AU2007200334A1 - Methods of using and compositions comprising dopamine reuptake inhibitors - Google Patents

Description

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Sepracor, Inc.

Actual Inventor(s): Thomas P Jerussi, Chrisantha H Senanayake, Qun K Fang Address for Service and Correspondence: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: METHODS OF USING AND COMPOSITIONS COMPRISING DOPAMINE REUPTAKE

INHIBITORS

Our Ref 792447 POF Code: 467260/70025 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): METHODS OF USING AND COMPOSITIONS COMPRISING DOPAMINE REUPTAKE INHIBITORS The present application is a divisional application from Australian patent application number 2004200875, the entire disclosure of which is incorporated herein by reference.

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]-3methylbutyl]-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 opamine. See, 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 5 3 rd ed., 1999).

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.

U:LEISAWNB\POFSpeCbcabOnSl20042OI875 (DIV).doc a- Sibutramine has a variety of adverse effects. See, e.g. Physician's Desk Reference® 1494-1498 53 rd ed., 1999). Compounds and compositions are desired that can be used for the treatment and 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. More particularly compounds and conditions 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 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 JMN U:lLEISAWMNBPOF S eCifaionS2004200875 (DIV).dOC -2therapeutically or prophylactically effective amount of a racemic or optically pure 0 sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate a thereof.

s 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 3 antagonist.

Cc Pharmaceutical compositions of the invention comprise a therapeutically or O prophylactically effective amount of a neuronal monoamine reuptake inhibitor.

10 Preferred neuronal monoamine reuptake inhibitors include, but are not limited to, Sapomorphine, 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.

The above discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia before the priority date of each claim of this application.

4. DETAILED DESCRIPTION OF THE INVENTION This invention relates to methods and compositions that inhibit the reuptake of neuronal monoamines 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 a human) in need of such treatment or prevention a therapeutically or prophylactically effective amount of neuronal monoamine reuptake inhibitor. Preferred neuronal monoamine JMN U:LEISAMNB\POFNSpecifc.atons2004200875 (DIV).doc -3- WO 00/10551 PCT/US99/19167 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 ;1 with abnormal neuronal monoamine levels. Disorders ameliorated by inhibition of neuronal monoamine reuptake include, but are not limited to, erectile dysfunction, affective S disorders, weight gain or obesity, cerebral function disorders, pain, obsessive-compulsive disorder, substance abuse, chronic disorders, anxiety, eating disorders, migraines, and 1 incontinence.

I A first embodiment of the invention encompasses a method of treating or preventing 1 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-HT3 antagonist. Preferred dopamine reuptake inhibitors include, but are not limited to, apomorphine, sibutramine, racemic and optically pure sibutramine i metabolites, and pharmaceutically acceptable salts, solvates, and clathrates thereof.

Particularly preferred dopamine reuptake inhibitors are racemic and optically pure sibutramine metabolites. Preferred 5-HT 3 antagonists are antiemetic agents. Examples of suitable 5-HT3 antagonists include, but are not limited to, granisetron (KYTRIL?), metoclopramide (REGLANO), ondansetron (ZOFRAN), renzapride, zacopride, tropisetron, 3 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 nasally, sublingually, or buccally). In a more preferred method of this embodiment, the dopamine reuptake inhibitor and the 5-HT3 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.

-4- WO 00/10551 PCT/US99/19167 r- 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 Streatment or prevention a therapeutically or prophylactically effective amount of a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or r, 5 clathrate thereof. Affective disorders include, but are not limited to, depression melancholia), attention deficit disorder (including attention deficit disorder with hyperactivity and attention deficit/hyperactivity disorder), bipolar and manic conditions, Sdysthymic disorder, and cyclothymic disorder. As used herein, the terms "attention deficit i disorder" (ADD), "attention deficit disorder with hyperactivity" (ADDH), and "attention O 10 deficit/hyperactivity disorder" (AD/HD), are used in accordance with their accepted meanings in the art. See, Diagnostic and Statistical Manual ofMental Disorders, Fourth Ed., American Psychiatric Association, 1997 (DSM-IV

M

and Diagnostic and Statistical Manual ofMental Disorders, 3 Ed., American Psychiatric Association (1981) (DSM-IIf).

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 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 WO 00/10551 PCTIUS99/19167 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, byperkinetic 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 cerebral 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 WO 00/10551 PCT/US99/19167 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, DSM-IV M and DSM-IITm.

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 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.

WO 00/10551 PCT/US99/19167 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 narcolepsy, 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, DSM-IVT M and DSM-IIITM. The term "methods of treating or preventing" when used in connection with these disorders means the 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 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 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 nasal, sublingual, buccal, rectal, and vaginal), parenteral 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 WO 00/10551 PCT/US99/19167 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, andgalacturonic 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 or a pharmaceutically acceptable salt, solvate, or clathrate thereof, can adjunctively administered with one or more additional pharmacologically active compounds, 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 orally, transdermally, or mucosally). Further, preferred pharmaceutical compositions and dosage forms of the invention can comprise a pharmaceutically acceptable excipient and/or at least 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 such as, but not limited to: 5-HT 5-HT 3 and WO 00/10551 PCT/US99/19167 agonists and antagonists; selective serotonin reuptake inhibitors ("SSRIs"); hypnotics and sedatives; drugs useful in treating psychiatric disorders including antipsychotic and 0 neuroleptic drugs, antianxiety drugs, antidepressants, and mood-stabilizers; CNS stimulants M such as amphetamines; dopamine receptor agonists; antimonic agents; antipanic agents; C 5 cardiovascular agents 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, 8 benzodiazepine compounds, tricyclic antidepressants, antipsychotic agents, anti-anxiolytic C agents, B-adrenergic antagonists, 5-HTIA receptor antagonists, and 5-HT 3 receptor agonists.

Even more specific drugs that act on the CNS include, but are not limited to, lorazepam, C 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 (PROZAC8) fluvoxamine (LUVOX); paroxetine (PAXIL); sertraline (ZOLOFT®); venlafaxine (EFFEXORO); 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 invention include, but are not limited to, those described in Goodman Gilman, The Pharmacological Basis of Therapeutics, 362-373 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-l-methyl-6-phenyl-4H-striazolo[4,3-a][l,4]benzodiazepine, is sold under the tradename XANAX. XANAXO is indicated for the management of anxiety disorder (a condition corresponding most closely to the DSM-IIIM diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. Physician's Desk Reference® 2516-2521 5 3 d ed., 1999).

1 WO 00/10551 PCT/US99/19167 l^ The hydrochloride salt of chlordiazepoxide, which is chemically named 7-chloro-2- 3 H-1,4-benzodiazepine 4-oxide hydrochloride, is sold under the C 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, C1 5 and preoperative apprehension and anxiety. Physician's Desk Reference" 1369-1370 (53" ed., 1999).

Clonazepam, which is chemically named 5-(2-chlorophenyl)-l,3-dihydro-7-nitro- S2H-1,4-benzodiazepin-2-one, is sold under the tradename KLONOPIN®.

KLONOPIN

R is CI useful alone or as an adjunct in the treatment of the Lennox-Gastaut syndrome (petit mal 0 10 variant), akinetic and myoclonic seizures. KLONOPIN® is also indicated for the treatment 'NI of panic disorder, with or without agoraphobia, as defined in DSM-IV

T

Physician 's Desk Reference® 2688-2691 53 d ed., 1999).

The dipotassium salt of clorazepate, which is chemically named 7-chloro-2,3dihydro-2,2-dihydroxy-5-phenyl-lH-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 5 3 rd ed., 1999).

Diazepam, which is chemically named 7-chloro-l,3-dihydro-l-methyl-5-phenyl-2H- 1,4-benzodiazepin-2-one, is sold under the tradepame 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 5 3 r d ed., 1999).

Estazolam, which is chemically named 8-chloro-6-phenyl-4H-s-triazolo[4-3a][1,4]benzodiazepine, is sold under the tradename PROSOMTM. PROSOM T M is indicated for the short-term management of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early moming awakenings. Physician 's Desk Reference® 473-475 5 3 r d 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 -12- WO 00/10551 pCTIUS99/1 9167 benzodiazepines for diagnostic and therapeutic procedures, and for the management of benzodiazepine overdose. Physician's Desk Reference" 2701-2704 53 ,d ed. 1999).

The hydrochloride salt of flurazepamn, which is chemically named 7-chloro-1 .42-(diethylamino)ethyl]5(o-fluorophenlD-l,3-dihydro-2H-1I,4-benzodiazepin-2-one dihydrochlonde, is sold under the tradenarne DALivANEO. 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"n ed., 1998).

Lorazeparn, which is chemically named 7-chloro-5-(o-chlorophelyl)-1 ,3-dihydro-3hyrx-H14bnoizpn2oe is sold under the tradenaine 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 rded. 1999).

The hydrochloride salt of midazolani, which is chemically named 8-chloro-6-(2floohnl--ehl4-mdz[,-]14bnoizpn hydrochloride, is sold under the tradenanie VERSED®. VERSED" is indicated for preoperative sedationlanxiolysis/am~nesia and general anesthesia. Physician 's Desk Reference® 2720- 2726 5 3 ,d ed., 1999).

Oxazepain, Which is chemically named 7-chioro- 1,3-dihydro-3-hydroxy-5-phenylk 2H-1,4-benzodiazepin- 2 -one, is sold under the tradenanie SER.AX0. SEP-AX® is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety. Physician's Desk Referenceo 3383-3384 5 3 rd ed., 1999).

SQuazepamn, which is chemnically named 7-chloro-5-(o-fluoro-pheflyl)-l ,3-dihydro-l (2,2,2-trifluoroethyl)2H-1 ,4-benzodiazepine-2-thione, is sold under the tradenarne DORALO. DORAL® 6is indicated for the treatment of insominia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings.

Physician 's Desk Reference® 2958 5 2 n ed., 1998).

Temazepamn, which is chemically named 7-ch~oro-1,3-dihydro-3-hydroxy-l-methyl- 5-hnl2-,-enoizpn2oe is sold under the tradenanie RESTORILO.

RESTORIL!® is indicated for the short-term treatment of insomnia. Physician 's Desk Reference® 2075-2078 5 3 r' ed., 1999).

Triazolam, which is chemically named 8-chloro-6-(o-chlorophenyl)- 1 -methyl-4H-stria-zolo-[4,3-a][l, 4 benzodiazepifle, is sold under the tradename HALCION't.

13 WO 00/10551 PCT/US99/19167 HALCION® is indicated for the short-term treatment of insomnia. Physician's Desk Reference® 2490-2493 5 3 r d 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 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 9 h 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)-2chlorphenothiazine, is sold under the tradename THORAZINE®. THORAZINE® is -14- WO 00/1 0551 PCT[US99/1 9167 indicated, inter alia, for the management of manifestations of psychotic disorders.

Physician's Desk Reference" 3101-3104 5 3 r 1999).

The besylate salt of mesoridazifle, which is chemically named 10-[2(l -methyl-2piperidyl)ethyl]-2-methyl-sylfinyl)-phenothiazne, is sold under the tradenarne SERENTIL.O. SERENTILO 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 d ed., 1999).- Perphenazine, which is chemically named 4-[3-(2-chlorophenothiazin- I 0-yI)propyl- 1 -piperazineethanol, is sold under the tradename TRILAFONO. TRILAFONO' 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 R eference 2886-2888 53 fd ed., 1999).

Trifluoperazine, which is chemically named 10-[3-(4-methyl- I-piperaziny)-propylIis sold under the tradename STELAZEE.

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 ReferenceO 3092-3094 (53rd ed., 1999).

Thiothixene, which is chemically named N,N--dimethyl-9-jj3-(4-methyl-

I-

piperazinyl)-propylidene]thioxanthene 2 sulfonamide, is sold under the tradename NAVANEO. NAVANE is indicated in the management of manifestations of psychotic disorders. Physician 's Desk Reference4 2396-2399 (53rd ed., 1999).

Clozapine, which is chemically named 8-chloro- I1-(4-methyl-I -piperazinyl)51 1 dibenzo[b,e][1,4ldiazepine, is sold under the tradename CLOZARILO. 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 5 3 d ed., 1999).

Haloperidol, which is chemically named 4-[4-(p-chlorophenyl)-4-hydroxypiperidonol4'-fluorobutyrophenole, is sold under the tradenamne UALDOL HALDOL is indicated for use in the management of patients requiring prolonged parenteral antipsychotic therapy patients with chronic schizophrenia). Physician 's Desk References' 2190-2192 5 3 [d ed., 1999).

Loxapine, which is chemically named 2-chloro-l I -(4-methyl-lIpiperazinyl)dibenz[bJ1- 4 ]oxaxepine, is sold under the tradename LOXITANE®.

WO 00/10551 PCT/US99/19167 LOXITANE® is indicated for the management of the manifestations of psychotic disorders.

O Physician's Desk Reference® 3224-3225 5 3 d ed., 1999).

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

C 5 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- 0 piperidinyl]-1,3-dihydro-2H-benzimidazole-2-one, is sold under the tradename

ORAP®.

I ORAP® is indicated for the suppression of motor and phonic tics in patients with Tourette's 0 10 Disorder who have failed to respond satisfactorily to standard treatment. Physician 's Desk C Reference® 1054-1056 ed., 1999).

Risperidone, chemically named 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,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 ed., 1999).

The hydrochloride salt of desipramine, which is chemically named Dibenz[bf]azepine-5-propanamine-10,11 -dihydro-N-methyl-monohydrochloride, is sold under the tradename NORPRAMIN®. NORPRAMIN® is indicated for the treatment of depression. Physician's Desk Reference® 1332-1334 53 rd 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 depression), anxiety, eating disorders, and cerebral function disorders 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 receptor antagonist and/or a B-adrenergic antagonist. Examples of 5-HT,, receptor antagonists and B-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 -16- WO 00/10551 PCT/US99/1 916.7 in U.S. Patent No. 5,552,429, which is incorporated herein by reference; pharmacologically active metabolites and stereosorners thereof;, and pharmnaceutically acceptable salts, solvates, clathrates thereof.

Aiprenolol, which is chemically named 1 -methylethyl)amino-3-1 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-methoxphelyl)pieai- y]2peypoaaie is described by U.S. Patent 4,988,814, which is incorporated herein by reference. See also, Cliffe el aL, J Med. Chem., 36:1509-15 (1993).

Spiperofle, which is chemically named 8-[4-(4-fluorophenyl)4-oxobutyll- I -phenyl- I ,3,8-triazaspiro[4,5]deCanA-ofle), 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 el Neuroch em. Res., 21(5):557-562 (1996).

(S)-UH-301, which is chemically named (S--loo8hdox--irplrio tetralin), is well known to pharmacologists and pharmaceutical chemists. See, Hillyer et J Med. Chem., 33:1541-44 (1990) and Moreau el Brain Res. Bull., 29:901-04 (1992).

Penbutolol, which is chemically named (1-tbutyamino)2-hydoxy3( 2 cyclopentyl-phenoxy)propane), is sold under the tradename LEVATOL'. LEVATOL' is indicated the treatment of mild to moderate arterial hypertension. Physician 's Desk Referenceo 2908-29 10 (53rd ed., 1999).

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

Physician's Desk Reference 3307-3309 53 id ed., 1999).

Tertatolol, chemically named 8-(3-tbutylamino2hydroxypropyloxy)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, -17- WO 00/10551 PCT/US99/19167 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 nonbenzodiazepine 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- 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 pyrimidinyl)-l-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-(pchlorobenzhydryl)- 4[2-(2-hydroxyethoxy)-ethyl] piperazine dihydrochloride, is sold under the tradename ATARAX®. ATARAXO 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, -18- PCT/US99/1 9167 WO 00/10551 tomoxetine, olanzapine, respiradone, buspirone, hydroxyzine, valium, pharmacrologically active metabolites and stercoisomers thereof, and pharmaceutically acceptable salts, solvates, clathrates thereof include, but are not limited to, anxiety, depression, hypertension, and attention deficit disorders.

N 5 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, certan 0 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: aiprazolam; quazepam; alprenolol; brotizolam; temazepam; WAY 100135; chlordiazepoxide; triazolarn; spiperone; clobazam; chlorpromazine; S(-)-pindolol; clonazepam; mesoridazine; R(+)-pindolol; clorazepate; thioridazine; racemic pindolol; demoxepam; acetophenazine; (S)-UH-301; diazepami; fluphenazine; penbutolol; estazolani; perphenazine; propranolol; flumazenil; trifluoperazile; tertatolol; flurazepam; chlorprothixele; desipraniine; halazepamn; thiothixefle; clonidine; lorazepain; clozapine; olanzapine; midawolam; haloperidol; methylphenidate; nitrazepam; loxapine; buspirone; nordazepain; molindone; hydroxyzine; and oxazepaxn; piniozide; tomoxetine.

prazepam; risperidone; 4.1 SYNTHESIS OF SIBUTRAMINE

METABOLITES

Racemic sibutramine, desmethylsibutramTifle, and didesmethylsibutramine can be prepared by methods known to those of ordinary skill in the art. See, U.S. Patent No.

4,806,570, which is incorporated herein by reference; J Med. Chemn., 2540 (1993) 19- WO 00/10551 PCT/US99/19167 (tosylation and azide replacement); Butler, 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. et al., J. Chem.

Soc. Perldn. 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 ofdiastereomeric 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 ofResolving Agents and Optical Resolutions 268 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 linited 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. 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.

WO 00/10551 PCT/US99/19167 Another preferred method of directly synthesizing racemic desmethylsibutramine S 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

N

I 5 subsequently reduced, converted to an intermediate comprising an aldehyde bound to the nitrogen atom, which intermediate is finally converted to desmethylsibutramine in a step CC that comprises the addition of a lewis acid. Preferred lewis acids are selected from the group 8 consisting of BH-THF, BF 3 -THF, La(O-i-Pr) 3 Zr(O-i-Pr) 4 Ti(O-i-Pr),C1 2 SnCI,, and MgBr 2 .OEt 2 A most preferred lewis acid is BH3-THF. This method is applied below in S 10 Example N 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 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 -21 WO 00/10551 PCT/US99/19167 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 ofracemic 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 morning 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 3 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 3 antagonists used. In general, the total daily dose of a 5-HT 3 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, efg., from about 2 mg to about 8 mg of sibutramine metabolite and optionally from about 15 ing to about 60 mg of 5-HT 3 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- WO 00/10551 PCT/US99/19167 O associated with racemic sibutramine include, but are not limited to, significant increases in N supine and standing heart rate, including tachycardia, increased blood pressure (hypertension), increased psychomotor activity, dry mouth, dental caries, constipation, hypohidrosis, blurred or blurry vision, tension, mydriasis, seizures, formation of gallstones,

N

I 5 renal/hepatic dysfunction, fevers, arthritis, agitation, leg cramps, hypertonia, abnormal thinking, bronchitis, dyspnea, pruritus, amblyopia, menstrual disorder, ecchymosis/bleeding disorders, interstitial nephritis, and nervousness. See, Physician 's Desk Reference 1494-1498 5 3ded., 1999).

SAdjunctively administering of two or more active ingredients in accordance with the 0 10 methods of the invention can be concurrent, sequential, or both. For example, a dopamine

C

I reuptake inhibitor and a 5-HT 3 antagonist can be administered as a combination, concurrently but separately, or by sequential administration.

Any suitable route of administration can be employed for providing the patient with a therapeutically or prophylactically effective dose of an active ingredient. For example, oral, mucosal nasal, sublingual, buccal, rectal, vaginal), parenteral intravenous, intramuscular), transdermal, and subcutaneous routes can be employed. Preferred routes of administration include oral, transdermal, and mucosal. As mentioned above, administration of an active ingredient for the treatment or prevention of erectile dysfunction is preferably mucosal or transdermal. Suitable dosage forms for such routes include, but are not limited to, transdermal patches, ophthalmic solutions, sprays, and aerosols. Transdermal compositions can also take the form of creams, lotions, and/or emulsions, which can be included in an appropriate adhesive for application to the skin or can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

A preferred transdermal dosage form is a "reservoir type" or "matrix type" patch, which is applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredient. For example, if an active ingredient is a sibutramine metabolite, a preferred patch is worn for 24 hours and provides a total daily dose of from about 0.1 mg to about 60 mg per 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. The patch can be replaced with a fresh patch when necessary to provide constant administration of the active ingredient to the patient.

23 WO 00/10551 PCT/US99/19167 Other dosage forms of the invention include, but are not limited to, tablets, caplets, N troches, lozenges, dispersions, suspensions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, plasters, solutions, capsules, soft elastic gelatin capsules, and patches.

In one embodiment, pharmaceutical compositions and dosage forms of the invention comprise a dopamine reuptake inhibitor, such as a racemic or optically pure sibutramine metabolite or a pharmaceutically acceptable salt, solvate, or clathrate thereof, and optionally 0 an additional pharmacologically active compound, such as a 5-HT 3 antagonist. Preferred N racemic or optically pure sibutramine metabolites are (+)-desmethylsibutramine, (-)-desmethylsibutramine, (±)-desmethylsibutramine, (+)-didesmethylsibutramine, N (-)-didesmethylsibutramine, and (+)-didesmethylsibutramine. The pharmaceutical compositions and dosage forms can contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients known to those skilled in the art.

In practical use, an active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.

The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, preferably without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, an active ingredient can also be administered by controlled release means or delivery devices that are well known to those of ordinary skill in the art, such as those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, the disclosures of which are -24- WO 00/10551 PCT/US99/19167 incorporated herein by reference. These dosage forms can be used to provide slow or c controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer tt coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the N 5 desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions of the invention. -The invention thus Sencompasses single unit dosage forms suitable for oral administration such as, but not Slimited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal of improving

C

drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include: 1) extended activity of the drug; 2) reduced dosage frequency; and 3) increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and thus can affect the occurrence of side effects.

Most controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various inducers, including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the WO 00/10551 PCT/US99/19167 compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.

For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

This invention further encompasses lactose-free pharmaceutical compositions and dosage forms. Lactose is used as an excipient in sibutramine formulations. See, e.g..

Physician's Desk Reference 1494 (53" ed., 1999). Unlike the parent drug, however, desmethylsibutramine and didesmethylsibutramine are secondary and primary amines, respectively, and so can potentially decompose over time when exposed to lactose. Thus, compositions of the invention that comprise sibutramine metabolites preferably contain little, if any, lactose other mono- or di-saccharides. As used herein, the term "lactose-free" means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.

Lactose-free compositions of the invention can comprise excipients which are well known in the art and are listed in the USP (XXI)/NF (XVI), which is incorporated herein by reference. In general, lactose-free compositions comprise an active ingredient, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Preferred lactose-free dosage forms comprise an active ingredient, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.

This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. For example, the addition of water is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, Jens T.

Carstensen, Drug Stability: Principles Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and heat accelerate decomposition. Thus the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly -26- WO 00/10551 PCT/US99/19167 encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms ofracemic or optically pure sibutramine metabolite which contain lactose are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

In this regard, the invention encompasses a method of preparing a solid pharmaceutical formulation comprising an active ingredient which method comprises admixing under anhydrous or low moisture/humidity conditions the active ingredient and an excipient lactose), wherein the ingredients are substantially free of water. The method can further comprise packaging the anhydrous or non-hygroscopic solid formulation under low moisture conditions. By using such conditions, the risk of contact with water is reduced and the degradation of the active ingredient can be prevented or substantially reduced.

Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, for example, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, and AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA, An exemplary suitable binder is a mixture of microcrystalline cellulose and -27- WO 00/10551 PCT/US99/19167 S sodium carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low N moisture excipients or additives include AVICEL-PH-103TM and Starch 1500 LM.

SExamples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The binder/filler in C pharmaceutical compositions of the present invention is typically present in about 50 to Sabout 99 weight percent of the pharmaceutical composition.

C

I Disintegrants are used in the compositions of the invention to provide tablets that 0 10 disintegrate when exposed to an aqueous environment. Too much of a disintegrant will produce tablets which may disintegrate in the bottle. Too little may be insufficient for -disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) should be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used varies based upon the type of formulation and mode of administration, and is readily discernible to those of ordinary skill in the art. Typically, about 0.5 to about weight percent of disintegrant, preferably about 1 to about 5 weight percent of disintegrant, can be used in the pharmaceutical composition.

Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, Texas), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass), or -28mixtures thereof. A lubricant can optionally be added, typically in an amount of less than about 1 weight percent of the pharmaceutical composition.

Dosage forms of the invention that comprise a sibutramine metabolite preferably contain from about 0.1 mg to about 60 mg of the metabolite or pharmaceutically acceptable salt, solvate, or clathrate thereof. For example, each tablet, cachet, or capsule contains from about 0.1 mg to about 60 mg of the active ingredient. Most preferably, the tablet, cachet, or capsule contains either one of three dosages, about 10 mg, about 20 mg, or about 30 mg of racemic or optically pure sibutramine metabolites (as scored lactose-free tablets, the preferable dose form).

The invention is further defined by reference to the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of this invention.

Throughout the description and claims of the specification the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, components, integers or steps.

EXAMPLES

Examples 1-2 describe the preparation of racemic and optically pure sibutramine.

Examples 3-8 describe the preparation of racemic and optically pure forms of desmethylsibutramine (DMS). In each of these examples, the enantiomeric purity of DMS was determined using a Chirobiotic V analytical column (10 pm, 4.6 mm x 25 mm) with 20 mM ammonium acetate/IPA (65:35) as the mobile phase.

The UV detector was set to a wavelength of 222 nm.

Examples 9-12 describe the preparation of racemic and optically pure forms of didesmethylsibutramine (DDMS). In each of these examples, the enantiomeric purity of DDMS was determined using an ULTRON ES-OVM analytical column (150 mm x 4.6 mm) with 0.01 M KH 2

PO

4 /MeOH (70:30) as the mobile phase. The UV detector was set to a wavelength of 200 nm.

Examples 13-14 describe methods of determining binding affinities of the compounds of the invention and binding affinities measured using those methods.

Finally, Example 15 describes oral formulations comprising compounds of the invention.

JMN U:LEISA\MNBPOFlSp fmeors\2O4200875 (Dl) doc -29- WO 00/10551 PCT/US99/19167 5.1. EXAMPLE 1: SYNTHESIS OF SIBUTRAMINE Synthesis of 1-(4-Chlorophenvl)cvclobutanecarbonitrile To a suspension of NaH (17.6 g 60%, washed with hexane) in dimethylsulfoxide (150 mL) at room temperature with mechanical stirring was added over a one hour period a mixture of chlorbenzylnitrile (30.3 g) and 1,3-dibromopropane (22.3 mL, 44.5 The reaction mixture was stirred for an additional 1 hour, and isopropyl alcohol (10 mL) was added slowly to quench excess NaH. Water (150 mL) was added. The reaction mixture was extracted with I-butyl methyl ether (MTBE) (2 x 200 mL), and the combined extracts were washed with water (3 x 200 mL), brine, and dried over MgSO 4 The solvent was removed in a rotoevaporator, and the final product was purified by distillation to give the title compound (22 g, 56%) as pale yellow oil, bp 110-120*C/1.0 mm Hg. The product was characterized by 'H NMR.

Synthesis of 1 -(4-chlorophenvl)cvclobutvll-3-methvlbutylamine A solution ofisobutylmagnesium bromide (2M, 108 mL) in diethyl ether (Aldrich) was concentrated to remove most of the ether. The residue was dissolved in toluene (150 mL), followed by addition of the nitrile made above (22 The reaction mixture was heated to 105 0 C for 17 hours. The reaction mixture was cooled to room temperature, and added to a slurry of NaBH 4 in isopropyl alcohol (450 mL). The reaction mixture was heated under reflux for 6 hours, cooled to room temperature and concentrated. The residue was diluted with water (350 mL), and extracted with ethyl acetate (3 x 200 mL). The combined extracts were washed with water (100 mL), and dried (MgSO), and concentrated to give 24.2 g crude product Synthesis of Sibutramine Free Base 1-[l-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (21.6 g) was added to formic acid (27 mL) and aqueous formaldehyde (46 mL). The reaction mixture was heated to C for 18 hours and was cooled to room temperature. 30% NaOH was added until the mixture was basic (pH 11). The solution was extracted with chloroform (3 x 200 mL) and the extracts were combined and washed with water and brine and concentrated to give 15 g product.

WO 00/10551 PCT/US99/19167 t Sibutramine HCI O Sibutramine free base (2.25 g) was dissolved in MTBE (20 mL) and that solution S was added to 20 mL M HCI in diethyl ether. The reaction mixture was stirred for S minutes, and the solid was collected by filtration to give 1.73 g after drying. The product C 5 was characterized by 'H NMR.

cr Resolution of Sibutramine 8 12.3 g racemic sibutramine was dissolved in ethyl acetate (85 mL), and a solution of S 21.7 g L-dibenzyltartaric acid ("L-DBTA") in ethyl acetate (85 mL) was added thereto. The reaction mixture was heated to reflux and cooled to room temperature. The white precipitate Swas collected (ee of salt is ca The solid was then suspended in 220 mL ethyl acetate and heated at reflux for 30 minutes. The solid was collected to give >95% ee. The salt was further crystallized in isopropyl alcohol (450 mL) to give 11.3 g of salt with >99.3% ee.

(-)-Sibutramine L-DBTA (yield Free base was obtained by treatment of the salt with saturated aqueous NaHCO 3 and extracted with chloroform. The (-)-sibutramine HCI salt was obtained with treatment of the free base with HCI/Et 2 O as described above. Optical rotation of the HCI salt was 3.15 (c 0.9, H 2 'H NMR "C (CD 3 OD), and M* 279.

The resolution mother liquor was treated with NaOH to give the partially enriched (+)-sibutramine and was then treated with D-DBTA as described above to give (+)-sibutramine-D-DBTA salt with 99.3% ee. The sibutramine enantiomers were characterized by 'H and "C NMR: M 279. The material was also characterized by HPLC and Chiral HPLC.

5.2. EXAMPLE 2. SIBUTRAMINE FROM ITS METABOLITES Racemic and optically pure sibutramine can also be prepared by methylation of desmethylsibutramine or dimethylation of didesmethylsibutramine under suitable reaction conditions. An example of this method is shown in Scheme 1.

-31 WO 00/10551 PCT/US99/19167 CH0/HCOOH Cl" RI R 2 CN or (S)-DDMS or or (S)-Sibutramine or (S)-DMS C) DDMS: RI R2 H DMS: R, H; R2 CH 3 CScheme 1 0 N 5.3. EXAMPLE 3. DESMETHYLSIBUTRAMINE FROM SIBUTRAMINE (-)-Sibutramine (1.25 g) was dissolved in toluene (90 mL) and diethylazodicarboxylate ("DEAD") was added (0.8 g, 1.1 eq). The reaction mixture was heated at for 6 hours, and 0.8 g DEAD was added. The reaction was heated at 50 0 C for another 6 hours, cooled to room temperature and the toluene was removed under vacuum. The residue was suspend in 45 mL of ethanol and 45 mL of saturated aqueous NH 4 C1. The reaction mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature and concentrated to remove ethanol. Aqueous NaHCO 3 was added until the concentrate was basic. The basic concentrate was extracted with dichloromethane, (3 x 50 mL). The extracts were combined, dried with sodium sulfate, filtered and concentrated to give a crude product. Flash column chromatography (SiO,) (ethyl acetate/TEA 99:1) gave 0.43 g product. It was characterized by 'H and 13C NMR, M* 266, and optical rotation [a] -10.6, c 3.3, (CHCI 3 The other enantiomer and racemate were prepared similarly and the isomer was characterized as the (-)-isomer.

Synthesis of desmethvlsibutramine hvdrochloride isomers To a solution of (-)-desmethylsibutramine (0.78 g) in ethyl acetate (5 mL) at 0 C was added HCl/diethyl ether (1 M, 5 mL). The reaction mixture was stirred for 1 hour and the solid was collected by filtration. The solid was then dried to give 0.68 g white solid.

The product was characterized by 'H and 3 C NMR (DMSO-d 6 and a chemical purity of> 99% was determined by HPLC. (c 0.5, H 2 The racemate and the other enantiomer were prepared and characterized in the same way.

-32- I I W 00/0551PCTIUS99/1 9167 r- EXAMJP-LE 4. (R-/S'-DESMETJy-LST3UT-RMTNE Another method of preparng racemic desmethylsibutramifle ((RIS)-DMS) is shown in Scheme 2 and described in detail below: CHO

CCBCDIL

BF

3 -OEt CH i-BuMgCIITHF C1 C1 H CH 3

(R/S)-DMS

Scheme 2 Preparatio ofI14G~rohf~YI-cyclobutvl carboxaldehyde, Following Scheme 2, diisobutylaluminm hydride (DIBAL-H) (87 niL, IM in THIF, 87.0 inmol) was added to a solution of l-(4-chlorophenyl) cyclobutanecarbonitnile

(CCBC;

l Og, 52.1 mniol) maintained at -20'C. The resulting mixture was stirred for 4-5 hours at 0 0 C and then poured into a 10% aqueous citric acid solution and diluted with 200 mL MTBE. The mixture was stirred at room temperature for 3-4 hours. The aqueous layer was washed with MTBE (1 x50 niL) and the combined organic layers were dried over MgSO, 4 and concentrated to give 9 g of the above-captioned aldehyde as an oil. 'H1 NMR

(CDGI

3 8 9.52 1Hl), 7.35-7.06 (in, 4H), 2.77-2.68 (in, 211), 2.43-2.32 9m, 2H1), 2.06-1.89 (in, 2H). 1 3 C NMR 5 198.9, 139.4, 132.9, 128.9, 127.8, 57.1, 28.3, 15.8.

Preparation of 14-hlorophenyL)- I -cvclobu vl N-m~ethlcarbaimine A mixture of 1-(4-chlorophenyl)-1-cyclobutyl carboxaldehyde (3g, 15.4 minol) and methyl amnine (12 rriL, 40% aqueous w/w, 154 nimol) was stirred at room temperature for 18-40 hours. The reaction mixture was extracted with MTBE (2x50 niL). The combined organic layers were dried over K 2 C0 3 and concentrated to give 2.5 g of the abovecaptioned imine as an oil. 'H NMIR (CDCI 3 5 7.65 (in, 1H), 7.33-7.11 (mn, 411), 3.34 (s, 33 WO 00/1 0551 PCTIuS99/J 9167 2.69-2.44 (in, 2H), 2.44-2.34 (in, 2H), 2.09-1.84 (mn, 2H); 1 3 C NMR 8 168.0, 144.0, 131.8, 128.4, 127.4, 50.6, 47.6, 30.6, 15.8.

Preparation of ]-4clrpey)Nmty--2mtypoy~ylbtnmtaie To a solution of I -{4-chlorophel)--cyclobutyl N-inethylcarbaimifle (0.5g, 2.4 mmol) cooled to 0 0 C was added BF 3 -OEt 2 (0.34g, 2.4 mm-ol). The mixture was stirred for I hour and then cooled to -78 0 C. At this temperature, isobutyl magnesium bromide (2.5 inL, 2M. in ether, 5 nol) was added to form a mixture which was stirred at -78 0 C for 2 hours and then warmed to room temperature and stirred overnight. The reaction was quenched with saturated NaIHCO 3 solution (10 m.L) and diluted with MTBE (15 inL). The organic layer was dried over MgSO,, concentrated, and purified by silicagel chromatography (eluting with 1% NEt, in ethyl acetate) to give 3 80 mg of the above captioned amine as an oil. 'H NMIR (CDCl,) 5 7.35-7.19 (in, 411), 2.65-2.74 (in, 111), 2.57 311), 2.20-2.56 (mn, 1.60-2.00 (mn, 3H1), 1.20-1.00 (in, 211), 0.95-0.90 (mn, 6H), 0.67-0.60 (mn, I '3C NMIR 6 144.7, 131.3, 129.1, 127.4, 65.5, 51.7, 41.4, 37.4, 33.7, 32.3, 25.4, 24.0, 22.0, 16.3.

EXAMPLE 5. (RM-)DESMET11YLSTBUTRAM1NEHCL A method of preparing the hydrochloride salt of raceinic desinethylsibutranlifle ((R/S)-DMS-HCI) is shown in Scheme 3: 34 WO00/10551 PCT/US99/19167 i-BuMgBr NaBH

CN

SI T MeOH I Toluene NMgBr

C

l B NMgjr

CCBC

IN,

0 NH 2 CI H CHO

(R/S)-DDMS

Cl 1) BH 3

-THF

2) HCVMTBE CI, N'CH3

HCI

(R/S)-DMS- HCI Scheme 3 Following Scheme 3, toluene (150 mL) and a solution of CCBC (50.0 g, 261 mmol) in toluene (45 mL) were added to a solution of isobutyl magnesium bromide in THF (392 mL, 1M in THF, 392 mmol). The resulting mixture was distilled until the internal temperature reached 105-110"C and was then refluxed at this temperature range for 2-4 hours. The reaction mixture was then cooled to 0°C and quenched with methanol (295 mL).

NaBH, (11 g, 339 mmol) was added portion-wise over 15 minutes to the reaction mixture at 0"C. After stirring for 15 minutes, the reaction mixture was transferred into a 2N aqueous HCI solution (365 mL). The organic phase was distilled until the internal temperature reached 105 C, and was then allowed to cool to room temperature. Formic acid (24 g, 522 mmol) was then added to the reaction mixture, which was then heated to reflux (92-96*C) for 6-8 hours after which time the reaction mixture was distilled until the internal temperature reached 108 C. The mixture was then cooled to 10°C and BH 3 ,THF (653 mL, M, 653 mmol) was added. The resulting mixture was heated to reflux (690C) for hours. The mixture was then cooled to 5 0 C, combined with methanol (105 mL), and refluxed again for 45 minutes. The reaction mixture was distilled until the internal temperature reached 116°C, and then allowed to cool to 250C. Hydrochloric acid in MTBE (373g, 18 wt of HCI, 1840 mmol) was then added to the mixture to provide a white slurry WO 00/1 0551 PCT/US99/19167 which was refluxed for 1 hour and then filtered to give 62.3 g of (RAS)-DMS-HCI.

NMR (CDCI 3 'H 0.85-1 .1 (in, 611, 1.24-1.5 2M1, 1.65-2.14 411), 2.2-2.5 (b, 4H), 2.5-2.7 (in, 2H), 3.4-3.6 111), 7.3-7.5 (in, 411), 9.0-9.5 2H). 3 C 15.5, 21.4, 23.5, 24.7, 31.4, 32.4, 33.2, 35.9, 49.1, 64.2, 128.5, 129.4, 133.0, 141.6.

5.6. EXAMPLE 6. (R)-DES dETRYLSBUTRAMINEHCL A method Of preparing the hydrochloride salt of (R)-desmethylsibutamine ((R.)-DMS-HCI) is shown in Scheme 4 and described in detail below: Et0Acheptane (1.0 0.4) I(R)-Mandelic acid

N

-(R)-Mandelate (R/.S)-DMS (R)-DMS- (R)-MA 1) EtOAc/heptane 2) NaOH/iHCVMTBE

N.

HCI

(R)-DMS- HCI Schemp 4 Formation of (R)-Mandelate Salt of (R)-DMS

(R/

1 )-Desmethylsibutraininfe HCl ((R/S)-DMS-HCl) (60 g) was added to ethyl acetate (300 rnL) and the resulting mixture was cooled to 0 Aqueous NaOH (1.5 N, 300 niL) was then added to the reaction mixture, which was then stirred for 30 minutes. The organic phase was separated, washed with water (150 mL), and concentrated. (R)-Mandelic acid (3 0.3 ethyl acetate (5 10 niL total), and heptane (204 mL) were then added to the concentrated organic phase. The resulting mixture was then heated to reflux for 1 hour, after which time it was cooled to 20-23 0 C. Filtration of the resulting slurry yielded 36.4 g of (R)-desmethylsibutramlifle.(R)mandelate 95.5% ee).

-36- WO 00/10551 WO 00/ 0551PCTIUS99/1 9167 Enrichment of (R)-DMS-(R):MA A mixture of (R)-DMS-(R)-MA (30 g, 0.072 mol), ethyl acetate (230 and heptane (230 mL) was heated to reflux for I hour. After cooling to 20-23 the product n was filtered and dried to give 29.6 g of (R)-DMS-(R)-MA (99.9% ee).

Formation of HCI Salt of (R)-DMS A mixture of (R)-DMS-(R)-MA (50 g, 0.12 mol), NaOH (lO0mmi; 3.0 and toluene (500 mL) was stirred for 30 minutes. The organic phase was washed with water (200 niL), concentrated to about 300 niL, and cooled to room temperature. HCV/MTBE (100 niL, 14%, 0.34 mol) was then slowly added to the mixture to form (R)-DMS-HCI. After stirring for ci minutes, the slurry was filtered and the resulting wet cake was washed two times with MTBE and dried to give 34.5 g of (R)-DMS-HCl (99.9% ee; 99.9% chemically pure by NMR). NMiR (CDCI 3 'H 0.85-1.1 (in, 6H1), 1.24-1.5 211), 1.65-2.14 4M), 2.2-2.5 411, 2.5-2.7 (in, 21H), 3.4-3.6 111), 7.3-7.5 (mn, 4H1), 9.0-9.5 2H1). 1 3 c '15.5, 21.4, 23.5, 24.7, 31.4, 32.4, 33.2, 35.9, 49.1, 64.2, 128.5, 129.4, 133.0, 141.6.

5.7. EXAMvPLE 7. (S)-DESMETIIYLSIBUTRAMINEHrCL A method of preparing the hydrochloride salt of (S)-desinethylsibutanine (S)-DMS-HCl) is shown in Scheme 5 and described in detail below: EtOActheptane (1.0 0.4) N (S)-Mandelic acid C Ir'(S)-Mandelate (R/S)-DMS (S)-DMS- (S)-MA 1) EtOAc/heptane 2) NaOHIBCUMTBE C1, N,

IC

VfM*-W Scheme 37 17 WO 00/1 0551 PCT/US99/I 9167 r- Formation of (S)-Mandelate Salt of (S)-DMS Following Scheme 5, a mixture of (R/S)-DMS-HCI (5.0 NaOH (1.5N, 20 mL) and ethyl acetate (50 mL) was stirred for 30 minutes. The organic phase was washed with water rnL) and concentrated to give desmethylsibutramlifle free base (4.2 g, 96%).

N1 5 DesmethylsibUtramifle free base (I.1Ig, 4.1 mnmol) was combined with (S)-mandelic acid (0.62 g, 4.1 mmol), ethyl acetate (1 IrnL), and heptane (4.4 mL). The resulting mixture was heated to reflux. for 30 minutes and cooled to 20-23 Filtration of the 0 resulting slurry gave 0.76 g of (S)-desmethylsibutramine-(S)-mandelate salt ci MA) (96% ee).

ci Enrichment o "(S)-DMS(S)-MA A mixture of (S)-Desmethylsibutramifle-(S}mandelate (0.76 ethyl acetate mL), and heptane (5 mL) was heated to reflux for 1 hour. After cooling to 20-23 the product was filtered and dried to give 0.72 g of (5)-DMS-{S)-MA (99.9% ee).

Recover, of (S)-Mandelate Salt of (S)-DMS from Mother Liguor of (S-DMS-(R)-MA A solution of (S)-DMS-(R)-MA in ethyl acetate-heptanfe (67% ee mother liquor) was charged with NaOH (3N, 400 mL) and the reaction mixture was stirred for 30 minutes. The organic phase was washed with water and concentrated. The resulting residue (130 g, 0.49 mol and 67% ee) was charged with (S)-mandelic acid (28.5 g, 0.49 mol), ethyl acetate (1400 mL), and heptane (580 mL). The mixture was heated. to reflux for 1 hour and then slowly cooled to room temperature. The resulting slurry was filtered and dried to give 147 g (86% based on (8)-isomer) of (8)-DMS-(S)-MA (99.9% ee).

Formation of HCI Salt of(S)-DMS (S)-Desmethylsibutramile-GS}-mandelate (20 g, 0.048 mol) was added to a mixture of NaGH (60ml, 3.0 N) and toluene (200 mL). The mixture was stirred for 30 minutes and the organic phase was then washed with water (100 mnL), concentrated to about 100 mL, and cooled to room temperature. Hydrochloric acid in MTBE (40 mL, 14%, 0.13 mol) was then added slowly to the mixture to form (S)-DMS-HCI. After stirring for 30 minutes, the slurry was filtered and the resulting wet cake was washed two times with MTBE and dried to give 14 g of (8)-DMS-(L)-MA (99.9% ee; 99.9% chemical purity). NMIR (CDCI 3 "l- 0.84-1.1 6H), 1.25-1.5.(b, 2H), 1.65-2.15 4H), 2.2-2.5 4H), 2.5-2.7 (mn, 2H), -38- -7 WO 00/1 0551 PCT/US99/1 9167 3.4-3.6 I 7.3-7.5 (in, 411), 9.0-9.5 2H). 3 C 15.5, 21.4, 23.5, 24.7, 31.4, 32.4, 33.2, 35.9, 49.1, 64.2, 128.5, 129.4,133.0,141.6.

EXAMPLE 8. DESMETHTYLSIBUTRAMINE

FROM

DIDESMETIJYLSIBUTRAMINE

Racemic and optically pure didesmethylsibutramife can also be prepared by methylation of didesmethylsibutramifle under suitable reaction conditions. An example of this method is shown in Scheme 6.

0: T- 1) Base 2) HCOOH 3) BI- 3

-THF

Tartarate or (S)-DDMS' (D)-TA or (S)-DMS Scheme 6 5.9. EXAMPLE 9. (RM-)DDESME-THYLSIBUTRAINE A preferred method of preparing racemic didesmethylsibutraniine free base is shown in Scheme 7 and described in detail below.

i-BuMgBr Toluene

CCBC

NaBH 4 MeOH-

(R/S)-DDMS

Scheme 7 -39- WO 00/1 0551 PCTJUS99/J 9167 Following Scheme 7, a I L three-necked round bottom flask was charged with iso'butyl magnesium bromide (200 mL, 2.0 M in diethyl ether) and toluene (159 mL) and the resulting mixture was distilled to remove most of the ether. After the mixture was cooled to CCBC (50.0 g in toluene (45 m.L) was added, and resulting mixture was refluxed for 2-4 hours. The reaction mixture was then cooled to 0 0 T and methanol (300 :mL) was added to it, followed slowly by NaBH 4 (1 The resultin g mixture was then stirred at about 0- 0 C for 15 mrinutes. The reaction mixture was then added slowly to an aqueous ilCi solution (365 niL, 2N) kept at 0 0 C, and the resulting mixture was warmed to room temperature with continual stirring. After separation of the organic phase, the aqueous phase was washed with toluene (200 The combined organic phases. were washed with water (200 mL) and concentrated to give (R/5)-DDMS (55 g, NMR (CDC1 3 'H 6), 0.6-0.8 (in, I 0.8- 1.0 61-1), 1.1-1.3 (in, I111), 1.6-2.6 (mn, 711), 3.0-3.3 (in, I1H), 7.0-7.6 (mn, 4M1. 1 3 C 15.4, 21.5, 24.3, 24.7, 31.5, 31.9, 41.1, 50.73, 56.3, 127.7, 129, 131.6, 144.2.

is 5.10. EXAMPLE 10. (R/S-DIDESMETHYLSIBUTRAINE.(D)-TARTRATE A preferred method of preparing the (D)-tartrate salt of racemic didesmethylsibutramfine is shown below in Scheme 8. It should be noted that the (L)-tartrate salt of racemic didesmnethylsibutranife can be prepared in an analogous manner.

CN i-BuMgBr 1 NaBH 4 It' Toluene CLc N M gBr j MeOH

CCBC

or (L)-Tartric Acid I toluene

NH

2

NH

2 CI or (L).Tartarate (R/S)-DDMS (R/.S).DDMS- (D)-TA or Scheme 8 -7 WO 00/10551 PCTIUS99/1916.7 Following Scheme 8, a mixture of racemnic didesm ethyl sbutramne (15.3 g) and toluene (160 mL) was heated to 70-80*C and (D)-tartaric acid (9.1 g) in water (20 mL) and acetone (10 mL) was added slowly. The resulting mixture was refluxed for 30 minutes, after which the water and acetone were removed by distillation. The resulting mixture was cooled to room temperature to provide a slurry which was then filtered. The resulting wet cake was washed two times with MTBE (20 mL x2) and dried to yield (R/S)-DDMS-(D)-TA (22.5g, NMR (DMS0): 'H 0.6-0.92 (mn, 6H1), 0.92-1.1 (in, 111), 1.1-1.3 (rn, 1H), 1.5-1.8 (mn, 2H), 1.8-2.1 (mn, 11,2.1-2.4 (in, 2.4-2.6 (in, 111), 3.4-3.6 1ff), 3.94.2 211), 6.4-7.2 6H, OH, COOH and NH 2 7.3-7.6 (in, 411). 3 C 15.5, 2.1, 23.3, 23.7, 31.5, 31.8, 37.7, 39.7, 54.5, 72.1, 128, 129.7, 131.3, 142.2, 174.6.

5.11. EXAMPLE 11. W E-()-ARTAT Resolution from Didesmethlsibuatranife Free Base A method of isolating the (D)-tartrate salt of (R)-didesmethylsibutranme from raceinic didesinethylsibutraine free base is shown in Scheme 9A and described in detail below: (D)-Tartaric acid NH ActonCIH 2 0IMCOH ciNH 2 CI NH (D)-Tartarte (R/S)-DDMS (R)-DDMS-

(D)-TA

Crystallization ActnH0 NH2 (R)-DDMS- (D)-TA Scheme 9A Following Scheme 9A, a mixture of (RIS)-didesmethylsibutrainine (20.3 g), acetone/water/methanol (3 50 inL, 1:0. 13:0.7, and (D)-tartaric acid (12.1 g) were added to a 500 mL three-necked round bottom. The reaction mixture was heated to reflux for 30 minutes and then cooled to 45 The reaction mixture was then seeded with (R)-DDMS.(D)-TA (10 ing; 99.6% ee) and stirred at 40-45'C for 30 minutes. The mixture -41 WO 00/10551 PCT/US99/19167 was then cooled to room temperature and stir-red for 1 hour. The resulting slurry was then filtered and the wet cake was washed with cold acetone/water and dried to give 10.3 g (33%) of (R)-DDMS-(D)-TA (90% ee).

Resolutiofrm(i Diemtvlsibutranmine.(D)-tarrate A method of isolating the (D)-tartrate salt. of (R)-didesmethylsibutramifle from the (D)-tartrate salt of racemic didesmethylsibutramine is shown in Scheme 9B and described in detail below: AcetoneIH 2 OfMCOH c-I NH2(D}.Tartarate

NH

2 (D)-Tartarate (R/S)-DDMS-(D)-TA (R)-DDMS- (D)-TA Scheme 9B Following Scheme 9B, a mixture of (R/S)-didesmethylsibutramlle(D)-TA (5.0 g) in acetone (50 mL), water (6.7 mL), and methanol (3.3 mL) was refluxed for 30 minutes. The mixture was then cooled to room temperature and the resulting slurry was filtered to provide a wet cake which was then washed with cold acetone and dried to give (R)-DDMS-(D)-TA (1.4 g, 28%; 92% ee).

Enrichment of (D)-Tartrate Salt of (R)-DDMS A mnixture of (R)-DDMS(D)-TA (25 g, 92% ee) and acetonitrile/water/ethanol (300 mL:30 mL) was refiuxed for 1 hour. The mixture was then cooled to room temperature to provide a slurry which was filtered and dried to give (R)-DDMS-(D)-TA (18 g, 71.3%; 99.7% ee; and 99.9 1 chemical purity). NMR (DMSO-d 6 'H 0.7-0.9 (in, 6H), 0.9-1.05 I 1. 1 -1.24 I 1.5 -1.8 2H), 1.8-2.02 1WH), 2.1-2.4 3H), 2.4-2.6 1W), 3.5 (mn, 1H), 4.0 2H), 7.1-7.6 (in, 4H, with 6H from NH 2 OH and COCH). 3 C 15.4, 21.5, 22.0,22.2, 32.0, 32.2, 38.4, 49.0, 54.0, 72.8, 128.8, 130.0, 132.0, 143.0, 175.5.

42 WO 00/1 0551 PCT/US99/I 9167 5.12. EXAMPLE 2. 6S-DIDESMET1YLSIBUTRAMINECL-TARTATE A method of isolating the (L)-tartrate salt of (S)-didesmethylsibutramifle from racemnic didesmethylSibutramifle free base is shown in Scheme and described in detail below: N- (L)-Tartaric acid yz

NHY

2 Acetondl-1 2 0/MeOH

N

2 CI -(L)-Taitarate (R/S)-DDMS (R)-DDMS- (L)-.TA Crystallization AcetonCIH7 2 O 'N NH .(L)-Tartarate (S)-DDMS' (L)-TA Scheme Formnation of(LVTartrate Salt of (S)-DDMS (RIS) Didesmethylsibutramihne (20.5 acetone/water/methanol (350 niL, 1:0.13:0.7, v:v:v) and (L)-tartaric acid (12:2g) were added to a 500 niL three-necked round bottom flask. The mixture was heated to reflux. for 30 minutes and then cooled to 45*C. The reaction mixture was then seeded with (S)-DDMS-(L)-TA (10 mg and 99.7% ee) and stirred at 40-45*C for 30 minutes. The mixture was cooled to room temperature and stirred for I hour. The resulting slunry was filtered to provide a wet cake, which was washed with cold acetonetwater and dried to give 10.8 g of (S)-DDMS-(L)-TA (89.7% ee).

Preparation of L-Tartrate Salt of (S)-DDMS from Mother Liquor of (R)-DDM S-(Dh-TA A solution of DDMS tartrate in acetone/water/methanol (mother liquor of DDMS-(D)-TA) was concentrated to remove acetone and methanol. The residue was treated with aqueous NaOI- (3N, 150 mL) and extracted with ethyl acetate. The organic phase was washed with water (100 mL) and concentrated to give didesmethylsibutramine free base g, 0.18 mol and 36% eeof (S)-isomer). The free amine was charged with (L)-tartaric acid (53.6 g, 0.35 mol), acetone (600 mL), water (80 and methanol (40 The mixture was heated to reflux for I hour and then cooled to room temperature. The resulting slurry -43- WO 00/10551 PCT/US99/19167 was filtered to provide a wet cake, which was then washed with cold acetone/water two times to give 26.7 g (56% based on (S)-didesmethylsibutramine) of (S)-DDMS-(L)-TA (96% ee).

Enrichment of (S)-DDMS-(L)-TA A mixture of (S)-DDMS-(L)-TA (26.7 g) in acetonitrile/water (475 mL; 1:0.2, v:v) was refluxed for 1 hour and then cooled to room temperature. The resulting slurry was filtered and dried to give 17.4 g of(S)-DDMS-(L)-TA (99.9% ee; 99.94% chemical purity). NMR (DMSO-d6): 'H 0.7-0.9 6H), 0.9-1.05 1H), 1.1-1.3 1H), 1.52-1.8 2H), 1.84-2.05 1H), 2.15-2.4 3H), 2.4-2.6 1H), 3.65-3.58 1H), 2H), 6.7-7.3 6H from NH,, OH and COOH) 7.1-7.6 4H). 'C 15.4, 21.5,22.0, 22.2,32.0, 32.2, 38.4, 49.0, 54.0, 72.8, 128.8, 130.0, 132.0, 143.0, 175.5.

5.13. EXAMPLE 13: DETERMINATION OF POTENCY AND SPECIFICITY A pharmacologic study is conducted to determine the relative potency, comparative efficacy, binding affinity, and toxicity of the racemic mixture of sibutramine, its enantiomers, the metabolites of sibutramine, and their enantiomers. The profile of relative specificity of monoamine reuptake inhibition is determined from the compounds' inhibition of norepinephrine (NE) reuptake in brain tissue with that of the inhibition of dopamine (DA) and serotonin (5-HT) reuptake.

High-affinity uptake of the 3 H-radiomonoamines is studied in synaptosomal preparations prepared from rat corpus striatum (for inhibition of DA reuptake) and cerebral cortex (for 5HT and NE) using methods published by Kula et al., Life Sciences 34(26): 2567-2575, 1984, and Baldessarini et al., Life Sciences 39:1765-1777, 1986. Tissues are freshly dissected on ice and weighed. Following homogenization by hand (14 strokes in vols of ice-cold isotonic 0.32M sucrose, containing nialamide, 34 pM) in a Teflon-onglass homogenizer, the tissue is centrifuged for ten minutes at 900 x g; the supernatant "solution" that results contains synaptosomes that are used without further treatment Each assay tube contains 50 pL of the cerebral homogenate, radiolabelled-'H-monoamine, and the test compound the pure sibutramine enantiomers, the racemate, and appropriate standards) in a freshly prepared physiologic buffer solution with a final volume of 0.5 mL.

Tissues are preincubated for 15 minutes at 37 C before the assay. Tubes are held on ice until the start of incubation, which is initiated by adding 3 H-amine to provide a final -44- WO 00/10551 PCT/US99/19167 concentration of 0.1 pM. Tubes are incubated at 37°C for 10 minutes with 'H-DA (26 Ci/mmol) and for 20 minutes with 'H-5HT (about 20 Ci/mmol) and 3 H-NE (about Ci/mmol). The specific activity of the radiomonoamine will vary with available material and is not critical. The reaction is terminated by immersion in ice and dilution with 3 mL of ice cold isotonic saline solution containing 20 mM TRIS buffer (pH These solutions are filtered through cellulose ester microfilters, followed by washing with two 3 mL volumes of the same buffer. The filter is then counted for 'H-radioactivity in 3.5 mL of Polyfluor at about 50% efficiency for tritium. Blanks (either incubated at 0"C or incubated with specific, known uptake inhibitors of DA [GRB-12909, 10 IM], 5HT- [zimelidine iM], or of NE [desipramine 10 pM]) are usually indistinguishable from assays performed without tissue and average 2-3% of total CPM.

Comparison of the amounts of 3 H-radioactivity retained on the filters provides an indication of the relative abilities of the pure enantiomers and racemic mixture of sibutramine (and of known DA, 5-HT, and NE reuptake inhibitors) to block the reuptake of these monoamines in those tissues. This information is useful in gauging the relative potency and efficacy of compounds of the invention dopamine reuptake inhibitors, such as a racemic or optically pure sibutramine metabolite, and 5-HT3 antagonists).

The acute toxicities of the compounds of the invention are determined in studies in which rats are administered progressively higher doses (mg/kg) of the pure isomers or racemate. That lethal dose which, when administered orally, causes death of 50% of the test animals, is reported as the LD. Comparison of LD, 5 values for the enantiomers and racemate provides a measure of the relative toxicity of the compositions.

5.14. EXAMPLE 14: BINDING AFFINITIES The binding affinities of racemic and optically pure sibutramine and (-)-sibutramine), desmethylsibutramine and and didesmethylsibutramine and (-)-didesMe) were determined at the nonselective muscarinic receptor and the serotonin (5-HT) uptake site from rat cerebral cortex, the human recombinant norepinephrine (NE) uptake site, and the 33-receptor from rat adipose tissue.

Compounds were tested initially at 10 lim in duplicate, and if 250% inhibition of specific binding was observed, they were tested further at 10 different concentrations in duplicate in order to obtain full competition curves. IC, 0 values (concentration required to inhibit PCT/US99191 67 WO 00/1 0551 specific binding) were then determined by nonlinear regression analysis of the curves and tabulated below.

Compound Binding IC 50 ___ValuesValuM) Muscaxinic Receptor

NE

Uptake 5-HT Uptake 5-HT Selectivity I L (=i)-Sibutramine (+)-Sibutramine (+)Sibutramine (±)-desMe (+)-desMe (_)-desMe (±)-didesMe 1)AI 350 2.800 1.200 35 2,8004 A AMA 110 2100 110J1 2100 090 2.300 4.900 1,500 n2__ 225_ 1,170 1 9 4 44 12 870 9.200 .1 4 -~870 63/14 39/26 1 1 13 1 140 18.9 MU I (-)-didesMe 6.2 4,300 12 Atropine 0.31 GBR 1909 5.6/2.6 Imipramine 145/32 Protriptyline 3.6/0.9 129 L1imid e U I~ I I 129____ None of the compounds showed more than 15% inhi-bition of binding at the P 3 -receptor, and affinity for the muscarinic site was weak compared to atropine. Further, binding to the NE and 5-fiT uptake sites was orders of magnitude less than that of the standards.

The above data, which was generated as described above in Example 13, shows that (+)-desmethylsibutramifle and (4)-didesmethylsibutramifle are potent inhibitors of NE uptake and 5-HT uptake, but have negligible activity at muscarinic receptors.

46 PCT/US99/19167 WO 00/10551 5.15. EXAMPLE 15: ORAL FORMULATION Hard gelatin capsule dosage forms that are lactose-free comprising sibutramine metabolites can be prepared using the following ingredients:

F

O1 Component Racemic or optically pure sibutramine metabolite MicrocrystaUine Cellulose Pre-gelatinized Starch Croscarmellose Magnesium Stearate 5 mg capsule 5.0 90.0 100.3 7.0 10 mg capsule 10.0 20 mg capsule 20.0 4 90.0 90.0

I

97.8 82.8 7.0 1 The racemic or optically pure sibutramine metabolite is sieved and blended with the excipients listed. The mixture is filled into suitably sized two-piece hard gelatin capsules using suitable machinery and methods well known in the art. See, Remington's Pharmaceutical Sciences, 16th or 18th Editions, each incorporated herein in its entirety by reference. Other doses can be prepared by altering the fill weight and, if necessary, changing the capsule size to suit. Any of the stable, non-lactose hard gelatin capsule formulations above can be formed.

Compressed tablet dosage forms of sibutramine metabolites can be prepared using the following ingredients: -47- WO 00/10551 PCT/US99/19167 cI

C-I

Component 5 mg capsule 10 mg capsule 20 mg capsule Racemic or optically pure sibutramine 5.0 10.0 20.0metabolite Microcrystalline 90.0 90.0 90.0 Cellulose Pre-gelatinized 100.3 97.8 82.8 Starch Croscarmellose 7.0 7.0 Magnesium 0.2 0.2 0.2 Stearate The racemic or optically pure sibutramine metabolite is sieved through a suitable sieve and blended with the non-lactose excipients until a uniform blend is formed. The dry blend is screened and blended with the magnesium stearate. The resulting powder blend is then compressed into tablets of desired shape and size. Tablets of other strengths can be prepared by altering the ratio of the active ingredient to the excipient(s) or modifying the table weight Z0 The embodiments of the invention described above are intended to be merely exemplary and those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. All such equivalents are considered to be within the scope of the invention and are encompassed by the following claims.

-48-

Claims (62)

1. A method of treating or preventing a disorder or condition ameliorated by inhibition of neuronal monoamine uptake 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, solvent, or clathrate thereof.

2. A method according to 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 method according to any one of claims 1 or 2 wherein the sibutramine metabolite is selected from the group consisting of (+)-desmethylsibutramine, (-)-desmethylsibutramine, (±)-desmethylsibutramine, (+)-didesmethylsibutramine, (-)-didesmethylsibutramine, and (±)-didesmethylsibutramine.

4. A method according to any one of claims 1 to 3 wherein the amount of sibutramine metabolite administered is from about 0.1 mg to about 60 mg/day. A method according to any one of claims 1 to 4 wherein the amount of sibutramine metabolite administered is from about 5 mg to about 30 mg/day.

6. A method according to any one of claims 1 to 5 wherein the amount of sibutramine metabolite administered is from about 5 mg to about 15 mg/day.

7. A method according to any one of claims 1 to 6 wherein the sibutramine metabolite is administered orally, mucosally, or transdermally.

8. 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 JMN U:%LEISAlMNBPOFSpecflCaicnons\2O4 2 00875 (DIV)doc -49- sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof.

9. A method according to claim 8 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. A method according to claim 9 wherein the affective disorder is depression or attention deficit disorder.

11. A method according to claim 9 wherein the affective disorder is attention deficit disorder and the sibutramine metabolite is (-)-desmethylsibutramine or (-)-didesmethylsibutramine.

12. A method according to claim 8 wherein the sibutramine metabolite is selected from the group consisting of (+)-desmethylsibutramine, (-)-desmethylsibutramine, (±)-desmethylsibutramine, (+)-didesmethylsibutramine, (-)-didesmethylsibutramine, and (±)-didesmethylsibutramine.

13. 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 racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof.

14. A method according to claim 13 wherein the sibutramine metabolite is selected from the group consisting of (+)-desmethylsibutramine, (-)-desmethylsibutramine, (±)-desmethylsibutramine, (+)-didesmethylsibutramine, (-)-didesmethylsibutramine, and (±)-didesmethylsibutramine. A method of treating or preventing 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. JMN U:%EISA\MNBPOFSpeications\2004200 8 7 5 (DIV)doc

16. A method to claim 15 wherein the pain is chronic pain.

17. A method according to any one of claims 15 or 16 wherein the sibutramine metabolite is selected from the group consisting of (+)-desmethylsibutramine, (-)-desmethylsibutramine, (±)-desmethylsibutramine, (+)-didesmethylsibutramine, (-)-didesmethylsibutramine, and (+)-didesmethylsibutramine.

18. A method of treating or preventing obsessive-compulsive disorder which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof.

19. A method according to claim 18 wherein the sibutramine metabolite is selected from the group consisting of (+)-desmethylsibutramine, (-)-desmethylsibutramine, (±)-desmethylsibutramine, (+)-didesmethylsibutramine, (-)-didesmethylsibutramine, and (±)-didesmethylsibutramine. 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.

21. A method according to claim 20 wherein the substance abuse is cocaine addiction.

22. A method according to any one of claims 20 and 21 wherein the sibutramine metabolite is selected from the group consisting of (+)-desmethylsibutramine, (-)-desmethylsibutramine, (±)-desmethylsibutramine, (+)-didesmethylsibutramine, (-)-didesmethylsibutramine, and (±)-didesmethylsibutramine.

23. A method of treating or preventing nicotine addiction which comprises administering to a patient in need of such treatment or prevention a JMN U .EISA\MNVAPO\SpeciOcalions\2002007420 5 (DIV).doc -51 therapeutically or prophylactically effective amount of racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof.

24. A method according to claim 23 wherein the sibutramine metabolite is selected from the group consisting of (+)-desmethylsibutramine, (-)-desmethylsibutramine, (±)-desmethylsibutramine, (+)-didesmethylsibutramine, (-)-didesmethylsibutramine, and (±)-didesmethylsibutramine. 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 pharmaceutically acceptable sale, solvate, or clathrate thereof.

26. A method according to claim 25 wherein the sibutramine metabolite is selected from the group consisting of (+)-desmethylsibutramine, (-)-desmethylsibutramine, (±)-desmethylsibutramine, (+)-didesmethylsibutramine, (-)-didesmethylsibutramine, and (±)-didesmethylsibutramine.

27. 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 racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate or clathrate thereof.

28. A method according to claim 27 wherein the sibutramine metabolite is selected from the group consisting of (+)-desmethylsibutramine, (-)-desmethylsibutramine, (±)-desmethylsibutramine, (+)-didesmethylsibutramine, (-)-didesmethylsibutramine, and (±)-didesmethylsibutramine.

29. A method of treating or preventing a chronic disorder selected from the group consisting of narcolepsy, chronic fatigue syndrome, seasonal affective disorder, fibromyalgia, and premenstrual syndrome which comprises JMN U: EISAWNB PorspecMl I (DN) O= -52- administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof.

30. A method according to claim 29 wherein the chronic disorder is narcolepsy, premenstrual syndrome, or chronic fatigue syndrome.

31. A method according to any one of claims 29 or 30 wherein the sibutramine metabolite is selected from the group consisting of (+)-desmethylsibutramine, (-)-desmethylsibutramine, (±)-desmethylsibutramine, (+)-didesmethylsibutramine, (-)-didesmethylsibutramine, and (±)-didesmethylsibutramine.

32. 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 racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof.

33. A method according to claim 32 wherein the sibutramine metabolite is selected from the group consisting of (+)-desmethylsibutramine, (-)-desmethylsibutramine, (±)-desmethylsibutramine, (+)-didesmethylsibutramine, (-)-didesmethylsibutramine, and (±)-didesmethylsibutramine.

34. A method of treating or preventing migraines 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 a clathrate thereof. A method according to claim 34 wherein the sibutramine metabolite is selected from the group consisting of (+)-desmethylsibutramine, (-)-desmethylsibutramine, (±)-desmethylsibutramine, JMN U:LEISA\NBPOFSpecil .aons20042008 7 5 (DIV) oc -53- (+)-didesmethylsibutramine, (-)-didesmethylsibutramine, and (±)-didesmethylsibutramine.

36. 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 racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof.

37. A method according to claim 36 wherein the incontinence is selected from the group consisting of fecal incontinence, stress urinary incontinence, urinary exertional incontinence, urge continence, reflex incontinence, passive incontinence, and overflow incontinence.

38. A method according to any one of claims 36 and 37 wherein the incontinence is stress urinary incontinence.

39. A method according to any one of the claims 36 to 38 wherein the sibutramine metabolite is selected from the group consisting of (+)-desmethylsibutramine, (-)-desmethylsibutramine, (±)-desmethylsibutramine, (+)-didesmethylsibutramine, (-)-didesmethylsibutramine, and (±)-didesmethylsibutramine. A method according to any one of claims 8, 13, 15, 18, 20, 25, 27, 29, 32, 34 or 36 which further comprises the administration of an additional pharmacologically active compound.

41. A method according to claim 40 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. JMN U .EISANBPOF Speci.,,mUM128OO2DD87 (IV).doc -54-

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

43. A pharmaceutical composition according to claim 42 wherein the sibutramine metabolite is selected from the group consisting of (+)-desmethylsibutramine, (-)-desmethylsibutramine, (±)-desmethylsibutramine, Cc (+)-didesmethylsibutramine, (-)-didesmethylsibutramine, and 0 (±)-didesmethylsibutramine.

44. A pharmaceutical composition according to any one of claims 42 or 43 wherein the sibutramine metabolite is selected from the group consisting of (+)-desmethylsibutramine, (-)-desmethylsibutramine, and (-)-didesmethylsibutramine. A pharmaceutical composition according to any one of claims 42 to 44 wherein the amount of sibutramine metabolite is from about 0.1 mg to about mg.

46. A pharmaceutical composition according to any one of claims 42 to wherein the amount of sibutramine metabolite is from about 2 mg to about mg.

47. A pharmaceutical composition according to any one of claims 42 to 46 wherein the amount of sibutramine metabolite is from about 5 mg to about mg.

48. A pharmaceutical composition according to any one of claims 42 to 47 wherein the pharmaceutical composition is adapted for oral, mucosal, rectal, parenteral, transdermal, or subcutaneous administration.

49. A pharmaceutical composition according to any one of claims 42 to 48 wherein the pharmaceutical composition is adapted for oral, mucosal, or transdermal administration. A pharmaceutical composition according to any one of claims 42 to 49 which further comprises an additional pharmacologically active compound. JMN U LEISAI\NB POF SPwflen~tom 00875 (IV).doc

51. A pharmaceutical composition according to any one of claims 42 to 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.

52. A pharmaceutical composition according to any one of claims 42 to 51 wherein the additional pharmacologically active compound is 5-HT3 antagonist.

53. A pharmaceutical composition according to any one of claims 51 to 52 wherein the 5-HT3 antagonist is an antiemetic agent.

54. A pharmaceutical composition according to any one of claims 51 to 53 wherein the 5-HT3 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. A pharmaceutical composition according to any one of claims 42 to 54 wherein the amount of 5-HT 3 antagonist is from about 0.5 mg to about 500 mg.

56. A pharmaceutical composition according to any one of claims 42 to 54 wherein the amount of 5-HT 3 antagonist is from about 1 mg to about 350 mg.

57. A pharmaceutical composition according to any one of claims 42 to 54 wherein the amount of 5-HT3 antagonist is from about 1 mg to about 250 mg.

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

59. A pharmaceutical composition according to claim 58 wherein the excipient is selected from the group consisting of croscarmellose sodium, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate. JMN U:LEISA\MNB\POFNSpclcalions\2004200875 [DV)doc -56- 4 A pharmaceutical composition according to any one of claims 58 and 59 wherein said pharmaceutical composition is substantially free of mono- or disaccharides.

61. A method of synthesis of sibutramine substantially as described herein with reference to any one of examples 1 or 2.

62. A composition comprising sibutramine prepared by a method according to claim 61.

63. A method of synthesis of desmethylsibutramine substantially as described herein with reference to any one of examples 3 to 8.

64. A composition comprising desmethylsibutramine prepared by a method according to claim 63. A method of synthesis of didesmethylsibutramine substantially as described herein with reference to any one of examples 9 to 12.

66. A composition comprising didesmethylsibutramine prepared by a method according to claim

67. An oral formulation substantially as described herein with reference to example

68. A compound of the formula: rN R C I and pharmaceutically acceptable salts, solvate, and clathrates thereof, wherein R is alkyl excluding methyl.

69. A compound of claim 68, wherein R is C 2 -C 6 alkyl. A method of preparing racemic or optically pure desmethylsibutramine, which comprises contacting a compound of the formula: JMN U:\LEISA\MNBPOFSpecfic sons2004200875 (DIV).doc -57- .N 'CH 3 with a metal salt of the isobutyl cation, excluding iBuMgCI.

71. A method for preparing (R)-mandelate salt of optically pure (R)-didesmethylsibutramine or a pharmaceutically acceptable salt, solvate, or clathrate thereof, which comprises contacting racemic didesmethylsibutramine with (R)-mandelic acid in a solvent which comprises a mixture of acetonitrile and methanol to form the (R)-mandelate salt of (R)-didesmethylsibutramine.

72. A method for preparing (S)-mandelate salt of optically pure (S)-didesmethylsibutramine or a pharmaceutically acceptable salt, solvate, or clathrate thereof, which comprises contacting racemic didesmethylsibutramine with (S)-mandelic acid in a solvent which comprises a mixture of acetonitrile and methanol to form the (S)-mandelate salt of (S)-didesmethylsibutramine.

73. A method of treating or preventing neuropathic pain, comprising administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof.

74. The method of claim 73, wherein the neuropathic pain is diabetic peripheral neuropathy.

75. The method of claim 73 or 74, wherein the racemic or optically pure sibutramine metabolite is (R)-desmethylsibutramine, (S)-desmethylsibutramine, (R)-didesmethylsibutramine, or (S)-didesmethylsibutramine. JMN U:k.EISA\MNB\POFlSpecFd.atlons\2004200875 (DIV).oc -58-