Substituted piperidine compounds and methods of their use
View Patent ↗3,4-Disubstituted-4-aryl-piperidine compounds are disclosed. Pharmaceutical compositions containing the 3,4-disubstituted-4-aryl-piperidine compounds and methods of their pharmaceutical uses are also disclosed. The compounds disclosed are useful, inter alia, as antagonists of opioid receptors.
1. A compound according of formula I:
wherein:
R 1 is —C(═O)OR 5 , —C(═O)NR 6 R 7 , or —NR 6 R 7 ;
R 2 and R 3 are each independently alkyl or alkenyl;
R 4 is:
H,
cycloalkyl,
heterocycloalkyl, or
C 1-10 alkyl which is substituted with at least one:
substituted aryl, wherein at least one of said aryl substituents is other than OH, nitro, amino, halo, CN, CH 2 CN, CONH 2 , C 1-4 alkyl, C 1-4 alkoxy, or C 1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms),
aryloxyaryl,
-aryl-N(H)R b ,
-aryl-N(R b )R b ,
heteroarylaryl,
alkoxyaryl, wherein the carbon chain of said alkoxy is interrupted by a nitrogen atom,
substituted alkoxyaryl, provided that when one or more substituents are present on the alkoxy group, at least one of said substituents is other than halo,
substituted cycloalkyl,
RS(═O) p substituted heteroaryl,
RS(═O) p substituted heterocycloalkyl,
RS(═O) p substituted aryl,
heterocycloalkylheteroaryl,
heteroarylheteroaryl,
bicycloalkyl,
bicycloalkenyl,
carboxy,
—CO 2 R a ,
—C(═O)N(R 6a )—R 6b —CO 2 H,
—C(═O)N(R 6a )—R 6b —CO 2 R,
—C(═O)N(R 6a )—R 6b —C(═O)NR 7a R 7b ,
—N(R 7c )C(═O)R 7d ,
—N(R 7c )S(═O) 2 R 7d ,
aralkoxyaryl,
substituted arylheteroaryl, or
substituted alkoxyheteroaryl, provided that when one or more substituents are present on the alkoxy group, at least one of said substituents is other than halo;
p is 0, 1, or 2;
R is alkyl, aralkyl, or aryl;
R a is H, alkyl, alkenyl, cycloalkyl, aryl, or heteroaryl, provided that R a is not C 1-6 alkyl;
each R b is independently alkyl, cycloalkyl, aralkyl, or aryl,
R 6a is H, alkyl, aralkyl, cycloalkyl, alkenyl, aryl, heteroaralkyl, or heteroaryl;
R 6b is lower alkylene, or lower aralkylene or, together with the nitrogen atom to which they are attached, R 6a and R 6b form a 4- to 7-membered heterocycloalkyl ring;
R 7a and R 7b are each independently H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aralkyl, or aryl, or together with the nitrogen atom to which they are attached, R 7a and R 7b form a 4- to 7-membered heterocycloalkyl ring, provided that at least one of R 7a and R 7b is other than H;
R 7c and R 7d are each independently H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aralkyl, or aryl;
R 5 is H or alkyl; and
each R 6 and R 7 is independently H, alkyl, or —C(═O)R, or, together with the nitrogen atom to which they are attached, R 6 and R 7 form a 4- to 7-membered heterocycloalkyl ring, provided that no more than one of R 6 and R 7 is —C(═O)R, and provided that when R 1 is NR 6 R 7 , R 4 can also be aralkyl;
provided that when R 4 is H and R 2 and R 3 are each independently alkyl, then R 1 is —C(═O)NR 6 R 7 or —NR 6 R 7 , wherein at least one of R 6 and R 7 is —C(═O)R, or, R 6 and R 7 taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocycloalkyl ring;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof, provided that R 2 and R 3 are not in the cis stereoisomer conformation when both R 2 and R 3 are methyl.
2. A compound according to claim 1 , wherein said compound is a compound of formula Ia:
3. A compound according to claim 2 , wherein R 2 is methyl.
4. A compound according to claim 3 , wherein R 3 is methyl.
5. A compound according to claim 4 , wherein said compound is a compound of formula IIa:
wherein:
R 8 is alkyl, aralkyl, cycloalkyl, alkylcycloalkyl, aryl, heteroaryl, or heteroaralkyl;
R 9 is H, alkyl, alkenyl, cycloalkyl, aryl, or heteroaryl provided that R 9 is not C 1-6 alkyl; and
n is an integer from 1 to 3.
6. A compound according to claim 5 , wherein said compound is a compound of formula IIIa:
7. A compound selected from the group consisting of:
3-(3R,4R-dimethyl-piperidin-4-yl)-benzoic acid;
3-(3R,4R-dimethyl-[1,4′]bipiperidinyl-4-yl)-benzoic acid; and
3-(3R,4R-dimethyl-piperidin-4-yl)-benzamide;
or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier; and
a therapeutically effective amount of a compound according to claim 1 .
9. A pharmaceutical composition according to claim 8 , further comprising a therapeutically effective amount of at least one opioid.
10. A pharmaceutical composition according to claim 9 , wherein said opioid is selected from 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.
11. A method for treating gastrointestinal dysfunction, comprising the step of:
administering to a patient in need thereof, an effective amount of a compound according to claim 1 .
12. A method for treating ileus, comprising the step of:
administering to a patient in need thereof, an effective amount of a compound according to claim 1 .
13. A method for treating a side effect associated with an opioid, comprising the step of:
administering to a patient in need thereof, an effective amount of a compound according to claim 1 .
14. A method according to claim 13 , further comprising administering to the patient an effective amount of at least one opioid.
15. A method according to claim 13 , wherein said side effect is selected from constipation, nausea or vomiting.
16. A method according to claim 13 , wherein said administering step occurs before, during or after a step of administering at least one opioid.
17. A method of treating pain, comprising the step of:
administering to a patient in need thereof, an effective amount of an opioid; and
an effective amount of a compound according to claim 1 .
18. A method according to claim 14 , wherein said opioid is selected from 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.
19. A method according to claim 17 , wherein said opioid is selected from 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.
20. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier; and
a therapeutically effective amount of a compound according to claim 7 .
21. A pharmaceutical composition according to claim 20 , further comprising a therapeutically effective amount of at least one opioid.
22. A pharmaceutical composition according to claim 21 , wherein said opioid is selected from 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.
23. A method for treating gastrointestinal dysfunction, comprising the step of:
administering to a patient in need thereof, an effective amount of a compound according to claim 7 .
24. A method for treating ileus, comprising the step of:
administering to a patient in need thereof, an effective amount of a compound according to claim 7 .
25. A method for treating a side effect associated with an opioid, comprising the step of:
administering to a patient in need thereof, an effective amount of a compound according to claim 7 .
26. A method according to claim 25 , further comprising administering to the patient an effective amount of at least one opioid.
27. A method according to claim 25 , wherein said side effect is selected from constipation, nausea or vomiting.
28. A method according to claim 25 , wherein said administering step occurs before, during or after a step of administering at least one opioid.
29. A method of treating pain, comprising the step of:
administering to a patient in need thereof, an effective amount of an opioid; and
an effective amount of a compound according to claim 7 .
30. A method according to claim 29 , wherein said opioid is selected from 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.
31. A method of binding opioid receptors in a patient in need thereof, comprising the step of:
administering to said patient a therapeutically effective amount of a compound according of formula Ib:
wherein:
R 1 is —C(═O)OR 5 , —C(═O)NR 6 R 7 , —NR 6 R 7 , or —CH 2 OR 5 ;
R 2 and R 3 are each independently alkyl or alkenyl;
R 4 is:
H,
cycloalkyl,
heterocycloalkyl, or
C 1-10 alkyl which is substituted with at least one:
substituted aryl, wherein at least one of said aryl substituents is other than OH, nitro, amino, halo, CN, CH 2 CN, CONH 2 , C 1-4 alkyl, C 1-4 alkoxy, or C 1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms),
aryloxyaryl,
-aryl-N(H)R b ,
-aryl-N(R b )R b ,
heteroarylaryl,
alkoxyaryl, wherein the carbon chain of said alkoxy is interrupted by a nitrogen atom,
substituted alkoxyaryl, provided that when one or more substituents are present on the alkoxy group, at least one of said substituents is other than halo,
substituted cycloalkyl,
RS(═O) p substituted heteroaryl,
RS(═O) p substituted heterocycloalkyl,
RS(═O) p substituted aryl,
heterocycloalkylheteroaryl,
heteroarylheteroaryl,
bicycloalkyl,
bicycloalkenyl,
carboxy,
—CO 2 R a ,
—C(═O)N(R 6a )—R 6b —CO 2 H,
—C(═O)N(R 6a )—R 6b CO 2 R,
—C(═O)N(R 6a )—R 6b —C(═)NR 7a R 7b ,
—N(R 7c )C(═O)R 7d ,
—N(R 7c )S(═O) 2 R 7d ,
aralkoxyaryl,
substituted arylheteroaryl, or
substituted alkoxyheteroaryl, provided that when one or more substituents are present on the alkoxy group, at least one of said substituents is other than halo;
p is 0, 1, or 2;
R is alkyl, aralkyl, or aryl;
R a is H, alkyl, alkenyl, cycloalkyl, aryl, or heteroaryl, provided that R a is not C 1-6 alkyl;
each R b is independently alkyl, cycloalkyl, aralkyl, or aryl,
R 6a is H, alkyl, aralkyl, cycloalkyl, alkenyl, aryl, heteroaralkyl, or heteroaryl;
R 6b is lower alkylene, or lower aralkylene or, together with the nitrogen atom to which they are attached, R 6a and R 6b form a 4- to 7-membered heterocycloalkyl ring;
R 7a and R 7b are each independently H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aralkyl, or aryl, or together with the nitrogen atom to which they are attached, R 7a and R 7b form a 4- to 7-membered heterocycloalkyl ring, provided that at least one of R 7a and R 7b is other than H;
R 7c and R 7d are each independently H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aralkyl, or aryl;
R 5 is H or alkyl; and
each R 6 and R 7 is independently H, alkyl, or —C(═O)R, or, together with the nitrogen atom to which they are attached, R 6 and R 7 form a 4- to 7-membered heterocycloalkyl ring, provided that no more than one of R 6 and R 7 is —C(═O)R, and provided that when R 1 is NR 6 R 7 , R 4 can also be aralkyl;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof, provided that R 2 and R 3 are not in the cis stereoisomer conformation when both R 2 and R 3 are methyl.
32. A method according to claim 31 , wherein said compound binds μ opioid receptors.
33. A method according to claim 32 , wherein said μ opioid receptors are located in the central nervous system.
34. A method according to claim 32 , wherein said μ opioid receptor are located peripherally to the central nervous system.
35. A method according to claim 31 , wherein said compound binds κ opioid receptors.
36. A method according to claim 35 , wherein said κ opioid receptors are located in the central nervous system.
37. A method according to claim 35 , wherein said κ opioid receptors are located peripherally to the central nervous system.
38. A method according to claim 31 , wherein said binding antagonizes the activity of said opioid receptors.
39. A method according to claim 31 , wherein said compound exhibits activity toward said opioid receptors.
40. A method according to claim 31 , wherein said compound does not substantially cross the blood-brain barrier.
41. A method according to claim 31 , wherein said patient is in need of treatment of a condition or disease caused by an opioid.
42. A method according to claim 41 , wherein said opioid is endogenous.
43. A method according to claim 41 , wherein said opioid is exogenous.
44. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier; and
a therapeutically effective amount of a compound of formula Ic:
wherein:
R 1 is —C(═O)OR 5 , —C(═O)NR 6 R 7 , —NR 6 R 7 , or —CH 2 OR 5 ;
R 2 and R 3 are each independently alkyl or alkenyl;
R 5 is H or alkyl;
each R 6 and R 7 is independently H, alkyl, or —C(═O)R, or, together with the nitrogen atom to which they are attached, R 6 and R 7 form a 4- to 7-membered heterocycloalkyl ring, provided that no more than one of R 6 and R 7 is —C(═O)R; and
R is alkyl, aralkyl, or aryl;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof, provided that R 2 and R 3 are not in the cis stereoisomer conformation when both R 2 and R 3 are methyl.
45. A pharmaceutical composition according to claim 44 , further comprising a therapeutically effective amount of at least one opioid.
46. A pharmaceutical composition according to claim 45 , wherein said opioid is selected from 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.
47. A method for treating gastrointestinal dysfunction, comprising the step of:
administering to a patient in need thereof an effective amount of a compound of formula Ic:
wherein:
R 1 is —C(═O)OR 5 , —C(═O)NR 6 R 7 , —NR 6 R 7 , or —CH 2 OR 5 ;
R 2 and R 3 are each independently alkyl or alkenyl;
R 5 is H or alkyl;
each R 6 and R 7 is independently H, alkyl, or —C(═O)R, or, together with the nitrogen atom to which they are attached, R 6 and R 7 form a 4- to 7-membered heterocycloalkyl ring, provided that no more than one of R 6 and R 7 is —C(═O)R; and
R is alkyl, aralkyl, or aryl;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof, provided that R 2 and R 3 are not in the cis stereoisomer conformation when both R 2 and R 3 are methyl.
48. A method for treating ileus, comprising the step of:
administering to a patient in need thereof an effective amount of a compound of formula Ic:
wherein:
R 1 is —C(═O)OR 5 , —C(═O)NR 6 R 7 , —NR 6 R 7 , or —CH 2 OR 5 ;
R 2 and R 3 are each independently alkyl or alkenyl;
R 5 is H or alkyl;
each R 6 and R 7 is independently H, alkyl, or —C(═O)R, or, together with the nitrogen atom to which they are attached, R 6 and R 7 form a 4- to 7-membered heterocycloalkyl ring, provided that no more than one of R 6 and R 7 is —C(═O)R; and
R is alkyl, aralkyl, or aryl;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof, provided that R 2 and R 3 are not in the cis stereoisomer conformation when both R 2 and R 3 are methyl.
49. A method for treating a side effect associated with an opioid, comprising the step of:
administering to a patient in need thereof an effective amount of a compound of formula Ic:
wherein:
R 1 is —C(═O)OR 5 , —C(═O)NR 6 R 7 , —NR 6 R 7 , or —CH 2 OR 5 ;
R 2 and R 3 are each independently alkyl or alkenyl;
R 5 is H or alkyl;
each R 6 and R 7 is independently H, alkyl, or —C(═O)R, or, together with the nitrogen atom to which they are attached, R 6 and R 7 form a 4- to 7-membered heterocycloalkyl ring, provided that no more than one of R 6 and R 7 is —C(═O)R; and
R is alkyl, aralkyl, or aryl;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof, provided that R 2 and R 3 are not in the cis stereoisomer conformation when both R 2 and R 3 are methyl.
50. A method according to claim 49 , further comprising administering to the patient an effective amount of at least one opioid.
51. A method according to claim 49 , wherein said side effect is selected from constipation, nausea or vomiting.
52. A method according to claim 49 , wherein said administering step occurs before, during or after a step of administering at least one opioid.
53. A method of treating pain, comprising the step of:
administering to a patient in need thereof an effective amount of an opioid; and
an effective amount of a compound of formula Ic:
wherein:
R 1 is —C(═O)OR 5 , —C(═O)NR 6 R 7 , —NR 6 R 7 , or —CH 2 OR 5 ;
R 2 and R 3 are each independently alkyl or alkenyl;
R 5 is H or alkyl;
each R 6 and R 7 is independently H, alkyl, or —C(═O)R, or, together with the nitrogen atom to which they are attached, R 6 and R 7 form a 4- to 7-membered heterocycloalkyl ring, provided that no more than one of R 6 and R 7 is —C(═O)R; and
R is alkyl, aralkyl, or aryl;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof, provided that R 2 and R 3 are not in the cis stereoisomer conformation when both R 2 and R 3 are methyl.
54. A method according to claim 50 , wherein said opioid is selected from 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.
55. A method according to claim 53 , wherein said opioid is selected from 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.