SUBSTITUTED PHENETHYLAMINES WITH SEROTONINERGIC AND/OR NOREPINEPHRINERGIC ACTIVITY

• US 20080234257A1
• Filed: 03/13/2008
• Published: 09/25/2008
• Est. Priority Date: 03/15/2007
• Status: Abandoned Application

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Auspex Pharmaceuticals, Inc. (Teva Pharmaceutical Industries Limited)
• Inventors: Sarshar, Sepehr, Gant, Thomas G., Woo, Soon Hyung
• Application Number:
  US12/048,012
• Publication Number:
  US 20080234257A1
• Time in Patent Office: Days
• US Class Current: 514/230.5
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07B 59/00 Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
• CPC Class Codes: C07C 211/64 having quaternised nitrogen atoms bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 215/64 with rings other than six-membered aromatic rings being part of the carbon skeleton
• CPC Class Codes: C07C 217/74 with rings other than six-membered aromatic rings being part of the carbon skeleton
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07D 265/16 with only hydrogen or carbon atoms directly attached in positions 2 and 4

Abstract

Chemical syntheses and medical uses of novel inhibitors of the uptake of monoamine neurotransmitters and pharmaceutically acceptable salts and prodrugs thereof, for the treatment and/or management of psychotropic disorders, anxiety disorder, generalized anxiety disorder, depression, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, hot flashes, senile dementia, migraine, hepatopulmonary syndrome, chronic pain, nociceptive pain, neuropathic pain, painful diabetic retinopathy, bipolar depression, obstructive sleep apnea, psychiatric disorders, premenstrual dysphoric disorder, social phobia, social anxiety disorder, urinary incontinence, anorexia, bulimia nervosa, obesity, ischemia, head injury, calcium overload in brain cells, drug dependence, attention deficit hyperactivity disorder, fibromyalgia, irritable bowel syndrome, and/or premature ejaculation are described.

Claims

1. A pharmaceutically acceptable acid addition salt of a compound having structural formula I:

2. The pharmaceutically acceptable salt as recited in claim 1, wherein said pharmaceutically acceptable salt is substantially a single enantiomer, a mixture of about 90% or more by weight of the (−

)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−

)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of any other diastereomer.

3. The pharmaceutically acceptable salt as recited in claim 1, wherein at least one of R₁-R₂₇ independently has deuterium enrichment of no less than about 1%.

4. The pharmaceutically acceptable salt as recited in claim 1, wherein at least one of R₁-R₂₇ independently has deuterium enrichment of no less than about 5%.

5. The pharmaceutically acceptable salt as recited in claim 1, wherein at least one of R₁-R₂₇ independently has deuterium enrichment of no less than about 10%.

6. The pharmaceutically acceptable salt as recited in claim 1, wherein at least one of R₁-R₂₇ independently has deuterium enrichment of no less than about 20%.

7. The pharmaceutically acceptable salt as recited in claim 1, wherein at least one of R₁-R₂₇ independently has deuterium enrichment of no less than about 50%.

8. The pharmaceutically acceptable salt as recited in claim 1, wherein at least one of R₁-R₂₇ independently has deuterium enrichment of no less than about 90%.

9. The pharmaceutically acceptable salt as recited in claim 1, wherein at least one of R₁-R₂₇ independently has deuterium enrichment of no less than about 98%.

10. The pharmaceutically acceptable salt as recited in claim 1, wherein said pharmaceutically acceptable salt is a hydrochloride salt.

11. The hydrochloride salt as recited in claim 10, having a structural formula selected from the group consisting of:

12. The hydrochloride salt as recited in claim 11, wherein said compound is substantially a single enantiomer, a mixture of about 90% or more by weight of the (−

)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−

)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of any other diastereomer.

13. The hydrochloride salt as recited in claim 11, wherein each of said positions represented as D have deuterium enrichment of at least 1%.

14. The hydrochloride salt as recited in claim 11, wherein each of said positions represented as D have deuterium enrichment of at least 5%.

15. The hydrochloride salt as recited in claim 11, wherein each of said positions represented as D have deuterium enrichment of at least 10%.

16. The hydrochloride salt as recited in claim 11, wherein each of said positions represented as D have deuterium enrichment of at least 20%.

17. The hydrochloride salt as recited in claim 11, wherein each of said positions represented as D have deuterium enrichment of at least 50%.

18. The hydrochloride salt as recited in claim 11, wherein each of said positions represented as D have deuterium enrichment of at least 90%.

