Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity

• US 7,838,535 B2
• Filed: 12/11/2007
• Issued: 11/23/2010
• 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: Dunham, Sarah, Mammen, Mathai
• Primary Examiner(s): SHIAO, REI TSANG
• Application Number:
  US12/001,363
• Publication Number:
  US 20080096911A1
• Time in Patent Office: 1,078 Days
• Field of Search: 514/323, 514/324, 514/320
• 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 method of producing bronchodilation in a patient, the method comprising administering to a patient a bronchodilation-producing amount of a compound of formula I:

3. The method of claim 1, wherein a dose of the compound for providing bronchodilation ranges from about 10 μ

g/day to about 200 μ

g/day.

2. A method of treating chronic obstructive pulmonary disease or asthma, the method comprising administering to a patient in need of treatment a compound of formula I:

4. The method of claim 2, wherein the compound is administered by inhalation.

5. The method of claim 2, wherein the compound is administered in multiple doses per day.

6. The method of claim 2, wherein the compound is administered in a single daily dose.

7. The method of claim 2, wherein a dose of the compound for treating chronic obstructive pulmonary disease or asthma ranges from about 10 μ

g/day to about 200 μ

g/day.

8. The method 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^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.

9. The method of claim 8, wherein R⁴ is a divalent group of the formula:

—

(R^4a)_d—

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

10. The method of claim 8, wherein R⁴ is —

(CH₂)₄—

, —

(CH₂)₅—

, —

(CH₂)₆—

, —

(CH₂)₇—

, —

(CH₂)₈—

, —

(CH₂)₉, or —

(CH₂)₁₀—

.

11. The method of claim 8, 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.

12. The method of claim 8, 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.

13. The method of claim 8, wherein R⁴ is a divalent group of the formula:

—

(R^4a)_d-(A ¹)_e-(R^4b)_f-Q-(R^4c)_g-(A²)_h-(R^4d)_i—

where Q is —

N(Q^a)C(O)—

or —

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

14. The method of claim 2, wherein the compound is a compound of formula Ia:

15. The method of claim 2, wherein the compound is a compound of formula Ib:

16. The method of claim 2, wherein the compound is a compound of formula Ic:

17. The method of claim 2, wherein the compound is a compound of formula Id: