8-Azabicyclo[3.2.1]octane compounds as mu opioid receptor antagonists

Abstract

The invention provides novel 8-azabicyclo[3.2.1]octane compounds of formula (I):

Description

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows an x-ray powder diffraction pattern of crystalline 3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide glycolate of the invention.

FIG. 2 shows an x-ray powder diffraction pattern of crystalline 3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide oxalate of the invention.

FIG. 3 shows an x-ray powder diffraction pattern of crystalline 3-endo-(8-{2-[(4,4-difluorocyclohexylmethyl)-(2-hydroxyacetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide phosphate of the invention.

Claims

1. A compound of formula (I):

2. The compound of claim 1 wherein: R2 is C3-12cycloalkyl or C6-10aryl, wherein C3-12cycloalkyl and C6-10aryl are each optionally substituted with one —ORa, with one or two halo, or with one or two C1-3alkyl optionally substituted with 2 or 3 halo;R3 is selected from hydrogen, —C(O)R4, and —C(O)NHR5; andR4 is C3-6cycloalkyl or C1-6alkyl,wherein C1-6alkyl is optionally substituted with one or two —ORa, or with one substituent selected from —C(O)ORa, —S(O)2R6, —C(O)NRaRb, —NRaRb, —NHC(O)NRaRb, C3-6cycloalkyl, -D-(CH2)j—R7, and phenyl, and Ra and Rb are each independently hydrogen or C1-3alkyl.

3. The compound of claim 1 wherein R1 is —ORa or —C(O)NRaRb.

4. The compound of claim 1 wherein 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.

5. The compound of claim 1 wherein A is —(CH2)2—, or —CH2— and G is —(CH2)2— or —CH2—.

6. The compound of claim 1 wherein R3 is selected from —C(O)R4, —S(O)2Rc, and —S(O)2NRaRb;R4 is C3-6cycloalkyl or C1-6alkyl,whereinC3-6cycloalkyl is optionally substituted with one —ORa, andC1-6alkyl 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.

7. The compound of claim 1 wherein R3 is —C(O)NHR5, andR5 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.

8. A compound of formula (I′):

9. The compound of claim 8 wherein R4 is C1-4alkyl optionally substituted with one or two substituents selected from —OH, —OCH3, —S(O)2CH3, —NH2, —NHCH3, and —NH(CH3)2.

10. The compound of claim 8 wherein R2 is cyclohexyl or 4,4-difluorocyclohexyl, and R4 is C1-2alkyl substituted with one or two —OH.