19. The hydrochloride salt as recited in claim 11, wherein each of said positions represented as D have deuterium enrichment of at least 98%.

20. The hydrochloride salt as recited in claim 11, wherein said hydrochloride salt is d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine) having the structural formula:

21. A polymorph of the hydrochloride salt of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine) as recited in claim 20, wherein said polymorph has an X-ray powder diffraction spectrum substantially the same as shown in FIG. 1.

22. A polymorph of the hydrochloride salt of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine) as recited in claim 20, wherein said polymorph exhibits high-intensity diffraction peaks at diffraction angles (2θ

) of 6.703, 8.321, 12.681, 13.5, 15.54, 18.918, 20.359, 21.161, 21.762, 25.04, and 28.518 in X-ray powder diffraction analysis.

23. A polymorph of the hydrochloride salt of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine) as recited in claim 20, wherein said polymorph exhibits an X-ray powder diffraction spectrum having characteristic peaks expressed in degrees (2θ

) at approximately;

24. A polymorph of the hydrochloride salt of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine) as recited in claim 20, wherein said polymorph has an X-ray powder diffraction spectrum substantially the same as shown in FIG. 2.

25. A polymorph of the hydrochloride salt of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine) as recited in claim 20, wherein said polymorph exhibits high-intensity diffraction peaks at diffraction angles (2θ

) of 6.683, 10.201, 13.441, 15.517, 18.198, 19.719, 20.258, 21.68, 22.658, 25.543, 28.022, and 35.02 in X-ray powder diffraction analysis.

26. A polymorph of the hydrochloride salt of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine) as recited in claim 20, wherein said polymorph exhibits an X-ray powder diffraction spectrum having characteristic peaks expressed in degrees (2θ

) at approximately;

27. A polymorph of the hydrochloride salt of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine) as recited in claim 20, wherein said polymorph has an X-ray powder diffraction spectrum substantially the same as shown in FIG. 3.

28. A polymorph of the hydrochloride salt of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine) as recited in claim 20, wherein said polymorph exhibits high-intensity diffraction peaks at diffraction angles (2θ

) of 6.718, 8.335, 12.68, 13.5, 15.539, 16.282, 18.902, 19.737, 20.34, 21.161, 21.758, 25.02, 25.601, 26.261, 28.518, 31.54, 33.198, 33.937, and 35.159 in X-ray powder diffraction analysis.

29. A polymorph of the hydrochloride salt of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine) as recited in claim 20, wherein said polymorph exhibits an X-ray powder diffraction spectrum having characteristic peaks expressed in degrees (2θ

) at approximately;

30. A polymorph of the hydrochloride salt of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine) as recited in claim 20, wherein said polymorph has an X-ray powder diffraction spectrum substantially the same as shown in FIG. 4.

31. A polymorph of the hydrochloride salt of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine) as recited in claim 20, wherein said polymorph exhibits high-intensity diffraction peaks at diffraction angles (2θ

) of 6.74, 7.421, 8.341, 10.219, 12.7, 13.502, 17.9, 15.541, 20.36, 21.221, 21.761, 25.078, 31.04, 34.018, and 35.139 in X-ray powder diffraction analysis.

32. A polymorph of the hydrochloride salt of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine) as recited in claim 20, wherein said polymorph exhibits an X-ray powder diffraction spectrum having characteristic peaks expressed in degrees (2θ

) at approximately;

33. A polymorph of the hydrochloride salt of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine) as recited in claim 20, wherein said polymorph has an X-ray powder diffraction spectrum substantially the same as shown in FIG. 5.

34. A polymorph of the hydrochloride salt of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine) as recited in claim 20, wherein said polymorph exhibits high-intensity diffraction peaks at diffraction angles (2θ

) of 5.597, 7.182, 9.078, 9.557, 11.201, 14.46, 14.76, 16.86, 17.497, 19.201, 19.619, 20.241, 20.66, 21.76, 22.596, 23.06, 24.4, 25.02, 26.519, 26.842, 31.52, and 35.438 in X-ray powder diffraction analysis.

35. A polymorph of the hydrochloride salt of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine) as recited in claim 20, wherein said polymorph exhibits an X-ray powder diffraction spectrum having characteristic peaks expressed in degrees (2θ

) at approximately;

36. A polymorph of the hydrochloride salt of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine) as recited in claim 20, wherein said polymorph has an X-ray powder diffraction spectrum substantially the same as shown in FIG. 6.

