Compounds having beta2 adrenergic receptor agonist and muscarinic receptor antagonist activity

• US 20080097105A1
• Filed: 12/11/2007
• Published: 04/24/2008
• Est. Priority Date: 11/21/2003
• Status: Active Grant

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Mathai Mammen, Sarah Dunham
• Inventors: Mammen, Mathai, Dunham, Sarah
• Granted Patent: US 7,842,704 B2
• Time in Patent Office: Days
• US Class Current: 546/209
• 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

1-15. -15. (canceled)

16. The compound of formula I:

18. The compound of claim 16, wherein the compound further possesses D₂ dopamine agonist activity.

39. The compound of claim 16, wherein W is O.

40. The compound of claim 16, wherein a, b, and c are each 0, and R⁵ is hydrogen.

41. The compound of claim 16, wherein d is 0.

42. The compound of claim 16, wherein d is 1;

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

43. The compound of claim 16, wherein m is 2.

44. The compound of claim 16, wherein G¹ is S and G² is NH.

45. The compound of claim 16, wherein R⁶ is hydrogen.

46. The compound of claim 16, wherein R⁶ is hydroxy.

47. The compound of claim 16, 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, (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.

48. The compound of claim 47, wherein R⁴ is a divalent group of the formula:

—

(R^4a)_d—

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

49. The compound of claim 48, wherein R⁴ is —

(CH₂)₄—

, —

(CH₂)₅—

, —

(CH₂)₆—

, —

(CH₂)₇—

, —

(CH₂)₈—

, —

(CH₂)₉—

, and —

(CH₂)₁₀—

.

50. The compound of claim 47, 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.

51. The compound of claim 47, 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.

52. The compound of claim 47, wherein Q is —

N(Q^a)C(O)—

or —

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

17. The compound of formula I:

53. The compound of claim 17, wherein the compound further possesses D₂ dopamine agonist activity.

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

55. The compound of claim 17, wherein a, b, and c are each 0, and R⁵ is hydrogen.

56. The compound of claim 17, wherein d is 0.

57. The compound of claim 17, wherein d is 1;

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

58. The compound of claim 17, wherein m is 2.

59. The compound of claim 17, wherein G¹ is S and G² is NH.

60. The compound of claim 17, wherein R⁶ is hydrogen.

61. The compound of claim 17, wherein R⁶ is hydroxy.

62. The compound of claim 17, 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, (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.

63. The compound of claim 62, wherein R⁴ is a divalent group of the formula:

—

(R^4a)_d—

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

64. The compound of claim 63, wherein R⁴ is —

(CH₂)₄—

, —

(CH₂)₅—

, —

(CH₂)₆—

, —

(CH₂)₇—

, —

(CH₂)₈—

, —

(CH₂)₉—

, and —

(CH₂)₁₀—

.

65. The compound of claim 62, 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.

66. The compound of claim 62, 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.

67. The compound of claim 62, wherein Q is —

N(Q^a)C(O)—

or —

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

19-38. -38. (canceled)