Bupropion metabolites and methods of use

Details Bupropion metabolites and methods of use Bupropion metabolites and methods of use

2000-08-18

2002-01-08

Jarvis, William R. A. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S649000, C514S653000

Reexamination Certificate

active

06337328

ABSTRACT:

1. FIELD OF THE INVENTION
This invention relates to the synthesis of, methods of using, and compositions comprising bupropion metabolites, their isomers, and salts thereof.
2. BACKGROUND OF THE INVENTION
Bupropion, a racemic mixture of (+)- and (−)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone, is an antidepressant of the aminoketone class, which is described in U.S. Pat. Nos. 3,819,706 and 3,885,046. The hydrochloride salt of bupropion is sold under the tradenames WELLBUTRIN® and WELLBUTRIN SR® (Glaxo Wellcome Inc.) for the treatment of depression. Bupropion is also sold under the tradename ZYBAN® (Glaxo Wellcome Inc.) as a drug useful to achieve smoking cessation. Additional benefits of bupropion maleate are reported in European Patent Application No. 118036.
Although its mechanism of action is poorly understood, bupropion is reportedly a weak but selective inhibitor of dopamine. Its potency as an inhibitor of norepinephrine reuptake is reportedly only half of that for dopamine, and it shows little affinity for the serotonergic transport system. Ascher, J. A., et al.,
J Clin. Psychiatry,
56:395-401 (1995).
Bupropion is extensively metabolized in man and animal. Three metabolites found in the plasma of healthy humans to whom it has been administered are shown in Scheme 1:
Posner, J., et al.,
Eur. J. Clin Pharmacal.,
29:97-103 (1985); Suckow, R. F., et al.,
Biomedical Chromatography,
11:174-179 (1997). Referring to Scheme 1, metabolite
1
has the chemical name 2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol; metabolite
2
has the chemical name 2-(tert-butylamino)-1-(3-chlorophenyl)-propane-1-ol; and metabolite
3
has the chemical name 1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone. Because bupropion is administered as a racemate and its metabolites are chiral, stereomeric mixtures of each of the metabolites
1, 2,
and
3
likely exist in human plasma following its administration.
The bupropion metabolite
1
, often referred to as “hydroxybupropion,” has two chiral carbon atoms and can thus theoretically exist as two pairs of enantiomers. These are shown in Scheme 2:
Based on studies using racemic bupropion in mice, it has been suggested that racemic hydroxybupropion may contribute to the antidepressant profile of racemic bupropion in depressed patients. Kelley, J. L., et al.,
J. Med. Chem.,
39:347-349 (1996). The mixture 1a has been isolated from human plasma and allegedly separated into its (S,S) and (R,R) components. Suckow, R. F., et al.,
Biomedical Chromatography,
11:174-179 (1997). However, activity of the individual enantiomers was not reported in Suckow.
The amino alcohol metabolite
2
, also referred to as “dihydrobupropion,” can also exist as two pairs of enantiomers. These are shown in Scheme 3:
The pair wherein the alcohol and amine moietics are cis to each other is commonly referred to as the erythro-amino alcohol metabolite; the pair wherein the two moieties are trans to each other is referred to as the threo-amino alcohol metabolite.
The tert-butyl alcohol metabolite
3
can exist as one of two enantiomers. This racemic metabolite, the accumulation of which in human plasma coincides with the elimination of a single dose of bupropion, is believed by some to be a precursor to hydroxybupropion. Posner, J., et al.,
Eur. J. Clin. Pharmacol.,
29:97-103 (1985); Suckow, R. F., et al., Biomedical Chromatography, 11: 174-179 (1997).
Clearly, the metabolism of bupropion, which is complicated and poorly understood, results in a complex array of chiral compounds. The structures of these molecules and their chirality provide the skilled artisan with difficult issues of asymmetric synthesis, chiral resolution, and pharmacological activity.
