8-azabicyclo[3.2.1]octane compounds as MU opioid receptor antagonists
AssigneeTheravance, Inc.
InventorsDaniel D. Long, Timothy J. Church, John R. Jacobsen, Lan Jiang, Daisuke Roland Saito, Ioanna Stergiades, Priscilla M. Van Dyke
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Abstract
The invention provides novel 8-azabicyclo[3.2.1]octane compounds of formula (I): wherein R1, R2, R3, A, and G are defined in the specification, or a pharmaceutically-acceptable salt or solvate thereof, that are antagonists at the mu opioid receptor. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat conditions associated with mu opioid receptor activity, and processes and intermediates useful for preparing such compounds.
Claims15
A method of treating a mammal having a medical condition ameliorated by treatment with a mu opioid receptor antagonist, wherein the medical condition is opioid-induced bowel dysfunction or post-operative ileus, the method comprising administering to the mammal a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of formula (I):
- wherein:
- R1 is —ORa or —C(O)NRaRb;
- R2 is selected from cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and phenyl, wherein cyclohexyl and phenyl are each optionally substituted with one or two halo or with C1-3alkyl substituted with two or three halo;
- A is —(CH2)2—, or —CH2—;
- G is —(CH2)2— or —CH2—;
- R3 is selected from —C(O)R4, —S(O)2Rc, —S(O)2NRaRb, and —C(O)NHR5;
- R4 is C3-6cycloalkyl or C1-6alkyl,
- wherein
- C3-6cycloalkyl is optionally substituted with one —ORa, and
- C1-6alkyl is optionally substituted with one or two substituents selected from —ORa, —C(O)ORa, —S(O)2R6, —C(O)NRaRb, —NRaRb, —CN, C3-6cycloalkyl, and phenyl, wherein R6 is C1-3alkyl optionally substituted with R7, wherein R7 is —C(O)ORa;
- and
- R5 is C1-4alkyl, benzo[1.3]dioxol, or —(CH2)q-phenyl, wherein q is 0 or 1 and phenyl is optionally substituted with one or two substituents selected from chloro, fluoro, —OH, and —OCF2;
- or a pharmaceutically-acceptable salt thereof.
A method of reducing or preventing a gastrointestinal side effect associated with use of an opioid agent in a mammal, the method comprising administering to the mammal an opioid agent and a compound of formula (I):
- wherein:
- R1 is —ORa or —C(O)NRaRb;
- R2 is selected from cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and phenyl, wherein cyclohexyl and phenyl are each optionally substituted with one or two halo or with C1-3alkyl substituted with two or three halo;
- A is —(CH2)2—, or —CH2—;
- G is —(CH2)2— or —CH2—;
- R3 is selected from —C(O)R4, —S(O)2Rc, —S(O)2NRaRb, and —C(O)NHR5;
- R4 is C3-6cycloalkyl or C1-6alkyl,
- wherein
- C3-6cycloalkyl is optionally substituted with one —ORa, and
- C1-6alkyl is optionally substituted with one or two substituents selected from —ORa, —C(O)ORa, —S(O)2R6, —C(O)NRaRb, —NRaRb, —CN, C3-6cycloalkyl, and phenyl, wherein R6 is C1-3alkyl optionally substituted with R7, wherein R7 is —C(O)ORa;
- and
- R5 is C1-4alkyl, benzo[1.3]dioxol, or —(CH2)q-phenyl, wherein q is 0 or 1 and phenyl is optionally substituted with one or two substituents selected from chloro, fluoro, —OH, and —OCF2;
- or a pharmaceutically-acceptable salt thereof.
A method of enhancing motility of the gastrointestinal tract in a mammal, the method comprising administering to the mammal a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of formula (I):
- wherein:
- R1 is —ORa or —C(O)NRaRb;
- R2 is selected from cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and phenyl, wherein cyclohexyl and phenyl are each optionally substituted with one or two halo or with C1-3alkyl substituted with two or three halo;
- A is —(CH2)2—, or —CH2—;
- G is —(CH2)2— or —CH2—;
- R3 is selected from —C(O)R4, —S(O)2Rc, —S(O)2NRaRb, and —C(O)NHR5;
- R4 is C3-6cycloalkyl or C1-6alkyl,
- wherein
- C3-6cycloalkyl is optionally substituted with one —ORa, and
- C1-6alkyl is optionally substituted with one or two substituents selected from —ORa, —C(O)ORa, —S(O)2R6, —C(O)NRaRb, —NRaRb, —CN, C3-6cycloalkyl, and phenyl,
- wherein R6 is C1-3alkyl optionally substituted with R7, wherein R7 is —C(O)ORa;
- and
- R5 is C1-4alkyl, benzo[1.3]dioxol, or —(CH2)q-phenyl, wherein q is 0 or 1 and phenyl is optionally substituted with one or two substituents selected from chloro, fluoro, —OH, and —OCF2;
- or a pharmaceutically-acceptable salt thereof.
Dependencies are inferred from the claim text.