Substituted piperidine compounds and methods of their use
View Patent ↗Certain 4-aryl-piperidine compounds, including N-substituted 9β-substituted-5-(3-substituted-phenyl)morphans and N-substituted octahydro-4a-(3-hydroxyphenyl)-10a-methyl-benzo[g]isoquinolines, pharmaceutical compositions, and methods of their use, inter alia, as opioid antagonists are disclosed.
1. A compound of formula I:
wherein:
R 1 is —OR 7 , —NR 7 R 8 , —COOR 7 , —CONR 7 R 8 , or —CH 2 OH;
each R 7 is independently H, alkyl, cycloalkyl, alkylcycloalkyl, or aralkyl;
each R 8 is independently H, alkyl, aralkyl, or aryl;
R 2 and R 3 together with the carbon atoms to which they are attached form a fused carbocycle, R 4 is alkyl, and R 5 is H;
R 6 is H or —(CHR 9 ) m W;
each R 9 is independently H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl or heteroaryl;
W is H, alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, alkylheterocycloalkyl, aryl, heteroaryl, —CH 2 OH, —CH 2 OR 7 , or —C(═O)R 10 ;
R 10 is —OR 7 or —NR 7 R 11 ;
R 11 is H, alkyl, aralkyl, aryl or —(CHR 9 ) n C(═O)R 12 ;
R 12 is —OR 7 or —NR 7 R 8 ;
m is an integer from 1 to 4; and
n is an integer from 1 to 4;
provided that:
(1) when R 1 is —OCH 3 , R 4 is CH 3 , R 5 is H, and R 2 and R 3 together with the carbon atoms to which they are attached form unsubstituted tetrahydronaphthalene, then W is other than H, alkyl, or phenyl;
(2) when R 1 is —OH, then W is heterocycloalkyl, alkylheterocycloalkyl, —CH 2 OH, or —C(═O)R 10 ; and
(3) when R 1 is —OH and W is heterocycloalkyl or alkylheterocycloalkyl in which the heterocyclic ring moiety of the heterocycloalkyl or alkylheterocycloalkyl contains only one heteroatom, wherein the heteroatom is nitrogen, then the heterocyclic ring moiety is connected to —(CHR 9 ) m — through a heterocyclic ring carbon atom;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
2. A compound according to claim 1 , wherein R 1 is —OR 7 , —NR 7 R 8 , or —CONR 7 R 8 .
3. A compound according to claim 2 , wherein R 1 is —OH, —NHR 8 , or —CONHR 8 .
4. A compound according to claim 1 , wherein R 6 is —(CHR 9 ) m W.
5. A compound according to claim 4 , wherein:
R 6 is:
and
R 9a is H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl or heteroaryl.
6. A compound according to claim 5 , wherein:
R 6 is:
7. A compound according to claim 5 , wherein:
R 6 is:
8. A compound according to claim 5 , wherein W is aryl, —CH 2 OH, —CH 2 OR 7 , or —C(═O)R 10 .
9. A compound according to claim 8 , wherein W is aryl, —CH 2 OH, or —C(═O)OH.
10. A compound according to claim 8 , wherein W is —C(═O)NR 7 R 11 .
11. A compound according to claim 10 , wherein W is —C(═O)NHR 11 .
12. A compound according to claim 11 , wherein R 11 is —(CHR 9 ) n C(═O)R 12 .
13. A compound according to claim 12 , wherein R 11 is —(CHR 9 ) n C(═O)OH.
14. A compound according to claim 1 , wherein m is 1 or 2.
15. A compound according to claim 1 , wherein n is 1 or 2.
16. A compound according to claim 15 , wherein n is 1.
17. A compound according to claim 1 , wherein the fused carbocycle is tetrahydroindene, tetrahydronaphthalene, or tetrahydroanthracene.
18. A compound according to claim 17 , wherein the fused carbocycle is tetrahydronaphthalene.
19. A compound according to claim 18 , of formula IV:
20. A compound according to claim 19 , of formula Va or Vb:
21. A compound according to claim 20 , wherein R 4 is methyl.
22. A compound according to claim 21 , wherein:
R 6 is:
and
R 9a is H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl or heteroaryl.
23. A compound according to claim 22 , wherein:
R 6 is:
24. A compound according to claim 22 , wherein:
R 6 is:
25. A compound according to claim 24 , of formula Va, wherein:
R 1 and R 10 are each —OR 7 ;
R 4 is methyl;
R 7 and R 9 are each H;
R 9a is benzyl;
W is —C(═O)R 10 ; and
m is 2.
26. A compound according to claim 24 , of formula Va, wherein:
R 1 and R 12 are each —OR 7 ;
R 4 is methyl;
R 7 and R 9 are each H;
R 9a is benzyl;
W is —C(═O)R 10 ;
R 10 is —NR 7 R 11 ;
R 11 is —(CHR 9 ) n C(═O)R 12 ;
n is 1; and
m is 2.
