RU2358719C2 - Compositions containing monoamine reuptake inhibitor and methods of their application - Google Patents

Abstract

FIELD: pharmacy.

SUBSTANCE: application of the (-)-didesmethylsibutramine or its pharmaceutically acceptable salts, solvate or clathrate for preparation of the pharmaceutical for Parkinson's disease treatment is claimed.

EFFECT: invention provides enhancing of the motion activity and release of Parkinsonism symptoms.

5 cl, 3 tbl, 15 ex

Description

This application claims the priority of provisional application for US patent No. 60/097665, filed August 24, 1998, and provisional application for US patent No. 60/099306, filed September 2, 1998., which are fully incorporated into the description by reference.

Technical field

This invention relates to compositions containing dopamine reuptake inhibitors, in particular racemic and optically pure sibutramine metabolites, and methods for their use.

BACKGROUND OF THE INVENTION

Sibutramine, chemically named [N-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl] -N, N-dimethylamine, is a monoamine reuptake inhibitor by neurons, which is described in US Pat. Nos. 4,746,680 and 4,806,570. Sibutramine inhibits the reuptake of norepinephrine and, to a lesser extent, serotonin and dopamine. See, for example, Buckett et al., Prog. Neuropsychopharm. & Biol. Psychiat., 12: 575-584, 1988; King et al., J. Clin. Pharm., 26: 607-611 (1989).

Racemic sibutramine is marketed as hydrochloride monohydrate under the trade name MERIDIA® and is intended for the treatment of obesity. Physician's Desk Reference® 1494-1498 (53 ^rd ed., 1999). The treatment of obesity using racemic sibutramine is described, for example, in US patent No. 5436272.

Comprehensive studies of sibutramine have established that it can be used to treat various diseases. For example, US Pat. Nos. 4,552,828, 4,746,680, 4,865,670 and 4,929,629 describe methods of treating depression using racemic sibutramine and US Pat. Nos. 4,871,774 and 4,939,175 describe methods for treating Parkinson's disease and senile dementia using racemic sibutramine, respectively. Other uses of sibutramine are described in PCT publications WO 95/20949, WO 95/21615, WO 98/11884 and WO 98/13033. In addition, the possibilities of using optically pure enantiomers of sibutramine were examined. For example, WO 94/00047 and 94/00114 describe methods for treating depression and related diseases using the (+) - and (-) - enantiomers of sibutramine, respectively.

Sibutramine is rapidly absorbed from the gastrointestinal tract after oral administration and is actively involved in the primary metabolism, resulting in the formation of primary metabolites, desmethylsibutramine and didesmethylsibutramine, shown below.

It was found that desmethylsibutramine and didesmethylsibutramine are more effective in vitro reuptake inhibitors of norepinephrine and 5-hydroxytryptamine (5HT, serotonin) than sibutramine. Stock, MJ, Int'l J. Obesity, 21 (Supp. 1): S25-S29 (1997). However, it was further established that sibutramine and its metabolites have an extremely low degree of affinity for a number of neurotransmitter receptors, including serotonergic (5-HT ₁ , 5-HT _1A , 5-HT _ID , 5-HT _2A , 5-HT _2C ), adrenergic , dopaminergic, muscarinic, histaminergic, glutamate and benzodiazepine receptors. In the same place.

Sibutramine causes many side effects. See, for example, Physician's Desk Reference® 1494-1498 (53 ^rd ed., 1999). Given the identified advantages and therapeutic disadvantages of sibutramine, the task was to create compounds and compositions that can be used to treat or prevent various diseases, including, but not limited to, erectile dysfunction, affective disorders, weight gain or obesity, brain dysfunction, pain syndrome, obsessive-compulsive disorder, substance abuse, chronic illnesses, anxiety, eating disorders, migraines and incontinence. In particular, compounds and compositions are needed which, when treating and preventing such diseases and disorders, cause far fewer side effects than sibutramine.

Summary of the invention

This invention relates to pharmaceutical compositions and dosage forms, as well as to methods of their use for the treatment and prevention of diseases, the weakening of the symptoms of which is achieved by inhibiting the absorption of monoamine by neurons in mammals, including humans. Examples of such diseases include, but are not limited to, erectile dysfunction, affective disorders, weight gain or obesity, brain dysfunction, pain syndrome, obsessive-compulsive disorder, substance abuse, chronic illnesses, anxiety, eating disorders, migraines and incontinence. The methods of this invention are that a subject in need of such treatment or prophylaxis is administered a therapeutically or prophylactically effective amount of a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof.

This invention also relates to a method of treating or preventing an erectile dysfunction, which comprises administering simultaneously to a subject in need of such treatment or prophylaxis, therapeutically or prophylactically effective amounts of a dopamine reuptake inhibitor and a 5-HT ₃ antagonist.

The pharmaceutical compositions of this invention comprise a therapeutically or prophylactically effective amount of a monoamine reuptake inhibitor by neurons. Preferred monoamine reuptake inhibitors by neurons are, but are not limited to, apomorphine, racemic and optically pure sibutramine metabolites, their pharmaceutically acceptable salts, solvates and clathrates. Pharmaceutically, the compositions of this invention may additionally contain other drugs that include, but are not limited to, 5-HT ₃ antagonists.

This invention relates to 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 (±) -desib.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to methods and compositions for inhibiting neuronal reuptake of monoamines (e.g., dopamine, serotonin and norepinephrine). This invention further relates to a method for treating or preventing a disease, the alleviation of the symptoms of which is achieved by inhibiting the reuptake of monoamine by neurons, which consists in administering to a subject (i.e. a person) in need of such treatment or prophylaxis a therapeutically or prophylactically effective amount of an inhibitor reuptake of monoamine by neurons. Preferred monoamine reuptake inhibitors by neurons are racemic and optically pure sibutramine metabolites, their pharmaceutically acceptable salts, solvates and clathrates.

As used herein, the term “treating or preventing a disease whose symptom reduction is achieved by inhibiting the reuptake of monoamine by neurons” means the alleviation of disease symptoms due to abnormal levels of monoamine in neurons. Diseases whose symptom relief is achieved by inhibiting reuptake of monoamine by neurons include, but are not limited to, erectile dysfunction, affective disorders, weight gain or obesity, brain dysfunction, pain, obsessive-compulsive disorder, substance abuse, chronic illnesses, condition anxiety, eating disorders, migraines and incontinence.

A first embodiment of the invention relates to a method of treating or preventing an erectile dysfunction, which comprises administering to a subject in need of such treatment or prophylaxis therapeutically or prophylactically effective amounts of a dopamine reuptake inhibitor and a 5-HT ₃ antagonist. Preferred dopamine reuptake inhibitors include, but are not limited to, apomorphine, sibutramine, racemic and optically pure sibutramine metabolites, their pharmaceutically acceptable salts, solvates and clathrates. Particularly preferred dopamine reuptake inhibitors are racemic and optically pure sibutramine metabolites. Preferred 5-HT ₃ antagonists are antiemetics. Examples of acceptable 5-HT ₃ antagonists include, but are not limited to, granisetron (KYTRIL®), metoclopramide (REGLAN®), ondansetron (ZOFRAN®), renzapride, zakoprid, tropisetron, their optically pure stereoisomers, active metabolites, pharmaceutically acceptable salts, clathrates and solvates.

In a preferred method of this invention, a dopamine reuptake inhibitor is administered transdermally or through the mucous membrane (e.g., nasally, sublingually or buccally). In a more preferred method of this embodiment, the dopamine reuptake inhibitor and the 5-HT ₃ antagonist are administered transdermally or through the mucosa.

A second embodiment of the invention relates to a method for treating or preventing an erectile dysfunction, which comprises administering to a subject in need of such treatment or prophylaxis a therapeutically or prophylactically effective amount of a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof. In a preferred method of this embodiment, the racemic or optically pure sibutramine metabolite, a pharmaceutically acceptable salt, solvate or clathrate thereof, is administered transdermally or via the mucosa.

A third embodiment of the invention relates to a method for treating or preventing an affective disorder, which comprises administering to a subject in need of such treatment or prophylaxis a therapeutically or prophylactically effective amount of a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof. Affective disorders include, but are not limited to, depression (e.g., melancholy), impaired attention (including lack of attention in combination with increased activity and a disease due to lack of attention / increased activity), bipolar and manic syndrome, dysthymia and cyclotymia. As used herein, the terms “attention disorder” (ADD), “attention deficit combined with increased activity” (ADDH), and “attention deficit disorder / increased activity” (AD / HD) are used in accordance with the meanings used in this area. See, for example, Diagnostic and Statistical Manual of Mental Disorders, Fourth Ed., American Psychiatric Association, 1997 (DSM-IV ™) and Diagnostic and Statistical Manual of Mental Disorders, 3 ^rd Ed., American Psychiatric Association (1981) (DSM -III ™).

A preferred method of this embodiment of the invention is a method for treating or preventing attention deficit, which comprises administering to a subject in need of such treatment or prophylaxis a therapeutically or prophylactically effective amount of a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate. For the treatment or prevention of attention deficit, an optically pure sibutramine metabolite and more preferably (-) - desmethylsibutramine or (-) - didesmethylsibutramine are used as a racemic or optically pure sibutramine metabolite.

Another preferred method for this embodiment of the invention is a method for treating or preventing depression, which comprises administering to a subject in need of such treatment or prophylaxis a therapeutically or prophylactically effective amount of a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof. As used, the term “treating or preventing depression” means reducing the intensity or preventing the onset of symptoms of depression, which include, but are not limited to, mood changes, feelings of deep depression, despair, slowing thinking, loss of concentration, pessimism, excitement, and low self-esteem. Using this method, you can eliminate or prevent physical changes that include, but are not limited to, insomnia, anorexia, decreased activity and libido, as well as abnormal hormonal circadian rhythms.

A fourth embodiment of the invention relates to a method of treating or preventing weight gain or obesity, which comprises administering to a subject in need of such treatment or prophylaxis a therapeutically or prophylactically effective amount of a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof. As used, the term “treatment or prevention of weight gain or obesity” means weight loss, getting rid of excess weight, stopping weight gain or getting rid of obesity, and preventing obesity, all of which are usually associated with excessive food intake.

A fifth embodiment of the invention relates to a method for treating or preventing a brain dysfunction, which comprises administering to a subject in need of such treatment or prophylaxis a therapeutically or prophylactically effective amount of a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof. Impairments in brain function include, but are not limited to, senile dementia, Alzheimer's disease, memory loss, amnesia / memory loss syndrome, impaired consciousness, coma, decreased attention, speech disorders, Parkinson's disease, Lennox syndrome, autism, epilepsy, hyperkinetic syndrome and schizophrenia. Impaired brain function can be caused by a variety of factors, which include, but are not limited to, cerebrovascular diseases such as cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral thrombophlebitis, and head injuries, as well as diseases characterized by the presence of symptoms selected from the group including consciousness disorder, senile dementia, coma, decreased attention and speech impairment. As used herein, the term “treating or preventing brain dysfunction” refers to ameliorating or preventing the occurrence of one or more symptoms associated with impaired brain function.

A sixth embodiment of the invention relates to a method for treating or preventing pain, including chronic pain, which comprises administering to a subject in need of such treatment or prophylaxis a therapeutically or prophylactically effective amount of a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof.

A seventh embodiment of the invention relates to a method for treating or preventing an obsessive-compulsive disorder, which method comprises administering to a subject in need of such treatment or prophylaxis a therapeutically or prophylactically effective amount of a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof.

An eighth embodiment of the invention relates to a method for treating or preventing substance abuse, which comprises administering to a subject in need of such treatment or prophylaxis a therapeutically or prophylactically effective amount of a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof. As used, the term “substance abuse” means abuse and physical and / or psychological addiction to drugs or alcohol. The term “substance abuse” further has the meaning adopted in this area. See, for example, DSM-IV ™ and DSM-III ™.

A preferred method for this embodiment of the invention is a method for treating or preventing addiction to cocaine and / or heroin.

A ninth embodiment of the invention relates to a method for treating or preventing nicotine addiction, which comprises administering to a subject in need of such treatment or prophylaxis a therapeutically or prophylactically effective amount of a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof. Addiction to nicotine includes all known forms of nicotine addiction, such as smoking cigarettes, cigars and / or pipes, as well as snuffing tobacco.

A tenth embodiment of the invention relates to a method of eliminating a smoking habit, which comprises administering to a subject used to smoking tobacco a therapeutically effective amount of a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof.

In a preferred method of this embodiment, the racemic or optically pure sibutramine metabolite, a pharmaceutically acceptable salt, solvate or clathrate thereof, is administered orally, via the mucous membrane, or transdermally. In a more preferred method, the racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof, is transdermally administered.

Another preferred method according to this embodiment of the invention is a method of eliminating the smoking habit, which comprises administering to a subject who is accustomed to smoking tobacco, therapeutically effective amounts of a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate and nicotine thereof. Nicotine and / or racemic or optically pure sibutramine metabolite, a pharmaceutically acceptable salt, solvate or clathrate thereof, are preferably administered orally, via the mucous membrane or transdermally. Nicotine and / or a racetically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof, is more preferably administered transdermally.

Another method according to this embodiment of the invention is a method for the treatment or prevention of weight gain due to breaking a smoking habit, which comprises administering to a subject in need of such treatment or prevention a therapeutically or prophylactically effective amount of a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate thereof or clathrate.

An eleventh embodiment of the invention relates to a method for treating or preventing a chronic disease selected from the group consisting of narcolepsy, chronic fatigue syndrome, seasonal affective disorder, fibromyalgia and premenstrual syndrome (or premenstrual dysphoria). This method comprises administering to a subject in need of such treatment or prophylaxis a therapeutically or prophylactically effective amount of a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof.

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

A twelfth embodiment of the invention relates to a method for treating or preventing anxiety, which comprises administering to a subject in need of such treatment or prophylaxis a therapeutically or prophylactically effective amount of a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof.

A thirteenth embodiment of the invention relates to a method for treating or preventing a nutritional disorder, which comprises administering to a subject in need of such treatment or prophylaxis a therapeutically or prophylactically effective amount of a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof.

A fourteenth embodiment of the invention relates to a method for treating or preventing migraine or headache, which comprises administering to a subject in need of such treatment or prophylaxis a therapeutically or prophylactically effective amount of a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof.

As used herein, the terms “obsessive-compulsive disorder”, “premenstrual syndrome”, “anxiety state”, “malnutrition” and “migraine” are used in the meanings adopted in this area. See, for example, DSM-IV ™ and DSM-III ™. The term “methods of treatment or prophylaxis”, used in combination with these diseases, means achieving positive dynamics of the disease, preventing the onset or amelioration of the symptoms and / or manifestations characteristic of these diseases.

A fifteenth embodiment of the invention relates to a method for treating or preventing incontinence, which comprises administering to a subject in need of such treatment or prophylaxis a therapeutically or prophylactically effective amount of a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof. In particular, racemic or optically pure sibutramine metabolite can be used to treat fecal incontinence, stress urinary incontinence (“SUI”), urinary incontinence, urinary incontinence, reflex incontinence, passive incontinence, and urinary incontinence due to overflow of the bladder .

As used herein, the term “treatment or prevention of incontinence” means treating, preventing the occurrence or amelioration of symptoms of incontinence, including involuntary excretion of feces or urine and leakage of feces or urine, which may be caused by one or more reasons, which include, but are not limited to , pathology of the sphincter control, loss of sensitivity, overstretching of the bladder, hyperreflection and / or involuntary relaxation of the urethra, weakening of the muscles of the urine eve bladder or neurological disorders.

A preferred method for this embodiment of the invention is a method for treating or preventing stress urinary incontinence. According to another preferred method of this embodiment, the needy subject is an elderly person over the age of 50 or a child under the age of 13.

A sixteenth embodiment of the invention relates to pharmaceutical compositions and dosage forms containing a racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof. These pharmaceutical compositions and dosage forms are particularly useful in the implementation of the above methods. The dosage forms of this invention are suitable for oral administration, administration through the mucous membrane (e.g., nasal, sublingual, buccal, rectal and vaginal), parenteral (e.g., intravenous and intramuscular), percutaneous or subcutaneous administration. Preferred dosage forms of this invention are for oral, transdermal or mucosal administration.

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

Optically pure sibutramine metabolites are most preferred. As used, the term “optically pure” means that the composition contains more than 90 wt.% Of the desired stereoisomer, preferably more than 95 wt.% Of the stereoisomer and most preferably more than 99 wt.% Of the desired stereoisomer, based on the total weight of the active ingredient. For example, optically pure (+) - desmethylsibutramine is substantially free of (-) - desmethylsibutramine. As used, the term “substantially free” means that the composition contains less than 10 wt.%, Preferably less than 5 wt.% And most preferably less than 1 wt.% Of the other compound.

It is contemplated that pharmaceutically acceptable salts, solvates and clathrates of racemic and optically pure sibutramine metabolites should be used in the pharmaceutical compositions, dosage forms and methods of this invention. As used, the term “pharmaceutically acceptable salt” means a salt derived from a pharmaceutically acceptable non-toxic inorganic or organic acid. Inorganic acids are, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric and phosphoric acids. Organic acids include, but are not limited to, aliphatic, aromatic, carboxylic and sulfonic organic acids, which include, but are not limited to, formic, acetic, propionic, succinic, benzoic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, apple, mucus, wine, paratoluene sulfonic, glycolic, glucuronic, maleic, furonic, glutamine, benzoic, anthranilic, salicylic, phenylacetic, almond, pamic, methanesulfonic, ethanesulfonic, pant otenoic, benzenesulfonic, stearic, sulfanilic, alginic and galacturonic acids. Particularly preferred acids are hydrobromic, hydrochloric, phosphoric and sulfuric acids, and the most preferred acid is hydrochloric acid.

In all methods of this invention, the sibutramine metabolite, or a pharmaceutically acceptable salt, solvate or clathrate thereof, can be administered together with one or more additional pharmacologically active compounds, i.e. the sibutramine metabolite and at least one additional pharmacologically active compound are administered as a combination, simultaneously, but separately, or sequentially in any suitable way (for example, orally, transdermally or through the mucous membrane). In addition, preferred pharmaceutical compositions and dosage forms of this invention may contain 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 this invention are, but are not limited to, drugs that affect the central nervous system (“CNS”), which include, but are not limited to, agonists and antagonists 5 -NT (e.g., 5-HT ₃ and 5-HT _1A ); selectively acting serotonin reuptake inhibitors (“SSRIs”); sleeping pills and sedatives; medicines for the treatment of psychiatric diseases, including antipsychotic and antipsychotic drugs, anti-fear drugs, antidepressants and tranquilizers; central nervous system stimulants such as amphetamines; dopamine receptor agonists; antimony acids; anti-panic agents; cardiovascular agents (e.g., beta-receptor blockers and angiotensin-converting enzyme inhibitors); antiviral agents; antibiotics antifungal agents and antitumor agents.

More specific drugs that affect the central nervous system include, but are not limited to, SSRIs, benzodiazepine compounds, tricyclic antidepressants, antipsychotics, tranquilizers, β-adrenergic receptor antagonists, 5-HT _1A receptor antagonists and 5-HT ₃ receptor agonists . Even more specific drugs that affect the central nervous system are, but are not limited to, lorazepam, tomoxetine, olanzapine, respiradone, buspirone, hydroxyzine and valium.

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

Benzodiazepine compounds that can be used in the methods and compositions of this invention include, but are not limited to, the compounds described in Goodman & Gilman, The Pharmacological Basis of Therapeptics, 362-373 (9 ^th ed. McGraw-Hill, 1996). Examples of specific benzodiazepines include, but are not limited to, alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, cllozepam, demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepamepamazepamazepamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazamazepamaz triazolam, their pharmacologically active metabolites and stereoisomers, pharmaceutically acceptable salts, solvates and clathrates. The following are trade names for some of these compounds.

Alprazolam, chemically named 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-α] [1,4] benzodiazepine, is sold under the trade name XANAX®. XANAX® is intended for the treatment of anxiety (the condition that is closest to the diagnosis of a generalized state of fear DSM-III ™) or for the short-term relief of symptoms of anxiety. Physician's Desk Reference® 2516-2521 (53 ^rd ed., 1999).

The hydrochloride salt of chlordiazepoxide, chemically named 7-chloro-2- (methylamino) -5-phenyl-3H-1,4-benzodiazepine-4-oxide hydrochloride, is sold under the trade name LIBRIUM®. LIBRIUM® is intended for the treatment of anxiety or short-term relief of symptoms of anxiety, relieve symptoms of intoxication, a sense of anxiety and fear of surgery. Physician's Desk Reference® 1369-1370 (53 ^rd ed., 1999).

Clonazepam, chemically named 5- (2-chlorophenyl) -1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one, is sold under the trade name KLONOPIN®. KLONOPIN® is intended for use as the main or auxiliary medicine in the treatment of Lennox-Gastot syndrome (a form of poor appetite), akinetic and myoclonic seizures. KLONOPIN® is also intended to treat a panic disorder with or without a agoraphobia diagnosed in DSM-IV ™. Physician's Desk Reference® 2688-2691 (53 ^rd ed., 1999).

Clorazepate dipotassium salt, chemically named 7-chloro-2,3-dihydro-2,2-dihydroxy-5-phenyl-1H-1,4-benzodiazepine-3-carboxyl dipotassium compound, is sold under the trade name TRANXENE®. TRANXENE® is intended for the treatment of anxiety or for the short-term relief of symptoms of anxiety, as an adjuvant for the treatment of partial seizures and for the relief of symptoms of alcohol withdrawal syndrome. Physician's Desk Reference® 475-476 (53 ^rd ed., 1999).

Diazepam, chemically named 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, is sold under the trade name VALIUM®. VALIUM® is intended for the treatment of anxiety or for the short-term relief of symptoms of anxiety. Physician's Desk Reference® 2735-2736 (53 ^rd ed., 1999).

Estazolam, chemically named 8-chloro-6-phenyl-4H-s-triazolo [4,3-α] [1,4] benzodiazepine, is sold under the trade name PROSOM®. PROSOM® is intended for the short-term treatment of insomnia, the characteristic symptoms of which are poor falling asleep, frequent waking up at night and / or early waking up in the morning. Physician's Desk Reference® 473-475 (53 ^rd ed., 1999).

The chemical name Flumazenil, ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate, is sold under the trade name ROMAZICON®. ROMAZICON® is intended for the complete or partial elimination of the sedative effect of benzodiazepines if used for anesthesia, for performing diagnostic and therapeutic procedures, and for treating the effects of an overdose of benzodiazepine. Physician's Desk Reference® 2701-2704 (53 ^rd ed., 1999).

Flurazepam hydrochloride, chemically named 7-chloro-1- [2- (diethylamino) ethyl] -5- (o-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one dihydrochloride, is sold under the trade name DALMANE®. DALMANE® is a sleeping pill designed to treat insomnia, the characteristic symptoms of which are poor falling asleep, frequent waking up at night and / or early waking up in the morning. Physician's Desk Reference® 2520 (52 ^rd ed., 1998).

