Claims for Patent: 7,491,736

Summary for Patent: 7,491,736

Title:	Biphenyl compounds useful as muscarinic receptor antagonists
Abstract:	This invention provides compounds of formula I: ##STR00001## wherein a, b, c, d, m, n, p, s, t, W, Ar.sup.1, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, and R.sup.8 are as defined in the specification. The compounds of formula I are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat pulmonary disorders.
Inventor(s):	Mammen; Mathai (Redwood Shores, CA), Ji; Yu-Hua (Redwood City, CA), Mu; YongQi (Los Altos, CA), Husfeld; Craig (Redwood City, CA), Li; Li (Sunnyvale, CA)
Assignee:	Theravance, Inc. (South San Francisco, CA)
Application Number:	11/880,007
Patent Claims:	1. A method of producing bronchodilation in a patient, the method comprising administering to a patient a bronchodilation-producing amount of a compound having the formula: ##STR00037## wherein: a is 0 or an integer of from 1 to 5; each R.sup.1 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, --OR.sup.1a, --C(O)OR.sup.1b, --SR.sup.1c, --S(O)R.sup.1d, --S(O).sub.2R.sup.1e, --NR.sup.1fR.sup.1g, --NR.sup.1hS(O).sub.2R.sup.1i, and --NR.sup.1jC(O)R.sup.1k; where each of R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, R.sup.1e, R.sup.1f, R.sup.1g, R.sup.1h, R.sup.1i, R.sup.1j, and R.sup.1k is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl; b is0 or an integer of from 1 to 4; each R.sup.2 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, --OR.sup.2a, --C(O)OR.sup.2b, --SR.sup.2c, --S(O)R.sup.2d, --S(O).sub.2R.sup.2e, --NR.sup.2fR.sup.2g, --NR.sup.2hS(O).sub.2R.sup.2i, and --NR.sup.2jC(O)R.sup.2k; where each of R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.2e, R.sup.2f, R.sup.2g, R.sup.2h, R.sup.2i, R.sup.2j, and R.sup.2k is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl; W represents O or NW.sup.a, where W.sup.a is hydrogen or (1-4C)alkyl; c is 0 or an integer from 1 to 5; each R.sup.3 independently represents (1-4C)alkyl or two R.sup.3 groups are joined to form (1-3C)alkylene, (2-3C)alkenylene or oxiran-2,3-diyl; m is 0 or 1; R.sup.4 is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl; s is 0, 1 or 2; Ar.sup.1 represents a phenylene group or a (3-5C)heteroarylene group containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen or sulfur; wherein the phenylene or heteroarylene group is substituted with (R.sup.5).sub.q where q is 0 or an integer from 1 to 4 and each R.sup.5 is independently selected from halo, hydroxy, (1-4C)alkyl or (1-4C)alkoxy; t is 0, 1 or 2; n is 0 or an integer from 1 to 3; d is 0 or an integer from 1 to 4; each R.sup.6 independently represents fluoro or (1-4C)alkyl; p is 0 or 1; and R.sup.7 and R.sup.8 are independently hydrogen or (1-4C)alkyl; wherein each alkyl and alkoxy group in R.sup.1, R.sup.1a-1k, R.sup.2, R.sup.2a-2k, R.sup.3, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 is optionally substituted with 1 to 5 fluoro substituents; or a pharmaceutically acceptable salt or stereoisomer thereof. 2. A method of treating chronic obstructive pulmonary disease or asthma, the method comprising administering to a patient a therapeutically effective amount of a compound having the formula: ##STR00038## wherein: a is 0 or an integer of from 1 to 5; each R.sup.1 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, --OR.sup.1a, --C(O)OR.sup.1b, --SR.sup.1c, --S(O)R.sup.1d, --S(O).sub.2R.sup.1e, --NR.sup.1fR.sup.1g, --NR.sup.1hS(O).sub.2R.sup.1i, and --NR.sup.1jC(O)R.sup.1k; where each of R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, R.sup.1e, R.sup.1f, R.sup.1g, R.sup.1h, R.sup.1i, R.sup.1j, and R.sup.1k is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl; b is 0 or an integer of from 1 to 4; each R.sup.2 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, --OR.sup.2a, --C(O)OR.sup.2b, --SR.sup.2c, --S(O)R.sup.2d, --S(O).sub.2R.sup.2e, --NR.sup.2fR.sup.2g, --NR.sup.2hS(O).sub.2R.sup.2i, and --NR.sup.2jC(O)R.sup.2k; where each of