JP2016518406A - Use of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane to treat addictive and alcohol related disorders - Google Patents

Abstract

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 alcohol-related or addictive disorders. (+)-1- (3,4-Dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof preferably contains substantially the corresponding (−)-enantiomer. Not included.

Description

  The present invention relates to (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof for treating an addictive disorder or an alcohol-related disorder Wherein (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is administered to a patient. To use.

  Alcohol, nicotine, and illicit drug abuse and addiction are a significant public health cost in the United States of over $ 500 billion per year, considering complex medical, economic, criminal, and social impacts (The Science of Addiction, NIH Pub. No 10-5605, Aug., 2010). In the United States, drug and alcohol abuse is estimated to contribute to the death of more than 100,000 people, whereas tobacco is associated with an estimated 440,000 deaths per year (The Science of Addiction, NIH Pub. No 10-5605, Aug., 2010).

  Addiction of certain drugs and threats is associated with dopamine-mediated enhancement / reward pathway excitement in the central nervous system (Abbott, 2002; Montague et al, 2004). Dopamine is a monoamine neurotransmitter that plays an important role in integrating the functions of the hypothalamus, pituitary gland, adrenal system and sensory, limbic, and motor systems. The mesolimbic dopamine pathway that dopamine cells in the ventral tegmental region provide to the nucleus accumbens appears to be important for drug reward (Wise, 2009). Other dopamine pathways now also include drug reward, including the midbrain striatum (dopamine cells in the substantia nigra) on the dorsal striatum, and the midbrain cortex (dopamine cells in the ventral tegmental area on the frontal cortex) And contributed to drug addiction (Wise, 2009). The method of dopamine cell firing also regulates the rewarding and conditioning effects of drugs (primarily transient dopamine cell firing) differently compared to the executive function changes seen in addiction (primarily persistent dopamine cell firing) (Wanat et al, 2009; Grace, 2000).

The primary mechanism of termination of dopamine neurotransmission is via reuptake of released dopamine by a Na ⁺ / Cl ⁻ -dependent cell membrane transporter (Hoffman et al, 1998, Front. Neuroendocrinol. 19 (3): 187-231 ). Depending on the ambient ionic conditions, the dopamine transporter can function as both an internal dopamine transporter (ie, “reuptake”) and an external dopamine transporter (ie, “release”). The functional importance of the dopamine transporter is its regulation of dopamine neurotransmission by terminating the action of dopamine in the synapse via reuptake (Hitri et al, 1994, Clin. Pharmacol. 17: 1-22 ).

  Dopamine transporters have been a target for drug treatment of abuse and / or addictive behavior. Targeting a dopamine transporter with a ligand is primarily expected that the ligand / drug will partially substitute for the abused drug (or act), resulting in reduced drug self-administration and Based on the hypothesis of minimizing craving. In accordance with these trends, the dopamine / norepinephrine uptake inhibitor, bupropion, has been shown to be useful for nicotine addiction and has been approved for its use (Hays et al., 2003). Similarly, bupropion has been shown to be useful in treating abuse of methamphetamine and other stimulants (Elkashef et al, 2008).

The Science of Addiction, NIH Pub.No 10-5605, Aug., 2010 Hoffman et al, 1998, Front. Neuroendocrinol. 19 (3): 187-231 Hitri et al, 1994, Clin. Pharmacol. 17: 1-22

  Despite progress by targeting dopamine transporters, there are effective therapies for alcohol, nicotine, and the abuse and addiction of illicit or abused drugs, as well as regular practices such as gambling and sex addiction It remains necessary.

  As described herein, triple reuptake inhibitors that selectively inhibit serotonin, then inhibit norepinephrine, to a lesser extent dopamine, surprisingly are addictive disorders and It has been found to be effective in treating alcohol related disorders.

  The present invention 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 composition of the present application may further comprise a pharmaceutically acceptable vehicle. These compositions are useful for the treatment or prevention of alcohol related disorders or addictive disorders.

  The present invention also treats ethanol consumption comprising an effective amount of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof. Alternatively, a pharmaceutical composition for prevention is provided.

  The present invention relates to ethanol consumption in a patient comprising an effective amount of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof, and Further provided is a pharmaceutical composition for treating or preventing depression.

  In another embodiment, the present invention is a method of treating or preventing ethanol consumption, wherein an effective amount of (+)-1- (3,4-dichlorophenyl) -3 is administered to a patient in need of the treatment or prevention. -Providing a method characterized by administering azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof.

  Preferably, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is used in particular in the method or composition of the present application. In some cases, the corresponding (-)-enantiomer is substantially free. In a preferred embodiment, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutical thereof substantially free of its corresponding (−)-enantiomer Acceptable salts are used to treat or prevent alcohol-related or addictive disorders.

  The present invention may be understood in more detail by reference to the detailed description and examples to illustrate non-limiting embodiments of the invention.

FIGS. 1A and 1B show (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane (DOV 21,) in a P rat rat binge operant responding assay. 947) is a graph showing an effect. FIG. 1A shows the effect of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane on ethanol consumption by P rats, whereas FIG. 1B shows sucrose consumption. Shows its effect on. FIG. 2 is a graph showing the effect of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane in the vindioperant response test of HAP mice, and the upper graph shows alcohol. The effect on consumption is shown and the graph below shows the effect on sucrose consumption.

  The present invention provides methods for treating or preventing various alcohol related disorders and addictive disorders. Using the methods of the invention, the disorder can be treated, prevented, and / or alleviated by inhibiting the reuptake of multiple biogenic amines that are causally related to the target disorder (s). It is. As shown herein, the triple reuptake inhibitor, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, is an alcohol consumption in rat and mouse models. It was effective in treating. The triple reuptake inhibitors have unbalanced serotonin-norepinephrine-dopamine reuptake inhibition rates in vitro of about 1: 2: 8, respectively (Skolnick et al, 2003).

  Given the well-developed association between dopamine transporters and alcohol-related and addictive disorders, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3. The potency of 1.0] hexane was surprising because the compound potently inhibited serotonin and norepinephrine reuptake rather than dopamine reuptake.

Example I shows alcohol-preferred rats that show the efficacy of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane for treating or preventing excessive alcohol consumption ( Provides evidence in the P rat) model. In a vindioperant response experiment, oral administration of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane to P rats resulted in a dose-dependent decrease in alcohol consumption. Brought.
Similarly, Example II is a high alcohol that demonstrates the efficacy of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane for treating or preventing excessive alcohol consumption. Provides evidence in the preference (HAP) mouse model. In the vindioperant reaction experiment described in Example II, infusion administration of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane to HAP mice is a dose of alcohol consumption. It brought about a dependent decline. The efficacy of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane in these widely accepted animal models of alcohol consumption is (+)-1- (3 , 4-Dichlorophenyl) -3-azabicyclo [3.1.0] hexane is equally effective in humans.

  As used herein (+)-l- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane agent is the corresponding (-)-enantiomer, (-)-l- (3 , 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane. The term “substantially free of the corresponding (−)-enantiomer” means that only about 5% by weight of the corresponding (−)-enantiomer, preferably only about 2% by weight of the corresponding (−)-enantiomer, more preferably Means only about 1% by weight of the corresponding (-)-enantiomer.

  The term “corresponding (−)-enantiomer” when used in reference to (+)-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.

  The synthesis of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane can be carried out by the method described in US Provisional Patent Application No. 61 / 419,769.

  (+)-1- (3,4-Dichlorophenyl) -3-azabicyclo [3.1.0] hexane is a preferred triple reuptake inhibitor for use in the methods of the present invention, but other triple reuptake inhibitors. Uptake inhibitors, particularly those that are unbalanced triple reuptake inhibitors, can be used as well. In a preferred embodiment, an unbalanced triple reuptake inhibitor is used that selectively inhibits serotonin and norepinephrine over dopamine. For example, a triple reuptake inhibitor can have an unbalanced serotonin-norepinephrine-dopamine reuptake inhibition rate in the range of about 1-2: 1-3: 4-12, respectively.

  The method of the present invention utilizes (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane as well as other unbalanced triple reuptake inhibitors. It should be noted that there are other attempts to use triple reuptake inhibitors that may treat various central neurological disorders associated with monoamine neurotransmitters. However, in some cases, triple reuptake inhibitors have been used with little or no success due to serious drawbacks. The triple reuptake inhibitor, PRC200-SS, has been tested as a potential antidepressant. However, further development and use of the compound is likely due to nephrotoxicity because the compound has been reported to cause acute degenerative damage to tubules in studies in cynomolgus monkeys (Guha et al., 2011). Not. Tensofensine is a triple reuptake inhibitor that is being tested in Phase II clinical trials. The compound has been reported to be ineffective in trials for the treatment of Parkinson's disease (Rascol et al, 2008) and gastrointestinal adverse events (thirst, nausea, nausea) in trials for its use in weight loss Abdominal pain, constipation, diarrhea) were reported to be two related (Astrup et al, 2008). The triple inhibitory compound, SEP-225289, has undergone Phase II clinical trials for use as an antidepressant and did not meet the primary efficacy endpoint compared to placebo (Sepracor Press Release, July 1, 2009). SEP-225289 was then shown by positron emission tomography occupancy studies to achieve serotonin transporter occupancy that was too low at the test dose to produce antidepressant effects (DeLorenzo et al.,). 2011). Similarly, NS2359 (or GSK372475), a balanced triple reuptake inhibitor intended to be used as an antidepressant, also did not demonstrate a significant effect compared to placebo. (Neuirosearch Press release, Feb. 4, 2009; Wilens et al. 2008). A triple inhibitor, sibutramine, has been demonstrated in clinical trials to cause a significant increase in the risk of severe heart events, including nonfatal and nonfatal strokes, in patients with chronic cardiovascular disease Later, it was voluntarily recovered from the market as a weight loss / obesity drug (FDA News Release, 2010; James et al, 2010).

  "Patient" is an animal including but not limited to cattle, monkeys, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, and guinea pigs, more preferably Mammals, most preferably humans.

  The phrase “pharmaceutically acceptable salt” as used herein refers to the basic nitrogen of an acid and (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane. A salt formed from a group. Examples of salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, superphosphorus Acid salt, isonicotinate, acetate, lactate, salicylate, citrate, acidic citrate, tartrate, oleate, tannate, pantothenate, hydrogen tartrate, ascorbate, succinate Acid salt, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfone Acid salts, p-toluenesulfonates, and pamoates (ie, 1,1-methylene-bis- (2-hydroxy-3-naphthoate)).

  According to the present invention, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof inhibits dopamine reuptake. Is administered to a patient, preferably a mammal, more preferably a human, for the treatment or prevention of a disorder alleviated by. In one embodiment, “treatment” or “treating” refers to a disorder that is alleviated by inhibiting dopamine reuptake, or an improvement in at least one distinguishable symptom thereof. In another embodiment, “treatment” or “treating” refers to an improvement in at least one measurable physical parameter that is not necessarily distinguishable by the patient. In yet another embodiment, “treatment” or “treating” refers to serotonin, either physically, eg, normalization of identifiable symptoms, physiological, eg, normalization of physical parameters, or both. Inhibiting the progression of disorders that are alleviated by inhibiting reuptake, norepinephrine, and dopamine. In yet another embodiment, “treatment” or “treating” refers to delaying the onset of a disorder that is alleviated by inhibiting serotonin, norepinephrine, and dopamine reuptake.

  In certain embodiments, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is used as a preventive measure against addictive disorders. Administered to a patient, preferably a mammal, more preferably a human. As used herein, “prevention” or “preventing” refers to a reduced risk of developing a disorder or a reduced risk of recurrence of a disorder that has been cured or recovered to normal. In one embodiment, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is administered as a prophylactic measure to a patient. The According to this embodiment, the patient may have a genetic predisposition to an addictive disorder that is alleviated by inhibiting dopamine reuptake, such as a family history of the disorder, or a non-genetic predisposition to an addictive disorder.

  The methods of the invention are useful for treating or preventing endogenous disorders that are alleviated by inhibiting serotonin, norepinephrine, and dopamine uptake. Such disorders include, but are not limited to, alcohol-related disorders, addictive disorders, and drug abuse disorders.

  Disorders that are alleviated by inhibiting serotonin, norepinephrine, and dopamine uptake are not limited to the specific disorders described herein, and the methods of the invention may treat and / or treat various additional disorders and related symptoms. Understood or readily ascertained to provide an effective therapeutic agent for prevention. For example, the methods of the present invention provide promising candidates for the treatment and / or prevention of forms and symptoms of alcohol abuse, drug abuse, cognitive impairment, gambling addiction, smoking, and abnormal behavior. Possible further obstacles for treatment using the methods of the invention are, for example, the Quick Reference to the Diagnostic Criteria from DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), The American Psychiatric Association, Washington, DC , 1994. Specific disorders for which definitions can be found in the reference are listed below.

  Addictive disorders that are suitable for treatment and / or prevention using the methods and compositions of the present invention 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, all of which are further subclassified as described below.

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

  With respect to alcohol-related disorders, including but not limited to alcohol abuse and alcoholism, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and its Pharmaceutically acceptable salts can be used to reduce ethanol consumption associated with the alcohol-related disorder. Accordingly, the present invention is a method of treating or preventing ethanol consumption, wherein an effective amount of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3] is administered to a patient in need of the treatment or prevention. .1.0] hexane or a pharmaceutically acceptable salt thereof is provided. The invention also provides a method of treating or preventing ethanol consumption and depression, wherein an effective amount of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo is administered to a patient in need of the treatment or prevention. [3.1.0] A method is provided comprising administering hexane or a pharmaceutically acceptable salt thereof. The present invention relates to a patient's ethanol consumption comprising an effective amount of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof. Further provided are pharmaceutical compositions for treating or preventing. The invention also provides ethanol consumption and depression in a patient comprising (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for treating or preventing is provided.

  The routes of administration, dosages and dosage forms described herein are (+)-1- (3, for prevention or treatment of both ethanol consumption or ethanol consumption and depression to a patient in need of treatment. 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof. Suitable forms of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane for use in the biologically active compositions and methods of the present invention include: The pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and prodrugs thereof are included.

  An effective amount of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutical thereof, alone or in combination with a second therapeutic agent, to a patient Administration of an acceptable salt would detectably treat or prevent the patient's ethanol consumption or both ethanol consumption and depression. In an exemplary embodiment, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, alone or in combination with a second therapeutic agent, to a patient Or administration of a pharmaceutically acceptable salt thereof is ethanol consumption, ethanol consumption and depression at least 0%, 20%, 30%, 50% or more, up to 75-90%, or 95% or more Both, or reduced alcohol withdrawal symptoms, ethanol consumption or both ethanol consumption and depression will result.

  Nicotine related disorders include, but are not limited to, nicotine addiction, nicotine withdrawal, and unspecified nicotine related disorders.

  Amphetamine-related disorders include, but are not limited to, amphetamine dependence, amphetamine abuse, amphetamine addiction, amphetamine withdrawal, amphetamine addiction delirium, delusional amphetamine-induced psychotic disorder, hallucination-induced amphetamine-induced psychotic disorder , Amphetamine-induced mood disorders, amphetamine-induced anxiety disorders, amphetamine-induced sexual dysfunction, amphetamine-induced sleep disorders, unspecified amphetamine-related disorders (NOS), and amphetamine withdrawal.

