Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity

• US 7,528,253 B2
• Filed: 08/15/2005
• Issued: 05/05/2009
• 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
• Primary Examiner(s): SEAMAN, D MARGARET M
• Application Number:
  US11/204,066
• Publication Number:
  US 20060116398A1
• Time in Patent Office: 1,359 Days
• Field of Search: 546/159, 546/163
• US Class Current: 546/159
• 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 antagonist 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 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^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);

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, or —

(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;

A² 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 V:

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

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

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

28. 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.

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

30. The pharmaceutical composition of claim 29, wherein the composition further comprises a therapeutically effective amount of a steroidal anti-inflammatory agent.

31. The pharmaceutical composition of claim 29, wherein the composition further comprises a therapeutically effective amount of a PDE₄ inhibitor.

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

(a) reacting a compound of formula 1;

33. The process of claim 32, wherein the process further comprises forming a pharmaceutically acceptable salt of the compound of formula I.

34. A compound of formula 12:

35. The compound of claim 34, wherein Y¹ is bromo.