Biphenyl derivatives having beta2 adrenergic receptor agonist and muscarinic receptor antagonist activity

• US 20040209860A1
• Filed: 02/13/2004
• Published: 10/21/2004
• Est. Priority Date: 02/14/2003
• Status: Abandoned Application

• Current Assignee: Theravance Respiratory Company, LLC (Royalty Pharma Plc)
• Original Assignee: Theravance Respiratory Company, LLC (Royalty Pharma Plc)
• Inventors: Hughes, Adam, Mammen, Mathai, Dunham, Sarah
• Application Number:
  US10/778,649
• Publication Number:
  US 20040209860A1
• Time in Patent Office: Days
• US Class Current: 514/183
• 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 containing (i) a (biphenyl-2-yl)oxycarbonylamino- or (biphenyl-2-yl)aminocarbonylamino-substituted (2-7C)azacycloalkyl or (5-10C)azabicycloalkyl group; (ii) a substituted 2-(4-hydroxyphenyl)-2-hydroxyethylamino group; and a divalent hydrocarbon group, where each group is further defined and optionally substituted as described in the specification. The biphenyl derivatives of the 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 comprising:

a (biphenyl-2-yl)oxycarbonylamino- or (biphenyl-2-yl)aminocarbonylamino-substituted (2-7C)azacycloalkyl or (5-10C)azabicycloalkyl group;

a 2-(4-hydroxyphenyl)-2-hydroxyethylamino group substituted on the phenyl group with a substituent selected from —

NR^ACR^B(O), —

CR^CR^DOR^E, —

NR^F C(O)CR^G═

CR^H— and

—

NR^IC(O)CR^JR^K—

CR^LR^M—

, where each of R^A, R^B, R^C, R^D, R^E, R^F, R^G, R^H, R^I, R^J, R^K, R^L and R^M is independently hydrogen or (1-4C)alkyl; and

a divalent hydrocarbon group containing from 4 to 28 carbon atoms and optionally containing from 1 to 10 heteroatoms selected independently from halo, oxygen, nitrogen and sulfur, wherein the divalent hydrocarbon group is attached to the amino group of the azacycloalkyl or azabicycloalkyl group and to the amino group of the 2-(4-hydroxyphenyl)-2-hydroxyethylamino group;

wherein the compound is optionally substituted with 1 to 12 substituents selected independently from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —

OR^N, —

C(O)OR^O, —

SR^P, —

S(O)R^Q, —

S(O)₂R^R, —

NR^SR^T, —

C(O)R^U, —

OC(O)R^V, C(O)NR^WR^X, —

NR^YC(O)R^Z, —

S(O)₂NR^AAR^AB, —

NR^ACS(O)₂R^AD, —

OC(O)NR^AER^AF and —

N(R^AG)C(O)NR^AHR^AI, where each of R^N, R^O, R^P, R^Q, R^R, R^S, R^T, R^U, R^V, R^W, R^X, R^Y, R^Z, R^AA, R^AB, R^AC, R^AD, R^AE, R^AF, R^AG, R^AH and R^AI is independently hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl or (3-6C)heterocyclyl;

wherein each aryl and heteraryl group is optionally substituted with 1 to 3 substitutents selected independently from (1-4C)alkyl, halo, (1-4C)alkoxy, trifluoromethyl or trifluoromethoxy;

each cycloalkyl or heterocyclyl is optionally substituted with 1 to 4 substituents independently selected from (1-4C)alkyl; and

each alkyl group is optionally substituted with 1 to 3 fluoro substituents; and

further wherein the compound has both muscarinic receptor antagonist activity and β

₂-adrenergic receptor agonist activity;

or a pharmaceutically acceptable salt or stereoisomer or solvate thereof.

2. The compound of claim 1, wherein the compound comprises a (biphenyl-2-yl)oxycarbonylamino-substituted (2-7C)azacycloalkyl group.

3. The compound of claim 1, wherein the compound comprises a 2-(4-hydroxyphenyl)-2-hydroxyethylamino group substituted on the phenyl group with a —

NR^ACR^B(O) substituent.

4. The compound of claim 1, wherein the compound comprises a 2-(4-hydroxyphenyl)-2-hydroxyethylamino group substituted on the phenyl group with a —

CR^CR^DOR^E substituent.

5. The compound of claim 1, wherein the compound comprises a 2-(4-hydroxyphenyl)-2-hydroxyethylamino group substituted on the phenyl group with a —

NR^FC(O)CR^G═

CR^H—

substituent.

6. The compound of claim 1, wherein the compound comprises a divalent hydrocarbon group containing from 4 to 24 carbon atoms and optionally containing from 1 to 8 heteroatoms selected independently from halo, oxygen, nitrogen and sulfur.

7. The compound of claim 1, wherein the compound comprises a divalent hydrocarbon group containing from 4 to 20 carbon atoms and optionally containing from 1 to 6 heteroatoms selected independently from halo, oxygen, nitrogen and sulfur.

18. The compound of any one of claims 1, 8, 14, 15 or 16, wherein the compound has an inhibitory constant K_i value for binding at the M₃ muscarinic receptor and an EC₅₀ value for β

₂ adrenergic receptor agonist activity of less than about 100 nM.

19. The compound of claim 18, wherein the compound has a ratio of the inhibitory constant K_i for the M₃ muscarinic receptor to the EC₅₀ for the β

₂ adrenergic receptor ranging from about 30;

1 to about 1;

30.

20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of claims 1, 8, 14, 15 or 16.

21. The pharmaceutical composition of claim 20, wherein the composition further comprises a therapeutically effective amount of a steroidal anti-inflammatory agent.

22. The pharmaceutical composition of claim 20, wherein the composition further comprises a therapeutically effective amount of a PDE₄ inhibitor.

23. A method for treating a pulmonary disorder, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of any one of claims 1, 8, 14, 15 or 16.

24. A method of providing bronchodilation in a patient, the method comprising administering to a patient requiring bronchodilation a therapeutically effective amount of a compound of any one of claims 1, 8, 14, 15 or 16.

25. A method of treating chronic obstructive pulmonary disease or asthma, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of any one of claims 1, 8, 14, 15 or 16.

8. A compound of formula I:

9. The compound of claim 8, wherein W is attached to the piperidine ring at the 4-position with respect to the nitrogen atom.

10. The compound of claim 8, wherein a, b, and c are each 0, and W^a and R⁵ are both hydrogen.

11. The compound of claim 8, wherein W represents O.

12. The compound of claim 8, wherein R⁶ is —

NHCHO or —

CH₂OH and R⁷ is hydrogen;

or R⁶ and R⁷ together form —

NHC(O)—

CH═

CH—

, —

CH═

CH—

C(O)—

NH—

, —

CH₂—

CH₂—

C(O)NH—

or —

NHC(O)—

CH₂—

CH₂—

.

13. The compound of claim 12, wherein R⁶ and R⁷ together form —

NHC(O)—

CH═

CH—

.

14. A compound of formula II:

17. The compound of any one of claims 14, 15 or 16, wherein W represents 0.

15. A compound of formula III:

16. A compound of formula IV: