptor, the method comprising contacting the biological system or sample with a muscarinic receptor antagonizing-amount of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethylamino]methyl}-2-methylphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.

18. A method of agonizing a β

₂ adrenergic receptor in a biological system or sample having a β

₂ adrenergic receptor, the method comprising contacting the biological system or sample with a β

₂ adrenergic receptor agonizing-amount of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethylamino]methyl}-2-methylphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.

19. A method of antagonizing a muscarinic receptor and agonizing a β

₂ adrenergic receptor in a biological system or sample having a muscarinic receptor and a β

₂ adrenergic receptor, the method comprising contacting the biological system or sample with a muscarinic receptor antagonizing- and β

₂ adrenergic receptor agonizing-amount of biphenyl-2-ylcarbamic acid 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2-methylphenylcarbamoyl)ethyl]-piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.