  Cannabis-related disorders include but are not limited to cannabis dependence, cannabis abuse, cannabis poisoning, cannabis poisoning delirium, cannabis-induced psychotic disorders with delusions, cannabis-induced psychotic disorders with hallucinations, cannabis induction Sexual anxiety disorders, unspecified cannabis-related disorders (NOS); and cannabis poisoning.

  Cocaine-related disorders include, but are not limited to, cocaine addiction, cocaine abuse, cocaine addiction, cocaine withdrawal, cocaine addiction delirium, cocaine-induced psychotic disorders with delusions, cocaine-induced psychotic disorders with hallucinations , Cocaine-induced mood disorders, cocaine-induced anxiety disorders, cocaine-induced sexual dysfunction, cocaine-induced sleep disorders, unspecified cocaine-related disorders (NOS), cocaine addiction, and cocaine withdrawal.

  Hallucinogen use disorders include, but are not limited to, hallucinogenism, hallucinogen abuse, hallucin poisoning, hallucinogen withdrawal, hallucinogen delirium delirium, hallucinogen-induced psychotic disorders with delusions, hallucinations Hallucinogen-induced psychotic disorder, hallucinogen-induced mood disorder, hallucinogen-induced anxiety disorder, hallucinogen-induced sexual dysfunction, hallucinogen-induced sleep disorder, unspecified hallucinogen-related disorder (NOS), Includes hallucinogen addiction and hallucinogen persistent sensory impairment (flashback).

  Inhalant-related disorders include, but are not limited to, inhalation dependence; inhalation abuse; inhalation poisoning; inhalation intoxication delirium; Include psychotic disorders; inhalant-induced anxiety disorders; unspecified inhalant-related disorders (NOS); and inhalant poisoning.

  Opioid-related disorders include but are not limited to opioid addiction, opioid abuse, opioid addiction, opioid addiction delirium, opioid-induced psychotic disorders with delusions, opioid-induced psychotic disorders with hallucinations, opioid induction Sexual anxiety disorders, unspecified opioid-related disorders (NOS), opioid addiction, and opioid withdrawal.

  In one embodiment of the invention, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is at least one other Can be used in combination therapy with other therapeutic agents. (+)-1- (3,4-Dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof and other therapeutic agents are additively or more preferably Can act synergistically. In a preferred embodiment, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is (+)-1- (3 , 4-Dichlorophenyl) -3-azabicyclo [3.1.0] hexane or another therapeutic agent that may be partially the same or different in composition from those comprising pharmaceutically acceptable salts thereof Are administered at the same time. Other therapeutic agents may be useful for treating and / or preventing secondary diseases (as described herein) resulting from disorders that are alleviated by inhibiting dopamine reuptake. In another embodiment, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is administered prior to administration of another therapeutic agent. Or later. Because (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and its pharmaceutically acceptable salts are useful for treatment, many disorders are chronic. In one embodiment, the combination therapy comprises (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof. And alternation between administration of a composition comprising another therapeutic agent. The administration period of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane, its pharmaceutically acceptable salt, or other therapeutic agent is, for example, 1 month It can be March, June, 1 year, or longer, eg, the patient's lifetime. In certain embodiments, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is not limited, When administered concurrently with another therapeutic agent that may cause side effects, including toxicity, the other therapeutic agents may be advantageously administered at a dose that is below the threshold value causing the side effects.

  The present invention also provides an effective amount of (+)-1- (3) to provide a combination formulation or method of co-administration that is effective in preventing or treating both ethanol consumption or ethanol consumption and depression in a patient. , 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane (or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, or prodrug thereof), and (+)- One or more additional active agent (s) formulated in combination with or co-administered with 1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane Combination formulations and coordinated administration methods. Specific combination formulations and coordinated treatment methods herein include, for example, one or more additional ones to prevent or treat a patient's ethanol consumption or consumption, alcohol withdrawal symptoms, and depression Or an effective amount of (+)-1- in combination with an ancillary therapeutic agent or method, eg, one or more anti-alcohol or antidepressant agent (s) and / or therapeutic method (s). (3,4-Dichlorophenyl) -3-azabicyclo [3.1.0] hexane is included.

In a related embodiment of the invention, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane (or a pharmaceutically acceptable salt, solvate thereof) Hydrates, polymorphs, or prodrugs) can be used in combination therapy with at least one other therapeutic agent or method. As used herein, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane is a second therapeutic agent, such as ethanol consumption or ethanol consumption and depression. Treat or prevent both or prevent or treat different disorder (s) or symptoms where (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane is administered Can be administered simultaneously or sequentially with the administration of the second agent acting to do so. The (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane and the second therapeutic agent can be combined in a single composition or administered in different compositions . Coordinated administration may be performed simultaneously or sequentially in any order, and only one or both (or all) active therapeutic agents may be individually and / or collectively, their biological activity and It can take time while exerting a therapeutic effect. A characteristic aspect of all the coordinated therapeutic methods is that (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane is provided by the second therapeutic agent. Regardless of its clinical response, it exerts at least some detectable therapeutic activity for the treatment or prevention of both ethanol consumption or ethanol consumption and depression. In many cases,
Coordinated administration of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane with a second therapeutic agent as indicated herein is (+)-1 -(3,4-dichlorophenyl) -3-azabicyclo [3.1.0] enhances the therapeutic response over that provided by either or both of the hexane and / or the second therapeutic agent.

  (+)-1- (3,4-Dichlorophenyl) -3-azabicyclo [3.1.0] hexane is chronically used in patients to prevent or treat both ethanol consumption or ethanol consumption and depression. In one embodiment, the combination therapy is (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane (or a pharmaceutically acceptable salt thereof). Alternating between administration of an acceptable salt, solvate, hydrate, polymorph, or prodrug) and a second therapeutic agent (ie, a therapeutic regimen between two drugs, eg, 1 Weekly, January, March, June, or alternately every year). Alternatively, the drug regimen herein reduces or reduces side effects, such as toxicity, that may be administered for a long period of time with one or both drugs.

  The other therapeutic agent can be an anti-addiction disorder agent. Useful anti-addictive disorders include, but are not limited to, tricyclic antidepressants; MAO inhibitors; glutamate agonists and antagonists such as ketamine HC1, dextromethorphan, dextrophan tartrate and dizocilpine (MK801) ); Degrading enzymes such as anesthetics and aspartic acid antagonists; GABA agonists such as baclofen and muscimol HBr; reuptake blockers; degrading enzyme blockers; glutamate agonists such as D-cycloserine, carboxyphenylglycine, L- Glutamic acid, and cis-piperidine-2,3-dicarboxylic acid; aspartic acid agonist; GABA antagonist such as gabadine (SR-95531), saclofen, bicuculline, picrotoxin, And (+) - apomorphine HC1; and dopamine antagonists, e.g., spiperone HC1, haloperidol, and (-) - include sulpiride.

  The other therapeutic agent can be an anti-alcohol agent. Useful antialcohols include, but are not limited to, disulfiram (Litten RZ et al., Development of medications for alcohol use disorders: recent advances and ongoing challenges, Expert Opin Emerg Drugs 10 (2): 323-43 , 2005); Naltrexone (Volpicelli, JR et al., Naltrexone in the treatment of alcohol dependence, Arch Gen Psychiatry 49: 876-880, 1992; O'Malley, SS et al., Naltrexone and coping skills therapy for alcohol dependence: A controlled study, Arch Gen Psychiatry 49 (11): 881-887, 1992); Acamprosate (Swift, RM Drug therapy for alcohol dependence, N Engl J Med 340 (1): 1482-1490, 1999) Ondansetron (Zofran®) (Pettinati, HMef al, Sertraline treatment for alcohol dependence: Interactive effects of medication and alcohol subtype, Alcohol Clin Exp Res 24 (7): 1041-1049, 2000; Stoltenberg, Scott; F .; Serotonergic Agents and Alcoholism Treatment: A Simulation, Alcoholism: Clinical & Experimental Research 27 (12): 1853-1859, 2003); Sertraline (Zolof®) (Pettinati, HM et al., Sertraline treatment for alcohol dependence: Interactive effects of medication and alcohol subtype, Alcohol Clin Exp Res 24 (7): 1041-1049, 2000); Chiapride (Shaw GK et al., Tiapride in the long-term management of alcoholics of anxious or depressive temperament, Br J Psychiatry 150: 164-8, 1987); -Hydroxybutyric acid (Poldrugo F. and Addolorato G., The role of g-hydroxybutyric acid in the treatment of alcoholism: from animal to clinical studies. Alcohol Alcoholism 34 (1), 15-24, 1999); Galantamine ( Novel pharmacotherapies and patents for alcohol abuse and alcoholism 1998-2001, Expert Opinion on Therapeutic Patents, Vol. 11, No. 10, pages 1497-1521 (2001); US Patent No. 5,932,238); Narmefene (Revex) (Drobes DJ et al., Effects of naltrexone and nalmefene on subjecti ve response to alcohol among non-treatment-seeking alcoholics and social drinkers, Alcohol Clin Exp Res., 28 (9): 1362-70 (2004)); Naloxone (Julius, D., and Renault, P., eds., Narcotic Antagonists: Naltrexone Progress Report, NIDA Research Monograph Series, Number 9.DHEW Publication No. (ADM) 76-387, Elethesda, MD: National Institute on Drug Abuse, 1976; Jenab, S., and Inturrisi, CE, Ethanol and naloxone differentially upregulate delta opioid receptor gene expression in neuroblastoma hybrid (NG108- 15) cells, Molecular Brain Research 27: 95-102, 1994); desoxypeganine (Doetkotte, RA et al., Effects Of Single And Repeated Administered Desoxypeganine On Ethanol Consumption Of Aa-Rats, Alcoholism: Clinical & Experimental Research, International Society for Biomedical Research on Alcoholism 12th World Congress on Biomedical Alcohol Research, September 29-October 2, 2004, Heidelburg / Mannheim, Germany, 28 (8) Supplement: 25 (A, 2004); benzodiazepines (Ntais C et al., Benzodiazepines for alcohol withdrawal, Cochrane Database Syst Rev. (3): CD005063, 2005; Mueller TI et al., Long-term use of benzodiazepines in participants with comorbid anxiety and alcohol use disorders, Alcohol Clin Exp Res. 29 (8): 141 1-8, 2005); neuroleptics such as levomepromazine (Neurocil®) and thioridazine (Melleril®); piracetam; clonidine; Carbamazepine; Cromethiazole (Distraneurin®); Levetiracetam; Quetiapine (Monnelly EP et al., Quetiapine for treatment of alcohol dependence, J Clin Psychopharmacol. 24 (5): 532-5, 2004); Risperidone; Rimonabant; Trazodone (Janiri L et al., Adjuvant trazodone in the treatment of alcoholism: an open study, Alcohol 33 (4): 362-5, 1998); Topiramate (Johnson BA et al., Oral t opiramate for treatment of alcohol dependence: a randomized controlled trial, Lancet 361: 1677-1685, 2003); aripiprazole (Beresford TP et al., Aripiprazole in schizophrenia with cocaine dependence: a pilot study. J Clin P ychopharmacol. 25 (4) : 363-6,2005); and Modafinil (Saletu B et al., On the treatment of the alcoholic organic brain syndrome with an alpha-adrenergic agonist modafinil: double-blind, placebo-controlled clinical, psychometric and neurophysiological studies, Prog Neuropsychopharmacol Biol Psychiatry 14 (2): 195-214, 1990).

  The other therapeutic agent can be an anti-nicotine agent. Useful antinicotine agents include but are not limited to clonidine and bupropion.

  The other therapeutic agent can be an anti-opiate agent. Useful anti-opiate agents include, but are not limited to, methadone, clonidine, lofexidine, levomethadyl acetate HCl, naltrexone, and buprenorphine.

  The other therapeutic agent can be an anti-cocaine agent. Useful anticocaine agents include, but are not limited to, desipramine, amantadine, fluoxidine, d-amphetamine and buprenorphine.

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

  The other therapeutic agent can be an anti-risergic acid diethylamide (“anti-LSD”) agent. Useful anti-LSD agents include, but are not limited to, diazepam.

  The other therapeutic agent can be an anti-phencyclidine (“anti-PCP”) agent. Useful anti-PCP agents include but are not limited to haloperidol.

  The other therapeutic agent can be an anti-parkinsonian agent. Useful antiparkinsonian agents include, but are not limited to, dopamine precursors such as levodopa, L-phenylalanine, and L-tyrosine; neuroprotective agents; dopamine agonists; dopamine reuptake inhibitors; For example, amantadine and memantine; and 1,3,5-trisubstituted adamantane such as l-amino-3,5-dimethyl-adamantane (US Patent No. 4,122,193 to Sherm et al).

  The other therapeutic agent can be an antidepressant. Useful antidepressants include, but are not limited to, amitriptyline, clomipramine, doxepin, duloxetine, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, fluoxetine, fluvoxamine, mirtazapine, paroxetine, sertraline, sertraline, Venlafaxine, bupropion, nafazodone, trazodone, phenelzine, tranylcypromine, selegiline, clonidine, gabapentin, bicifazine and 2-pyridinyl [7- (pyridine with at least one substituent on both the 2- and 4-pyridinyl rings -4-yl) pyrazolo [1,5-a] pyrimidin-3-yl] methanone compounds are included. Useful classes of antidepressants include, but are not limited to, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, tricyclic antidepressants, tetracyclic antidepressants, norepinephrine uptake inhibitors, Selective norepinephrine reuptake inhibitors, and serotonin and norepinephrine uptake inhibitors are included.

  The other therapeutic agent can be an anxiolytic agent. Useful anti-anxiety agents include, but are not limited to, benzodiazepines such as alprazolam, chlordiazeposide, clonazepam, chlorazepart, diazepam, halazepam, lorazepam, oxazepam, and prazepam; non-benzodiazepines; For example, buspirone; and tranquilizers such as barbituate.

  The other therapeutic agent can be an anxiolytic agent. Useful anti-anxiety agents include, but are not limited to, benzodiazepines such as alprazolam, chlordiazeposide, clonazepam, chlorazepart, diazepam, halazepam, lorazepam, oxazepam, and prazepam; non-benzodiazepines; For example, buspirone; and tranquilizers such as barbituate.

  The other therapeutic agent can be an antipsychotic agent. Useful antipsychotics include, but are not limited to, phenothiazines such as chlorpromazine, mesoridazine besylate, thioridazine, acetophenazine maleate, fluphenazine, perphenazine, and trifluoperazine; thioxanthenes such as , Chlorprothixene, and thiothixene; and other heterocyclic compounds such as clozapine, haloperidol, loxapine, molindone, pimozide, and risperidone. Additional antipsychotics include olanzapine, aripiprazole, quetiapine, and ziprasidone. Preferred antipsychotics include chlorpromazine HCl, thioridazine HCl, fluphenazine HCl, thiothixene HCl, and molindone HCl.

  The other therapeutic agent can be an antiobesity agent. Useful anti-obesity agents include, but are not limited to, β-adrenergic receptor agonists, preferably β3-receptor agonists such as, but not limited to, fenfluramine; dexfenfluramine; Bupropion; fluoxetine; phentermine; amphetamine; methamphetamine; dexamphetamine; benzphetamine; phendimetrazine; diethylpropion; mazindol; phenylpropanolamine; norepinephrine; serotonin reuptake inhibitors For example, orlistat is included.

  An effective amount of (+)-1- (3 Administration of 4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane will detectably reduce, eliminate or prevent the target disorder and / or associated symptom (s). In a specific embodiment, administration of the (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane composition to a suitable test subject is a placebo-treated control. 1 associated with the selected disorder by at least 10%, 20%, 30%, 50% or more, up to 75-90%, or 95% or more compared to a person or other suitable control One or more target symptom (s) will result in a decrease in pain, for example, and will result in a decrease in target disease or one or more target symptom (s). Similar efficacy of treatment or prevention using the methods of the invention is believed to cover the full range of alcohol-related or addictive disorders, as well as related diseases and symptoms.

  “Effective amount”, “therapeutic amount” of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane agent and / or psychotherapeutic agent as used herein, “Therapeutically effective amount” or “effective dose” means an effective amount or dose of an active compound described herein sufficient to exert a desired pharmacological or therapeutic effect in a human subject. Such an effect is typically one or more of the disorders, including any combination of neurological and / or psychiatric symptoms, diseases, or conditions associated with or resulting from the target disorder in the subject. It results in a significant decrease in the onset, frequency, or severity of these symptoms (s). In certain embodiments, when a compound described herein is administered to treat a disorder, an effective amount of the compound delays or eliminates the onset of symptoms or deleterious activity of the target disease or disorder An amount in vivo sufficient to delay or eliminate.

  Alternatively, the therapeutic effect may be due to a decrease in the frequency or severity of symptoms associated with the treated alcohol-related disease or disorder or addictive disease or disorder, or the characteristics, onset of symptoms associated with the treated disease or disorder, Can be evidenced by recurrence or change in duration. As used herein, an “effective amount”, “therapeutic amount”, “therapeutically effective amount”, and “effective dose” of a triple reuptake inhibitor described herein are often referred to as routine clinical factors. Or, based on patient specific factors, can be readily determined by one of ordinary skill in the art according to the teachings of the present disclosure and using means and methods well known in the art.

  Suitable routes of administration of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane agents in the methods described herein are not limited. Oral, buccal, nasal, aerosol, topical, transdermal, mucosal, injection, sustained release, controlled release, iontophoresis, sonophoresis, and other normal delivery routes, devices and methods. Injection delivery methods are also believed to include, but are not limited to, intravenous injection, intramuscular injection, intraperitoneal injection, meningeal injection, intraventricular injection, intraarterial injection, and subcutaneous injection.

  Suitable effective unit dosages of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compounds described herein for mammalian subjects range from about 1 to about 1800 mg. , About 10 to about 1800 mg, 25 to about 1800 mg, about 50 to about 1000 mg, about 75 to about 900 mg, about 100 to about 750 mg, or about 150 to about 500 mg. In certain embodiments, an effective dosage is, for example, about 5 to about 10 mg, 10 to about 25 mg, about 30 to about 50 mg, about 10 to about 300 mg, about 25 to about 300 mg, about 50 to about 100 mg, about 100 to about It is selected within a narrower range of about 250 mg, or about 250 to about 500 mg. These and other effective unit dosages are administered in a single dose or in the form of a daily, weekly or monthly dose, eg, per day, per week, or per month. It can be administered in a dosing regimen comprising 1 to 4 or 2 to 3 doses. In specific embodiments, a dosage of about 10 to about 25 mg, about 30 to about 50 mg, about 25 to about 150 mg, about 50 to about 100 mg, about 100 to about 250 mg, or about 250 to about 500 mg per day Administer once, twice, three times, or four times. In more detailed embodiments, a dose of about 50-75 mg, about 100-200 mg, about 250-400 mg, or about 400-600 mg is administered once or twice daily. In a more detailed embodiment, a dose of about 50-100 mg is administered twice daily. In another embodiment, the dosage is calculated based on body weight, such as from about 0.5 mg / kg to about 20 mg / kg per day, 1 mg / kg to about 15 mg / kg per day, 1 mg / kg per day It can be administered in an amount of about 10 mg / kg, 2 mg / kg to about 20 mg / kg per day, 2 mg / kg to about 10 mg / kg per day, or 3 mg / kg to about 15 mg / kg per day.

  The amount, time of delivery of a composition comprising an effective amount of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane agent for use in the methods described herein. And whether the administration is for prevention or treatment, usually according to factors such as the weight, age, sex, and condition of the individual, the degree of progression of the disease to be treated and / or related symptoms, and Individually adjusted based on drug delivery, absorption, pharmacokinetics (including half-life), and other factors known to provide efficacy. An effective dose or multiple dose treatment regimen of a compound of the invention typically includes one or more symptom (s) of a neurological or psychiatric disorder in the subject, as described herein. Is selected to approach the minimum dosage regimen necessary and sufficient to substantially prevent or reduce. Accordingly, of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compounds or pharmaceutically acceptable salts thereof described in the formulations and methods herein. After administration, the test subject is one or more of a disorder affected by the targeted monoamine neurotransmitter or other neurological or psychiatric disorder compared to a placebo-treated control or other suitable control or A 10%, 20%, 30%, 50% or more decrease in symptoms, a maximum 75-90% decrease, or a 95% or more decrease.

  Pharmaceutical dosage forms of the compounds used in the present invention may optionally include excipients recognized in the field of pharmaceutical compounds suitable for the preparation of the above dosage units. Such excipients are not intended to be limiting, but include binders, fillers, lubricants, emulsifiers, suspending agents, sweeteners, flavoring agents, preservatives, buffering agents, wetting agents. Disintegrants, foaming agents and other conventional excipients and additives.

  Pharmaceutical dosage forms of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compositions can include inorganic and organic acid addition salts. Pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salts, potassium salts, cesium salts, etc .; alkaline earth metal salts such as calcium salts, magnesium salts, etc .; organic amines Salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt and the like; organic acid salt such as acetate salt, citrate salt, Lactate, succinate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate, etc .; sulfonate, eg methanesulfone Acid salts, benzene sulfonate, p-toluene sulfonate, etc .; and amino acid salts such as arginate, asparagine Salt, glutamate, tartrate salts, gluconates, and the like.

  Within the various combinations or coordinated treatment methods described herein, additional therapeutic agents and (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compounds Alternatively, the pharmaceutically acceptable salt can be administered by any of a variety of delivery routes and methods, each of which can be the same or different for each drug.

  The additional psychotherapeutic compounds and / or (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane administered herein are often oral agents Formulated and administered in a form, optionally combined with a carrier or other additive (s). Suitable carriers common to pharmaceutical formulation techniques include, but are not limited to, microcrystalline cellulose, lactose, sucrose, fructose, glucose, dextrose or other saccharides, dibasic calcium phosphate, calcium sulfate, cellulose, Methyl cellulose, cellulose derivatives, kaolin, mannitol, lactitol, maltitol, xylitol, sorbitol or other sugar alcohol, dry starch, dextrin, maltodextrin or other polysaccharide, inositol, or mixtures thereof are included. Examples of oral unit dosage forms used in the present invention include tablets and capsules, which are prepared by any conventional method of preparing pharmaceutical oral unit dosage forms that can be utilized to prepare oral unit dosage forms. Can be done. Oral unit dosage forms, such as tablets or capsules, include but are not limited to release modifiers, glidants, compression aids, disintegrants, lubricants, binders, flavoring agents, flavor enhancers, One or more conventional additional formulation ingredients may be included, including sweeteners and / or preservatives. Suitable lubricants include stearic acid, magnesium stearate, talc, calcium stearate, hydrogenated vegetable oil, sodium benzoate, leucine carbowax, magnesium lauryl sulfate, colloidal silicon dioxide and glyceryl monostearate. Suitable glidants include colloidal silica, fumed silicon dioxide, silica, talc, fumed silica, gypsum and glyceryl monostearate. Materials that can be used for coating include hydroxypropylcellulose, titanium oxide, talc, sweeteners and colorants. The aforementioned foaming agents and disintegrants are useful for formulating fast disintegrating tablets known to those skilled in the art. These typically disintegrate in the oral cavity in less than 1 minute, preferably in less than 30 seconds. By blowing agent is meant a pair, typically an organic acid and a carboxylate or dicarboxylate.

  The (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane composition described herein can be any of a variety of inhalation or nasal delivery forms known in the art. Prepared and administered. Devices capable of placing an aerosolized formulation of a triple reuptake inhibitor compound of the present invention or a pharmaceutically acceptable salt thereof in a patient's sinus cavity or alveoli include a metering nebulizer, a nebulizer, Includes dry powder generators, sprayers, etc. Pulmonary delivery to the lungs for rapid transport through the alveolar epithelium into the bloodstream can be particularly useful for treating impending depression episodes. Methods and compositions suitable for pulmonary delivery of drugs for systemic effects are well known in the art. For example, suitable formulations in which the carrier is a liquid, for administration as a nasal spray or nasal spray, include an aqueous or oily solution of the compound of the invention, and any additional active or inactive ingredient (s) Can be.

  Intranasal administration passes the active compound described herein directly into the bloodstream after an effective amount of the compound has been administered to the nose, without requiring the product to accumulate in the lungs. Moreover, intranasal administration can achieve direct or increased delivery of the active compound to the nervous system. In these and other embodiments, intranasal administration of the compounds of the present invention may be advantageous for treating disorders affected by monoamine neurotransmitters by providing rapid absorption and delivery.

  For intranasal and pulmonary administration, liquid aerosol formulations often contain an active compound described herein in combination with a dispersing agent and / or a physiologically acceptable excipient. Alternatively, the dry powder aerosol formulation may contain a finely divided solid subject compound and a dispersant that allows rapid dispersion of the dry powder particles. Using either liquid or dry powder aerosol formulations, the formulation must be aerosolized into small liquid or solid particles to ensure that the nebulized dose reaches the nasal or lung mucosa. The term “aerosol particles” describes liquid or solid particles of sufficiently small particle size, eg, in the range of about 2-5 microns, for nasal or pulmonary distribution to the targeted mucosa or alveolar membrane. As used herein. Other considerations include delivery device construction, additional components in the formulation, and particle characteristics. These aspects of nasal or pulmonary administration of drugs are well known in the art, and formulation operations, aerosolization techniques, and construction of delivery devices are within the level of skill in the art.

  A still further method of the invention is provided by topical administration of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof. The Topical compositions are in the form of aerosol sprays, powders, skin patches, sticks, granules, creams, pastes, gels, lotions, syrups, ointments, impregnated sponges, swabs, or aqueous liquids, non-aqueous liquids, oil-in-water emulsions, Or as a solution or suspension in a water-in-oil liquid emulsion, which may include the compounds described herein and other active ingredient (s) or inert ingredient (s) incorporated into a skin or mucosal acceptable carrier . These topical compositions can include the compounds described herein dissolved or dispersed in water or other solvents or liquids incorporated into the topical composition or delivery device. It can be readily appreciated that the transdermal route of administration can be enhanced by the use of skin permeation enhancers known to those skilled in the art. Formulations suitable for the dosage form include excipients commonly utilized in procedures, for example, structures or matrices, particularly for prolonged absorption of the drug over a long period of time, for example 24 hours. Incorporate

  Aqueous and non-aqueous sterile injection solutions optionally containing antioxidants, buffers, bacteriostats and / or solutes that render the formulation isotonic with mammalian subject blood; suspending agents and / or Still further formulations of the compounds used in the present invention, including aqueous and non-aqueous sterile suspensions that may contain thickeners; dispersions; emulsions, are provided for parenteral administration. The formulation can be contained in single or multiple dose containers. Pharmaceutically acceptable formulations and ingredients are typically sterilized or easily sterilizable, biologically inert, and easily administered. Parenteral formulations typically contain buffering agents and preservatives and can be lyophilized for reconstitution at the time of administration.

  Parenteral formulations can also include a polymer for sustained release after parenteral administration. Such polymeric materials are well known to those skilled in the pharmaceutical compound art. Immediate release injection solutions, emulsions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or multiple daily dose units of the active ingredient (s) or suitable subdivisions thereof.

  Within the scope of the specific compositions and dosage forms used in the methods of the invention, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [ 3.1.0] The hexane compound or pharmaceutically acceptable salt thereof is administered in a sustained or sustained release formulation. In these formulations, the sustained release composition of the formulation has a sustained duration of up to about 24 hours or more over a sustained delivery period of about 8 hours or more, or over a sustained delivery period of about 18 hours or more. Provided is a concentration of active compound (1R, 5S)-or a pharmaceutically acceptable salt thereof in plasma that is therapeutically effective during the delivery period.

  In a specific embodiment, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof is a sustained release vehicle, Combined with a matrix, binder, or coating material. As used herein, the term “sustained release vehicle, matrix, binder, or coating material” refers to the dissolution provided by the “immediate release” formulation described herein for the same dose of active compound. And / or effectively and significantly delayed in vitro dissolution of the active compound and / or to the subject's bloodstream (or other in vivo target active site) after administration (e.g., oral administration) compared to delivery. Refers to any vehicle, matrix, binder, or coating material that delays, improves or extends the delivery of the active compound. Thus, as used herein, the term “sustained release vehicle, matrix, binder, or coating material” refers to “sustained release”, “delayed release”, “slow release”, “ All such vehicles, matrices, bindings known in the art as "extended release", "controlled release", "controlled release", and "pulse release" vehicles, matrices, binders and coatings It is intended to include agents and coating materials.

  In one embodiment, the present invention provides for administering (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compounds or pharmaceutically acceptable salts thereof. Including a method of using an oral sustained release dosage composition. In a related aspect, the present invention relates to (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compounds or pharmaceutically acceptable compounds thereof by using sustained release formulations. Comprising administering an oral dosage form of the salt to reduce one or more side effects. Within the scope of the method, the active agent after oral administration of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof In a sustained release, delayed release, sustained release or controlled release delivery method, a triple reuptake inhibiting compound or pharmaceutically acceptable salt thereof is added to a patient's plasma, tissue, organ or other target active site It is released into the subject's digestive tract (eg, intestinal lumen) over several hours while reaching (eg, central nervous system tissue, fluid or compartment) and being maintained at a therapeutic concentration. When performed in the method, the side effect profile of the triple reuptake inhibiting compound or pharmaceutically acceptable salt thereof is the equivalent dose of the triple reuptake inhibiting compound or pharmaceutically acceptable dose administered in an immediate release oral dosage form. Less than acceptable salt side effect profile.

  In certain embodiments, the (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof is a sustained release composition of the present invention. Products and dosage forms, over at least about 6 hours, often over at least about 8 hours, at least about 12 hours, or at least about 18 hours, and in other embodiments about 24 hours or more Over time, delivered to plasma or other target active sites in the subject at sustained therapeutic concentrations. A sustained therapeutic concentration means a plasma concentration that is at least the lower limit of the therapeutic dosage range set forth herein. In more detailed embodiments of the invention, the sustained release compositions and dosage forms take at least about 6 hours, at least about 8 hours, at least about 12 hours, at least about 18 hours, or up to 24 hours or more. A mammal at a desired dosage (eg, 5, 10, 25, 50, 100, 200, 400, 600, or 800 mg) that results in a minimum plasma concentration that is at least the lower limit of the therapeutic dosage range provided herein. A therapeutic concentration of the triple reuptake inhibiting compound or a pharmaceutically acceptable salt thereof is provided after administration to the subject. In another embodiment of the invention, the sustained release compositions and dosage forms take at least about 6 hours, at least about 8 hours, at least about 12 hours, at least about 18 hours, or up to 24 hours or more, After administration to a mammalian subject at a desired dose (eg, 5, 10, 25, 50, 100, 200, 400, 600, or 800 mg) that results in the minimum plasma concentration known to be associated with a clinical effect It provides a therapeutic concentration of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof.

  In certain embodiments, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof is about 0% to 20% Release and deliver active compound within 0-2 hours (eg, as determined by measuring plasma concentration) and release and deliver 20% -50% active compound within about 2-12 hours Sustained release, characterized in that 50% to 85% of the active compound is released and delivered within about 3 to 20 hours, and 75% or more of the active compound is released and delivered within about 5 to 18 hours In profile, released from the compositions and dosage forms described herein, the subject's plasma or other target active site (region of the brain, eg, prefrontal cortex, frontal lobe, thalamus, striatum, ventral tegment Areas, other cortical areas , Hippocampus, hypothalamus, or including the nucleus accumbens, is delivered to, but not limited to).

  In a more detailed embodiment of the present invention, a composition of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof and An oral dosage form is provided, wherein the composition and dosage form are (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compounds over time after ingestion. Or a concentration curve of a pharmaceutically acceptable salt thereof, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound to be administered, or a pharmaceutically acceptable salt thereof To a curve having an area under the concentration curve (AUC) approximately proportional to the dose of salt administered, and (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] to be administered Xanthine compounds or pharmaceutically Obtain the maximum concentration (Cmax) that is proportional to the dose of volume salts.

  In another detailed embodiment, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound obtained after oral administration of the composition or dosage form of the invention or The Cmax of the pharmaceutically acceptable salt is less than about 80%, often less than about 75% of the Cmax obtained after administering an equivalent dose of the active compound in an immediate release oral dosage form, In some embodiments, less than about 60% or 50%.

  Within the specific embodiments of the invention, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compounds or pharmaceutically acceptable salts thereof and Compositions and dosage forms comprising a sustained release vehicle, matrix, binding agent or coding agent are (+)-1- (3,4-) in the treated subject after administration of the composition or dosage form to the mammalian treated subject. The Cmax of the dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof is the same amount of (+)-1- (3,4-) in the immediate release formulation. The active compound is maintained to be less than about 80% of the Cmax obtained in the control after administration of the dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof. To deliver to.

  As used herein, the term “immediate release dosage form” means that the active compound dissolves readily when contacted with a liquid physiological medium such as phosphate buffered saline (PBS) or natural or artificial gastric fluid. , (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the immediate release formulation is characterized in that it dissolves at least 70% of the active compound within 30 minutes after contacting the dosage form with the liquid physiological medium. In another embodiment, at least 80%, 85%, 90% or more, or up to 100% of the active compound in the immediate release dosage form is the dosage form in an art recognized in vitro lysis assay. Dissolves within 30 minutes after contact with the liquid physiological medium. These general characteristics of immediate-release dosage forms are that (+) in encapsulated dosage forms, for example (+) in gelatin capsule dosage forms, where dissolution often occurs relatively soon after dissolution / breakage of gelatin capsules. Related to powder or granule compositions of -1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compounds or pharmaceutically acceptable salts thereof. In another embodiment, the immediate release dosage form is a compressed tablet when the dissolution profile is often more immediate release (eg, at least 85% to 95% of the active compound is dissolved within 30 minutes). , Granular formulations, powders, or liquid dosage forms.

  In a further embodiment of the invention, the immediate release dosage form is (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof. Compositions in which the salt is not mixed, bound, coated or associated with formulation ingredients that substantially prevent in vitro or in vivo dissolution and / or in vivo bioavailability of the active compound. Within certain embodiments, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof has a substantial amount of persistence. Provided in an immediate release dosage form that does not contain a releasable vehicle, matrix, binder or coating material. As used herein, the term “substantial sustained release vehicle, matrix, binder or coating material” is provided in a composition that is any amount of the material but is essentially free of the material. At least 5% more than the dissolution of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof. (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] in formulations containing at least 10% and up to at least 15% to 20% of the substance. It is not intended to exclude an amount sufficient to prevent in vitro or in vivo dissolution of a hexane compound or a pharmaceutically acceptable salt thereof.

  In another embodiment of the present invention, an immediate release agent of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof. Form is FDA Biopharmaceutical Classification System (BCS) guidance definition of “Highly Soluble Substances in Fast Dissolving Formulations” (see eg http://www.fda.gov/cder/OPS/BCS_guidance.htm) Any dosage form containing a compound compatible with In a specific embodiment, the (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or pharmaceutically acceptable salt thereof described in this aspect of the invention. An immediate release formulation of the salt comprises at least about 85% of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or pharmaceutically thereof in the formulation. It exhibits rapid dissolution properties as described in the BCS guidance parameters such that acceptable salts dissolve in the test solution within about 30 minutes at pH 1, pH 4.5, and pH 6.8.

  So far, the compositions, dosage forms and methods described herein include (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compounds or pharmaceuticals thereof. Included are novel means for coordinated treatment of disorders contributed by monoamine neurotransmitters by providing sustained release and / or sustained delivery of acceptable salts. As used herein, “sustained release” and “sustained delivery” are sustained, delayed, extended or improved in vitro or in vivo dissolution rates, in vivo release rates and / or delivery rates, and / or in vivo pharmacokinetic values ( More than one) or revealed by profile.

  The sustained release dosage form used in the method of the present invention may take any form as long as it meets one or more of the above-mentioned dissolution characteristics, release characteristics, delivery characteristics and / or pharmacokinetic characteristics. Within exemplary embodiments, the composition or dosage form is a drug release polymer, matrix, bead, microcapsule, or other solid drug release vehicle; drug release sustained release low dose pills or minitablets; Compressed solid drug delivery vehicles; controlled release binders; multilayer tablets or multilayer or multi-component dosage forms; drug release liquids; drug release waxes; and various other sustained drug release properties shown herein (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] combined with any one of the substances or combinations thereof or formulated into an osmotic dosage form It may contain a hexane compound or a pharmaceutically acceptable salt thereof.

  Thus, the present invention provides in certain embodiments, for example, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo, which is suitable for providing sustained release of active compound (s) after oral administration. [3.1.0] Includes various sustained release compositions and dosage forms of hexane compounds and pharmaceutically acceptable salts thereof. Sustained release vehicles, matrices, binders and coatings used in accordance with the present specification are inert to the active agent and can be physically combined, mixed or integrated with the active compound. Any biocompatible sustained release material is included. Useful sustained release substances may gradually dissolve, degrade, disintegrate and / or metabolize under physiological conditions after delivery (eg, after delivery to the subject's gastrointestinal tract or after contact with gastric or other bodily fluids). Can be done. Useful sustained-release materials are typically non-toxic and inert when in contact with bodily fluids and tissues in mammalian subjects and do not cause significant adverse side effects such as hypersensitivity, immune response, inflammation, etc. . They are typically metabolized to metabolites that are biocompatible and easily eliminated from the body.

  In some embodiments, the sustained release polymeric material is used as a sustained release vehicle, matrix, binder, or coating (eg, “Medical Applications of Controlled Release”, Langer and Wise (eds.), CRC Press. ., Boca Raton, Fla. (1974); "Controlled Drug Bioavailability", Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, NY (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: See also 105, each of which is incorporated herein by reference). Within a specific embodiment, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compounds or to obtain a sustained release composition or dosage form Useful polymers for formulating with pharmaceutically acceptable salts thereof include ethyl cellulose, hydroxyethyl cellulose; hydroxyethyl methyl cellulose; hydroxypropyl cellulose; hydroxypropyl methyl cellulose; hydroxypropyl methyl cellulose phthalate; hydroxypropyl methyl cellulose succinate; Hydroxypropylmethylcellulose acetate phthalate; sodium carboxymethylcellulose; cellulose acetate phthalate; cellulose acetate trimellitic acid; polyoxyethylene stearate; polyvinylpyrrolidone; Alcohol, copolymers of polyvinyl pyrrolidone and polyvinyl alcohol; polymethacrylic acid copolymers; but, and mixtures thereof include, but are not limited to.

