MXPA01001955A - Methods of using and compositions comprising dopamine reuptake inhibitors - Google Patents
Methods of using and compositions comprising dopamine reuptake inhibitorsInfo
- Publication number
- MXPA01001955A MXPA01001955A MXPA/A/2001/001955A MXPA01001955A MXPA01001955A MX PA01001955 A MXPA01001955 A MX PA01001955A MX PA01001955 A MXPA01001955 A MX PA01001955A MX PA01001955 A MXPA01001955 A MX PA01001955A
- Authority
- MX
- Mexico
- Prior art keywords
- metabolite
- sibutramine
- didesmethylsibutramine
- treatment
- prevention
- Prior art date
Links
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Abstract
Methods are disclosed for the treatment and prevention of disorders and conditions including, but are not limited to, erectile dysfunction, affective disorders, weight gain, cerebral functional disorders, pain, obsessive-compulsive disorder, substance abuse, chronic disorders, anxiety, eating disorders, migraines, and incontinence. The methods comprise the administration of a dopamine reuptake inhibitor and optionally an additional pharmacologically active compound. Pharmaceutical compositions and dosage forms are also disclosed that comprise a dopamine reuptake inhibitor and optionally an additional pharmacologically active compound. Preferred dopamine reuptake inhibitors are racemic or optically pure sibutramine metabolites and pharmaceutically acceptable salts, solvates, and clathrates thereof. Preferred additional pharmacologically active compounds include drugs that affect the central nervous system, such as 5-HT3, antagonists.
Description
METHODS OF USE AND COMPOSITIONS CONTAINING INHIBITORS OF THE RECOVERY OF DOPAMINE
This application claims the benefit of United States Provisional Application No. 60 / 097,665, filed on August 24, 1998, and United States Provisional Application No. 60 / 099,306 filed on September 2, 1998, which they incorporate in the present in their strengths as a reference.
1. FIELD OF THE INVENTION The invention relates to methods of use, and to compositions containing inhibitors of dopamine reuptake and, in particular, the racemic and optically pure metabolites of sibutramine.
2. BACKGROUND OF THE INVENTION Sibutramine, chemically named [Nl- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl] -N, N-dimethylamine, is a neuronal monoamine reuptake inhibitor that was originally described in U.S. Patent Nos. 4,746,680 and 4,806,570. Sibutramine inhibits the reuptake of norepinephrine and, to a lesser extent, serotonin and dopamine. See, for example, Buckett et al., Prog. Neuro-psychopharm. & Biol. Psychiat, 12: 575-584, 1988; King et al., J. Clin.
Pharm. 26: 607-611 (1989). Racemic sibutramine is marketed as a monohydrated hydrochloride with the trademark MERIDIA®, and is indicated for the treatment of obesity. Physician's Desk Reference® 1494-1498 (53rd edition, 199). The treatment of obesity using racemic sibutramine is described, for example, in U.S. Patent No. 5,436,272. It seems that sibutramine has been extensively studied, and it has been reported that it can be used in the treatment of some disorders. For example, U.S. Patent Nos. 4,552,828, 4,746,680, 4,806,570 and 4,929,629 describe methods for the treatment of depression using racemic sibutramine, and U.S. Patent Nos. 4,871,774 and 4,939,175 describe methods of treating Parkinson's disease and senile dementia, respectively , using racemic sibutramine. 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 optically pure enantiomers of sibutramine have been considered for development. For example, PCT publications WO 94/00047 and 94/00114 describe methods of treating depression and related disorders using the (+) and (-) enantiomers of sibutramine, respectively. Sibutramine is rapidly absorbed from the tract
Gastrointestinal after oral administration and undergoes an extensive first-pass metabolism that produces the primary metabolites, desmethylsibutramine and didesmethylsibutramine, as shown below.
sibutramine
d «methylsibutra ine didesme hylsíbutraminc
It has been reported that desmetilsibutramine and didesmethylsibutramine are inhibitors of the reuptake of noradrenaline and 5-hydroxytryptamine (5HT; serotonin) in vitro more potent than sibutramine. Stock, M. J. Inf 1 J. Obesi ty, 21 (supp.l): S25-S29 (1997). However, it has also been reported that sibutramine and its metabolites have negligible affinities for a wide range of neurotransmitter receptors, including the serotonergic receptors (5HT ?, 5HT1A, 5HT1D, 5HT2A, 5HT2C), adrenergic, dopaninergic, muscarinic, histaminergic receptors,
glutamate and for benzodiazepine, Id. Sibutramine has some adverse effects, see, for example, Physician's Desk Reference® 1494-1498 (53rd edition, 199). Coupled with the reported benefits and inadequate therapeutics of sibutramine, this fact has stimulated the discovery of compounds and compositions that can be used in the treatment or prevention of disorders such as, but not limited to erectile dysfunction, affective disorders, Weight gain or obesity, disorders of brain function, pain, obsessive-compulsive disorder, substance abuse, chronic disorders, anxiety, eating disorders, migraines and incontinence. In particular, it is desired that the compounds and compositions can be used for the treatment and prevention of such conditions and disorders while incurring in fewer adverse effects associated with sibutramine.
3. SUMMARY OF THE INVENTION This invention encompasses methods, pharmaceutical compositions and dosage forms for the treatment and prevention of disorders that are alleviated by the inhibition of neuronal monoamine uptake in mammals, including humans. Examples of these disorders include, but are not limited to, dysfunction
erectile, affective disorders, weight gain or obesity, disorders of brain function, pain, obsessive-compulsive disorders, substance abuse, chronic disorders, anxiety, eating disorders, migraines and incontinence. The methods of the invention consist in administering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate or clathrate thereof. This invention also comprises a method of treatment or prevention of erectile dysfunction which consists of administering as a coadjuvant to a patient in need of such treatment or prevention effective amounts for therapeutic or prophylactic use of a dopamine reuptake inhibitor and an antiemetic antagonist. -HT3. The pharmaceutical compositions of the invention contain an effective amount for therapeutic or prophylactic use of a neuronal monoamine reuptake inhibitor. Preferred neuronal monoamine reuptake inhibitors include, but are not limited to, apomorphine, racemic and optically pure sibutramine metabolites, and pharmaceutically acceptable salts, solvates and clathrates thereof. The pharmaceutical compositions of the invention can also be
contain other medicinal substances, including, but not limited to, 5-HT3 antagonists. The invention comprises the use of racemic and optically pure sibutramine metabolites as effective inhibitors of the reuptake of dopamine, serotonin and norepinephrine. Racemic and optically pure sibutramine metabolites include, but are not limited to, (+) - desmethylsibutramine, (-) -desmethylsibutramine, (±) -desmethylsibutramine, (+) -didesmethylsibutramine, (-) - didesmethylsibutramine, (±) - didesmetilsibutramine.
4. DETAILED DESCRIPTION OF THE INVENTION This invention relates to methods and compositions that inhibit the reuptake of neuronal monoamines (eg, dopamine, serotonin and norepinephrine). The invention herein provides a method of treating or preventing a condition ameliorated by the inhibition of neuronal monoamine reuptake, which is to administer to a patient (i.e., a human) in need of such treatment or prevention, of an effective amount for therapeutic or prophylactic use of the neuronal monoamine reuptake inhibitor. The preferred neuronal monoamine reuptake inhibitors are racemic and optically pure sibutramine metabolites and salts, solvates and clathrates acceptable for use
pharmaceutical of these. When used herein, the term "treatment or prevention of ailments" that are ameliorated by the inhibition of neuronal monoamine reuptake "means the alleviation of the symptoms of the conditions associated with abnormal concentrations of neuronal monoamine. are reduced by the inhibition of neuronal monoamine reuptake include, but are not limited to, erectile dysfunction, affective disorders, weight gain or obesity, brain function disorders, pain, obsessive compulsive disorder, substance abuse, chronic disorders, anxiety, eating disorders, migraines and incontinence A first embodiment of the invention comprises a method of treatment or prevention of erectile dysfunction consisting of administering, as a coadjuvant, to a patient in need of such treatment or prevention, effective amounts for use Therapeutic or prophylactic dopamine reuptake inhibitor a and a 5-HT3 antagonist. Preferred dopamine reuptake inhibitors include, but are not limited to, apomorphine, sibutramine, racemic and optically pure metabolites of sibutramine and the pharmaceutically acceptable salts, solvates and clathrates thereof. Particularly preferred dopamine reuptake inhibitors are metabolites
racemic and optically pure sibutramine. Preferred 5-HT3 antagonists are antiemetic agents. Examples of suitable 5-HT3 antagonists include, but are not limited to, granisetron (KYTRIL®), metoclopramide (REGLAN®), ondansentron (ZOFRAN®), renzapride, zacopride, tropisetron and the optically pure stereoisomers, active metabolites and acceptable salts for pharmaceutical use, clathrates and solvates thereof. In a preferred method of this embodiment, the dopamine reuptake inhibitor is administered transdermally or mucosally (eg, 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 mucosally. A second embodiment of the invention comprises a method of treatment or prevention of erectile dysfunction, which consists in administering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutramine, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof. In a preferred method of this embodiment, the metabolite of racemic or optically pure sibutramine or the salt, solvate or claret acetable for pharmaceutical use thereof is
administered transdermally or mucosally. A third embodiment of the invention comprises a method of treating or preventing an effective disorder, which comprises administering to a patient in need of such treatment or prevention, an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite. of sibutramine, or a solvate or clathrate salt acceptable for pharmaceutical use thereof. Affective disorders, include, but are not limited to, depression (eg, melancholia), attention deficit disorder (including attention deficit hyperactivity disorder and attention deficit / hyperactivity disorder), bipolar states and maniacs, distinctive disorders and cyclothinic disorder. When used herein, the terms "attention deficit disorders" (ADD), "attention deficit hyperactivity disorder" (ADDH), and attention deficit / hyperactivity disorder (AD / HD), are used according to their accepted meanings in the art, see, for example, Diagnostic and Statistical Manual of Mental Disorders, fourth edition, American Psychia tric Association, 1997, (DSM-IV ™) and Diagnostic and Sta tiscal Manual of Mental Disorders 3rd edition, American Psychiatric Association (1981) (DSM-III ™) A preferred method of this modality is a method of
treatment or prevention of attention deficit disorder consisting in administering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutrami, or a salt, solvate or clathrate acceptable for pharmaceutical use of this. In the treatment or prevention of attention deficit disorder, the racemic or optically pure metabolite of sibutramine is an optically pure metabolite of sibutramine, and more preferably (-) - demethylsibutramine or (-) - didesmethylsibutramine. Another preferred method of this modality is a method of treatment or prevention of depression, which consists of administering to a patient in need of such treatment or prevention, an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutramine, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof. When used herein, the term "treatment or prevention of depression" means alleviating or preventing symptoms of depression including, but not limited to, mood swings, feelings of intense sadness, hopelessness, mental slowness, loss of concentration, pessimistic worry, agitation and humility. Physical changes can also be alleviated or prevented by
This method includes, but is not limited to, insomnia, anorexia, decreased energy and libido, and abnormal hormonal circadian rhythms. A fourth embodiment of the invention comprises a method of treatment or prevention of weight gain or obesity, which consists of administering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutramine, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof. When used herein, the term "treatment or prevention of weight gain or obesity" means weight reduction, relief of overweight, relief of weight gain or alleviation of obesity, and prevention of weight gain, all which are usually due to unnecessary consumption of food. A fifth embodiment of the invention comprises a method of treating or preventing a disorder of cerebral function, which consists in administering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutramine, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof. Disorders of brain function include, but are not limited to, senile dementia, Alzheimer's type dementia, loss
of memory, amnesia / amnestic syndrome, disorders of consciousness, coma, decreased attention, voice disorders, Parkinson's disease, Lennox syndrome, autism, epilepsy, hyperkinetic syndrome and schizophrenia. Disorders of brain function can be induced by factors including, but not limited to, cerebrovascular diseases such as cerebral infarction, cerebral hemorrhage, arteriosclerosis, cerebral, cerebral venous thrombosis and head injuries, and conditions with symptoms selected from the group that It consists of disorders of consciousness, senile dementia, coma, decreased attention and voice disorders. When used herein, the term "treatment or prevention of a disorder of brain function" means the alleviation or prevention of one or more symptoms associated with disorders of brain function. A sixth embodiment of the invention comprises a method of treatment or prevention of pain, including chronic pain, which consists of administering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically metabolite pure sibutramine, or a salt, solvate or clathrate acceptable for pharmaceutical use of this. A seventh embodiment of the invention, consists of a method of treatment or prevention of an obsessive disorder
compulsive, which consists of administering to a patient in need of such treatment or prevention, an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof. An eighth embodiment of the invention comprises a method of treatment or prevention of substance abuse, which comprises administering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutramine or a salt, solvate or clathrate acceptable for pharmaceutical use thereof. When used herein, the term "substance abuse" includes abuse of, and physical and / or psychological addiction to, medications or alcohol. The term "substance abuse" further comprises its accepted meaning in the art, see, for example, DS -IV ™ and DSM-III ™. A preferred method comprised by this modality is a method of treatment or prevention of cocaine and / or heroin abuse. A ninth embodiment of the invention comprises a method of treatment or prevention of nicotine addiction, which consists of administering to a patient in need of such treatment or prevention, an effective amount for therapeutic or prophylactic use of a racemic metabolite or
optically pure sibutramine, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof. Nicotine addiction includes addiction to nicotine in all known ways, such as the consumption of cigarettes, cigars and / or pipes and also the addiction to chew tobacco. A tenth embodiment of the invention comprises a method for stopping the smoking habit, which consists of administering to a patient who smokes tobacco an effective amount for therapeutic use of a racemic or optically pure metabolite of sibutramine, or a salt, solvate or clathrate acceptable for pharmaceutical use of this. In a preferred method comprised by this embodiment, the racemic or optically pure metabolite of sibutramine or the pharmaceutically acceptable salt, solvate or clathrate thereof is administered orally, mucosally or transdermally. In a preferred method, the racemic or optically pure metabolite of sibutramine or the pharmaceutically acceptable salt, solvate or clathrate thereof is administered transdermally. Another preferred method comprised by this modality is a method to interrupt the habit of smoking, which consists in administering as a coadjuvant to a patient who smokes tobacco effective amounts for therapeutic use of a racemic or optically pure metabolite of sibutramine, or a salt, solvate or acceptable clathrate for pharmaceutical use of
this, and nicotine. Preferably, the nicotine and / or the racemic or optically pure metabolite of sibutramine or the pharmaceutically acceptable salt, solvate or clathrate thereof are administered orally, mucosally or transdermally. More preferably, the nicotine and / or the racemic or optically pure metabolite of sibutramine or the salt, solvate or clathrate acceptable for pharmaceutical use thereof is administered transdermally. Another method comprised by this method is a method of treatment or prevention of weight gain associated with the cessation of smoking which consists of administering to a patient in need of such treatment or prevention an effective amount for prophylactic therapeutic use of a drug. racemic or optically pure metabolite of sibutramine, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof. An eleventh embodiment of the invention comprises a method of treating or preventing a chronic disorder selected from the group consisting of narcolepsy, chronic fatigue syndrome, temporary affective disorder, fibromyalgia and premenstrual syndrome (or premenstrual dysphoric disorder). This method consists of administering to a patient in need of treatment or prevention an effective amount for prophylactic therapeutic use of a racemic or optically pure metabolite of sibutramine, or a
salt, solvate or clathrate acceptable for pharmaceutical use of this. Preferred methods of this modality are methods of treatment or prevention of premenstrual syndrome, narcolepsy and chronic fatigue. A twelfth embodiment of this invention comprises a method of treatment or prevention of anxiety, which consists of administering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutramine, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof. A thirteenth embodiment of the invention comprises a method of treatment or prevention of a disorder in the diet, which consists in administering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutramine, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof. A fourteenth embodiment of the invention comprises a method of treating or preventing migraine or migraine headache which consists in administering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutramine, or a salt,
solvate or acceptable clathrate for pharmaceutical use of this. When used in the present, the terms
"obsessive compulsive disorder", "premenstrual syndrome",
"anxiety", "eating disorders" and "migraine" are used consistently with their meanings accepted in the art. See, for example, DSM-IV ™ and DSM-III ™. The term "treatment or prevention methods" when used in connection with these conditions means the reduction, prevention or alleviation of the symptoms and / or effects associated with these conditions. A fifth embodiment of the invention comprises a method of treating or preventing incontinence, which comprises administering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutramine, or a salt, solvate or clathrate acceptable for pharmaceutical use of this. In particular, it is possible to use a racemic or optically pure metabolite to treat faecal incontinence, stress urinary incontinence ("SUI"), urinary stress incontinence, incontinence to the stimulus, reflex incontinence, passive incontinence and excess incontinence. When used herein, the term "treatment or prevention of incontinence" means the
treatment, prevention or relief of incontinence symptoms including the involuntary emptying of faeces or urine, and the leakage or leakage of feces or urine, which may be due to one or more causes including, but not limited to, alteration pathological control of the sphincter, loss of cognitive function, on distension of the bladder, hyper-reflexia and / or involuntary relaxation of the urethra, weakness of the muscles associated with the bladder or neurological abnormalities. A preferred method comprised by this modality is a method of treatment or prevention of stress urinary incontinence. In another preferred method comprised by this embodiment, the patient is a human adult of greater age than 50 or child of an age less than 13. A sixteenth embodiment of the invention comprises pharmaceutical compositions and dosage forms containing a racemic or optically metabolite pure or a salt, solvate or clathrate acceptable for pharmaceutical use of this. These pharmaceutical compositions and dosage forms are particularly useful in the methods described above, for example, the dosage forms of the invention are useful for oral, mucosal (eg, nasal, sublingual, buccal, rectal and vaginal), parenteral ( for example, intravenous and intramuscular), transdermal or subcutaneous. Dosage forms
Preferred of the invention are suitable for oral, mucosal or transdermal administration. Preferred racemic and optically pure sibutramine metabolites include, but are not limited to: (+) -desmethylsibutra ina, (-) -desmethylsibutramine, (+) -desmethylsibutramine, (±) -didesmethylsibutramine, (-) - didesmethylsibutramine, and ( +) didesmethylsibutramine. Optically pure sibutramine metabolites are more preferred. When used herein, the term "optically pure" means that a composition contains more than about 90% of the desired stereoisomer by weight, preferably more than about 95% by weight of the desired stereoisomer, and, more preferably, greater than about 99% by weight of the stereoisomer, desired, based on the total weight of the active ingredient. For example, optically pure (+) -desmethylsibutramine is practically free of (-) -desmethylsibutramine. When used herein, the term "substantially free" means that a composition contains less than about 10% by weight, preferably less than about 5% by weight and more preferably less than about 1% by weight of a compound. It is contemplated that the pharmaceutically acceptable salts, solvates and clathrates of the racemic and optically pure metabolites of sibutramine will be used in the
methods, pharmaceutical compositions and dosage forms of the invention. When used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a non-toxic inorganic or organic acid acceptable for pharmaceutical use. Inorganic acids include, 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 sulphonic organic acids including, but not limited to: formic, acetic, propionic, succinic, benzoic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamico), mentansulfonic, ethanesulfonic, pantothenic, benzenesulfonic stearic, sulphanilic, alginic and galacturonic. Particularly preferred acids are hydrobromic, hydrochloric, phosphoric and sulfuric and more particularly preferred is hydrochloric acid. In each of the methods of the invention, a metabolite of sibutramine or a salt, solvate or clathrate acceptable for pharmaceutical use thereof, can be administered as an adjuvant with one or more compounds
active substances for additional pharmacological use, ie, the metabolite of sibutramine and at least one active compound for further pharmacological use are administered as a combination, at the same time but separately, or sequentially by any convenient route (e.g. orally, transdermal or mucosal). In addition, preferred pharmaceutical compositions and dosage forms of the invention may comprise an excipient acceptable for pharmaceutical use and / or at least one active compound for further pharmacological use. Additional active compounds for pharmacological use that can be used in the methods and compositions of the invention, include, but are not limited to, drugs that act on the central nervous system ("CNS"), such as, but not limited to, : 5-HT agonists and antagonists (e.g., 5-HT3 and 5-HT? A); selective serotonin reuptake inhibitors ("SSRIs"); hypnotics and sedatives; drugs useful in the treatment of psychiatric disorders including anti-psychotic and neuroleptic drugs, antianxiety drugs, anti-depressants, and mood stabilizers; CNS stimulants such as amphetamines; Dopamine receptor agonists; anti-monic agents; anti-panic agents; cardiovascular agents (for example, beta-blockers and converting enzyme inhibitors)
angionetensin); antivirals; antibiotics, anti-mycotic and anti-neoplastic. More specific drugs that act on the CNS include, but are not limited to, SSRIs, benzodiazepine compounds, tricyclic anti-depressants, anti-psychotic agents, anti-anxiolytic agents, β-adrenergic antagonists, 5-HT receptor antagonists. and 5-HT3 receptor agonists. Even more specific drugs that act on the CNS include, but are not limited to, lorazepam, tomoxetine, olanzapine, respiradone, buspirone, hydroxyzine, and valium. Selective serotonin reuptake inhibitors are compounds that inhibit serotonin uptake in the central nervous system while having reduced or limited affinity for other neurologically active receptors. Examples of SSRIs include, but are not limited to, citalopram (CELEXA®); fluoxetine
(PROZAC®); fluvoxamine (LUVOX®); paroxetine (PAXIL®); sertraline (ZOLOFT®); venlafaxine (EFFEXOR®); and optically pure stereoisomers, active metabolites and salts, solvates or acceptable clathrates thereof. Benzodiazepine compounds that can be used in the methods and compositions of the invention include, but are not limited to, those described in Goodman & Gilman, the Pharmacological Basis of Therapeutics, 362-373 (9th edition)
McGraw-Hill, 19996). Examples of specific benzodiazepines include, but are not limited to: alprazolam, brotizolam, clordizepoxide, clobazam, clonazepam, clorazepate, demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, pharmacologically active metabolites and stereoisomers thereof, and the salts, solvates or clathrates acceptable for pharmaceutically acceptable use thereof. Trademarks of some of these compounds are provided below. Alprazolam, whose chemical name is 8-chloro-l-methyl-6-phenyl-4H-s-triazolo [4, 3-a] [1,4] benzodiazepine, is marketed under the brand name XANAX®. XANAX® is indicated for the management of anxiety disorders (a condition more closely associated with DSM-III ™ diagnosis of generalized anxiety disorder) or short-term relief of anxiety symptoms. Physician's Desk Reference® 2516-2521 (53rd ed., 1999). The diazephoxide hydrochloride salt, which has the chemical name of 7-chloro-2- (methylamino) -5-phenyl-3H-l, 4-benzodiazepine 4-oxide hydrochloride, is marketed under the trademark LIBRIUM®. LIBRIUM® is indicated for the management of anxiety disorders or for the short-term relief of symptoms of anxiety, withdrawal symptoms of
acute alcoholism and pre-operative apprehension and anxiety. Physician's Desk Reference® 1369-1370 (53rd ed., 1999). Clonazepam, which has the chemical name 5- (2-chlorophenyl) -1,3-dihydro-7-nitro-2H-l, 4-benzodiazepin-2-one, is marketed under the trademark KLONOPIN®. KLONOPIN® is useful alone or as an adjunct in the treatment of Lennox-Gastaut syndrome (variant of petit mal), akinetic and myoclonic seizures. KLONOPIN® is also indicated for the treatment of panic disorders, with or without agoraphobia, as defined in DSM-IV ™. Physician 's Desk Reference® 2688-2691 (53rd ed., 1999). The chlorozepate dipotassium salt, which has the chemical name 7-chloro-2,3-dihydro-2,2-dihydroxy-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid dipotassium, is marketed under the trademark TRANXENE® . TRANXENE® is indicated for the management of anxiety disorders or for the short-term relief of anxiety symptoms, as adjunctive treatment in the management of partial seizures, and for the symptomatic relief of abstinence from acute alcoholism. Physician's Desk Reference® 475-476 (53rd ed., 1999). Diazepam, under the tradename 7-chloro-l, 3-dihydro-l-methyl-5-phenyl-2H-l, 4-benzodiazepin-2-one, is marketed under the trademark VALIUM®. VALIUM® is indicated for the management of anxiety disorders or for the short-term relief of anxiety symptoms; Physician 's Desk Reference®
2735-2736 (53rd ed., 1999). Estazolam, with the chemical name 8-chloro-6-phenyl-4H-s-triazolo [4-3-a] [1,4] benzodiazepine, is marketed under the trademark PROSOM®. PROSOM® is indicated for the short-term management of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings and / or early nocturnal awakenings. Physician's Desk Reference® 473-475 (53rd ed., 1999). Flumazenil, with the chemical name 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1, 5a] (1,4) benzodiazepin-3-carboxylate ethyl, is marketed under the trademark ROMAZICON®. ROMAZICON® is indicated for the complete or partial reversal of the sedative effects of benzodiazepines in cases where general anesthesia has been induced and / or maintained with benzodiazepines, where sedation has been produced with benzodiazepines for diagnostic and therapeutic procedures, and for the management of benzodiazepine overdose. Physician's Desk Reference® 2701-2704 (53rd ed., 1999). The hydrochloride salt of flurazepam, with the chemical name dichlorhidate of 7-chloro-l- [2- (di-ethylamino) ethyl] -5- (o-fluorophenyl) -1,3-dihydro-2H-l, 4-benzodiazepin -2-ona, is marketed under the DALMANE® brand. DALMANE® is a hypnotic agent useful for the treatment of insomnia characterized by difficulty in falling asleep, awakenings
frequent nocturnal and / or early morning awakenings. Physician's Desk Reference® 2520 (52nd ed. 1998).
Lorazepam, under the trade name 7-chloro-5- (o-chlorophenyl) -1,3-dihydro-3-hydroxy-2H-l, 4-benzodiazepin-2-one, is marketed under the trademark ATIVAN®. ATIVAN® is indicated for the management of anxiety disorders and for short-term relief of anxiety or anxiety symptoms associated with depressive symptoms Physician's Desk Reference® 3267-3272 (53rd ed., 1999). The midazolam hydrochloride salt, with the chemical name 8-chloro-6- (2-fluorophenyl) -l-methyl-4H-imidazo [1, 5-a] [1,4] benzodiazepine hydrochloride is marketed under the trademark VERSED ®. VERSED® is indicated for sedation, anxiolysis, preoperative amnesia and general anesthesia. Physician's Desk Reference® 2720-2726 (53rd ed., 1999). Oxazepam, with the chemical name 7-chloro-l, 3-dihydro-3-hydroxy-5-phenyl-2H-l, 4-benzodiazepin-2-one, is marketed under the trademark SERAX®. SERAX® is indicated for the management of anxiety disorders or for the short-term relief of anxiety symptoms. Physician's Desk Reference® 3338-3384 (53rd ed., 1999). Quazepam, with the chemical name 7-chloro-5- (o-fluorophenyl) -1, 3-dihydro-l- (2, 2, 2-trifluoroethyl) 2H-1,4-benzodiazepin-2-thione, is marketed with the DORAL® brand. DORAL® is indicated for the treatment of insomnia
characterized by difficulty in falling asleep, frequent nocturnal awakenings and / or early morning awakenings. Physician's Desk Reference® 2958 (52nd ed. 1998). Temazepam, with the chemical name 7-chloro-l, 3-dihydro-3-hydroxy-l-methyl-5-phenyl-2H-l, 4-benzodiazepin-2-one, is sold under the brand name RESTORIL®. RESTORIL® is indicated for the short-term treatment of insomnia. Physician's Desk Reference® 2075-2078 (53rd ed., 1999). Triazolam, with the chemical name 8-chloro-6- (o-chlorophenyl) -l-methyl-4H-s-triazolo- [4,3-a] [1,4] benzodiazepine, is marketed under the trademark HALCION®. HALCION® is indicated for the short-term treatment of insomnia. Physician's Desk Reference® 2490-2493 (53rd ed., 1999). The clinician, physician or psychiatrist will realize that the above compounds can be used in combination with a racemic or optically pure metabolite of sibutramine, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof, for the treatment or prevention of a condition determined, although preferred combinations are described herein. Disorders that can be treated or prevented using a racemic or optically pure metabolite of sibutramine or a salt, solvate or clathrate acceptable for use
Pharmaceutical thereof, in combination with a benzodiazepine such as those mentioned in the foregoing include, but are not limited to, affective disorders (e.g., depression), anxiety, eating disorders, and disorders of brain function such as those described herein. . The invention further comprises methods of use and pharmaceutical compositions containing a racemic or optically pure metabolite of sibutramine, or a pharmaceutically acceptable salt, solvate or clathrate thereof, in combination with an anti-psychotic agent. The anti-psychotic agents are used mainly in the management of patients with psychotic or other serious psychiatric diseases in which agitation and impaired reasoning is observed. These medications have other properties that are possibly clinically useful, including the anti-emetic and anti-histamine effects, and the ability to potentiate analgesics, sedatives and general anesthetics. Specific anti-psychotic drugs are tricyclic anti-psychotic drugs of which there are three subtypes: phenothiazines, thioxanthenes and other heterocyclic compounds, all of which can be used in the methods and compositions of the invention. See, for example, Goodman & Gilman, The Pharmacological Basis of Therapeutics, 404 (9th ed McGraw-Hill, 1996). The tricyclic, specific anti-psychotic compounds
include, but are not limited to, chlorpromazine, mesoridazine, trioridazine, acetophenazine, fluophenazine, perphenazine, trifluoperazine, chlorprothixene, thiothixene, clozapine, haloperidol, loxapine, molindone, pimozide, risperidone, desipramine, the pharmacologically active metabolites and stereoisomers thereof, and the salts, solvates and clathrates acceptable for pharmaceutical use of these. Trademarks of these compounds are provided herein. Chloropromazine, whose chemical name is 10- (3-dimethylamidopropyl) -2-chlorophenothiazine, is marketed under the name THORAZINE®. THORAZINE® is indicated, inter alia, for the management of manic manifestations of psychotic disorders. Physician's Desk Reference® 3101-3104 (53rd ed., 1999). The besylate salt of mesoridazine, whose chemical name is 10- [2 (l-methyl-2-piperidyl) ethyl] -2-methyl-sulfinyl) -phenothiazine, is marketed under the name SERENTIL®. SERENTIL® is indicated in the treatment of schizophrenia, behavioral problems in mental deficiency and chronic brain syndrome, alcoholism and psychoneurotic manifestations. Physician 's Desk Reference® 764-766 (53rd ed., 1999). Perphenazine, whose chemical name is 4- [3- (2-chlorophenothiazin-10-yl) propyl-1-piperazine ethanol, is marketed under the name TRILAFON®. TRILAFON® is
indicated for use in the management of manifestations of psychotic disorders and for the control of severe nausea and vomiting in adults. Physician's Desk Reference® 2826-2888 (53rd ed., 1999). Trifluoperazine, whose trade name is 10- [3- (4-methyl-1-piperazinyl) -propyl] -2- (trifluoromethyl) -10H-phenothiazine, is marketed under the trademark STELAZINE®. STELAZINE® is indicated for the management of manifestations of psychotic disorders and for the short-term treatment of generalized non-psychotic anxiety. Physician, s Desk Reference® 3092-2094 (53rd ed., 1999). Tiotixene, whose chemical name is N, N-dimethyl-9- [3, (4-methyl-1-piperazinyl) -propylidene] thioxanten-2-sulfonamide is sold under the name NAVANE®. NAVANE® is indicated in the management of manifestations of psychotic disorders. Physician's Desk Reference® 2396-2399 (53rd ed., 1999). Clozapine, whose chemical name is 8-chloro-ll- (4-methyl-1-piperazinyl) -5H-dibenzo [b, e] [1,4] diazepine is sold under the name CLOZARIL®. CLOZARIL® is indicated for the management of severely ill schizophrenic patients who do not respond adequately to the treatment of normal anti-psychotic medications. Physician's Desk Reference® 2004-2009 (53rd ed., 1999). Haloperidol, whose chemical name is 4- [4- (p-chlorophenyl) -4-hydroxy-piperidonol-4 '-fluorobutyrophenone, is marketed
with the HALDOL® brand. HALDOL® is indicated for use in the management of patients requiring prolonged parenteral anti-psychotic treatment (eg, patients with chronic schizophrenia). Physician's Desk Reference® 2190-2192 (53rd ed., 1999). Loxapine, whose chemical name is 2-chloro-ll- (4-methyl-l-piperazinyl) dibenzo [£., F] [1-4] oxaxepine, is marketed under the trademark LOXITANE®. LOXITANE® is indicated for the management of the manifestations of psychotic disorders. Physician's Desk Reference® 3224-3225 (53rd ed., 1999). Molindone, whose chemical name is 3-ethyl-6,7-dihydro-2-methyl-5- (morpholinomethyl) indole-4 (5H) -one hydrochloride is sold under the name MOBAN®. MOBAN® is indicated for the management of manifestations of psychotic disorders. Physician's Desk Reference® 978-979 (53rd ed., 1999). Pimozide, whose chemical name is 1- [1- [4,4-bis (4-fluorophenyl) butyl] 4-piperidinyl] -1,3-dihydro-2H-benzimidazol-2-one, is marketed under the tradename ORAP ®. ORAP® is indicated for the suppression of motor and phonic tics in patients with Tourette's disorder who have failed to respond satisfactorily to normal treatment. Physician's Desk Reference® 1054-1056 (53rd ed., 1999). Risperidone, whose chemical name is 3- [2- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -6, 7,8,9-
tetrahydro-2-methyl-4H-pyrido [1, 2-a] pyrimidin-4-one is marketed under the trademark RISPERDAL®. RISPERDAL® is indicated for the management of the manifestations of psychotic disorders. Physician's Desk Reference® 1432-1436 (53rd ed., 1999). The desipramine hydrochloride salt, whose chemical name is 5H-dibenz [bf] azepin-5-propamin-10, 11-dihydro-N-methyl-monohydrochloride, is marketed under the trademark NORPRAMIN®. NORPRAMIN® is indicated for the treatment of depression. Physician's Desk Reference® 1332-1334 (53rd ed., 1999). Disorders that can be treated or prevented using a racemic or optically pure metabolite of sibutramine, or a pharmaceutically acceptable salt, solvate or clathrate thereof, in combination with an anti-psychotic compound, and particularly a tricyclic anti-psychotic compound include , but not limited to, affective disorders (eg, depression), anxiety, eating disorders and disorders of brain function (eg, schizophrenia) such as those described herein. The invention further comprises methods of use and pharmaceutical compositions containing a racemic or optically pure metabolite of sibutramine, or a pharmaceutically acceptable salt, solvate or clathrate thereof, in combination with a 5-HT? A receptor antagonist and / or a
ß-adrenergic antagonist. Examples of the 5-HTiA receptor antagonists and the β-adrenergic antagonists that can be used in the methods and compositions of the invention include, but are not limited to: alprenolol WAY 100135; spiperone; pindolol, (S) -UH-301; penbutolol, propranolol, tertatolol; a compound of the formula I as described in U.S. Patent No. 5,552,429, which is incorporated herein by reference, the pharmacologically active metabolites and stereoisomers thereof and the salts, solvates and clathrates acceptable for pharmaceutical use thereof. Alprenolol, whose chemical name is 1- (1-methylethyl) -3-amino- [2- (2-propenyl) phenoxy] -2-propanol, is described in US Pat. No. 3,466,325, which is incorporated herein by reference. present as a reference. WAY 100135, whose chemical name is N- (t-butyl) -3- [4- (2-methoxyphenyl) -piperazin-1-yl] -2-phenylpropanamide, is described in U.S. Patent No. 4,998,814, which is incorporated herein by reference. incorporated herein as a reference. See, also Cliffe, et al., J. Med. Chem. , 36: 1509-1510 (1993). Spiperone, whose chemical name is 8- [4- (4-fluorophenyl) -4-oxobutyl] -1-phenyl-1,3,8-triazaspiro [4,5] decan-4-one), is described in the Patents US Nos. 3,155,669, and 3,155,670, which are incorporated herein by reference. See also, Middlmiss et al., Neurosci. and
Biobehav. Rev., 16: 75-82 (1992). Pindolol, whose chemical name is 4- (2-hydroxy-3-isopropylaminopropoxy) -indole, is described in the patent
No. 3,471,515, which is incorporated herein by reference. See also Dreshfield et al.,
Neuroche,. Res. , 21 (5): 557-562 (1996). (S) -UH-301, whose chemical name is (S) -5-fluoro-8-hydroxy-2-dipropylamino-tetralin), is well known to pharmacological and pharmaceutical chemists. See, for example, Hillyer et al., J. Med. Chem. 33: 1541-44 81990) and
Moreau et al., Brain Res. Bull. 29: 901-04 (1992). Penbutolol, whose chemical name is (1- (t-butylamino) -2-hydroxy-3- (2-cyclopentyl-phenoxy) propane), is marketed under the brand LEVATOL®, LEVATOL® is indicated for the treatment of mild arterial hypertension a moderate.
Physician's Desk Reference® 2908-2910 (53rd ed., 1999). The hydrochloride salt of propranolol, whose chemical name is l-isopropylamino-3- (1-naphthalenyloxy) -2-propanol hydrochloride, is marketed under the brand name INDERAL®. INDERAL® is indicated in the management of hypertension. Physician 's Desk
Reference® 3308-3309 (53rd ed. 1999). Tertatolol, chemical name 8- (3-t-butylamino-2-hydroxypropyloxy) -thiochroman, is described in US Patent No. 3,960,891, which is incorporated herein by reference.
Disorders that can be treated or prevented using a racemic or optically pure metabolite of sibutramine, or a pharmaceutically acceptable salt, solvate or clathrate thereof, in combination with a 5-HT? A receptor antagonist, include, but are not limited to, depression, obsessive-compulsive disorders, eating disorders, hypertension, migraine, essential tremor, subaortic hypertrophic stenosis and pheochromocytoma. A specific disorder that can be treated or prevented is post-traumatic depression disorder. Disorders that can be treated or prevented using a racemic or optically pure metabolite of sibutramine or a pharmaceutically acceptable salt, solvate or clathrate thereof, in combination with a β-adrenergic antagonist include, but are not limited to, depression subsequent to myocardial infarction. Specific β-adrenergic antagonists include, but are not limited to, S (-) pindolol, penbutolol, and propranolol. The invention further comprises methods of use and pharmaceutical compositions containing a racemic or optically pure metabolite of sibutramine or a pharmaceutically acceptable salt, solvate or clathrate thereof, in combination with non-benzodiazepine or non-tricyclic agents. Examples of these additional pharmacologically active compounds include, but are not limited to:
olanzapine, buspirone, hydroxyzine, tomoxetine, the pharmacologically active metabolites and stereoisomers thereof and the pharmaceutically acceptable salts, solvates, clathrates acceptable for these. Olanzapine, whose chemical name is 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thien [2, 3-b] [1,5] benzodiazepine, is marketed under the trademark ZYPREXA®. ZYPREXA® is indicated for the management of manifestations of psychotic disorders. Physician's Desk Reference® 1641-1645 (53rd ed., 1999). The hydrochloride salt of buspirone, whose chemical name is 8- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -8-azaspiro- [4.5] decan-7, 9-dione monohydrochloride, is marketed with the BUSPAR® brand. BUSPAR® is indicated for the management of anxiety disorders or short-term relief of anxiety symptoms. Physician's Desk Reference® 823-825 (53rd ed., 1999). The hydroxyzine hydrochloride salt, whose chemical name is 1- (p-chlorbenzydril) -4 [2- (2-hydroxyethoxy) -ethyl] piperazine dihydrochloride, is sold under the trademark ATARAX®. ATARAX® is indicated by the symptomatic relief of anxiety and tension associated with psychoneurosis and as a coadjuvant in organic disease states in which anxiety is manifested. Physician's Desk Reference® 2367-2368 (53rd ed., 1999).
Disorders that can be treated or prevented using a racemic or optically pure metabolite of sibutramine or a pharmaceutically acceptable salt, solvate or clathrate thereof, in combination with a compound selected from the group consisting of lorazepa, tomoxetine, olanzapine, repiradone, buspirone, hydroxyzine, valium, active metabolites and stereoisomers for pharmacological use thereof, and salts, solvates, clathrates acceptable for pharmaceutical use thereof, include, but are not limited to, anxiety disorders, depression, hypertension, and deficiency in the attention Although all combinations of the racemic or optically pure metabolites of sibutramine, or a pharmaceutically acceptable salt, solvate or clathrate thereof, and one or more of the pharmacologically active compounds described above may be useful and valuable, certain combinations are particularly preferred. . Examples of the preferred combinations include those in which a racemic or optically pure metabolite of sibutramine, or a pharmaceutically acceptable salt, solvate or clathrate thereof is combined with one of the following:
alprazolam; quazepam; alprenolol; brotizolam; temazepam; WAY 100135; chlordiazepox.de; triazolam; spiperone; clobazaxp; chlorpromazine; S (-) - pi ?? dolol; clonazcpam; csoridazine; R (+) - pindolol; clorazepacic; thioridazine; racemic pindolol; demoxepam; acetophenazine; (SJ-UH-301; diazepam; fluphenazine; penbutolol; estazolam; pcrp enazine; propranolol; I flumazenil; trifluoperazine; tertatolol; flurazqpam; chlorprothixene; desipramine; halazepam; thiothixepe; clonidine; lorazepam; clozapine; olanzapine; midazolam; haloperidol; methylphenidate; picatrapani; loxapinc; buspirone; nordazepam; molindon; hydroxyzine; and oxazepam; pimozide; tomoxetine. prazepam; risperidone;
4. 1 SYNTHESIS OF SIBUTRAMINE METABOLITES Racemic sibutramine, desmethylsibutramine and didesmethylsibutramine can be prepared by methods known to those skilled in the art. See, for example, U.S. Patent No. 4,806,570, which is incorporated herein by reference; J. Med. Chem. 2540 (1993) (tosilation and azide replacement); Butler, D., J. Org. Chem. , 36: 1308 (1971) (cycloalkilation in DMSO); Tetrahedron Lett., 155-58 (1980) (Grignard addition to
nitrile in benzene); Tetrahedron Lett, 857 (1997) (OH to azide) and Jeffery, J. E., et al., J. Chem. Soc. Perkln. Trans 1, 2583 (1996). A preferred method of preparation of racemic sibutramine is provided below in Example 1. Racemic sibutramine, desmethylsibutramine and didesmethylsibutramine can be prepared one from the other, as well as the optically pure forms of the compounds. Preferred methods of preparing the compounds one from the other are provided below in Examples 2, 3 and 8. The optically pure enantiomers of sibutramine and its metabolites can be prepared using known techniques. A preferred technique is the resolution by fractional crystallization of the diastereomeric salts that are formed with optically active resolving agents. see, for example, "Enantiomers, Racemates and Resolutions," by J. Jacques, A. Collet, and S. H. Wilen, (Wiley-Interscience, New York, 1981); S. H. Wilen, A. Collet and J. Jacques, Tetrahedron, 2725 (1997); E. L. Eliel Stereochemistry of Coal Compounds (McGraw-Hill, NY, 1962); S. H. Wilen Tables of resolving agents and optical resolutions 268 (E. L. Eliel et al., Univ. Of Notre Dame Press, Notre Dame, IN, 1972). Because sibutramine, desmethylsibutramine and didesmethylsibutramine are basic amines, the salts
The diastereomers of these compounds which are suitable for separation by fractional crystallization are easily formed by the addition of the optically pure acid or chiral resolving agents. Suitable resolving agents include, but are not limited to, tartaric acid, optically pure, camphorsulfonic acid, mandelic acid and derivatives thereof. The optically pure isomers of sibutramine, desmethylsibutramine and didesmethylsibutramine can be recovered from the crystallized diastereomer or mother liquor, depending on the solubility properties of the particular acidic resolving agent that is employed and the particular acid enantiomer that is used. The identity and optical purity of the particular sibutramine or the isomer of the sibutramine metabolite thus recovered can be determined by polarimetry or other analytical methods. The racemic and optically pure metabolites of sibutramine are preferably synthesized directly by methods such as those described by Jeffery, J. E. et al., J. Chem. Soc. Perkin. Trans 1, 2583 (1996). A preferred method for directly synthesizing racemic desmethylsibutramine • consists in the reduction of cyclobutanecarbonitrile (CCBC) to form an aldehyde intermediate which is subsequently reacted with an amine such as, but not limited to, methylamine. This method is applied later in
Example 4. Another preferred method for directly synthesizing racemic desmethylsibutramine is the reaction of CBBC with a compound of the formula i-BuMX; wherein X is Br or I and M is selected from the group consisting of Li, Mg, Zn, Cr and Mn. Preferably, the compound is of the formula i-BuMgBr. This reaction produces a product that is subsequently reduced, it becomes an intermediate consisting of an aldehyde attached to the nitrogen atom, whose intermediate is finally converted to desmethylsibutramine in a step comprising the addition of a Lewis acid. Preferred Lewis acids are selected from the group consisting of BH3-THF, BF3-THG, La (0-i-Pr) 3, Zr (0-i-Pr) 4, Ti (Oi-Pr) 2C12, SnCl Y MgBr2OEt2. a more preferred Lewis acid is BH3-THF. This method is applied later in Example 5.
The enantiomers of desmethylsibutramine can be resolved by the formation of chiral salts as described above. Preferred chiral acids used to form the chiral salts include, but are not limited to, tartaric and mandelic acids. If tartaric acid is used, preferred solvent systems include, but are not limited to, ethanol / water and isopropyl alcohol / water. If mandelic acid is used, a preferred solvent system is ethyl acetate / hexane. The resolution of desmethylsibutramine is shown below in
Examples 6 and 7. A preferred method for directly synthesizing racemic didesmethylsibutramine consists in the reaction of CCBC with a compound of the formula i-BuMx, wherein X is Br or I, and M is selected from the group consisting of Li, Mg , Zn, Cr and Mn. Preferably, the compound is of the formula i-BuMgBr. The product of this reaction is then reduced under convenient reaction conditions *. The application of this method is shown below in Example 9. The enantiomers of didesmethylsibutramine can be resolved by the formation of chiral salts, as described above. Preferred chiral acids which are used to form the chiral salts include, but are not limited to, tartaric acid. Preferred solvent systems include, but are not limited to, acetonitrile / water / methanol and acetonitrile / methanol. The resolution of didesmethylsibutramine is shown below in Examples 11 and 12.
4. 2 PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE The magnitude of a prophylactic and therapeutic dose of an active ingredient in the acute or chronic management of a disorder or condition will vary with the severity of the disorder or condition to be treated and the route of administration. The dose, and maybe the frequency of the
dose, will also vary according to the patient's age, body weight, response and medical history. Those skilled in the art will readily select suitable dosing schemes with due consideration to these factors. Convenient daily doses for the treatment or prevention of a condition described herein can easily be determined by one skilled in the art. A recommended dose of a racemic or optically pure metabolite of sibutramine is from about 0.1 mg to about 60 mg per day, given as a single dose once a day in the morning or as a divided dose during the day. Preferably, a daily dose is from about 2 mg to about 30 mg per day, more preferably from about 5 mg to about 15 mg per day. Convenient daily dose ranges for additional pharmacologically active compounds that can be administered as adjuvants with a racemic or optically pure metabolite of sibutramine can be readily determined by those skilled in the art following the dosages reported in the literature and recommended in the Physician. s Desk Reference® (53rd ed. 1999). For example, the daily dose ranges
Convenient 5-HT 3 antagonists can be readily determined by those skilled in the art and will vary depending on factors such as those described above and the particular 5-HT 3 antagonists that are used. In general, the total daily dose of a 5-HT3 antagonist for the treatment or prevention of a disorder described herein is from about 0.5 mg to about 500 mg, preferably from about 1 mg to about 350 mg, and more preferably from about 2 mg to about 200 mg per day. Therapeutic or prophylactic administration of an active ingredient of the invention is preferably initiated at lower doses, for example from about 2 mg to about 8 mg of the sibutramine metabolite and optionally from about 15 mg to about 60 mg of the 5-HT3 antagonist, and it is increased, as necessary, up to the recommended daily dose as a single dose or as divided doses, depending on the general response of the patient. It is further recommended that patients over the age of 65 years should receive doses of the sibutramine metabolite in the range of about 5 mg to about 30 mg per day, depending on the overall response. It may be necessary to use dosages outside these ranges, which will be easily determined by an expert in the
pharmaceutical technique. The dosage amounts and frequencies provided in the above are comprised by the terms "effective for therapeutic use", "effective for prophylactic use" and "effective for therapeutic or prophylactic use" when used herein. When used in connection with an amount of a racemic or optically pure metabolite of sibutramine, these terms further comprise an amount of the racemic or optically pure metabolite which induces minor less serious adverse effects that are associated with the administration of racemic sibutramine. Adverse effects associated with racemic sibutramine include, but are not limited to, significant increases in heart rate in the supine and standing position, including tachycardia, increased blood pressure (hypertension), increased psychomotor activity, dry mouth, dental caries, constipation, hypohidrosis, blurred vision, tension, mydriasis, convulsions, formation of gallstones, renal / hepatic dysfunction, fevers, arthritis, agitation, leg cramps, hypertonia, abnormal thoughts, bronchitis, dyspnea, pruritus, amblyopia, menstrual disorder, disorders of ecchymosis / hemorrhage, interstitial nephritis and nervousness. See, for example, Physician's Desk Reference® 1494-1498 (53rd ed., 1999).
The administration as adjuvant of two or more active ingredients according to the methods of the invention may be concurrent, in sequence or both. For example, a dopamine reuptake inhibitor and a 5-HT 3 antagonist can be administered as a combination, concurrently or separately, or by sequential administration. Any convenient route of administration may be employed to provide the patient with the effective dose for therapeutic or prophylactic use of an active ingredient. For example, it is possible to employ oral, mucosal (eg, nasal, sublingual, buccal, rectal, vaginal), parenteral (eg, intravenous, intramuscular), transdermal and subcutaneous routes. Preferred routes of administration include oral, transdermal and mucosal. As already mentioned, the route of administration of an active ingredient for the treatment or prevention of erectile dysfunction is preferably mucosal or "transdermal." Suitable dosage forms for such routes include, but are not limited to, transdermal patches, solutions Ophthalmic agents, sprays and aerosols The transdermal compositions can also take the form of cream, lotions and / or emulsions, which can be included in a suitable adhesive for application to the skin or can be included in a transdermal patch of the skin.
type of matrix or reservoir as are traditional in the art for this purpose. A preferred transdermal dosage form is a "reservoir type" or "matrix type" patch, which is applied to the skin and used for a specific time to allow the penetration of a desired amount of the active ingredient. For example, if an active ingredient is a metabolite of sibutramine, a preferred patch is used for 24 hours and provides a total daily dose of from about 0.1 mg to about 60 mg per day. Preferably, a daily dose is from about 2 mg to about 30 mg per day, more preferably, from about 5 mg to about 15 mg per day. The patch can be replaced by a fresh patch when necessary to provide constant administration of the active ingredient to the patient. Other dosage forms of the invention include, but are not limited to, tablets, dragees, troches, dispersions, suspensions, suppositories, ointments, cataplasms, pastes, powders, dressings, creams, plasters, solutions, capsules, soft elastic gelatin capsules. and patches. In one embodiment, the pharmaceutical compositions and dosage forms of the invention contain a dopamine reuptake inhibitor, such as
racemic or optically pure metabolite of sibutramine, or a pharmaceutically acceptable salt, solvate or clathrate thereof, and optionally, an additional pharmacologically active compound such as a 5-HT3 antagonist. Preferred racemic or optically pure metabolites of sibutramine are (+) -desmethylsibutramine (-) - desmethylsibutramine, (±) -desmethylsibutramine, (+) - didesmethylsibutramine, (-) -didesmethylsibutramine, and (±) -didesmethylsibutramine. The pharmaceutical compositions and dosage forms may contain an acceptable carrier for pharmaceutical use and optionally other therapeutic ingredients known to those skilled in the art. In practical use, the active ingredient may be combined in an intimate mixture with a pharmaceutical carrier according to the traditional pharmaceutical composition techniques. The carrier can take a wide variety of forms, depending on the form of preparation desired for administration. During the preparation of the compositions for an oral dosage form, it is possible to employ any of the normal pharmaceutical media as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations (such as suspensions, solutions and elixirs) or aerosols; or carriers like starches,
sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents can be used in the case of oral solid preparations, preferably without employing the use of lactose. For example, suitable carriers include powders, capsules and tablets, with solid oral preparations being preferred over liquid preparations. Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are employed. If desired, the tablets may be coated by normal aqueous or non-aqueous techniques. In addition to the common dosage forms set forth above, it is also possible to administer an active ingredient by controlled release means or delivery devices that are well known to those skilled in the art, such as those described in US Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556 and 5,733,566, the descriptions of which are incorporated herein by reference. These dosage forms can be used to provide slow or controlled release of one or more active ingredients using, for example,
hydropropylmethylcellulose [sic], other polymeric matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes or microspheres or a combination thereof to provide the desired release profile in different proportions. Suitable controlled release formulations known to those skilled in the art, including those described herein, can be readily selected for use with pharmaceutical compositions of the invention. The invention thus comprises individual unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelatin capsules and lozenges which are adapted for controlled release. All controlled release pharmaceutical products have a common goal of improving drug treatment over that obtained by their non-controlled counterparts. Theoretically, the use of a controlled release preparation optimally designed in medical treatment is characterized by a minimum of drug substance used to cure or control the condition in a minimum amount of time. The advantages of controlled release formulations include: 1) prolonged activity of the medicament; 2) reduction in the frequency of the dose; and 3) greater comfort
for the patient. In addition, it is possible to use controlled release formulations to affect the time of onset of action or other characteristics, such as blood concentrations of the drug and thus affect the occurrence of side effects. Most controlled release formulations are designed to initially release a quantity of medicament that rapidly produces the desired therapeutic effect, and gradually and continuously release other amounts of medicament to maintain this concentration, of the therapeutic effect for a prolonged time. In order to maintain this constant concentration of medication in the body, the medication must be released from the dosage form at a rate that replaces the amount of medication that is being metabolized and excreted from the body. The controlled release of an active ingredient can be stimulated by different inducers including, but not limited to, pH, temperature, enzymes, water or other physiological conditions or compounds. The pharmaceutical compositions of the invention suitable for oral administration can be presented as a small dosage form, such as capsules, dragees or tablets or aerosol sprays each containing a predetermined amount of an active ingredient as a powder
or in granules, a solution or suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. These dosage forms can be prepared by any of the methods of the pharmacy, but all methods include the step of placing the active ingredient in association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a convenient machine the active ingredient in a free-flowing form as a powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent and / or an agent with activated or dispersing surface. The molded tablets can be prepared by molding in a convenient machine a mixture of the powdered compound moistened with an inert liquid diluent. This invention also comprises the compositions
pharmaceuticals and lactose-free dosage forms. Lactose is used as an excipient in sibutramine formulations. See, for example, Physician's, Desk Reference® 1494 (53rd ed., 1999). However, unlike the precursor drug, desmethylsibutramine and didesmethylsibutramine are secondary and primary amines, respectively, and thus potentially can decompose with time when exposed to lactose. Thus, compositions of the invention containing sibutramine metabolites preferably contain little, if any, mono or disaccharides of lactose. When used herein, the term "lactose-free" means that the amount of lactose present, if any, is insufficient to substantially increase the rate of degradation of the active ingredient. The lactose-free compositions of the invention may contain excipients that are well known in the art and are mentioned in USP (XXI) / NF (XVI), which are incorporated herein by reference. In general, the lactose-free compositions comprise an active ingredient, a binder / filler and a lubricant in amounts acceptable for pharmaceutical use and compatible with pharmaceutical use. Preferred lactose-free dosage forms comprise an active ingredient, microcrystalline cellulose, pregelatinized starch and
magnesium stearate. This invention further comprises anhydrous pharmaceutical compositions and dosage forms containing an active ingredient, since water can facilitate the degradation of some compounds, for example, the addition of water (eg, 5%) is widely accepted in the art. Pharmaceutical technique as a means to stimulate long-term storage in order to determine the characteristics such as shelf life or the stability of the formulations over time. See, for example, Jens, T. Carstensen, Drug Stability: Principies & Practice, 2nd ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and heat accelerate decomposition. Thus, the effect of water in a formulation can be of great importance since during the manufacturing, packaging handling, storage, shipping and use of the formulations moisture is usually found. The anhydrous pharmaceutical compositions and the dosage forms of the invention can be prepared using anhydrous ingredients or containing low moisture and low humidity conditions. The pharmaceutical compositions and dosage forms of the racemic or optically pure metabolite of sibutramine containing lactose are preferably anhydrous if substantial contact with moisture is expected during manufacture, packaging and / or
storage . An anhydrous pharmaceutical composition should be prepared and stored so that its anhydrous nature is maintained. Accordingly, the anhydrous compositions are preferably packaged using known materials to avoid exposure to water so that they can be included in convenient formulation kits. Examples of convenient packaging include, but are not limited to, hermetically sealed sheets, plastic and the like, unit dose containers, blister or blister packs, and strip packages. In this regard, the invention comprises a method of preparing a solid pharmaceutical formulation containing an active ingredient whose method comprises mixing under anhydrous or low-moisture conditions the active ingredient and an excipient (eg, lactose), wherein the ingredients are practically in water. The method may further comprise packaging the solid formulation anhydrous or non-hygroscopic under low humidity conditions. By using such conditions, the risk of contact with water is reduced and the degradation of the active ingredient can be substantially avoided or reduced. Convenient binders for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural gums and
synthetics such as acacia, sodium alginate, alginic acid, other alginates, tragacanth powder, guar gum, cellulose and their derivatives (for example, ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methylcellulose, (for example, Nos. 2208, 2906, 2910), microcrystalline cellulose and mixtures thereof. Suitable microcrystalline cellulose forms include, for example, materials marketed as
AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581 and AVICEL-PH-105
(available from FMC Corporation, American Viseóse Division,
Avicel Sales, Marcus Hook, EU.). A convenient, exemplary binder is a mixture of microcrystalline cellulose and commercialized sodium carboxymethylcellulose as AVICEL-RC-581. Suitable anhydrous or low moisture excipients or additives include, AVICEL-RC-103® and 1500 LM starch. Examples of suitable filler materials for use in the pharmaceutical compositions and dosage forms described herein include, but are not limited to, talcum, calcium carbonate, (eg, granules or powders), microcrystalline cellulose, powdered cellulose , dextrose, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch and mixtures thereof. He
binder / filler in the pharmaceutical compositions of the present invention is normally present in about 50 to about 99% by weight of the pharmaceutical composition. Disintegrators are used in the compositions of the invention to provide tablets that degrade when exposed to an aqueous environment. Too much disintegrant will produce tablets that can disintegrate in the bottle. Too little may be insufficient for disintegration to occur and thus may alter the rate and degree of release of the active ingredient (s) from the dosage form. Thus, a sufficient amount of the disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient (s) should be used for the dosage forms of the compounds described herein. The amount of the disintegrant used varies based on the type of formulation and the mode of administration, and can be readily ascertained by one skilled in the art. Usually, about 0.5 to about 15% by weight of disintegrant, preferably about 1 to about 5% by weight of disintegrant can be used in the pharmaceutical composition. The disintegrants that can be used to form the pharmaceutical compositions and the dosage forms of
the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, glycolate sodium starch, potato starch or tapioca, other starches, pregelatinized starch, other starches, clays, other algin, other celluloses, gums or mixtures thereof. Lubricants that can be used to form the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talcum, hydrogenated vegetable oil (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and bean oil) soy), zinc stearate, ethyl oleate, ethyl laurate, agar or mixtures thereof. Additional lubricants include, for example, siloid silica gel (AEROSIL 200, manufactured by W. R. Grace Co. of
Baltimore, MD), a synthetic silica coagulated aerosol
(marketed by Degussa Co. of Plano, Texas), CAB-O-SIL
(a pyrogenic silicon dioxide product marketed by Cabot Co. of Boston, Mass.), or mixtures thereof. As an option, it is possible to add a lubricant, usually in.
an amount of less than about 1% by weight of the pharmaceutical composition. Dosage forms of the invention containing a metabolite of sibutramine preferably contain from about 0.1 mg to about 60 mg of the metabolite or pharmaceutically acceptable salt, solvate or clathrate thereof. For example, each tablet, dragee or capsule contains from about 0.1 mg to about 60 mg of the active ingredient. More preferably, the tablet, dragee or capsule contains one of three doses, for example, about 10 mg, about 20 mg or about 30 mg of the racemic or optically pure metabolites of sibutramine,
(such as lactose-free tablets with registration, preferable dosage form). The invention is further defined by reference to the following examples. It will be apparent to those skilled in the art that multiple modifications to materials and methods can be practiced without departing from the scope of this invention.
. EXAMPLES Examples 1-2 describe the preparation of racemic or optically pure sibutramine. Examples 3-8 describe the preparation of the forms
racemic and optically pure of desmethylsibutramine (DMS). In each of these examples, the enantiomeric purity of DMS was determined using a Chirobiotic V analytical column (10 μ, 4.6 mm x 25 mm) with 20 mM ammonium acetate / IPA (65:35) as the mobile phase. The UV detector was established with a wavelength of 222 nm. Examples 9-12 describe the preparation of the racemic and optically pure forms of didesmethylsibutramine (DDMS). In each of these examples, the enantiomeric purity of DDMS determined using a ULTRON ES-OVM analytical column (150 mm x 4.6 mm) with 0.01 M KH2P04 / MeOH (70:30), as the mobile phase. The UV detector was established with a wavelength of 200 nm. Examples 13-14 describe the methods for determining the binding affinities of the compounds of the invention and the binding affinities measured using these methods. Finally, Example 15 describes oral formulations containing the compounds of the invention.
. 1 EXAMPLE 1: SYNTHESIS OF SIBUTRAMINE Synthesis of 1- (4-chlorophenyl) cyclobutanecarbonitrile To a suspension of NaH (17.6 g 60%, washed with hexane) in dimethylsulfoxide (150 ml) at room temperature with mechanical stirring was added over a period of one hour a mixture of chlorbenzyl nitrile [sic] (30.3 g) and 1.3-
dibromopropane (22.3 ml, 44.5 g). The reaction mixture was stirred for an additional 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 t-butylmethyl ether (MTBE) (2 x 200 ml), and the combined extracts were washed with water (3 x 200 ml), brine and dried over MgSO4. The solvent was removed in a rotary evaporator and the final product was purified by distillation to obtain the title compound (22 g, 56% as a pale yellow oil, p.b. 110-120 ° C / 1.0 mm Hg. was characterized by 1 H-NMR.
Synthesis of 1- [(4-chlorophenyl) cyclobutyl] -3-methylbutylamine A solution of isobutyl magnesium bromide (2M, 108 ml) in diethyl ether (Aldrich) was concentrated to remove most of the ether. The residue was dissolved in toluene
(150 ml). Followed by addition of nitrile prepared before (22 g). The reaction mixture was heated at 105 ° C for 17 hours. The reaction mixture was cooled to room temperature and added to a slurry of NaBH in isopropyl alcohol (450 ml). The reaction mixture was heated to reflux for 6 hours, cooled to room temperature and concentrated. The residue was diluted with water (350 ml), and extracted with ethyl acetate (3 x 200 ml). The extracts
combined were washed with water (100 ml), and dried (MgSO) and concentrated to obtain 24.2 g of crude product (83%).
Synthesis of the sibutramine free base 1- [(4-chlorophenyl) cyclobutyl] -3-methylbutylamine (21.6 g) was added to formic acid (27 ml) and aqueous formaldehyde (46 ml). The reaction mixture was heated at 85-95 ° C for 18 hours and cooled to room temperature. 30% NaOH was added until the mixture was basic (pH > 11). The solution was extracted with chloroform (3 x 200 ml) and the extracts were combined and washed with water and brine and concentrates to obtain 15 g of the product.
HCl sibutramine The free base of sibutramine (2.25 g) was dissolved in MTBE (20 ml) and this solution was added to 20 ml of 1 M HCl in diethyl ether. The reaction mixture was stirred for 30 minutes, and the solid was collected by filtration to obtain 1.73 g after drying. The product was characterized by XH NMR.
Resolution of sibutramine 12.3 g of racemic sibutramine were dissolved in
ethyl acetate (85 ml), and to this was added a solution of 21.7 g of L-dibenzyltartaric acid ("L-DBTA") in ethyl acetate (85 ml). The reaction mixture was heated to reflux and cooled to room temperature. The white precipitate was collected (salt ee is ca 85%). The solid was then suspended in 220 ml of ethyl acetate and heated to reflux for 30 minutes. The solid was collected to obtain > 95% us The salt was further crystallized from isopropyl alcohol (450 ml) to obtain 11.3 g of the salt with > 99.3% ee (-) -sibutramine L-DBTA (76% yield). The free base was obtained by treating the salt with aqueous NaHC03, saturated and extracted with chloroform. The HCl salt of (-) -sibutramine was obtained with treatment of the free base with HCl / Et20 as already described. The optical rotation of the HCl salt was [a] = 3.15 (c = 0.9, H20), ^ NMR 13C
(CD3OD), and M + = 279. The mother liquor of the resolution was treated with NaOH to obtain the partially enriched (+) -sibutramine and was then treated with D-DBTA as and described to obtain the salt (+) -sibutramine -D-DBTA with > 99.3% ee The sibutramine enantiomers were characterized by 1H and 12C NMR: M + = 279. The material was also characterized by HPLC and chiral HPLC.
. 2. EXAMPLE 2. SIBUTRAMINE FROM ITS METABOLITES Racemic and optically pure sibutramine was also prepared by methylation of desmethylsibutramine or dimethylation of didesmethylsibutramine under convenient reaction conditions. An example of this method is shown in Scheme 1.
()) -or (S DDMSor (A) - or (S) -Sibutramne (? or (5 DMS DDMS: R? ~ R2 «H DMS: R, -H; R2» CH3 Scheme 1
. 3. EXAMPLE 3. DESMETILSIBUTRAMINE FROM SIBUTRAMINE
(-) -Sibutramine (1.25 g) was dissolved in toluene (90 ml) and diethylazo dicarboxylate ("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 was heated at 50 ° C for another 6 hours, cooled to room temperature and the toluene was removed in vacuo. The residue was suspended in 45 ml of ethanol and 45 ml of aqueous, saturated NHC1. The reaction mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and concentrated to remove ethanol.
The aqueous NaHC03 was added until the concentrate was basic. The basic concentrate was extracted with dichloromethane, (3 x 50 ml). The extracts were combined, dried with sodium sulfate, filtered and concentrated to obtain a crude product. Flash column chromatography (Si02) (ethyl acetate / TEA 99: 1) gave 0.43 g of product. This was characterized by 1H and 13C NMR, M + = 266, and optical rotation [a] = -10.6, c = 3.3, (CHC13). The other enantiomers and racemates were prepared in the same way and the isomer was characterized as the (-) -isomer.
Synthesis of desmethylsibutramine hydrochloride isomers To a solution of (-) - demethylsibutramine (0.78 g) in ethyl acetate (5 ml) at 0 ° C was added HCl / diethyl ether (1 M, 5 ml). The reaction mixture was stirred for one hour and the solid was collected by filtration. The solid was then dried to obtain 0.68 g of a white solid. The product was characterized by 1 H and 13 C NMR (DMSO-d 6), and a chemical purity of > 99% [ce] = -5 °) c = 0.5, H20). The racemate and the other enantiomer was prepared and characterized in the same manner.
. 4. EXAMPLE 4. (R / S-DEMETILSIBUTRAMINE) Another method of preparation of racemic desmethylsibutamine ((J./S) -DMS is shown in Scheme 2 and is described
in more detail later:
(? 5J-DMS
Scheme 2
Preparation of 1- (4-chlorophenyl) -1-cyclobutyl carboxaldehyde Following in Scheme 2, diisobutylaluminum hydride (DIBAL-H) (87 ml, 1 M in THF, 87.0 mmol) was added to a solution of 1- (4- chlorophenyl) cyclobutanecarbonitrile (CCBC, 10 g, 52.1 mmol) which was maintained at -20 ° C. The resulting mixture was stirred for 4-5 hours at 0 ° C and then 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) and the combined organic layers were dried over MgSO and concentrated to obtain 9 g (89%) of the above title aldehyde as an oil. 1H NMR (CDC13) d 9.52 (s, 1H), 7.35-7.06 (m, 4H), 2.77-2.68 (m, 2H), 2.43-2.32 9m, 2H), 2.06-1.89 (m, 2H). 13C NMR d 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-cyclobutyl carboxaldehyde (3 g, 15.4 mmol) and methylamine (12 mL, 40% aqueous w / w , 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 K2C03 and concentrated to obtain 2.5 g (78%) of the imine from the previous title as an oil. 1H NMR (CDC13) d 7.65 (m 1 H), 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); 3C NMR d 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-methylcarbaimine (0.5 g, 2.4 mmol) cooled to 0 ° C was added BF3 * Oet2 (0.34 g, 2.4 mmol). The mixture was stirred for one hour and then cooled to -78 ° C. At this temperature, isobutyl magnesium bromide (2.5 ml, 2M in ether, 5 mmol) was added to form a mixture which was stirred at -78 ° C for 2 hours and then warmed to room temperature and stirred overnight. The reaction was quenched with saturated NaHCO 3 solution (10 ml) and
diluted with MTBE (15 ml). The organic layer was dried over MgSO0, concentrated and purified by chromatography on silica gel (eluting with 1% NEt3 in ethyl acetate) to obtain 380 mg of the amine of the above title as an oil.
. 'HNMR (CDC13) d 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, IH). llC NMR d 144.7, 131.3, 129.1, 127.4, 65.5, 51.7, 1.4, 37.4, 33.7, 32.3, 25.4, 24.0, 22.0, 16.3.
. 5. EXAMPLE 5. (R / S) -DESMETILSIBUTRAMINE-HC1 A method of preparation of the racemic desmethylsibutramine hydrochloride salt ( {R / S) DMS-HCl) is shown in Scheme 3:
Scheme 3
Following Scheme 3, toluene (150 ml) and a solution of CCBC (50.0 g, 261 mmol) in toluene (45 ml) were added to a solution of isobutyl magnesium bromide in THF (392 ml, IM in THF, 392 mmol ). The resulting mixture was distilled until the -international temperature reached 105-110 ° C and was then refluxed in this temperature range for 2-4 hours. The reaction mixture was then cooled to 0 ° C and quenched with methanol (295 ml). NaBH (11 g, 339 mmol) was added in portions over 15 minutes to the reaction mixture at 0 ° C. After stirring for 15 minutes, the reaction mixture was transferred to a 2N aqueous solution of HCl (365 ml). The organic phase was distilled until the internal temperature reached 105 ° C, and then it was allowed to cool to room temperature. Then formic acid (24 g, 522 mmol) was added to the reaction temperature, which was then heated to reflux (92-96 ° C) for 6-8 hours after which time the reaction mixture was distilled until that the internal temperature reached 108 ° C. The mixture was then cooled to 10 ° C and BH3-THF (653 mL, 1.0, 653 mmol) was added. The resulting mixture was heated to reflux (69 ° C) for 15 hours.
The mixture was then cooled to 5 ° C, combined with methanol
(105 ml) and refluxed again for 45 minutes.
The reaction mixture was distilled until the internal temperature reached 11 ° C, and then it was allowed to cool to 25 ° C. Acid
Hydrochloric acid in MTBE (373 g, 18% by weight HCl, 1840 mmol) was then added to the mixture to provide a white slurry which was refluxed for one hour and then filtered to obtain 62.3 g (79.0%) of. { R / S) -DMS- HCl.
NMR (CDC13): 'H (d), 0.85-1.1 (m, 6H), 1.24-1.5 (b, 2H), 1.65-2.14 (b, 4H), 2.2-2.5 (b, 4H), 2.5-2.7 (m, 2H), 3.4-3.6 (b, 1H), 7.3-7.5 (m, 4H), 9.0-9.5 (b, 2H). , 3C (d): 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.
. 6. EXAMPLE 6. (R) -DESMETILSIBUTRAMINE- HCl A method of preparing the hydrochloride salt of. { R) -desmethylsibutramine ( {R) -DMS * HCl) is shown in Scheme 4 and is described in detail below:
of you
(/ Q-DMS- HCl
Scheme 4
Salt formation. { R) -mandelato of. { R) -DMS (R / S) -desmethylsibutramine HCl ( { R / S) -DMS • HCl) (60 g) was added to ethyl acetate (300 ml) and the mixture
The resultant was cooled to 0 ° C. Aqueous NaOH (1.5 N, 300 ml) was then added to the reaction mixture, which was then stirred for 30 minutes. The organic phase was separated, washed with water (150 ml) and concentrated. Then (R) -mandelic acid (30.3 g), ethyl acetate (510 ml total), and heptane (204 ml) were added to the concentrated organic phase. The resulting mixture was then heated to reflux for one hour, after which time it was cooled to 20-23 ° C. Filtration to the resulting slurry yielded 36.4 g (43.8%) of (i?) -mandelate from. { R) -desmethylsibutramine ( { R) -DMS •. { R) -MA; 95.5% ee).
Enrichment of (R) -DMS - (R) -MA A mixture of. { R) -DMS • (R) -MA (30 g, 0.072 mol), ethyl acetate (230 ml), and heptane (230 ml) was heated at reflux for one hour. After cooling to 20-23 ° C, the product was filtered and dried to obtain 29.6 g (98%) of
(J) -DMS-. { R) -MA (99.9% ee).
Formation of the salt HCl of (J.) - DMS A mixture of (R) -DMS • (R) -MA (50 g, 0.12 mol), NaOH (100 ml, 3.0 N) and toluene (500 ml) was stirred for 30 minutes. The organic phase was washed with water (200 ml), concentrated approximately 300 ml, and cooled to room temperature. HC1 / MTBE (100 ml, 14%, 0.34 mol) was then
added slowly to the mixture to form (R) -DMS • HCl. After stirring for 30 minutes, the slurry was filtered and the resulting wet cake was washed twice with MTBE and dried to obtain 34.5 g (95.9%) (R) -DMS-HCl (99.9% ee; 99.9% chemically pure by NMR ).
NMR). NMR (CDClj): 'H (d), 0.85-1.1 (m, 6H), 1.24-1.5 (b, 2H), 1.65-2.14 (b, 4H), 2.2-2.5 (b, 4H), 2.5-2.7 (ra, 2H), 3.4-3.6 (b, 1H), 7.3-7.5 (m, 4H), 9.0-9.5 (b, 2H) .13C (d): 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.
. 7. EXAMPLE 7- (S) -DESMETILSIBUTRAMINE-HC1 A method of preparing the hydrochloride salt of (S) -desmethylsibutramine (S) -DMS-HCl) is shown in Scheme 5 and is described in detail hereinafter:
HCI (S) -DMS- HCI
Scheme 5
Salt formation. { S) -mandelate of (S) -DMS Following Scheme 5, a mixture of was stirred for 30 minutes. { R / S) -DMS • HCl (5.0 g), NaOH (1.5 N, 20 ml) and ethyl acetate (50 ml). 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 combined 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 reflux for 30 minutes and cooled to 20-23 ° C. Filtration of the resulting slurry yielded 0.76 g of the (S) -mandelate salt of (S) -desmethylsibutramine ((S) -DMS * (S) -MA) (96% ee).
Enrichment of (5) -DMS * (S) -M A mixture of was refluxed for one hour. { S) ~ desmethylsibutramine • (S) -mandelate (0.76 g), ethyl acetate
(5 ml) and heptane (5 ml). After cooling to 20-23 ° C, the product was filtered and dried to obtain 0.72 g (95%) of (S) -DMS- (S) -MA (99.9% ee).
Recovery of the salt (S) -mandelate of (5) -DMS from the mother liquor of (5) -DMS-. { R) -MA A solution of (5) -DMS- (i?) -MA in ethyl acetate-heptane (mother liquor 67% ee) was charged with NaOH (3N, 400
ml) and the reaction mixture was stirred for 30 minutes. The organic phase was washed with water and concentrated. The resulting residue (130 g, 0.49 mol and 67% ee) was charged with (5) -mandelic acid (28.5 g, 0.49 mol), ethyl acetate (1400 ml) and heptane (580 ml). The mixture was heated to reflux for one hour and then slowly cooled to room temperature. The resulting slurry was filtered and dried to obtain 147 g (86% based on the (S) isomer) of (S) -DMS- (S) -MA (99.9% ee).
Formation of the HCl salt of (5) -DMS (S) -desmethylsibutramine- (5) -mandelate (20 g, 0.048 mol) was added to a mixture of NaOH (60 ml, 3.0 N) and toluene (200 ml). The mixture was stirred for 30 minutes and the organic phase was then 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 then slowly added to the mixture to form (S) -DMS-HCl. After stirring for 30 minutes, the slurry was filtered and the resulting wet cake was washed twice with MTBE and dried to obtain 14 g (96.7%) of (S) -DMS • (L) -MA (99.9% ee; Chemistry 99.95). NMR (CDC13): XH (d), 0.84-1.1 (m, 6H), 1.25-1.5 (b, 2H), 1.65-2.15 (b, 4H), 2.2-2.5 (b, 4H), 2.5-2.7 ( m, 2H), 3.4-3.6 (b, 1H), 7.3-7.5 (m, 4H), 9.0-9.5 (b, 2H)? 3 C (d): 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.
. 8. EXAMPLE 8. DEMETILSIBUTRAMINE FROM DIDESMETILSIBUTRAMINE Racemic and optically pure diesmethylsibutramine can be prepared by methylation of didesmethylsibutramine under convenient reaction conditions. An example of this method is shown in Scheme 6.
(/.)- or (5) -DDMS- (D) -TA Scheme 6
. 9. EXAMPLE 9. (R / S) -DIDESMETILSIBUTRAMINE 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.
(& $) - DDMS
Scheme 7
Following Scheme 7, a one-liter, three-necked, flat bottom flask was charged with isobutyl magnesium bromide (200 ml, 2.0 M in diethyl ether) and toluene (159 ml) and the resulting mixture was distilled to remove the most of the ether. After the mixture was cooled to 20 ° C, CCBC (50.0 g) in toluene (45 ml) was added, and the resulting mixture was refluxed for 2-4 hours. The reaction mixture was then cooled to 0 ° C and added to this methanol (300 ml), followed by NaBH 4 (11 g) slowly. The resulting mixture was then stirred at about 0-10 ° C for 15 minutes. The reaction mixture was then slowly added to an aqueous solution of HCl (365 ml, 2N) which was maintained at 0 ° C, and the resulting mixture was heated to room temperature with continuous stirring.
After separation of the organic phase, the aqueous phase was washed with toluene (200 ml). The combined organic phases were washed with water (200 ml) and concentrated to obtain (? / 5) -DDMS (55 g, 85%). NMR (CDC1,):? (d), 0.6-0.8 (m, 1H), 0.8-1.0 (ra, 6H), 1.1-1.3 (m, 1H), 1.6-2.6 (m, 7H), 3.0-3.3 (ra, 1H), 7.0 -7.6 (m, 4H) .13C (d): 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.
. 10. EXAMPLE 10. (R / S) -DIDESMETILSIBUTRAMINE- (D) -TARTRATE
A preferred method of preparation of the racemic (D) -DDMS (D) -TA salt (D) -tartrate of racemic didesmethylsibutramine is shown below in Scheme 8. It should be noted that the salt (L ) - racemic didesmethylsibutramine tartrate ( {R / S) -DDMS • (L) -TA) can be prepared in an analogous manner.
(? / S) -DDMS (? ÍS) -DDMS- (D) -TA or (? ÍS) -DDMS- (L) -TA
Scheme 8
Following Scheme 8, a mixture of racemic didesmethylsibutramine (15.3 g) and toluene (160 ml) was heated to 70-80 ° C and added. slowly (D) -tartaric acid (9.1 g) in water (20 ml) and acetone (10 ml). The resulting mixture was refluxed for 30 minutes, after which water and acetone were distilled off. The resulting mixture was cooled to room temperature to provide a slurry which was then filtered. The resulting wet cake was washed twice with MTBE (20 ml x 2) and dried to yield (AS) -DDMS- (Z)) - TA (22.5g, 98%). NMR (DMSO): lH (d), 0.6-0.92 (m, 6H), 0.92-1.1 (ra, 1?), 1.1-1.3 (m, 1H), 1.5-1.8 (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, IH), 3.9-4.2 (s, 2H), 6.4-7.2 (b, 6H, OH , COOH andNi-y, 7.3-7.6 (m, 4H). "C (d): 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 .
. 11. EXAMPLE 11. (R) -DIDESMETILSIBUTRAMINE- (D) -TARTRATE
Resolution from free base didesmethylsibutramine A method to isolate the (D) -tartrate salt of (R) -didesmethylsibutramine ( { R / S) -DDMS • (D) -TA) from the racemic free base of didesmethylsibutramine is shown in Scheme 9A and is described in more detail later:
• (£) -Ta? Tarate (WS) -DDMS (?) - DDMS- < 0 > -TA
Cr stallization Acetone? JO r r Y • (D) -Tartarale (?) - DDMS- (D) -TA
Scheme 9A
Following Scheme 9A, a mixture of (R / S) -didesmethylsibutramine (20.3 g), acetone / water / methanol (350 ml, 1: 0.13: 0.7, v: v: v), and (D) -tartaric acid ( 12.1 g) were added to a 500 ml three-necked round bottom flask. The reaction mixture was heated to reflux for 30 minutes and then cooled to 45 ° C. The reaction mixture was then seeded [sic] with (R) -DDMS- (D) -TA (10 mg, 99.6% ee) and stirred at 40-45 ° C, for 30 minutes. The mixture was then cooled to room temperature and stirred for one hour. The resulting slurry was then filtered and the wet cake was washed with acetone / cold water and dried to obtain 10.3 g (33%) of (R) -DDMS- (D) -TA (90% ee).
Resolution from (R / S) -didesmethylsibutramine- (£) tartrate A method to isolate the (D) -tartrate salt of (R) -didesmethylsibutramine ((R) -DDMS • (D) -TA) from of the racemic (D) -tertrate of racemic didesmethylsibutramine is shown in Scheme 9B and is described in detail below:
rUfate * (/)} -Tar rate (/ 2S) -DDMS '(£)) - TA < 7.) - DD S- < D) -T?
Scheme 9B
Following Scheme 9B, a mixture of (R / S) -didesmethylsibutramine- (D) -TA (5.0 g) in acetone (50 ml), water (6.7 ml) and methanol (3.3 ml) was refluxed for 30 minutes . The mixture was then cooled to room temperature and the resulting slurry was filtered to provide a wet cake which was then washed with cold acetone and dried to obtain (R) -DDMS • (D) -TA (1.4 g, 39%; 92% ee).
Enrichment of salt (D) -tartrate of (R) -DDMS A mixture of. { R) -DDMS • (D) -TA (25 g, 92% ee) and acetonitrile / water / ethanol (300 ml: 65 ml: 30 ml) was submitted
reflux for one hour. The mixture was then cooled to room temperature to provide a slurry that was filtered and dried to obtain (R) -DDMS • (D) -TA 818 g, 71.3%; 99.7% ee; and chemical purity of 99.91%). NMR. (DMSO-):? (d), 0.7-0.9 (m, 6H), 0.9-1.05 (t, 1H), 1.1-1.24 (b, 1H), 1.5-1.8 (b, 2H), 1.8-2.02 (b, 1H), 2.1 -2.4 (3, 3H), 2.4-2.6 (b, 1H), 3.5 (m, IH), 4.0 (s, 2H), 7.1-7.6 (m, 4H, with 6H from NH2, OH and COOH). , 3C (d): 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.
. 12. EXAMPLE 12. (S) -DIDESMETILSIBUTRAMINE- (L) -TARTRATE A method to isolate the (L) -tartrate of (S) -dides ethylsibutramine ((S) -DDMS- (L) -TA) from racemic free base didesmethylsibutramine is shown in Scheme 10 and is described in more detail below:
rt? i "Ue < S / S -DDMS <?) - DDMS- (¿) -TA
CrystaUization Acetone / HjO
• (£) -T «tarate (S) -DDMS- (¿) -TA
Scheme 10
Formation of the salt (L) -tartrate of (S) -DDMS (R / S) -didesmethylsibutramine (20.5 g), acetone / water / methanol (350 ml, 1: 0.13: 0.7, v: v: v) and acid (L) -tartaric (12.2 g) were added to a 500 ml three-necked round bottom flask. The mixture was heated to reflux for 30 minutes and then cooled to 45 ° C. The reaction mixture was then seeded [sic] with (S) -DDMS- (L) -TA (10 mg and 99.7% ee) and stirred at 40-45 ° C for 30 minutes. The mixture was cooled to room temperature and stirred for one hour. The resulting slurry was filtered to provide a wet cake, which was washed with cold acetone / water and dried to obtain 10.8 g (33.4%) of (S) -DDMS- (L) -TA (87.7% ee).
Preparation of (L) -tartrate (S) -DDMS from the mother liquor of (R) -DDMS • (D) -TA A solution of DMZ tartrate in acetone / water / methanol (mother liquor of (R) ) -DDMS • (D) -TA was concentrated to remove acetone and methanol.The residue was treated with aqueous NaOH (3N, 150 ml) and extracted with ethyl acetate.The organic phase was washed with water (100 ml) and concentrated to obtain free base didesmethylsibutramine (45 g, 0.18 mol and 36% ee of the (S) isomer) The free amine was charged with (L) -tartaric acid (53-6 g, 0.35 mol), acetone 8600 ml), water (80 ml) and methanol (40 ml). The mixture was heated to
reflux for one hour and then cooled to room temperature. The resulting slurry was filtered to provide a wet cake which was then washed with cold acetone / water twice to obtain 26.7 g (56% based on (S) -didesmethylsibutramine) of (S) -DDMS • (L) -TA ( 96% ee).
Enrichment of (S) -DDMS • (L) -TA A mixture of (S) -DDMS • (L) -TA (26.7 g) in acetonitrile / water (475 mlM 1: 0.2, v: v) was refluxed for one hour and then cooled to room temperature. The resulting slurry was filtered and dried to obtain 17.4 g (65%) of (S) -DDMS- (L) -TA (99.9% ee, 99.94% chemical purity). NMR (DMSO-d6): lH (d), 0.7-0.9 (m, 6H), 0.9-1.05 (m, 1H), 1.1-1.3 (b, 1H), 1.52-1.8 (b, 2H), 1.84- 2.05 (b, IH), 2.15-2.4 (b, 3H), 2.4-2.6 (b, 1H), 3.65-3.58 (m, 1H), 4.0 (s, 2H), 6.7-7.3 (b, 6H fromNH2, OH andCOOH) 7.1-7.6 (ra, 4H). , 3C (d): 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.
. 13. EXAMPLE 13: DETERMINATION OF STRENGTH AND SPECIFICITY A pharmacological study was conducted to determine the relative potency, comparative efficacy, binding affinity and toxicity of the racemic mixture of sibutramine, its enantiomers, the metabolites of sibutramine and itsenantiomers The profile of the relative specificity of monoamine reuptake inhibition is determined from the inhibition of norepinephrine reuptake (NE) compounds in brain tissue with that of inhibition of dopamine reuptake (DA) and serotonin (5-HT). The uptake with high affinity of 3H-radiomonoamines is studied in synaptosomal preparations prepared from rat striatum (for inhibition of DA reuptake) and cerebral cortex (for 5HT and NE) using the methods published by Kula et al., Life Sciences 34 (26): 2567-2575, 1984 and Baldessarini et al., Life Sciences 3_9: 1765-1777, 1986. The tissues are dissected fresh on ice and weighed. After manual homogenization (14 strokes in 10-35 volumes of ice-cold isotonic sucrose 0.32 M, containing nialamide, 34 μM) in a Teflon homogenizer on glass, the tissue is centrifuged for 10 minutes at 900 x g; the resulting "solution" supernatant. It contains synaptosomes that are used without further treatment. Each test tube contains 50 μL of the brain homogenate, radiolabeled 3H-monoamine and the test compound (for example the pure sibutramine enantiomers, the racemates and the appropriate standards) in a freshly prepared physiological buffer with a final volume of 0.5 ml . The tissues are pre-incubated
for 15 minutes at 37 ° C before the test. The tubes are kept on ice until incubation begins, which is initiated by adding 3H-amine to provide a final concentration of 0.1 μM. The tubes are incubated at 37 ° C for 10 minutes with 3H-DA (26 Ci / mmol) and for 20 minutes with 3H-5HT - (approximately 20 Ci / mmol) and 3H-NE (approximately 20 Ci / mmol). The specific activity of the radiomonoamine will vary with the available material and is not important. The reaction is terminated by immersion in ice and dilution with 3 ml of ice-cold isotonic saline containing 20 mM TRIS buffer (pH 7.0). These solutions are filtered through cellulose ester microfilters, followed by washing with two 3 ml volumes of the same buffer solution. The filter is then counted for the radioactivity of 3H in 3.5 ml of Polyfluor at approximately 50% efficiency for tritium. Whites (incubated at 0 ° C or incubated with specific uptake inhibitors, known DA [GRB-12909, 10 μM], 5HT- [zimelidine 10 μM] or NE [desipramine 10 μM]) are usually indistinguishable from the tests performed without tissue and averaged 2-3% of total CPM. The comparison of the counts of the 3H radioactivity retained in the filters provides an indication of the relative capacities of the pure enantiomers the racemic mixtures of sibutramine (and of the inhibitors of the
reuptake of DA, 5-HT and known NE) to block the reuptake of these monoamines in those tissues. This information is useful for calibrating the relative potency and efficacy of the compounds of the invention (for example dopamine reuptake inhibitors such as the racemic and optically pure metabolites of sibutramine, and 5-HT3 antagonists). The studies determine the acute toxicities of the compounds of the invention, in which progressively higher doses (mg / kg) of the pure isomers or racemates are administered. This lethal dose, when administered orally, causes the death of 50% of the test animals, is reported as LD50. Comparison of the LD50 values for the enantiomers and the racemate provide a measure of the relative toxicity of the compositions.
. EXAMPLE 14: UNION AFFINITIES The binding affinities of racemic and optically pure sibutramine (sibutramine (+), (+) and (-), desmethylsibutramine (desMe (±), (+) and (-)), and didesmethylsibutramine ( didesMe (±), (+) and (-)) were determined at the non-selective muscarinic receptor and the serotonin (5-HT) uptake site from the rat cerebral cortex, the norepinephrine uptake site (NE ) recombinant human, and the ß3 receptor of
rat adipose tissue. The compounds were tested initially at 10 μM [sic] in duplicate, and if observed > 50% inhibition of specific binding, these were also tested in 10 different concentrations in duplicate to obtain complete competition curves. The IC50 values (the concentration necessary to inhibit 50% of the specific binding) were then determined by linear regression analysis of the cures and tabulated in the following.
None of the compounds showed more than 15% inhibition of β3 receptor binding, and affinity for the muscarinic site was weak compared to atropine. In addition, the binding to the NE and 5-HT uptake sites was orders of magnitude lower than those of the standards. The above data, which were generated as already described in Example 13, show that (+) - demethylsibutramine and (+) -didesmethylsibutramine are potent inhibitors of NE uptake and 5-HT uptake, but have negligible activity in the muscarinic receptors.
. 15. EXAMPLE 15: ORAL FORMULATION With the following ingredients it is possible to prepare dosage forms in hard gelatin capsules that are free of lactose and that contain sibutramine metabolites:
The metabolite of racemic or optically pure sibutramine is screened and mixed with the excipients mentioned. The mixture is filled into two-piece hard gelatin capsules of convenient size using the machinery and convenient methods well known in the art. See, for example, Remington's Pharmaceutical Sciences, editions 16 or 18, each incorporated herein by reference. Other doses can be prepared by modifying the filling weight and, if necessary, changing the size of the capsule to the appropriate one. Any of the stable, lactose-free, hard gelatin capsule formulations above can be formed. Dosage forms of compressed tablets of sibutramine metabolites can be prepared using the following ingredients:
The racemic or optically pure metabolite of sibutramine is sieved through a convenient mesh and mixed with the excipients without lactose until a uniform mass is formed. The dried mixture is sifted and mixed with magnesium stearate. The resulting powder mixture is then compressed into tablets of the desired size and shape. It is possible to prepare tablets of other strengths by modifying the ratio of the active ingredient to the excipient (s) or by modifying the weight of the tablet. The embodiments of the invention described above are proposed to be examples only and those skilled in the art will realize, or may find out using no more than usual experience, numerous equivalents to the specific procedures described herein. All these equivalents are considered within the scope of the invention and are comprised by the following clauses.
Claims (68)
1. A method of treatment or prevention of a condition or disorder that is ameliorated by inhibition of neuronal monoamine uptake, which is to administer to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic metabolite or optically pure sibutramine, or a salt, solvate or cl-atrato acceptable for pharmaceutical use thereof.
The method of claim 1, wherein the disorder and condition that is alleviated by inhibition of neuronal monoamine uptake is selected from the group consisting. in erectile dysfunction, affective disorders, weight gain, disorders of brain function, pain, obsessive-compulsive disorder, substance abuse, chronic disorders, anxiety, eating disorders, migraine and incontinence.
The method of claim 1, wherein the metabolite of sibutramine is selected from the group consisting of (+) - demethylsibutramine, (-) - desmethylsibutramine, (±) -desmethylsibutramine, (+) -didesmethylsibutramine, (-) - didesmethylsibutramine and (±) -didesmethylsibutramine.
4. The method of claim 1, wherein the Amount of the metabolite of sibutramine to be administered is from about 0.1 mg to about 60 mg / day.
The method of claim 4, wherein the amount of the sibutramine metabolite that is administered is from about 2 mg to about 30 mg / day.
6. The method of claim 5, wherein the amount of the sibutramine metabolite that is administered is from about 5 mg to about 15 mg / day.
The method of claim 1, wherein the metabolite of sibutramine is administered orally, mucosally or transdermally.
8. A method for the treatment or prevention of erectile dysfunction, which consists of co-administering to a patient in need of such treatment or prevention effective amounts for therapeutic or prophylactic use of a dopamine reuptake inhibitor and an antagonist of 5-HT3.
The method of claim 8, wherein the dopamine reuptake inhibitor is a racemic or optically pure metabolite of sibutramine, or a pharmaceutically acceptable salt, solvate or clathrate thereof.
The method of claim 9, wherein the metabolite of sibutramine is selected from the group consisting of (+) -desmethylsibutramine, (-) - desmethylsibutramine, (±) -desmethylsibutramine, (+) - didesmethylsibutramine, (-) -didesmethylsibutramine and (±) -didesmethylsibutramine.
The method of claim 10, wherein the amount of the sibutramine metabolite that is administered is from about 0.1 mg to about 60 mg / day.
The method of claim 11, wherein the amount of the sibutramine metabolite that is administered is from about 2 mg to about 30 mg / day.
The method of claim 12, wherein the amount of the sibutramine metabolite that is administered is from about 5 mg to about 15 mg / day.
14. The method of claim 8, wherein the 5-HT3 antagonist is an antiemetic agent.
15. The method of claim 8, wherein the 5-HT3 antagonist is selected from the group consisting of granisetron, metoclopramide, ondansetron, renzapride, zacopride, tropisetron and the optically pure stereoisomers, active metabolites and acceptable salts, clathrates and solvates for pharmaceutical use of these.
16. The method of claim 8, wherein the dopamine reuptake inhibitor and / or the 5-HT3 antagonist is administered transdermally or mucosally.
17. A method of treatment or prevention of erectile dysfunction consisting of administering to a patient in need of such treatment or prevention an amount effective for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutramine, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof.
18. The method of claim 17, wherein the sibutramine metabolite is selected from the group consisting of (+) -desmethylsibutramine, (-) - desmethylsibutramine, (±) -desmethylsibutramine, (+) - didesmethylsibutramine, (-) -didesmethylsibutramine and (+) - didesmethylsibutramine.
The method of claim 17, wherein the metabolite of sibutramine is administered transdermally or mucosally.
20. A method of treating or preventing an affective disorder consisting of administering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutramine, or a salt, solvate or acceptable clathrate for pharmaceutical use thereof.
The method of claim 20, wherein the affective disorder is selected from the group consisting of: depression, attention deficit disorders, attention deficit hyperactivity disorder, bipolar and manic disorders, dysthymic disorder and cyclothymic disorder.
22. The method of claim 21, wherein the Affective disorder is depression or attention deficit disorder.
23. The method of claim 21, wherein the affective disorder is attention deficit disorder and the metabolite of sibutramine is (-) -desmethylsibutramine or (-) -didesmethylsibutramine.
The method of claim 20, wherein the metabolite of sibutramine is selected from the group consisting of (+) - demethylsibutramine, (-) - desmethylsibutramine, (±) -desmethylsibutramine, (+) - didesmethylsibutramine, (-) - didesmethylsibutramine and (+) -didesmethylsibutramine.
25. A method of treatment or prevention of weight gain or obesity which consists in administering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutramine, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof.
26. The method of claim 25, wherein the metabolite of sibutramine is selected from the group consisting of (+) - demethylsibutramine, (-) - desmethylsibutramine, (±) -desmethylsibutramine, (+) - didesmethylsibutramine, (-) - didesmethylsibutramine and (±) -didesmethylsibutramine.
27. A method of treatment or prevention of disorders of the cerebral function consisting of administering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutramine, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof.
28. The method of claim 27, wherein the disorder of brain function is selected from the group consisting of: senile dementia, Alzheimer type dementia, memory loss, amnesia / amnestic syndrome, consciousness disorders, coma, decrease of attention, speech disorders, Parkinson's disease, Lennox syndrome, autism, epilepsy, hyperkinetic syndrome and schizophrenia.
29. The method of claim 27, wherein the metabolite of sibutramine is selected from the group consisting of (+) - demethylsibutramine, (-) - desmethylsibutramine, (+) - demethylsibutramine, (+) - didesmethylsibutramine, (-) - didesmethylsibutramine and (±) -didesmethylsibutramine.
30. A method of treating or preventing pain, which comprises administering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutramine, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof.
31. The method of claim 30, wherein the pain is chronic pain.
The method of claim 30, wherein the metabolite of sibutramine is selected from the group consisting of (+) - demethylsibutramine, (-) - desmethylsibutramine, (+) - demethylsibutramine, (+) - didesmethylsibutramine, (-) - didesmethylsibutramine and (+) -didesmethylsibutramine.
33. A method of treating or preventing obsessive-compulsive disorder consisting of administering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutramine, or a salt, solvate or acceptable clathrate for pharmaceutical use thereof.
34. The method of claim 33, wherein the metabolite of sibutramine is selected from the group consisting of (+) -desmethylsibutramine, (-) - desmethylsibutramine, (±) -desmethylsibutramine, (+) -didesmethylsibutramine, (-) - didesmethylsibutramine and (+) -didesmethylsibutramine.
35. A method of treatment or prevention of substance abuse, which consists of administering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a metabolite racemic or optically pure sibutramine, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof.
36. The method of claim 25, wherein the substance abuse is cocaine addiction.
37. The method of claim 35, wherein the metabolite of sibutramine is selected from the group consisting of (+) -desmethylsibutramine, (-) - desmethylsibutramine, (+) -desmethylsibutramine, (+) - didesmethylsibutramine, (-) -didesmethylsibutramine and (+) - didesmethylsibutramine.
38. A method of treatment or prevention of addiction to nicotine, which consists in administering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutramine, or a salt, solvate or acceptable clathrate for pharmaceutical use thereof. '
39. The method of claim 38, wherein the metabolite of sibutra is selected from the group consisting of (+) -desmethylsibutra, (-) - desmethylsibutra, (±) -desmethylsibutra, (+) - didesmethylsibutra, (-) -didesmethylsibutra and (±) -didesmethylsibutra.
40. A method to quit smoking, which consists in adstering to a patient who smokes tobacco an effective amount for therapeutic use of a metabolite racemic or optically pure sibutra, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof.
41. The method of claim 40, wherein the metabolite of sibutra is selected from the group consisting of (+) - demethylsibutra, (-) - desmethylsibutra, (±) -desmethylsibutra, (+) - didesmethylsibutra, (-) - didesmethylsibutra and (±) -didesmethylsibutra.
42. A method of treatment or prevention of weight gain associated with smoking cessation, which comprises adstering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutra, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof.
43. The method of claim 42, wherein the metabolite of sibutra is selected from the group consisting of (+) - demethylsibutra, (-) - desmethylsibutra, (+) - desmethylsibutra, (+) - didesmethylsibutra, (-) - didesmethylsibutra and (±) -didesmethylsibutra.
44. A method of treatment or prevention of a chronic disorder selected from the group consisting of narcolepsy, chronic fatigue syndrome, temporary affective disorder, fibromyalgia and premenstrual syndrome, consisting of in adstering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutra, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof.
45. The method of claim 44, wherein the chronic disorder is narcolepsy, premenstrual syndrome or chronic fatigue syndrome.
46. The method of claim 44, wherein the metabolite of sibutra is selected from the group consisting of (+) - demethylsibutra, (-) - desmethylsibutra, (±) -desmethylsibutra, (+) - didesmethylsibutra, (-) -didesmethylsibutra and (±) -didesmethylsibutra.
47. An anxiety treatment or prevention method which consists of adstering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutra, or an acceptable salt, solvate or clathrate for pharmaceutical use thereof.
48. The method of claim 47, wherein the metabolite of sibutra is selected from the group consisting of - (+) - demethylsibutra, (-) - desmethylsibutra, (±) -desmethylsibutra, (+) - didesmethylsibutra, (-) -didesmethylsibutra and (±) - didesmetilsibutra.
49. A method of treating or preventing a disorder in the diet, which consists in adstering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutra, or a salt , solvate or clathrate acceptable for pharmaceutical use thereof.
50. The method of claim 49, wherein the metabolite of sibutra is selected from the group consisting of (+) - demethylsibutra, (-) - desmethylsibutra, (±) -desmethylsibutra, (+) - didesmethylsibutra, (-) - didesmethylsibutra and (±) -didesmethylsibutra.
51. A method of treatment or prevention of migraine, which consists in adstering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure metabolite of sibutra, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof.
52. The method of claim 51, wherein the metabolite of sibutra is selected from the group consisting of (+) - demethylsibutra, (-) - desmethylsibutra, (+) - desmethylsibutra, (+) - didesmethylsibutra, (-) - didesmetilsibutra and (±) - didesmetilsibutramine.
53. A method of treating or preventing incontinence, comprising administering to a patient in need of such treatment or prevention an effective amount for therapeutic or prophylactic use of a racemic or optically pure sibutramine metabolite of, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof.
54. The method of claim 53, wherein the incontinence is selected from the group consisting of: fecal incontinence, stress urinary incontinence, urinary incontinence, incontinence stimulation, reflex incontinence, passive incontinence or overflow incontinence.
55. The method of claim 54, wherein the incontinence is stress urinary incontinence.
56. The method of claim 53, wherein the sibutramine metabolite is selected from the group consisting of (+) -desmetilsibutramina, (-) - desmethylsibutramine, (+) -desmetilsibutramina ,. (+) - didesmethylsibutramine, (-) -didesmethylsibutramine and (+) - didesmethylsibutramine.
57. The method of claim 20, 25, 27, 30, 33, 35, 38, 40, 42, 44, 47, 49, 51 or 53 which further comprises administration of an active compound for further pharmacological use.
58. The method of claim 57, wherein the additional active pharmacological compound is a drug that affects the central nervous system, selected from the group consisting of: selective serotonin reuptake inhibitors; 5-HT agonists and antagonists; hypnotics and sedatives; medicines useful in the treatment of psychiatric disorders, CNS stimulants; Dopamine receptor agonists; antimonic agents; anti-panic agents, cardiovascular agents; antivirals; antibiotics; antifungal and antineoplastics.
59. A pharmaceutical composition containing a metabolite of sibutramine, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof and an excipient acceptable for pharmaceutical use.
60. The pharmaceutical composition of the claim 59, wherein the sibutramine metabolite is selected from the group consisting of (+) -desmetilsibutramina, (-) - desmethylsibutramine, (±) -desmetilsibutramina, (+) - didesmethylsibutramine, (-) -didesmethylsibutramine and (±) -didesmethylsibutramine .
61. The pharmaceutical composition of the claim 60, wherein the sibutramine metabolite is selected from the group consisting of (+) -desmetilsibutramina, (-) - desmethylsibutramine, (+) -didesmethylsibutramine and (-) - didesmethylsibutramine.
62. The pharmaceutical composition of claim 59, wherein the amount of the metabolite of sibutramine is from about 0.1 mg to about 60 mg.
63. The pharmaceutical composition of claim 5, wherein the amount of metabolite of sibutramine is from about 2 mg to about 30 mg.
64. The pharmaceutical composition of claim 63, wherein the amount of sibutramine metabolite is from about 5 mg to about 15 mg.
65. The pharmaceutical composition of claim 59, wherein the pharmaceutical composition is adapted for oral, mucosal, rectal, parenteral, transdermal or subcutaneous administration.
66. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is adapted for oral, mucosal or transdermal administration.
67. The pharmaceutical composition of claim 59, further containing an active compound for further pharmacological use. 20 68. The pharmaceutical composition of claim 67, wherein the additional active compound for pharmacological use is a drug that affects the central nervous system selected from the group consisting of agonists and antagonists of 5-HT, hypnotics and sedatives; medicines 25 useful in the treatment of psychiatric disorders; about 2 mg to about 250 mg. 75. A lactose-free pharmaceutical composition containing a metabolite of sibutramine, or a salt, solvate or clathrate acceptable for pharmaceutical use thereof and an excipient acceptable for pharmaceutical use. 76. The pharmaceutical composition of claim 75, wherein the excipient is selected from the group consisting of croscarmellose sodium, microcrystalline cellulose, pregelatinized starch and magnesium stearate. 77. The pharmaceutical composition of claim 75, wherein the pharmaceutical composition is practically free of mono- or disaccharides.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US60/097.665 | 1998-08-24 | ||
US60/099.306 | 1998-09-02 | ||
US09372158 | 1999-08-11 |
Publications (1)
Publication Number | Publication Date |
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MXPA01001955A true MXPA01001955A (en) | 2002-03-05 |
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