37. A polymorph of the hydrochloride salt of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine) as recited in claim 20, wherein said polymorph exhibits high-intensity diffraction peaks at diffraction angles (2θ

) of 5.581, 7.186, 11.22, 14.499, 14.802, 16.882, 19.242, 20.317, 21.798, 22.637, and 35.445 in X-ray powder diffraction analysis.

38. A polymorph of the hydrochloride salt of d₉-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol hydrochloride (d₉-venlafaxine) as recited in claim 20, wherein said polymorph exhibits an X-ray powder diffraction spectrum having characteristic peaks expressed in degrees (2θ

) at approximately;

81. The use of a compound as recited in claim 39 for the manufacture of a pharmaceutically acceptable acid addition salt as recited in claim 1.

82. The use of a compound as recited in claim 59 for the manufacture of a pharmaceutically acceptable acid addition salt as recited in claim 1.

103. A pharmaceutical composition comprising the compound as recited in claim 1 and one or more pharmaceutically acceptable carriers.

104. The pharmaceutical composition as recited in claim 103, further comprising one or more release-controlling carriers.

105. The pharmaceutical composition as recited in claim 103, further comprising one or more non-release controlling carriers.

106. The pharmaceutical composition as recited in claim 103, wherein the composition is suitable for oral, parenteral, or intravenous infusion administration.

107. The pharmaceutical composition as recited in claim 106, wherein the oral dosage form is a tablet or capsule.

108. The pharmaceutical composition as recited in claim 103, wherein the compound is administered in a dose of about 0.5 milligrams to about 1,000 milligrams.

109. The pharmaceutical composition as recited in claim 108, wherein the compound is administered in a dose of about 0.5 milligrams to about 400 milligrams.

110. A method for the treatment of a monoamine-related disorder, comprising administering to a subject a therapeutically effective amount of the compound as recited in claim 1.

111. The method as recited in claim 110, wherein the monoamine-related disorder is selected from the group consisting of psychotropic disorders, anxiety disorder, generalized anxiety disorder, depression, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, hot flashes, senile dementia, migraine, hepatopulmonary syndrome, chronic pain, nociceptive pain, neuropathic pain, painful diabetic retinopathy, bipolar depression, obstructive sleep apnea, psychiatric disorders, premenstrual dysphoric disorder, social phobia, social anxiety disorder, urinary incontinence, anorexia, bulimia nervosa, obesity, ischemia, head injury, calcium overload in brain cells, drug dependence, Gilles de la Tourette syndrome, Shy Drager syndrome, vasomotor flushing, chronic fatigue syndrome, cognition enhancement, attention deficit hyperactivity disorder, fibromyalgia, irritable bowel syndrome, and premature ejaculation.

112. The method as recited in claim 111 wherein said disorder is drug dependence.

113. The method as recited in claim 112, wherein said drug dependence is selected from the group consisting of tobacco addiction, alcohol addiction, marijuana addiction, and cocaine addiction.

114. The method as recited in claim 112, wherein said compound elicits an improved clinical effect for the treatment of drug dependence selected from the group consisting of accelerated rate of healing, accelerated rate of symptom relief, improved patient compliance, and reduced withdrawal symptomology during the treatment.

115. The method as recited in claim 110, wherein said compound elicits an improved clinical effect selected from the group consisting of improvement of pain indices and improvement of depression indices.

116. The method as recited in claim 110, wherein said compound has at least one of the following properties:

a. decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound;

b. increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;

c. decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;

d. increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; and

e. an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

117. The method as recited in claim 110, wherein said compound has at least two of the following properties:

a. decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound;

b. increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;

c. decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;

d. increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; and

e. an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

118. The method as recited in claim 110, wherein said compound has a decreased metabolism by at least one polymorphically-expressed cytochrome P₄₅₀ isoform in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

119. The method as recited in claim 118, wherein said cytochrome P₄₅₀ isoform is selected from the group consisting of CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

120. The method as recited in claim 110, wherein said compound is characterized by decreased inhibition of at least one cytochrome P₄₅₀ or monoamine oxidase isoform in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

121. The method as recited in claim 120, wherein said cytochrome P₄₅₀ or monoamine oxidase isoform is selected from the group consisting of CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO_A, and MAO_B.

122. The method as recited in claim 110, wherein the method affects the treatment of the disorder while reducing or eliminating a deleterious change in a diagnostic hepatobiliary function endpoint, as compared to the corresponding non-isotopically enriched compound.

123. The method as recited in claim 122, wherein the diagnostic hepatobiliary function endpoint is selected from the group consisting of alanine aminotransferase (“

ALT”

), serum glutamic-pyruvic transaminase (“

SGPT”

), aspartate aminotransferase (“

AST,”

“

SGOT”

), ALT/AST ratios, serum aldolase, alkaline phosphatase (“

ALP”

), ammonia levels, bilirubin, gamma-glutamyl transpeptidase (“

GGTP,”

“

Y-GTP,”

“

GGT”

), leucine aminopeptidase (“

LAP”

), liver biopsy, liver ultrasonography, liver nuclear scan, 5′

-nucleotidase, and blood protein.

124. The method as recited in claim 110 wherein said compound is administered in combination with another therapeutic agent.

125. The method as recited in claim 124 wherein said therapeutic agent is a modulator of an NMDA-receptor.

126. The method as recited in claim 124 wherein said therapeutic agent is selected from the group consisting of phencyclidine (PCP), amantadine, ibogaine, memantine, dextrorphan, ketamine, nitrous oxide, and dextromethorphan.

127. The method as recited in claim 124 wherein said therapeutic agent is an opiod.

128. The method as recited in claim 127 wherein said opioid is selected from the group consisting of morphine, codeine, thebain, diacetylmorphine, oxycodone, hydrocodone, hydromorphone, oxymorphone, nicomorphine, fentanyl, α

-methyl fentanyl, alfentanil, sufentanil, remifentanyl, carfentanyl, ohmefentanyl, pethidine, ketobemidone, propoxyphene, dextropropoxyphene, methadone, loperamide, pentazocine, buprenorphine, etorphine, butorphanol, nalbufine, levorphanol, naloxone, naltrexone, and tramadol.

129. The method as recited in claim 124 wherein said therapeutic agent is an opiod antagonist.

130. The method as recited in claim 129 wherein said opioid antagonist is selected from the group consisting of nalmefene, naltrexone, and naloxone.

131. The method as recited in claim 124 wherein said therapeutic agent is an anesthetic or sedative.

132. The method as recited in claim 131 wherein said anesthetic or sedative is selected from the group consisting of propofol, procaine, lidocaine, prilocaine, bupivacaine, levobupivicaine, nitrous oxide, halothane, enflurane, isoflurane, sevoflurane, desflurane, thiopental, methohexital, etomidate, diazepam, midazolam, lorazepam, succinylcholine, vecuroniurn, rocuronium, pipecuronium, rapacuronium, tubocurarine, and gallamine.

163. A method for modulating a target selected from the group consisting of a serotonin receptor, a norepinephrine receptor, a serotonin transporter, and a norepinephrine transporter, comprising contacting said target with the pharmaceutically acceptable acid addition salt as recited in claim 1.

39. A compound having structural formula II:

40. The compound as recited in claim 39, wherein said compound is substantially a single enantiomer, a mixture of about 90% or more by weight of the (−

)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−

)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of any other diastereomer.

41. The compound as recited in claim 39, wherein at least one of R₂₈-R₅₇ independently has deuterium enrichment of no less than about 1%.

42. The compound as recited in claim 39, wherein at least one of R₂₈-R₅₇ independently has deuterium enrichment of no less than about 5%.

43. The compound as recited in claim 39, wherein at least one of R₂₈-R₅₇ independently has deuterium enrichment of no less than about 10%.

44. The compound as recited in claim 39, wherein at least one of R₂₈-R₅₇ independently has deuterium enrichment of no less than about 20%.

45. The compound as recited in claim 39, wherein at least one of R₂₈-R₅₇ independently has deuterium enrichment of no less than about 50%.

46. The compound as recited in claim 39, wherein at least one of R₂₈-R₅₇ independently has deuterium enrichment of no less than about 90%.

47. The compound as recited in claim 39, wherein at least one of R₂₈-R₅₇ independently has deuterium enrichment of no less than about 98%.

48. The compound as recited in claim 39, wherein X is selected from the group consisting of halogen, alkylsulfonate, arylsulfonate, perhaloalkanesulfonate, CH₃OSO₃⁻

, and CD₃OSO₃⁻

.

49. The compound as recited in claim 39, wherein X is iodide.

50. The compound as recited in claim 39, having a structural formula selected from the group consisting of:

51. The compound as recited in claim 50, wherein said compound is substantially a single enantiomer, a mixture of about 90% or more by weight of the (−

)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−

)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of any other diastereomer.

52. The compound as recited in claim 50, wherein each of said positions represented as D have deuterium enrichment of at least 1%.

53. The compound as recited in claim 50, wherein each of said positions represented as D have deuterium enrichment of at least 5%.

54. The compound as recited in claim 50, wherein each of said positions represented as D have deuterium enrichment of at least 10%.

55. The compound as recited in claim 50, wherein each of said positions represented as D have deuterium enrichment of at least 20%.

56. The compound as recited in claim 50, wherein each of said positions represented as D have deuterium enrichment of at least 50%.

57. The compound as recited in claim 50, wherein each of said positions represented as D have deuterium enrichment of at least 90%.

58. The compound as recited in claim 50, wherein each of said positions represented as D have deuterium enrichment of at least 98%.

59. A compound having structural formula III:

60. The compound as recited in claim 59, wherein said compound is substantially a single enantiomer, a mixture of about 90% or more by weight of the (−

)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−

)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of any other diastereomer.

61. The compound as recited in claim 59, wherein at least one of R₅₈-R₈₂ independently has deuterium enrichment of no less than about 1%.

62. The compound as recited in claim 59, wherein at least one of R₅₈-R₈₂ independently has deuterium enrichment of no less than about 5%.

63. The compound as recited in claim 59, wherein at least one of R₅₈-R₈₂ independently has deuterium enrichment of no less than about 10%.

64. The compound as recited in claim 59, wherein at least one of R₅₈-R₈₂ independently has deuterium enrichment of no less than about 20%.

65. The compound as recited in claim 59, wherein at least one of R₅₈-R₈₂ independently has deuterium enrichment of no less than about 50%.

66. The compound as recited in claim 59, wherein at least one of R₅₈-R₈₂ independently has deuterium enrichment of no less than about 90%.

67. The compound as recited in claim 59, wherein at least one of R₅₈ R₅₈-R₈₂ independently has deuterium enrichment of no less than about 98%.

68. The compound as recited in claim 59, having a structural formula selected from the group consisting of:

69. The compound as recited in claim 68, wherein said compound is substantially a single enantiomer, a mixture of about 90% or more by weight of the (−

)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−

)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of any other diastereomer.

70. The compound as recited in claim 68, wherein each of said positions represented as D have deuterium enrichment of at least 1%.

71. The compound as recited in claim 68, wherein each of said positions represented as D have deuterium enrichment of at least 5%.

72. The compound as recited in claim 68, wherein each of said positions represented as D have deuterium enrichment of at least 10%.

73. The compound as recited in claim 68, wherein each of said positions represented as D have deuterium enrichment of at least 20%.

74. The compound as recited in claim 68, wherein each of said positions represented as D have deuterium enrichment of at least 50%.

75. The compound as recited in claim 68, wherein each of said positions represented as D have deuterium enrichment of at least 90%.

76. The compound as recited in claim 68, wherein each of said positions represented as D have deuterium enrichment of at least 98%.

77. A process for preparing a compound having structural formula I comprising reacting a compound having structural formula II under suitable conditions to form a compound having structural formula I:

78. The process as recited in claim 77, wherein the reaction is carried out in the presence of focused microwave radiation using a quartz reactor at a pressure from about 1 Bar to about 25 Bar, a power setting from about 1 W per liter of solvent to about 900 W per liter of solvent, at a temperature from about 0°

C. to about 500°

C., for 0.01 to 5 hours, and at a pH from about 1 to about 14.

79. A process for preparing a compound having structural formula I comprising reacting a compound having structural formula III under suitable conditions to form a compound having structural formula I:

80. The process as recited in claim 79, wherein the reaction is carried out in the presence of focused microwave radiation using a quartz reactor at a pressure from about 1 Bar to about 25 Bar, a power setting from about 1 W per liter of solvent to about 900 W per liter of solvent, at a temperature from about 0°

C. to about 500°

C., for 0.01 to 5 hours, and at a pH from about 1 to about 14.

83. A compound having structural formula IV:

84. The compound as recited in claim 83, wherein said compound is substantially a single enantiomer, a mixture of about 90% or more by weight of the (−

)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−

)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of any other diastereomer.

