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    • 专利摘要:
    The present invention relates to (-)-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 or a pharmaceutically acceptable salt thereof, and a method for treating or preventing a disorder alleviated by inhibiting dopamine reuptake. In one embodiment, the disorder is attention-deficiency disorder, depression, obesity, Parkinson's disease, convulsion disorder, or addiction disorder. (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is preferably substantially free of the corresponding (+)-enantiomer.
    公开号:KR20040065549A
    申请号:KR10-2004-7002741
    申请日:2002-08-14
    公开日:2004-07-22
    发明作者:리파아놀드스탠；엡스타인조셉윌리암스
    申请人:도브 파마슈티칼 인코포레이티드；
    IPC主号:
    专利说明:

    (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, compositions thereof, and use as dopamine-reuptake inhibitors {(-)-1- (3,4-DICHLOROPHENYL ) -3-AZABICYCLO [3.1.0] HEXANE, COMPOSITIONS THEREOF, AND USES AS A DOPAMINE-REUPTAKE INHIBITOR}
    [2] Dopamine is a monoamine neurotransmitter that plays an important role in the functioning of the hypothalamic pituitary and the accumulation of information in the sensory, limbic and motor systems. Note mechanism for termination of dopamine neurotransmission is Na + / Cl - is through reuptake of released dopamine by-dependent plasma membrane transporters (lit. [Hoffman et al, 1998, Front Neuroendocrinol 1993...): 187- 231). Depending on the ambient ionic conditions, the dopamine transporter can function as a mediator of inward dopamine transport (ie, "reabsorption") and outward dopamine transport (ie, "release"). The functional importance of the dopamine transporter is in the regulation of dopamine neurotransmission by terminating the action of dopamine at synapses through resorption (see Hitri et al., 1994, Clin. Pharmacol. 17: 1-22). .
    [3] Attention deficit disorder is a learning disorder associated with inattention that is inappropriate for development with or without hyperactivity. The primary signs of attention deficit disorder are the carelessness and impulsivity of the patient. Inappropriate inattention causes an increased rate of activity or rebellion to participate or respond. Patients with attention deficit disorder show more frequent and serious sustained patterns of inattention and / or hyperactivity-impulse than those typically observed in people with comparable developmental levels (see, eg, US Pat. No. 6,121,261 to Glat et al. Reference).
    [4] A patient with Parkinson's disease exhibits limb, head and jaw swinging motions. Parkinson's disease is associated with motor slowness, stiffness and conduction (see Stacy et al., 1996, Am. Fan. Phys. 53: 1281-1287). Behavioral disturbances observed in Parkinson's disease patients result from degeneration of dopamine neurons, damage to nerve endings, and dopamine deficiency. It is hypothesized that the cause of degeneration of dopamine neurons is the result of apoptosis resulting from increased levels of cytokines (see Nagatsu et al., 2000, J. Neural Transm. Suppl. 60 (277-290)). Abnormalities in dopamine transporters have been related to Parkinson's disease (see Hitri et al., 1994, Clin. Neuropharmacol. 17: 1-22) .The signs of Parkinson's disease are associated with pergolides that mimic the action of dopamine. It can be attenuated by the same compound or a compound that inhibits dopamine metabolism (eg carbidopa) or a dopamine precursor (eg L-DOPA ± carbidopa).
    [5] Appetite suppression means a decrease or decrease in appetite, or an amelioration of appetite in case of ingestion of excess food. This inhibition reduces the cravings or cravings for food. Appetite suppression can cause as much weight loss or weight control as desired. Appetite suppression can regulate food absorption through the administration of drugs to one or more systems known to play a role in food digestion (see, eg, Sullivan et al., "Mechanisms of Appetite Modulation By Drugs," Federation Proceedings, Volume 44). No. 1, Part 1, pages 139-144 (1985)). Methods of controlling appetite suppression include controlling serotonin levels, heat generation and fat formation inhibition (see US Pat. No. 5,911,992 to Braswell et al.).
    [6] Depression is one of the most common psychosis, with an incidence of over 10% of the total population. Depression is characterized by emotional states such as strong sad feelings, hopelessness, mental retardation, decreased concentration, pessimistic worry, excitement, and self-deprecation (Harrison's Principles of Internal Medicine 2490-2497 (Fauci). et al. eds., 14 th ed. 1998). Depression can have physical symptoms including insomnia, excessive sleep, anorexia, weight loss, overheating, loss of energy, loss of libido and activity, disruption of the normal circadian rhythm of body temperature and endocrine function. Indeed, 10-15% of depressed individuals exhibit suicidal behavior (RJ Baldessarini, Drugs and the Treatment of Psychiatric Disorders: Depression and Mania, in Goodman and Gilman's The Pharmacological Basis of Therapeutics 431 (9 th ed. 1996). )] Reference). Anesthesia is one of the main symptoms of depression. The dopamine pathway is associated with pleasure seeking behavior and strategies for increasing the synaptic concentration of dopamine have been proposed as antidepressant therapies (see, for example, D'Aquila et al., 2000, Eur. J. Pharmaco. 405: 365-373 ] Reference).
    [7] Obesity is often referred to as increased weight due to overfat. Antiobesity drugs can be divided into three classes: (1) reducing food absorption, for example, drugs that interfere with monoamine receptors such as noradrenergic receptors, serotonin receptors, dopamine receptors and histamine receptors. ; (2) increasing metabolism; And (3) reducing fat absorption or increasing heat generation by inhibiting pancreatic lipase (Bray, 2000, Nutrition 16: 953-960 and Leonhardt et al., 1999, Eur. J. Nutr. 38: 1-13).
    [8] Many drugs can cause physical and / or psychological addiction. Known as such drugs are opiates such as heroin, opiates and morphine; Sympathetic drugs including cocaine and amphetamines; Sedative hypnotics including alcohols, benzodiazepines and barbiturates; And nicotine similar to opioids and sympathetic agents. Drug addiction is characterized by the desire and desire to ingest such drugs and the inability to suppress drug absorption. In addition, drug dependence is associated with drug resistance, loss of repeated dosing and withdrawal effects after drug, and appearance of physical behavioral signs of no drug intake. Sensitization occurs when repeated administration of the drug causes an increased response to each dose. Resistance, sensitization, and withdrawal are phenomena that demonstrate changes in the central nervous system resulting from continuous drug use. This change causes addicts to continue to consume drugs despite serious social, legal, physical and / or occupationally important issues (see US Pat. No. 6,109,269 to Rise et al.). Cocaine addiction remains one of the major health problems in the United States. Basic research in a number of laboratories has shown that cocaine blocks dopamine uptake from synaptic clefts from dopamine transporters (see Kreek, 1996, J. Addict. Dis. 15: 73-96). However, the inhibitory action of cocaine, for example upon reuptake of released dopamine, does not fully explain the development and maintenance of addictive behavior. The persistence of functionally antagonistic inhibitory action upon dopamine release and reuptake of released dopamine can be a source of oscillations in dopamine transport (see Kyatkin, 1994, Int. J. Neurosci. 78: 75-101). ).
    [9] Certain pharmaceutical agents may be administered for the treatment of addiction. US Pat. No. 5,556,838 to Mayer et al. Discloses the use of non-toxic NMDA-blockers administered concurrently with addictive substances to prevent the development of resistance or withdrawal signs. US Pat. No. 5,574,052 to Rose et al. Discloses co-administration of an addictive agent and an antagonist to partially block the pharmacological effects of the substance. Mendelson et al. US Pat. No. 5,075,341 discloses the use of mixed opiate agonists / antagonists to treat cocaine and opiate intoxication. US Pat. No. 5,232,934 to Downs et al. Discloses administration of 3-phenoxypyridine to treat addiction. US Pat. Nos. 5,039,680 and 5,198,459 to Imperato et al. Disclose the use of serotonin antagonists to treat chemical poisoning. US Patent 5,556,837 to Nestler et al. Discloses injecting BDNF or NT-4 growth factors to inhibit or reverse neurological adaptation changes associated with behavioral changes in addicts. Sagan, US Pat. No. 5,762,925, describes encapsulating adrenal myeloid cells in the patient's central nervous system to inhibit the development of opioid intolerance. Bupropion has dopamine reuptake inhibitory properties and is used to treat nicotine poisoning.
    [10] Dopamine reward pathways have been associated with disorders resulting from addictive behavior. Variants of the dopamine D2 receptor gene have been associated with alcoholism, obesity, pathological gambling, attention deficit hyperactivity disorder, Tourette syndrome, cocaine dependence, nicotine dependence, compound abuse and other drug dependence (Noble, 1994, Alcohol). Supp. 1: 35-43 and Blum et al., 1995, Pharmacogenetics 5: 121-141). It has been suggested that dopamine D2 receptors may be either augmenting or compensating genes because degraded dopamine function is found in people with a minor Al allele of the dopamine D2 receptor (Noble, 1994, Alcohol Supp. 2: 35-43). Reference). In addition, several studies suggest that the association of dopamine D2 receptor gene polymorphisms is associated with impulsive drug-dependent compulsive behavior, namely "Reward Deficiency Syndrome" (Blum et al. , 1995, Pharmacogenetics 5: 121-141).
    [11] US Patent No. 4,435,419 to Epstein et al. Discloses racemic (±) -1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane for use as an antidepressant. .
    [12] US Pat. No. 6,204,284 to Beer et al. Discloses racemic (±) -1- (3,4-dichlorophenyl)-for use in the prevention or alleviation of withdrawal syndrome resulting from the addition of drugs or for the treatment of drug dependence. 3-azabicyclo [3.1.0] hexane is disclosed.
    [13] The racemic, ie 50:50, mixture of the (+)-enantiomer and (-)-enantiomer of the drug, for example racemic (±) -1- (3,4-dichlorophenyl) -3-azabicyclo [ 3.1.0] administration of hexane to patients may be disadvantageous. First, racemic mixtures are less pharmacologically active than one of the enantiomers, making racemic drugs inherently inefficient. Second, the racemic mixture is more toxic to the patient than one of the enantiomers, which can result in undesirable side effects in the patient when the racemic mixture is administered.
    [14] Thus, there is a clear need for enantiomers in the art, which enantiomers are preferably substantially free of the corresponding opposite enantiomers, which makes it possible to overcome one or both of the aforementioned disadvantages. .
    [15] The references mentioned in the Background section of this specification should not be construed as prior art herein.
    [16] Summary of the Invention
    [17] In one embodiment, the present invention provides (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and its pharmaceutically acceptable salts. (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and its pharmaceutically acceptable salts are useful for treating or preventing disorders that are alleviated by inhibiting dopamine reuptake. .
    [18] The present invention also provides a composition comprising an effective amount of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof. The invention may further comprise a pharmaceutically acceptable vehicle. The composition is useful for treating or preventing a disorder that is alleviated by inhibiting dopamine reuptake.
    [19] In another embodiment, the invention provides an effective amount of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable thereof to a patient in need thereof. Provided are methods of treating or preventing a disorder alleviated by inhibiting dopamine reuptake, comprising administering a salt.
    [20] In another embodiment, the invention provides an effective amount of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable thereof to a patient in need of treatment or prevention Provided are methods of treating or preventing attention-deficiency disorders, depression, obesity, Parkinson's disease, convulsive disorders or addiction disorders, including administering possible salts.
    [21] Preferably, (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof, especially when used in the process or composition of the present invention, Substantially free of the (+)-enantiomer. In a preferred embodiment, (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is substantially free of (+)-enantiomer. It is used to treat or prevent a disorder that is alleviated by selectively inhibiting resorption. The use according to this preferred embodiment surprisingly and advantageously does not block norepinephrine or serotonin transport, in particular norepinephrine or serotonin uptake. (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof that is substantially free of the corresponding (+)-enantiomer inhibits dopamine absorption It has been unexpectedly found that when used in the treatment or prevention of disorders alleviated by it, side effects such as cardiovascular effects, sleep disturbances, hypertension or sexual dysfunction associated with norepinephrine or serotonin uptake inhibitors can be avoided.
    [22] In another embodiment, the invention provides a solution of (a) an organic eluent and a solution of (±) -1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane through a chiral polysaccharide stationary phase To provide a first fraction containing (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane; And (b) passing the first fraction through a chiral polysaccharide stationary phase to give (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0 substantially free of the (+)-enantiomer. ] (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1. Substantially free of corresponding (+)-enantiomers, comprising providing a second fraction containing hexanes. 0] provides a method for obtaining hexane.
    [23] In another embodiment, the invention provides a solution of (a) an organic eluent and a solution of (±) -1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane through a chiral polysaccharide stationary phase To provide a first fraction containing (-)-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 a chiral polysaccharide stationary phase to give (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [substantially free of (+)-enantiomers. 3.1.0] (-)-1- (3,4-dichlorophenyl) -3-azabicyclo substantially free of the corresponding (+)-enantiomer, comprising providing a second fraction containing hexane [3.1.0] A method of obtaining hexane is provided.
    [24] The invention may be more fully understood by reference to the detailed description and examples which are intended to illustrate non-limiting embodiments of the invention.
    [1] The present invention relates to (-)-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 or a pharmaceutically acceptable salt thereof, and (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] A method of treating or preventing a disorder alleviated by inhibiting dopamine reuptake, comprising administering hexane or a pharmaceutically acceptable salt thereof to a patient.
    [25] 1. Definition
    [26] The term “substantially free of the corresponding (+)-enantiomer” means about 5% w / w or less of the corresponding (+)-enantiomer, preferably about 2% w of the corresponding (+)-enantiomer. / w or less, more preferably about 1% w / w or less of the corresponding (+)-enantiomer.
    [27] The term "corresponding (+)-enantiomer" is used in connection with (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof. "(+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane" or a pharmaceutically acceptable salt thereof.
    [28] The term "patient" is an animal, including but not limited to animals such as cattle, monkeys, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits and guinea pigs, more preferably Is a mammal, most preferably a human.
    [29] The phrase "pharmaceutically acceptable salt" is a salt formed herein from the acid and basic nitrogen groups of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane. Preferred salts are 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, genticinate, fumarate, gluconate, glucaronate, saccharide, fort Mate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (ie 1,1'-methylene-bis- (2-hydroxy-3-naphthoate) )) Salts, including, but not limited to.
    [30] 2. (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane
    [31] Substantially free of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, preferably the corresponding (+)-enantiomer is (±) -1- ( Can be obtained from 3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane using chiral chromatography methods such as high performance liquid chromatography ("HPLC") using a suitable, preferably chiral column have. (±) -1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane can be obtained using the method disclosed in US Pat. No. 4,435,419 to Epstein et al.
    [32] In a preferred embodiment, (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane is an organic eluent and (±) -1- (3,4-dichlorophenyl) -3 Obtained by passing a solution of azabicyclo [3.1.0] hexane through a chiral polysaccharide stationary phase. Preferably, the polysaccharide is a starch or starch derivative. Advantageously, the chiral stationary phase is a chiral HPLC column, for example a CHIRALPAK AD column manufactured by Daicel and commercially available from Chral Technologies, Inc., Exton, Pennsylvania. , More preferably in a 1 cm × 25 cm CHIRALPAK AD HPLC column. Preferred eluents are hydrocarbon solvents in which the polarity is adjusted to a miscible polar organic solvent. Preferably, the organic eluent contains a nonpolar hydrocarbon solvent present at about 95% to about 99.5% (volume / volume) and a polar organic solvent present at about 5 to about 0.5% (volume / volume). In a preferred embodiment, the hydrocarbon solvent is hexane and the miscible polar organic solvent is isopropylamine.
    [33] The organic eluent and a solution of (±) -1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane were passed through a chiral polysaccharide stationary phase to give (-)-1- (3,4- A first fraction (ie, one or more fractions) containing dichlorophenyl) -3-azabicyclo [3.1.0] hexane is provided. The first fraction is passed directly to the chiral polysaccharide stationary phase to give (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane substantially free of the corresponding (+)-enantiomer. Providing a second class (ie, one or more classes) containing Alternatively, the first fraction can be concentrated to provide a residue and diluted with an organic eluent, and the resulting solution is passed through a chiral polysaccharide stationary phase to give (-)-substantially free of the corresponding (+)-enantiomer. A second fraction (ie, one or more fractions) containing 1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane is provided. In both, the second fraction is preferably concentrated in vacuo so that (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0 is substantially free of the corresponding (+)-enantiomer. ] Solid form of hexane can be obtained.
    [34] 3. Therapeutic uses of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane
    [35] According to the invention, (-)-1- (3,4-dichlorophenyl) -3- to patients, preferably mammals, more preferably humans, for the treatment or treatment of a disorder alleviated by inhibiting dopamine reuptake. Azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is administered. In one embodiment, “treatment” or “treatment” refers to amelioration of the disorder, or one or more recognizable symptoms thereof, that is alleviated by inhibiting dopamine reuptake. In other embodiments, “treatment” or “treatment” refers to the improvement of one or more measurable physical parameters that are not necessarily recognizable by the patient. In another embodiment, “treatment” or “treatment” refers to the progression of the disorder that is alleviated by inhibiting dopamine reuptake physically, such as by normalizing recognizable symptoms, physiologically, such as by normalizing physical parameters. Refers to inhibition by, or both. In another embodiment, “treatment” or “treatment” refers to delaying the onset of the disorder that is alleviated by inhibiting dopamine reuptake.
    [36] In certain embodiments, the disorder is alleviated by inhibiting dopamine reuptake of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof. Administration to a patient, preferably a mammal, more preferably a human, as a measure to prevent this. As used herein, "prevention" or "prevention" refers to reducing the risk of developing a disorder that is alleviated by inhibiting dopamine reuptake, or reducing the risk of recurrence of a disorder that has been treated or has returned 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 the patient as a prophylactic measure. According to this embodiment, the patient has a genetic predisposition to a disorder that is alleviated by inhibiting dopamine reuptake, eg, a family history of biochemical imbalances in the brain, or a non-genetic predisposition for a disorder alleviated by inhibiting dopamine reuptake Can have Thus, (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof treats one sign of a disorder that is alleviated by inhibiting dopamine reuptake. And for the prevention of other symptoms.
    [37] 3.1. Disorders alleviated with (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane
    [38] (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and its pharmaceutically acceptable salts are useful for treating or preventing endogenous disorders that are alleviated by inhibiting dopamine reuptake. useful. Such disorders include, but are not limited to, attention-deficiency disorders, depression, obesity, Parkinson's disease, convulsion disorders, and addiction disorders.
    [39] Disorders ameliorated by inhibiting dopamine reuptake are not limited to the specific disorders described herein because many types of disorders can result from primary disorders. For example, as disclosed in US Pat. No. 6,132,724 to Bloom, attention-deficit hyperactivity disorders include alcohol abuse, drug abuse, compulsive behavior, learning disabilities, reading problems, gambling, mania, phobias, Panic attacks, hostile defiant behavior, behavioral disorders, school problems, smoking, abnormal sexual behavior, schizophrenic behavior, somatic symptoms, depression, sleep disorders, general anxiety, stuttering and convulsion disorders. All these and other behaviors described herein in connection with disorders alleviated by inhibiting dopamine reuptake are included as disorders that are part of the present invention. In addition, the clinical terms used herein for many specific disorders are described in Quik Reference to the Diagnostic Criteria From DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition), The American Psychiatric Association, Washington, DC, 1994, 358p. Specific disorders found in these documents are as follows.
    [40] Attention-deficiency disorders include, but are not limited to, attention-deficiency / hyperactivity disorders, mainly neglected types; Attention-deficiency / hyperactivity disorders, mainly hyperactivity-impulsive types; Attention-deficiency / hyperactivity disorder, complex type; (NOS) attention-deficiency / hyperactivity disorder not otherwise specified; Behavioral disorders; Hostile opposition disorders; And other unspecified (NOS) disruptive behavioral disorders.
    [41] Depression, including but not limited to recurrent major depression; Mood alteration; Depression unless otherwise defined (NOS); And single episode major depression.
    [42] Parkinson's disease includes, but is not limited to, neuroleptic-induced Parkinson's disease.
    [43] Addiction 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, and Opioid-related disorders are included, all of which are further classified as listed below.
    [44] Eating disorders include, but are not limited to, bulimia nervosa, nonpurging type; Bullia nerbosa, purging type; And eating disorders otherwise defined (NOS).
    [45] Impulse control disorders include, but are not limited to, intermittent explosive disorders, pathological barriers, arson, pathological gambling, hair growth, and other unspecified impulse control disorders.
    [46] Alcohol-related disorders include, but are not limited to, alcohol-induced psychosis (delusion), alcohol abuse, alcoholism, alcohol withdrawal, alcoholism delirium, alcohol withdrawal delirium, alcohol-induced persistent dementia, alcohol-induced persistent forgetfulness , Alcohol dependence, alcohol-induced psychosis (psychedelic), alcohol-induced mood disorder, alcohol-induced anxiety, alcohol-induced sexual dysfunction, alcohol-induced sleep disorder, alcohol-related otherwise undefined (NOS) Disorders, alcoholism and alcohol withdrawal.
    [47] Nicotine-related disorders include, but are not limited to, nicotine dependence, nicotine withdrawal and otherwise undefined (NOS) nicotine-related disorders.
    [48] Amphetamine-related disorders include, but are not limited to, amphetamine dependence, amphetamine abuse, amphetamine poisoning, amphetamine withdrawal, amphetamine intoxication delirium, amphetamine-induced psychosis (delusion), amphetamine-induced psychosis (psychedelic), amphetamine-induced mood Disorders, amphetamine-induced anxiety, amphetamine-induced sexual dysfunction, amphetamine-induced sleep disorders, other unspecified (NOS) amphetamine related disorders, amphetamine poisoning, and amphetamine withdrawal.
    [49] Cannabis-related disorders include, but are not limited to, cannabis dependency; Cannabis abuse, cannabis addiction, cannabis addiction delirium, cannabis-induced psychosis (delusion), cannabis-induced psychosis (psychedelic), cannabis-induced anxiety, other unspecified (NOS) cannabis related disorders and cannabis addiction .
    [50] Cocaine-related disorders include, but are not limited to, cocaine dependence, cocaine abuse, cocaine addiction, cocaine withdrawal, cocaine addiction delirium, cocaine-induced psychosis (delusion), cocaine-induced psychosis (psychedelic), cocaine-induced mood Disorders, cocaine-induced anxiety, cocaine-induced sexual dysfunction, cocaine-induced sleep disorders, other unspecified (NOS) cocaine related disorders, cocaine addiction, and cocaine withdrawal.
    [51] Hallucinogen-use disorders include, but are not limited to, hallucinogen dependency, hallucinogen abuse, hallucinogen poisoning, hallucinogen withdrawal, hallucinogen poisoning delirium, hallucinogen-induced psychosis (delusion), hallucinogen-induced psychosis (psychiatric), hallucinogen-induced mood Disorders, hallucinogen-induced anxiety, hallucinogen-induced sexual dysfunction, hallucinogen-induced sleep disorders, hallucinogen related disorders not otherwise defined (NOS), hallucinogen poisoning, and hallucinogenic persistent cognitive impairment (reproduction of hallucinations).
    [52] Inhalant-related disorders include, but are not limited to, inhalant dependence, inhalant abuse, inhalant addiction, inhalant addiction delirium, inhalant-induced psychosis (delusion), inhalant-induced psychosis (psychedelic), inhalant-induced anxiety, otherwise prescribed NOS Inhalant related disorders and inhalant poisoning.
    [53] Opiate-related disorders include, but are not limited to, opiate dependence, opiate abuse, opiate addiction, opiate addiction delirium, opiate-induced psychosis (delusion), opiate-induced Psychosis (psychedelic), opioid-induced anxiety, opioid-related disorders not otherwise defined (NOS) and opioid addiction.
    [54] Spasm disorders include, but are not limited to, Tourette syndrome, chronic motor or vocal muscle spasm disorders, temporary spasm disorders, other unspecified (NOS) spasm disorders, stuttering, autism, and somatic disorders.
    [55] 4. Therapeutic / prophylactic administration and compositions of the present invention
    [56] (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and its pharmaceutically acceptable salts are advantageously used in veterinary medicine and medicine because of their activity. As described above, (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and its pharmaceutically acceptable salts can be used to treat a disorder that is alleviated by inhibiting dopamine reuptake. It is useful for prevention.
    [57] When administered to a patient, (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof optionally comprises a pharmaceutically acceptable vehicle. It is preferably administered as a component of the composition. The composition of the present invention comprising an effective amount of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is preferably administered orally. . The compositions of the present invention may also be administered by other convenient routes, for example by infusion or injection by injection, by absorption through the epithelial or mucosal layer (e.g., oral mucosa, rectal and small intestinal mucosa, etc.) and another bioactive It can be administered with a formulation. It can be administered systemically or locally. Various delivery systems are known, such as capsules, particulates, microcapsules and capsules by liposomes, which contain (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and its pharmaceuticals May be used to administer an acceptable salt.
    [58] 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. Can be.
    [59] Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracranial, intravaginal, transdermal, rectal, inhaled, or local, especially ear, nose, Administration to the eye or skin is included. The mode of administration is left to the discretion of the specialist. In most cases, administration will release (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or its pharmaceutically acceptable salts into the bloodstream.
    [60] In certain embodiments, it may be desirable to topically administer (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof. This includes, but is not limited to, for example, local injections during surgery, topical application (such as with postoperative wound dressings), injections, catheters, suppositories, or implants (which include membranes such as porosity including sialastic membranes or fibers), A nonporous or gelatinous material).
    [61] In certain embodiments, (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is intraventricular, intrathecal and epidural injection It may be desirable to be introduced into the central nervous system by any suitable route, including. Intraventricular injection can be facilitated by an intraventricular catheter attached to a reservoir such as, for example, an Ommaya reservoir.
    [62] Alternatively, pulmonary administration may be used, for example, by the use of inhalers or nebulizers, and in combination with aerosolizing agents, or through perfusion in fluorocarbons or synthetic lung surfactants. In certain embodiments (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and its pharmaceutically acceptable salts are used as suppositories with traditional binders and vehicles such as triglycerides. Can be formulated.
    [63] In another embodiment, (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and its pharmaceutically acceptable salts can be delivered by vesicles, in particular liposomes. Langer, 1990, Science 249: 1527-1533, Treat et al., In Liposomes in the Therapy of Infectious Disease and Cnacer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353- 365 (1989), Lopez-Berestein, Hom., Pp. 317-327; generally see the book.
    [64] In another embodiment, (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and its pharmaceutically acceptable salts can be delivered to a controlled release system ( See, eg, Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984). Other controlled release systems discussed in Langer, 1990, Science 249: 1527-1533 may also be used. In one embodiment, a pump may be used (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 can be used (Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., 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. Neurol . 25 : 351, Howard et al., 1989, J. Neurosurg. 71 : 105). In another embodiment, the controlled release system is a target of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof, such as the spinal column. Or in close proximity to the brain, and therefore only require a portion of the systemic dose.
    [65] Optionally, the present compositions may include a suitable amount of a pharmaceutically acceptable vehicle to provide a form for proper administration to a patient.
    [66] In certain embodiments, the term 'pharmaceutically acceptable' means that use to animals, mammals, and more particularly humans, is permitted by federal or state supervisory authorities, or US pharmacopoeia or other generally recognized pharmacopoeia It is described. The term vehicle refers to a diluent, adjuvant, excipient or carrier with which a compound of the present invention is administered. Such pharmaceutical vehicles include liquids such as water and oils including petroleum, animal, vegetable or synthetic oils such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Pharmaceutical vehicles also include saline, acacia gum, gelatin, starch dough, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliaries, stabilizers, thickeners, lubricants and colorants may also be used. When administered to a patient, the pharmaceutically acceptable vehicle is preferably sterile. Water is the preferred vehicle for intravenous administration of a compound of the invention. Saline solutions, and aqueous dextrose and glycerol solutions can also be used, in particular as liquid vehicles for injection solutions. Suitable pharmaceutical vehicles also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dry skim milk, Excipients such as glycerol, propylene, glycol, water, ethanol and the like. In addition, the present compositions may include small amounts of wetting or emulsifying agents, or pH buffers as needed.
    [67] The compositions of the present invention may be in solution, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained release preparations, suppositories, emulsions, aerosols, sprays, suspensions or other forms suitable for use. It can have In one embodiment, the pharmaceutically acceptable vehicle is a capsule (see, eg, US Pat. No. 5,698,155). Other examples of suitable pharmaceutical vehicles are described in Remington's Pharmaceutical Sciences , Alfonso R. Gennaro ed., Mack Publishing Co., Easton, PA, 19th ed., 1995, pp. 1447-1676.
    [68] In a preferred embodiment, (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is suitable for oral administration to humans according to conventional procedures. It may be formulated into a suitable pharmaceutical composition. Compositions for oral delivery may be, for example, in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs. Oral dosage compositions may include one or more agents such as sweeteners such as fructose, aspartame or saccharin; Flavoring agents such as peppermint, oil of wintergreen or cherry; coloring agent; And preservatives can be provided as a tasty pharmaceutical formulation. Moreover, in the case of tablets or pills, the composition may be coated to delay disintegration and absorption in the gastrointestinal tract to provide long term action. Selective permeable membranes surrounding the osmotic activity-inducing compounds are also suitable for oral administration compositions. In this latter manner, the triggering compound absorbs the fluid around the capsule and thereby swells to release the agent or agent composition through the aperture. This mode of delivery can provide essentially zero order delivery profiles as opposed to the spiked profiles of immediate release formulations. Time delay materials such as glycerol monostearate or glycerol stearate may also be used. Oral compositions may include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose and magnesium carbonate. Such vehicles are preferably for pharmaceutical use. Typically, compositions for intravenous administration include sterile isotonic aqueous buffer. If desired, this composition may also include a solubilizer.
    [69] In other embodiments, (-)-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 lignocane to relieve pain at the site of injection. Generally, the components are provided alone or in admixture together in unit dosage form, for example anhydrous lyophilized powder or anhydrous concentrate, in a sealed container such as an ampoule or sachette which indicates the amount of active agent. . When (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or its pharmaceutically acceptable salts are administered by infusion, for example pharmaceutical sterile water or physiological saline It can be administered using an infusion bottle comprising a. When (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or its pharmaceutically acceptable salts are administered by injection, the components may be mixed prior to administration. Ampoules of sterile water or physiological saline may be provided.
    [70] The amount of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof effective for treating a particular disorder or condition disclosed herein is indicative of the nature of the disorder or condition. And can be determined by standard clinical techniques. In addition, in vitro or in vivo assays may optionally be applied as an aid to identify optimal dosage ranges. In addition, the exact dosage available will depend on the route of administration and the severity of the disease or condition and should be determined by the judgment of the practitioner and the circumstances of each patient. However, suitable dosage ranges for oral administration are generally those of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or its pharmaceutically acceptable salts per kilogram of body weight per day. From about 0.001 to about 200 mg. In a particularly preferred embodiment of the invention, the oral dosage is about 0.01 to about 100 mg, more preferably about 0.1 to about 75 mg, even more preferably about 0.5 to about 50 mg, even more per kg body weight per day. Preferably about 1 to about 30 mg. In another preferred embodiment, the oral dosage is (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane of the present invention per kilogram of body weight per day or a pharmaceutically acceptable thereof About 1 mg to about 3 mg of possible salt. In another preferred embodiment, the oral dosage is (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane of the invention per kg of body weight once or twice daily or its From about 0.1 to about 2 mg of pharmaceutically acceptable salt. Dosage described herein means the total amount administered; That is, when (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and / or one or more pharmaceutically acceptable salts thereof are administered, the preferred dosage is administered Corresponds to the total amount. Oral compositions preferably comprise about 10 to about 95 weight percent active ingredient.
    [71] Suitable dosage ranges for intravenous administration are from about 0.01 to about 100 mg, preferably from about 0.1 to about 35 mg, more preferably from about 1 to about 10 mg per kg of body weight per day. Suitable dosage ranges for intranasal administration are generally from about 0.01 pg to about 1 mg / kg body weight per day. Suppositories generally contain about 0.01 to about 50 mg of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof per kilogram of body weight per day And from about 0.5 to about 10% by weight of active ingredient.
    [72] Recommended dosages for intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, intrabrain, intravaginal or transdermal, or inhaled administration range from about 0.001 to about 200 mg / kg body weight per day. Suitable dosages for topical administration range from about 0.001 to about 1 mg, depending on the administration area. Effective dosages can be extrapolated from dose-response curves derived from in vitro or animal model test systems. Such animal models and systems are well known in the art.
    [73] The present invention also provides a pharmaceutical pack having one or more containers containing (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof. Or provide a kit. Notice is optionally associated with the container, the notice reflecting approval for human administration as a notice in the form defined by a governmental agency regulating the manufacture, use, or sale of a pharmaceutical or biological product. 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 other embodiments, the kit comprises a therapeutic agent and (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof.
    [74] (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and its pharmaceutically acceptable salts are preferably used for the desired therapeutic or prophylactic activity before use in humans. Analyze in vitro or in vivo. For example, in vitro assays involve administering (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, its pharmaceutically acceptable salts and / or other therapeutic agents. It can be used to determine if it is desirable. Animal model systems can be used to demonstrate safety and efficacy.
    [75] Other methods are known to those skilled in the art and are within the scope of the present invention.
    [76] 5. Combination Therapy
    [77] In certain embodiments of the invention, (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is used in combination therapy with one or more therapeutic agents. Can be used. (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof and other therapeutic agents additionally acting, or more preferably synergistically Can work. In a preferred embodiment, the composition comprising (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is simultaneously present with the administration of the other therapeutic agent. Wherein the other therapeutic agent is part of the same composition as the composition comprising (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof or Different compositions. Other therapeutic agents may be useful for treating and / or preventing (as defined herein) a second chronic disease resulting from a disorder alleviated by inhibiting dopamine reuptake. In another embodiment, a composition comprising (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof may be administered prior to the administration of another therapeutic agent or Administered later. Many of the disorders in which (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and its pharmaceutically acceptable salts are useful for treatment are chronic, so in one embodiment the combination Treatment alternates between a composition comprising (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof and a composition comprising another therapeutic agent. It includes. The duration of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, its pharmaceutically acceptable salts or other therapeutic agents can be, for example, 1 month, 3 months, 6 months, 1 year, or even longer, such as the life of the patient. In certain embodiments, when a composition of the present invention is administered concurrently with, but not limited to, other therapeutic agents that potentially cause side effects, including toxicity, the other therapeutic agents are administered at a dosage lowered below the threshold for eliciting side effects. It is advantageous.
    [78] Another therapeutic agent may be an anti-attention-deficit-disorder agent. Useful anti-attention deficit agents include methylphenidate; Dextroseamphetamine; Tricyclic antidepressants such as imipramine, desipramine and nortriptyline; And psychostimulants such as phenolin and deanol.
    [79] Other therapeutic agents may be anti-addictive-disorder agents. Useful anti-addictive agents include tricyclic antidepressants; MAO inhibitors; Glutamate antagonists such as ketamine HCl, dextromethorphan, dextropan tartrate and dizocilpin (MK801); Degrading enzymes such as anesthetics and aspartate antagonists; GABA agonists such as baclofen and non molar HBr; Reuptake blockers; Degrading enzyme blockers; Glutamate agonists such as D-cycloserine, carboxyphenylglycine, L-glutamic acid and cis-piperidine-2,3-dicarboxylic acid; Aspartate agonists; GABA antagonists such as gabazine (SR-95531), saclofen, bicuculin, picrotoxin and (+) apomorphine HCl; Dopamine antagonists such as, but not limited to, sphyfferone HCl, haloperidol, and (-) sulfidedes.
    [80] Another therapeutic agent may be an anti-alcohol agent. Useful antialcoholic agents include, but are not limited to, disulfiram and naltrexone.
    [81] Another therapeutic agent may be an anti-nicotine agent. Useful antinicotine agents include, but are not limited to, clonidine.
    [82] Another therapeutic agent may be an anti-opium agent. Useful anti opiates include, but are not limited to methadone, clonidine, ropecidine, levomethadyl acetate HCl, naltrexone and buprenorphine.
    [83] Another therapeutic agent may be an anti-cocaine agent. Useful anti-cocaine agents include, but are not limited to, desipramine, amantadine, fluoxydine, and buprenorphine.
    [84] Another therapeutic agent may be an appetite suppressant. Useful appetite suppressants include, but are not limited to, fenfluramine, fennelpropanolamine and marginol.
    [85] Another therapeutic agent may be an anti-lysergic acid diethylamide ("anti-LSD") agent. Useful anti-LSD agents include but are not limited to diazepam.
    [86] Another therapeutic agent may be an anti-phencyclidine (“anti-PCP”) agent. Useful anti-PCP agents include but are not limited to haloperidol.
    [87] Another therapeutic agent may be an anti-Parkinson's disease (“anti-PCP”) treatment. Useful anti-Parkinson's disease therapies include dopamine precursors such as levodopa, L-phenylalanine and L-tyrosine; Neuroprotective agents; Dopamine agonists; Dopamine reuptake inhibitors; Anticholinergic agents such as amantadine and memantine; And 1,3,5-trisubstituted adamantanes, for example 1-amino-3,5-dimethyl-adamantane (Sherm et al., US Pat. No. 4,122,193). .
    [88] Another therapeutic agent may be an anti-depressant. Useful anti-depressants include amitriptyline, clomipramine, doxepin, imipramine, trimimipramine, amoxapine, decipramin, mapproline, nortriptyline, protrippyrine, fluoxetine, fluvoxamine , But not limited to, paroxetine, setraline, venlafaxine, bupropion, nefazodone, trazodone, phenelzin, tranilcipromin and selegiline.
    [89] Another therapeutic agent may be an anxiolytic. Useful destabilizing agents include benzodiazepines such as alprazolam, clodiazepoxide, clonazepam, clolazephate, diazepam, halazepam, lorazepam, oxazelpam and prazepam; Non-benzodiazepines, such as buspyrone; And neurostabilizers such as barbiturates.
    [90] Another therapeutic agent may be an anti-psychotic drug. Useful antipsychotic drugs include phenothiazines such as clopromazine, mesodazine besylate, thiolidazine, acetophenazine maleate, flufenazine, perfenazine and trifluoroperazine; Thioxanthenes such as cloproticcene and thiotitice; And other heterocyclic compounds such as clozapine, haloperidol, roxapin, molindon, pimozide and risperidone. Preferred anti-psychiatric drugs include chloropromazine HCl, thiolidazine HCl, flufenazine HCl, thioticen HCl and mollindon HCl.
    [91] Another therapeutic agent may be an anti-obesity agent. Useful anti-obesity drugs include β-adrenergic receptor agonists, preferably β-3 receptor agonists, including but not limited to fenfluramine; Dexfenfluramine; Sibutramine; Bupropion; Fluoxetine; Phentermine; Amphetamine; Metamphetamine; Dextroamphetamine; Benzpetamine; Pendimethazine; Diethylpropion; Margin stones; Phenylpropanolamine; Norepinephrine-serotonin absorption inhibitors such as sibutramine; And pancreatic lipase inhibitors such as orlistat.
    [92] Example: (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride
    [93] Epstein et al., J. Med. Chem. , 24: 481-490 (1981), 7 ml of 279 mg of (±) -1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride obtained using the method described in Hexane: isopropyl alcohol (= 9: 1) was added followed by 8 drops of diethylamine. Isopropyl alcohol was added dropwise to the resulting mixture until a solution was obtained. The solution was concentrated to a volume of 6 ml using a helium gas stream, and the 1 ml portion of the concentrate was subjected to high performance using an HPLC instrument equipped with a 1 cm x 25 cm Daicel CHIRALPAK AD column (Chral Technologies, Exton, PA). Treatment was by liquid chromatography. Elution was carried out at ambient temperature using a 95: 5 (v / v) hexanes: isopropyl alcohol solution containing 0.05% diethylamine as the mobile phase at a flow rate of 6 ml / min. The fractions eluted at about 26.08 to 34 minutes were collected and concentrated to give a first residue which was dissolved in a minimum amount of ethyl acetate. Using a nitrogen stream, the ethyl acetate solution was evaporated to give a second residue, which was dissolved in 1 ml of diethyl ether. To this ethyl ether solution was added 1 ml of diethyl ether saturated with gaseous hydrochloric acid. A precipitate formed which was filtered off, washed with 2 ml of diethyl ether and dried to give an 88% enantiomeric excess of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane 33 mg of hydrochloride were provided. Chromatography of the above conditions was used to refine this material. The fraction eluted at about 28 to about 34 minutes was concentrated, acidified and dried as above to 16.0 mg of (-)-1- (3,4-dichlorophenyl) -1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride was provided: light rotation [a] at 2 mg / ml in methanol [ 25 ] 25 D = -56 °; 99.1% optical isomer excess.
    [94] 2. Example: (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane HCl and (±) -1 in dopamine, norepinephrine and serotonin transporter binding assays Activity Comparison of-(3,4-Dichlorophenyl) -3-azabicyclo [3.1.0] hexane HCl
    [95] (±) -1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride and (-)-1- (3,4-dichloro using standard dopamine transporter binding assays Dopamine, norepinephrine and serotonin uptake-inhibitory activities of phenyl) -3-azabicyclo [3.1.0] hexane hydrochloride were compared.
    [96] 2.1. Substances and Methods
    [97] 2.1.1. Dopamine Transporter Assay
    [98] Madras et al . , 1989, Mol. Pharmacol. 36 (4): 518-524 and Javitch et al., 1984. Mol. Pharmacol. 26 (1): 35-44, a dopamine uptake transporter binding assay was performed. Receptor source is guinea pig striatal membrane; The radioligand is [ 3 H] WIN 35,428 (Dupon-Nen, Boston, MA) (60-87 Ci / mmol), which is the final ligand concentration of 2.0 nM; Non-specific determinant 1 μM 1- [2- [bis (4-fluorophenyl) methoxy] ethyl] -4- [3-phenylpropyl] piperazine dihydrochloride ("GBR 12909") (high-affinity Dopamine absorption inhibitors); The reference compound was also GBR 12909. According to the method of Example 5, (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride was obtained. The reaction was carried out in 50 mM TRIS-HCl (pH 7.4) containing 120 mM NaCl for 2 hours at 0 ° C to 4 ° C. The reaction was terminated in the glass fiber filter by high speed vacuum filtration. Radioactivity captured in the filter was measured and compared to control values to confirm the interaction of the dopamine absorption site with the test compound. The data is reported in Table 1 below.
    [99] 2.1.2. Norepinephrine Transporter Assay
    [100] Raisman et al . , 1982, Eur. Jrnl. Pharmacol. 78: 345-351 and Langer et al., 1981. Eur. Jrnl. Pharmacol. 72: 423, a norepinephrine uptake transporter binding assay was performed. Receptor source is the rat's frontal membrane; Radioligand is [ 3 H] nisoxetine (60-85 Ci / mmol), the final ligand concentration of 1.0 nM; Non-specific determinant 1 μM decipramine (“DMI”) (high-affinity norepinephrine uptake inhibitor); Reference compounds were desipramine (“DMI”), imipramine, amitriptyline or nixetcetin. According to the method of Example 5, (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane hydrochloride was obtained. The reaction was carried out at 50 mM TRIS-HCl, pH 7.4, containing 300 mM NaCl and 5 mM KCl for 4 hours at 0 ° C to 4 ° C. The reaction was terminated in the glass fiber filter by high speed vacuum filtration. Radioactivity captured in the filter was measured and compared to control values to confirm the interaction of the test compound with the norepinephrine uptake site. The data is reported in Table 2 below.
    [101] 2.1.3. Serotonin Transporter Assay
    [102] D'Amato et al. , 1987, Jrnl. Pharmacol. & Exp. Ther. 242: 364-371 and Brown et al., 1986. Eur. Jrnl. Pharmacol. 123: 161-165, a serotonin uptake transporter binding assay was performed. The receptor source is human platelet membrane; Radioligand is [ 3 H] citalopram (70-87 Ci / mmol), the final ligand concentration of 0.7 nM; Non-specific determinant 1 μM clamipramine (high-affinity serotonin uptake inhibitor); The reference compound was imipramine. According to the method of Example 5, (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane HCl was obtained. The reaction was carried out at 50 mM TRIS-HCl, pH 7.4, containing 120 mM NaCl and 5 mM KCl for 1 hour at 25 ° C. The reaction was terminated in the glass fiber filter by high speed vacuum filtration. The radioactivity trapped in the filter was measured and compared with control values to confirm the interaction of the serotonin uptake site with the test compound. The data is reported in Table 3 below.
    [103] 2.2. result
    [104]
    [105]
    [106]
    [107] The data in Table 1 is based on (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane HCl and (±) -1- (3,4-dichlorophenyl) -3-azabi It is shown that both cyclo [3.1.0] hexane HCl have affinity for dopamine absorption sites. Conversely, the data in Tables 2 and 3 show that (±) -1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane HCl has affinity for norepinephrine and serotonin uptake sites. In contrast, (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane HCl shows no affinity for norepinephrine and serotonin uptake sites. Although (±) -1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane HCl was reduced to (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1. Although the binding affinity to the dopamine reuptake site is higher than that of hexane HCl, the use of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane HCl for inhibition of dopamine absorption This is more useful than (±) -1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane HCl, which is (-)-1- (3,4-dichlorophenyl) -3-azabi This is because cyclo [3.1.0] hexane HCl has specificity for inhibiting dopamine absorption. In other words, (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane HCl has undesirable side effects associated with norepinephrine uptake and inhibition of serotonin uptake (eg, hypertension and Sexual dysfunction).
    [108] Successful inhibition of dopamine reuptake has been associated with the treatment of attention-deficiency disorders, depression, obesity, Parkinson's disease, convulsive disorders and addiction disorders (Hitri et al., 1994, Clin. Pharmacol. 17: 1-22; Noble, 1994, Alcohol Supp. 2: 35-43; and Blum et al., 1995, Pharmacogenetics 5: 121-141). Because of its specificity for inhibiting dopamine absorption, (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0 for the treatment or prevention of disorders alleviated by inhibiting dopamine reuptake in patients. ] Hexane or a pharmaceutically acceptable salt thereof is more useful than (±) -1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof.
    [109] The scope of the present invention is not limited by the specific embodiments disclosed in the examples intended for the description of some embodiments of the present invention and any embodiments that are functionally equivalent within the scope of the present invention. Indeed, those shown and described herein in addition to various modifications of the invention will be apparent to those skilled in the art, which are intended to be included within the scope of the appended claims.
    [110] Many references have been cited, the entire disclosures of which are incorporated herein by reference.
    权利要求:
    Claims (56)
    [1" claim-type="Currently amended] (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof, each substantially free of the corresponding (+)-enantiomer.
    [2" claim-type="Currently amended] The method of claim 1,
    (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, or a pharmaceutically acceptable thereof, having a corresponding (+)-enantiomer of about 2% w / w or less salt.
    [3" claim-type="Currently amended] The method of claim 1,
    (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or its pharmaceutically acceptable having a corresponding (+)-enantiomer of about 1% w / w or less salt.
    [4" claim-type="Currently amended] An effective amount of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof, each of which is substantially free of the corresponding (+)-enantiomer Composition comprising a.
    [5" claim-type="Currently amended] The method of claim 4, wherein
    A composition further comprising a pharmaceutically acceptable carrier or vehicle.
    [6" claim-type="Currently amended] The method of claim 4, wherein
    A composition further comprising another therapeutic agent.
    [7" claim-type="Currently amended] The method of claim 6,
    A composition wherein the other therapeutic agent is an anti-attention deficit disorder.
    [8" claim-type="Currently amended] The method of claim 6,
    The other therapeutic agent is an anti-addictive agent.
    [9" claim-type="Currently amended] The method of claim 6,
    The other therapeutic agent is an anti-alcoholic agent.
    [10" claim-type="Currently amended] The method of claim 6,
    The other therapeutic agent is an antinicotine agent.
    [11" claim-type="Currently amended] The method of claim 6,
    A composition wherein the other therapeutic agent is an anti-opium agent.
    [12" claim-type="Currently amended] The method of claim 6,
    The other therapeutic agent is an anti-cocaine agent.
    [13" claim-type="Currently amended] The method of claim 6,
    A composition wherein the other therapeutic agent is an appetite suppressant.
    [14" claim-type="Currently amended] The method of claim 6,
    The other therapeutic agent is an anti-LSD agent.
    [15" claim-type="Currently amended] The method of claim 6,
    The other therapeutic agent is an anti-PCT agent.
    [16" claim-type="Currently amended] The method of claim 6,
    The other therapeutic agent is an anti-Parkinson's disease.
    [17" claim-type="Currently amended] The method of claim 6,
    A composition wherein the other therapeutic agent is an anti-depressant.
    [18" claim-type="Currently amended] The method of claim 6,
    A composition wherein the other therapeutic agent is an anxiolytic agent.
    [19" claim-type="Currently amended] The method of claim 6,
    Wherein the other therapeutic agent is an anti-psychotic agent.
    [20" claim-type="Currently amended] The method of claim 6,
    A composition wherein the other therapeutic agent is an anti-obesity agent.
    [21" claim-type="Currently amended] An effective amount of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or substantially free of the corresponding (+)-enantiomer in a patient in need of treatment or prevention or A method of treating or preventing a disorder alleviated by inhibiting dopamine reuptake, comprising administering a pharmaceutically acceptable salt thereof.
    [22" claim-type="Currently amended] The method of claim 21,
    (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof may contain up to about 2% w / w of the corresponding (+)-enantiomer How to have.
    [23" claim-type="Currently amended] The method of claim 21,
    (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof may contain up to about 1% w / w of the corresponding (+)-enantiomer How to have.
    [24" claim-type="Currently amended] A method of treating or preventing a disorder that is alleviated by inhibiting dopamine reuptake, selected from attention-deficiency disorders, depression, obesity, Parkinson's disease, and seizure disorders, which corresponds to patients in need of treatment or prevention of such disorders Administering an effective amount of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof, substantially free of the enantiomer Way.
    [25" claim-type="Currently amended] An effective amount of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or substantially free of the corresponding (+)-enantiomer in a patient in need of treatment or prevention or A method of treating or preventing a disabled addiction disorder which is alleviated by inhibiting dopamine reuptake, comprising administering a pharmaceutically acceptable salt thereof.
    [26" claim-type="Currently amended] The method of claim 24,
    Attention-deficiency disorders are attention-deficiency / hyperactivity disorders, mainly neglected types; Attention-deficiency / hyperactivity disorders, mainly hyperactivity-impulsive types; Attention-deficiency / hyperactivity disorder, complex type; Behavioral disorders; And a hostile oppositional disorder.
    [27" claim-type="Currently amended] The method of claim 24,
    Depression is recurrent major depression; Mood alteration; And single episode major depression.
    [28" claim-type="Currently amended] The method of claim 24,
    Parkinson's disease is a neuroleptic-induced Parkinson's disease.
    [29" claim-type="Currently amended] The method of claim 24,
    Spasm disorder is selected from the group consisting of Tourette syndrome, chronic motor muscle disorder, vocal muscle spasm disorder, temporary spasm disorder, stuttering, autism and somatic disorder.
    [30" claim-type="Currently amended] The method of claim 25,
    Addiction disorders include eating disorders, impulse control disorders, alcohol-related disorders, nicotine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogenic disorders, inhalant-related disorders and opioid-related disorders The method is selected from the group consisting of.
    [31" claim-type="Currently amended] An effective amount of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or substantially free of the corresponding (+)-enantiomer in a patient in need of treatment or prevention or A method of treating or preventing attention-deficiency disorders, comprising administering a pharmaceutically acceptable salt thereof.
    [32" claim-type="Currently amended] The method of claim 31, wherein
    (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof may contain up to about 2% w / w of the corresponding (+)-enantiomer How to have.
    [33" claim-type="Currently amended] The method of claim 31, wherein
    (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof may contain up to about 1% w / w of the corresponding (+)-enantiomer How to have.
    [34" claim-type="Currently amended] The method of claim 31, wherein
    Attention-deficiency disorders are attention-deficiency / hyperactivity disorders, mainly neglected types; Attention-deficiency / hyperactivity disorders, mainly hyperactivity-impulsive types; Attention-deficiency / hyperactivity disorder, complex type; Behavioral disorders; And a hostile oppositional disorder.
    [35" claim-type="Currently amended] An effective amount of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or substantially free of the corresponding (+)-enantiomer in a patient in need of treatment or prevention or A method of treating or preventing depression, comprising administering a pharmaceutically acceptable salt thereof.
    [36" claim-type="Currently amended] 36. The method of claim 35 wherein
    (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof may contain up to about 2% w / w of the corresponding (+)-enantiomer How to have.
    [37" claim-type="Currently amended] 36. The method of claim 35 wherein
    (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof may contain up to about 1% w / w of the corresponding (+)-enantiomer How to have.
    [38" claim-type="Currently amended] 36. The method of claim 35 wherein
    Depression is major depression, relapse; Mood alteration; And major depression, a single episode.
    [39" claim-type="Currently amended] An effective amount of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or substantially free of the corresponding (+)-enantiomer in a patient in need of treatment or prevention or A method of treating or preventing obesity, comprising administering a pharmaceutically acceptable salt thereof.
    [40" claim-type="Currently amended] The method of claim 39,
    (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof may contain up to about 2% w / w of the corresponding (+)-enantiomer How to have.
    [41" claim-type="Currently amended] The method of claim 39,
    (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof may contain up to about 1% w / w of the corresponding (+)-enantiomer How to have.
    [42" claim-type="Currently amended] An effective amount of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or substantially free of the corresponding (+)-enantiomer in a patient in need of treatment or prevention or A method of treating or preventing Parkinson's disease, comprising administering a pharmaceutically acceptable salt thereof.
    [43" claim-type="Currently amended] The method of claim 42,
    (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof may contain up to about 2% w / w of the corresponding (+)-enantiomer How to have.
    [44" claim-type="Currently amended] The method of claim 42,
    (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof may contain up to about 1% w / w of the corresponding (+)-enantiomer How to have.
    [45" claim-type="Currently amended] An effective amount of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or substantially free of the corresponding (+)-enantiomer in a patient in need of treatment or prevention or A method of treating or preventing an addiction disorder, comprising administering a pharmaceutically acceptable salt thereof.
    [46" claim-type="Currently amended] The method of claim 45,
    (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof may contain up to about 2% w / w of the corresponding (+)-enantiomer How to have.
    [47" claim-type="Currently amended] The method of claim 45,
    (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof may contain up to about 1% w / w of the corresponding (+)-enantiomer How to have.
    [48" claim-type="Currently amended] The method of claim 45,
    Addiction disorders include eating disorders, impulse control disorders, alcohol-related disorders, nicotine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogenic disorders, inhalant-related disorders and opioid-related disorders The method is selected from the group consisting of.
    [49" claim-type="Currently amended] An effective amount of (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or substantially free of the corresponding (+)-enantiomer in a patient in need of treatment or prevention or A method of treating or preventing a spasm disorder, comprising administering a pharmaceutically acceptable salt thereof.
    [50" claim-type="Currently amended] The method of claim 49,
    (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof may contain up to about 2% w / w of the corresponding (+)-enantiomer How to have.
    [51" claim-type="Currently amended] The method of claim 49,
    (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof may contain up to about 1% w / w of the corresponding (+)-enantiomer How to have.
    [52" claim-type="Currently amended] The method of claim 49,
    Spasm disorder is selected from the group consisting of Tourette syndrome, chronic motor muscle disorder, vocal muscle spasm disorder, temporary spasm disorder, stuttering, autism and somatic disorder.
    [53" claim-type="Currently amended] (a) A solution of organic eluent and (±) -1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane was passed through a chiral polysaccharide stationary phase to give (-)-1- (3 Providing a first fraction containing, 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane; And (b) passing the first fraction through a chiral polysaccharide stationary phase to give (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0 substantially free of the (+)-enantiomer. A process for obtaining (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexanes of claim 1, comprising providing a second fraction containing hexanes.
    [54" claim-type="Currently amended] The method of claim 53, wherein
    (c) further comprising concentrating the second fraction.
    [55" claim-type="Currently amended] (a) A solution of organic eluent and (±) -1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane was passed through a chiral polysaccharide stationary phase to give (-)-1- (3 Providing a first fraction containing, 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 a chiral polysaccharide stationary phase to give (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [substantially free of (+)-enantiomers. 3.1.0] obtaining (-)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexanes of claim 1, comprising providing a second fraction containing hexanes Way.
    [56" claim-type="Currently amended] The method of claim 55,
    (d) further comprising concentrating the second fraction.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-08-24|Priority to US09/939,071
    2001-08-24|Priority to US09/939,071
    2002-08-14|Application filed by 도브 파마슈티칼 인코포레이티드
    2002-08-14|Priority to PCT/US2002/025870
    2004-07-22|Publication of KR20040065549A
    优先权:
    申请号 | 申请日 | 专利标题
    US09/939,071|2001-08-24|
    US09/939,071|US6569887B2|2001-08-24|2001-08-24|-1--3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as a dopamine-reuptake|
    PCT/US2002/025870|WO2003017927A2|2001-08-24|2002-08-14|-1--3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as a dopamine-reuptake inhibitor|
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