27. A compound according to claim 22 , of formula Vb, wherein:
R 1 is C(═O)NR 7 R 8 ;
R 4 is methyl;
R 7 , R 8 , R 9 , and R 9a are each H;
W is phenyl; and
m is 2.
28. A compound according to claim 1 , wherein the compound is:
2-benzyl-3-[4a-(3-hydroxy-phenyl)-10a-methyl-3,4,4a,5,10,10a-hexahydro-1H-benzo[g]isoquinolin-2-yl]-propionic acid;
{2-benzyl-3-[4a-(3-hydroxy-phenyl)-10a-methyl-3,4,4a,5,10,10a-hexahydro-1H-benzo[g]isoquinolin-2-yl]-propionylamino}-acetic acid; or
3-(10a-methyl-2-phenethyl-1,3,4,5,10,10a-hexahydro-2H-benzo[g]isoquinolin-4-a-yl)-benzamide;
or a stereoisomer thereof.
29. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier; and
an effective amount of a compound according to claim 1 .
30. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier;
an effective amount of at least one opioid; and
an effective amount of a compound according to claim 1 .
31. A pharmaceutical composition according to claim 30 ,
wherein the opioid is alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil, tramadol or mixtures thereof.
32. A method of binding opioid receptors in a patient in need thereof, comprising the step of:
administering to the patient a composition comprising an effective amount of a compound according to claim 1 .
33. A method according to claim 32 , wherein the compound binds μ opioid receptors.
34. A method according to claim 33 , wherein the μ opioid receptors are located in the central nervous system.
35. A method according to claim 33 , wherein the μ opioid receptors are located peripherally to the central nervous system.
36. A method according to claim 32 , wherein the compound binds κ opioid receptors.
37. A method according to claim 36 , wherein the κ opioid receptors are located in the central nervous system.
38. A method according to claim 36 , wherein the κ opioid receptors are located peripherally to the central nervous system.
39. A method according to claim 32 , wherein the compound binds δ opioid receptors.
40. A method according to claim 39 , wherein the δ opioid receptors are located in the central nervous system.
41. A method according to claim 39 , wherein the δ opioid receptors are located peripherally to the central nervous system.
42. A method according to claim 32 , wherein the binding antagonizes the activity of the opioid receptors.
43. A method according to claim 32 , wherein the compound exhibits activity toward the opioid receptors.
44. A method according to claim 32 , wherein the compound does not substantially cross the blood-brain barrier.
45. A method according to claim 32 , which is for the prevention or treatment of a disease or condition selected from the group consisting of a condition or disease caused by an opioid, gastrointestinal dysfunction, ileus, obesity, and pain.
46. A method according to claim 45 , wherein the condition or disease is caused by an opioid.
47. A method according to claim 46 , wherein the opioid is endogenous.
48. A method according to claim 46 , wherein the opioid is exogenous.
49. A method according to claim 32 , wherein the composition further comprises an effective amount of at least one opioid.
50. A method according to claim 45 , wherein the disease or condition is gastrointestinal dysfunction.
51. A method according to claim 45 , wherein the disease or condition is ileus.
52. A method of claim 51 , wherein the ileus is post-operative ileus.
53. A method according to claim 45 , wherein the disease or condition is obesity.
54. A method according to claim 46 , wherein the disease or condition is a side effect associated with an opioid.
55. A method according to claim 54 , wherein the side effect is selected from the group consisting of constipation, nausea, vomiting, and combinations thereof.
56. A method according to claim 54 , wherein the administering step occurs before, during or after a step of administering at least one opioid.
57. A method according to claim 56 , wherein the opioid is alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil, tramadol or mixtures thereof.
58. A method according to claim 45 , wherein the disease or condition is pain.
59. A method according to claim 58 , wherein the opioid is alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine (pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, propoxyphene, sufentanil, tramadol or mixtures thereof.
60. A compound according to claim 28 which is 2-benzyl-3-[4a-(3-hydroxy-phenyl)-10a-methyl-3,4,4a,5,10,10a-hexahydro-1H-benzo[g]isoquinolin-2-yl]-propionic acid or a stereoisomer thereof.
61. A compound according to claim 28 which is {2-benzyl-3-[4a-(3-hydroxy-phenyl)-10a-methyl-3,4,4a,5,10,10a-hexahydro-1H-benzo[g]isoquinolin-2-yl]-propionylamino}-acetic acid or a stereoisomer thereof.
62. A compound according to claim 28 which is 3-(10a-methyl-2-phenethyl-1,3,4,5,10,10a-hexahydro-2H-benzo[g]isoquinolin-4a-yl)-benzamide or a stereoisomer thereof.