85. The compound as recited in claim 83, wherein at least one of R₈₃-R₁₀₇ independently has deuterium enrichment of no less than about 1%.

86. The compound as recited in claim 83, wherein at least one of R₈₃-R₁₀₇ independently has deuterium enrichment of no less than about 5%.

87. The compound as recited in claim 83, wherein at least one of R₈₃-R₁₀₇ independently has deuterium enrichment of no less than about 10%.

88. The compound as recited in claim 83, wherein at least one of R₈₃-R₁₀₇ independently has deuterium enrichment of no less than about 20%.

89. The compound as recited in claim 83, wherein at least one of R₈₃-R₁₀₇ independently has deuterium enrichment of no less than about 50%.

90. The compound as recited in claim 83, wherein at least one of R₈₃-R₁₀₇ independently has deuterium enrichment of no less than about 90%.

91. The compound as recited in claim 83, wherein at least one of R₈₃-R₁₀₇ independently has deuterium enrichment of no less than about 98%.

92. The compound as recited in claim 83, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having a structural formula selected from the group consisting of:

93. The compound as recited in claim 92, wherein said compound is substantially a single enantiomer, a mixture of about 90% or more by weight of the (−

)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−

)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of any other diastereomer.

94. The compound as recited in claim 92, wherein each of said positions represented as D have deuterium enrichment of at least 1%.

95. The compound as recited in claim 92, wherein each of said positions represented as D have deuterium enrichment of at least 5%.

96. The compound as recited in claim 92, wherein each of said positions represented as D have deuterium enrichment of at least 10%.

97. The compound as recited in claim 92, wherein each of said positions represented as D have deuterium enrichment of at least 20%.

98. The compound as recited in claim 92, wherein each of said positions represented as D have deuterium enrichment of at least 50%.

99. The compound as recited in claim 92, wherein each of said positions represented as D have deuterium enrichment of at least 90%.

100. The compound as recited in claim 92, wherein each of said positions represented as D have deuterium enrichment of at least 98%.

101. The compound as recited in claim 83, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having the structural formula:

102. The compound as recited in claim 101, wherein said compound contains about 50% or more by weight of the (−

)-enantiomer of said compound and about 50% or less by weight of (+)-enantiomer of said compound or about 50% or more by weight of the (+)-enantiomer of said compound and about 50% or less by weight of (−

)-enantiomer of said compound.

133. A pharmaceutical composition comprising the compound as recited in claim 83 and one or more pharmaceutically acceptable carriers.

134. The pharmaceutical composition as recited in claim 133, further comprising one or more release-controlling carriers.

135. The pharmaceutical composition as recited in claim 133, further comprising one or more non-release controlling carriers.

136. The pharmaceutical composition as recited in claim 133, wherein the composition is suitable for oral, parenteral, or intravenous infusion administration.

137. The pharmaceutical composition as recited in claim 136, wherein the oral dosage form is a tablet or capsule.

138. The pharmaceutical composition as recited in claim 133, wherein the compound is administered in a dose of about 0.5 milligrams to about 1,000 milligrams.

139. The pharmaceutical composition as recited in claim 138, wherein the compound is administered in a dose of about 0.5 milligrams to about 400 milligrams.

140. A method for the treatment of a monoamine-related disorder, comprising administering to a subject a therapeutically effective amount of the compound as recited in claim 83.

141. The method as recited in claim 140, wherein the monoamine-related disorder is selected from the group consisting of psychotropic disorders, anxiety disorder, generalized anxiety disorder, depression, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, hot flashes, senile dementia, migraine, hepatopulmonary syndrome, chronic pain, nociceptive pain, neuropathic pain, painful diabetic retinopathy, bipolar depression, obstructive sleep apnea, psychiatric disorders, premenstrual dysphoric disorder, social phobia, social anxiety disorder, urinary incontinence, anorexia, bulimia nervosa, obesity, ischemia, head injury, calcium overload in brain cells, drug dependence, Gilles de la Tourette syndrome, Shy Drager syndrome, vasomotor flushing, chronic fatigue syndrome, cognition enhancement, attention deficit hyperactivity disorder, fibromyalgia, irritable bowel syndrome, and premature ejaculation.

142. The method as recited in claim 141 wherein said disorder is drug dependence.

143. The method as recited in claim 142, wherein said drug dependence is selected from the group consisting of tobacco addiction, alcohol addiction, marijuana addiction, and cocaine addiction.

