HK1065794A - (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions and uses thereof - Google Patents

Description

(+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Hexane (C) And composition and application thereof

1. Technical Field

The present invention relates to (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and pharmaceutically acceptable salts thereof, compositions comprising (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salts thereof, and methods for treating or preventing the recurrence of depression, anxiety, eating disorders, or urinary incontinence in a patient comprising administering (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salts thereof to the patient.

2. Background of the invention

Depression is one of the most common mental disorders, with an incidence of more than 10% in the general population. Depression is characterized by intense sadness of emotion, disappointment, mental relaxation, decreased concentration, pessimistic anxiety, agitation, and self-depreciation (Harrison's Principles of internal Medicine 2490-. Depression can have physical symptoms including insomnia, hypersomnia, anorexia, weight loss, overeating, decreased vitality, decreased libido, and a disruption in the circadian rhythm of 24 hours with normal activity, body temperature, and endosine function. In fact, as many as 10% to 15% of depressed individuals exhibit suicidal behavior. Baldessoini, drugs and treatment of psychiatric disorders: depression and mania, Goodman and Gilman's The Pharmacological basis of Therapeutics431 (9 th edition, 1996).

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

Administration of a racemate, i.e., a mixture of the 50: 50, (+) -and (-) -enantiomers of any drug, such as (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, to a patient may have some disadvantages. First, the pharmacological activity of the racemic mixture may be lower than one of its enantiomers, representing the inherent inefficiencies of racemic drugs. Second, the racemic mixture is more toxic to the patient than one of its enantiomers, so that administration of the racemic mixture may cause the patient to experience undesirable side effects.

Thus, there is a clear need in the art for an enantiomer of (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane that is preferably substantially free of the corresponding opposite enantiomer that overcomes one or both of the above-mentioned disadvantages.

Any reference cited in section 2 of this application for identification is not to be taken 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 for treating or preventing the recurrence of depression in a subject.

The 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 composition of the present invention may further comprise a pharmaceutically acceptable excipient. These compositions are useful for treating or preventing the recurrence of depression in a patient.

In another embodiment, the invention provides a method of treating or preventing the recurrence of depression in a patient, comprising administering to the 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 yet another embodiment of the present invention, there is provided a method of treating or preventing the recurrence of anxiety, eating disorders, or urinary incontinence in a patient, which comprises 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, particularly when used in the methods or compositions of the present invention, is substantially free of its corresponding (-) -enantiomer, namely (-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane. Such enantiomeric purity can be obtained by using chromatographic resolution techniques such as chiral chromatography or simulated moving bed techniques, or by chemical separation using optically active resolving agents.

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

Applicants have discovered that (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, and pharmaceutically acceptable salts thereof, surprisingly and unexpectedly has greater activity than (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane for use in treating or preventing the recurrence of depression in a patient.

4.1. Definition of

The term "substantially free of its corresponding (-) -enantiomer" is defined to mean containing up to about 5% w/w of the corresponding (-) -enantiomer, preferably up to about 2% w/w of the corresponding (-) -enantiomer, more preferably up to 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, is defined to mean "(-) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane" or a pharmaceutically acceptable salt thereof.

"patient" refers to an animal, including without limitation animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, and guinea pigs, more preferably mammals, and most preferably humans.

The phrase "pharmaceutically acceptable salt" as used herein refers to a salt formed between an acid and the basic nitrogen group of (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane. Preferred salts include, without limitation, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, 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 (glucaronate), sucrose, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1, 1' -methylene-bis- (2-hydroxy-3-naphthoate)).

4.2 (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Hexane (C)

(+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, preferably substantially free of its corresponding (-) -enantiomer, can 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 by the method disclosed in U.S. patent No. 4,435,419 to Epstein et al.

In a preferred embodiment, (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane is obtained by resolution of (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane using a chiral polysaccharide stationary phase and an organic eluent. Preferably, the polysaccharide is starch or a starch derivative. Advantageously, a Chiral HPLC column may be used, such as CHIRALPAK AD column manufactured by Daicel and available from chiraltechnologies, inc., Exton, pa, more preferably a 1cm x 25cm CHIRALPAK AD HPLC column. The preferred eluent is a hydrocarbon solvent that is polar-adjusted with a miscible polar organic solvent. Preferably, the organic eluent comprises from about 95% to about 99.5% (v/v) of a non-polar hydrocarbon solvent and from about 5 to about 0.5% (v/v) of a polar organic solvent. In a preferred embodiment, the hydrocarbon solvent is hexane and the miscible polar organic solvent is isopropylamine.

In another preferred embodiment, (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane can be resolved using another alternative chromatographic procedure known as Simulated Moving Bed (SMB) chromatography. In the pharmaceutical industry, SMB has gradually become the method of choice for large-scale enantiomeric separations (see Chemical and engineering News, 2001, volume 79, phase 20, page 47).

In yet another embodiment, (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane may be obtained by resolving the racemic (. + -.) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane using an optically active resolving acid by forming a salt of the resulting enantiomer and subsequently isolating the salt. Common chiral acids used for this purpose include: tartaric and O-acyl tartaric acids, mandelic and O-substituted mandelic acids, 1 '-binaphthyl-2, 2' -diyl hydrogen phosphate, camphoric acid, camphorsulfonic acid, and other readily available optically active acids (both commercially available and readily synthesized).

For a general discussion of the separation of stereoisomers, see Eliel and Wilen, the stereochemistry of organic compounds; wiley: 1994, 297-464, and references incorporated therein.

4.3. (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Therapeutic uses of hexanes

According to the present invention, (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof can be administered to a patient, preferably a mammal, more preferably a human, for the treatment or prevention of conditions including, but not limited to, depression, anxiety, eating disorders and urinary incontinence. In one embodiment, "treatment" or "treating" refers to an improvement in the disorder or at least one identifiable symptom thereof. In another embodiment, "treating" or "treatment" refers to an improvement in at least one measurable physical parameter, not necessarily patient-recognizable. In yet another embodiment, "treating" or "treatment" refers to physically or physiologically or both physically and physiologically inhibiting the progression of such disorders, wherein physical inhibition may, for example, identify the normalization of symptoms and physiological inhibition may, for example, normalize a physical parameter. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of such disorders.

4.3.1 Using (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Hexane for depression The symptoms are relieved

In certain 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 against the recurrence of depression. As used herein, "prevention" or "prevention" refers to a reduction in the risk of recurrence in a patient suffering from depression. 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 against relapse. According to this embodiment, the patient may have a genetic predisposition to depression, such as a family history of biochemical disturbances in the brain, or a non-genetic predisposition to depression. Thus, (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and pharmaceutically acceptable salts thereof can be used to treat one manifestation of depression and can be used to prevent the other.

(+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and pharmaceutically acceptable salts thereof are also useful in the treatment or prevention of endogenous depression, unipolar depression, exercise-inhibited depression, catatonic depression, bipolar depression, postpartum depression, depression with anxiety, depression with obsessive compulsive disorder, depression with disorders that can cause seizures, dysthymia, seasonal affective disorder, diurnal mood changes, depression associated with menopause, and the recurrence of depression associated with medical disorders, alcohol, or substance abuse.

4.3.2 Using (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Hexane for anxiety The symptoms are relieved

(+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and pharmaceutically acceptable salts thereof are also useful in the treatment or prevention of recurrence of anxiety (for a review of anxiety see Derogatiss L.R. & Wise, T.N., "anxiety and depression in medical patients," Washington, DC, American Psychiatric Press, 1989, and references cited therein). Such conditions include, without limitation, panic disorder; panic attacks; agoraphobia; generalized anxiety disorder; obsessive-compulsive disorder; phobias and post-traumatic stress disorder, some of which may be further sub-classified as listed below.

Phobic-related conditions include, without limitation, specific phobias such as hypertension, pain fear, spider phobia, flash point phobia, aviphobia (Aviaphobia), claustrophobia, canine phobia, terrorism (Demophobia), hemophobia, solitary phobia, night phobia, disease phobia, flame phobia, death phobia, and animal phobia; generalized social phobia; specific social phobia and non-specific (NOS) phobia.

Obsessive-compulsive related disorders include, without limitation, trichotillomania, somatoform disorders, picnic disorders, tic disorders; tourette's syndrome and non-specific (NOS) obsessive-compulsive disorder.

Conditions associated with post-traumatic injury include, without limitation, acute stress disorder; and non-specific (NOS) post-traumatic conditions.

4.3.3 Using (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.01]Slowing down with hexane Other symptoms of remission

Other conditions which may be alleviated by (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane also include eating disorders and urinary incontinence and are not limited to the specific conditions described herein, as many types of conditions may be manifested by a particular primary condition. For example, attention-deficit hyperactivity disorder can manifest itself in the form of alcohol abuse, drug abuse, obsessive-compulsive behavior, learning disorders, reading problems, gambling, manic symptoms, phobias, panic attacks, oppositional aggressive behavior, commanding behavior, school problems in school, smoking, allergic sexual behavior, schizophrenic behavior, somatization symptoms, depression, sleep disorders, generalized anxiety, stuttering, and tic disorders, as disclosed by Blum in U.S. patent No. 6,132,724. Furthermore, many of The clinical terms used herein for specific diseases can be found in The quick reference to The diagnostic criteria obtained from DSM-IV (handbook of diagnosis and statistics of psychosis, fourth edition), The American Psychiatric Association, Washington, D.C., 1994, page 358. Specific disorders related to the indicated disorder may also be found in such reference. In addition, a detailed discussion of eating disorders can be found in. For further discussion of urinary incontinence and related disorders, see.

Eating disorders include, without limitation, anorexia nervosa; binge-eating disorder; bulimia nervosa, non-purgative; purgative bulimia nervosa; and Nonspecific (NOS) feeding disorders.

Urinary incontinence includes, without limitation, urge incontinence; stress incontinence; (ii) overflow incontinence; functional incontinence; neurogenic incontinence and post-prostatectomy incontinence.

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 pharmaceutically acceptable salts thereof 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 can be used to treat or prevent the recurrence of depression, anxiety, eating disorders and conditions associated with urinary incontinence in a subject.

When administered to a subject, (+) -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 or may not contain pharmaceutically acceptable excipients. The compositions of the present invention comprising (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof are preferably administered orally. The compositions of the invention may also be administered by any other conventional route, for example by infusion or bolus injection, absorption through epithelial or mucosal layers (e.g. oral mucosa, rectal, and small intestinal mucosa, etc.) and may be administered together with another biologically active substance. Systemic administration or local administration may be carried out. Various delivery systems are known, for example, encapsulation in liposomes, microparticles, microcapsules, and the like and can be used to administer (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and pharmaceutically acceptable salts thereof.

In certain 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, without limitation, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical administration, particularly to the ear, nose, eye, or skin. The physician has the right to decide the mode of administration. 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 blood stream.

In certain embodiments, 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 done, for example, without limitation, by local infusion during surgery, by local application, for example, in conjunction with a wound dressing after surgery, by injection, by catheter, suppository, or by an implant that is a porous, non-porous, or gelatinous material, including membranes such as sialastic membranes, or fibers.

In certain embodiments, it is 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 injection, intrathecal injection, and epidural injection. Intraventricular injections can be facilitated by the use of an intraventricular catheter connected to a reservoir, such as an Ommaya reservoir.

Pulmonary administration can also be used, for example by preparation using an inhaler or nebulizer and with an aerosolizing agent, or by infusion in fluorocarbons or synthetic pulmonary surfactants. In certain embodiments, (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and pharmaceutically acceptable salts thereof can be prepared as suppositories with conventional binders and excipients such as triglycerides.

In another embodiment, (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Hexane and pharmaceutically acceptable salts thereof can be delivered in vesicles, particularly liposomes (see Langer, 1990, Science)249: 1527 and 1533; treat et al, liposomes in the treatment of infectious diseases and cancer, Lopez-Berestein and Fidler (ed.), Liss, New York, p. 353-365 (1989); Lopez-Berestein, supra, page 317-; see generally, supra).

In yet another embodiment, (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Hexane and pharmaceutically acceptable salts thereof can be delivered in the form of a controlled release system (see, for example, Goodson, medical applications for controlled release, supra, Vol.2, pp.115-138 (1984)). Other controlled release systems discussed in the review may be used, Langer, 1990, Science 249: 1527-1533). In one embodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. biomed. Eng.14: 201; buchwald et al, 1980, Surgery88: 507 Saudek et al, 1989, N.Engl.J.Med.321: 574). In another embodiment, polymers may be used (see controlled release medical applications, Langer and Wise, ed., CRC Pres., Boca Ra)ton, Florida (1974); bioavailability of controlled release drugs, design and performance of drug products, Smolen and Ball (ed.), 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, JNeurosurg.71: 105). In yet another embodiment, a controlled release system may also be placed on the targeting agent (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]The proximity of hexane or a pharmaceutically acceptable salt thereof, for example, to target the spine or brain, requires only a small fraction of systemic administration.

The compositions of the present invention may or may not contain a suitable amount of a pharmaceutically acceptable excipient to provide a suitable form of administration to a patient.

In certain embodiments, the term "pharmaceutically acceptable" is defined to mean approved by an authority of the federal or a state government for use in animals, mammals, and, more particularly, humans or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia. The term "excipient" is defined to mean a diluent, adjuvant, vehicle, or carrier with which the compound of the invention is administered. Such pharmaceutical excipients may be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutically acceptable excipient may be saline, gum arabic, gelatin, starch slurry, talc, keratin, colloidal silica, urea, or the like. In addition, adjuvants, stabilizers, thickeners, lubricants and colorants may also be used. The pharmaceutically acceptable excipient is preferably sterile when administered to a patient. Water is a preferred excipient when the compounds of the invention are administered intravenously. Saline solutions as well as aqueous dextrose and glycerol solutions may also be employed as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients also include excipients (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, ethylene 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, liquid-containing capsules, powders, sustained release formulations, suppositories, emulsions, aerosols, sprays, suspensions or any other form suitable for use. In one embodiment, the pharmaceutically acceptable excipient is a capsule (see, e.g., U.S. patent No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington's pharmaceutical Sciences, Alfonso R.Gennaro, eds, Mack publishing Co.Easton, Pa, 19 th edition, 1995, pages 1447 to 1676, which are 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 prepared by conventional means into a pharmaceutical composition suitable for oral administration to a human. Compositions for oral delivery 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 contain one or more agents to provide a palatable pharmaceutical preparation, e.g., a sweetening agent such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; a colorant; and a preservative. In addition, in the case of tablet or pill form, the composition may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a prolonged period of time. Selectively permeable membranes surrounding a compound that osmotically drives an active agent are also suitable for compositions for oral administration. In these latter platforms, liquid from the environment surrounding the capsule is absorbed by the driving compound, which expands to displace the agent or composition through a small hole. This delivery plateau may provide a substantially zero order delivery profile as opposed to the peak profile of an immediate release formulation. A time delay material such as glyceryl monostearate or glyceryl stearate may also be used. Oral compositions may include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose and magnesium carbonate. Such excipients are preferably of pharmaceutical grade. Compositions for intravenous administration typically comprise sterile isotonic aqueous buffer. Where desired, the composition may also include a solubilizing agent.

In another embodiment, (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, or a pharmaceutically acceptable salt thereof, can be prepared for intravenous administration. Compositions for intravenous administration may or may not include a local anesthetic such as lidocaine to reduce pain at the injection site. Generally, the components are supplied separately or mixed together in a unit dosage form, for example, as a dry lyophilized powder or a non-aqueous concentrate in a hermetically sealed container such as an ampoule or sachet indicating the amount of active substance. For example, where (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is to be administered by infusion, it may be dispersed, for example, in an infusion vial containing sterile pharmaceutical grade water or saline. In the case where (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is administered by injection, an ampoule of sterile water or saline for injection 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 that is effective to treat a particular depression, anxiety, eating disorder or disorder associated with urinary incontinence will depend on the nature of the disorder or condition and can be determined by standard clinical techniques. In addition, in vivo or in vitro experiments can be used as desired to help determine the optimal dosage range. The precise dose employed will also depend on the route of administration and the severity of the disease or condition, and should be decided according to the judgment of the practitioner and the details of the individual patient. However, suitable dosage ranges for oral administration are generally from about 0.2 mg to about 2.0 mg (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, or a pharmaceutically acceptable salt thereof, per kg body weight per day. In certain preferred embodiments of the invention, the oral dosage is from about 0.01 mg to about 100 mg per kg of body weight per day, more preferably from about 0.1 mg to about 75 mg per kg of body weight per day, more preferably from about 0.5 mg to about 50 mg per kg of body weight per day, and still more preferably from about 1mg to about 30 mg per kg of body weight per day. In another preferred embodiment, the oral dosage is from about 1mg to about 3 mg of (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof of the present invention per kg body weight per day. The dosage referred to herein refers to the total amount administered; that is, if (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and/or one or more pharmaceutically acceptable salts thereof is administered, the preferred dosage corresponds to the total amount administered. Oral compositions preferably comprise from about 10% to about 95% by weight of the active ingredient.

Suitable dosage ranges for intravenous (i.v.) administration are from about 0.01 to about 100 mg per kg of body weight per day, from about 0.1 to about 35 mg per kg of body weight per day, and from about 1 to about 10 mg per kg of body weight per day. Suitable dosage ranges for intranasal administration are generally from about 0.01pg/kg body weight per day to about 1mg/kg body weight per day. Suppositories will 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 kg 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, vaginal, transdermal or inhalation administration, the recommended dosage is in the range of about 0.001 mg to about 200 mg per kg body weight per day. Suitable dosages for topical administration range from about 0.001 mg to about 1mg, depending on the area of administration. Effective doses can be extrapolated using dose-response curves derived from in vitro assays or animal model experimental systems. Such animal models and systems are well known in the art.

The 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 container(s) may or may not contain a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale of substances for administration to humans. In certain 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 a pharmaceutically acceptable salt thereof.

Prior to human use, (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and pharmaceutically acceptable salts thereof are preferably tested in vitro or in vivo for the desired therapeutic or prophylactic activity. For example, in vitro assays may be used to determine whether it may be preferably administered using (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, a pharmaceutically acceptable salt thereof, and/or an additional therapeutic agent. 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 certain 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. The effects of (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof and the other therapeutic agent may be additive, more preferably synergistic. In a preferred embodiment, a composition comprising (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is administered concurrently with another therapeutic agent, either as part of the same composition or a different composition than the composition comprising (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof. In another embodiment, a composition comprising (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, or a pharmaceutically acceptable salt thereof, is administered prior to or after administration of the additional therapeutic agent. Because many of the conditions being treated with (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and pharmaceutically acceptable salts thereof are chronic, in one embodiment the combination therapy comprises 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 other therapeutic agent can be, for example, one month, three months, six months, one year, or longer, such as for life-long administration to a patient. In certain embodiments, when the compositions of the present invention are administered concurrently with additional therapeutic agents that may cause adverse side effects, including, without limitation, toxicity, the additional therapeutic agents may advantageously be administered at a dosage below the threshold that may cause the adverse side effects.

The other therapeutic agent may be an antidepressant. Useful antidepressants include, without limitation, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, fluoxetine, fluvoxamine, paroxetine, setraline, venlafaxine, bupropion, nefazodone, trazodone, pheuelzine, tranylcypromine, and selegiline.

The other therapeutic agent may be an anxiolytic agent. Useful anxiolytics include, without limitation, benzodiazepines  classes such as alprazolam, clonazepam , clonazepam , diazepam, halazepam, lorazepam, oxazepam, and pramipepam; non-benzodiazepines , such as buspirone; and tranquilizers, such as barbiturates (barbiturates).

The other therapeutic agent may be an antipsychotic. Useful antipsychotics include, without limitation, phenothiazines, such as chlorpromazine, mesoridazine besylate, thioridazine, acetophenazine maleate, fluphenazine, perphenazine, and trifluoperazine; thioxanthenes, such as chlorthioxanthene, and thiothioxanthene; and other heterocyclic compounds such as clozapine, haloperidol, loxapine, molindone, pimozide, and risperidone. Preferred antipsychotic agents include chlorpromazine HCl, thioridazine HCl, fluphenazine HCl, thiothixene HCl, and molindone HCl.

The other therapeutic agent may be an anti-obesity agent. Anti-obesity agents for use in combination with the compounds of the present invention include, without limitation, beta-adrenergic receptor agonists, preferably beta-3 receptor agonists: fenfluramine; d-fenfluramine; sibutramine; bupropion; fluoxetine; phentermine; amphetamine; methamphetamine; dextro-amphetamine; benzphetamine; phendimetrazine; fenmetrazine; bupropion; mazindol; and phenylpropanolamine.

Detailed Description

5. Example (b): (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.01 hexane

5.1 Resolution of racemates by chiral chromatography

To a patient treated with Epstein et al, j.med.chem,24: 481-490(1981) 279mg of (. + -.) -1- (3, 4-dichlorophenyl) -3-azabicyclo [ 3.1.0)]To the hexane hydrochloride was added 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 with a helium gas stream and the concentrate was used in 6 1-mL concentrates for high performance liquid chromatography using an HPLC instrument equipped with a 1cm x 25cm Daicel CHIRALPAK AD column (chiraltechnologies, inc., Exton, pa). At ambient temperatureElution was performed with a 95: 5(v/v) hexane: isopropanol solution containing 0.05% diethylamine as the mobile phase, at a flow rate of 6 mL/min. The eluate is collected for about 21.5 to 26 minutes and concentrated to give a first residue, which is dissolved with a minimum amount of ethyl acetate. The ethyl acetate solution was evaporated with a nitrogen stream to give a second residue, which was dissolved in 1mL of diethyl ether. To the diethyl ether solution was added 1mL of diethyl ether saturated with gaseous hydrochloric acid. A colourless precipitate formed which was filtered off, washed with 2mL diethyl ether and dried to give 73.4mg (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Hexane hydrochloride salt: optical rotation [ alpha ] in methanol at 2mg/ml]25D +60 °; 99.7% enantiomeric excess.

5.2 By using L-di- (O-benzoyl) tartaric acid as chiral resolving agent Resolution of racemates

A sample of 2.68g (0.0101mol) (. + -.) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride as described in Epstein et al, J.Med.chem., 1981, 24, 481-490 was dissolved in 50mL of water and the solution was made alkaline to pH 11 with 10N sodium hydroxide solution and the precipitated free base was extracted into 25mL of dichloromethane. The solution was dried over sodium sulfate and filtered. To the filtrate was added a solution of 3.70g (0.1030mol) L-di- (O-benzoyl) tartaric acid in 25mL of methanol, and this solution was boiled until crystallization occurred. The mixture was cooled to room temperature and allowed to stand for 1 hour. The crystals were collected to give 3.21g of colorless crystals, which were boiled in 50mL of methanol, and this mixture was cooled with an ice bath and then filtered to give 2.04g of colorless crystals, which were the mono-salt of (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and L-bis- (O-benzoyl) tartaric acid having an m.p. of 185-187 ℃. The salt was stirred with 5N aqueous sodium hydroxide and the free base liberated was extracted into ethyl acetate. The organic layer was washed with a dilute aqueous sodium hydroxide solution, then with water, and then dried with sodium sulfate. Filtration and treatment of the filtrate with HCl solution in ether until no further precipitation occurred. The crystals were collected by filtration and air dried to give 0.748g of (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride as colorless crystals m.p.173-173 ℃, (. alpha.) +64.2 °, C. ═ 6.7, MeOH, which was essentially free of the corresponding (-) -enantiomer.

6. Example (b): (+) -1- (3, 4-dichlorophenyl) -3-chloroheterobicyclo [3.1.0]Hexane and (±) -1- (3, 4 dichlorophenyl) -3-azabicyclo [3.1.0]Comparison of Hexane Activity

6.1. Norepinephrine transporter binding assay

The antidepressant properties of (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride and of (. + -.) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride were compared using a standard norepinephrine transporter binding assay.

6.1.1. Materials and methods

Noradrenaline binding assays were performed using Raisman et al, Eur.J. Pharmacol.78: 345-351(1982) and Langer et al, Eur.J. Pharmacol.72: 423 (1981). The source of the receptor is the rat's forebrain membrane; the radioligand is [ alpha ], [ beta ], [ alpha ] having a final ligand concentration of 1.0nM³H]-guaifenesin (60-85 Ci/mmol); nonspecific stator [1.0 μm](ii) a The reference compound and positive control were (±) -desmethyl imipramine HCl. (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Hexane HCl was obtained by the method of example 5 above. The reaction was carried out in 50mM Tris-HCl (pH 7.4) containing 300mM NaCl and 5mM KCl at 0 ℃ to 4 ℃ for 4 hours. The reaction was terminated by rapid vacuum filtration on a glass fiber filter. The radioactivity trapped in the filter is measured and compared to control values to determine the interaction of the test compound with the noradrenaline uptake site. The data are reported in table 1 below.

6.1.2. Results

Table 1: norepinephrine transporter binding assay

Compound (I) Ki

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

(+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Hexane HCl 8.20X 10^-8

(±) -demethylimipramine HCl 1.13 × 10^-9

The data in Table 1 show that the affinity of (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane HCl for the noradrenaline uptake site is much higher than that of (. + -.) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane HCl. Successful inhibition of norepinephrine reuptake has been linked to The treatment of one or more symptoms of depression (R.J. Baldesarini, drugs and treatments for psychiatric disorders: depression and mania, ingGoodman & Gilman's The Pharmacological Basis of Therapeutics431-459 (9 th edition 1996)). Thus, the activity of (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof will be substantially greater than (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof for the treatment or prevention of recurrence of depression in a patient.

6.2. Serotonin transporter binding assays

The antidepressant properties of (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride and of (. + -.) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride were compared using a standard serotonin transporter binding assay.

6.2.1. Materials and methods

Serotonin binding assays were performed using D' Amato et al, J.242: 364-.123: 161-165 (1986). The source of the receptor is the rat's forebrain membrane; the radioligand is [ 2 ] having a final ligand concentration of 0.7nM³H]-citalopram (70-87 Ci/mmol); the non-specific stator being clomipramine [10 μm ]](ii) a And the reference compound and positive control were (±) -desmethyl imipramine. (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Hexane HCl was obtained by 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 60 minutes to complete. The reaction was terminated by rapid vacuum filtration on a glass fiber filter. The radioactivity trapped in the filter is measured by liquid scintillation spectrometry and compared to control values to determine the interaction of the test compound with the serotonin transporter binding site. The data are reported in table 2 below.

6.2.2 Results

Table 2: serotonin transporter binding assays

Compound (I) Ki

(±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Hexane HCl 1.18X 10^-7

(+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0]Hexane HCl 5.08X 10^-8

(±) -demethylimipramine HCl 2.64 × 10^-8

The data in Table 2 show that the affinity of (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane HCl for the serotonin uptake site is much higher than the affinity of (. + -.) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane HCl for the site. Successful inhibition of serotonin reuptake has been linked to The treatment of one or more symptoms of depression (R.J. Baldesarini, drugs and treatments for psychiatric disorders: depression and mania, in Goodman & Gilman's The Pharmacological Basis of Therapeutics431-459 (9 th edition 1996)). Thus, the activity of (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof will be substantially greater than (±) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof for the treatment or prevention of recurrence of depression in a patient.

The scope of the invention is not to be limited by the specific embodiments disclosed in the examples, which are intended as illustrations of 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 intended to fall within the scope of the appended claims.

A number of references are cited herein, the entire disclosures of which are incorporated herein by reference.

Claims (38)

1. (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof, each substantially free of its corresponding (-) -enantiomer.
2. 2. (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof according to claim 1 having up to about 2% w/w of the corresponding (-) -enantiomer.
3. 3. (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof according to claim 1 having up to about 1% w/w of the corresponding (-) -enantiomer.
4. 4. 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.
5. 5. The composition of claim 4, further comprising a pharmaceutically acceptable carrier or excipient.
6. 6. The composition of claim 4, further comprising an additional therapeutic agent.
7. 7. The composition of claim 6, wherein the additional therapeutic agent is an antidepressant.
8. 8. The composition of claim 6, wherein the other therapeutic agent is an anxiolytic.
9. 9. The composition of claim 6, wherein the additional therapeutic agent is an antipsychotic.
10. 10. The composition of claim 6, wherein the additional therapeutic agent is an anti-obesity agent.
11. 11. The composition of claim 7, wherein the antidepressant is selected from the group consisting of amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, fluoxetine, fluvoxamine, paroxetine, setraline, venlafaxine, bupropion, nefazodone, trazodone, pheuelzine, tranylcypromine, and selegiline.
12. 12. The composition according to claim 8, wherein the anxiolytic is selected from the group consisting of alprazolam, chlorine nitrogen , clonazepam, clonazepate, diazepam, halazepam, lorazepam, oxazepam, pramipepam, and buspirone.
13. 13. The composition according to claim 9, wherein the antipsychotic agent is selected from chlorpromazine, mesoridazine besylate, thioridazine, acetophenazine maleate, fluphenazine, perphenazine, trifluoperazine, chlorprothixene, thiothixene, clozapine, haloperidol, loxapine, molindone, pimozide, and risperidone.
14. 14. The composition according to claim 10, wherein the anti-obesity agent is selected from the group consisting of fenfluramine, dexfenfluramine, sibutramine, bupropion, fluoxetine, phentermine, amphetamine, methamphetamine, dextroamphetamine, benzphetamine, phendimetrazine, phenmetrazine, bupropion, mazindol, and phenylpropanolamine.
15. 15. A method of treating or preventing the recurrence of depression in a patient in need of such treatment or prevention, which comprises 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, each substantially free of its corresponding (-) -enantiomer.
16. 16. The method of claim 15, wherein the (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof has up to about 2% w/w of the corresponding (-) -enantiomer.
17. 17. The method of claim 15, wherein the (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof has up to about 1% w/w of the corresponding (-) -enantiomer.
18. 18. The method of claim 15, wherein the depression is selected from the group consisting of endogenous depression, unipolar depression, movement-suppressing depression, agitated depression, bipolar depression, post-partum depression, depression with anxiety, depression with obsessive compulsive disorder, depression with disorders that can cause seizures, dysthymia, seasonal affective disorder, diurnal mood changes, depression associated with menopause, depression associated with medical disorders, depression associated with alcohol, and depression associated with substance abuse.
19. 19. The method of claim 16, wherein the depression is selected from the group consisting of endogenous depression, unipolar depression, movement-suppressing depression, agitated depression, bipolar depression, post-partum depression, depression with anxiety, depression with obsessive compulsive disorder, depression with disorders that can cause seizures, dysthymia, seasonal affective disorder, diurnal mood changes, depression associated with menopause, depression associated with medical disorders, depression associated with alcohol, and depression associated with substance abuse.
20. 20. The method of claim 17, wherein the depression is selected from the group consisting of endogenous depression, unipolar depression, movement-suppressing depression, agitated depression, bipolar depression, post-partum depression, depression with anxiety, depression with obsessive compulsive disorder, depression with disorders that can cause seizures, dysthymia, seasonal affective disorder, diurnal mood changes, depression associated with menopause, depression associated with medical disorders, depression associated with alcohol, and depression associated with substance abuse.
21. 21. A method of treating or preventing the recurrence of anxiety in a patient in need of such treatment or prevention comprising administering to a patient in need thereof 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.
22. 22. The method of claim 21, wherein the (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof has up to about 2% w/w of the corresponding (-) -enantiomer.
23. 23. The method of claim 21, wherein the (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof has up to about 1% w/w of the corresponding (-) -enantiomer.
24. 24. The method of claim 21, wherein the anxiety disorder is selected from the group consisting of panic disorder, panic attack, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, phobias, and post-traumatic stress disorder.
25. 25. The method of claim 22, wherein the anxiety disorder is selected from the group consisting of panic disorder, panic attack, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, phobias, and post-traumatic stress disorder.
26. 26. The method of claim 23, wherein the anxiety disorder is selected from the group consisting of panic disorder, panic attack, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, phobias, and post-traumatic stress disorder.
27. 27. A method of treating or preventing the recurrence of eating disorders in a patient, which comprises 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, each substantially free of its corresponding (-) -enantiomer.
28. 28. The method of claim 27, wherein the (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof has up to about 2% w/w of the corresponding (-) -enantiomer.
29. 29. The method of claim 27, wherein the (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof has up to about 1% w/w of the corresponding (-) -enantiomer.
30. 30. The method of claim 27, wherein the eating disorder is selected from the group consisting of anorexia nervosa, Binge-eating disorder, bulimia nervosa non-purgative, and bulimia nervosa purgative.
31. 31. The method of claim 28, wherein the eating disorder is selected from the group consisting of anorexia nervosa, Binge-eating disorder; bulimia nervosa of non-purgative type and bulimia nervosa of purgative type.
32. 32. The method of claim 29, wherein the eating disorder is selected from the group consisting of anorexia nervosa, Binge-eating disorder, bulimia nervosa non-purgative, and bulimia nervosa purgative.
33. 33. A method of treating or preventing the recurrence of a urinary incontinence condition in a patient, which method comprises 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, each substantially free of its corresponding (-) -enantiomer.
34. 34. The method of claim 33, wherein the (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof has up to about 2% w/w of the corresponding (-) -enantiomer.
35. 35. The method of claim 33, wherein the (+) -1- (3, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or pharmaceutically acceptable salt thereof has up to about 1% w/w of the corresponding (-) -enantiomer.
36. 36. The method of claim 33, wherein the urinary incontinence disorder is selected from the group consisting of urge incontinence; stress urinary incontinence, overflow incontinence, functional incontinence, neurogenic incontinence and post-prostatectomy incontinence.
37. 37. The method of claim 34, wherein the urinary incontinence disorder is selected from the group consisting of urge incontinence, stress incontinence, overflow incontinence, functional incontinence, neurogenic incontinence and post-prostatectomy incontinence.
38. 38. The method of claim 35, wherein the urinary incontinence disorder is selected from the group consisting of urge incontinence, stress incontinence, overflow incontinence, functional incontinence, neurogenic incontinence and post-prostatectomy incontinence.