11. The compound of claim 1 wherein the compound is selected from: 3-endo-(8-{2-[cyclohexylmethyl-(2-hydroxyacetyl)-amino]-ethyl}-8-azabicyclo[3.2.1]oct-3 -yl)-benzamide;3-endo-(8-{2-[benzyl-(2-hydroxyacetyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[cyclohexylmethyl-(2-methanesulfonyl-acetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[(2-hydroxyacetyl)phenethylamino]-ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[(4,4-difluorocyclohexylmethyl)-(2-hydroxyacetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-{8-[2-(3-benzo[1,3]dioxol-5-yl-1-cyclohexylmethylureido)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-benzamide;3-endo-{8-[2-(1-cyclohexylmethyl-3-isopropylureido)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-benzamide;3-endo-(8-{3-[cyclohexylmethyl-(2-hydroxy-acetyl)amino]propyl}-8-azabicyclo[3.2.1]oct-3 -yl)-benzamide;3-endo-(8-{2-[cyclohexylmethyl-(4-dimethylamino-butyryl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[benzyl-(2-methanesulfonylacetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[(2,6-difluorobenzyl)-(2-hydroxy-acetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[(2-methanesulfonylacetyl)-(4-trifluoromethyl-benzyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[(2,6-difluorobenzyl)-(2-methanesulfonylacetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3 -yl)-benzamide;3-endo-(8-{3-[benzyl-(2-hydroxyacetyl)amino]-propyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[(4,4-difluorocyclohexylmethyl)-(2-methanesulfonylacetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[[2-(4-fluorophenyl)ethyl]-(2-hydroxyacetyl)amino]-ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[(3-fluorobenzyl)-(2-methanesulfonyl-acetyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[[2-(4-fluorophenyl)ethyl]-(2-methanesulfonyl-acetyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[(4-fluorocyclohexylmethyl)-(2-hydroxyacetyl)amino]-ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[(2-hydroxyacetyl)-(5-hydroxy-tricyclo[3.3.1.1(3,7)]decan-2-ylmethyl)-amino]-ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[cyclohexylmethyl-((S)-3-hydroxy-2-methylaminopropionyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[(2,6-difluorobenzyl)-(2-hydroxy-2-methylpropionyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[(2,6-difluorobenzyl)-(2-methoxyacetyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[(2,6-difluorobenzyl)-((S)-2-hydroxypropionyl)amino]-ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[(2-cyanoacetyl)-(2,6-difluorobenzyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3 -yl)-benzamide;3-endo-(8-{2-[(2,6-difluorobenzyl)-(trans-4-hydroxycyclohexanecarbonyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[cyclopentylmethyl-(2-methanesulfonylacetyl)-amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[cyclopentylmethyl-(2-hydroxyacetyl)amino]-ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[benzyl-((R)-3-hydroxy-2-(S)-hydroxybutyryl)amino]-ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[benzyl-(2,2-dimethylpropionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[benzyl-(2-hydroxy-2-methylpropionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[benzyl-((S)-2-hydroxy-1-oxopropyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{3-[benzyl-((S)-2-hydroxypropionyl)-amino]propyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[cyclohexylmethyl-((S)-4-dimethylamino-2-hydroxy-butyryl)-amino]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-{2-[cyclohexylmethyl-(3-dimethylamino-2-hydroxypropionyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-2-[(4,4-difluorocyclohexylmethyl)-((S)-2-hydroxypropionyl)-amino]ethyl-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;3-endo-(8-2-[cyclohexylmethyl-((S)-2,4-dihydroxybutyryl)amino]ethyl-8-azabicyclo[3.2.1]oct-3-yl)-benzamide; and3-endo-(8-{2-[cyclohexylmethyl-(4-hydroxy-butyryl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;or a pharmaceutically-acceptable salt or solvate thereof.

12. The compound of claim 11 wherein the compound is selected from: 3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamide;3-endo-(8-{2-[(4,4-difluorocyclohexylmethyl)-(2-hydroxyacetyl)amino]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)benzamide; and3-endo-(8-2-[(4,4-difluorocyclohexylmethyl)-((S)-2-hydroxypropionyl)-amino]ethyl-8-azabicyclo[3.2.1]oct-3-yl)-benzamide;or a pharmaceutically-acceptable salt or solvate thereof.

13. The compound of claim 12, wherein the compound is 3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamide glycolate.

14. The compound of claim 12, wherein the compound is 3-endo-(8-{2-[cyclohexylmethyl-((S)-2,3-dihydroxy-propionyl)amino]ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)benzamide oxalate.

15. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

16. A pharmaceutical composition comprising the compound of claim 8 and a pharmaceutically acceptable carrier.

17. A process for preparing a compound of formula (1),

18. A compound of formula (II):

19. The compound of claim 18 wherein R1 is —C(O)NH2;R2 is cyclohexyl or phenyl wherein cyclohexyl and phenyl are each optionally substituted with one or two halo;G is —CH2—; andA is —CH2—.

20. A compound of formula (III):

21. The compound of claim 20 wherein R1 is —OH or —C(O)NH2.

22. A method of treating a mammal having a medical condition associated with mu opioid receptor activity, the method comprising administering to the mammal, a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of claim 1.

23. The method of claim 22 wherein the medical condition is selected from opioid-induced bowel dysfunction and post-operative ileus.

24. A method of treating a mammal having a medical condition associated with mu opioid receptor activity, the method comprising administering to the mammal, a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of claim 8.

25. The method of claim 24 wherein the medical condition is selected from opioid-induced bowel dysfunction and post-operative ileus.

26. A method of studying a biological system or sample comprising a mu opioid receptor, the method comprising: (a) contacting the biological system or sample with a compound of claim 1; and(b) determining the effect caused by the compound on the biological system or sample.