144. The method as recited in claim 142, wherein said compound elicits an improved clinical effect for the treatment of drug dependence selected from the group consisting of accelerated rate of healing, accelerated rate of symptom relief, improved patient compliance, and reduced withdrawal symptomology during the treatment.

145. The method as recited in claim 144, wherein said improved clinical effect is selected from the group consisting of improvement of pain indices and improvement of depression indices.

146. The method as recited in claim 140, wherein said compound has at least one of the following properties:

a. decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound;

b. increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;

c. decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;

d. increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; and

e. an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

147. The method as recited in claim 140, wherein said compound has at least two of the following properties:

a. decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound;

b. increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;

c. decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;

d. increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; and

e. an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

148. The method as recited in claim 140, wherein said compound has a decreased metabolism by at least one polymorphically-expressed cytochrome P₄₅₀ isoform in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

149. The method as recited in claim 148, wherein said cytochrome P₄₅₀ isoform is selected from the group consisting of CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

150. The method as recited in claim 140, wherein said compound is characterized by decreased inhibition of at least one cytochrome P₄₅₀ or monoamine oxidase isoform in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

151. The method as recited in claim 150, wherein said cytochrome P₄₅₀ or monoamine oxidase isoform is selected from the group consisting of CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO_A, and MAO_B.

152. The method as recited in claim 140, wherein the method affects the treatment of the disorder while reducing or eliminating a deleterious change in a diagnostic hepatobiliary function endpoint, as compared to the corresponding non-isotopically enriched compound.

153. The method as recited in claim 152, wherein the diagnostic hepatobiliary function endpoint is selected from the group consisting of alanine aminotransferase (“

ALT”

), serum glutamic-pyruvic transaminase (“

SGPT”

), aspartate aminotransferase (“

AST,”

“

SGOT”

), ALT/AST ratios, serum aldolase, alkaline phosphatase (“

ALP”

), ammonia levels, bilirubin, gamma-glutamyl transpeptidase (“

GGTP,”

“

γ

-GTP,”

“

GGT”

), leucine aminopeptidase (“

LAP”

), liver biopsy, liver ultrasonography, liver nuclear scan, 5′

-nucleotidase, and blood protein.

154. The method as recited in claim 140 wherein said compound is administered in combination with another therapeutic agent.

155. The method as recited in claim 154 wherein said therapeutic agent is a modulator of a target selected from the group consisting of a serotonin receptor, a norepinephrine receptor, a serotonin transporter, and a norepinephrine transporter.

156. The method as recited in claim 154 wherein said therapeutic agent is selected from the group consisting of phencyclidine (PCP), amantadine, ibogaine, memantine, dextrorphan, ketamine, nitrous oxide, and dextromethorphan.

157. The method as recited in claim 154 wherein said therapeutic agent is an opiod.

158. The method as recited in claim 157 wherein said opioid is selected from the group consisting of morphine, codeine, thebain, diacetylmorphine, oxycodone, hydrocodone, hydromorphone, oxymorphone, nicomorphine, fentanyl, α

-methyl fentanyl, alfentanil, sufentanil, remifentanyl, carfentanyl, ohmefentanyl, pethidine, ketobemidone, propoxyphene, dextropropoxyphene, methadone, loperamide, pentazocine, buprenorphine, etorphine, butorphanol, nalbufine, levorphanol, naloxone, naltrexone, and tramadol.

159. The method as recited in claim 154 wherein said therapeutic agent is an opiod antagonist.

160. The method as recited in claim 159 wherein said opioid antagonist is selected from the group consisting of nalmefene, naltrexone, and naloxone.

161. The method as recited in claim 154 wherein said therapeutic agent is an anesthetic or sedative.

162. The method as recited in claim 161 wherein said anesthetic or sedative is selected from the group consisting of propofol, procaine, lidocaine, prilocaine, bupivacaine, levobupivicaine, nitrous oxide, halothane, enflurane, isoflurane, sevoflurane, desflurane, thiopental, methohexital, etomidate, diazepam, midazolam, lorazepam, succinylcholine, vecuroniurn, rocuronium, pipecuronium, rapacuronium, tubocurarine, and gallamine.

164. A method for modulating a target selected from the group consisting of a serotonin receptor, a norepinephrine receptor, a serotonin transporter, and a norepinephrine transporter, comprising contacting said target with the compound as recited in claim 83.