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US 7,732,441 B2Granted
Azabicycloalkane compounds
AssigneeTheravance, Inc.
InventorsMathai Mammen, Adam Hughes
Life of this patent
Estimating the term…
Abstract
This invention provides compounds of formula I: wherein R1, R2, R3, R4, R5, R6 and R7 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 agonist and muscarinic receptor antagonist activity. Such compounds are useful for treating pulmonary disorders, such as chronic obstructive pulmonary disease and asthma.
Claims18
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:
- wherein
- R1 represents —CH2CH2—, —CH═CH—, —CH2CH2CH2—, —CH2CH(OCH3)— or
- R2 represents an electron pair or (1-6C)alkyl which is unsubstituted or substituted with a hydroxy group or from 1 to 3 fluoro substituents;
- provided that when R2 is an alkyl group, the nitrogen atom to which it is attached is positively charged and a pharmaceutically acceptable anion, X−, is present;
- R3 represents —OC(O)CR3aR3bR3c or —NHC(O)R3d;
- R3a represents hydrogen, hydroxy, (1-4C)alkyl or hydroxy(1-4C)alkyl;
- R3b represents phenyl, (3-6C)cycloalkyl, (3-5C)heteroaryl or (3-5C)heterocyclyl;
- wherein each phenyl, cycloalkyl, heteroaryl and heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents selected independently from halo, (1-4C)alkyl and (1-4C)alkoxy;
- and wherein the heteroaryl and heterocyclyl groups contain 1 or 2 ring heteroatoms selected independently from oxygen, nitrogen and sulfur;
- R3c represents hydrogen, phenyl, (3-6C)cycloalkyl, (3-5C)heteroaryl or (3-5C)heterocyclyl;
- wherein each phenyl, cycloalkyl, heteroaryl and heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents selected independently from halo, (1-4C)alkyl and (1-4C)alkoxy;
- and wherein the heteroaryl and heterocyclyl groups contain 1 or 2 ring heteroatoms selected independently from oxygen, nitrogen and sulfur;
- or R3b and R3c together with R3a and the carbon atom to which they are attached form a group of formula (a):
- wherein R3e represents —O—, —S—, —CH2—, —CH2CH2—, —CH2O—, or —CH2S—;
- R3d represents an indazol-3-yl group which is unsubstituted or substituted with (1-4C)allyl at the 1-position;
- R4 is a divalent group of the formula:
- -(R4a)d-(A1)e-(R4b)f-Q-(R4c)g-(A2)h-(R4d)i-
- wherein
- d, e, f, g, h and i are each independently selected from 0 and 1;
- R4a, R4b, R4c and R4d are each independently selected from (1-10C)allylene, (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 R4d 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)-(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(Qa)C(O)—, —C(O)N(Qb)-, —N(Qc)S(O)2—, —S(O)2N(Qd)-, —N(Qe)C(O)N(Qf)-, —N(Qg)S(O)2N(Qh)-, —OC(O)N(Qi)-, —N(Qj)C(O)O— and —N(Qk);
- Qa, Qb, Qc, Qd, Qe, Qf, Qg, Qh, Qi, Qj and Qk 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 R4b or R4c 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;
- provided that 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 4 to 16;
- R5 represents hydrogen or (1-4C)alkyl;
- R6 is —NR6aCR6b(O) or —CR6cR6dOR6e and R7 is hydrogen;
- or R6 and R7 together form —NR7aC(O)—CR7b═CR7c—, —CR7d═CR7e—C(O)—NR7f—, —NR7gC(O)—CR7hR7i—CR7jR7k— or —CR7lR7m—CR7nR7o—C(O)—NR7p—;
- each of R6a, R6b, R6c, R6d and R6e is independently hydrogen or (1-4C)alkyl;
- and
- each of R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R7l, R7m, R7n, R7o and R7p is independently hydrogen or (1-4C)alkyl;
- or a pharmaceutically acceptable salt or stereoisomer thereof.
31 more elements
A method of treating chronic obstructive pulmonary disease or asthma, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula I:
- wherein
- R1 represents —CH2CH2—, —CH═CH—, —CH2CH2CH2—, —CH2CH(OCH3)— or
- R2 represents an electron pair or (1-6C)alkyl which is unsubstituted or substituted with a hydroxy group or from 1 to 3 fluoro substituents;
- provided that when R2 is an alkyl group, the nitrogen atom to which it is attached is positively charged and a pharmaceutically acceptable anion, X−, is present;
- R3 represents —OC(O)CR3aR3bR3c or —NHC(O)R3d;
- R3a represents hydrogen, hydroxy, (1-4C)alkyl or hydroxy(1-4C)alkyl;
- R3b represents phenyl, (3-6C)cycloalkyl, (3-5C)heteroaryl or (3-5C)heterocyclyl;
- wherein each phenyl, cycloalkyl, heteroaryl and heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents selected independently from halo, (1-4C)alkyl and (1-4C)alkoxy;
- and wherein the heteroaryl and heterocyclyl groups contain 1 or 2 ring heteroatoms selected independently from oxygen, nitrogen and sulfur;
- R3c represents hydrogen, phenyl, (3-6C)cycloalkyl, (3-5C)heteroaryl or (3-5C)heterocyclyl;
- wherein each phenyl, cycloalkyl, heteroaryl and heterocyclyl group is unsubstituted or substituted with from 1 to 4 substituents selected independently from halo, (1-4C)alkyl and (1-4C)alkoxy;
- and wherein the heteroaryl and heterocyclyl groups contain 1 or 2 ring heteroatoms selected independently from oxygen, nitrogen and sulfur;
- or R3b and R3c together with R3a and the carbon atom to which they are attached form a group of formula (a):
- wherein R3e represents —O—, —S—, —CH2—, —CH2CH2—, —CH2O—, or —CH2S—;
- R3d represents an indazol-3-yl group which is unsubstituted or substituted with (1-4C)alkyl at the 1-position;
- R4 is a divalent group of the formula:
- -(R4a)d-(A1)e-(Rb)f-Q-(R4c)g-(A2)h-(R4d)i-
- wherein
- d, e, f, g, h and i are each independently selected from 0 and 1;
- R4a, R4b, R4c and R4d 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 R4d 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(Qa)C(O)—, —C(O)N(Qb)-, —N(Qc)S(O)2—, —S(O)N(Qd)-, —(Qe)C(O)N(Qf)-, —N(Qg)S(O)2N(Qh)-, —OC(O)N(Qi)-, —N(Qj)C(O)O— and —N(Qk);
- Qa, Qb, Qc, Qd, Qe, Qf, Qg, Qh, Qi, Qj and Qk 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 R4b or R4c 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;
- provided that 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 4 to 16;
- R5 represents hydrogen or (1-4C)alkyl;
- R6 is —NR6aCR6b(O) or —CR6cR6dOR6e and R7 is hydrogen;
- or R6 and R7 together form —NR7aC(O)—CR7b═CR7c—, —CR7d═CR7e—C(O)—NR7f—, —NR7gC(O)—CR7hR7i—CR7jR7k— or —CR7lR7m—CR7nR7o—C(O)—NR7p—;
- each of R6a, R6b, R6c, R6d and R6e is independently hydrogen or (1-4C)alkyl;
- and
- each of R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R7l, R7m, R7n, R7o and R7p is independently hydrogen or (1-4C)alkyl;
- or a pharmaceutically acceptable salt or stereoisomer thereof.
31 more elements
Dependencies are inferred from the claim text.