R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.2e, R.sup.2f, R.sup.2g, R.sup.2h, R.sup.2i, R.sup.2j, and R.sup.2k is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl; W represents O or NW.sup.a, where W.sup.a is hydrogen or (1-4C)alkyl; c is 0 or an integer from 1 to 5; each R.sup.3 independently represents (1-4C)alkyl or two R.sup.3 groups are joined to form (1-3C)alkylene, (2-3C)alkenylene or oxiran-2,3-diyl; m is 0 or 1; R.sup.4 is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl; s is 0, 1 or 2; Ar.sup.1 represents a phenylene group or a (3-5C)heteroarylene group containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen or sulfur; wherein the phenylene or heteroarylene group is substituted with (R.sup.5).sub.q where q is 0 or an integer from 1 to 4 and each R.sup.5 is independently selected from halo, hydroxy, (1-4C)alkyl or (1-4C)alkoxy; t is 0, 1 or 2; n is 0 or an integer from 1 to 3; d is 0 or an integer from 1 to 4; each R.sup.6 independently represents fluoro or (1-4C)alkyl; p is 0 or 1; and R.sup.7 and R.sup.8 are independently hydrogen or (1-4C)alkyl; wherein each alkyl and alkoxy group in R.sup.1, R.sup.1a-1k, R.sup.2, R.sup.2a-2k, R.sup.3, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 is optionally substituted with 1 to 5 fluoro substituents; or a pharmaceutically acceptable salt or stereoisomer thereof. 3. The method of claims 1 or 2, wherein the compound is administered by inhalation. 4. The method of claim 3, wherein the compound is administered in the form of an aerosol. 5. The method of claim 3, wherein the compound is administered in the form of a powder. 6. The method of claim 3, wherein the compound is administered in the form of a solution. 7. The method of claim 3, wherein the compound is administered using a nebulizer inhaler. 8. The method of claim 3, wherein the compound is administered using a metered-dose inhaler. 9. The method of claim 3, wherein the compound is administered using a dry powder inhaler. 10. The method of claims 1 or 2, wherein a, b and c each represent 0. 11. The method of claims 1 or 2, wherein W represents O. 12. The method of claims 1 or 2, wherein m is 0, s is 0 and t is 1. 13. The method of claims 1 or 2, wherein the --CONR.sup.7R.sup.8 group is in the para position, d is 0 and n is 2. 14. The method of claims 1 or 2, wherein Ar.sup.1 represents phen-1,3-ylene, phen-1, 4-ylene, 2,4-thienylene or 2,5-thienylene; wherein the phenylene or thienylene group is optionally substituted with one or two R.sup.5 substituents. 15. The method of claim 14, wherein Ar.sup.1 represents phen-1, 4-ylene or 2,4-thienylene, optionally substituted with one or two R.sup.5 substituents. 16. The method of claims 1 or 2, wherein R.sup.4 selected from hydrogen, methyl and ethyl. 17. The method of claims 1 or 2, wherein R.sup.7 is selected from hydrogen, methyl, ethyl, n-propyl and isopropyl; and R.sup.8 is hydrogen. 18. The method of claims 1 or 2, wherein R.sup.7 and R.sup.8 are ethyl. 19. The method of claims 1 or 2, wherein a, b and c each represent 0; W represents O; m is 0; s is 0; t is 1; Ar.sup.1 represents phen-1,4-ylene optionally substituted with one or two R.sup.5 substituents; d is 0; n is 2, the --CONR.sup.7R.sup.8 group is in the para position; and R.sup.8 is hydrogen. 20. The method of claim 19, wherein R.sup.5 is independently selected from halo, (1-4C)alkyl or (1-4C)alkoxy, wherein each alkyl and alkoxy group is optionally substituted with from 1 to 3 fluoro substituents. 21. The method of claims 1 or 2, wherein the compound is selected from: biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piper- idin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]ethylamino}ethyl)piperi- din-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{methyl-[4-(4-methylcarbamoylpiperidin-1-ylmethyl)benzoyl]amino}ethy- l)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-ethylcarbamoylpiperidin-1-ylmethyl) benzoyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{methyl-[4-(4-propylcarbamoylpiperidin-1-ylmethyl)benzoyl]amino- }ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-isopropylcarbamoylpiperidin-1-ylmethyl) benzoyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[4-(4-carbamoylpiperidin-1-ylmethyl)-2-fluorobenzoylamino]ethyl- }piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[2,5-dibromo-4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino- }ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)-2-fluorobenzoyl]methylamino}et- hyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[4-(4-diethylcarbamoylpiperidin-1-ylmethyl)-2-fluorobenzoylamino]eth- yl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-diethylcarbamoylpiperidin-1-ylmethyl)-2-fluorobenzoyl]methyla- mino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-diethylcarbamoylpiperidin-1-ylmethyl) benzoyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(3-(S)-diethylcarbamoylpiperidin-1-ylmethyl)benzoyl]methyla- mino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[4-(2-carbamoyl-piperidin-1-ylmethyl) benzoyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[4-(4-carbamoyl-piperidin-1-ylmethyl)-2-methoxybenzoyl]methyla- mino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-(4-carbamoylpiperidin-1-ylmethyl)thiophene-2-carbonyl]methylamin- o}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-((R)-3-diethylcarbamoylpiperidin-1-ylmethyl)thiophene-2-carbonyl- ]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-((R)-3-diethylcarbamoylpiperidin-1-ylmethyl)thiophene-2-carbonyl- ]amino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-(4-carbamoylpiperidin-1-ylmethyl)thiophene-2-carbonyl]amino}ethy- l)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-((R)-3-diethylcarbamoylpiperidin-1-ylmethyl)-1H -pyrrole-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-(4-carbamoylpiperidin-1-ylmethyl)-1H-pyrrole-2-carbonyl]methylam- ino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-((R)-3-diethylcarbamoylpiperidin-1-ylmethyl)furan-2-carbonyl]met- hylamino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-(4-diethylcarbamoyl-piperidin-1-ylmethyl)furan-2-carbonyl]methyl- amino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-(4-carbamoylpiperidin-1-ylmethyl)furan-2-carbonyl]-amino}ethyl)p- iperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-((R)-3-diethylcarbamoylpiperidin-1-ylmethyl)furan-2-carbonyl]ami- no}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-[2-({3-[4-(3-carbamoylpiperidin-1-ylmethyl)phenyl]propionyl}methylamino- )ethyl]piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-[2-({3-[4-(4-carbamoylpiperidin-1-ylmethyl)phenyl]propionyl}methylamino- )ethyl]piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{3-[4-(4-carbamoylpiperidin-1-ylmethyl)phenyl]propionylamino}ethyl)p- iperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{3-[4-(4-diethylcarbamoylpiperidin-1-ylmethyl)phenyl]propionylamino}- ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{3-[4-(3-diethylcarbamoylpiperidin-1-ylmethyl)phenyl]propionylamino}- ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[4-(4-carbamoylpiperidin-1-ylmethyl) benzoylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)-2-chloro-benzoyl]methylamino}e- thyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)-2-chloro-5-methoxyberizoyl]met- hylamino}ethyl)piperidin-4-yl ester; and biphenyl-2-ylcarbamic acid 1-[2-({2-[4-(4-carbamoylpiperidin-1-ylmethyl)phenyl]acetyl}methylamino)et- hyl]piperidin-4-yl ester; or a pharmaceutically acceptable salt thereof. 22. The method of claim 21, wherein the compound is biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl) benzoyl]methylamino}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable salt thereof. 23. The method of claims 1 or 2, which further comprises administering a therapeutically effective amount of an agent selected from .beta..sub.2 adrenergic receptor agonists, steroidal anti-inflammatory agents, phosphodiesterase-4 inhibitors, and combinations thereof. 24. The method of claim 23, wherein a .beta..sub.2 adrenergic receptor agonist and a steroidal anti-inflammatory agent are administered.