Spirocyclic heterocyclic derivatives and methods of their use
View Patent ↗Spirocyclic heterocyclic derivatives, pharmaceutical compositions containing these compounds, and methods for their pharmaceutical use are disclosed. In certain embodiments, the spirocyclic heterocyclic derivatives are ligands of the δ opioid receptor and may be useful, inter alia, for treating and/or preventing pain, anxiety, gastrointestinal disorders, and other δ opioid receptor-mediated conditions.
1. A compound of formula XIVA:
wherein:
W 2 is aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with 0-3 groups selected independently from hydroxy, aminocarbonyl (—C(═O)—NH 2 ), N-alkylaminocarbonyl (—C(═O)—NH(alkyl)), and N,N-dialkylaminocarbonyl (—C(═O)—N(alkyl)(alkyl));
R 23 and R 24 are each independently H or alkyl, provided that at least one of R 23 and R 24 is alkyl;
A 2 and B 2 are each H, or together form a double bond; and
X 2 is —CH 2 — or —O—;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
2. A compound according to claim 1 , wherein W 2 is:
3. A compound according to claim 2 , wherein W 2 is:
4. A compound according to claim 1 , wherein X 2 is —O—.
5. A compound according to claim 1 , wherein A 2 and B 2 together form a double bond.
6. A compound according to claim 1 , of formula XVA:
7. A compound according to claim 1 , of formula XVIA:
8. A compound of formula XVII:
wherein:
W 2 is aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with 0-3 groups selected independently from hydroxy, aminocarbonyl (—C(═O)—NH 2 ), N-alkylaminocarbonyl (—C(═O)—NH(alkyl)), and N,N-dialkylaminocarbonyl (—C(═O)—N(alkyl)(alkyl));
R 23 and R 24 are each independently H or alkyl;
A 2 and B 2 are each H, or together form a double bond;
X 2 is —CH 2 — or —O—; and
J 2 when taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with 0-3 groups selected independently from halo, hydroxy, and —S(═O) 2 -alkyl;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;
provided that:
when W 2 is para-diethylaminocarbonylphenyl, X 2 is O, and A 2 and B 2 together form a double bond, then the aryl ring of J 2 is substituted with at least one group selected independently from halo, and —S(═O) 2 -alkyl in which the alkyl group is C 2 -C 6 alkyl;
when W 2 is para-diethylaminocarbonylphenyl, X 2 is O, and A 2 and B 2 are each H, then the aryl ring of J 2 is substituted with 1-3 groups selected independently from halo, hydroxy, and —S(═O) 2 -alkyl; and
the compound of formula XVII is other than:
9. A compound according to claim 8 , wherein W 2 is:
10. A compound according to claim 8 , wherein R 23 and R 24 are each H.
11. A compound according to claim 8 , of formula XVIII:
wherein:
Q 1 and Q 2 are each independently H, halo, hydroxy, or —S(═O) 2 -alkyl.
12. A compound according to claim 8 , wherein A 2 and B 2 together form a double bond.
13. A compound according to claim 8 , wherein X 2 is —O—.
14. A compound according to claim 8 , wherein halo is fluoro.
15. A compound according to claim 11 , of formula XIX:
16. A compound according to claim 8 , wherein the compound is:
17. A compound according to claim 16 , wherein the compound is:
18. A compound according to claim 17 , wherein the compound is:
19. A compound according to claim 18 , wherein the compound is:
20. A compound of formula XXVA:
wherein:
W 2 is aryl optionally substituted with —C(═O)-alkyl or —C(═O)-aryl;
R 23 and R 24 are each independently H or alkyl;
A 2 and B 2 are each H, or together form a double bond;
X 2 is —CH 2 — or —O—; and
J 2 when taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with 0-3 groups selected independently from hydroxy, alkoxy, —S(═O) 2 -alkyl, —S(═O) 2 —NH 2 , —S(═O) 2 —NH(alkyl), —S(═O) 2 —N(alkyl)(alkyO, —C(═O)—N(alkyl)(alkyl), carboxy (—COOH), and —C(═O)—O- alkyl;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
21. A compound according to claim 20 , wherein R 23 and R 24 are each H.
22. A compound according to claim 20 of formula XXVIA:
wherein:
Q 1 and Q 2 are each independently H, hydroxy, alkoxy, —S(═O) 2 -alkyl, —S(═O) 2 —NH 2 , —S(═O) 2 —NH(alkyl), —S(═O) 2 —N(alkyl)(alkyl), —C(═O)—N(alkyl)(alkyl), carboxy (—COOH), or —C(═O)—O-alkyl.
23. A compound according to claim 20 , wherein A 2 and B 2 taken together form a double bond.
24. A compound according to claim 23 , wherein X 2 is —O—.
25. A compound of formula XXVIIIA:
wherein:
D is:
K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));
R 23 , R 24 , and R 26 are each independently H or alkyl;
A 2 and B 2 are each H, or together form a double bond; and
X 2 is —CH 2 — or —O—;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
26. A compound according to claim 25 , wherein R 23 and R 24 are each H.
27. A compound according to claim 25 , wherein R 26 is H.
28. A compound of formula XXIXA:
wherein:
W 2 is para-N(alkyl),N(alkyl-Z)aminocarbonylaryl or para-N(alkyl),N(alkyl-Z)aminocarbonylheteroaryl, wherein the aryl or heteroaryl ring of W 2 is substituted with 0-2 groups selected independently from hydroxy and alkoxy;
Z is alkoxy, alkylamino, or dialkylamino;
R 23 and R 24 are each independently H or alkyl;
A 2 and B 2 are each H, or together form a double bond; and
X 2 is —CH 2 — or —O—;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
29. A compound according to claim 28 , wherein W 2 is:
30. A compound according to claim 29 , wherein W 2 is:
31. A compound according to claim 28 , wherein A 2 and B 2 together form a double bond.
32. A compound according to claim 28 , wherein X 2 is —O—.
33. A compound according to claim 28 , wherein R 23 and R 24 are each H.
34. A compound of formula XXXA:
wherein:
W 2 is:
R 23 and R 24 are each independently H or alkyl;
A 2 and B 2 are each H, or together form a double bond;
X 2 is —CH 2 — or —O—; and
J 2 when taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with 1-3 groups selected independently from halo and haloalkoxy;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;
provided that when W 2 is:
then the aryl ring of J 2 is substituted with at least one haloalkoxy.
35. A compound according to claim 34 , wherein R 23 and R 24 are each H.
36. A compound according to claim 34 , of formula XXXIA:
wherein:
Q 1 and Q 2 are each independently H, halo, or haloalkoxy, provided that at least one of Q 1 and Q 2 is other than H.
37. A compound according to claim 36 , wherein R 23 and R 24 are each H.
38. A compound of formula XXXIIA:
wherein:
D is N(alkyl),N(alkyl)aminocarbonylheteroaryl;
R 23 , R 24 , and R 26 are each independently H or alkyl;
A 2 and B 2 are each H, or together form a double bond; and
X 2 is —CH 2 — or —O—;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;
provided that when D is:
and X 2 is —O—, then A 2 and B 2 are each H.
39. A compound according to claim 38 , wherein A 2 and B 2 are each H.
40. A compound according to claim 38 , wherein X 2 is —O—.
41. A compound according to claim 38 , wherein the heteroaryl ring of D is thienyl or pyridyl.
42. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 .
43. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier;
a compound of formula XIV:
wherein:
W 2 is aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with 0-3 groups selected independently from hydroxy, aminocarbonyl (—C(═O)—NH 2 ), N-alkylaminocarbonyl (—C(═O)—NH(alkyl)), and N,N-dialkylaminocarbonyl (—C(═O)—N(alkyl)(alkyl));
R 23 and R 24 are each independently H or alkyl, provided that at least one of R 23 and R 24 is alkyl;
p is 2;
A 2 and B 2 are each H, or together form a double bond; and
X 2 is —CH 2 — or —O—;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof; and
an opioid, an agent for the treatment of neuralgia/neuropathic pain, an agent for the treatment of depression, an agent for the treatment of incontinence, or an anti-Parkinson's agent.
44. A pharmaceutical composition according to claim 43 , wherein said opioid is alfentanil, allylprodine, alphaprodine, anileridine, benzyl-morphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, loperamide, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpinanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phanazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sulfentanil, tilidine, tramadol, a diastereoisomer thereof, a pharmaceutically acceptable salt thereof, a complex thereof, or a mixture thereof.
45. A pharmaceutical composition according to claim 43 , wherein said agent for the treatment of neuralgia/neuropathic pain is a mild OTC analgesic, a narcotic analgesic, an anti-seizure medication or an anti-depressant.
46. A pharmaceutical composition according to claim 43 , wherein said agent for the treatment of depression is a selective serotonin re-uptake inhibitor, a tricyclic compound, a monoamine oxidase inhibitor, or an antidepressant compound belonging to the heterocyclic class.
47. A pharmaceutical composition according to claim 43 , wherein said agent for the treatment of urge incontinence is an anticholinergic agent, an antispasmodic medication, a tricyclic antidepressant, a calcium channel blocker or a beta agonist.
48. A pharmaceutical composition comprising:
a pharmaceutically acceptable carrier;
a compound of formula XIV:
wherein:
W 2 is aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with 0-3 groups selected independently from hydroxy, aminocarbonyl (—C(═O)—NH 2 ), N-alkylaminocarbonyl (—C(═O)—NH(alkyl)), and N,N-dialkylaminocarbonyl (—C(═O)—N(alkyl)(alkyl));
R 23 and R 24 are each independently H or alkyl, provided that at least one of R 23 and R 24 is alkyl;
p is 2;
A 2 and B 2 are each H, or together form a double bond; and
X 2 is —CH 2 — or —O—;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof; and
an antibiotic, an antiviral, an antifungal, an anti-inflammatory, an anesthetic, or a mixture thereof.
49. A method of binding opioid delta receptors in a patient in need thereof, comprising the step of:
administering to said patient an effective amount of a compound of formula XIV:
wherein:
W 2 is aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with 0-3 groups selected independently from hydroxy, aminocarbonyl (—C(═O)—NH 2 ), N-alkylaminocarbonyl (—C(═O)—NH(alkyl)), and N,N-dialkylaminocarbonyl (—C(═O)—N(alkyl)(alkyl));
R 23 and R 24 are each independently H or alkyl, provided that at least one of R 23 and R 24 is alkyl;
p is 2;
A 2 and B 2 are each H, or together form a double bond; and
X 2 is —CH 2 — or —O—;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
50. A method according to claim 49 , wherein said δ opioid receptors are located in the central nervous system.
51. A method according to claim 49 , wherein said δ opioid receptors are located peripherally to the central nervous system.
52. A method according to claim 49 , wherein said binding modulates the activity of said opioid receptors.
53. A method according to claim 52 , wherein said binding agonizes the activity of said opioid receptors.
54. A method according to claim 51 , wherein said compound does not substantially cross the blood-brain barrier.
55. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 8 .
56. A pharmaceutical composition according to claim 55 , further comprising an opioid, an agent for the treatment of neuralgia/neuropathic pain, an agent for the treatment of depression, an agent for the treatment of incontinence, or an anti-Parkinson's agent.
57. A pharmaceutical composition according to claim 56 , wherein said opioid is alfentanil, allylprodine, alphaprodine, anileridine, benzyl-morphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, loperamide, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpinanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phanazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sulfentanil, tilidine, tramadol, a diastereoisomer thereof, a pharmaceutically acceptable salt thereof, a complex thereof, or a mixture thereof.
58. A pharmaceutical composition according to claim 56 , wherein said agent for the treatment of neuralgia/neuropathic pain is a mild OTC analgesic, a narcotic analgesic, an anti-seizure medication or an anti-depressant.
59. A pharmaceutical composition according to claim 56 , wherein said agent for the treatment of depression is a selective serotonin re-uptake inhibitor, a tricyclic compound, a monoamine oxidase inhibitor, or an antidepressant compound belonging to the heterocyclic class.
60. A pharmaceutical composition according to claim 56 , wherein said agent for the treatment of urge incontinence is an anticholinergic agent, an antispasmodic medication, a tricyclic antidepressant, a calcium channel blocker or a beta agonist.
61. A pharmaceutical composition according to claim 55 , further comprising an antibiotic, an antiviral, an antifungal, an anti-inflammatory, an anesthetic, or a mixture thereof.
62. A method of binding opioid delta receptors in a patient in need thereof, comprising the step of:
administering to said patient an effective amount of a compound according to claim 8 .
63. A method according to claim 62 , wherein said δ opioid receptors are located in the central nervous system.
64. A method according to claim 62 , wherein said δ opioid receptors are located peripherally to the central nervous system.
65. A method according to claim 62 , wherein said binding modulates the activity of said opioid receptors.
66. A method according to claim 65 , wherein said binding agonizes the activity of said opioid receptors.
67. A method according to claim 64 , wherein said compound does not substantially cross the blood-brain barrier.
68. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier;
a compound of formula XXV:
wherein:
W 2 is aryl optionally substituted with —C(═O)-alkyl or —C(═O)-aryl;
R 23 and R 24 are each independently H or alkyl;
p is 2;
A 2 and B 2 are each H, or together form a double bond;
X 2 is —CH 2 — or —O—; and
J 2 when taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with 0-3 groups selected independently from hydroxy, alkoxy, —S(═O) 2 -alkyl, —S(═O) 2 —NH 2 , —S(═O) 2 —NH(alkyl), —S(═O) 2 —N(alkyl)(alkyl), —C(═O)—N(alkyl)(alkyl), carboxy (—COOH), and —C(═O)—O—alkyl;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof; and
an opioid, an agent for the treatment of neuralgia/neuropathic pain, an agent for the treatment of depression, an agent for the treatment of incontinence, or an anti-Parkinson's agent;
provided that the compound of formula XXV is other than 4-phenyl-spiro [2H,1-benzopyran-2,4′ -piperidine].
69. A pharmaceutical composition according to claim 68 , wherein said opioid is alfentanil, allylprodine, alphaprodine, anileridine, benzyl-morphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, loperamide, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpinanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phanazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sulfentanil, tilidine, tramadol, a diastereoisomer thereof, a pharmaceutically acceptable salt thereof, a complex thereof, or a mixture thereof.
70. A pharmaceutical composition according to claim 68 , wherein said agent for the treatment of neuralgia/neuropathic pain is a mild OTC analgesic, a narcotic analgesic, an anti-seizure medication or an anti-depressant.
71. A pharmaceutical composition according to claim 68 , wherein said agent for the treatment of depression is a selective serotonin re-uptake inhibitor, a tricyclic compound, a monoamine oxidase inhibitor, or an antidepressant compound belonging to the heterocyclic class.
72. A pharmaceutical composition according to claim 68 , wherein said agent for the treatment of urge incontinence is an anticholinergic agent, an antispasmodic medication, a tricyclic antidepressant, a calcium channel blocker or a beta agonist.
73. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier;
a compound of formula XXV:
wherein:
W 2 is aryl optionally substituted with —C(═O)-alkyl or —C(═O)-aryl;
R 23 and R 24 are each independently H or alkyl;
p is 2;
A 2 and B 2 are each H, or together form a double bond;
X 2 is —CH 2 — or —O—; and
J 2 when taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with 0-3 groups selected independently from hydroxy, alkoxy, —S(═O) 2 -alkyl, —S(═O) 2 —NH 2 , —S(═O) 2 —NH(alkyl), —S(═O) 2 —N(alkyl)(alkyl), —C(═O)—N(alkyl)(alkyl), carboxy (—COOH), and —C(═O)—O—alkyl;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof; and
an antibiotic, an antiviral, an antifungal, an anti-inflammatory, an anesthetic, or a mixture thereof;
provided that the compound of formula XXV is other than 4-phenyl-spiro [2H,1-benzopyran-2,4′ -piperidine].
74. A method of binding opioid delta receptors in a patient in need thereof, comprising the step of:
administering to said patient an effective amount of a compound of formula XXV:
wherein:
W 2 is aryl optionally substituted with —C(═O)-alkyl or —C(═O)-aryl;
R 23 and R 24 are each independently H or alkyl;
p is 2;
A 2 and B 2 are each H, or together form a double bond;
X 2 is —CH 2 — or —O—; and
J 2 when taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with 0-3 groups selected independently from hydroxy, alkoxy, —S(═O) 2 -alkyl, —S(═O) 2 —NH 2 , —S(═O) 2 —NH(alkyl), —S(═O) 2 —N(alkyl)(alkyl), —C(═O)—N(alkyl)(alkyl), carboxy (—COOH), and —C(═O)—O—alkyl;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;
provided that the compound of formula XXV is other than 4-phenyl-Spiro[2H,1-benzopyran-2,4′-piperidine].
75. A method according to claim 74 , wherein said δ opioid receptors are located in the central nervous system.
76. A method according to claim 74 , wherein said δ opioid receptors are located peripherally to the central nervous system.
77. A method according to claim 74 , wherein said binding modulates the activity of said opioid receptors.
78. A method according to claim 77 , wherein said binding agonizes the activity of said opioid receptors.
79. A method according to claim 76 , wherein said compound does not substantially cross the blood-brain barrier.
80. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier; and a compound of formula XXVIIIA:
wherein:
D is:
K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));
R 23 , R 24 , and R 26 are each independently H or alkyl;
A 2 and B 2 are each H, or together form a double bond; and
X 2 is —CH 2 — or —O—;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
81. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier;
a compound of formula XXVIII:
wherein:
D is:
K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));
R 23 , R 24 , and R 26 are each independently H or alkyl;
p is 2;
A 2 and B 2 are each H, or together form a double bond; and
X 2 is —CH 2 — or —O—;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof; and
an opioid, an agent for the treatment of neuralgia/neuropathic pain, an agent for the treatment of depression, an agent for the treatment of incontinence, or an anti-Parkinson's agent.
82. A pharmaceutical composition according to claim 81 , wherein said opioid is alfentanil, allylprodine, alphaprodine, anileridine, benzyl-morphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, loperamide, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpinanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phanazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sulfentanil, tilidine, tramadol, a diastereoisomer thereof, a pharmaceutically acceptable salt thereof, a complex thereof, or a mixture thereof.
83. A pharmaceutical composition according to claim 81 , wherein said agent for the treatment of neuralgia/neuropathic pain is a mild OTC analgesic, a narcotic analgesic, an anti-seizure medication or an anti-depressant.
84. A pharmaceutical composition according to claim 81 , wherein said agent for the treatment of depression is a selective serotonin re-uptake inhibitor, a tricyclic compound, a monoamine oxidase inhibitor, or an antidepressant compound belonging to the heterocyclic class.
85. A pharmaceutical composition according to claim 81 , wherein said agent for the treatment of urge incontinence is an anticholinergic agent, an antispasmodic medication, a tricyclic antidepressant, a calcium channel blocker or a beta agonist.
86. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier;
a compound of formula XXVIII:
wherein:
D is:
K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));
R 23 , R 24 , and R 26 are each independently H or alkyl;
p is 2;
A 2 and B 2 are each H, or together form a double bond; and
X 2 is —CH 2 — or —O—;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof; and
an antibiotic, an antiviral, an antifungal, an anti-inflammatory, an anesthetic, or a mixture thereof.
87. A method of binding opioid delta receptors in a patient in need thereof, comprising the step of:
administering to said patient an effective amount of a compound of formula XXVIII:
wherein:
D is:
K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));
R 23 , R 24 , and R 26 are each independently H or alkyl;
p is 2;
A 2 and B 2 are each H, or together form a double bond; and
X 2 is —CH 2 — or —O—;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
88. A method according to claim 87 , wherein said δ opioid receptors are located in the central nervous system.
89. A method according to claim 87 , wherein said δ opioid receptors are located peripherally to the central nervous system.
90. A method according to claim 87 , wherein said binding modulates the activity of said opioid receptors.
91. A method according to claim 90 , wherein said binding agonizes the activity of said opioid receptors.
92. A method according to claim 89 , wherein said compound does not substantially cross the blood-brain barrier.
93. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 28 .
94. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier;
a compound of formula XXIX:
wherein:
W 2 is para-N(alkyl),N(alkyl-Z)aminocarbonylaryl or para-N(alkyl),N(alkyl-Z)aminocarbonylheteroaryl, wherein the aryl or heteroaryl ring of W 2 is substituted with 0-2 groups selected independently from hydroxy and alkoxy;
Z is alkoxy, alkylamino, or dialkylamino;
R 23 and R 24 are each independently H or alkyl;
p is 2;
A 2 and B 2 are each H, or together form a double bond; and
X 2 is —CH 2 — or —O—;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof; and
an opioid, an agent for the treatment of neuralgia/neuropathic pain, an agent for the treatment of depression, an agent for the treatment of incontinence, or an anti-Parkinson's agent.
95. A pharmaceutical composition according to claim 94 , wherein said opioid is alfentanil, allylprodine, alphaprodine, anileridine, benzyl-morphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, loperamide, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpinanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phanazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sulfentanil, tilidine, tramadol, a diastereoisomer thereof, a pharmaceutically acceptable salt thereof, a complex thereof, or a mixture thereof.
96. A pharmaceutical composition according to claim 94 , wherein said agent for the treatment of neuralgia/neuropathic pain is a mild OTC analgesic, a narcotic analgesic, an anti-seizure medication or an anti-depressant.
97. A pharmaceutical composition according to claim 94 , wherein said agent for the treatment of depression is a selective serotonin re-uptake inhibitor, a tricyclic compound, a monoamine oxidase inhibitor, or an antidepressant compound belonging to the heterocyclic class.
98. A pharmaceutical composition according to claim 94 , wherein said agent for the treatment of urge incontinence is an anticholinergic agent, an antispasmodic medication, a tricyclic antidepressant, a calcium channel blocker or a beta agonist.
99. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier;
a compound of formula XXIX:
wherein:
W 2 is para-N(alkyl),N(alkyl-Z)aminocarbonylaryl or para-N(alkyl),N(alky-Z)aminocarbonylheteroaryl, wherein the aryl or heteroaryl ring of W 2 is substituted with 0-2 groups selected independently from hydroxy and alkoxy;
Z is alkoxy, alkylamino, or dialkylamino;
R 23 and R 24 are each independently H or alkyl;
p is 2;
A 2 and B 2 are each H, or together form a double bond; and
X 2 is —CH 2 — or —O—;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof; and
an antibiotic, antiviral, antifungal, anti-inflammatory, anesthetic, or mixture thereof.
100. A method of binding opiod delta receptors in a patient in need therof, compromising the steps of:
administering to said patient an effective amount of a compound of formula XXIX:
wherein:
W 2 is para-N(alkyl),N(alkyl-Z)aminocarbonylaryl or para-N(alkyl),N(alky-Z)aminocarbonylheteroaryl, wherein the aryl or heteroaryl ring of W 2 is substituted with 0-2 groups selected independently from hydroxy and alkoxy;
Z is alkoxy, alkylamino, or dialkylamino;
R 23 and R 24 are each independently H or alkyl;
p is 2;
A 2 and B 2 are each H, or together form a double bond; and
X 2 is —CH 2 — or —O—;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.
101. A method according to claim 100 , wherein said δ opioid receptors are located in the central nervous system.
102. A method according to claim 100 , wherein said δ opioid receptors are located peripherally to the central nervous system.
103. A method according to claim 100 , wherein said binding modulates the activity of said opioid receptors.
104. A method according to claim 103 , wherein said binding agonizes the activity of said opioid receptors.
105. A method according to claim 102 , wherein said compound does not substantially cross the blood-brain barrier.
106. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 34 .
107. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier;
a compound of formula XXX:
wherein:
W 2 is:
R 23 and R 24 are each independently H or alkyl;
p is 2;
A 2 and B 2 are each H, or together form a double bond;
X 2 is —CH 2 — or —O—; and
J 2 when taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with 1-3 groups selected independently from halo or haloalkoxy;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof; and
an opioid, an agent for the treatment of neuralgia/neuropathic pain, an agent for the treatment of depression, an agent for the treatment of incontinence, or an anti-Parkinson's agent;
provided that when W 2 is:
then the aryl ring of J 2 is substituted with at least one haloalkoxy.
108. A pharmaceutical composition according to claim 107 , wherein said opioid is alfentanil, allylprodine, alphaprodine, anileridine, benzyl-morphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, loperamide, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpinanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phanazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sulfentanil, tilidine, tramadol, a diastereoisomer thereof, a pharmaceutically acceptable salt thereof, a complex thereof, or a mixture thereof.
109. A pharmaceutical composition according to claim 107 , wherein said agent for the treatment of neuralgia/neuropathic pain is a mild OTC analgesic, a narcotic analgesic, an anti-seizure medication or an anti-depressant.
110. A pharmaceutical composition according to claim 107 , wherein said agent for the treatment of depression is a selective serotonin re-uptake inhibitor, a tricyclic compound, a monoamine oxidase inhibitor, or an antidepressant compound belonging to the heterocyclic class.
111. A pharmaceutical composition according to claim 107 , wherein said agent for the treatment of urge incontinence is an anticholinergic agent, an antispasmodic medication, a tricyclic antidepressant, a calcium channel blocker or a beta agonist.
112. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier;
a compound of formula XXX:
wherein:
W 2 is:
R 23 and R 24 are each independently H or alkyl;
p is 2;
A 2 and B 2 are each H, or together form a double bond;
X 2 is —CH 2 — or —O—; and
J 2 when taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with 1-3 groups selected independently from halo or haloalkoxy;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof; and
an antibiotic, an antiviral, an antifungal, an anti-inflammatory, an anesthetic, or a mixture thereof;
provided that when W 2 is:
then the aryl ring of J 2 is substituted with at least one haloalkoxy.
113. A method of binding opioid delta receptors in a patient in need thereof, comprising the step of:
administering to said patient an effective amount of a compound of formula XXX:
wherein:
W 2 is:
R 23 and R 24 are each independently H or alkyl;
p is 2;
A 2 and B 2 are each H, or together form a double bond;
X 2 is —CH 2 — or —O—; and
J 2 when taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with 1-3 groups selected independently from halo or haloalkoxy;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;
provided that when W 2 is:
then the aryl ring of J 2 is substituted with at least one haloalkoxy.
114. A method according to claim 113 , wherein said δ opioid receptors are located in the central nervous system.
115. A method according to claim 113 , wherein said δ opioid receptors are located peripherally to the central nervous system.
116. A method according to claim 113 , wherein said binding modulates the activity of said opioid receptors.
117. A method according to claim 116 , wherein said binding agonizes the activity of said opioid receptors.
118. A method according to claim 115 , wherein said compound does not substantially cross the blood-brain barrier.
119. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 34 .
120. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier;
a compound of formula XXXII:
wherein:
D is N(alkyl),N(alkyl)aminocarbonylheteroaryl;
R 23 , R 24 , and R 26 are each independently H or alkyl;
p is 2;
A 2 and B 2 are each H, or together form a double bond; and
X 2 is —CH 2 — or —O—;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof; and
an opioid, an agent for the treatment of neuralgia/neuropathic pain, an agent for the treatment of depression, an agent for the treatment of incontinence, or an anti-Parkinson's agent;
provided that when D is:
and X 2 is —O—, then A 2 and B 2 are each H.
121. A pharmaceutical composition according to claim 120 , wherein said opioid is alfentanil, allylprodine, alphaprodine, anileridine, benzyl-morphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, loperamide, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpinanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phanazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sulfentanil, tilidine, tramadol, a diastereoisomer thereof, a pharmaceutically acceptable salt thereof, a complex thereof, or a mixture thereof.
122. A pharmaceutical composition according to claim 120 , wherein said agent for the treatment of neuralgia/neuropathic pain is a mild OTC analgesic, a narcotic analgesic, an anti-seizure medication or an anti-depressant.
123. A pharmaceutical composition according to claim 120 , wherein said agent for the treatment of depression is a selective serotonin re-uptake inhibitor, a tricyclic compound, a monoamine oxidase inhibitor, or an antidepressant compound belonging to the heterocyclic class.
124. A pharmaceutical composition according to claim 120 , wherein said agent for the treatment of urge incontinence is an anticholinergic agent, an antispasmodic medication, a tricyclic antidepressant, a calcium channel blocker or a beta agonist.
125. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier;
a compound of formula XXXII:
wherein:
D is N(alkyl),N(alkyl)aminocarbonylheteroaryl;
R 23 , R 24 , and R 26 are each independently H or alkyl;
p is 2;
A 2 and B 2 are each H, or together form a double bond; and
X 2 is —CH 2 — or —O—;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof; and
an antibiotic, an antiviral, an antifungal, an anti-inflammatory, an anesthetic, or a mixture thereof;
provided that when D is:
and X 2 is —O—, then A 2 and B 2 are each H.
126. A method of binding opioid delta receptors in a patient in need thereof, comprising the step of:
administering to said patient an effective amount of a compound of formula XXXII:
wherein:
D is N(alkyl),N(alkyl)aminocarbonylheteroaryl;
R 23 , R 24 , and R 26 are each independently H or alkyl;
p is 2;
A 2 and B 2 are each H, or together form a double bond; and
X 2 is —CH 2 — or —O—;
or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof; and
provided that when D is:
and X 2 is —O—, then A 2 and B 2 are each H.
127. A method according to claim 126 , wherein said δ opioid receptors are located in the central nervous system.
128. A method according to claim 126 , wherein said δ opioid receptors are located peripherally to the central nervous system.
129. A method according to claim 126 , wherein said binding modulates the activity of said opioid receptors.
130. A method according to claim 129 , wherein said binding agonizes the activity of said opioid receptors.
131. A method according to claim 128 , wherein said compound does not substantially cross the blood-brain barrier.
132. A compound according to claim 8 , wherein the compound is:
133. A compound according to claim 16 , wherein the compound is:
134. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier; and a compound according to claim 133 .
135. A pharmaceutical composition according to claim 134 , further comprising an opioid, an agent for the treatment of neuralgia/neuropathic pain, an agent for the treatment of depression, an agent for the treatment of incontinence, or an anti-Parkinson's agent.
136. A pharmaceutical composition according to claim 135 , wherein said opioid is alfentanil, allylprodine, alphaprodine, anileridine, benzyl-morphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, loperamide, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpinanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phanazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sulfentanil, tilidine, tramadol, a diastereoisomer thereof, a pharmaceutically acceptable salt thereof, a complex thereof, or a mixture thereof.
137. A pharmaceutical composition according to claim 135 , wherein said agent for the treatment of neuralgia/neuropathic pain is a mild OTC analgesic, a narcotic analgesic, an anti-seizure medication or an anti-depressant.
138. A pharmaceutical composition according to claim 135 , wherein said agent for the treatment of depression is a selective serotonin re-uptake inhibitor, a tricyclic compound, a monoamine oxidase inhibitor, or an antidepressent compound belonging to the heterocyclic class.
139. A pharmaceutical composition according to claim 135 , wherein said agent for the treatment of urge incontinence is an anticholinergic agent, an antispasmodic medication, a tricyclic antidepressant, a calcium channel blocker or a beta agonist.
140. A pharmaceutical composition according to claim 135 , further comprising:
an antibiotic, antiviral, antifungal, anti-inflammatory, anesthetic, or mixture thereof.
141. A method of binding opioid delta receptors in a patient in need thereof, comprising the step of:
administering to said patient an effective amount of a compound according to claim 133 .
142. A method according to claim 141 , wherein said δ opioid receptors are located in the central nervous system.
143. A method according to claim 141 , wherein said δ opioid receptors are located peripherally to the central nervous system.
144. A method according to claim 141 , wherein said binding modulates the activity of said opioid receptors.
145. A method according to claim 144 , wherein said binding agonizes the activity of said opioid receptors.
146. A method according to claim 143 , wherein said compound does not substantially cross the blood-brain barrier.
147. A method of inhibiting or treating pain, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 1 .
148. A method according to claim 147 , wherein the pain is neuralgia or neuropathic pain.
149. A method according to claim 148 , further comprising the step of administering to said patient an effective amount of an agent for the treatment of neuralgia or neuropathic pain.
150. A method according to claim 147 , further comprising the step of administering to said patient an effective amount of an opioid.
151. A method of inhibiting or treating incontinence, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 1 .
152. A method according to claim 151 , further comprising the step of administering to said patient an effective amount of an of an agent for the treatment of incontinence.
153. A method of inhibiting or treating depression, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 1 .
154. A method according to claim 153 , further comprising the step of administering to said patient an effective amount of an of an agent for the treatment of depression.
155. A method of inhibiting or treating Parkinson's disease, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 1 .
156. A method according to claim 155 , further comprising the step of administering to said patient an effective amount of an anti-Parkinson's disease agent.
157. A method of inhibiting or treating pain, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 8 .
158. A method according to claim 157 , wherein the pain is neuralgia or neuropathic pain.
159. A method according to claim 158 , further comprising the step of administering to said patient an effective amount of an agent for the treatment of neuralgia or neuropathic pain.
160. A method according to claim 157 , further comprising the step of administering to said patient an effective amount of an opioid.
161. A method of inhibiting or treating incontinence, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 8 .
162. A method according to claim 161 , further comprising the step of administering to said patient an effective amount of an of an agent for the treatment of incontinence.
163. A method of inhibiting or treating depression, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 8 .
164. A method according to claim 163 , further comprising the step of administering to said patient an effective amount of an of an agent for the treatment of depression.
165. A method of inhibiting or treating Parkinson's disease, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 8 .
166. A method according to claim 165 , further comprising the step of administering to said patient an effective amount of an anti-Parkinson's disease agent.
167. A method of inhibiting or treating pain, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 20 .
168. A method according to claim 167 , wherein the pain is neuralgia or neuropathic pain.
169. A method according to claim 168 , further comprising the step of administering to said patient an effective amount of an agent for the treatment of neuralgia or neuropathic pain.
170. A method according to claim 167 , further comprising the step of administering to said patient an effective amount of an opioid.
171. A method of inhibiting or treating incontinence, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 20 .
172. A method according to claim 171 , further comprising the step of administering to said patient an effective amount of an of an agent for the treatment of incontinence.
173. A method of inhibiting or treating depression, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 20 .
174. A method according to claim 171 , further comprising the step of administering to said patient an effective amount of an of an agent for the treatment of depression.
175. A method of inhibiting or treating Parkinson's disease, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 20 .
176. A method according to claim 175 , further comprising the step of administering to said patient an effective amount of an anti-Parkinson's disease agent.
177. A method of inhibiting or treating pain, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 25 .
178. A method according to claim 177 , wherein the pain is neuralgia or neuropathic pain.
179. A method according to claim 178 , further comprising the step of administering to said patient an effective amount of an agent for the treatment of neuralgia or neuropathic pain.
180. A method according to claim 177 , further comprising the step of administering to said patient an effective amount of an opioid.
181. A method of inhibiting or treating incontinence, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 25 .
182. A method according to claim 181 , further comprising the step of administering to said patient an effective amount of an of an agent for the treatment of incontinence.
183. A method of inhibiting or treating depression, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 25 .
184. A method according to claim 183 , further comprising the step of administering to said patient an effective amount of an of an agent for the treatment of depression.
185. A method of inhibiting or treating Parkinson's disease, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 25 .
186. A method according to claim 185 , further comprising the step of administering to said patient an effective amount of an anti-Parkinson's disease agent.
187. A method of inhibiting or treating pain, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 34 .
188. A method according to claim 187 , wherein the pain is neuralgia or neuropathic pain.
189. A method according to claim 188 , further comprising the step of administering to said patient an effective amount of an agent for the treatment of neuralgia or neuropathic pain.
190. A method according to claim 187 , further comprising the step of administering to said patient an effective amount of an opioid.
191. A method of inhibiting or treating incontinence, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 34 .
192. A method according to claim 191 , further comprising the step of administering to said patient an effective amount of an of an agent for the treatment of incontinence.
193. A method of inhibiting or treating depression, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 34 .
194. A method according to claim 193 , further comprising the step of administering to said patient an effective amount of an of an agent for the treatment of depression.
195. A method of inhibiting or treating Parkinson's disease, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 34 .
196. A method according to claim 195 , further comprising the step of administering to said patient an effective amount of an anti-Parkinson's disease agent.
197. A method of inhibiting or treating pain, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 38 .
198. A method according to claim 197 , wherein the pain is neuralgia or neuropathic pain.
199. A method according to claim 198 , further comprising the step of administering to said patient an effective amount of an agent for the treatment of neuralgia or neuropathic pain.
200. A method according to claim 197 , further comprising the step of administering to said patient an effective amount of an opioid.
201. A method of inhibiting or treating incontinence, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 38 .
202. A method according to claim 201 , further comprising the step of administering to said patient an effective amount of an of an agent for the treatment of incontinence.
203. A method of inhibiting or treating depression, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 38 .
204. A method according to claim 203 , further comprising the step of administering to said patient an effective amount of an of an agent for the treatment of depression.
205. A method of inhibiting or treating Parkinson's disease, comprising the step of administering to a patient in need thereof an effective amount of a compound according to claim 38 .
206. A method according to claim 205 , further comprising the step of administering to said patient an effective amount of an anti-Parkinson's disease agent.