Racemic bupropion is widely used to treat affective disorders in patients who do not respond to, or cannot tolerate, other antidepressants such as tricyclic agents or monoamine oxidase inhibitors. Examples of affective disorders are depression and bipolar manic-depression. Racemic bupropion is also useful in the treatment of other diseases or conditions associated with the reuptake of neuronal monoamines such as serotonin and norepinephrine. These reportedly include: schizophrenia (U.S. Pat. No. 5,447,948); attention-deficit disorder; psycho-sexual dysfunction (U.S. Pat. No. 4,507,323); bulimia and other eating disorders; Parkinson's disease; migraine (U.S. Pat. No. 5,753,712); and chronic pain. Racemic bupropion also reportedly increases success rates in some smoking cessation treatments. Rose, J. E.,
Annu. Rev. Med.,
47:493-507 (1996); Ferry, L. H. et al.,
J. Addict. Dis.,
13:A9 (1994); and Lief, H. I.,
Am. J. Psychiatry,
153(3):442 (1996).
Further uses of racemic bupropion reportedly include the treatment of: the effects of ethanol (U.S. Pat. No. 4,393,078); tardive dyskinesia (U.S. Pat. No. 4,425,363); drowsiness (U.S. Pat. Nos. 4,571,395 and 4,798,826); minimal brain dysfunction (U.S. Pat. No. 4,435,449); psychosexual dysfunction (U.S. Pat. No. 4,507,323); prostate hypertrophy and sexual dysfunction (U.S. Pat. No. 4,835,147); psychostimulant addiction (U.S. Pat. No. 4,935,429); substance abuse (U.S. Pat. No. 5,217,987); high cholesterol (U.S. Pat. No. 4,438,138); and weight gain (U.S. Pat. No. 4,895,845).
Certain advantages exist in using bupropion for the treatment of diseases and conditions. For example, bupropion does not inhibit monoamine oxidase or block the reuptake of serotonin, unlike other neuronal monoamine reuptake inhibitors. Administration of bupropion can thus avoid or lessen many adverse effects commonly associated with other antidepressants such as tricyclic agents and monoamine oxidase inhibitors.
Unfortunately, racemic bupropion is not free of adverse effects. Administration of the drug can cause seizures, especially in patients currently taking the monoamine oxidase inhibitor phenelzine. Other frequently reported adverse effects associated with the use of racemic bupropion include nausea, vomiting, excitement, agitation, blurred or blurry vision, restlessness, postural tremors, hallucinations/confusional states with the potential for abuse, anxiety, insomnia, headaches and/or migraines, dry mouth, constipation, tremor, seizures, sleeping disturbances, dermatologic problems (e.g., rashes), neuropsychiatric signs and symptoms (e.g. delusions and paranoia), and weight loss or gain. See, e.g.,
Physicians' Desk Reference®
1252-1258 (53
rd
ed. 1999). These effects are dose limiting in a number of patients, and can be particularly dangerous for Parkinson's patients.
Thus, there remains a need for a drug that provides the advantages of racemic bupropion, but with fewer disadvantages. Compounds and pharmaceutical compositions are desired that can be used for the treatment and prevention of disorders and conditions while reducing or avoiding adverse effects associated with the administration of racemic bupropion.
3. SUMMARY OF THE INVENTION
This invention encompasses methods of making and using bupropion metabolites and pharmaceutically acceptable salts, solvates, hydrates, and clathrates thereof, and pharmaceutical compositions and dosage forms comprising bupropion metabolites and pharmaceutically acceptable salts, solvates, hydrates, and clathrates thereof. In particular, the invention provides methods of synthesizing optically pure (S,S)-hydroxybupropion, and optically pure (R,R)-hydroxybupropion. In addition, the invention encompasses methods of synthesizing optically pure (S,S)-dihydrobupropion, (R,R)-dihydrobupropion, (S,R)-dihydrobupropion, and (R,S)-dihydrobupropion.
The invention further provides methods of treating and preventing conditions that include, but are not limited to, sexual dysfunction, affective disorders, cerebral function disorders, substance addiction, tobacco smoking, and incontinence. Methods of the invention comprise administering to a patient in need of such treatment or prevention, a therapeutically or prophylactically effective amount of a bupropion metabolite, or a pharmaceutically acce

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