Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity

• US 7,842,704 B2
• Filed: 12/11/2007
• Issued: 11/30/2010
• Est. Priority Date: 11/21/2003
• Status: Expired due to Fees

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Theravance, Inc
• Inventors: Mammen, Mathai, Dunham, Sarah
• Primary Examiner(s): SHIAO, REI TSANG
• Application Number:
  US12/001,362
• Publication Number:
  US 20080097105A1
• Time in Patent Office: 1,085 Days
• Field of Search: 514/323, 514/324, 514/320, 546/202, 546/200, 546/201
• US Class Current: 514/323
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• 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: C07D 277/68 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

The invention is directed to compounds of formula I:

• • wherein R¹, R², R³, R⁴, R⁵, R⁶, R^7a, R^7b, W, G¹, G², a, b, c, d and m are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The invention is also directed to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

Claims

1. A compound of formula I:

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

4. The compound of claim 1, wherein a, b, and c are each 0, and R⁵ is hydrogen.

5. The compound of claim 1, wherein d is 0.

6. The compound of claim 1, wherein d is 1;

and

R^7a and R^7b are both hydrogen.

7. The compound of claim 1, wherein m is 2.

8. The compound of claim 1, wherein G¹ is S and G² is NH.

9. The compound of claim 1, wherein R⁶ is hydrogen.

10. The compound of claim 1, wherein R⁶ is hydroxy.

11. 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^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-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);

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 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.

12. The compound of claim 11, wherein R⁴ is a divalent group of the formula:

—

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

13. The compound of claim 12, wherein R⁴ is —

(CH₂)₄—

, —

(CH₂)₅—

, —

(CH₂)₆—

, —

(CH₂)₇—

, —

(CH₂)₈—

, —

(CH₂)₉—

, or —

(CH₂)₁₀—

.

14. The compound of claim 11, wherein R⁴ is a divalent group of the formula:

—

(R^4a)_d-(A²)_h-(R^4d)_i—

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

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

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

15. The compound of claim 11, wherein R⁴ is a divalent group of the formula:

—

(R^4a)_d-(A²)_h-(R^4d)_i—

where Q is —

OR—

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.

16. The compound of claim 11, wherein Q is —

N(Q^a)C(O)—

or —

C(O)N(Q^b)-.

2. A compound of formula I:

17. The compound of claim 2, wherein W is O.

18. The compound of claim 2, wherein a, b, and c are each 0, and R⁵ is hydrogen.

19. The compound of claim 2, wherein d is 0.

20. The compound of claim 2, wherein d is 1;

and

R^7a and R^7b are both hydrogen.

21. The compound of claim 2, wherein m is 2.

22. The compound of claim 2, wherein G^l is S and G² is NH.

23. The compound of claim 2, wherein R⁶ is hydrogen.

24. The compound of claim 2, wherein R⁶ is hydroxy.

25. The compound of claim 2, 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;

A^l and A² are each independently selected from (3-7C)cycloalkylene, (6-1 OC)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);

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 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.

26. The compound of claim 25, wherein R⁴ is a divalent group of the formula:

—

(R^4a)_d—

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

27. The compound of claim 26, wherein R⁴ is —

(CH₂)₄—

, —

(CH₂)₅—

, —

(CH₂)₆—

, —

(CH₂)₇—

, —

(CH₂)₈—

, —

(CH₂)₉—

, or —

(CH₂)₁₀—

.

28. The compound of claim 25, wherein R⁴ is a divalent group of the formula:

—

(R^4a)_d-(A²)_h-(R^4d)_i—

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

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

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

29. The compound of claim 25, wherein R⁴ is a divalent group of the formula:

—

(R^4a)_d-Q-(A²)_h-(R^4d)_i—

where 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.

30. The compound of claim 25, wherein Q is —

N(Q^a)C(O)—

or —

C(O)N(Q^b)-.