Library of biphenyl derivatives

• US 20040209915A1
• 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:
  US10/778,290
• Publication Number:
  US 20040209915A1
• Time in Patent Office: Days
• US Class Current: 514/317
• 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 a library of 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 salt or stereoisomer thereof. The library is useful for identifying compounds having both β₂ adrenergic receptor agonist and muscarinic receptor antagonist activity.

Accordingly, this invention also provides methods of evaluating or screening a library of biphenyl derivatives to identifying compounds having such bifunctional activity.

Claims

1. A library comprising compounds of formula I:

2. The library of claim 1, wherein the library contains a compound of formula I in which W is attached to the piperidine ring at the 4-position with respect to the nitrogen atom.

3. The library of claim 1, wherein the library contains a compound of formula I in which a, b, and c are each 0, and W^a and R⁵ are both hydrogen.

4. The library of claim 1, wherein the library contains a compound of formula I in which W represents O.

5. The library of claim 1, wherein the library contains a compound of formula I in which 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—

.

6. The library of claim 1, wherein the library contains a compound of formula I in which R⁴ is a divalent group of the formula:

—

(R^4a)_d—

(A¹)_e—

(R^4b)_f—

Q—

(R^4c)_g—

(A²)_h—

(R^4d)_i—

wherein

d, e, f, g, h and i are each independently selected from 0 and 1;

R^4a, R^4b, R^4c and R^4d are each independently selected from (1-10C)alkylene, (2-10C)alkenylene and (2-10C)alkynylene, wherein each alkylene, alkenylene or alkynylene group is unsubstituted or substituted with from 1 to 5 substituents independently selected from (1-4C)alkyl, fluoro, hydroxy, phenyl and phenyl-(1-4C)alkyl;

A¹ and A² are each independently selected from (3-7C)cycloalkylene, (6-10C)arylene, —

O—

(6-10C)arylene, (6-10C)arylene-O—

, (2-9C)heteroarylene, —

O—

(2-9C) heteroarylene, (2-9C)heteroarylene-O— and

(3-6C)heterocyclene, wherein each cycloalkylene is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl, (1-4C)alkoxy, —

S-(1-4C)alkyl, —

S(O)-(1-4C)alkyl, —

S(O)₂-(1-4C)alkyl, —

C(O)O(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifluoromethyl and trifluoromethoxy;

Q is selected from a bond, —

O—

, —

C(O)O—

, —

OC(O)—

, —

S—

, —

S(O)—

, —

S(O)₂—

, —

N(Q^a)C(O), —

C(O)N(Q^b)—

, —

N(Q^c)S(O)₂—

, —

S(O)₂N(Q^d)—

, —

N(Q^e)C(O)N(Q^f)—

, —

N(Q^g)S(O)₂N(Q^h)—

, —

OC(O)N(Qⁱ)—

, —

N(Q^j)C(O)O— and

—

N(Q^k);

Q^a, Q^b, Q^c, Q^d, Q^e, Q^f, Q^g, Q^h, Qⁱ, Q^j and Q^k are each independently selected from hydrogen, (1-6C)alkyl, A³ and (1-4C)alkylene-A⁴, wherein the alkyl group is unsubstituted or substituted with from 1 to 3 substituents independently selected from fluoro, hydroxy and (1-4C)alkoxy;

or together with the nitrogen atom and the group R^4b or R^4c to which they are attached, form a 4-6 membered azacycloalkylene group;

A³ and A⁴ are each independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyclyl, wherein each cycloalkyl is unsubstituted or substituted with from 1 to 4 substitutents selected independently from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents independently selected from halo, (1-4C)alkyl and (1-4C)alkoxy.

7. The library of claim 6, wherein the library contains a compound of formula I in which R⁴ is a divalent group of the formula:

—

(R^4a)_d—

where R^4a is (4-10C)alkylene.

8. The library of claim 6, wherein the library contains a compound of formula I in which R⁴ is —

(CH₂)₈—

, —

(CH₂)₉, and —

(CH₂)₁₀—

.

9. The library of claim 6, wherein the library contains a compound of formula I in which R⁴ is a divalent group of the formula:

—

(R^4a)_d—

(A²)_h—

(R^4d)_i—

wherein R^4a is (1-10C)alkylene;

A² is (6-10C)arylene or (2-9C)heteroarylene; and

R^4d is (1-10C)alkylene.

10. The library of claim 6, wherein the library contains a compound of formula I in which R⁴ is a divalent group of the formula:

—

(R^4a)_d—

(A²)_h—

(R^4d)_i—

wherein Q is —

O—

or —

N(Q^k)—

;

Q^k is hydrogen or (1-3C)alkyl;

R^4a is (1-10C)alkylene;

A² is (6-10C)arylene or (2-9C)heteroarylene; and

R^4d is (1-10C)alkylene.

11. The library of claim 6, wherein the library contains a compound of formula I in which Q is —

N(Q^a)C(O)—

or —

C(O)N(Q^b)—

.

12. The library of claim 1, wherein the library contains a compound of formula I in which R⁴ is selected from:

13. The library of claim 1, wherein the library contains a compound of formula II:

14. The library of claim 1, wherein the library contains a compound of formula III:

15. The library of claim 1, wherein the library contains a compound of formula IV:

16. A method of identifying a compound of formula I having both β

₂ adrenergic receptor agonist activity and muscarinic receptor antagonist activity;

the method comprising;

evaluating the library of any one of claims 1, 13, 14 or 15 to determine whether a compound of formula I in the library has both β

₂ adrenergic receptor agonist activity and muscarinic receptor antagonist activity.

17. A method of identifying a compound of formula I having both β

₂ adrenergic receptor agonist activity and muscarinic receptor antagonist activity;

the method comprising;

(a) preparing the library of any one of claims 1 to 15;

(b) evaluating the compounds of formula I in the library to determine whether a compound has both β

₂ adrenergic receptor agonist activity and muscarinic receptor antagonist activity.

18. A method of identifying a compound of formula I that binds to a β

₂ adrenergic receptor and a muscarinic receptor;

the method comprising;

evaluating the library of any one of claims 1, 13, 14 or 15 to determine whether a compound of formula I in the library has a K_i value of less than about 300 nM for a β

₂ adrenergic receptor and a K_i value less than 300 nM for a muscarinic receptor.

19. A method of identifying a compound of formula I that binds to a β

₂ adrenergic receptor and a muscarinic receptor;

the method comprising;

(a) preparing the library of any one of claims 1 to 15; and

(b) evaluating the compounds of formula I in the library to determine whether a compound has a K_i value of less than about 300 nM for a β

₂ adrenergic receptor and a K_i value less than 300 nM for a muscarinic receptor.

20. A method of identifying a compound of formula I that binds to a β

₂ adrenergic receptor and a muscarinic receptor;

the method comprising;

evaluating the library of any one of claims 1, 13, 14 or 15 to determine whether a compound of formula I in the library has an EC₅₀ value of less than about 100 nM for a β

₂ adrenergic receptor and a K_i value less than 100 nM for a muscarinic receptor.

21. A method of identifying a compound of formula I that binds to a β

₂ adrenergic receptor and a muscarinic receptor;

the method comprising;

(a) preparing the library of any one of claims 1 to 15;

(b) evaluating the compounds of formula I in the library to determine whether a compound has a EC₅₀ value of less than about 100 nM for a β

₂ adrenergic receptor and a K_i value less than 100 nM for a muscarinic receptor.

22. A process for preparing a library comprising compounds of formula I: