Compounds having beta2 adrenergic receptor agonist and muscarinic receptor antagonist activity

• US 20060116398A1
• Filed: 08/15/2005
• Published: 06/01/2006
• Est. Priority Date: 08/16/2004
• Status: Active Grant

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Theravance, Inc
• Inventors: Mammen, Mathai, Mischki, Trevor
• Granted Patent: US 7,528,253 B2
• Time in Patent Office: Days
• US Class Current: 514/317
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 271/28 to a carbon atom of a non-condensed six-membered aromatic ring
• CPC Class Codes: C07D 213/40 Acylated substituent nitrogen atom
• CPC Class Codes: C07D 215/26 Alcohols; Ethers thereof
• CPC Class Codes: C07D 277/28 Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 333/20 by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links

Abstract

This invention provides compounds of formula I:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R^8a, R^8b, W, a and b are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The compounds of this invention possess both β₂ adrenergic receptor agonist and muscarinic receptor antagonist activity. Accordingly, such compounds are expected to be useful as therapeutic agents for treating pulmonary disorders, such as chronic obstructive pulmonary disease and asthma.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein R¹ is an unsubstituted or substituted aryl or heteroaryl group selected from a phenyl, naphthalene, pyrrole, imidazole, thiazole, oxazole, furan, thiophene, triazole, pyrazole, isoxazole, isothiazole, pyridine, pyridine N-oxide, pyrazine, pyridazine, pyrimidine, triazine, indole, benzofuran, benzothiophene, benzimidazole, benzthiazole, quinoline, isoquinoline, quinazoline and quinoxaline ring, where the point of attachment is at any available carbon or nitrogen ring atom.

3. The compound of claim 2, wherein R¹ is an unsubstituted or substituted phenyl group.

4. The compound of claim 2, wherein R¹ is an unsubstituted or substituted thienyl group.

5. The compound of claim 2, wherein R¹ is an unsubstituted or substituted thiazole group.

6. The compound of claim 2, wherein R¹ is an unsubstituted or substituted pyridyl or pyridyl N-oxide group.

7. The compound of claim 1, wherein W is O.

8. The compound of claim 1, wherein b is 2, 3 or 4.

9. The compound of claim 1, wherein b is 3, and R^8a and R^8b on the —

CR^8aR^8b—

unit attached to W are methyl, and the remaining R^8a and R^8b groups are hydrogen.

10. The compound of claim 1, wherein R³ is methyl.

11. The compound of claim 1, wherein R⁶ is —

NHCHO or —

CH₂OH and R⁷ is hydrogen;

or R⁶ and R⁷ together form —

NHC(O)CH═

CH—

, —

CH═

CHC(O)NH—

, —

CH₂CH₂C(O)NH—

or —

NHC(O)CH₂CH₂—

.

12. The compound of claim 11, wherein R⁶ and R⁷ together form —

NHC(O)CH═

CH—

.

13. The compound of claim 1, wherein the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R⁴ is attached is in the range of from 8 to 14.

14. The compound of claim 13, wherein the number of contiguous atoms in the shortest chain between the two nitrogen atoms to which R⁴ is attached is 8, 9, 10 or 11.

15. The compound of claim 1, wherein 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^d 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;

or R^4d represents (1-6C)alkylene-NHC(O)-(1-6C)alkylene;

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 substituents 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<sup>b )—

, —

N(Qc</sup>)S(O)₂—

, —

S(O)₂N(Q^d)—

, N(Q^e)C(O)N(Q<sup>f)—

, —

N(Qg</sup>)S(O)₂N(Q^h)—

, —

OC(O)N(Qⁱ)—

, —

N(Q^j)C(O)O— and

—

N(Q^k);

where 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 to 6 membered azacycloalkylene group; and

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 substituents 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.

16. The compound of claim 15, wherein R⁴ is a divalent group of the formula:

—

(R^4a)_d—

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

17. The compound of claim 16, wherein R⁴ is —

(CH₂)₈—

, —

(CH₂)₉, and —

(CH₂)₁₀—

.

18. The compound of claim 15, wherein 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.

19. The compound of claim 15, wherein R⁴ is a divalent group of the formula:

—

(R^4a)_d-Q-(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;

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

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

20. The compound of claim 15, wherein Q is —

N(Q^a)C(O)—

or —

C(O)N(Q^b)—

.

21. The compound of claim 20, wherein R⁴ is selected from:

22. The compound of claim 1, wherein R⁴ is selected from:

—

(CH₂)₇—

;

—

(CH₂)₈—

;

—

(CH₂)₉—

;

—

(CH₂)₁₀—

;

—

(CH₂)₁₁—

;

—

(CH₂)₂C(O)NH(CH₂)₅—

;

—

(CH₂)₂N(CH₃)C(O)(CH₂)₅—

;

—

(CH₂)₂C(O)NH(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂NHC(O)(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂NHC(O)NH(CH₂)₅—

;

—

(CH₂)₃NHC(O)NH(CH₂)₅—

;

—

(CH₂)₂C(O)NHCH₂(cyclohex-1,3-ylene)CH₂—

;

—

(CH₂)₂NHC(O)(cyclopent-1,3-ylene)-;

—

(CH₂)₂NHC(O)NH(phen-1,4-ylene)(CH₂)₂—

;

1-[—

(CH₂)₂C(O)](piperidin-4-yl)(CH₂)₂—

;

—

(CH₂)₂NHC(O)(trans-cyclohex-1,4-ylene)CH₂—

;

—

(CH₂)₂NHC(O)(cis-cyclopent-1,3-ylene)-;

—

(CH₂)₂NH(phen-1,4-ylene)(CH₂)₂—

;

1-[—

(CH₂)₂NHC(O)](piperidin-4-yl)(CH₂)₂—

;

—

CH₂(phen-1,4-ylene)NH(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NHCH₂(phen-1,3-ylene)CH₂—

;

—

(CH₂)₂C(O)NHCH₂(pyrid-2,6-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(cis-cyclohex-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(trans-cyclohex-1,4-ylene)CH₂—

;

—

(CH₂)₂NHC(O)(cis-cyclopent-1,3-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)C(O)(phen-1,3-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)C(O)(trans-cyclohex-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(phen-1,4-ylene)C*H(CH₃)—

((S)-isomer);

—

(CH₂)₂C(O)NH(phen-1,4-ylene)C*H(CH₃)—

((R)-isomer);

2-[(S)-(—

CH₂-](pyrrolidin-1-yl)C(O)(CH₂)₄—

;

2-[(S)-(—

CH₂-](pyrrolidin-1-yl)C(O)(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(4-chlorophen-1,3-ylene)CH₂—

;

—

CH₂(2-fluorophen-1,3-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(4-methylphen-1,3-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(6-chlorophen-1,3-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(2-chlorophen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(2,6-dichlorophen-1,4-ylene)CH₂—

;

—

(CH₂)₂NHC(O)NHCH₂(phen-1,3-ylene)CH₂—

;

4-[—

CH₂-](piperidin-1-yl)C(O)(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)N(CH₂CH₃)(phen-1,4-ylene)CH₂—

;

1-[—

(CH₂)₂NHC(O)](piperidin-4-yl)—

;

—

(CH₂)₂C(O)NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₂NHC(O)(thien-2,5-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)C(O)(3-nitrophen-1,4-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)C(O)(trans-cyclohex-1,4-ylene)-;

1-[—

CH₂(2-fluorophen-1,3-ylene)CH₂](piperidin-4-yl)—

;

5-[—

(CH₂)₂NHC(O)](pyrid-2-yl)CH₂—

;

—

(CH₂)₂(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₃(thien-2,5-ylene)(CH₂)₃—

;

—

(CH₂)₂(phen-1,4-ylene)NH(phen-1,4-ylene)(CH₂)₂—

;

—

CH₂(phen-1,2-ylene)NH(phen-1,4-ylene)(CH₂)₂—

;

1-[—

CH₂(2-fluorophen-1,3-ylene)CH₂](piperidin-4-yl)(CH₂)₂—

;

1-[—

CH₂(2-fluorophen-1,3-ylene)CH₂](piperidin-4-yl)CH₂—

;

—

(CH₂)₂C(O)NH(3-chlorophen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(2-(CF₃O—

)phen-1,4-ylene)CH₂—

;

—

(CH₂)₃(phen-1,3-ylene)NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₂S(O)₂NH(CH₂)₅—

;

—

CH₂(phen-1,3-ylene)NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₂C(O)NH(2-iodophen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(2-chloro-5-methoxyphen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(2-chloro-6-methylphen-1,4-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)S(O)₂(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(2-bromophen-1,4-ylene)CH₂—

;

—

(CH₂)₃(phen-1,4-ylene)NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₃(phen-1,2-ylene)NH(phen-1,4-ylene)(CH₂)₂—

;

1-[—

CH₂(2-fluorophen-1,3-ylene)CH₂](piperidin-4-yl)(CH₂)₃—

;

—

(CH₂)₂C(O)NH(2-methoxyphen-1,4-ylene)CH₂—

;

—

(CH₂)₅NH(phen-1,4-ylene)(CH₂)₂—

;

4-[—

(CH₂)₂-](piperidin-1-yl)(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₂C(O)NH(phen-1,4-ylene)CH(CH₃)CH₂—

;

—

(CH₂)₂-(trans-cyclohex-1,4-ylene)NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₂C(O)NH(2-fluorophen-1,4-ylene)CH₂—

;

—

(CH₂)₂(phen-1,3-ylene)NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₂C(O)NH(2,5-difluorophen-1,4-ylene)CH₂—

;

—

(CH₂)₂NHC(O)(phen-1,4-ylene)(CH₂)₂—

;

1-[—

CH₂(pyrid-2,6-ylene)CH₂](piperidin-4-yl)CH₂—

;

—

(CH₂)₃NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₂NH(naphth-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₃O(phen-1,4-ylene)CH₂—

;

1-[—

(CH₂)₃](piperidin-4-yl)CH₂—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)(phen-1,4-ylene)CH₂—

;

—

(CH₂)₃(phen-1,4-ylene)NHC(O)(CH₂)₂—

;

—

(CH₂)₃O(phen-1,4-ylene)(CH₂)₂—

;

2-[—

(CH₂)₂](benzimidazol-5-yl)CH₂—

;

—

(CH₂)₂-(trans-cyclohex-1,4-ylene)NHC(O)(CH₂)₂—

;

—

(CH₂)₂-(trans-cyclohex-1,4-ylene)NHC(O)(CH₂)₄—

;

—

(CH₂)₂-(trans-cyclohex-1,4-ylene)NHC(O)(CH₂)₅—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)(CH₂)₂—

;

—

(CH₂)₂NHC(O)NH(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)(CH₂)₂(cis-cyclohex-1,4-ylene)-;

—

(CH₂)₂C(O)NH(2,3,5,6-tetrafluorophen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(2,6-diiodophen-1,4-ylene)CH₂—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)(CH₂)₃—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)(CH₂)₄—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)(CH₂)₅—

;

—

(CH₂)₂C(O)NHCH₂(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂NHC(O)NHCH₂(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(2-methylphen-1,4-ylene)CH₂—

;

1-[—

(CH₂)₃O(phen-1,4-ylene)(CH₂)₂](piperidin-4-yl)CH₂—

;

—

(CH₂)₂C(O)NHCH₂(phen-1,3-ylene)(CH₂)₂—

;

—

(CH₂)₂O(phen-1,3-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)C(O)CH₂O(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)C(O)CH₂O(phen-1,3-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)C(O)(fur-2,5-ylene)CH₂—

;

—

(CH₂)₂N(CH₃)C(O)(thien-2,5-ylene)CH₂—

;

—

(CH₂)₂O(phen-1,4-ylene)O(CH₂)₂—

;

—

(CH₂)₂(trans-cyclohex-1,4-ylene)NHC(O)(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂(trans-cyclohex-1,4-ylene)NHC(O)CH₂O(phen-1,2-ylene)CH₂—

;

—

(CH₂)₂(trans-cyclohex-1,4-ylene)NHC(O)CH₂O(phen-1,3-ylene)CH₂—

;

