Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-22
2002-01-29
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
06342496
ABSTRACT:
1. FIELD OF THE INVENTION
This invention relates to synthesis of, methods of using, and compositions comprising bupropion metabolites and isomers 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, and is described in U.S. Pat. Nos. 3,819,706 and 3,885,046. The hydrochloride salt of bupropion is sold under the trade names WELLBUTRIN® and WELLBUTRIN SR® for the treatment of depression. Bupropion is also sold under the trade name ZYBAN® 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 which 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 1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanol; and metabolite 3 has the chemical name 1-(3-chlorophenyl)-2-[(1,1-dimethylethanol)amino]-1-propanone. Because bupropion is racemic and its metabolites are chiral, enantiomers 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 exist as two pairs of enantiomers. These are shown in Scheme 2:
Pair 1a is reportedly the most active human metabolite bupropion. 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).
The amino alcohol metabolite 2 can also exist as two pairs of enantiomers. The pair wherein the alcohol and amine moieties are cis 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 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 optically active compounds. The structures of these molecules and their chirality provides the skilled artisan with difficult issues of asymmetric synthesis, chiral resolution, and pharmacological activity.
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. 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. 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 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 such as those provided above. For example, it 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 of the adverse side effects commonly associated with other antidepressants such as tricyclic agents and monoamine oxidase inhibitors.
Unfortunately, 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 bupropion include nausea, vomiting, excitement, agitation, blurred or blurry vision, restlessness, postural tremor, hallucinations/confusional states with the potential for abuse, anxiety, insomnia, headaches and/or migraines, dry mouth, constipation, tremor, sleeping disturbances, dermatologic problems (e.g., rashes), neuropsychiatric signs and symptoms (e.g., delusions and paranoia), and weight loss or gain.
Physicians' Desk References
® 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.
There thus remains a need for a drug that provides the advantages of 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 incurring fewer of the adverse effects associated with bupropion.
3. SUMMARY OF THE INVENTION
This invention encompasses methods of making and using bupropion metabolites and pharmaceutical compositions and dosage forms comprising bupropion metabolites. In particular, the invention provides methods of synthesizing optically pure (S,S)-hydroxybupropion and optically pure (R,R)-hydroxybupropion.
The invention further provides methods of treating and preventing conditions that include, but are not limited to, erectile dysfunction, affective disorders, cerebral function disorders, 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 acceptable salt, solvate, or clathrate thereof. Preferred methods of the invention further comprise the use of at least one additional physiologically active agent such as a selective serotonin reuptake inhibitor (“SSRI”), 5-HT
3
antagonist, or nicotine with a bupropion metabolite.
Pharmaceutical compositions and dosage forms of the invention comprise a therapeutically or prophylactically effective amount of a bupropion metabolite and optionally at least one additional physiologically active agent such as a SSRI, 5-HT
3
antagonist, or nicotine.
3.2. DEFINITIONS
As used herein, the term “patient” includes mammal, which includes human.
As used herein, the term “bupropion metabolite” includes, but is not limited to, 2-(3-chlorophenyl)-2-hydroxy-3,5,5-trimethyl-morpholinol, 1-(3-chlorophenyl)-2-[(
Fang Qun K.
Jerussi Thomas P.
McCullough John R.
Senanayake Chrisantha H.
Pennie & Edmonds LLP
Sepracor Inc.
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