METHODS OF TREATING NEUROLOGICAL AND OTHER DISORDERS USING ENANTIOPURE DEUTERIUM-ENRICHED BUPROPION

1 . A method of treating a disorder selected from the group consisting of obesity, sexual dysfunction, neuropathic pain, attention deficit disorder, attention deficit hyperactivity disorder, and Parkinson's disease, comprising administering to a patient in need thereof a therapeutically effective amount of a deuterium-enriched compound of Formula I having an optical purity of at least 75% enantiomeric excess to treat the disorder, wherein Formula I is represented by:

or a pharmaceutically acceptable salt thereof, wherein:

A 1 , A 2 , A 3 , and A 4 are independently —C(R 6 )(R 7 )(R 8 );

R 1 , R 2 , R 3 , R 4 , and R 5 are independently H or D;

R 6 , R 7 , and R 8 each represent independently for each occurrence H or D; and

Z is H or D, provided that the abundance of deuterium in Z is at least 30%.

2 . The method of claim 1 , wherein the disorder is obesity.

3 . The method of claim 1 , wherein the disorder is sexual dysfunction.

4 . The method of claim 1 , wherein the disorder is female sexual dysfunction.

5 . The method of claim 1 , wherein the disorder is neuropathic pain.

6 . The method of claim 5 , wherein the neuropathic pain is a postherpetic neuralgia, a trigeminal neuralgia, phantom limb pain, pain associated with diabetic neuropathy, or pain associated with carpal tunnel syndrome.

7 . The method of claim 1 , wherein the disorder is attention deficit hyperactivity disorder.

8 . A method of treating a disorder selected from the group consisting of (i) seasonal affective disorder, (ii) depression in a patient suffering from Parkinson's disease, and (iii) treatment-resistant depression, comprising administering to a patient in need thereof a therapeutically effective amount of a deuterium-enriched compound of Formula I having an optical purity of at least 75% enantiomeric excess to treat the disorder, wherein Formula I is represented by:

or a pharmaceutically acceptable salt thereof, wherein:

A 1 , A 2 , A 3 , and A 4 are independently —C(R 6 )(R 7 )(R 8 );

R 1 , R 2 , R 3 , R 4 , and R 5 are independently H or D;

R 6 , R 7 , and R 8 each represent independently for each occurrence H or D; and

Z is H or D, provided that the abundance of deuterium in Z is at least 30%.

9 . The method of claim 8 , wherein the disorder is seasonal affective disorder.

10 . The method of claim 8 , wherein the disorder is depression in a patient suffering from Parkinson's disease.

11 . A method of treating a neurological disorder selected from the group consisting of Alzheimer's disease, tardive dyskinesia, Tourette syndrome, Huntington's disease, Rett syndrome, Prader-Willi syndrome, restless leg syndrome, narcolepsy, ataxia, corticobasal ganglionic degeneration dyskinesia, dystonia, tremors, multiple system atrophy, progressive supranuclear palsy, olivopontocerebellar atrophy, diffuse Lewy body disease, stiff man syndrome, apathy, generalized anxiety, panic disorder, addiction, bipolar disorder, social anxiety disorder, obsessive compulsive disorder, post-traumatic stress disorder, a sleep disorder, an eating disorder, a neuropathic condition, diabetic neuropathy, a cognitive disorder, a psychotic disorder, psychosexual dysfunction, prostate hypertrophy, migraine, bipolar depression, depression in a patient suffering from Alzheimer's disease, depression in a patient suffering from dementia, and depression in a patient suffering from hypothyroidism, comprising administering to a patient in need thereof a therapeutically effective amount of a deuterium-enriched compound of Formula I having an optical purity of at least 75% enantiomeric excess to treat the disorder, wherein Formula I is represented by:

or a pharmaceutically acceptable salt thereof, wherein:

A 1 , A 2 , A 3 , and A 4 are independently —C(R 6 )(R 7 )(R 8 );

R 1 , R 2 , R 3 , R 4 , and R 5 are independently H or D;

R 6 , R 7 , and R 8 each represent independently for each occurrence H or D; and

Z is H or D, provided that the abundance of deuterium in Z is at least 30%.

