Biphenyl derivatives

• US 20060229334A1
• Filed: 06/07/2006
• Published: 10/12/2006
• Est. Priority Date: 02/14/2003
• Status: Active Grant

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Adam Hughes, Mathai Mammen, Yan Chen
• Inventors: Hughes, Adam, Mammen, Mathai, Chen, Yan
• Granted Patent: US 7,521,561 B2
• Time in Patent Office: Days
• US Class Current: 514/312
• 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

1-43. -43. (canceled)

44. A compound of the formula:

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

46. The compound of claim 45, wherein the compound is in the form of a pharmaceutically acceptable salt.

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

48. A pharmaceutical composition comprising:

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

(b) a therapeutically effective amount of a steroidal anti-inflammatory agent; and

(c) a pharmaceutically acceptable carrier.

49. 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-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt or solvate thereof.

50. A pharmaceutical composition comprising:

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

(b) a pharmaceutically acceptable carrier;

wherein the pharmaceutical composition is a dry powder.

51. The pharmaceutical composition of claim 50, wherein the carrier is lactose or starch.

52. A pharmaceutical composition comprising:

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

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

m and about 100 μ

m.

53. A pharmaceutical composition comprising:

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

(b) a propellant.

54. The pharmaceutical composition of claim 53, wherein the propellant is a hydrofluoroalkane.

55. 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-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt or solvate thereof.

56. 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-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt or solvate thereof;

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

57. 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-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenyl-carbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt or solvate thereof.

58. A method of treating chronic obstructive pulmonary disease, the method comprising administering to a patient in need of treatment about 10 μ

g/day to about 200 μ

g/day of biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenyl-carbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt or solvate thereof.

59. 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-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt or solvate thereof.

60. A method of treating asthma, the method comprising administering to a patient in need of treatment about 10 μ

g/day to about 200 μ

g/day of biphenyl-2-ylcarbamic acid 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt or solvate thereof.

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

62. 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-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt or solvate thereof.

63. 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-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenyl-carbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt or solvate thereof.

64. A method of antagonizing a muscarinic receptor and agonizing a 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-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenyl-carbamoyl)ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt or solvate thereof.