Methods and compositions for the treatment and prevention of...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...

Reexamination Certificate

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Reexamination Certificate

active

06339106

ABSTRACT:

1. FIELD OF THE INVENTION
The invention relates to methods of using, and compositions comprising, dopamine reuptake inhibitors and, in particular, racemic and optically pure metabolites of sibutramine.
2. BACKGROUND OF THE INVENTION
Sibutramine, chemically named [N-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-N,N-dimethylamine, is a neuronal monoamine reuptake inhibitor which was originally disclosed in U.S. Pat. Nos. 4,746,680 and 4,806,570. Sibutramine inhibits the reuptake of norepinephrine and, to a lesser extent, serotonin and dopamine. See, e.g., Buckett et al.,
Prog. Neuro-psychopharm
. &
Biol. Psychiat
., 12:575-584, 1988; King et al.,
J. Clin. Pharm
., 26:607-611 (1989).
Racemic sibutrainine is sold as a hydrochloride monohydrate under the tradename MERIDIA®, and is indicated for the treatment of obesity.
Physician's Desk Reference
® 1494-1498 (53
rd
ed., 1999). The treatment of obesity using racemic sibutramine is disclosed, for example, in U.S. Pat. No.5,436,272.
Sibutramine appears to have been extensively studied, and reportedly could be used in the treatment of a variety of disorders. For example, U.S. Pat. Nos. 4,552,828, 4,746,680, 4,806,570, and 4,929,629 disclose methods of treating depression using racemic sibutramine, and U.S. Pat. Nos. 4,871,774 and 4,939,175 disclose methods of treating Parkinson's disease and senile dementia, respectively, using racemic sibutramine. Other uses of sibutramine are disclosed by PCT publications WO 95/20949, WO 95/21615, WO 98/11884, and WO 98/13033. Further, the optically pure entantiomers of sibutramine have been considered for development. For example, PCT publications WO 94/00047 and 94/00114 disclose methods of treating depression and related disorders using the (+)- and (−)-enantiomers of sibutramine, respectively.
Sibuitramine is rapidly absorbed from the gastrointestinal tract following oral administration and undergoes an extensive first-pass metabolism that yields the primary metabolites, desmethylsibutramine and didesmethylsibutramine, shown below.
It has been repotted that desmethylsibutramine and didesmethylsibutramine are more potent in vitro noradrenaline and 5-hydroxytryptamine (5HT; serotonin) reuptake inhibitors than sibutramine. Stock, M. J.,
Int'l J. Obesity
, 21(Supp. 1):S25-S29 (1997). It has further been reported, however, that sibutramine and its metabolites have negligible affinities for a wide range of mettrotransmitter receptors, including serotonergie (5-HT
1
, 5-HT
1A
, 5-HT
ID
, 5-HT
2A
, 5-HT
2C
), adrenergic, dopaminergic, musearinic, histaminergic, glutamate, and benzodiazepine receptors. Id.
Sibutramine has a variety of adverse effects. See, e.g.,
Physician's Desk Reference®
1494-1498 (53
rd
ed., 1999). Coupled with the reported benefits and therapeutic insufficiencies of sibutramine, this fact has encouraged the discovery of compounds and compositions that can be used in the treatment or prevention of disorders such as, but not limited to, sexual (e.g., erectile) dysfunction, affective disorders, weight gain or obesity, cerebral function disorders, pain, obsessive-compulsive disorder, substance abuse, chronic disorders, anxiety, eating disorders, migraines, and incontinence. In particular, compounds and compositions are desired that can be used for the treatment and prevention of such disorders and conditions while incurring fewer of the adverse effects associated with sibutramine.
3. SUMMARY OF THE INVENTION
This invention encompasses methods, pharmaceutical compositions, and dosage forms for the treatment and prevention of disorders that are ameliorated by the inhibition of neuronial monoamine uptake in mammals, including humans. Examples of such disorders include, but are not limited to, sexual (e.g., erectile) dysfunction, affective disorders, weight gain or obesity, cerebral function disorders, pain, obsessive-compulsive disorder, substance abuse, chronic disorders, anxiety, eating disorders, migraines, and incontinence. The methods of the invention comprise administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof.
This invention also encompasses a method of treating or preventing sexual dysfunction which comprises adjunctively administering to a patient in need of such treatment or prevention therapeutically or prophylactically effective amounts of a dopamine reuptake inhibitor and a 5-HT
3
antagonist. Examples of sexual dysfunction include, but are not limited to, erectile dysfunction.
Pharmaceutical compositions of the invention comprise a therapeutically or prophylactically effective amount of a neuronal monoamine reuptake inhibitor. Preferred neuronal monoamine reuptake inhibitors include, but are not limited to, apomorphinie, racemic and optically pure sibutramine metabolites, and pharmaceutically acceptable salts, solvates, and clathrate thereof. Pharmaceutical compositions of the invention can further comprise other drug substances, including, but not limited to, 5-HT
3
antagonists.
The invention encompasses the use of racemic and optically pure sibutramine metabolites as effective dopamine, serotonin, and norepinephrine reuptake inhibitors. Racemic and optically pure sibutramine metabolites include, but are not limited to, (+)-desmethylsibutramine, (−)-desmethylsibutramine, (±)-desmethylsibutramine, (+)-didesmethylsibutramine, (−)-didesmethylsibutramine, and (±)-didesmethylsibutramine.
4. DETAILED DESCRIPTION OF THE INVENTION
This invention relates to methods and compositions that inhibit the reuptake of neuronal monoamines (e.g., dopamine, serotonin, and norepinephrine). The invention thereby provides a method of treating or preventing a disorder ameliorated by the inhibition of neuronal monoamine reuptake which comprises administering to a patient (i.e., a human) in need of such treatment or prevention a therapeutically or prophylactically effective amount of neuronal monoamine reuptake inhibitor. Preferred neuronial monoamine reuptake inhibitors are racemic and optically pure sibutramine metabolites and pharmaceutically acceptable salts, solvates, and clathrates thereof.
As used herein, the term “treating or preventing disorders ameliorated by inhibition of neuronal monoamine reuptake” means relief from symptoms of conditions associated with abnormal neuronial monoamine levels. Disorders ameliorated by inhibition of neuronal monoamine reuptake include, but are not limited to, sexual (e.g., erectile) dysfunction, affective disorders, weight gain or obesity, cerebral function disorders, pain, obsessive-compulsive disorder, substance abuse, chronic disorders, anxiety, eating disorders, migraines, and incontinence.
A first embodiment of the invention encompasses a method of treating or preventing sexual dysfunction which comprises adjunctively administering to a patient in need of such treatment or prevention therapeutically or prophylactically effective amounts of a dopamine reuptake inhibitor and a 5-HT
3
antagonist.
As used herein, the term “sexual dysfunction” encompasses sexual dysfunction in men and women caused by psychological and/or physiological factors. Examples of sexual dysfunction include, but are not limited to, erectile dysfunction, vaginal dryness, lack of sexual excitement, or inability to obtain orgasm. The term “sexual dysfunction” further encompasses psycho-sexual dysfunction. Examples of psycho-sexual dysfunction include, but are not limited to, inhibited sexual desire, inhibited sexual excitement, inhibited female orgasm, inhibited male orgasm, premature ejaculation, functional dyspareunia, functional vaginismus, and atypical psychosexual dysfunction.
In preferred methods of this embodiment, the dopamine inhibitor is selected from the group which includes, but is not limited to, apomolphine, sibutramine, racemic and optically pure sibutramine metabolites, and pharmace

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