12 . A method of treating a movement disorder selected from the group consisting of hereditary spastic paraplegia, myoclonus, spasticity, chorea, athetosis, ballism, stereotypy, tardive dystonia, tics, hemiballismus, hemi-facial spasm, psychomotor retardation, painful legs moving toes syndrome, a gait disorder, and a drug-induced movement disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a deuterium-enriched compound of Formula I having an optical purity of at least 75% enantiomeric excess to treat the disorder, wherein Formula I is represented by:

or a pharmaceutically acceptable salt thereof, wherein:

A 1 , A 2 , A 3 , and A 4 are independently —C(R 6 )(R 7 )(R 8 );

R 1 , R 2 , R 3 , R 4 , and R 5 are independently H or D;

R 6 , R 7 , and R 8 each represent independently for each occurrence H or D; and

Z is H or D, provided that the abundance of deuterium in Z is at least 30%.

13 . A method of treating a disorder selected from the group consisting of inflammatory bowel disease, psoriasis, hypotension, presyncope, syncope, Wilson's disease, shift work sleep disorder, akinetic mutism, chronic fatigue syndrome, fibromyalgia, premenstrual syndrome, premenstrual dysphoric disorder, pain, a viral infection, a cardiovascular disease, hepatic steatosis, diabetes, insulin resistance, sleep apnea, arthritis, vascular dementia, gout, calculi, and a disorder requiring a stimulant effect, comprising administering to a patient in need thereof a therapeutically effective amount of a deuterium-enriched compound of Formula I having an optical purity of at least 75% enantiomeric excess to treat the disorder, wherein Formula I is represented by:

or a pharmaceutically acceptable salt thereof, wherein:

A 1 , A 2 , A 3 , and A 4 are independently —C(R 6 )(R 7 )(R 8 );

R 1 , R 2 , R 3 , R 4 , and R 5 are independently H or D;

R 6 , R 7 , and R 8 each represent independently for each occurrence H or D; and

Z is H or D, provided that the abundance of deuterium in Z is at least 30%.

14 . A method of reducing dependence by a patient to a substance selected from the group consisting of an opioid, an amphetamine, a tropane alkaloid, a hypnotic, an anti-depressant, a hallucinogen, a pain medication, a sleep medication, and combinations thereof, comprising administering to a patient in need thereof a therapeutically effective amount of a deuterium-enriched compound of Formula I having an optical purity of at least 75% enantiomeric excess to reduce said substance dependence, wherein Formula I is represented by:

or a pharmaceutically acceptable salt thereof, wherein:

A 1 , A 2 , A 3 , and A 4 are independently —C(R 6 )(R 7 )(R 8 );

R 1 , R 2 , R 3 , R 4 , and R 5 are independently H or D;

R 6 , R 7 , and R 8 each represent independently for each occurrence H or D; and

Z is H or D, provided that the abundance of deuterium in Z is at least 30%.

15 . The method of claim 14 , wherein the substance dependence is dependence on methamphetamine or cocaine.

16 . The method of any one of claims 1 - 15 , wherein R 1 , R 2 , R 3 , R 4 , and R 5 are H.

17 . The method of any one of claims 1 - 15 , wherein A 1 , A 2 , A 3 , and A 4 are —CH 3 .

18 . The method of any one of claims 1 - 15 , wherein the compound is a compound of Formula I-A having an optical purity of at least 75% enantiomeric excess, wherein Formula I-A is represented by:

or a pharmaceutically acceptable salt thereof, wherein Z is H or D, provided that the abundance of deuterium in Z is at least 30%.

19 . The compound of any one of claims 1 - 18 wherein the abundance of deuterium in Z is at least 60%.

20 . The compound of any one of claims 1 - 18 , wherein the abundance of deuterium in Z is at least 75%.

21 . The compound of any one of claims 1 - 18 , wherein the abundance of deuterium in Z is at least 90%.

22 . The compound of any one of claims 1 - 21 , wherein the compound has an enantiomeric excess of at least 85%.

23 . The compound of any one of claims 1 - 21 , wherein the compound has an enantiomeric excess of at least 90%.

24 . The compound of any one of claims 1 - 21 , wherein the compound has an enantiomeric excess of at least 95%.

25 . The method of any one of claims 1 - 15 , wherein the compound is:

or a pharmaceutically acceptable salt thereof, each having an optical purity of at least 90% enantiomeric excess.

26 . The method of any one of claims 1 - 15 , wherein the compound is:

having an optical purity of at least 90% enantiomeric excess.

27 . The method of any one of claims 1 - 15 , wherein the compound is:

or a pharmaceutically acceptable salt thereof, each having an optical purity of at least 95% enantiomeric excess.

28 . The method of any one of claims 1 - 15 , wherein the compound is:

having an optical purity of at least 95% enantiomeric excess.

