ZA200101498B - Methods of using and compositions comprising dopamine reuptake inhibitors. - Google Patents

Description

i WO 00/10551 PCT/US99/19167 : METHODS OF USING AND COMPOSITIONS

COMPRISING DOPAMINE REUPTAKE INHIBITORS

This application claims the benefit of U.S. Provisional Application No. 60/097,665, filed August 24, 1998, and U.S. Provisional Application No. 60/099,306, filed September 2, 1998, both of which are incorporated herein in their entireties by reference. 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. Patent 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 sibutramine 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 ed., 1999). The treatment of obesity using racemic sibutramine is disclosed, for example, in U.S. Patent 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. Patent 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. Patent 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.

Sibutramine 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. oY

Cl CH” CH; sibutramine

J oY — oT

NH NH cl CHy cl 2 desmethylsibutramine didesmethylsibutramine

It has been reported that desmethylsibutramine and didesmethylsibutramine are } more potent in vitro noradrenaline and 5-hydroxytryptamine (SHT; serotonin) reuptake inhibitors than sibutramine. Stock, M.J., Int'l J. Obesity, 21(Supp. 1):5S25-829 (1997). It . has further been reported, however, that sibutramine and its metabolites have negligible affinities for a wide range of neurotransmitter receptors, including serotonergic (5-HT,, 5- ' HT,,, 5-HT,, 5-HT,,, 5-HT,), adrenergic, dopaminergic, muscarinic, histaminergic, glutamate, and benzodiazepine receptors. Id. - 25 Sibutramine has a variety of adverse effects. See, e.g., Physician's Desk Reference® 1494-1498 (53% 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, 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. _2-

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 neuronal monoamine uptake in mammals, including humans. Examples of such disorders include, but are not limited to, 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 erectile 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, antagonist.

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, apomorphine, ] racemic and optically pure sibutramine metabolites, and pharmaceutically acceptable salts, solvates, and clathrate thereof. Pharmaceutical compositions of the invention can further i 20 comprise other drug substances, including, but not limited to, 5-HT, 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 neuronal 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 neuronal monoamine levels. Disorders ameliorated by inhibition of neuronal monoamine reuptake include, but are not limited to, 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 erectile 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, antagonist. Preferred dopamine reuptake inhibitors include, but are not limited to, apomorphine, sibutramine, racemic and optically pure sibutramine metabolites, and pharmaceutically acceptable salts, solvates, and clathrates thereof.

Particularly preferred dopamine reuptake inhibitors are racemic and optically pure sibutramine metabolites. Preferred 5-HT, antagonists are antiemetic agents. Examples of suitable 5-HT, antagonists include, but are not limited to, granisetron (KYTRIL®), . metoclopramide (REGLAN®), ondansetron (ZOFRAN®), renzapride, zacopride, tropisetron, and optically pure stereoisomers, active metabolites, and pharmaceutically acceptable salts, : clathrates, and solvates thereof.

In a preferred method of this embodiment, the dopamine reuptake inhibitor is administered transdermally or mucosally (e.g., nasally, sublingually, or buccally). Ina more preferred method of this embodiment, the dopamine reuptake inhibitor and the 5-HT, antagonist are both administered transdermally or mucosally.

A second embodiment of the invention encompasses a method of treating or preventing erectile dysfunction which comprises 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. In a preferred method of this embodiment, the racemic or optically pure sibutramine metabolite or pharmaceutically acceptable salt, solvate, or clathrate thereof is administered transdermally or mucosally.

A third embodiment of the invention encompasses a method of treating or : preventing an affective disorder which comprises 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. Affective disorders include, but are not limited to, depression (e.g., melancholia), attention deficit disorder (including attention deficit disorder with hyperactivity and attention deficit/hyperactivity disorder), bipolar and manic conditions, dysthymic disorder, and cyclothymic disorder. As used herein, the terms "attention deficit disorder" (ADD), "attention deficit disorder with hyperactivity" (ADDH), and “attention deficit/hyperactivity disorder” (AD/HD), are used in accordance with their accepted meanings in the art. See, e.g., Diagnostic and Statistical Manual of Mental Disorders,

Fourth Ed., American Psychiatric Association, 1997 (DSM-IV™,) and Diagnostic and

Statistical Manual of Mental Disorders, 3" Ed., American Psychiatric Association (1981) ~ (DSM-HI™),

A preferred method of this embodiment is a method of treating or preventing attention deficit disorder which comprises 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. In the treatment or prevention of attention deficit disorder, the racemic or : 20 optically pure sibutramine metabolite is an optically pure sibutramine metabolite, and more preferably is (-)-desmethylsibutramine or (-)-didesmethylsibutramine.

Another preferred method of this embodiment is a method of treating or preventing depression which comprises 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, As used herein, the term "treating or preventing depression" means relief from or prevention of the symptoms of depression which include, but are not limited to, changes in mood, feelings of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, and self-deprecation. Physical changes can also be relieved or prevented by this method, and include, but are not limited to, insomnia, anorexia, decreased energy and libido, and abnormal hormonal circadian rhythms.

A fourth embodiment of the invention encompasses a method of treating or preventing weight gain or obesity which comprises 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. As used herein, the term "treating or preventing weight gain or obesity" means reduction of weight, relief from being overweight, relief from gaining . weight, or relief from obesity, and prevention from gaining weight, all of which are usually due to unnecessary consumption of food.

A fifth embodiment of the invention encompasses a method of treating or preventing a cerebral function disorder which comprises 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. Cerebral function disorders include, but are not limited to, senile dementia, Alzheimer's type dementia, memory loss, amnesia/amnestic syndrome, disturbance of consciousness, coma, lowering of attention, speech disorders, Parkinson's disease, Lennox syndrome, autism, epilepsy, hyperkinetic syndrome, and schizophrenia.

Cerebral function disorders can be induced by factors including, but not limited to, cerebrovascular diseases, such as cerebral infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis, and head injuries, and conditions having symptoms selected from the group consisting of disturbances of consciousness, senile "dementia, coma, lowering of attention, and speech disorders. As used herein, the term “treating or preventing a cerebral function disorder” means relief from or prevention of one or more symptoms associated with cercbral function disorders.

A sixth embodiment of the invention encompasses a method of treating or preventing pain, including chronic pain, which comprises 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.

A seventh embodiment of the invention encompasses a method of treating or preventing an obsessive-compulsive disorder which comprises 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.

An eighth embodiment of the invention encompasses a method of treating or preventing substance abuse which comprises 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. As used herein, the term “substance abuse” encompasses the abuse of; : and physical and/or psychological addiction to, drugs or alcohol. The term “substance abuse” further encompasses its accepted meaning in the art. See, e.g., DSM-IV™ and

DSM-III™.

A preferred method encompassed by this embodiment is a method of treating or preventing cocaine and/or heroin abuse.

A ninth embodiment of the invention encompasses a method of treating or preventing nicotine addiction which comprises 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. Nicotine addiction includes nicotine addiction of all known forms, such as smoking cigarettes, cigars and/or pipes, and addiction to chewing tobacco.

A tenth embodiment of the invention encompasses a method of eliciting smoking cessation which comprises administering to a patient who smokes tobacco a therapeutically effective amount of a racemic or optically pure sibutramine metabolite, or a i pharmaceutically acceptable salt, solvate, or clathrate thereof.

In a preferred method encompassed by this embodiment, the racemic or optically pure sibutramine metabolite or pharmaceutically acceptable salt, solvate, or clathrate thereof is administered orally, mucosally, or transdermally. In a more preferred method, the racemic or optically pure sibutramine metabolite or pharmaceutically acceptable salt, solvate, or clathrate thereof is administered transdermally.

Another preferred method encompassed by this embodiment is a method of eliciting smoking cessation which comprises adjunctively administering to a patient who smokes tobacco therapeutically effective amounts of a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, and nicotine.

Preferably, the nicotine and/or racemic or optically pure sibutramine metabolite or pharmaceutically acceptable salt, solvate, or clathrate thereof is administered orally, mucosally, or transdermally. More preferably, the nicotine and/or racemic or optically pure sibutramine metabolite or pharmaceutically acceptable salt, solvate, or clathrate thereof is administered transdermally.

Another method encompassed by this embodiment is a method of treating or preventing weight gain associated with smoking cessation which comprises 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.

An eleventh embodiment of the invention encompasses a method of treating or preventing a chronic disorder selected from the group consisting of nareolepsy, chronic fatigue syndrome, seasonal affective disorder, fibromyalgia, and premenstrual syndrome (or premenstrual dysphoric disorder). This method comprises 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.

Preferred methods of this embodiment are methods of treating or preventing premenstrual syndrome, narcolepsy, and chronic fatigue.

A twelfth embodiment of the invention encompasses a method of treating or preventing anxiety which comprises 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.

A thirteenth embodiment of the invention encompasses a method of treating or : preventing an eating disorder which comprises 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.

A fourteenth embodiment of the invention encompasses a method of treating or preventing a migraine or migraine headache which comprises 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.

As used herein, the terms “obsessive-compulsive disorder," "pre-menstrual syndrome," "anxiety," "eating disorder," and "migraine" are used consistently with their accepted meanings in the art. See, e.g., DSM-IV™ and DSM-III™. The term "methods of treating or preventing" when used in connection with these disorders means the k WO 00/10551 PCT/US99/19167 amelioration, prevention, or relief from symptoms and/or effects associated with these disorders.

A fifteenth embodiment of the invention encompasses a method of treating or : preventing incontinence which comprises 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. In particular, a racemic or optically pure sibutramine metabolite can be used to treat fecal incontinence, stress urinary incontinence ("SUI"), urinary exertional incontinence, urge incontinence, reflex incontinence, passive incontinence and overflow incontinence.

As used herein, the term "treating or preventing incontinence" means treatment, prevention of, or relief from the symptoms of incontinence including involuntary voiding of feces or urine, and dribbling or leakage or feces or urine, which may be due to one or more - causes including, but not limited to, pathology altering sphincter control, loss of cognitive function, overdistention of the bladder, hyper-reflexia and/or involuntary urethral relaxation, weakness of the muscles associated with the bladder or neurologic abnormalities. . A preferred method encompassed by this embodiment is a method of treating or preventing stress urinary incontinence. In a further preferred method encompassed by this . 20 embodiment, the patient is an elder human of an age greater than 50 or a child of an age less than 13.

A sixteenth embodiment of the invention encompasses pharmaceutical compositions and dosage forms comprising a racemic or optically pure sibutramine metabolite or a pharmaceutically acceptable salt, solvate, or clathrate thereof. These pharmaceutical compositions and dosage forms are particularly useful in the methods described above. For example, dosage forms of the invention are suitable for oral, mucosal (e.g., nasal, sublingual, buccal, rectal, and vaginal), parenteral (e.g., intravenous and intramuscular), transdermal, or subcutaneous administration. Preferred dosage forms of the invention are suitable for oral, mucosal, or transdermal administration.

Preferred racemic and optically pure sibutramine metabolites include, but are not limited to, (+)-desmethylsibutramine, (-)-desmethylsibutramine, (+)-desmethylsibutramine, (+)-didesmethylsibutramine, (-)-didesmethylsibutramine, and (+)-didesmethylsibutramine.

Optically pure metabolites of sibutramine are most preferred. As used herein, the term "optically pure" means that a composition contains greater than about 90% of the desired stereoisomer by weight, preferably greater than about 95% of the desired : stereoisomer by weight, and more preferably greater than about 99% of the desired stereoisomer by weight, based upon the total weight of the active ingredient. For example, . optically pure (+)-desmethylsibutramine is substantially free of (-)-desmethylsibutramine.

As used herein, the term “substantially free” means that a composition contains less than about 10 weight percent, preferably less than about 5 weight percent, and more preferably less than about 1 weight percent of a compound.

It is contemplated that pharmaceutically acceptable salts, solvates, and clathrates of racemic and optically pure sibutramine metabolites be used in the methods, pharmaceutical compositions, and dosage forms of the invention. As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic inorganic or organic acid. Inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, and phosphoric. Organic acids include, but are not limited to, aliphatic, aromatic, carboxylic, and sulfonic organic acids including, but not limited to, formic, acetic, propionic, succinic, benzoic camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, } mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic, stearic, sulfanilic, alginic, and galacturonic acid. Particularly preferred } acids are hydrobromic, hydrochloric, phosphoric, and sulfuric acids, and most particularly preferred is hydrochloric acid.

In each of the methods of the invention, a sibutramine metabolite ora pharmaceutically acceptable salt, solvate, or clathrate thereof, can adjunctively administered with one or more additional pharmacologically active compounds, i.e., the sibutramine metabolite and at least one additional pharmacologically active compound are administered as a combination, concurrently but separately, or sequentially by any suitable route (e.g., orally, transdermally, or mucosally). Further, preferred pharmaceutical compositions and dosage forms of the invention can comprise a pharmaceutically acceptable excipient and/or atleast one additional pharmacologically active compound.

Additional pharmacologically active compounds that can be used in the methods and compositions of the invention include, but are not limited to, drugs that act on the central nervous system ("CNS"), such as, but not limited to: 5-HT (e.g., 5-HT, and 5-HT,,)

agonists and antagonists; selective serotonin reuptake inhibitors (“SSRIs”); hypnotics and sedatives; drugs useful in treating psychiatric disorders including antipsychotic and neuroleptic drugs, antianxiety drugs, antidepressants, and mood-stabilizers; CNS stimulants . such as amphetamines; dopamine receptor agonists; antimonic agents; antipanic agents; cardiovascular agents (e.g., beta blockers and angiotensin converting enzyme inhibitors); antivirals; antibiotics; antifungals; and antineoplastics.

More specific drugs that act on the CNS include, but are not limited to, SSRIs, benzodiazepine compounds, tricyclic antidepressants, antipsychotic agents, anti-anxiolytic agents, B-adrenergic antagonists, 5-HT,, receptor antagonists, and 5-HT, receptor agonists.

Even more specific drugs that act on the CNS include, but are not limited to, lorazepam, tomoxetine, olanzapine, respiradone, buspirone, hydroxyzine, and valium.

Selective serotonin reuptake inhibitors are compounds that inhibit the central nervous system uptake of serotonin while having reduced or limited affinity for other neurologically active receptors. Examples of SSRIs include, but are not limited to, citalopram (CELEXA®); fluoxetine (PROZAC®) fluvoxamine (LUVOX®); paroxetine (PAXIL®); sertraline (ZOLOFT®); venlafaxine (EFFEXOR®); and optically pure stereoisomers, active metabolites, and pharmaceutically acceptable salts, solvates, and clathrates thereof.

Benzodiazepine compounds that can be used in the methods and compositions of the . 20 invention include, but are not limited to, those described in Goodman & Gilman, The

Pharmacological Basis of Therapeutics, 362-373 (9" ed. McGraw-Hill, 1996). Examples of specific benzodiazepines include, but are not limited to, alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, pharmacologically active metabolites and stereoisomers thereof, and pharmaceutically acceptable salts, solvates, clathrates thereof. The tradenames of some of these compounds are provided below.

Alprazolam, which is chemically named 8-chloro-1-methyl-6-phenyl-4H-s- triazolo[4,3-a][1,4]benzodiazepine, is sold under the tradename XANAX®. XANAX® is indicated for the management of anxiety disorder (a condition corresponding most closely to the DSM-III™ diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. Physician's Desk Reference® 2516-2521 (53" ed., 1999).

The hydrochloride salt of chlordiazepoxide, which is chemically named 7-chloro-2- (methylamino)-5-phenyl-3H-1,4-benzodiazepine 4-oxide hydrochloride, is sold under the tradename LIBRIUM®. LIBRIUM® is indicated for the management of anxiety disorders or for the short-term relief of symptoms of anxiety, withdrawal symptoms of acute alcoholism, : and preoperative apprehension and anxiety. Physician's Desk Reference® 1369-1370 (53" ed., 1999).

Clonazepam, which is chemically named 5-(2-chlorophenyl)-1,3-dihydro-7-nitro- 2H-1,4-benzodiazepin-2-one, is sold under the tradename KLONOPIN®., KLONOPIN® is useful alone or as an adjunct in the treatment of the Lennox-Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures. KLONOPIN® is also indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV™. Physician's Desk

Reference® 2688-2691 (53" ed., 1999).

The dipotassium salt of clorazepate, which is chemically named 7-chloro-2,3- dihydro-2,2-dihydroxy-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic dipotassium, is sold under the tradename TRANXENE®. TRANXENE?® is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety, as adjunctive therapy in the management of partial seizures, and for the symptomatic relief of acute alcohol withdrawal. Physician's Desk Reference® 475-476 (53™ ed., 1999).

Diazepam, which is chemically named 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H- 1,4-benzodiazepin-2-one, is sold under the tradename VALIUM®. VALIUM?® is indicated . for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Physician's Desk Reference® 2735-2736 (53 ed., 1999).

Estazolam, which is chemically named 8-chloro-6-phenyl-4H-s-triazolo[4-3- «]{1,4]benzodiazepine, is sold under the tradename PROSOM™. PROSOM™ is indicated for the short-term management of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. Physician's Desk

Reference® 473-475 (53" ed., 1999).

Flumazenil, which is chemically named ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo- 4H-imidazo[1,5-a](1,4)benzodiazepine-3-carboxylate, is sold under the tradename

ROMAZICON®. ROMAZICON?® is indicated for the complete or partial reversal of the sedative effects of benzodiazepines in cases where general anesthesia has been induced and/or maintained with benzodiazepines, where sedation has been produced with benzodiazepines for diagnostic and therapeutic procedures, and for the management of : benzodiazepine overdose. Physician's Desk Reference® 2701-2704 (53" ed., 1999).

The hydrochloride salt of flurazepam, which is chemically named 7-chloro-1-[2-(di- ethylamino)ethyl]-5-(o-fluorophenyl)-1,3-dihydro-2 H-1,4-benzodiazepin-2-one dihydrochloride, is sold under the tradename DALMANE®. DALMANE? is a hypnotic agent useful for the treatment of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. Physician's Desk

Reference® 2520 (52™ ed., 1998).

Lorazepam, which is chemically named 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3- hydroxy-2H-1,4-benzodiazepin-2-one, is sold under the tradename ATIVAN®. ATIVAN® is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety or anxiety associated with depressive symptoms. Physician's Desk

Reference® 3267-3272 (53 ed., 1999). : The hydrochloride salt of midazolam, which is chemically named 8-chloro-6-(2- fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine hydrochloride, is sold under the tradename VERSED®. VERSED? is indicated for preoperative sedation/anxiolysis/amnesia and general anesthesia. Physician's Desk Reference® 2720- 2726 (53“ ed., 1999).

Oxazepam, which is chemically named 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl- : 20 2H-1,4-benzodiazepin-2-one, is sold under the tradename SERAX®. SERAX® is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Physician's Desk Reference® 3383-3384 (53" ed., 1999).

Quazepam, which is chemically named 7-chloro-5-(o-fluoro-phenyl)-1,3-dihydro-1- (2,2,2-trifluoroethyl)2H-1,4-benzodiazepine-2-thione, is sold under the tradename

DORAL®. DORAL? is indicated for the treatment of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings.

Physician's Desk Reference® 2958 (52 ed., 1998).

Temazepam, which is chemically named 7-chloro-1,3-dihydro-3-hydroxy-1-methyl- 5-phenyl-2H-1,4-benzodiazepin-2-one, is sold under the tradename RESTORILP®.

RESTORIL® is indicated for the short-term treatment of insomnia. Physician's Desk

Reference® 2075-2078 (53 ed., 1999).

Triazolam, which is chemically named 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s- tria-zolo-[4,3-a][1,4] benzodiazepine, is sold under the tradename HALCION®.

HALCION?® is indicated for the short-term treatment of insomnia. Physician's Desk

Reference® 2490-2493 (53" ed., 1999).

The clinician, physician, or psychiatrist will appreciate which of the above compounds can be used in combination with a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, for the treatment or prevention of a given disorder, although preferred combinations are disclosed herein.

Disorders that can be treated or prevented using a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, in combination with a benzodiazepine such as those listed above include, but are not limited to, affective disorders (e.g., depression), anxiety, eating disorders, and cerebral function disorders such as those described herein.

The invention further encompasses methods of using and pharmaceutical compositions comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, in combination with an antipsychotic agent. Antipsychotic agents are used primarily in the management of patients with psychotic or other serious psychiatric illness marked by agitation and impaired reasoning. These drugs have other properties that possibly are useful clinically, including antiemetic and antihistamine effects and the ability to potentiate analgesics, sedatives, and general anesthetics. Specific antipsychotic drugs are tricyclic antipsychotic drugs, of which . there are three subtypes: phenothiazines, thioxanthenes, and other heterocyclic compounds, all of which can be used in the methods and compositions of the invention. See, e.g.,

Goodman & Gilman, The Pharmacological Basis of Therapeutics, 404 oo" ed. McGraw-

Hill, 1996).

Specific tricyclic antipsychotic compounds include, but are not limited to, chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine, trifluoperazine, chlorprothixene, thiothixene, clozapine, haloperidol, loxapine, molindone, pimozide, risperidone, desipramine, pharmacologically active metabolites and stereoisomers thereof, and pharmaceutically acceptable salts, solvates, clathrates thereof. The tradenames of some of these compounds are provided herein.

Chlorpromazine, which is chemically named 10-(3-dimethylaminopropyl)-2- chlorphenothiazine, is sold under the tradename THORAZINE®. THORAZINE® is indicated, inter alia, for the management of manifestations of psychotic disorders. } Physician's Desk Reference® 3101-3104 (53" ed., 1999).

The besylate salt of mesoridazine, which is chemically named 10-[2(1-methyi-2- : piperidyl)ethyl]-2-methyl-sylfinyl)-phenothiazine, is sold under the tradename SERENTIL®. SERENTIL? is indicated in the treatment of schizophrenia, behavioral problems in mental deficiency and chronic brain syndrome, alcoholism, and psychoneurotic manifestations. Physician's Desk Reference® 764-766 (53" ed., 1999).

Perphenazine, which is chemically named 4-{3-(2-chlorophenothiazin-10-yl)propyl- 1-piperazineethanol, is sold under the tradename TRILAFON®. TRILAFON® is indicated for use in the management of the manifestations of psychotic disorders and for the control of severe nausea and vomiting in adults. Physician's Desk Reference® 2886-2888 (53" ed., 1999).

Trifluoperazine, which is chemically named 10-[3-(4-methyl-1-piperazinyl)-propyl]- 2-(trifluoromethyl)- 10H-phenothiazine, is sold under the tradename STELAZINE®.

STELAZINE® is indicated for the management of the manifestations of psychotic disorders and for the short-term treatment of generalized non-psychotic anxiety. Physician’s Desk

Reference® 3092-3094 (53“ ed., 1999). } Thiothixene, which is chemically named N,N-dimethyl-9-[3-(4-methyl-1- piperazinyl)-propylidene]thioxanthene-2-sulfonamide, is sold under the tradename x 20 NAVANE®. NAVANE? is indicated in the management of manifestations of psychotic disorders. Physician's Desk Reference® 2396-2399 (53 ed., 1999).

Clozapine, which is chemically named 8-chloro-11-(4-methyl-1-piperazinyl)5H- dibenzo[b,e][1,4]diazepine, is sold under the tradename CLOZARIL®. CLOZARIL® is indicated for the management of severely ill schizophrenic patients who fail to respond adequately to standard antipsychotic drug treatment. Physician's Desk Reference® 2004- 2009 (53 ed., 1999).

Haloperidol, which is chemically named 4-[4-(p-chlorophenyl)-4-hydroxy- piperidonol-4'-fluorobutyrophenone, is sold under the tradename HALDOL®. HALDOL® is indicated for use in the management of patients requiring prolonged parenteral antipsychotic therapy (e.g., patients with chronic schizophrenia). Physician's Desk

Reference® 2190-2192 (53 ed., 1999).

Loxapine, which is chemically named 2-chloro-11-(4-methyl-1- piperazinyl)dibenz[b,f)[ 1-4]oxaxepine, is sold under the tradename LOXITANE®.

LOXITANE? is indicated for the management of the manifestations of psychotic disorders.

Physician's Desk Reference® 3224-3225 (53" ed., 1999). :

Molindone, which is chemically named 3-ethyl-6,7-dihydro-2-methyl-5- (morpholinomethyl) indol-4(5H)-one hydrochloride, is sold under the tradename MOBAN®. :

MOBAN? is indicated for the management of the manifestations of psychotic disorders.

Physician's Desk Reference® 978-979 (53™ ed., 1999).

Pimozide, which is chemically named, 1-[1-[4,4-bis(4-fluorophenyl)butyl}4- piperidinyl}-1,3-dihydro-2 H-benzimidazole-2-one, is sold under the tradename ORAP®.

ORAP® is indicated for the suppression of motor and phonic tics in patients with Tourette’s

Disorder who have failed to respond satisfactorily to standard treatment. Physician's Desk

Reference® 1054-1056 (53™ ed., 1999).

Risperidone, chemically named 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[ 1,2-a]pyrimidin-4-one, is sold under the tradename RISPERDAL®. RISPERDAL? is indicated for the management of the manifestations of psychotic disorders. Physician's Desk Reference® 1432-1436 (539ed, 1999).

The hydrochloride salt of desipramine, which is chemically named 5H-

Dibenz[bf}azepine-5-propanamine-10,11-dihydro-N-methyl-monohydrochloride, is sold under the tradename NORPRAMIN®. NORPRAMINP® is indicated for the treatment of depression. Physician’s Desk Reference® 1332-1334 (53“ ed., 1999). :

Disorders that can be treated or prevented using a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, in combination with an antipsychotic compound, and particularly a tricyclic antipsychotic compound, include, but are not limited to, affective disorders (e.g., depression), anxiety, eating disorders, and cerebral function disorders (e.g., schizophrenia) such as those described herein.

The invention further encompasses methods of using and pharmaceutical compositions comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, in combination with a 5-HT,, receptor antagonist and/or a B-adrenergic antagonist. Examples of 5-HT),, receptor antagonists and -adrenergic antagonists that can be used in the methods and compositions of the invention include, but are limited to: alprenolol; WAY 100135; spiperone; pindolol; (S)-UH-301; penbutolol; propranolol; tertatolol; a compound of the formula I as disclosed in U.S. Patent No. 5,552,429, which is incorporated herein by reference; pharmacologically : active metabolites and stereoisomers thereof; and pharmaceutically acceptable salts, solvates, clathrates thereof. : Alprenolol, which is chemically named 1-(1-methylethyl)amino-3-[2-(2- propenyl)phenoxy]-2-propanol, is described by U.S. Patent No. 3,466,325, which is incorporated herein by reference.

WAY 100135, which is chemically named N-(t-butyl)-3-[4-(2-methoxphenyl)- piperazin-1-yl]-2-phenylpropanamide, is described by U.S. Patent 4,988,814, which is incorporated herein by reference. See also, Cliffe et al., J. Med. Chem., 36:1509-1510 (1993).

Spiperone, which is chemically named 8-[4-(4-fluorophenyl)-4-oxobutyl]-1-phenyl- 1,3,8-triazaspiro[4,5]decan-4-one), is described by U.S. Patent Nos. 3,155,669 and 3,155,670, both of which are incorporated herein by reference. See also, Middimiss et al.,

Neurosci. and Biobehav. Rev., 16:75-82 (1992).

Pindolol, which is chemically named 4-(2-hydroxy-3-isopropylaminopropoxy)- indole, is described by U.S. Patent No. 3,471,515, which is incorporated herein by reference. See also, Dreshfield et al., Neurochem. Res., 21(5):557-562 (1996). : (S)-UH-301, which is chemically named (S)-5-fluoro-8-hydroxy-2-dipropylamino- tetralin), is well known to pharmacologists and pharmaceutical chemists. See, e.g., Hillyer etal,J Med Chem.,33:1541-44 (1990) and Moreau et al., Brain Res. Bull., 29:901-04 (1992).

Penbutolol, which is chemically named (1-(t-butylamino)-2-hydroxy-3-(2- cyclopentyl-phenoxy)propane), is sold under the tradename LEVATOL®. LEVATOL® is indicated the treatment of mild to moderate arterial hypertension. Physician's Desk Reference® 2908-2910 (53“ ed., 1999).

The hydrochloride salt of propranolol, which is chemically named 1- isopropylamino-3-(1-naphthalenyloxy)-2-propanol hydrochloride, is sold under the tradename INDERAL®. INDERAL® is indicated in the management of hypertension.

Physician's Desk Reference® 3307-3309 (53" ed., 1999).

Tertatolol, chemically named 8-(3-t-butylamino-2-hydroxypropyloxy)-thiochroman, is described by U.S. Patent No. 3,960,891, which is incorporated herein by reference.

Disorders that can be treated or prevented using a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof,

in combination with a 5-HT,, receptor antagonist include, but are not limited to, depression, obsessive-compulsive disorders, eating disorders, hypertension, migraine, essential tremor, : hypertrophic subaortic stenosis and pheochromocytoma. A specific disorder that can be treated or prevented is posttraumatic depression disorder.

Disorders that can be treated or prevented using a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, in combination with a B-adrenergic antagonist include, but are not limited to, post myocardial infarction depression. Specific B-adrenergic antagonists include, but are not limited to, S(-)-pindolol, penbutolol, and propranolol.

The invention further encompasses methods of using and pharmaceutical compositions comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, in combination with a non- benzodiazepine or non-tricyclic agents. Examples of such additional pharmacologically active compounds include, but are limited to: olanzapine, buspirone, hydroxyzine, tomoxetine, pharmacologically active metabolites and stereoisomers thereof, and pharmaceutically acceptable salts, solvates, clathrates thereof.

Olanzapine, which is chemically named 2-methyl-4-(4-methyl-1-piperazinyl)-10H- thieno[2,3-b][1,5]benzodiazepine, is sold under the tradename ZYPREXA®. ZYPREXA® is : indicated for the management of the manifestations of psychotic disorders. Physician's

Desk Reference® 1641-1645 (53“ ed., 1999).

The hydrochloride salt of buspirone, which is chemically named 8-[4-[4-(2- pyrimidinyl)-1-piperazinyl]butyl}-8-azaspiro-[4.5]decane-7,9-dione monohydrochloride, is sold under the tradename BUSPAR®. BUSPAR® is indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. Physician's Desk Reference® 823-825 (53 ed., 1999).

The hydrochloride salt of hydroxyzine, which is chemically named 1-(p- chlorobenzhydryl)- 4[2-(2-hydroxyethoxy)-ethyl] piperazine dihydrochloride, is sold under the tradename ATARAX®. ATARAX? is indicated for symptomatic relief of anxiety and tension associated with psychoneurosis and as an adjunct in organic disease states in which anxiety is manifested. Physician's Desk Reference® 2367-2368 (53 ed., 1999).

Disorders that can be treated or prevented using a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, in combination with a compound selected from the group consisting of lorazepam,

tomoxetine, olanzapine, respiradone, buspirone, hydroxyzine, valium, pharmacologically - active metabolites and stereoisomers thereof, and pharmaceutically acceptable salts, solvates, clathrates thereof include, but are not limited to, anxiety, depression, hypertension, : and attention deficit disorders.

While all combinations of racemic and optically pure sibutramine metabolites and pharmaceutically acceptable salts, solvates, and clathrate thereof, and one or more above described pharmacologically active compounds can be useful and valuable, certain combinations are particularly preferred. Examples of preferred combinations include those wherein a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, is combined with one of the following: alprazolam; quazepam,; alprenolol; brotizolam, temazepam, WAY 100135; chlordiazepoxide; triazolam; spiperone; clobazam; chlorpromazine; S(-)-pindolol; clonazepam; mesoridazine; R(+)-pindolol; clorazepate; thioridazine; racemic pindolol; demoxepam; acetophenazine; (S)-UH-301; : : diazepam; fluphenazine; penbutolol; estazolam,; perphenazine; propranolol; . 20 flumazenil,; trifluoperazine; tertatolol; flurazepam,; chlorprothixene; desipramine; halazepam; thiothixene; clonidine; lorazepam, clozapine; olanzapine; midazolam; haloperidol; methylphenidate; nitrazepam, loxapine; buspirone; nordazepam; molindone; hydroxyzine; and oxazepam,; pimozide; tomoxetine. prazepam,; risperidone; 4,1 SYNTHESIS OF SIBUTRAMINE METABOLITES

Racemic sibutramine, desmethylsibutramine, and didesmethylsibutramine can be prepared by methods known to those of ordinary skill in the art. See, e.g., U.S. Patent No. 4,806,570, which is incorporated herein by reference; J. Med. Chem., 2540 (1993)

(tosylation and azide replacement); Butler, D., J. Org. Chem., 36:1308 (1971) (cycloalkylation in DMSO); Tetrahedron Lett., 155-58 (1980) (Grignard addition to nitrile : in benzene); Tetrahedron Lett., 857 (1997) (OH to azide); and Jeffery, J. E., et al., J. Chem.

Soc. Perkin. Trans 1, 2583 (1996). A preferred method preparing racemic sibutramine is provided below in Example 1.

Racemic sibutramine, desmethylsibutramine, and didesmethylsibutramine can be prepared from each other, as can optically pure forms of the compounds. Preferred methods of preparing compounds from one another are provided below in Examples 2, 3, and 8.

Optically pure enantiomers of sibutramine and its metabolites can be prepared using techniques known in the art. A preferred technique is resolution by fractional crystallization of diastereomeric salts formed with optically active resolving agents. See, e.g., "Enantiomers, Racemates and Resolutions," by J. Jacques, A. Collet, and S.-H. Wilen, (Wiley-Interscience, New York, 1981); S.H. Wilen, A. Collet, and J. Jacques, Tetrahedron, 2725 (1977); E.L. Eliel Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and S.H. Wilen Tables of Resolving Agents and Optical Resolutions 268 (E.L. Eliel ed.,

Univ. of Notre Dame Press, Notre Dame, IN, 1972).

Because sibutramine, desmethylsibutramine, and didesmethylsibutramine are basic amines, diastereomeric salts of these compounds that are suitable for separation by fractional : crystallization are readily formed by addition of optically pure chiral acid resolving agents.

Suitable resolving agents include, but are not limited to, optically pure tartaric, : camphorsulfonic acid, mandelic acid, and derivatives thereof. Optically pure isomers of sibutramine, desmethylsibutramine, and didesmethylsibutramine can be recovered either from the crystallized diastereomer or from the mother liquor, depending on the solubility properties of the particular acid resolving agent employed and the particular acid enantiomer used. The identity and optical purity of the particular sibutramine or sibutramine metabolite isomer so recovered can be determined by polarimetry or other analytical methods.

Racemic and optically pure sibutramine metabolites are preferably synthesized directly by methods such as those disclosed by Jeffery, J. E., et al., J. Chem. Soc. Perkin.

Trans 1,2583 (1996). A preferred method of directly synthesizing racemic desmethylsibutramine comprises the reduction of cyclobutanecarbonitrile (CCBC) to form an aldehyde intermediate which is subsequently reacted with an amine such as, but not limited to, methylamine. This method is applied below in Example 4.

Another preferred method of directly synthesizing racemic desmethylsibutramine comprises the reaction of CCBC with a compound of formula i-BuMX, wherein X is Br or I and M is selected from the group consisting of Li, Mg, Zn, Cr, and Mn. Preferably, the : compound is of the formula i-BuMgBr. This reaction produces a product which is subsequently reduced, converted to an intermediate comprising an aldehyde bound to the nitrogen atom, which intermediate is finally converted to desmethylsibutramine in a step that comprises the addition of a lewis acid. Preferred lewis acids are selected from the group consisting of BH, THF, BF,"THF, La(O-i-Pr),, Zr(O-i-Pr),, Ti(O-i-Pr),Cl,, SnCl,, and

MgBr,-OEt,. A most preferred lewis acid is BH; THF. This method is applied below in

Example 5.

The enantiomers of desmethylsibutramine can be resolved by the formation of chiral salts as described above. Preferred chiral acids used to form the chiral salts include, but are not limited to, tartaric and mandelic acids. If tartaric acid is used, preferred solvent systems include, but are not limited to, ethanol/water and isopropyl alchol/water. If mandelic acid is used, a preferred solvent system is ethyl acetate/hexane. The resolution of desmethylsibutramine is shown below in Examples 6 and 7.

A preferred method of directly synthesizing racemic didesmethylsibutramine comprises the reaction of CCBC with a compound of formula i-BuMX, wherein X is Br or I and M is selected from the group consisting of Li, Mg, Zn, Cr, and Mn. Preferably, the : 20 compound is of the formula i-BuMgBr. The product of this reaction is then reduced under suitable reaction conditions. Application of this method is shown below in Example 9.

The enantiomers of didesmethylsibutramine can be resolved by the formation of chiral salts, as described above. Preferred chiral acids used to form the chiral salts include, but are not limited to, tartaric acid. Preferred solvent systems include, but are not limited to, acetonitrile/water/methanol and acetonitrile/methanol. The resolution of didesmethylsibutramine is shown below in Examples 11 and 12. 4.2 PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE

The magnitude of a prophylactic or therapeutic dose of an active ingredient in the acute or chronic management of a disorder or condition will vary with the severity of the disorder or condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to age, body weight, response, and the past medical history of the patient. Suitable dosing regimens can be readily selected by those skilled in the art with due consideration of such factors.

Suitable daily doses for the treatment or prevention of a disorder described herein can be readily determined by those skilled in the art. A recommended dose of racemic or : optically pure sibutramine metabolite is from about 0.1 mg to about 60 mg per day, given as a single once-a-day dose in the moming or as divided doses throughout the day. Preferably, a daily dose is from about 2 mg to about 30 mg per day, more preferably from about 5 mg to about 15 mg per day.

Suitable daily dosage ranges of additional pharmacologically active compounds that can be adjunctively administered with a racemic or optically pure sibutramine metabolite can be readily determined by those skilled in the art following dosages reported in the literature and recommended in the Physician's Desk Reference® (53 ed., 1999).

For example, suitable daily dosage ranges of 5-HT, antagonists can be readily determined by those skilled in the art and will vary depending on factors such as those described above and the particular 5-HT, antagonists used. In general, the total daily dose of a 5-HT, antagonist for the treatment or prevention of a disorder described herein is from about 0.5 mg to about 500 mg, preferably from about 1 mg to about 350 mg, and more preferably from about 2 mg to about 250 mg per day.

The therapeutic or prophylactic administration of an active ingredient of the invention is preferably initiated at a lower dose, e.g., from about 2 mg to about 8 mg of . sibutramine metabolite and optionally from about 15 mg to about 60 mg of 5-HT, antagonist, and increased, if necessary, up to the recommended daily dose as either a single dose or as divided doses, depending on the global response of the patient. It is further recommended that patients aged over 65 years should receive doses of sibutramine metabolite in the range of from about 5 mg to about 30 mg per day depending on global response. It may be necessary to use dosages outside these ranges, which will be readily determinable by one of ordinary skill in the pharmaceutical art.

The dosage amounts and frequencies provided above are encompassed by the terms “therapeutically effective,” “prophylactically effective,” and “therapeutically or prophylactically effective” as used herein. When used in connection with an amount of a racemic or optically pure sibutramine metabolite, these terms further encompass an amount of racemic or optically pure sibutramine metabolite that induces fewer or less sever adverse effects than are associated with the administration of racemic sibutramine. Adverse effects _22.

Claims (59)

THE CLAIMS What is claimed is:

1. A compound comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, for use in a method of treating or preventing a disorder or condition ameliorated by inhibition of neuronal monoamine uptake, wherein the treatment or prevention comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of said compound.

2. A compound as claimed in claim 1, wherein the disorder and condition ameliorated by inhibition of neuronal monoamine uptake is selected from the group consisting of erectile dysfunction, affective disorders, weight gain, cerebral function disorders, pain, obsessive-compulsive disorder, substance abuse, chronic disorders, anxiety, eating disorders, migraines, and incontinence.

3. A compound as claimed in claim 1, wherein the sibutramine metabolite is administered orally, mucosally, or transdermally.

4. A compound comprising a dopamine reuptake inhibitor for use in treating or preventing erectile dysfunction, wherein the treatment or prevention comprises adjunctively . administering to a patient in need of such treatment or prevention therapeutically or prophylactically effective amounts of said dopamine reuptake inhibitor and a 5-HT; antagonist.

5. A compound as claimed in claim 4, wherein the dopamine reuptake inhibitor is a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof.

6. A compound as claimed in claim 4, wherein the 5-HT; antagonist is an antiemetic agent or is selected from the group consisting of granisetron, metoclopramide, ondansetron, renzapride, zacopride, tropisetron, and optically pure stereoisomers, active metabolites, and pharmaceutically acceptable salts, clathrates, and solvates thereof. -49 - Amended Sheet 18/01/2001

7. A compound as claimed in claim 4, wherein the dopamine reuptake inhibitor and/or the 5-HT), antagonist is administered transdermally or mucosally.

8. A compound comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, for use in treating or preventing erectile dysfunction, wherein the treatment or prevention comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of said compound.

9. A compound as claimed in claim 8, wherein the sibutramine metabolite is administered transdermally or mucosally.

10. A compound comprising a racemic or optically pure sibutramine metabolite, or a : pharmaceutically acceptable salt, solvate, or clathrate thereof, for use in treating or preventing an affective disorder, wherein the treatment or prevention comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of said compound.

11. A compound as claimed in claim 10, wherein the affective disorder is selected from the group consisting of depression, attention deficit disorder, attention deficit disorder with hyperactivity, bipolar and manic conditions, dysthymic disorder, and cyclothymic disorder.

12. A compound as claimed in claim 11, wherein the affective disorder is depression + or attention deficit disorder.

13. A compound as claimed in claim 10, wherein the affective disorder is attention deficit disorder and the sibutramine metabolite is (-)- desmethylsibutramine or (-)- didesmethylsibutramine.

14. A compound comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, for use in treating or preventing weight gain or obesity, wherein the treatment or prevention comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of said compound. -50- Amended Sheet 18/01/2001

15. A compound comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, for use in treating or preventing cerebral function disorders, wherein the treatment or prevention comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of said compound.

16. A compound as claimed in claim 15, wherein the cerebral function disorder is selected from the group consisting of senile dementia, Alzheimer’s type dementia, memory loss, amnesia/amnestic syndrome, disturbance of consciousness, coma, lowering of attention, speech disorders, Parkinson’s disease, Lennox syndrome, autism, epilepsy, hyperkinetic syndrome and schizophrenia.

17. A compound comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, for use in treating or preventing pain, wherein the treatment or prevention comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of said compound.

18. A compound as claimed in claim 17, wherein the pain is chronic pain.

19. A compound comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, for use in treating or preventing obsessive-compulsive disorder, wherein the treatment or prevention comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of said compound.

20. A compound comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, for use in treating or preventing substance abuse, wherein the treatment or prevention comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of said compound.

21. A compound as claimed in claim 20, wherein the substance abuse is cocaine addiction. -51- Amended Sheet 18/01/2001

22. A compound comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, for use in treating or preventing nicotine addiction, wherein the treatment or prevention comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of said compound.

23. A compound comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, for use in eliciting smoking cessation, wherein the eliciting of smoking cessation comprises administering to a patient who smokes tobacco a therapeutically or prophylactically effective amount of said compound.

24, A compound comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, for use in treating or preventing weight gain associated with smoking cessation, wherein the treatment or prevention comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of said compound.

25. A compound comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, for use in treating or preventing a chronic disorder selected from the group consisting of narcolepsy, chronic fatigue syndrome, seasonal affective disorder, fibromyalgia, and premenstrual syndrome, wherein the treatment or prevention comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of said compound.

26. A compound as claimed in claim 25, wherein the chronic disorder is narcolepsy, premenstrual syndrome, or chronic fatigue syndrome.

217. A compound comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, for use in treating or preventing anxiety, wherein the treatment or prevention comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of said compound. -52- Amended Sheet 18/01/2001

28. A compound comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, for use in treating or preventing an eating disorder, wherein the treatment or prevention comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of said compound.

29. A compound comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, for use in treating or preventing migraines, wherein the treatment or prevention comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of said compound.

30. A compound comprising a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, for use in treating or preventing incontinence, wherein the treatment or prevention comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of said compound.

31. A compound as claimed in claim 30, wherein the incontinence is selected from the group consisting of fecal incontinence, stress urinary incontinence, urinary exertional incontinence, urge incontinence, reflex incontinence, passive incontinence, and overflow incontinence.

32. A compound as claimed in claim 31, wherein the incontinence is stress urinary incontinence.

33. The compound as claimed in any one of claims 1, 5, 8, 20, 14, 15, 17, 19, 20, 22-25 and 27-30, wherein the sibutramine metabolite is selected from the group consisting of (+)-desmethylsibutramine, (-)-desmethylsibutramine, (4 )-desmethylsibutramine, (+)-didesmethylsibutramine, (-)-didesmethylsibutramine, and (4 )-didesmethylsibutramine.

34. The compound as claimed in either of claims 1 and 5, wherein the amount of sibutramine metabolite administered is from about 0.1 mg to about 60 mg/day. -53- Amended Sheet 18/01/2001

35. A compound as claimed in claim 34, wherein the amount of sibutramine metabolite administered is from about 2 mg to about 30 mg/day. :

36. A compound as claimed in claim 35, wherein the amount of sibutramine metabolite administered is from about 5 mg to about 15 mg/day.

37. The compound as claimed in any one of claims 10, 14, 15, 17, 19, 20, 22-25 and 27-30, which further comprises the administration of an additional pharmacologically active compound.

38. The compound as claimed in claim 37, wherein the additional pharmacologically active compound is a drug that affects the central nervous system selected from the group consisting of: selective serotonin reuptake inhibitors; 5-HT agonists and antagonists; hypnotics and sedatives; drugs useful in treating psychiatric disorders; CNS stimulants; dopamine receptor agonists; antimonic agents; antipanic agents; cardiovascular agents; antivirals; antibiotics; antifungals; and antineoplastics.

39. A pharmaceutical composition comprising a sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, and a pharmaceutically acceptable excipient.

40. The pharmaceutical composition as claimed in claim 39, wherein the sibutramine metabolite is selected from the group consisting of (+ )-desmethylsibutramine, (-)- desmethylsibutramine, ( +)-desmethylsibutramine, (+)-didesmethylsibutramine, (-)- didesmethylsibutramine, and (+ )-didesmethylsibutramine.

41. The pharmaceutical composition as claimed in claim 40, wherein the sibutramine metabolite is selected from the group consisting of (+)-desmethylsibutramine, (-)- desmethylsibutramine, (+)-didesmethylsibutramine, and (-)-didesmethylsibutramine.

42. The pharmaceutical composition as claimed in claim 39, wherein the amount of sibutramine metabolite is from about 0.1 mg to about 60 mg.

43. The pharmaceutical composition as claimed in claim 42, wherein the amount of sibutramine metabolite is from about 2 mg to about 30 mg. -54- Amended Sheet 18/01/2001

44, The pharmaceutical composition as claimed in claim 43, wherein the amount of sibutramine metabolite is from about 5 mg to about 15 mg.

45. The pharmaceutical composition as claimed in claim 39, wherein the pharmaceutical composition is adapted for oral, mucosal, rectal, parenteral, transdermal, or subcutaneous administration.

46. The pharmaceutical composition as claimed in claim 45, wherein the pharmaceutical composition is adapted for oral, mucosal, or transdermal administration.

47. The pharmaceutical composition as claimed in claim 39, which further comprises an additional pharmacologically active compound.

48. The pharmaceutical composition as claimed in claim 47, wherein the additional pharmacologically active compound is a drug that affects the central nervous system selected from the group consisting of: 5-HT agonists and antagonists; hypnotics and sedatives; drugs useful in treating psychiatric disorders; CNS stimulants; dopamine receptor agonists; antimonic agents; antipanic agents; cardiovascular agents; antivirals; antibiotics; antifungals; and antineoplastics.

49. The pharmaceutical composition as claimed in claim 48, wherein the additional pharmacologically active compounds is a 5-HT; antagonist.

50. The pharmaceutical composition as claimed in claim 49, wherein the 5-HT, antagonists is an antiemetic agent.

51. The pharmaceutical composition as claimed in claim 49, wherein the 5-HT, antagonist is selected from the group consisting of granisetron, metoclopramide, ondansetron, renzapride, zacopride, tropisetron, optically pure stereoisomers, active metabolites thereof, and pharmaceutically acceptable salts, clathrates, or solvates thereof.

52. The pharmaceutical composition as claimed in claim 49, wherein the amount of 5-HT, antagonist is from about 0.5 mg to about 500 mg. -55- Amended Sheet 18/01/2001

53. The pharmaceutical composition as claimed in claim 52, wherein the amount of 5-HT; antagonist is from about 1 mg to about 350 mg.

54. The pharmaceutical composition as claimed in claim 53, wherein the amount of 5-HT; antagonist is from about 2 mg to about 250 mg.

55. A lactose-free pharmaceutical composition which comprises a sibutramine metabolite, or a pharmaceutical acceptable salt, solvate, or clathrate thereof and a pharmaceutically acceptable excipient.

56. The pharmaceutical composition as claimed in claim 55, wherein the excipient is selected from the group consisting of croscarmellose sodium, microcrystalline cellulose, pre- gelatinized starch, and magnesium stearate.

57. The pharmaceutical composition as claimed in claim 55, wherein said pharmaceutical composition is substantially free of mono- or di-saccharides.

58. Use of a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, for the manufacture of a medicament for treating or preventing: a disorder or condition ameliorated by inhibition of neuronal monoamine uptake; erectile dysfunction; an affective disorder; weight gain or obesity; cerebral function disorders; pain; obsessive-compulsive disorder; substance abuse; nicotine addiction; weight gain associated with smoking cessation; chronic disorder selected from the group consisting of narcolepsy, chronic fatigue syndrome, seasonal affective disorder, fibromyalgia, and premenstrual syndrome; anxiety; an eating disorder; migraines; ot incontinence; or for eliciting smoking cessation.

59. A pharmaceutical composition according to claim 39, substantially as herein described with reference to Example 15. -56- Amended Sheet 18/01/2001