HK1108451A - (-)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as a dopamine-reuptake inhibitor - Google Patents

Description

(-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, compositions thereof and use as dopamine reuptake inhibitor

This application is a divisional patent application filed on 8/14/2002 as patent application No. 02821199.5 entitled "(-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, compositions thereof and use thereof as a dopamine reuptake inhibitor.

1. Field of the invention

The present invention relates to (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and pharmaceutically acceptable salts thereof, compositions containing (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salts thereof, and methods of treating or preventing conditions which can be alleviated by the inhibition of dopamine reuptake comprising administering (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salts thereof to a patient.

2. Background of the invention

Dopamine is a monoamine neurotransmitter that plays a crucial role in the function of the hypothalamic-pituitary-adrenal axis and in the integration of information within the sensory, limbic and motor systems. The primary mechanism for dopamine neurotransmission termination is via Na⁺/Cl^-Reuptake of released dopamine by property-dependent membrane transporters (Hoffman et al, 1998, front. neuroendicolin.19 (3): 187-231). Depending on the surrounding ionic conditions, dopamine transporters may act as mediators of both inward dopamine transport (i.e., "reuptake") and outward dopamine transport (i.e., "release"). The importance of dopamine transporter function is that it regulates dopamine neurotransmission by terminating the role of dopamine in the synapse through reuptake (Hitri et al, 1994, Clin. Pharmacol.17: 1-22).

Attention deficit disorder (attention deficit disorder) is a learning disorder that involves inappropriate inattention with or without hyperactivity (hyperactivity). The main symptoms of attention deficit disorder are patient inattention and impulsivity. Improper inattention causes an increased rate of activity or is unwilling to participate or respond. Patients with attention deficit disorder show a consistent pattern: both the frequency and severity of inattention and/or hyperactivity are greater than those typically observed in individuals of comparable developmental levels (see, e.g., Glatt et al, U.S. patent 6,121,261).

Parkinson patients exhibit tremoric movements of the limbs, head and jaw. Parkinson's disease is associated with bradykinesia, stiffness and falling (falling) (Stacy et al, 1996, am. fam. Phys.53: 1281-1287). The dyskinesias observed in parkinson's disease patients are due to dopamine neuron degeneration, loss of nerve endings and dopamine deficiency. It is hypothesized that dopamine neuronal degeneration is caused by apoptosis due to increased cytokine levels (Nagatsu et al, 2000, J. neural Transm. supply.60: 277-290). Abnormalities in dopamine transporters have been shown to be associated with Parkinson's disease (Hitri et al, 1994, Clin. neuropharmacol. 17: 1-22). Symptoms of parkinson's disease can be alleviated by compounds that mimic dopamine action, such as pergolide or compounds that inhibit dopamine metabolism (e.g. carbidopa) or dopamine precursors (e.g. L-DOPA ± carbidopa).

Appetite suppression is the reduction of appetite, or for excessive food consumption, the improvement of appetite. This inhibition reduces the need and craving for food. Appetite suppression allows for weight loss or weight control as desired. Appetite suppression may regulate food intake by systemic administration to one or more systems known to play a role in food digestion. See, for example, Sullivan et al, "Mechanisms of apparatus Modulation By Drugs," FederationProcedings, Volume 44, No.1, Pary 1, p.139-144 (1985). Methods of controlling appetite suppression include modulating serotonin levels, thermogenesis, and suppression of lipogenesis (see, e.g., U.S. patent 5,911,992 to Braswell et al).

Depression is one of the most common psychiatric disorders, with an incidence of more than 10% in the general population. Depression is characterized by feeling of intense sadness, despair, mental retardation (mental retardation), attentiveness reduction, pessimistic distress, anxiety and self-depreciation (Harrison's Principles of internal Medicine 2490-^thed.1998)). Depression can have physical manifestations including insomnia, hypersomnia, anorexia, weight loss, overeating, reduced energy, decreased libido and normal 24 hour rhythmic activity, body temperature and endosine dysfunction. In fact, as many as 10% -15% of depressed individuals exhibit suicidal behavior. Baldesarini, Drugs and the Treatment of psychiatric disorders: depression and Mania, in Goodman and Gilman's the pharmacological Basis of Therapeutics 431 (9)^thed.1996). Anhedonia is a major (core) symptom of depression. Dopamine pathways have been shown to be involved in happy-seeking behavior, and strategies to increase synaptic concentrations of dopamine have been proposed for antidepressant therapy (see, e.g., D' Aquila et al, 2000, Eur. J. Pharmacol. 405: 365-.

Obesity generally refers to a condition of weight gain due to excess fat. Drugs for the treatment of obesity can be divided into three categories: (1) drugs that reduce food intake, for example drugs that interfere with monoamine receptors such as the noradrenergic receptor, serotonin receptor, dopamine receptor, and histamine receptor; (2) drugs that increase metabolism; and (3) drugs that increase thermogenesis or decrease fat uptake by inhibiting pancreatic lipase (Bray, 2000, Nutrition 16: 953-960 and Leonhardt et al, 1999, Eur. J. Nutr.38: 1-13).

Many drugs can cause physical and/or psychological addiction. The best known drugs include opioids, such as heroin, opium and morphine; sympathomimetic agents, including cocaine and amphetamines; sedative hypnotics including alcohol, benzodiazepines * and barbiturates; and nicotine which acts like opioids and sympathomimetics. Drug addiction is characterized by the desire or compulsive intake of drugs and the inability to limit their intake. In addition, drug dependence is associated with drug tolerance, loss of drug action after repeated dosing and withdrawal, physical and behavioral symptoms when the drug is not ingested. Sensitization occurs if repeated use of the drug results in an enhanced response to each dose. Drug resistance, sensitization and withdrawal are phenomena that demonstrate changes in the central nervous system that result from continued use of drugs. This change stimulates addicted individuals to continue to take medications regardless of serious social, legal, physical and/or occupational consequences (see, e.g., Rise et al, U.S. patent 6,109,269). Cocaine addiction remains one of the major health problems in the united states. Many basic laboratory studies have shown that cocaine blocks dopamine uptake from the synaptic cleft from the dopamine transporter (Kreek, 1996, J.Addict.Dis.15: 73-96). However, for example, the effects of cocaine on the reuptake of released dopamine is not fully accounting for the development and maintenance of addictive behaviors. The coexistence of functional antagonism, inhibition of dopamine release and dopamine reuptake by cocaine may be responsible for fluctuations in dopamine transmission (Kiyatkin, 1994, int. J. Neurosci. 78: 75-101).

Several pharmaceutically active agents have been used to treat addiction. U.S. patent No. 5,556,838 to Mayer et al discloses the administration of a nontoxic NMDA blocker in combination with an addictive substance to prevent the development of resistance or withdrawal symptoms. U.S. patent No. 5,574,052 to Rose et al discloses the administration of an addictive drug in combination with an antagonist to partially block the pharmacological effect of the addictive substance. U.S. patent No. 5,075,341 to Mendelson et al discloses the use of mixed opioid agonists/antagonists for the treatment of cocaine and opioid addiction. U.S. patent 5,232,934 to Downs discloses the administration of 3-phenoxypyridines to treat addiction. U.S. patents 5,039,680 and 5,198,459 to imparato et al disclose the use of serotonin antagonists to treat chemical addiction. U.S. patent 5,556,837 to Nestler et al discloses infusion of BDNF or NT-4 growth factors to inhibit or reverse the neurological adaptive changes associated with behavioral changes in addicted individuals. U.S. patent 5,762,925 to Sagan discloses implanting encapsulated adrenal medulla cells into the central nervous system of a patient to inhibit the development of opioid intolerance. Bupropion has dopamine reuptake inhibiting properties and can be used to treat nicotine addiction.

Dopaminergic rewarded pathways (dopaminergic rewarded pathways) are shown to be associated with conditions resulting from addictive behaviors. The dopamine D2 receptor gene variants are associated with alcoholism, obesity, pathological gambling, attention deficit hyperactivity disorder (attention deficiency disorder), Tourette syndrome, cocaine dependence, nicotine dependence, multiple substance abuse and other drug dependence (Noble, 1994, Alcohol supp.2: 35-43 and Blum et al, 1995, Pharmacogenetics 5: 121-. Since a decrease in dopamine function has been found in individuals with the dopamine D2 receptor side A1 allele, it has been proposed that the dopamine D2 receptor gene may be an enhancement or reward gene (Noble, 1994, Alcohol supp.2: 35-43). In addition, several studies have shown that dopamine D2 receptor gene polymorphism binding is associated with impulse-addiction-compulsive behavior, i.e. "reward deficiency syndrome" (reviewed by Blum et al, 1995, pharmacopoetics 5: 121-141).

Epstein et al, U.S. Pat. No. 4,435,419, discloses racemic (. + -.) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane for use as an antidepressant.

U.S. Pat. No. 6,204,284 to Beer et al discloses racemic (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane for the prevention or alleviation of withdrawal symptoms due to drug addiction and for the treatment of chemical dependence.

It may be disadvantageous to administer the racemate, i.e., a 50: 50 mixture of (+) -and (-) -enantiomers of any drug, e.g., (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, to a patient. First, the pharmacological activity of a racemic mixture may be lower than one of its enantiomers, rendering the racemic drug itself ineffective. Second, the racemic mixture may be more toxic to the patient than one enantiomer, and thus administration of the racemic mixture may cause adverse side effects to the patient.

Thus, there is a clear need in the art for enantiomers, preferably substantially free of the corresponding opposite enantiomer, which would overcome one or both of the above disadvantages.

Any reference cited in section 2 of this application is not to be construed as an admission that such reference is prior art to the present application.

3. Summary of the invention

In one embodiment, the present invention provides (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and pharmaceutically acceptable salts thereof. (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and pharmaceutically acceptable salts thereof are useful in the treatment or prevention of disorders which can be alleviated by the inhibition of dopamine reuptake.

The present invention also provides compositions comprising an effective amount of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof. The compositions of the present invention may also comprise a pharmaceutically acceptable carrier. These compositions are useful for treating or preventing conditions which can be alleviated by the inhibition of dopamine reuptake.

In another embodiment, the invention provides a method of treating or preventing a condition which is alleviated by the inhibition of dopamine reuptake comprising administering to a patient in need of such treatment or prevention an effective amount of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method of treating or preventing attention deficit disorder, depression, obesity, Parkinson's disease, tic disorders, or addictive disorders, comprising administering to a patient in need of such treatment or prevention an effective amount of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof.

Preferably, (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is substantially free of its corresponding (+) -enantiomer, particularly when used in the methods or compositions of the present invention. In a preferred embodiment (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, or a pharmaceutically acceptable salt thereof, substantially free of its corresponding (+) -enantiomer is used to treat or prevent a condition that can be alleviated by selective inhibition of dopamine reuptake. According to the use of this preferred embodiment, it is surprising and advantageous not to block norepinephrine or serotonin transport, in particular norepinephrine or serotonin reuptake. It has been unexpectedly found that the use of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, or a pharmaceutically acceptable salt thereof, substantially free of its corresponding (+) -enantiomer for the treatment or prevention of conditions alleviated by the inhibition of dopamine reuptake avoids the side effects associated with norepinephrine or serotonin reuptake inhibitors such as cardiovascular effects, sleep disturbances, hypertension or sexual dysfunction.

In another embodiment, the present invention provides a process for obtaining (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane substantially free of its corresponding (+) -enantiomer comprising the steps of:

(a) flowing a solution of an organic eluent and (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane through a chiral polysaccharide stationary phase to provide a first fraction comprising (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane; and

(b) the first fraction is passed over a chiral polysaccharide stationary phase to provide a second fraction containing (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane substantially free of its corresponding (+) -enantiomer.

In another embodiment, the present invention provides a process for obtaining (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane substantially free of its corresponding (+) -enantiomer comprising the steps of:

(a) flowing a solution of an organic eluent and (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane through a chiral polysaccharide stationary phase to provide a first fraction comprising (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane;

(b) concentrating the first fraction to provide a residue; and

(c) passing a solution of the organic eluent and the residue through the chiral polysaccharide stationary phase to provide a second fraction containing (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane substantially free of its corresponding (+) -enantiomer.

The present invention may be understood more fully by reference to the detailed description and examples, which are intended to illustrate non-limiting embodiments of the invention.

4. Detailed description of the invention

4.1. Definition of

The term "substantially free of its corresponding (+) -enantiomer" means containing no more than about 5% w/w of the corresponding (+) -enantiomer, preferably no more than about 2% w/w of the corresponding (+) -enantiomer, more preferably no more than about 1% w/w of the corresponding (+) -enantiomer.

The term "corresponding (+) -enantiomer" when used in conjunction with (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof, refers to "(+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane" or a pharmaceutically acceptable salt thereof.

By "patient" is meant an animal, including but not limited to animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, and guinea pigs, more preferably a mammal, and most preferably a human.

The term "pharmaceutically acceptable salt" as used herein is a salt formed from an acid and the basic nitrogen group of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane. Preferred salts include, but are not limited to, sulfate, citrate, acetate, oxalate, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucarate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1' -methylene-bis- (2-hydroxy-3-naphthoate)). 4.2(-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane

(-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, preferably (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, substantially free of its corresponding (+) -enantiomer, may be obtained from (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane by chiral chromatography, such as high performance liquid chromatography ("HPLC"), using a suitable column, preferably a chiral column. (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane can be obtained using the method disclosed in U.S. patent 4435419 to Epstein et al.

In a preferred embodiment, (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane is obtained by passing an organic eluent and a solution of (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane through a chiral polysaccharide stationary phase. The polysaccharide is preferably starch or a starch derivative. Advantageously, the Chiral stationary phase is on a Chiral HPLC column, such as an CHIRALPAK AD column manufactured by Daicel and commercially available from chiraltechnologies, inc., Exton, Pennsylvania, preferably a 1cm x 25cm CHIRALPAK AD HPLC column. Preferred eluents are hydrocarbon solvents adjusted in polarity with polar organic solvents miscible therewith. Preferably, the organic eluent comprises from about 95% to about 99.5% (v/v) of the non-polar hydrocarbon solvent and from about 5% to about 0.5% (v/v) of the polar organic solvent. In a preferred embodiment, the hydrocarbon solvent is hexane and the polar organic solvent miscible therewith is isopropylamine.

Flowing a solution of an organic eluent and (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane over the chiral polysaccharide stationary phase provides a first fraction (i.e., one or more fractions) comprising (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane. The first fraction may be passed directly through the chiral polysaccharide stationary phase to provide a second fraction (i.e. one or more fractions) containing (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane substantially free of its corresponding (+) -enantiomer. Alternatively, the first fraction may be concentrated to provide a residue, the residue may be diluted with an organic eluent, and the resulting solution may be passed over a chiral polysaccharide stationary phase to provide a second fraction containing (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane substantially free of its corresponding (+) -enantiomer. For either method, the second fraction may be concentrated, preferably in vacuo, to obtain (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane substantially free of its corresponding (+) -enantiomer in solid form.

Therapeutic use of 3(-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane

In accordance with the present invention, (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is administered to a patient, preferably a mammal, more preferably a human, for the treatment or prevention of a condition which can be alleviated by the inhibition of dopamine reuptake. In one embodiment, "treating" refers to ameliorating a condition or at least one perceptible symptom that can be alleviated by the inhibition of dopamine reuptake. In another embodiment, "treating" refers to improving at least one measurable physical parameter that is not necessarily detectable by the patient. In another embodiment, "treating" or "treatment" refers to inhibiting the progression of a condition that can be alleviated by inhibition of dopamine reuptake, which inhibition is physical inhibition, e.g., normalizing a perceptible symptom, physiological inhibition, e.g., normalizing a physical parameter, or both physical and physiological inhibition. In another embodiment, "treating" refers to delaying the onset of a condition that can be alleviated by inhibiting dopamine reuptake.

In some embodiments, (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is administered to a patient, preferably a mammal, more preferably a human, as a prophylactic measure to avoid a condition that can be alleviated by inhibition of dopamine reuptake. The term "prevention" as used herein means reducing the risk of developing a condition which can be alleviated by inhibition of dopamine reuptake, or reducing the risk of recurrence of the condition after healing or return to a normal state. In one embodiment, (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is administered to a patient as a prophylactic measure. According to this embodiment, the patient may be genetically predisposed to a condition that can be alleviated by inhibition of dopamine reuptake, for example having a family history of biochemical imbalances in the brain, or non-genetically predisposed to a condition that can be alleviated by inhibition of dopamine reuptake. Thus, (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and pharmaceutically acceptable salts thereof may be useful in treating one manifestation of a disorder that can be alleviated by inhibiting dopamine reuptake and preventing the other manifestation.

4.3.1 use of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane for alleviating disorders

(-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and pharmaceutically acceptable salts thereof are useful in the treatment of endogenous disorders that can be alleviated by inhibition of dopamine reuptake. Such disorders include, but are not limited to, attention deficit disorder, depression, obesity, parkinson's disease, tic disorders, and addictive disorders.

Disorders that can be alleviated by inhibition of dopamine reuptake are not limited to the specific disorders described herein, as many types of disorders can be manifested from a primary disorder. For example, as disclosed in Blum's U.S. patent 6132724, attention deficit hyperactivity disorder may manifest itself in the following form: alcohol abuse, drug abuse, obsessive compulsive disorders, learning disorders, reading disorders, gambling, manic symptoms, phobias, panic attacks, oppositional defiant behaviors, behavioral disorders, learning problems in school, smoking, abnormal behaviors, schizophrenic behaviors, somatization, depression, sleep disorders, generalized anxiety disorder, stuttering, and tic disorders. These and other behaviors described herein that are associated with conditions that can be alleviated by inhibition of dopamine reuptake are included as part of the conditions described herein. In addition, as used herein, clinical terminology for a number of specific conditions may be found in Quick Reference to The Diagnostic Criteria From DSM-IV (Diagnostic and statistical Manual of Mental Disorders, 4 th edition), The American psychiatric Association, Washington, D.C., 1994, page 358. The specific disorders for which definitions may be found in this reference are as follows.

Attention deficit disorders include, but are not limited to, attention deficit/hyperactivity disorder, predominantly inattentive; attention deficit/hyperactivity disorder, predominantly hyperactive-impulsive type; attention deficit/hyperactivity disorder, combination type; (NOS) attention deficit/hyperactivity disorder not otherwise specified; a behavioral disorder; oppositional defiant disorder (oppositional defiant disorder); and (NOS) destructive behavioral disorders, not otherwise specified.

Depression includes, but is not limited to, recurrent major depression; dysthymic condition; non-otherwise specified (NOS) depression; and single-episode major depression.

Parkinson's disease includes, but is not limited to, parkinsonism caused by neuroleptic drugs.

Addictive disorders include, but are not limited to, eating disorders, impulse control disorders, alcohol-related disorders, nicotine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen use disorders, inhalant-related disorders, opioid-related disorders, all of which can be further subdivided as described below.

Eating disorders include, but are not limited to, bulimia nervosa, non-diarrheal type; neurogenic bulimia, diarrhea type; and (NOS) eating disorders not otherwise specified.

Impulse control disorders include, but are not limited to, intermittent explosive disorder, kleptomania, pyromania, pathological gambling, trichotillomania, and non-specified (NOS) impulse control disorders.

Alcohol-related disorders include, but are not limited to, alcohol-induced psychotic disorders with delusions; alcohol abuse; alcoholism; alcohol withdrawal; alcohol intoxication delirium; alcohol withdrawal delirium; persistent dementia caused by alcohol; persistent amnesia caused by alcohol; alcohol dependence; alcohol-induced psychotic disorder with hallucinations; mood disorders caused by alcohol; anxiety disorder caused by alcohol; sexual dysfunction caused by alcohol; sleep disorders caused by alcohol; (NOS) alcohol-related disorders not otherwise specified; alcoholism; and alcohol withdrawal.

Nicotine-related conditions include, but are not limited to, nicotine dependence, nicotine withdrawal, and non-specified (NOS) nicotine-related conditions.

Amphetamine-related disorders include, but are not limited to, amphetamine dependence, amphetamine abuse, amphetamine intoxication, amphetamine withdrawal, amphetamine intoxication delirium, amphetamine-induced psychotic disorder with delusions, amphetamine-induced psychotic disorder with hallucinations, amphetamine-induced mood disorder, amphetamine-induced anxiety disorder, amphetamine-induced sexual dysfunction, amphetamine-induced sleep disorder, non-specified (NOS) amphetamine-related disorder, amphetamine intoxication, and amphetamine withdrawal.

Cannabis-related disorders include, but are not limited to, cannabis dependence; cannabis abuse; cannabis intoxication; cannabis intoxication delirium; cannabis-induced psychotic disorder with delusions; cannabis-induced psychotic disorder with hallucinations; cannabis-induced anxiety disorder; not Otherwise Stated (NOS) cannabis-related disorders and cannabis intoxication.

Cocaine-related disorders include, but are not limited to, cocaine dependence, cocaine abuse, cocaine intoxication, cocaine withdrawal, cocaine intoxication delirium, cocaine-induced psychotic disorder with delusions, cocaine-induced psychotic disorder with hallucinations, cocaine-induced mood disorder, cocaine-induced anxiety disorder, cocaine-induced sexual dysfunction, cocaine-induced sleep disorder, cocaine-related disorder Not Otherwise Specified (NOS), cocaine intoxication, and cocaine withdrawal.

Hallucinogenic agent use disorders include, but are not limited to, hallucinogenic agent dependence, hallucinogenic agent abuse, hallucinogenic agent intoxication, hallucinogenic agent withdrawal, hallucinogenic agent intoxication delirium, hallucinogenic agent-induced psychotic disorder with delusions, hallucinogenic agent-induced psychotic disorder, hallucinogenic agent-induced anxiety disorder, hallucinogenic agent-induced sexual dysfunction, hallucinogenic agent-induced sleep disorder, non-hallucinogenic agent related (NOS) disorder, hallucinogenic agent intoxication and hallucinogenic agent persistent perceptual disorder (hallucinogenic reappearance).

Inhalant-related conditions include, but are not limited to, inhalant dependence; inhalant abuse; (ii) inhalation toxicosis; inhalant intoxication delirium; psychoses caused by inhalants with delusions; inhalant-induced psychotic disorder with hallucinations; anxiety disorders caused by inhalation; (NOS) inhalant-related disorders not otherwise specified; and inhalation poisoning.

Opioid-related disorders include, but are not limited to, opioid dependence, opioid abuse, opioid intoxication delirium, opioid-induced psychotic disorder with delusions, opioid-induced psychotic disorder with hallucinations, opioid-induced anxiety disorder, non-separately prescribed (NOS) opioid-related disorder, opioid intoxication and opioid intoxication.

Tic disorders include, but are not limited to, Tourette's disorder, chronic motor or vocal tic disorder, transient tic disorder, non-episodic (NOS) tic disorder, stuttering, autism, and somatization disorder.

4.4. Therapeutic/prophylactic administration and compositions of the invention

Due to their activity, (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and its pharmaceutically acceptable salts are advantageously used in veterinary and human medicine. As noted above, (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, and pharmaceutically acceptable salts thereof, may be useful in the treatment or prevention of conditions which can be alleviated by the inhibition of dopamine reuptake.

When administered to a patient, (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is preferably administered as a component of a composition which may optionally contain a pharmaceutically acceptable carrier. Compositions of the present invention comprising an effective amount of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof are preferably administered orally. The compositions of the present invention may also be administered by any other suitable route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and may be administered with another biologically active agent. Administration can be systemic or local. Various delivery systems are known, such as encapsulation in liposomes, microparticles, microcapsules and capsules, and are useful for the administration of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and pharmaceutically acceptable salts thereof.

In some embodiments, the compositions of the present invention may comprise (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and/or one or more pharmaceutically acceptable salts thereof.

Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectal, inhalation, or topical administration, particularly to the ear, nose, eye, or skin. The mode of administration is determined by the physician. In most cases, administration will result in the release of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof into the bloodstream.

In a particular embodiment, it may be desirable to administer (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof topically. This can be achieved, for example, but not limited to, the following: local infusion during surgery, local application, e.g. in combination with wound dressing after surgery, administration by injection, administration through a catheter, administration through a suppository, or administration through an implant which is a porous, non-porous or gelatin material, including membranes such as salivary gland (sialastic) membranes or fibres.

In some embodiments, it may be desirable to introduce (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof into the central nervous system by any suitable route, including intraventricular, intrathecal, and epidural injection. Intraventricular injection may be assisted by an intraventricular catheter, for example attached to a reservoir, such as an Ommaya reservoir.

Pulmonary administration may also be employed, for example by use of an inhaler or nebulizer, for example formulated with a nebulizer, or by infusion in a fluorocarbon or synthetic pulmonary surfactant. In some embodiments, (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and its pharmaceutically acceptable salts may be formulated as a suppository with conventional binders and carriers such as triglycerides.

In another embodiment, (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and pharmaceutically acceptable salts thereof can be administered in vesicles, particularly Liposomes (see Langer, 1990, Science 249: 1527-.

In another embodiment, (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [ 3.1.0)]Hexane and its pharmaceutically acceptable salts are administered in a Controlled Release system (see, e.g., Goodson, Medical Applications of Controlled Release, supra, vol.2, pp.115-138 (1984)). Can be used in Langer, 1990, Science 249: 1527 and 1533. In one embodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. biomed. Eng.14: 201; Buchwald et al, 1980, Surgery 88: 507 Saudek et al, 1989, N.Engl. J. Med. 321: 574). In another embodiment, polymeric materials may be used (see medical applications of Controlled Release, Langer and Wise, CRCPres, Boca)Raton, Florida (1974); controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); ranger and Peppas, 1983, j.macromol. sci.rev.macromol. chem.23: 61; see also Levy et al, 1985, Science 228: 190; during et al, 1989, ann.25: 351, a step of; howard et al, 1989, j.71: 105). In another embodiment, the controlled release system may be placed on (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]A target vicinity of hexane or a pharmaceutically acceptable salt thereof, such as the spinal column or brain, such that only a fraction of the systemic dose is required.

The compositions of the present invention may optionally comprise a suitable amount of a pharmaceutically acceptable carrier to provide a form suitable for administration to a patient.

In a particular embodiment, the term "pharmaceutically acceptable" means approved by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, mammals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a compound of the invention is administered. Such pharmaceutical carriers can be liquids such as water and oils, including petroleum, animal, vegetable or synthetic oils, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical carrier may be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. In addition, adjuvants, stabilizers, thickeners, lubricants and colorants may also be used. When administered to a patient, the pharmaceutically acceptable carrier is preferably sterile. When the compounds of the invention are administered intravenously, water is the preferred carrier. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The compositions of the present invention may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired.

The compositions of the present invention may be in the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules containing liquids, powders, sustained release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. In one embodiment, the pharmaceutically acceptable carrier is a capsule (see, e.g., U.S. patent 5,698,155). Other examples of suitable Pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Alfonso R.Gennaro ed., Mack Publishing Co.Easton, PA, 19th ed., 1995, pp.1447-1676, which is incorporated herein by reference.

In a preferred embodiment, (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, or a pharmaceutically acceptable salt thereof, is formulated in accordance with routine procedures as a pharmaceutical composition suitable for oral administration to a human. Compositions for oral administration may be in the form of, for example, tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs. Compositions for oral administration may also contain one or more substances, for example sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; a colorant; and a preservative to provide a pharmaceutically acceptable palatable preparation. In addition, when in the form of tablets or pills, the composition may be coated to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a long period of time. The selectively permeable membrane surrounding the osmotically active driving compound is also suitable for oral administration of the composition. In these latter platforms, the driving compound draws fluid out of the environment surrounding the capsule, where it expands to displace the active agent or active agent composition through the pores. These release platforms may provide a substantially zero order release profile, as opposed to the peaked release profile of an immediate release formulation. Time delay materials such as glycerol monostearate or glycerol stearate may also be used. Oral compositions can include standard carriers such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, and magnesium carbonate. Such carriers are preferably pharmaceutical grade. Intravenous administration compositions typically comprise sterile isotonic aqueous buffers. The composition may further comprise a solubilizer, if necessary.

In another embodiment, (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, or a pharmaceutically acceptable salt thereof, may be formulated for intravenous administration. Compositions for intravenous administration may optionally include a local anesthetic such as lidocaine to reduce pain at the site of injection. The components are typically provided separately or mixed together in unit dosage form, for example as a lyophilized powder or a non-aqueous concentrate in a sealed container such as an ampoule or sachet indicating the amount of active ingredient. When (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is administered by infusion, it can be dispensed from an infusion bottle containing sterile pharmaceutical grade water or saline. When (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is administered by injection, an ampoule of water for injection or saline may be provided so that the components may be mixed prior to administration.

The amount of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof effective to treat a particular disorder described herein will depend on the nature of the disease or condition and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays may optionally be employed to help determine optimal dosage ranges. The precise dose to be employed will also depend on the route of administration and the severity of the disease or condition, and should be determined at the discretion of the attendant physician and in the individual case. However, for oral administration, suitable dosages will generally be from about 0.001 mg to about 200 mg of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof per kilogram body weight per day. In a particular embodiment of the invention, the oral dosage is from about 0.01 mg to about 100 mg/kg body weight/day, more preferably from about 0.1 mg to about 75 mg/kg body weight/day, more preferably from about 0.5 mg to about 50 mg/kg body weight/day, and still more preferably from about 1mg to about 30 mg/kg body weight/day. In another embodiment, the oral dosage is from about 1mg to about 3mg of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof per kilogram body weight per day. In another embodiment, the oral dosage is from about 0.1 mg to about 2mg of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof per kilogram body weight per day for 1 to 2 times daily. The doses mentioned herein refer to the total amount administered, that is to say, if (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and/or one or more pharmaceutically acceptable salts thereof is administered, the preferred dose corresponds to the total amount administered. Oral compositions preferably contain from about 10% to about 95% by weight of the active ingredient.

For intravenous (i.v.) administration, suitable dosages are from about 0.01 mg to about 100 mg/kg body weight/day, from about 0.1 mg to about 35 mg/kg body weight/day, and from about 1mg to about 10 mg/kg body weight/day. For intranasal administration, suitable dosages will generally range from about 0.01pg/kg body weight/day to about 1mg/kg body weight/day. Suppositories generally contain from about 0.01 mg to about 50 mg of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof per kilogram of body weight per day and contain from about 0.5% to about 10% by weight of the active ingredient.

For intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, intracerebral, intravaginal, transdermal or inhalation administration, a dosage of about 0.001 mg to about 200 mg per kilogram of body weight per day is recommended. For topical administration, suitable dosages are from about 0.001 mg to about 1mg, depending on the area of administration. Effective doses can be derived from dose-response curves obtained from in vitro or animal model test systems. Such animal models and systems are well known in the art.

The present invention also provides a pharmaceutical pack or kit comprising one or more containers containing (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof. Such containers may optionally be provided with instructions approved by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, such instructions reflecting approval by the agency of manufacture, use or sale of such pharmaceuticals for administration to humans. In some embodiments, the kit comprises (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and/or one or more pharmaceutically acceptable salts thereof. In another embodiment, the kit comprises a therapeutic agent and (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof.

The desired therapeutic or prophylactic activity of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and pharmaceutically acceptable salts thereof is determined prior to use in humans, preferably in vitro or in vivo. For example, an in vitro assay may be used to determine whether administration of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, a pharmaceutically acceptable salt thereof, and/or another therapeutic agent is preferred. Animal model systems can be used to demonstrate safety and efficacy.

Other methods are known to those skilled in the art and are within the scope of the invention.

4.5. Combination therapy

In some embodiments of the invention, (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, or a pharmaceutically acceptable salt thereof, may be used in combination therapy with at least one other therapeutic agent. (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof and the additional therapeutic agent may act in an additive manner or, more preferably, in a synergistic manner. In a preferred embodiment, (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is administered concurrently with an additional therapeutic agent, which may be in the same or a different composition as (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof. The additional therapeutic agent may be used to treat and/or prevent (as defined herein) a secondary disease resulting from a condition that can be alleviated by inhibition of dopamine reuptake. In another embodiment, (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is administered either before or after administration of the additional therapeutic agent. Because many of the conditions treatable with (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and pharmaceutically acceptable salts thereof are chronic, in one embodiment, combination therapy involves alternating administration of a composition comprising (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof and a composition comprising an additional therapeutic agent. The duration of administration of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, a pharmaceutically acceptable salt thereof, or an additional therapeutic agent can be, for example, one month, three months, six months, one year, or longer, e.g., for the lifetime of the patient. In some embodiments, when (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is administered concurrently with an additional therapeutic agent that may cause adverse side effects, including but not limited to toxicity, the additional therapeutic agent may be advantageously administered at a dose below the threshold that causes adverse side effects, as desired.

The additional therapeutic agent may be an anti-attention deficit disorder agent. Useful anti-attention deficit disorder agents include, but are not limited to, methylphenidate; dextroamphetamine; tricyclic antidepressants such as imipramine, desipramine and nortriptyline; and psychostimulants such as pimulin and dinor.

The additional therapeutic agent may be an anti-addictive disorder agent. Useful anti-addictive disorder agents include, but are not limited to, tricyclic antidepressants; MAO inhibitors; glutamate antagonists such as ketamine hydrochloride, dextromethorphan, dextrorphan tartrate, and dezocine (MK 801); degradative enzymes such as anesthetics and aspartate antagonists; GABA agonists such as baclofen and muscimol hydrobromide; a reuptake blocker; a degrading enzyme blocking agent; glutamate agonists such as D-cycloserine, carboxyphenylglycine, L-glutamate and cis-piperidine-2, 3-dicarboxylic acid; an aspartic acid agonist; GABA antagonists such as gabazine (SR-95531), saclofen, bicumyline base, tetrandrine, and (+) apomorphine hydrochloride; and dopamine antagonists such as spiperone hydrochloride, haloperidol and (-) sulpiride.

The additional therapeutic agent may be an anti-alcohol agent. Useful anti-alcohol agents include, but are not limited to disulfiram and naltrexone.

The additional therapeutic agent may be an anti-nicotine agent. Useful anti-nicotine agents include, but are not limited to, clonidine.

The additional therapeutic agent may be an anti-opioid agent. Useful anti-opioid agents include, but are not limited to, methadone, clonidine, lofexidine, levomethadol hydrochloride, naltrexone, and buprenorphine.

The additional therapeutic agent may be an anti-cocaine agent. Useful anti-cocaine agents include, but are not limited to, desipramine, amantadine, fluoxetine, and buprenorphine.

The additional therapeutic agent may be an appetite suppressant. Useful appetite suppressants include, but are not limited to, fenfluramine, phenylpropanolamine, and mazindol.

The additional therapeutic agent may be an anti-lysergic acid diethylamide ("anti-LSD") agent. Useful anti-LSD agents include, but are not limited to, diazepam.

The additional therapeutic agent may be an anti-phencyclidine ("anti-PCP") agent. Useful anti-PCP agents include, but are not limited to, haloperidol.

The additional therapeutic agent may be an anti-parkinson agent. Useful anti-parkinson agents include, but are not limited to, dopamine precursors such as levodopa, L-phenylalanine, and L-tyrosine; a neuroprotective agent; a dopamine agonist; dopamine reuptake inhibitors; anticholinergic agents such as amantadine and memantine; and 1, 3, 5-trisubstituted adamantanes such as 1-amino-3, 5-dimethyl-adamantane (Sherm et al, U.S. patent 4,122,193).

The additional therapeutic agent may be an antidepressant. Useful antidepressants include, but are not limited to, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, fluoxetine, fluvoxamine, paroxetine, setraline, venlafaxine, bupropion, nefazodone, trazodone, phenelzine, tranylcypromine and selegiline.

The additional therapeutic agent may be an anxiolytic agent. Useful anxiolytics include, but are not limited to, benzodiazepine * class anxiolytics such as alprazolam, clonazepam *, clonazepam, halazepam, lorazepam, oxazepam, and pramipepam; non-benzodiazepine * class anxiolytics, such as buspirone; and neuroleptic agents such as barbiturates.

The additional therapeutic agent may be an antipsychotic. Useful antipsychotic agents include, but are not limited to, phenothiazines, such as chlorpromazine, mesoridazine besylate, thioridazine, acetophenazine maleate, fluphenazine, perphenazine and trifluoperazine; thioxanthenes such as chlorprothixene and thiothixene; and other heterocyclic compounds such as clozapine, haloperidol, loxapine, maindione, pimozide, and risperidone. Preferred antipsychotic agents include chlorpromazine hydrochloride, thioridazine hydrochloride, fluphenazine hydrochloride, thiothixene hydrochloride, and malintone hydrochloride.

The additional therapeutic agent may be an anti-obesity drug. Useful anti-obesity drugs include, but are not limited to, beta adrenergic receptor agonists, preferably beta-3 receptor agonists, such as, but not limited to, fenfluramine; dexfenfluramine; sibutramine; bupropion; fluoxetine; phentermine; amphetamine; methamphetamine; dextroamphetamine; benzphetamine; benzyltrimetazidine; bupropion; mazindol; phenylpropanolamine; norepinephrine-serotonin reuptake inhibitors, such as sibutramine; and pancreatic lipase inhibitors such as orlistat.

5. Example (b): (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride

To 279mg of (. + -.) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Hexane hydrochloride (obtained using the method described in Epstein et al, J.Med.chem., 24: 481-490 (1981)) was added to 7mL of 9: 1 Hexane: isopropanol followed by 8 drops of diethylamine. To the resulting mixture, isopropanol was added dropwise until a solution was obtained. The solution was concentrated to a volume of 6mL using a helium gas stream, and 6 parts (1 mL each) of the concentrate were subjected to high performance liquid chromatography using an HPLC apparatus equipped with a 1cm × 25cm Daicel CHIRALPAK AD column (ChiralTechnologies, inc., Exton, Pennsylvania). Elution was performed at room temperature using a 95: 5(v/v) hexane: isopropanol solution containing 0.05% diethylamine as the mobile phase at a flow rate of 6 mL/min. Collecting fractions eluted at about 26.08 to 34 minutesAnd concentrated to give a first residue, which was dissolved in the minimum necessary amount of ethyl acetate. The ethyl acetate solution was evaporated using a nitrogen stream to give a second residue, which was dissolved in 1mL of diethyl ether. To the ether solution was added 1mL of ether saturated with hydrogen chloride gas. A precipitate formed, which was filtered, washed with 2mL of diethyl ether and dried to yield 33mg of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [ 3.1.0%]Hexane hydrochloride having an enantiomeric excess of 88%. The product was purified again using the chromatographic conditions described above. The fractions eluted at about 28 to about 34 minutes were concentrated, acidified and dried as described above to give 16.0mg of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [ 3.1.0%]Hexane hydrochloride salt: optical rotation [ a ] in methanol at a concentration of 2mg/mL]²⁵ _D-56 °; 99.1% enantiomeric excess.

6. Example (b): comparison of Activity of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride and (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride in a dopamine, norepinephrine and serotonin transporter binding assay

Standard dopamine binding assays were used to compare dopamine, norepinephrine and serotonin uptake inhibitory activity of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride to (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride.

6.1. Materials and methods

6.1.1. Dopamine transporter assay

Dopamine uptake transporter binding assays were performed according to Madras et al, 1989, mol. 518-524 and Javitch et al, 1984, mol. 35-44, respectively. The recipient source is guinea pig striatal membrane; the radioligand is [ alpha ]³H]WIN 35, 428(Dupont-NEN, Boston, Massachusetts) (60-87Ci/mmol), with a final ligand concentration of 2.0 nM; the non-specific determinant is 1. mu.M 1- [2- [ bis (4-fluorophenyl) methoxy]Ethyl radical]-4- [ 3-phenylpropyl]Piperazine dihydrochloride ("GBR 12909"), a highly philic salt(ii) a compound dopamine uptake inhibitor; the reference compound is also GBR 12909. (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Hexane hydrochloride was obtained according to the method of example 5 above. The reaction was carried out in 50mM TRIS-HCl (pH 7.4) containing 120mM NaCl at 0 ℃ to 4 ℃ for 2 hours. The reaction was terminated by rapid vacuum filtration onto a glass fiber filter. Radioactivity trapped in the filter is determined and compared to control values to determine the interaction of the test compound with the dopamine uptake site. The data are listed in table 1 below.

6.1.3. Norepinephrine transporter assay

The norepinephrine transporter binding assay is based on the principle of rassman et al, 1982, eur.jrnl.pharmacol.78: 345-351 and Langer et al, 1981, Eur.J.Pharmacol.72: 423. The recipient source is rat forebrain membrane; the radioligand was [3H ] nisoxetine (60-85Ci/mmol), with a final ligand concentration of 1.0 nM; the non-specific determinant is 1 μ M desipramine ("DMI"), a high affinity norepinephrine uptake inhibitor; the reference compound is desipramine ("DMI"), imipramine, amitriptyline or nisoxetine. (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride was obtained according to the procedure of example 5 above. The reaction was carried out in 50mM TRIS-HCl (pH 7.4) containing 300mM NaCl and 5mM KCl at 0 ℃ for 4 hours at 4 ℃. The reaction was terminated by rapid vacuum filtration onto a glass fiber filter. Radioactivity trapped in the filter is determined and compared to control values to determine the interaction of the test compound with the norepinephrine uptake site. The data are listed in table 2 below.

6.1.3. Serotonin transporter assay

Serotonin transporter binding assays are based on D 'Amato et al, 1987, J' rnl.&Exp, ther, 242: 364-371 and Brown et al, 1986, Eur.Jrnl.Pharmacol.123: the method described in 161-165. The recipient source is human platelet membrane; the radioligand is [ alpha ]³H]Citalopram (70-87Ci/mmol) with a final ligand concentration of 0.7 nM; the nonspecific determinant was 1. mu.M-chlorimipramine, a high affinity serotonin uptake inhibitor; the reference compound was imipramine. (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Hexane hydrochloride was obtained according to the method of example 5 above. The reaction was carried out in 50mM TRIS-HCl (pH 7.4) containing 120mM NaCl and 5mM KCl at 25 ℃ for 1 hour. The reaction was terminated by rapid vacuum filtration onto a glass fiber filter. Radioactivity trapped in the filters is determined and compared to control values to determine the interaction of the test compound with the serotonin uptake site. The data are listed in table 3 below.

6.2. Results

Table 1: dopamine transporter binding assay

Compound Ki

(-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Hexane hydrochloride 2.61X 10^-7

(±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Hexane hydrochloride 1.54X 10^-7

GBR 12909 1.16×10^-8

Table 2: norepinephrine transporter binding assay

Compound Ki

(-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride N/A

(±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Hexane hydrochloride 1.42X 10^-7

Dixipamine hydrochloride ('DMI') 1.13×10^-9

N/A-no measurable affinity

Table 3: serotonin transporter binding assays

Compound Ki

(-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride N/A

(±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Hexane hydrochloride 1.87X 10^-7

Imipramine hydrochloride 2.64X 10^-8

N/A-no measurable affinity

The data in Table 1 show that (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride and (. + -.) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride both have an affinity for the dopamine uptake site. In contrast, the data in tables 2 and 3 show that (. + -.) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride has an affinity for both the norepinephrine and serotonin uptake sites, while (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride has no measurable affinity for both the norepinephrine and serotonin uptake sites. Although (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride has a higher binding affinity for dopamine uptake sites than (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride, the use of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride to inhibit dopamine uptake may be more advantageous than (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride because it is specific for inhibiting dopamine uptake. In other words, the use of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride prevents the adverse side effects associated with inhibiting norepinephrine uptake and serotonin uptake, such as hypertension and sexual dysfunction.

Successful inhibition of dopamine reuptake has been shown to be associated with the treatment of attention deficit disorders, depression, obesity, Parkinson's disease, tic disorders and addictive disorders (Hitri et al, 1994, Clin. Pharmacol.17: 1-22; Noble, 1994, Alcohol supp.2: 35-43; and Blum et al, 1995, Pharmacogenetics 5: 121-. Because of its specificity for inhibiting dopamine uptake, (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, or a pharmaceutically acceptable salt thereof, is more advantageous than (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride, or a pharmaceutically acceptable salt thereof, in treating or preventing a condition which can be alleviated by inhibition of dopamine reuptake in a patient.

The scope of the invention is not limited to the specific embodiments disclosed in the examples, which are intended to illustrate several aspects of the invention, and any embodiments that are functionally equivalent are within the scope of the invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are within the scope of the claims.

The various references cited are incorporated by reference herein in their entirety.

Claims (14)

1. (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof, each substantially free of its corresponding (+) -enantiomer.

2. A composition comprising an effective amount of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof, each substantially free of its corresponding (+) -enantiomer.

3. The composition of claim 2, wherein the composition further comprises an additional therapeutic agent.

4. Use of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, each substantially free of its corresponding (+) -enantiomer, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a condition which can be alleviated by inhibition of dopamine reuptake.

5. Use of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, each substantially free of its corresponding (+) -enantiomer, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a condition which is alleviated by inhibition of dopamine reuptake, wherein the condition is selected from the group consisting of attention deficit disorder, depression, obesity, parkinson's disease, and tic condition.

6. Use of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, each substantially free of its corresponding (+) -enantiomer, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a condition which is alleviated by inhibition of dopamine reuptake, wherein the condition is an addictive condition.

7. Use of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, each substantially free of its corresponding (+) -enantiomer, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of attention deficit disorder.

8. Use of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, each substantially free of its corresponding (+) -enantiomer, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing depression in a patient.

9. Use of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, each substantially free of its corresponding (+) -enantiomer, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of obesity in a patient.

10. Use of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, each substantially free of its corresponding (+) -enantiomer, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing parkinson's disease in a patient.

11. Use of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, each substantially free of its corresponding (+) -enantiomer, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing an addictive disorder in a patient.

12. Use of (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, each substantially free of its corresponding (+) -enantiomer, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a tic disorder in a patient.

13. A process for obtaining (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane according to claim 1, comprising the steps of:

(a) flowing a solution of an organic eluent and (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane through a chiral polysaccharide stationary phase to provide a first fraction comprising (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane; and

(b) the first fraction is passed over a chiral polysaccharide stationary phase to provide a second fraction containing (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane substantially free of its corresponding (+) -enantiomer.

14. A process for obtaining (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane according to claim 1, comprising the steps of:

(a) flowing a solution of an organic eluent and (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane through a chiral polysaccharide stationary phase to provide a first fraction comprising (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane;

(b) concentrating the first fraction to provide a residue; and

(c) passing a solution of the organic eluent and the residue through the chiral polysaccharide stationary phase to provide a second fraction containing (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane substantially free of its corresponding (+) -enantiomer.