29 . A method of treating a disorder selected from the group consisting of obesity, sexual dysfunction, neuropathic pain, attention deficit disorder, attention deficit hyperactivity disorder, and Parkinson's disease, comprising administering to a patient in need thereof a therapeutically effective amount of a deuterium-enriched compound of Formula II having an optical purity of at least 75% enantiomeric excess to treat the disorder, wherein Formula II is represented by:

or a pharmaceutically acceptable salt thereof, wherein:

A 1 , A 2 , A 3 , and A 4 are independently —C(R 6 )(R 7 )(R 8 );

R 1 , R 2 , R 3 , R 4 , and R 5 are independently H or D;

R 6 , R 7 , and R 8 each represent independently for each occurrence H or D; and

Z is H or D, provided that the abundance of deuterium in Z is at least 30%.

30 . The method of claim 29 , wherein the disorder is obesity.

31 . The method of claim 29 , wherein the disorder is sexual dysfunction.

32 . The method of claim 29 , wherein the disorder is female sexual dysfunction.

33 . The method of claim 29 , wherein the disorder is neuropathic pain.

34 . The method of claim 33 , wherein the neuropathic pain is a postherpetic neuralgia, a trigeminal neuralgia, phantom limb pain, pain associated with diabetic neuropathy, or pain associated with carpal tunnel syndrome.

35 . The method of claim 29 , wherein the disorder is attention deficit hyperactivity disorder.

36 . A method of treating a disorder selected from the group consisting of (i) seasonal affective disorder, (ii) depression in a patient suffering from Parkinson's disease, and (iii) treatment-resistant depression, comprising administering to a patient in need thereof a therapeutically effective amount of a deuterium-enriched compound of Formula II having an optical purity of at least 75% enantiomeric excess to treat the disorder, wherein Formula II is represented by:

or a pharmaceutically acceptable salt thereof, wherein:

A 1 , A 2 , A 3 , and A 4 are independently —C(R 6 )(R 7 )(R 8 );

R 1 , R 2 , R 3 , R 4 , and R 5 are independently H or D;

R 6 , R 7 , and R 8 each represent independently for each occurrence H or D; and

Z is H or D, provided that the abundance of deuterium in Z is at least 30%.

37 . The method of claim 36 , wherein the disorder is seasonal affective disorder.

38 . The method of claim 36 , wherein the disorder is depression in a patient suffering from Parkinson's disease.

39 . A method of treating a neurological disorder selected from the group consisting of Alzheimer's disease, tardive dyskinesia, Tourette syndrome, Huntington's disease, Rett syndrome, Prader-Willi syndrome, restless leg syndrome, narcolepsy, ataxia, corticobasal ganglionic degeneration dyskinesia, dystonia, tremors, multiple system atrophy, progressive supranuclear palsy, olivopontocerebellar atrophy, diffuse Lewy body disease, stiff man syndrome, apathy, generalized anxiety, panic disorder, addiction, bipolar disorder, social anxiety disorder, obsessive compulsive disorder, post-traumatic stress disorder, a sleep disorder, an eating disorder, a neuropathic condition, diabetic neuropathy, a cognitive disorder, a psychotic disorder, psychosexual dysfunction, prostate hypertrophy, migraine, bipolar depression, depression in a patient suffering from Alzheimer's disease, depression in a patient suffering from dementia, and depression in a patient suffering from hypothyroidism, comprising administering to a patient in need thereof a therapeutically effective amount of a deuterium-enriched compound of Formula II having an optical purity of at least 75% enantiomeric excess to treat the disorder, wherein Formula II is represented by:

or a pharmaceutically acceptable salt thereof, wherein:

A 1 , A 2 , A 3 , and A 4 are independently —C(R 6 )(R 7 )(R 8 );

R 1 , R 2 , R 3 , R 4 , and R 5 are independently H or D;

R 6 , R 7 , and R 8 each represent independently for each occurrence H or D; and

Z is H or D, provided that the abundance of deuterium in Z is at least 30%.

40 . A method of treating a movement disorder selected from the group consisting of hereditary spastic paraplegia, myoclonus, spasticity, chorea, athetosis, ballism, stereotypy, tardive dystonia, tics, hemiballismus, hemi-facial spasm, psychomotor retardation, painful legs moving toes syndrome, a gait disorder, and a drug-induced movement disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a deuterium-enriched compound of Formula II having an optical purity of at least 75% enantiomeric excess to treat the disorder, wherein Formula II is represented by:

or a pharmaceutically acceptable salt thereof, wherein:

A 1 , A 2 , A 3 , and A 4 are independently —C(R 6 )(R 7 )(R 8 );

R 1 , R 2 , R 3 , R 4 , and R 5 are independently H or D;

R 6 , R 7 , and R 8 each represent independently for each occurrence H or D; and

Z is H or D, provided that the abundance of deuterium in Z is at least 30%.