—

(CH₂)₂(trans-cyclohex-1,4-ylene)NHC(O)CH₂O(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂(trans-cyclohex-1,4-ylene)NHC(O)(fur-2,5-ylene)CH₂—

;

—

(CH₂)₂(trans-cyclohex-1,4-ylene)NHC(O)(thien-2,5-ylene)CH₂—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)CH₂O(phen-1,2-ylene)CH₂—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)CH₂O(phen-1,3-ylene)CH₂—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)CH₂O(phen-1,4-ylene)CH₂—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)(fur-2,5-ylene)CH₂—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)(thien-2,5-ylene)CH₂—

;

—

(CH₂)₂(phen-1,4-ylene)NHC(O)(phen-1,3-ylene)CH₂—

;

—

(CH₂)₂(phen-1,4-ylene)NHC(O)(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂(phen-1,4-ylene)NHC(O)CH₂O(phen-1,2-ylene)CH₂—

;

—

(CH₂)₂(phen-1,4-ylene)NHC(O)CH₂O(phen-1,3-ylene)CH₂—

;

—

(CH₂)₂(phen-1,4-ylene)NHC(O)CH₂O(phen-1,4-ylene)CH₂—

;

—

(CH₂)₂(phen-1,4-ylene)NHC(O)(fur-2,5-ylene)CH₂—

;

—

(CH₂)₂(phen-1,4-ylene)NHC(O)(thien-2,5-ylene)CH₂—

;

—

(CH₂)₂(trans-cyclohex-1,4-ylene)NHC(O)(phen-1,3-ylene)CH₂—

;

—

(CH₂)₃O(phen-1,3-ylene)CH₂—

;

—

CH₂CH(OH)CH₂NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₄NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₂C(O)NH(phen-1,4-ylene)CH₂NHC(O)CH₂—

;

—

(CH₂)₂C(O)NH(phen-1,4-ylene)(CH₂)₂NHC(O)CH₂—

;

—

(CH₂)₂C(O)NHCH₂(trans-cyclohex-1,4-ylene)CH₂—

;

—

(CH₂)₂NHC(O)(CH₂)₅—

;

—

(CH₂)₂O(phen-1,3-ylene)O(CH₂)₂—

;

—

(CH₂)₂O(phen-1,2-ylene)O(CH₂)₂—

;

—

CH₂(phen-1,2-ylene)O(phen-1,2-ylene)CH₂—

;

—

(CH₂)₂C(O)NH(CH₂)₆—

;

—

(CH₂)₃(phen-1,4-ylene)(CH₂)₃—

;

—

(CH₂)₃(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₄(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₃(furan-2,5-ylene)(CH₂)₃—

;

—

(CH₂)₂N(CH₃)C(O)NH(phen-1,4-ylene)(CH₂)₂—

;

4-[—

(CH₂)₂](piperidin-1-yl)C(O)NH(phen-1,4-ylene)(CH₂)₂—

;

—

(CH₂)₃(phen-1,3-ylene)(CH₂)₃—

;

—

(CH₂)₃(tetrahydrofuran-2,5-ylene)(CH₂)₃—

; and

—

(CH₂)₂O(phen-1,4-ylene)C(O)(CH₂)₂—

.

23. The compound of claim 1, wherein the compound is a compound of formula II:

24. The compound of claim 1, wherein the compound is a compound of formula III:

25. The compound of claim 1, wherein the compound is a compound of formula IV:

26. The compound of claim 1, wherein the compound is a compound of formula V:

27. The compound of claim 1, wherein the compound is a compound of formula VI:

28. The compound of claim 1, wherein the compound is a compound of formula VII:

29. The compound of claim 1, wherein the compound is a compound of formula VIII:

30. The compound of claim 1, wherein the compound is selected from:

biphenyl-2-ylcarbamic acid 3-({9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydro-quinolin-5-yl)ethylamino]nonyl}methylamino)-1,1-dimethylpropyl ester;

(2-thien-3-ylphenyl)carbamic acid 3-({9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]nonyl}methylamino)-1,1-dimethylpropyl ester;

biphenyl-2-ylcarbamic acid 3-{[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}benzoylamino)ethyl]methylamino}-1,1-dimethylpropyl ester;

biphenyl-2-ylcarbamic acid 3-{[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenyl)butyl]methylamino}-1,1-dimethyl-propyl ester; and

biphenyl-2-ylcarbamic acid 3-{[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-5-methoxyphenylcarbamoyl)ethyl]-methylamino}-1,1-dimethylpropyl ester.

31. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1.

32. The pharmaceutical composition of claim 31, wherein the composition further comprises a therapeutically effective amount of a steroidal anti-inflammatory agent.

33. The pharmaceutical composition of claim 31, wherein the composition further comprises a therapeutically effective amount of a PDE₄ inhibitor.

34. 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 claim 1.

35. A method of producing bronchodilation in a patient, the method comprising administering to a patient a bronchodilation-producing amount of a compound of claim 1.

36. 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 claim 1.

37. A method of studying a biological system or sample comprising a muscarinic receptor or a β

₂ adrenergic receptor, the method comprising;

(a) contacting the biological system or sample with a muscarinic receptor antagonizing or a β

₂ adrenergic receptor agonizing amount of a compound of claim 1;

and

(b) determining or measuring the effects caused by the compound on the biological system or sample.

38. A process for preparing a compound of claim 1, the process comprising:

(a) reacting a compound of formula 1;

or a salt thereof;

with a compound of formula 2;

wherein X¹ represents a leaving group, and P¹ and P² each independently represent a hydrogen atom or a hydroxyl-protecting group;

(b) reacting a compound of formula 3;

or salt thereof;

with a compound of formula 4;

wherein X² represents a leaving group, and P³ and P⁴ each independently represent a hydrogen atom or a hydroxyl-protecting group;

(c) coupling a compound of formula 5;

with a compound of formula 6;

wherein X^Qa and X^Qb each independently represent functional groups that couple to form a group Q, P^5a represents a hydrogen atom or an amino-protecting group; and

P^5b and P⁶ each independently represent a hydrogen atom or a hydroxyl-protecting group;

(d) for a compound of formula I wherein R⁵ represents a hydrogen atom, reacting a compound of formula 3 with a compound of formula 7;

or a hydrate thereof (e.g., a glyoxal), in the presence of a reducing agent, wherein P⁷ represents a hydrogen atom or a hydroxyl-protecting group;

(e) reacting a compound of formula I with a compound of formula 8;

or a hydrate thereof, in the presence of a reducing agent, wherein P⁸ and P⁹ each independently represent a hydrogen atom or a hydroxyl-protecting group, P¹⁰ represents a hydrogen atom or an amino-protecting group, and R⁴ represents a residue that, together with the carbon to which it is attached, affords a group R⁴ upon completion of the reaction;

(f) reacting a compound of formula 9;

wherein X³ represents a leaving group, with a compound of formula 10;

wherein P¹¹ and P¹² each independently represent a hydrogen atom or a hydroxyl-protecting group, and P¹³ represents a hydrogen atom or an amino-protecting group;

or

(g) reacting a compound of formula 11;

or a hydrate thereof;

wherein R⁴ represents a residue that, together with the carbon to which it is attached, affords a group R⁴ upon completion of the reaction;

with a compound of formula 10 in the presence of a reducing agent;

(h) reacting a compound of formula 12;

wherein Y¹ represents chloro, bromo, iodo or CF₃SO₂O—

, P¹⁴ represents a hydrogen atom or an amino-protecting group; and

P¹⁵ and P¹⁶ each independently represent a hydrogen atom or a hydroxyl-protecting group;

with a compound of the formula;

R¹—

B(OH)₂ in the presence of a coupling catalyst; and

then removing any protecting group P¹, P², P³, P⁴, P^5a, P^5b, P⁶, P⁷, P⁸, P⁹, P¹⁰, P¹¹, P¹², P¹³, P¹⁴, P¹⁵ and P¹⁶ to provide a compound of formula I, or a salt thereof.

39. The process of claim 37, wherein the process further comprises forming a pharmaceutically acceptable salt of the compound of formula I.

40. A compound of formula 12:

41. The compound of claim 40, wherein Y¹ is bromo.