Lorazepam, chemically named 7-chloro-5- (o-chlorophenyl) -1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one, is sold under the trade name ATIVAN®. ATIVAN® is intended for the treatment of anxiety or for the short-term relief of symptoms of anxiety or anxiety associated with depressive symptoms. Physician's Desk Reference® 3267-3272 (53 ^rd ed., 1999).

The midazolam hydrochloride salt, chemically named 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine hydrochloride, is sold under the trade name VERSED®. VERSED® is intended for preoperative sedation / suppression of anxiety / amnesia and general anesthesia. Physician's Desk Reference® 2720-2726 (53 ^rd ed., 1999).

Oxazepam, chemically named 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one, is sold under the trade name SERAX®. SERAX® is intended for the treatment of anxiety or for the short-term relief of symptoms of anxiety. Physician's Desk Reference® 3383-3384 (53 ^rd ed., 1999).

The chemical name quasepam, 7-chloro-5- (o-fluorophenyl) -1,3-dihydro-1- (2,2,2-trifluoroethyl) -2H-1,4-benzodiazepin-2-thion, is sold under the trade name DORAL®. DORAL® is intended for the treatment of insomnia, the characteristic symptoms of which are poor falling asleep, frequent waking up at night and / or early waking up in the morning. Physician's Desk Reference® 2958 (52 ^rd ed., 1998).

Temazepam, chemically named 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, is sold under the trade name RESTORIL®. RESTORIL® is intended for the short-term treatment of insomnia. Physician's Desk Reference® 2075-2078 (53 ^rd ed., 1999).

Triazolam, chemically named 8-chloro-6- (o-chlorophenyl) -1-methyl-4H-s-triazolo [4,3-α] [1,4] benzodiazepine, is sold under the trade name HALCION®. HALCION® is intended for the short-term treatment of insomnia. Physician's Desk Reference® 2490-2493 (53 ^rd ed., 1999).

Clinicians, doctors or psychiatrists should be aware which of the above compounds can be used in combination with a racemic or optically pure metabolite of sibutramine, its pharmaceutically acceptable salt, solvate or clathrate for the treatment or prevention of this disease, although only preferred combinations are considered in this description of the invention.

Diseases that can be treated or prevented using the racemic or optically pure sibutramine metabolite, its pharmaceutically acceptable salt, solvate or clathrate in combination with benzodiazepine similar to the above compounds include, but are not limited to, affective disorders (e.g. depression), anxiety , nutritional disorders and impaired brain function.

This invention further relates to pharmaceutical compositions comprising a racemic or optically pure sibutramine metabolite, a pharmaceutically acceptable salt, solvate or clathrate thereof in combination with an antipsychotic agent, and methods for their use. Antipsychotic drugs are used primarily for the treatment of patients suffering from psychotic or other serious psychiatric diseases, the characteristic symptoms of which are anxiety and impaired logical thinking. These drugs also have other properties that are useful in a clinical setting, including antiemetic and antihistamine effects and the ability to enhance the action of analgesics, sedatives, and general anesthetics. Specific antipsychotics are tricyclic antipsychotics, which can be divided into three types: phenothiazines, thioxanthenes, and other heterocyclic compounds that can be used in the methods and compositions of this invention. See, for example, Goodman & Gilman, The Pharmacological Basis of Therapeutics, 404 (9 ^th ed. McGraw-Hill, 1996).

Specific tricyclic antipsychotic compounds include, but are not limited to, chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine, trifluoperazin, chlorprotixene, thiotixen, clozapine, haloperidol, loxapine, steremonidipinone, medindimer desinipride, meridone disinprop, indindropide, meindone dimeripinone, medinone disinprop, indindromide, dimerindipin, indone medipin, isopropyl, indone medipin, isopridone, and pharmaceutically acceptable salts, solvates and clathrates. The following are trade names for some of these compounds.

Chlorpromazine, chemically named 10- (3-dimethylaminopropyl) -2-chlorophenothiazine, is sold under the trade name THORAZINE®. THORAZINE® is intended, among other things, for the treatment of psychotic disorders. Physician's Desk Reference® 3101-3104 (53 ^rd ed., 1999).

The mesoridazine besylate, chemically named 10- [2- (1-methyl-2-piperidyl) ethyl] -2-methylsilphinyl) phenothiazine, is sold under the trade name SERENTIL®. SERENTIL® is intended for the treatment of schizophrenia, behavioral disorders in mental disability and chronic brain syndrome, alcoholism and psychoneurotic disorders. Physician's Desk Reference® 764-766 (53 ^rd ed., 1999).

Perphenazine, chemically named 4- [3- (2-chlorophenothiazin-10-yl) propyl-1-piperazine ethanol, is sold under the trade name TRILAFON®. TRILAFON® is intended for the treatment of psychotic disorders, severe nausea and vomiting in adults. Physician's Desk Reference® 2886-2888 (53 ^rd ed., 1999).

Trifluoperazine, chemically named 10- [3- (4-methyl-1-piperazinyl) propyl] -2- (trifluoromethyl) -10H-phenothiazine, is sold under the trade name STELAZINE®. STELAZINE® is intended for the treatment of psychotic disorders and for the short-term treatment of a generalized non-psychotic state of fear. Physician's Desk Reference® 3092-3094 (53 ^rd ed., 1999).

Thiotixen, chemically named N, N-dimethyl-9- [3- (4-methyl-1-piperazinyl) propylidene] thioxanthen-2-sulfonamide, is sold under the trade name NAVANE®. NAVANE® is intended for the treatment of psychotic disorders. Physician's Desk Reference® 2396-2399 (53 ^rd ed., 1999).

Clozapine, chemically named 8-chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo [b, e] [1,4] diazepine, is sold under the trade name CLOZARIL®. CLOZARIL® is intended for the treatment of patients with severe schizophrenia who inadequately respond to treatment with standard antipsychotic drugs. Physician's Desk Reference® 2004-2009 (53 ^rd ed., 1999).

Haloperidol, chemically named 4- [4- (p-chlorophenyl) -4-hydroxypiperidonol-4'-fluorobutyrophenone, is sold under the trade name HALDOL®. HALDOL® is intended for the treatment of patients requiring long-term parenteral administration of antipsychotic drugs (for example, patients suffering from chronic schizophrenia). Physician's Desk Reference® 2190-2192 (53 ^rd ed., 1999).

Loxapine, chemically named 2-chloro-11- (4-methyl-1-piperazinyl) dibenz [b, f] [1,4] oxaxepine, is sold under the trade name LOXITANE®. LOXITANE® is intended for the treatment of psychotic disorders. Physician's Desk Reference® 3224-3225 (53 ^rd ed., 1999).

Molindone, chemically named 3-ethyl-6,7-dihydro-2-methyl-5- (morpholinomethyl) indol-4 (5H) -one hydrochloride, is sold under the trade name MOBAN®. MOBAN® is intended for the treatment of psychotic disorders. Physician's Desk Reference® 978-979 (53 ^rd ed., 1999).

Pimoside, chemically named 1- [1- [4,4-bis (4-fluorophenyl) butyl] -4-piperidinyl] -1,3-dihydro-2H-benzimide-zol-2-one, is sold under the trade name ORAP®. ORAP® is designed to suppress motor and vocal tics in patients with Tourette’s disease, whose treatment with standard methods does not give satisfactory results. Physician's Desk Reference® 1054-1056 (53 ^rd ed., 1999).

Risperidone, chemically named 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -6,7,8,9-tetrahydro-2-methyl- 4H-pyrido [1,2-a] pyrimidin-4-one, sold under the trade name RISPERDAL®. RISPERDAL® is intended for the treatment of psychotic disorders. Physician's Desk Reference® 1432-1436 (53 ^rd ed., 1999).

The desipramine hydrochloride salt, chemically named 5H-dibenz [b, f] azepine-5-propanamine-10,11-dihydro-N-methylmonohydrochloride, is sold under the trade name NORPRAMIN®. NORPRAMIN® is intended to treat depression. Physician's Desk Reference® 1332-1334 (53 ^rd ed., 1999).

Diseases that can be treated or prevented using the racemic or optically pure metabolite of sibutramine, a pharmaceutically acceptable salt, solvate or clathrate thereof in combination with an antipsychotic compound, and in particular a tricyclic antipsychotic compound, include, but are not limited to, affective disorders (e.g. , depression), anxiety, eating disorders and impaired brain function (eg, schizophrenia), which are similar to those described in this description of the invention.

This invention further relates to pharmaceutical compositions comprising a racemic or optically pure sibutramine metabolite, a pharmaceutically acceptable salt, solvate or clathrate thereof in combination with a receptor antagonist

5-HT _1A and / or β-adrenergic receptor antagonist, and methods for their use. Examples of 5-HT _1A receptor antagonists and β-adrenergic receptor antagonists that can be used in the methods and compositions of this invention include, but are not limited to, alprenolol, WAY 100135, spiperone, pindolol, (S) -UH-301, penbutolol , propranolol, tertatolol, a compound of formula I as described in US Pat. No. 5,552,429, which is incorporated herein by reference; their pharmacologically active metabolites and stereoisomers, pharmaceutically acceptable salts, solvates and clathrates.

Alprenolol having the chemical name 1- (1-methylethyl) amino-3- [2- (2-propenyl) phenoxy] -2-propanol is described in US Pat. No. 3,466,325, which is incorporated herein by reference.

WAY 100135, having the chemical name N- (tert-butyl) -3- [4- (2-methoxyphenyl) piperazin-1-yl] -2-phenylpropanamide, is described in US patent No. 4988814, which is included in this description of the invention as links. See also Cliffe et al., J. Med. Chem., 36: 1509-1510 (1993).

The spiperone having the chemical name 8- [4- (4-fluorophenyl) -4-oxobutyl] -1-phenyl-1,3,8-triazaspiro [4,5] decan-4-one is described in US Pat. No. 3155669 and 3155670, which are incorporated into this description by reference. See also Middlmiss et al., Neurosci. and Biobehav. Rev. 16: 75-82 (1992).

Pindolol having the chemical name 4- (2-hydroxy-3-isopropylaminopropoxy) indole is described in US Pat. No. 3,471,515, which is incorporated herein by reference. See also Dreshfield et al., Neurochem. Res. 21 (5): 557-562 (1996).

(S) -UH-301, having the chemical name (S) -5-fluoro-8-hydroxy-2-dipropylaminotetralin, is well known to pharmacologists and pharmacists. See, for example, Hillyer et al., J. Med. Chem., 33: 1541-44 (1990) and Moreau et al., Brain Res. Bull., 29: 901-04 (1992).

Penbutolol, chemically named (1- (tert-butylamino) -2-hydroxy-3- (2-cyclopentylphenoxy) propane), is sold under the trade name LEVATOL®. LEVATOL® is intended for the treatment of mild to moderate hypertension. Physician's Desk Reference® 2908-2910 (53 ^rd ed., 1999).

The propranolol hydrochloride salt, chemically named 1-isopropylamino-3- (1-naphthalenyloxy) -2-propanol hydrochloride, is sold under the trade name INDERAL®. INDERAL® is intended for the treatment of hypertension. Physician's Desk Reference® 3307-3309 (53 ^rd ed., 1999).

Tertatolol, having the chemical name 8- (3-tert-butylamino-2-hydroxypropyloxy) thiochroman, is described in US Pat. No. 3,960,891, which is incorporated herein by reference.

Diseases that can be treated or prevented using the racemic or optically pure sibutramine metabolite, its pharmaceutically acceptable salt, solvate or clathrate in combination with a 5-HT _1A receptor antagonist include, but are not limited to, depression, obsessive-compulsive disorders, eating disorders , hypertension, migraine, essential tremor, hypertrophic subaortic muscle stenosis and pheochromocytoma. Using these compounds, it is possible to treat or prevent a specific disease such as post-traumatic depression.

Diseases that can be treated or prevented using the racemic or optically pure sibutramine metabolite, its pharmaceutically acceptable salt, solvate or clathrate in combination with a β-adrenergic receptor antagonist include, but are not limited to, depression after myocardial infarction. Specific antagonists of β-adrenergic receptors are, but are not limited to, S (-) - pindolol, penbutolol and propranolol.

This invention further relates to pharmaceutical compositions containing a racemic or optically pure sibutramine metabolite, a pharmaceutically acceptable salt, solvate or clathrate thereof in combination with non-benzodiazepine or tricyclic agents, and methods for their use. Examples of such additional pharmacologically active compounds are, but are not limited to, olanzapine, buspirone, hydroxyzine, tomoxetine, their pharmacologically active metabolites and stereoisomers, pharmaceutically acceptable salts, solvates and clathrates.

Olanzapine, chemically named 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine, is sold under the trade name ZYPREXA®. ZYPREXA® is intended for the treatment of psychotic disorders. Physician's Desk Reference® 1641-1645 (53 ^rd ed., 1999).

Buspirone hydrochloride, chemically named 8- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -8-azaspiro [4,5] decan-7,9-dione monohydrochloride, is sold under the trade name BUSPAR ®. BUSPAR® is intended for the treatment of a state of fear or for the short-term relief of symptoms of fear. Physician's Desk Reference® 823-825 (53 ^rd ed., 1999).

The hydroxyzine hydrochloride salt, chemically named 1- (p-chlorobenzhydryl) -4 [2- (2-hydroxyethoxy) ethyl] piperazine dihydrochloride, is sold under the trade name ATARAX®. ATARAX® is intended to relieve symptoms of fear and tension associated with psychoneurosis, and as an adjunct in the treatment of diseases of various organs accompanied by a state of fear. Physician's Desk Reference® 2367-2368 (53 ^rd ed., 1999).

Diseases that can be treated or prevented using the racemic or optically pure sibutramine metabolite, its pharmaceutically acceptable salt, solvate or clathrate in combination with a compound selected from the group consisting of lorazepam, tomoxetine, olanzapine, respradone, buspirone, hydroxyzine, valium, their pharmacologically active metabolites and stereoisomers, pharmaceutically acceptable salts, solvates, clathrates, include, but are not limited to, anxiety, depression, hypertension, and impaired attention.

Although all combinations of racemic and optically pure sibutramine metabolites, their pharmaceutically acceptable salts, solvates and clathrates and one or more of the pharmacologically active compounds described above are useful and valuable, some combinations are particularly preferred. Examples of preferred combinations are those combinations in which a racemic or optically pure sibutramine metabolite, a pharmaceutically acceptable salt, solvate or clathrate thereof is used together with one of the following compounds:

alprazolam; quasepam; alprenolol; brotizolam; temazepam; WAY 100 135; chlordiazepoxide; triazolam; spiperone; clobazam; chlorpromazine; S (-) - pindolol; clonazepam; mesoridazine; R (+) - pindolol; clorazepate; thioridazine; racemic pindolol; demoxepam; acetophenazine; (S) -UH-301; diazepam; fluphenazine; penbutolol; estazolam; perphenazine; propranolol; flumazenil; trifluoperazin; tertatolol; flurazepam; chlorprotixen; desipramine; galazepam; thiotixen; clonidine; lorazepam; clozapine; olanzapine; midazolam; haloperidol; methylphenidate; nitrazepam; loxapine; buspirone; nordazepam; molindone; hydroxyzine; oxazepam; pimozide; tomoxetine. prazepam; risperidone;

Synthesis of sibutramine metabolites

Racemic sibutramine, desmethylsibutramine and didesmethylsibutramine can be prepared using methods well known to those skilled in the art. See, for example, US patent No. 4806570, which is incorporated into this description by reference; J. Med. Chem., 2540 (1993) (tosylation and azide displacement); Butler, D., J. Org. Chem., 36: 1308 (1971) (cycloalkylation in DMSO); Tetrahedron Lett., 155-58 (1980) (reaction of addition of the Grignard reagent to nitrile in benzene); Tetrahedron Lett., 857 (1997) (OH to azide); and Jeffery, J.E., et al., J. Chem. Soc. Perkin. Trans 1, 2583 (1996).

A preferred method for the preparation of racemic sibutramine is described in the following Example 1.

Racemic sibutramine, desmethylsibutramine and didesmethylsibutramine can be obtained from each other in the same way as optically pure forms of these compounds. Preferred methods for preparing one compound from another are described in the following Examples 2, 3, and 8. Optically pure enantiomers of sibutramine and its metabolites can be obtained using methods known in the art. A preferred method is fractional crystallization of diastereomeric salts obtained with optically active resolving agents. See, for example, “Enantiomers, Racemates and Resolutions”, by J. Jacques, A. Collet, ans S.H. Wilen, (Wiley-Interscience, New York, 1981); S.H. Wilen, A. Collet, and J. Jacques, Tetrahedron, 2725 (1977); E.L. Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill. NY, 1962); and S.H. Wilen, Tables of Resolving Agents and Optical Resolutions 268 (E.L. Eliel ed., Univ. Of Notre Dame Press, Notre Dame, IN, 1972).

Since sibutramine, desmethylsibutramine and didesmethylsibutramine are the main amines, the diastereomeric salts of these compounds, suitable for fractional crystallization separation, can be easily prepared by coupling the resolving agents based on optically pure chiral acids. Acceptable resolving agents include, but are not limited to, optically pure tartaric, camphorsulfonic, mandelic acids and their derivatives. Optically pure isomers of sibutramine, desmethylsibutramine and didesmethylsibutramine can be isolated from the crystallized diastereomer or mother liquor depending on the solubility of the acid-based resolving agent used and the acid enantiomer used. The identity and optical purity of the thus obtained sibutramine or isomer of the metabolite of sibutramine can be determined using polarimetry or other analytical methods.

Racemic and optically pure sibutramine metabolites are preferably synthesized by methods described by Jeffery, J.E., et al., J. Chem. Soc. Perkin. Trans 1, 2583 (1996). A preferred method for the direct synthesis of racemic desmethylsibutramine involves the reduction of cyclobutanecarbonitrile (CCBC) to produce an intermediate aldehyde, which is then reacted with an amine, such as methylamine. This method is used in the following example 4.

Another preferred method for the direct synthesis of racemic desmethylsibutramine involves reacting CBCS with a compound of formula i-BuMX in which X is Br or I and M is selected from the group consisting of Li, Mg, Zn, Cr and Mn. This compound preferably has the formula i-BuMgBr. As a result of this reaction, a product is obtained, which is then reduced, converted into an intermediate compound, which is an aldehyde bound to a nitrogen atom, which is ultimately converted to desmethylsibutramine in the Lewis acid addition step. Preferred Lewis acids are selected from the group consisting of BH ₃ ^. THF, BF ₃ ^. THF, La (Oi-Pr) ₃ , Zr (Oi-Pr) ₄ , Ti (Oi-Pr) ₂ Cl ₂ , SnCl ₄ and MgBr ₂ ^. OEt ₂ . The most preferred Lewis acid is BH ₃ ^. THF This method is used in the following example 5.

The enantiomers of desmethylsibutramine can be obtained by the formation of chiral salts, as described above. Preferred chiral acids used to prepare chiral salts include, but are not limited to, tartaric and mandelic acids. When using tartaric acid, preferred solvent systems include, but are not limited to, ethanol / water and isopropyl alcohol / water. When using mandelic acid, the preferred solvent system is ethyl acetate / hexane. The isolation of desmethylsibutramine is described in the following Examples 6 and 7.

A preferred method for the direct synthesis of racemic didesmethylsibutramine involves reacting CBCS with a compound of formula i-BuMX in which X is Br or I and M is selected from the group consisting of Li, Mg, Zn, Cr and Mn. This compound preferably has the formula i-BuMgBr. The product of this reaction is then reduced under acceptable reaction conditions. The application of this method is shown in the following example 9.

The enantiomers of didesmethylsibutramine can be obtained by the formation of chiral salts, as described above. A preferred chiral acid used to prepare chiral salts is, but is not limited to, tartaric acid. Preferred solvent systems are, but are not limited to, acetonitrile / water / methanol and acetonitrile / methanol. The isolation of didesmethylsibutramine is described in the following Examples 11 and 12.

Pharmaceutical compositions and methods for their use

The value of the prophylactic or therapeutic dose of the active ingredient in the treatment of an acute or chronic form of a disease or disorder varies depending on the severity of the disease and the route of administration. The magnitude of the dose and the frequency of administration of the drug also depend on the age, body weight, reaction and medical history of the patient. One of skill in the art can easily select suitable drug regimens for these factors.

Acceptable daily doses of drugs intended for the treatment or prevention of the diseases described herein can be easily determined. The recommended dose of racemic or optically pure sibutramine metabolite is from about 0.1 mg to about 60 mg / day when administered as a single dose once a day in the morning or as multiple doses throughout the day. The daily dose is preferably from about 2 mg to about 30 mg / day, more preferably from about 5 mg to about 15 mg / day.

Acceptable daily doses of additional pharmacologically active compounds that can be administered together with a racemic or optically pure sibutramine metabolite can be easily determined taking into account the doses indicated in the scientific literature and recommended in the Physician's Desk Reference® (53 ^rd ed., 1999).

For example, acceptable, easily detectable daily doses of 5-HT ₃ antagonists vary depending on the above factors and the specific 5-HT ₃ antagonists used. Typically, the total daily dose of a 5-HT ₃ antagonist for treating or preventing the disease 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 / day.

Administration of the active ingredient of this invention for therapeutic or prophylactic purposes begins with a lower dose, for example, from about 2 mg to about 8 mg of a sibutramine metabolite and optionally from about 15 mg to about 60 mg of a 5-HT ₃ antagonist, and then increase the dose if necessary up to the recommended daily dose, administered as a single dose or in multiple divided doses, depending on the overall response of the patient. Patients over the age of 65 are advised to administer doses of sibutramine metabolite from about 5 mg to about 30 mg / day, depending on the patient's overall response. Sometimes, doses that fall outside the specified ranges may be required, which can be easily determined by those skilled in the pharmaceutical field.

The amount and frequency of doses of a drug is defined by the terms “therapeutically effective”, “prophylactically effective” and “therapeutically or prophylactically effective” as used. When used to determine the amount of racemic or optically pure sibutramine metabolite, these terms further mean the amount of racemic or optically pure sibutramine metabolite that causes fewer or less serious adverse effects associated with the administration of racemic sibutramine. Side effects caused by racemic sibutramine include, but are not limited to, a significant increase in heart rate while lying on your back and while standing, including tachycardia, increased blood pressure (hypertension), increased psychomotor activity, dry mouth, tooth decay, constipation, hypohydrosis, blurred vision, tension, mydriasis, seizures, formation of bile calculus, impaired renal / liver function, fever, arthritis, anxiety arousal, calf muscle cramps, hypertension, wrong noe thinking, bronchitis, dyspnea, pruritus, amblyopia, menstrual disorder, ecchymosis / bleeding, interstitial nephritis, and hyperexcitability. See, for example, Physician's Desk Reference® 1494-1498 (53 ^rd ed., 1999).

Co-administration of two or more active ingredients in accordance with the methods of this invention may be simultaneous, sequential, or both. For example, a dopamine reuptake inhibitor and a 5-HT ₃ antagonist can be administered in combination, simultaneously, but separately or sequentially.

Any suitable method of administering to the patient a therapeutically or prophylactically effective dose of the active ingredient may be used. For example, methods such as oral administration, mucosal administration (e.g., nasal, sublingual, buccal, rectal, vaginal), parenteral (e.g., intravenous, intramuscular), percutaneous and subcutaneous administration can be used. Preferred routes of administration are oral, transdermal, and transmucosal. As indicated above, for the treatment or prevention of erectile dysfunction, the active ingredient is preferably administered through the mucous membrane or transdermally. Suitable dosage forms for such routes of administration include, but are not limited to, transdermal patches, eye drops, nebulized solutions, and aerosols. Compositions for transdermal administration can also be obtained in the form of creams, lotions and / or emulsions, which can be mixed with an appropriate binder for fixing on the skin or introduced into the transdermal patch matrix or capacitive type, usually used for this purpose.

A preferred transdermal dosage form is a “capacitive type” or “matrix type” patch, which is fixed to the skin for a certain period of time to allow the required amount of active ingredient to pass through the skin. For example, if the active ingredient is a sibutramine metabolite, the preferred patch is fixed to the skin for 24 hours, resulting in a total daily dose of about 0.1 mg to about 60 mg / day. The daily dose is preferably from about 2 mg to about 30 mg / day, more preferably from about 5 mg to about 15 mg / day. This patch can be replaced with a fresh patch if it is necessary to ensure continuous administration of the active ingredient to the patient.

Other dosage forms of this invention include, but are not limited to, tablets, pills, lozenges, lozenges, dispersions, suspensions, suppositories, ointments, poultices, pastes, powders, dressings, creams, plasters, solutions, capsules, soft elastic gelatin capsules and stickers.

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

In practical use, the active ingredient can be used to obtain a homogeneous mixture with a pharmaceutical carrier in accordance with known pharmaceutical mixing methods. The carrier can be used in different forms depending on the desired form of the drug. In the manufacture of compositions for oral dosage form, conventional pharmaceutical media such as, for example, water, glycols, oils, alcohols, flavors, preservatives, colorants and the like, intended for liquid oral preparations (such as suspensions, solutions and elixirs) or aerosols; and in the manufacture of solid oral preparations, preferably without lactose, carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents can be used. For example, acceptable carriers are powders, capsules and tablets, with solid oral formulations being more preferred than liquid formulations.

Because of their ease of administration, tablets and capsules are the most preferred oral dosage forms in which solid pharmaceutical carriers are employed. If desired, tablets can be coated with standard aqueous or non-aqueous methods.

In addition to the above conventional dosage forms, the active ingredient may also be administered by controlled release devices or drug delivery devices that are well known to those skilled in the art and are similar to those described in US Pat. Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4008,719, 5674533, 5059595, 5591767, 5120548, 5073543, 5639476, 5354556 and 5733566, which are incorporated herein by reference. These dosage forms can be used to slow or controlled release of one or more active ingredients using, for example, hydropropyl methyl cellulose and other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to achieve the desired release profile in varying proportions. For use with the pharmaceutical compositions of this invention, it is easy to select suitable controlled release formulations known to those skilled in the art, including those discussed herein. Thus, it is within the scope of this invention to administer single dosage forms suitable for oral administration, such as tablets, capsules, pills and lozenges, which are formulated for controlled release.

All controlled-release pharmaceutical products are used to achieve better drug treatment results compared to unregulated-release drugs. In the ideal case, the use of a controlled-release drug in medical practice is characterized in that the patient's recovery or improvement is achieved by using a minimum amount of the drug for a minimum period of time. Controlled-release preparations have the following advantages: 1) a longer duration of action of the drug; 2) large time intervals between drug administration and 3) better patient compliance with treatment regimen and treatment regimen. In addition, controlled release formulations can be used to alter exposure times or other characteristics, such as drug drug levels in the blood, so that side effects can be controlled.

Most controlled-release preparations are made with the possibility of the initial release of such an amount of a drug that immediately provides the desired therapeutic effect, and the subsequent gradual release of other quantities of the drug to maintain the obtained therapeutic effect over an extended period of time. To maintain a constant level of the drug in the body, this drug must be released from the dosage form at a rate that allows the amount of the drug involved in the metabolism and excreted to be renewed. Controlled release of the active ingredient can be stimulated by various inducers, which include, but are not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

The pharmaceutical compositions of this invention suitable for oral administration can be obtained in the form of separate dosage forms, such as capsules, starches, tablets or aerosols, which contain a predetermined amount of the active ingredient in the form of a powder, granules, solution or suspension in aqueous or non-aqueous solution, an emulsion of oil in water or a liquid emulsion of water in oil. Such dosage forms can be obtained by any methods used in pharmacy, but all these methods include the stage of mixing the active ingredient with a carrier, which consists of one or more necessary ingredients. Typically, such compositions are obtained by uniformly mixing the active ingredient with liquid carriers, finely divided solid carriers, or both together, if necessary, followed by giving the product the desired shape.

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

This invention further relates to pharmaceutical compositions and dosage forms without lactose. Lactose is used as a filler in sibutramine-based preparations. See, for example, Physician's Desk Reference® 1494 (53 ^rd ed., 1999). However, unlike the parent drug, desmethylsibutramine and didesmethylsibutramine are respectively secondary and primary amines and therefore can decompose over time under the action of lactose. Thus, the compositions of this invention, which include metabolites of sibutramine, preferably contain a small amount or do not contain lactose and other mono - or disaccharides. As used herein, the term “lactose free” means that the available amount of lactose, if used at all, is insufficient to significantly increase the rate of decomposition of the active ingredient.

The lactose-free compositions of this invention may contain excipients that are well known in the art and are given in USP (XXI) / NF (XVI), incorporated herein by reference. Typically, lactose-free compositions contain an active ingredient, a binder / excipient and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Preferred lactose-free dosage forms contain the active ingredient, microcrystalline cellulose, pregelatinized starch and magnesium stearate.

This invention further relates to anhydrous pharmaceutical compositions and dosage forms containing the active ingredient, since water facilitates the decomposition of certain compounds. For example, it is common practice in the pharmaceutical field to add water (e.g., 5%) as a way to simulate long-term storage in order to determine characteristics such as shelf life or drug stability over time. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. Water and heat really accelerate decomposition. Thus, water can be important, because during the manufacture, packaging, packaging, storage, transportation and use of drugs it is difficult to avoid exposure to moisture and / or humidity.

Anhydrous pharmaceutical compositions and dosage forms of this invention can be prepared using anhydrous or low moisture ingredients in low humidity conditions. Pharmaceutical compositions and dosage forms containing a racemic or optically pure sibutramine metabolite in combination with lactose are preferably anhydrous if they are expected to be exposed to moisture and / or humid conditions during manufacture, packaging and / or storage.

An anhydrous pharmaceutical composition must be obtained and stored so that it remains anhydrous. Therefore, for the packaging of anhydrous compositions, it is preferable to use materials that are known to prevent the penetration of water, completing several dosage forms in one package. Examples of acceptable packaging are, but are not limited to, sealed foil packaging, plastic or the like, standard dose containers, blister packs, and strip packaging.

In this regard, it should be noted that this invention relates to a method for producing a solid pharmaceutical preparation containing the active ingredient, which consists in the fact that the active ingredient and excipient (e.g. lactose), practically free of water, are mixed under anhydrous conditions or under low conditions. humidity. This method further includes packaging an anhydrous or non-hygroscopic solid preparation in low humidity conditions. By creating such conditions, the risk of contact with water is reduced, which helps to prevent or significantly reduce the decomposition of the active ingredient.

The binders used 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 gum arabic, sodium alginate, alginic acid, other alginates, powdered tragacanth , guar gum, cellulose and its derivatives (e.g. ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre ritelno pregelatinized starch, hydroxypropylmethylcellulose (e.g., №№ 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Acceptable forms of microcrystalline cellulose are, for example, materials sold under the trademarks AVICEL-PH-101, AVICEL-PH-103, AVICEL-RC-581 and AVICEL-PH-105 (FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA, USA). A typical acceptable binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold under the trademark AVICEL-RC-581. Acceptable anhydrous or low moisture fillers or additives are AVICEL-PH-103 ™ and 1500 LM starch.

Examples of acceptable excipients used in the pharmaceutical compositions and dosage forms of this invention include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol , starch, pregelatinized starch and mixtures thereof. The binder / excipient in the pharmaceutical compositions of the present invention typically comprises from about 50 to about 99 wt.% By weight of the pharmaceutical composition.

Disintegrants are used in the compositions of this invention to produce tablets disintegrating under aqueous conditions. If you use too much disintegrant, the tablets may disintegrate already in the bottle. Too small a disintegrant may not be sufficient to disintegrate the tablets, as a result of which the rate and degree of release of the active ingredient from the dosage form may change. Thus, to obtain dosage forms containing the compounds described herein, it is necessary to use a sufficient amount of disintegrant, which should not be too small or too large. The amount of disintegrator used varies depending on the type of preparation and route of administration and can be easily determined by those skilled in the art. The pharmaceutical composition typically contains from about 0.5 to about 15 wt.%, Preferably from about 1 to about 5 wt.% Disintegrant.

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

Lubricants that can be used to produce the pharmaceutical compositions and dosage forms of this 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 (e.g. peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate , Ethyl oleate, etillaureat, agar, or mixtures thereof. Additional lubricants are, for example, silica gel (AEROSIL 200 from WR Grace Co. of Baltimore, MD), coagulated aerosol of synthetic silica (from Degussa Co. of Plano, Texas), CAB-O-SIL (Cabot fumed silica product Co. of Boston, Mass.) Or mixtures thereof. A lubricant is optionally added in an amount of less than about 1 wt.% By weight of the pharmaceutical composition.

The dosage forms of this invention, which include the sibutramine metabolite, preferably contain from about 0.1 to about 60 mg of the metabolite, its pharmaceutically acceptable salt, solvate or clathrate. For example, a tablet, cachet, or capsule contains from about 0.1 mg to about 60 mg of the active ingredient. A tablet, cachet, or capsule most preferably contains one of three doses, for example, about 10 mg, about 20 mg, or about 30 mg of racemic or optically pure sibutramine metabolites (in the form of lactose-free tablets, which are the preferred dosage form).

This invention is further described with reference to the following examples. Specialists in this field should be clear that the scope of this invention includes numerous modifications that apply to both substances and methods.

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 all of these examples, the enantiomeric purity of the DMS was determined using a Chirobiotic V assay column (10 μm, 4.6 mm x 25 mm) with 20 mM ammonium acetate / IPA (65:35) as the mobile phase. An ultraviolet detector is installed at a wavelength of 222 nm.

Examples 9-12 describe the preparation of racemic and optically pure forms of didesmethylsibutramine (DDMS). In all these examples, the enantiomeric purity of DDMS was determined using a ULTRON ES-OVM assay column (150 mm x 4.6 mm) with 0.01 M KH ₂ PO ₄ / MeOH (70:30) as the mobile phase. An ultraviolet detector is installed at a wavelength of 200 nm.

Examples 13-14 describe methods for determining the binding affinity of the compounds of this invention and show the binding affinity values measured by these methods.

Finally, Example 15 describes oral preparations containing the compounds of this invention.

Example 1. Synthesis of sibutramine

Synthesis of 1- (4-chlorophenyl) cyclobutanecarbonitrile

To a suspension of NaH (17.6 g of 60% washed with hexane) in dimethyl sulfoxide (150 ml), stirred with a mechanical stirrer, a mixture of chlorobenzyl nitrile (30.3 g) and 1,3-dibromopropane was added at room temperature over one hour (22, 3 ml, 44.5 g). The reaction mixture was stirred for another hour and isopropyl alcohol (10 ml) was slowly added to quench the excess NaH. Water (150 ml) was added. The reaction mixture was extracted with tert-butyl methyl ether (MTBE) (2 x 200 ml), the combined extracts were washed with water (3 x 200 ml), brine and dried over MgSO ₄ . The solvent is removed in a rotary evaporator and the final product is purified by distillation, which gives the target compound (22 g, 56%) as a pale yellow oil, because 110-120 ° C / 1.0 mm Hg. The product was examined using ¹ H NMR.

Synthesis of 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine

A solution of isobutyl magnesium bromide (2 M solution, 108 ml) in diethyl ether (Aldrich) was concentrated to remove most of the ether. The residue was dissolved in toluene (150 ml) and the nitrile obtained above (22 g) was added. The reaction mixture is heated to 105 ° C for 17 hours. The reaction mixture was cooled to room temperature and a suspension of NaBH ₄ in isopropyl alcohol (450 ml) was added. The reaction mixture was refluxed 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), dried (MgSO ₄ ) and concentrated to give 24.2 g of crude product (83%).

Synthesis of Sibutramine Free Base

1- [1- (4-Chlorophenyl) cyclobutyl] -3-methylbutylamine (21.6 g) was added to formic acid (27 ml) and aqueous formaldehyde (46 ml). The reaction mixture is heated to 85-95 ° C for 18 hours and cooled to room temperature. Add 30% NaOH until the mixture becomes basic (pH> 11). The solution was extracted with chloroform (3 x 200 ml), the extracts were combined, washed with water and brine, and concentrated to give 15 g of product.

Sibutramine Hydrochloride

The free base of sibutramine (2.25 g) was dissolved in MTBE (20 ml) and the resulting solution was added to 20 ml of a 1 M solution of HCl in diethyl ether. The reaction mixture was stirred for 30 minutes, the solid was collected by filtration and dried to obtain 1.73 g of product. The resulting product was examined using ¹ H NMR.

Separation of sibutramine

12.3 g of racemic sibutramine was dissolved in ethyl acetate (85 ml) and a solution of 21.7 g of L-dibenzyl tartaric acid (“L-DBTA”) in ethyl acetate (85 ml) was added. The reaction mixture was heated to reflux and cooled to room temperature. A white precipitate was collected (salt production efficiency of approximately 85%). The solid is then suspended in 220 ml of ethyl acetate and heated at the boiling temperature under reflux for 30 minutes. The solid is collected with a production efficiency of> 95%. The salt is crystallized in isopropyl alcohol (450 ml), which gives 11.3 g of salt with an efficiency of> 99.3% L-DBTA (-) - sibutramine (yield 76%). The free base is obtained by treating the salt with a saturated aqueous solution of NaHCO ₃ and extracting it with chloroform. The hydrochloride salt of (-) - sibutramine is obtained by treating the free base with HCl / Et ₂ O as described above. The optical rotation of the hydrochloride salt is [α] = 3.15 (c = 0.9, H ₂ O), ¹ H NMR ¹³ C (CD ₃ OD) and M ⁺ = 279. The separated mother liquor is first treated with NaOH, which partially gives enriched (+) - sibutramine, and then treated with D-DBTA, as described above, which gives the salt of D-DBTA (+) - sibutramine with an efficiency of> 99.3%. The enantiomers of sibutramine are examined using ¹ H and ¹³ C NMR: M ⁺ = 179. This substance is also investigated by HPLC and chiral HPLC.

Example 2. Obtaining sibutramine from its metabolites

Racemic and optically pure sibutramine can also be obtained by methylation of desmethylsibutramine or dimethylation of didesmethylsibutramine under acceptable reaction conditions. An example of this method is shown in diagram 1.

Scheme 1

Example 3. Obtaining desmethylsibutramine from sibutramine

(-) - Sibutramine (1.25 g) was dissolved in toluene (90 ml) and diethyl azodicarboxylate (“DEAD”) (0.8 g, 1.1 eq.) Was added. The reaction mixture was heated at 50 ° C for 6 hours and 0.8 g of DEAD was added. The reaction mixture was heated at 50 ° C for another 6 hours, cooled to room temperature and toluene was removed in vacuo. The residue was suspended in 45 ml of ethanol and 45 ml of a saturated aqueous solution of NH ₄ Cl. The reaction mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature and concentrated to remove ethanol. An aqueous solution of NaHCO _{3 is} added until the concentrate becomes basic. The basic concentrate was extracted with dichloromethane (3 x 50 ml). The extracts are combined, dried with sodium sulfate, filtered and concentrated to give a crude product. Flash chromatography on (SiO ₂ ) columns (ethyl acetate / TEA, 99: 1) afforded 0.43 g of product. The resulting product was examined using ¹ H and ¹³ C NMR, M ⁺ = 266 and optical rotation [α] = -10.6, c = 3.3 (CHCl ₃ ). The other enantiomer and racemate are obtained in a similar manner, and this isomer is examined as the (-) isomer.

Synthesis of Desmethylsibutramine Hydrochloride Isomers

To a solution of (-) - desmethylsibutramine (0.78 g) in ethyl acetate (5 ml) at 0 ° C was added HCl / diethyl ether (1 M solution, 5 ml). The reaction mixture was stirred for 1 hour and the solid was collected by filtration. Then, the solid was dried to obtain 0.68 g of a white solid. The product was examined using ¹ H and ¹³ C NMR (DMSO-d ₆ ) and a chemical purity of> 99% was determined by HPLC. [α] = -5 ° (c = 0.5, H ₂ O). The racemate and other enantiomer are prepared and tested in a similar manner.

Example 4. (R / S) -Desmethylsibutramine

Another method for the preparation of racemic desmethylsibutramine ((R / S) -DMS) is shown in Scheme 2 and is described in detail below:

Scheme 2

Preparation of 1- (4-chlorophenyl) -1-cyclobutylcarboxaldehyde

In accordance with Scheme 2, diisobutylaluminum hydride (DIBAL-H) (87 ml, 1 M solution in THF, 87.0 mmol) was added to a solution of 1- (4-chlorophenyl) cyclobutanecarbonitrile (SSBC; 10 g, 52.1 mmol), located at -20 ° C. The resulting mixture was stirred for 4-5 hours at 0 ° C, poured into a 10% aqueous solution of citric acid and diluted with 200 ml of MTBE. The mixture was stirred at room temperature for 3-4 hours. The aqueous layer was washed with MTBE (1 x 50 ml), the combined organic layers were dried over MgSO ₄ and concentrated to give 9 g (89%) of the above aldehyde as an oil. Spectrum ¹ H NMR (CDCl ₃ ) δ 9.52 (s, 1H), 7.35-7.06 (m, 4H), 2.77-2.68 (m, 2H), 2.43-2, 32 (m, 2H), 2.06-1.89 (m, 2H). Spectrum ¹³ C NMR δ 198.9, 139.4, 132.9, 128.9, 127.8, 57.1, 28.3, 15.8.

Preparation of 1- (4-chlorophenyl) -1-cyclobutyl-N-methylcarbaimine

A mixture of 1- (4-chlorophenyl) -1-cyclobutylcarboxaldehyde (3 g, 15.4 mmol) and methylamine (12 ml, 40% aqueous solution by weight, 154 mmol) was stirred at room temperature for 18-40 hours. The reaction mixture was extracted with MTBE (2 x 50 ml). The combined organic layers were dried over K ₂ CO ₃ and concentrated to give 2.5 g (78%) of the above imine as an oil. Spectrum ¹ H NMR (CDCl ₃ ) δ 7.65 (m, 1H), 7.33-7.11 (m, 4H), 3.34 (s, 3H), 2.69-2.44 (m, 2H), 2.44-2.34 (m, 2H), 2.09-1.84 (m, 2H). Spectrum ¹³ C NMR δ 168.0, 144.0, 131.8, 128.4, 127.4, 50.6, 47.6, 30.6, 15.8.

Preparation of 1- (4-chlorophenyl) -N-methyl-2- (2-methylpropyl) -

cyclobutanmethamine

To a solution of 1- (4-chlorophenyl) -1-cyclobutyl-N-methylcarbayamine (0.5 g, 2.4 mmol) cooled to 0 ° C., BF _{3 was} added ^. OEt ₂ (0.34 g, 2.4 mmol). The mixture is stirred for 1 hour and cooled to -78 ° C. At this temperature, isobutyl magnesium bromide (2.5 ml, 2 M solution in ether, 5 mmol) was added, the resulting mixture was stirred at -78 ° C for 2 hours, warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated NaHCO ₃ solution (10 ml) and diluted with MTBE (15 ml). The organic layer was dried over MgSO ₄ , concentrated and purified by silica gel chromatography (eluting with 1% NEt ₃ in ethyl acetate) to give 380 mg of the above amine as an oil. Spectrum ¹ H NMR (CDCl ₃ ) δ 7.35-7.19 (m, 4H), 2.65-2.74 (m, 1H), 2.57 (s, 3H), 2.20-2, 56 (m, 5H), 1.60-2.00 (m, 3H), 1.20-1.00 (m, 2H), 0.95-0.90 (m, 6H), 0.67- 0.60 (m, 1H). Spectrum ¹³ C NMR δ 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. The hydrochloride salt of (R / S) -desmethylsibutramine

The method for producing the hydrochloric salt of racemic desmethylsibutramine ((R / S) -DMS ^. HCl) is shown in Scheme 3.

Scheme 3

In accordance with Scheme 3, toluene (150 ml) and a solution of CBS (50.0 g, 261 mmol) in toluene (45 ml) are added to a solution of isobutyl magnesium bromide in THF (392 ml, 1 M solution in THF, 392 mmol). The resulting mixture is distilled until the temperature inside it reaches 105-110 ° C, and heated under reflux at this temperature for 2-4 hours. Then the reaction mixture was cooled to 0 ° C and quenched with methanol (295 ml). NaBH ₄ (11 g, 339 mmol) was added portionwise to the reaction mixture at 0 ° C. over 15 minutes. The reaction mixture was stirred for 15 minutes and transferred into a 2 N aqueous HCl solution (365 ml). The organic phase is distilled until the temperature inside it reaches 105 ° C, and left to cool to room temperature. Then, formic acid (24 g, 522 mmol) is added to the reaction mixture and heated to the boiling point under reflux (92-96 ° C) for 6-8 hours, after which the reaction mixture is distilled until the temperature inside it reaches 108 ° FROM. The mixture was cooled to 10 ° C. and BH _{3 was} added ^. THF (653 ml, 1.0 M solution, 653 mmol). The resulting mixture was heated to reflux (69 ° C) for 15 hours. The mixture was cooled to 5 ° C, mixed with methanol (105 ml) and heated again under reflux for 45 minutes. The reaction mixture is distilled until the temperature inside it reaches 116 ° C, and left to cool to 25 ° C. Then, hydrochloric acid in MTBE (373 g, 18 wt.% HCl, 1840 mmol) was added to the mixture to give a white suspension, which was heated under reflux for 1 hour and filtered, to give 62.3 g (79.0%) (R / S) -DMS ^. HCl. Spectrum ¹ H NMR (CDCl ₃ ) δ 0.85-1.1 (m, 6H), 1.24-1.5 (w, 2H), 1.65-2.14 (w, 4H), 2, 2-2.5 (w, 4H), 2.5-2.7 (m, 2H), 3.4-3.6 (w, 1H), 7.3-7.5 (m, 4H), 9.0-9.5 (w, 2H). Spectrum ¹³ C NMR δ 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 6. Hydrochloride salt of (R) -desmethylsibutramine

The method for producing the hydrochloride salt of (R) -desmethylsibutramine ((R) -DMS ^. HCl) is shown in Scheme 4 and is described in detail below.

Scheme 4

Obtaining (R) -mandelate (R) -DMS

(R / S) -desmethylsibutramine hydrochloride salt ((R / S) -DMS ^. HCl) (60 g) was added to ethyl acetate (300 ml) and the resulting mixture was cooled to 0 ° C. Then, an aqueous solution of NaOH (1.5 N solution, 300 ml) was added to the reaction mixture and stirred for 30 minutes. The organic phase is separated, washed with water (150 ml) and concentrated. (R) -Mindic acid (30.3 g), ethyl acetate (510 ml total) and heptane (204 ml) are added to the concentrated organic phase. The resulting mixture was heated to boiling temperature under reflux for 1 hour and cooled to 20-23 ° C. The resulting suspension was filtered to give 36.4 g (43.8%) of (R) -mandelate (R) -desmethylsibutramine ((R) -DMS ^. (R) -MA; efficiency 95.5%).

Enrichment (R) -DMS ^. (R) -MA

A mixture of (R) -DMS ^. (R) -MA (30 g, 0.072 mol), ethyl acetate (230 ml) and heptane (230 ml) are heated to reflux for 1 hour. The product is cooled to 20-23 ° C., filtered and dried, yielding 29.6 g (98%) of (R) -DMS ^. (R) -MA (efficiency 99.9%).

Obtaining hydrochloride salt of (R) -DMS

A mixture of (R) -DMS ^. (R) -MA (50 g, 0.12 mol), NaOH (100 ml, 3.0 N solution) and toluene (500 ml) were stirred for 30 minutes. The organic phase is washed with water (200 ml), concentrated to about 300 ml and cooled to room temperature. HCl / MTBE (100 ml, 14%, 0.34 mol) was slowly added to the mixture to give (R) -DMS ^. HCl. The suspension is stirred for 30 minutes and filtered, the resulting wet filter cake is washed twice with MTBE and dried, giving 34.5 g (95.5%) of (R) -DMS ^. HCl (99.9% efficiency; 99.9% chemical purity by NMR). Spectrum ¹ H NMR (CDCl ₃ ) δ 0.85-1.1 (m, 6H), 1.24-1.5 (w, 2H), 1.65-2.14 (w, 4H), 2, 2-2.5 (w, 4H), 2.5-2.7 (m, 2H), 3.4-3.6 (w, 1H), 7.3-7.5 (m, 4H), 9.0-9.5 (w, 2H). Spectrum ¹³ C NMR δ 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 7. The hydrochloride salt of (S) -desmethylsibutramine

The method for producing the hydrochloride salt of (S) -desmethylsibutramine ((S) -DMS ^. HCl) is shown in Scheme 5 and is described in detail below.

Scheme 5

Obtaining (S) -Mandelate (S) -DMS

In accordance with scheme 5, the mixture (R / S) -DMS ^. HCl (5.0 g, NaOH (1.5 N solution, 20 ml) and ethyl acetate (50 ml) were stirred for 30 minutes. The organic phase was washed with water (20 ml) and concentrated to obtain the free base of desmethylsibutramine (4.2 g , 96%).

The free base of desmethylsibutramine (1.1 g, 4.1 mmol) was mixed with (S)-mandelic acid (0.62 g, 4.1 mmol), ethyl acetate (11 ml) and heptane (4.4 ml). The resulting mixture was heated to boiling temperature under reflux for 30 minutes and cooled to 20-23 ° C. The resulting suspension was filtered to give 0.76 g of (S) -mandelate of (S) -desmethylsibutramine ((S) -DMS ^. (S) -MA) (efficiency 96%).

Enrichment (S) -DMS ^. (S) -MA

A mixture of (S) -mandelate (S) -desmethylsibutramine (0.76 g), ethyl acetate (5 ml) and heptane (5 ml) was heated to reflux for 1 hour. The product is cooled to 20-23 ° C, filtered and dried, giving 0.72 g (95%) of (S) -DMS ^. (S) -MA (99.9% efficiency).

Isolation of (S) -mandelate (S) -DMS from the mother liquor

(S) -DMS ^. (R) -MA

To a solution of (S) -DMS ^. (R) -MA in ethyl acetate / heptane (mother liquor with a yield of 67%), NaOH (3 N solution, 400 ml) was added and the reaction mixture was stirred for 30 minutes. The organic phase is washed with water and concentrated. To the resulting residue (130 g, 0.49 mol and 67% production efficiency) are added (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 slowly cooled to room temperature. The resulting suspension was filtered and dried, giving 147 g (86% based on the (S) -isomer) (S) -DMS ^. (S) -MA (99.9% efficiency).

Obtaining hydrochloride salt (S) -DMS

(S) -Mandelate of (S) -desmethylsibutramine (20 g, 0.048 mol) was added to a mixture of NaOH (60 ml, 3.0 N solution) and toluene (200 ml). The mixture is stirred for 30 minutes, the organic phase is washed with water (100 ml), concentrated to about 100 ml and cooled to room temperature. Hydrochloric acid in MTBE (40 ml, 14%, 0.13 mol) was slowly added to the mixture to give (S) -DMS ^. HCl. The suspension is stirred for 30 minutes and filtered, the resulting wet filter cake is washed twice with MTBE and dried, giving 14 g (96.7%) of (S) -DMS ^. (L) -MA (efficiency 99.9%; chemical purity 99.9%). ¹ H NMR spectrum (CDCl ₃ ) δ 0.84-1.1 (m, 6H), 1.25-1.5 ( W, 2H), 1.65-2.15 (W, 4H), 2.2-2.5 (W, 4H), 2.5-2.7 (m, 2H), 3.4-3, 6 (w, 1H), 7.3-7.5 (m, 4H), 9.0-9.5 (w, 2H). Spectrum ¹³ C NMR δ 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. Obtaining desmethylsibutramine from didesmethyl-sibutramine

Racemic and optically pure didesmethylsibutramine can also be prepared by methylation of didesmethylsibutramine under acceptable reaction conditions. An example of this method is shown in scheme 6.

Scheme 6

Example 9. (R / S) -Didesmethylsibutramine

A preferred method for preparing the free base of racemic didesmethylsibutramine ((R / S) -DDMS) is shown in Scheme 7 and is described in detail below.

Scheme 7

In accordance with Scheme 7, isobutyl magnesium bromide (200 ml, 2.0 M solution in diethyl ether) and toluene (159 ml) are introduced into a 1-liter, three-necked round-bottomed flask and the resulting mixture is distilled to remove most of the ether. The mixture was cooled to 20 ° C., CBS (50.0 g) in toluene (45 ml) was added, and the resulting mixture was heated under reflux for 2-4 hours. The reaction mixture was cooled to 0 ° C, methanol (300 ml) was added, and then NaBH ₄ (11 g) was slowly added. The resulting mixture was stirred at 0-10 ° C for 15 minutes. The reaction mixture was slowly added to an aqueous HCl solution (365 ml, 2 N solution) at 0 ° C., and the resulting mixture was warmed to room temperature with continuous stirring. The organic phase is separated and the aqueous phase washed with toluene (200 ml). The combined organic phases were washed with water (200 ml) and concentrated to give (R / S) -DDMS (55 g, 85%). ¹ H NMR spectrum (CDCl ₃ ) δ 0.6-0.8 (m, 1H), 0.8-1.0 (m, 6H), 1.1-1.3 (m, 1H), 1, 6-2.6 (m, 7H), 3.0-3.3 (m, 1H), 7.0-7.6 (m, 4H). Spectrum ¹³ C NMR δ 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,

Example 10. (D) -Tartrate of (R / S) -didesmethylsibutramine

A preferred process for the preparation of (D) tartrate of racemic didesmethylsibutramine ((R / S) -DDMS ^. (D) -TA) is shown in Scheme 8. It should be noted that the (L) tartrate of racemic didemethylsibutramine ((R / S) -DDMS ^. (L) -TA) can be obtained in a similar way.

Scheme 8

In accordance with scheme 8, a mixture of racemic didesmethylsibutramine (15.3 g) and toluene (160 ml) is heated to 70-80 ° C and (D) -varic acid (9.1 g) in water (20 ml) and acetone are slowly added. (10 ml). The resulting mixture was heated under reflux for 30 minutes, after which water and acetone were distilled off. The reaction mixture was cooled to room temperature and the resulting suspension was filtered. The wet filter cake was washed twice with MTBE (20 ml x 2) and dried to give (R / S) -DDMS ^. (D) -TA (22.5 g, 98%). Spectrum ¹ H NMR (DMSO) δ 0.6-0.92 (m, 6H), 0.92-1.1 (m, 1H), 1.1-1.3 (m, 1H), 1.5 -2.8 (m, 2H), 1.8-2.1 (m, 1H), 2.1-2.4 (m, 3H), 2.4-2.6 (m, 1H), 3 4-3.6 (m, 1H), 3.9-4.2 (s, 2H), 6.4-7.2 (br, 6H, OH, COOH and NH ₂ ), 7.3-7 6 (m, 4H). Spectrum ¹³ C NMR δ 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.

Example 11. (D) -Tartrate of (R) -Didemethylsibutramine

Isolation from the free base of didesmethylsibutramine

The method for the isolation of (D) -tartrate of (R) -desidemethylsibutramine ((R) -DDMS ^. (D) -TA from the free base of racemic didemethylsibutramine is shown in Scheme 9A and described in detail below.

Scheme 9A

According to Scheme 9A, a mixture of (R / S) -didemethylsibutramine (20.3 g), acetone / water / methanol (350 ml, 1: 0.13: 0.7, v / v) and (D) -vic acid (12.1 g) was introduced into a 500 ml three-necked round-bottom flask. The reaction mixture is heated to the boiling temperature under reflux for 30 minutes and cooled to 45 ° C. Then, (R) -DDMS is added to the reaction mixture ^. (D) -TA (10 mg, 99.6% efficiency) and stirred at 40-45 ° C. for 30 minutes. The mixture was cooled to room temperature and stirred for 1 hour. The resulting suspension was filtered, the wet filter cake was washed with a cold mixture of acetone / water and dried, giving 10.3 g (33%) of (R) -DDMS ^. (D) -TA (90% efficiency).

Isolation of (D) -tartrate of (R / S) -didemethylsibutramine

The method for the isolation of (D) -tartrate of (R) -didemethylsibutramine ((R) -DDMS ^. (D) -TA) from the (D) -tartrate of racemic didesmethylsibutramine is shown in Scheme 9B and is described in detail below.

9V circuit

According to Scheme 9B, a mixture of (D) -tartrate (R / S) -didemethylsibutramine (5.0 g) in acetone (50 ml), water (6.7 ml) and methanol (3.3 ml) is heated under reflux within 30 minutes. The mixture was then cooled to room temperature, the resulting suspension was filtered, and the wet filter cake was washed with cold acetone and dried to give (R) -DDMS ^. (D) -TA (1.4 g, 28%; efficiency 92%).

Enrichment of (D) -tartrate (R) -DDMS

A mixture of (R) -DDMS ^. (D) -TA (25 g, efficiency 92%) and acetonitrile / water / ethanol (300 ml: 65 ml: 30 ml) were heated under reflux for 1 hour. The mixture was then cooled to room temperature, the resulting suspension was filtered and dried to give (R) -DDMS ^. (D) -TA (18 g, 71.3%, 99.7% efficiency and 99.91% chemical purity). ¹ H NMR spectrum (DMSO-d ₆ ) δ 0.7-0.9 (m, 6H), 0.9-1.05 (t, 1H), 1.1-1.24 (w, 1H), 1.5-1.8 (br, 2H), 1.8-2.02 (br, 1H), 2.1-2.4 (3, 3H), 2.4-2.6 (br, 1H) ), 3.5 (m, 1H), 4.0 (s, 2H), 7.1-7.6 (m, 4H, with 6H from NH ₂ , OH and COOH). Spectrum ¹³ C NMR δ 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.

Example 12. (L) -Tartrate of (S) -Didemethylsibutramine

Method for the isolation of (L) -tartrate of (S) -didemethylsibutramine (S) -DDMS ^. (L) -TA from the free base of racemic didesmethylsibutramine is shown in Scheme 10 and is described in detail below.

Pattern 10

Obtaining (L) -tartrate (S) -DDMS

(R / S) -Didemethylsibutramine (20.5 g), acetone / water / methanol (350 ml, 1: 0.13: 0.7, v / v) and (L) -vic acid (12.2 g) introduced into a three-neck round-bottomed flask with a capacity of 500 ml. The mixture is heated to the boiling temperature under reflux for 30 minutes and cooled to 45 ° C. Then, (S) -DDMS is added to the reaction mixture ^. (L) -TA (10 mg and 99.7% efficiency) and stirred at 40-45 ° C for 30 minutes. The mixture was cooled to room temperature and stirred for 1 hour. The resulting suspension was filtered, the wet filter cake was washed with a cold mixture of acetone / water and dried to give 10.8 g (33.4%) of (S) -DDMS ^. (L) -TA (efficiency 89.7%).

Obtaining (L) -tartrate (S) -DDMS from the mother liquor

(R) -DDMS ^. (D) -TA

A solution of DDMS tartrate in acetone / water / methanol (mother liquor (R) -DDMS ^. (D) -TA) was concentrated to remove acetone and methanol. The residue was taken up in aqueous NaOH (3 N solution, 150 ml) and extracted with ethyl acetate. The organic phase is washed with water (100 ml) and concentrated, which gives the free base of didesmethylsibutramine (45 g, 0.18 mol and the efficiency of obtaining the (S) -isomer 36%). To the free amine, (L) -varic acid (53.6 g, 0.35 mol), acetone (600 ml), water (80 ml) and methanol (40 ml) are added. The mixture was heated to reflux for 1 hour and cooled to room temperature. The resulting suspension is filtered and the wet filter cake washed twice with a cold mixture of acetone / water, which gives 26.7 g (56% based on (S) -Didemethylsibutramine) (S) -DDMS ^. (L) -TA (efficiency 96%).

Enrichment (S) -DDMS ^. (L) -TA

A mixture of (S) -DDMS ^. (L) -TA (26.7 g) in acetonitrile / water (475 ml, 1: 0.2, volume ratio) was heated under reflux for 1 hour and cooled to room temperature. The resulting suspension was filtered and dried, giving 17.4 g (65%) of (S) -DDMS ^. (L) -TA (efficiency 99.9%; chemical purity 99.94%). ¹ H NMR spectrum (DMSO-d ₆ ) δ 0.7-0.9 (m, 6H), 0.9-1.05 (m, 1H), 1.1-1.3 (w, 1H), 1.52-1.8 (br, 2H), 1.84-2.05 (br, 1H), 2.15-2.4 (br, 3H), 2.4-2.6 (br, 1H) ), 3.65-3.58 (m, 1H), 4.0 (s, 2H), 6.7-7.3 (w, 6H from NH ₂ , OH and COOH), 7.1-7, 6 (m, 4H). Spectrum ¹³ C NMR δ 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.

Example 13. Determination of activity and specificity

A pharmacological study is performed to determine the relative activity, comparative efficacy, binding affinity and toxicity of the racemic mixture of sibutramine, its enantiomers, sibutramine metabolites and their enantiomers. The relative specificity profile of monoamine reuptake inhibition is determined based on the inhibition of norepinephrine (NE) reuptake by test compounds in the brain tissue compared to dopamine (DA) and serotonin (5-HT) reuptake inhibition.

High affinity uptake of ³ H-radioactive monoamines was investigated using synaptosomal preparations obtained from rat striatum (to inhibit DA reuptake) and cerebral cortex (for 5-HT and NE) using the methods described by Kula et al., Life Science 34 (26): 2567-2575, 1984, and Baldessarini et al., Life Science 39: 1765-1777, 1986. Fresh tissues were excised on ice and weighed. The resulting tissue is manually homogenized (14 strokes in 10-35 volumes of ice-cooled 0.32 M isotonic sucrose solution containing nialamide, 34 μM) in a Teflon coated glass homogenizer, after which the fabric is centrifuged for ten minutes at a speed of 900 x gradient; the resulting “solution” of the supernatant contains synaptosomes that are used without further processing. 50 μl of the brain homogenate labeled with the radioactive isotopes of ³ H-monoamine and the test compound (for example, the pure enantiomers of sibutramine, racemate and the corresponding standards) in freshly prepared physiological saline with a buffer with a final volume of 0.5 ml are introduced into each tube. Before analysis, tissues are pre-incubated for 15 minutes at 37 ° C. Tubes are placed on ice until incubation begins, which is started by adding ³ H-amine until a final concentration of 0.1 μM is reached. Tubes are incubated at 37 ° C for 10 minutes with ³ H-DA (26 Ci / mmol) and for 20 minutes with ³ H-5HT (about 20 Ci / mmol) and ³ H-NE (about 20 Ci / mmol) . The specific activity of radioactive monoamine varies, depending on the substance used, to insignificant limits. The reaction is terminated by immersing the tubes in ice and diluting their contents with 3 ml of ice-cooled isotonic saline containing 20 mM TRIS buffer (pH 7.0). These solutions are filtered through cellulose ester microfilters and washed with two 3 ml volumes of a similar buffer. The ³ H-radioactivity of the filter was then counted in 3.5 ml of Polyfluor at approximately 50% tritium efficiency. The results obtained for control samples (incubated either at 0 ° C, or with known specific absorption inhibitors DA [GRB-12909, 10 μM], 5HT [zimelidine, 10 μM] or NE [desipramine, 10 μM], usually do not differ from the results of analyzes performed without the use of tissue, and on average make up 2-3% of the total number of pulses per minute (CPM).

A comparison of the ³ H-radioactivity values on the filters allows us to determine the relative ability of the pure enantiomers and the racemic mixture of sibutramine (and the known DA, 5-HT and NE reuptake inhibitors) to block the reuptake of these monoamines by these tissues. These data are useful for determining the relative activity and effectiveness of the compounds of this invention (for example, dopamine reuptake inhibitors, such as racemic or optically pure sibutramine metabolite, and 5-HT ₃ antagonists).

The acute toxicity of the compounds of this invention is determined by performing studies during which increasing doses (mg / kg) of pure isomers or racemate are administered to rats. The lethal dose, which, when administered orally, causes the death of 50% of the experimental animals, is defined as LD ₅₀ . A comparison of the LD ₅₀ values for enantiomers and racemate allows the relative toxicity of the compositions to be determined.

Example 14. The affinity of binding

The affinity of binding of racemic and optically pure sibutramine ((±) -, (+) - and

(-) - sibutramine), desmethylsibutramine ((±) -, (+) - and (-) - desMe) and didesmethylsibutramine ((±) -, (+) - and (-) - dideMe) are determined using the indiscriminate muscarine receptor and a serotonin reuptake site (5-HT) from rat cerebral cortex, a recombinant human norepinephrine (NE) reuptake site and human β ₃ receptor from rat adipose tissue. First, the compounds are double tested in an amount of 10 μm, and when detecting ≥50% inhibition of specific binding, these compounds are then double tested in 10 different concentrations to obtain complete competition success curves. IC ₅₀ values (concentration necessary to inhibit 50% of specific binding) are determined using non-linear regression analysis of the curves, and the data obtained are shown in the table below.

Values (nM) IC ₅₀ binding Compound Muskorin Receptor NE absorption 5-HT Absorption 5-HT Selectivity (NE / 5-HT) (±) -sibutramine 2650 350 2800 1200 (+) - sibutramine 4010 110 2100 650 (-) - sibutramine 3020 2500 4900 1500 (±) -desMe 1170 10 21 19 (+) - desMe - four 44 12 (-) - desMe 654 870 9200 180 (±) -DideMe - 16 63/14 39/26 (+) - DideMe - 13 140 8.9 (-) - DideMe 0 6.2 4300 12 Atropine 0.31 - - - GBR 1909 - - - 5.6 / 2.6 Imipramine - - 145/32 - Protriptyline - 3.6 / 0.9 - - Zimelidine - - 129 -

None of the compounds is characterized by more than 15% inhibition of binding to the β ₃ receptor, and the affinity for the muscarine uptake site is weak compared to atropine. In addition, the binding to the NE and 5-HT absorption sites is several orders of magnitude smaller than the similar values for the standards.

The above data, obtained in accordance with the description given in Example 13, show that (+) - desmethylsibutramine and (+) - didesmethylsibutramine are potent inhibitors of NE and 5-HT uptake, but have negligible activity in muscarinic receptor sites.

Example 15. The drug for oral administration

Lactose-free dosage forms containing sibutramine metabolites in hard gelatin capsules can be prepared using the following ingredients.

Component 5 mg
capsule 10 mg
capsule 20 mg
capsule Racemic or optically pure sibutramine metabolite 5,0 10.0 20,0 Microcrystalline cellulose 90.0 90.0 90.0 Pregelatinized Starch 100.3 97.8 82.8 Croscarmellose 7.0 6.0 7.0 Magnesium stearate 0.2 0.2 0.2

The racemic or optically pure sibutramine metabolite is sieved and mixed with the above excipients. Hard gelatine capsules of the required size, consisting of two parts, are filled with the resulting mixture using appropriate mechanisms and methods known in the art for this purpose. See., E.g., Remington's Pharmaceutical Sciences, 16 ^th or 18 ^th Editions, which is fully incorporated herein by reference. You can make dosage forms with other doses, for which you need to change the mass of the excipient and, if necessary, change the size of the capsule properly. You can get any of the above stable preparations without lactose in hard gelatin capsules.

Dosage forms in the form of compressed tablets containing sibutramine metabolites can be obtained using the following ingredients.

Component 5 mg capsule 10 mg capsule 20 mg capsule Racemic or optically pure sibutramine metabolite 5,0 10.0 20,0 Microcrystalline cellulose 90.0 90.0 90.0 Pregelatinized Starch 100.3 97.8 82.8 Croscarmellose 7.0 6.0 7.0 Magnesium stearate 0.2 0.2 0.2

The racemic or optically pure sibutramine metabolite is sieved through a suitable sieve and mixed with lactose-free excipients until a homogeneous mixture is formed. The dry mixture is sieved and mixed with magnesium stearate. The resulting powdery mixture is compressed into tablets of the desired shape and size. Tablets with other degrees of strength can be obtained by changing the ratio of the active ingredient to the excipient (s) or by changing the weight of the components.

The above-described embodiments of this invention are given only as examples, and those skilled in the art should understand, or they can verify by simple experimentation, that there are numerous equivalent methods described. All such equivalents are included in the scope of this invention and are set forth in the following claims.

Claims (5)

1. The use of (-) - didesmethylsibutramine or a pharmaceutically acceptable salt, solvate or clathrate thereof for the manufacture of a medicament for the treatment of Parkinson's disease. 2. The use according to claim 1, where the metabolite of sibutramine is administered orally, through the mucous membrane or transdermally. 3. The use according to claim 1, where the drug is adapted for the introduction of (-) - didesmethylsibutramine in an amount of from about 0.1 mg to about 60 mg per day. 4. The use according to claim 3, where the drug is adapted for the introduction of (-) - didesmethylsibutramine in an amount of from about 2 mg to about 30 mg per day. 5. The use according to claim 1, where the drug is adapted for the introduction of (-) - didesmethylsibutramine in an amount of from about 5 mg to about 15 mg per day.