41 . A method of treating a disorder selected from the group consisting of inflammatory bowel disease, psoriasis, hypotension, presyncope, syncope, Wilson's disease, shift work sleep disorder, akinetic mutism, chronic fatigue syndrome, fibromyalgia, premenstrual syndrome, premenstrual dysphoric disorder, pain, a viral infection, a cardiovascular disease, hepatic steatosis, diabetes, insulin resistance, sleep apnea, arthritis, vascular dementia, gout, calculi, and a disorder requiring a stimulant effect, comprising administering to a patient in need thereof a therapeutically effective amount of a deuterium-enriched compound of Formula II having an optical purity of at least 75% enantiomeric excess to treat the disorder, wherein Formula II is represented by:

or a pharmaceutically acceptable salt thereof, wherein:

A 1 , A 2 , A 3 , and A 4 are independently —C(R 6 )(R 7 )(R 8 );

R 1 , R 2 , R 3 , R 4 , and R 5 are independently H or D;

R 6 , R 7 , and R 8 each represent independently for each occurrence H or D; and

Z is H or D, provided that the abundance of deuterium in Z is at least 30%.

42 . A method of reducing dependence by a patient to a substance selected from the group consisting of an opioid, an amphetamine, a tropane alkaloid, a hypnotic, an anti-depressant, a hallucinogen, a pain medication, a sleep medication, and combinations thereof, comprising administering to a patient in need thereof a therapeutically effective amount of a deuterium-enriched compound of Formula II having an optical purity of at least 75% enantiomeric excess to reduce said substance dependence, wherein Formula II is represented by:

or a pharmaceutically acceptable salt thereof, wherein:

A 1 , A 2 , A 3 , and A 4 are independently —C(R 6 )(R 7 )(R 8 );

R 1 , R 2 , R 3 , R 4 , and R 5 are independently H or D;

R 6 , R 7 , and R 8 each represent independently for each occurrence H or D; and

Z is H or D, provided that the abundance of deuterium in Z is at least 30%.

43 . The method of claim 42 , wherein the substance dependence is dependence on methamphetamine or cocaine.

44 . The method of any one of claims 29 - 43 , wherein R 1 , R 2 , R 3 , R 4 , and R 5 are H.

45 . The method of any one of claims 29 - 43 , wherein A 1 , A 2 , A 3 , and A 4 are —CH 3 .

46 . The method of any one of claims 29 - 43 , wherein the compound is a compound of Formula II-A having an optical purity of at least 75% enantiomeric excess, wherein Formula II-A is represented by:

or a pharmaceutically acceptable salt thereof, wherein Z is H or D, provided that the abundance of deuterium in Z is at least 30%.

47 . The compound of any one of claims 29 - 46 , wherein the abundance of deuterium in Z is at least 60%.

48 . The compound of any one of claims 29 - 46 , wherein the abundance of deuterium in Z is at least 75%.

49 . The compound of any one of claims 29 - 46 , wherein the abundance of deuterium in Z is at least 90%.

50 . The compound of any one of claims 29 - 49 , wherein the compound has an enantiomeric excess of at least 85%.

51 . The compound of any one of claims 29 - 49 , wherein the compound has an enantiomeric excess of at least 90%.

52 . The compound of any one of claims 29 - 49 , wherein the compound has an enantiomeric excess of at least 95%.

53 . The method of any one of claims 29 - 43 , wherein the compound is:

or a pharmaceutically acceptable salt thereof, each having an optical purity of at least 90% enantiomeric excess.

54 . The method of any one of claims 29 - 43 , wherein the compound is:

having an optical purity of at least 90% enantiomeric excess.

55 . The method of any one of claims 29 - 43 , wherein the compound is:

56 .

or pharmaceutically acceptable salt thereof, each having an optical purity of at least 95% enantiomeric excess.

57 . The method of any one of claims 29 - 43 , wherein the compound is:

having an optical purity of at least 9500 enantiomeric excess.

58 . The method of any one of claims 1 - 57 , wherein the compound is administered at a daily dose in the range of about 50 mg to 75 mg, 75 mg to 100 mg, 100 mg to 125 mg, 125 mg to 150 mg, 150 mg to 175 mg, 175 mg to 200 mg, 200 mg to 225 mg, 225 mg to 250 mg, 250 mg to 275 mg, or 275 mg to 300 mg.

59 . The method of any one of claims 1 - 57 , wherein the compound is administered at a daily dose in the range of about 50 mg to 175 mg, or about 125 mg to 175 mg.