  Additional polymeric materials for use as sustained release vehicles, matrices, binders, or coatings within the compositions and dosage forms used in the present invention include, for example, Alderman, Int. J. Pharm. Tech. & Prod Mfr., 1984, 5 (3) 1-9 (cited herein), including but not limited to additional cellulose ethers. Other useful polymeric materials and matrices are derived from copolymeric and homopolymeric polyesters having hydrolysable ester linkages. Many of these are known in the art to be biodegradable, leading to degradation products that are non-toxic or of low toxicity. Examples of polymers herein include polyglycolic acid (PGA) and polylactic acid (PLA), poly (DL-lactic acid-co-glycolic acid) (DL PLGA), poly (D-lactic acid-co-glycolic acid) ( D PLGA) and poly (L-lactic acid-co-glycolic acid) (L PLGA). Other biodegradable or biodegradable polymers for use in the present invention include poly (ε-caprolactone), poly (ε-aprolactone-CO-lactic acid), poly (ε-caprolactone-CO—). Glycolic acid), poly (β-hydroxybutyric acid), poly (alkyl-2-cyanoacrylate), hydrogels such as poly (hydroxyethyl methacrylate), polyamides, poly-amino acids (eg poly-L-leucine, poly- Polymers such as glutamic acid, poly-L-aspartic acid, etc.), poly (ester urea), poly (2-hydroxyethyl-DL-aspartamide), polyacetal polymer, polyorthoester, polycarbonate, polymaleamide, polysaccharide, And copolymers thereof. Methods for producing pharmaceutical formulations using these polymeric substances are generally known to those skilled in the art (eg, Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dek., Inc.). , New York, 1978, which is hereby incorporated by reference).

  In another embodiment of the present invention, compositions and agents of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compounds or pharmaceutically acceptable salts thereof. The form is coated with a polymeric material. The polymer can be an erodible or non-erodible polymer. The coated material can be combined with itself to obtain a bilayer polymer drug dosage form. For example, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compounds or pharmaceutically acceptable salts thereof are polymers, eg, polypeptides, collagens, gelatins , Pyrivinyl alcohol, polyorthoesters, polyacetyl, or polyorthocarbonates, and the coated polymers themselves combine to give a bilayer dosage form. In operation, the biodegradable dosage form erodes at a controlled rate until the active compound is dispersed over a sustained release period. Representative biodegradable polymers for use in this and other aspects of the invention include, for example, biodegradable poly (amides), poly (amino acids), poly (esters), poly (Lactic acid), poly (glycolic acid), poly (carbohydrate), poly (orthoester), poly (orthocarbonate), poly (acetyl), poly (anhydride), biodegradable poly (dehydropyran), or poly (E.g., Rosoff, Controlled Release of Drugs, Chap. 2, pp. 53-95 (1989); and U.S. Pat. Nos. 3,811,444; 3,962,414; 4,066,747, 4,070,347; 4,079,038; and 4,093,709).

  In another embodiment of the invention, the dosage form is loaded into a polymer that releases drug by diffusion from the polymer, by flowing through a gap or by breakage of the polymer matrix (+)-1- (3,4) Dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof. Drug delivery polymeric dosage forms comprise the active compound contained in or on the polymer. The dosage form includes at least one exposed surface at the beginning of dose delivery. The unexposed surface, if present, can be coated with a pharmaceutically acceptable material that is impermeable to the passage of the drug. The dosage form can be prepared by a method known in the art, for example by mixing a pharmaceutically acceptable carrier such as polyethylene glycol with a predetermined amount of active compound (s) at an elevated temperature (eg 37 ° C.) For example, by adding to a silastic medical grade elastomer with octanoate and then molding. The process is repeated for each desired continuous layer. The system can be timed to obtain a dosage form. Representative polymers for making the sustained release dosage form include olefins and vinyl, shown as polyethylene, polypropylene, polyvinyl acetate, polymethyl acrylate, polybutyl acrylate, polyalginate, polyamide and polysilicon. Polymers, addition polymers, condensation polymers, carbohydrate polymers, and silicone polymers include, but are not limited to. These polymers and methods for their production are described in the prior art (eg, Coleman et al., Polymers 1990, 31, 1187-1231; Roerdink et al., Drug Carrier Systems 1989, 9, 57-10; Leong et al, Adv. Drug Delivery Rev. 1987, 1, 199-233; and Roffef al, Handbook of Common Polymers 1971, CRC Press; US Pat. No. 3,992,518).

In another embodiment of the invention, a composition comprising (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof and The dosage form is combined with beads that dissolve or disperse to release the active compound over an extended period of time, for example, for at least 6 hours, for at least 8 hours, for at least 12 hours, or for up to 24 hours or more, or Contained in the beads. The drug-releasing beads comprise (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. And a central composition or core that includes both one or more desired excipients, such as lubricants, antioxidants, dispersants, and buffers. The beads can be a pharmaceutical formulation having a diameter of about 1-2 mm. In a specific embodiment, they are formed from non-crosslinked materials to facilitate their release from the gastrointestinal tract. The beads can be coated with a release rate controlling polymer that provides a sustained release pharmacokinetic profile. In another embodiment, the beads can be made into tablets for pharmaceutically effective drug administration. The beads can be made into matrix tablets by direct compression of a plurality of beads, for example, coated with an acrylic resin and mixed with excipients such as hydroxypropylmethylcellulose. The manufacture and processing of beads for use in the present invention has been described in the prior art (eg, Lu, Int. J. Pharm., 1994, 112, 117-124; Pharmaceutical Sciences by Remington, 14 ^th ed, pp1626 -1628 (1970); Fincher, J. Pharm. Sci. 1968, 57, 1825-1835; and US Pat.No. 4,083,949, each cited herein) as has the manufacture of tablets (Pharmaceutical Sciences, ^{by Remington, 17 th Ed, Ch} . 90, pp1603-1625, 1985, which is incorporated by herein).

  In another embodiment of the invention, the dosage form comprises a plurality of low dose pills or mini doublets. Low dose pills or mini doublets provide a number of individual doses to provide various time doses to achieve a sustained release drug delivery profile over a long period of time, up to 24 hours. Low-dose pills or mini doublets are polysaccharides, agar, agarose, natural rubber, alkaline alginate (including sodium alginate), carrageenan, fucoidan, far celerin, laminaran, hypnea, gum arabic, gum ghatti, karaya gum , Tragacanth gum, locust bean gum, pectin, amylopectin, gelatin, and a hydrophilic polymer selected from the group consisting of hydrocolloids. The hydrophilic polymer is a low-dose pill or mini doublet, each of which has a predetermined amount of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof. Multiple (eg, 4-50) low-dose pills, including amounts of acceptable salts, eg, about 10 ng, 0.5 mg, 1 mg, 1.2 mg, 1.4 mg, 1.6 mg, 5.0 mg, etc. Or it can be formed in a mini doublet. The low dose pills and mini doublets further comprise a release rate control wall that is 0.001-10 mm thick to provide sustained release of the active compound. Typical wall-forming materials include glyceryl tristearate, glyceryl monostearate, glyceryl dipalmitate, glyceryl laureate, glyceryl didecenoate and glyceryl tridenoate A triglycerol ester selected from the group consisting of: Other wall forming materials include polyvinyl acetate, phthalate, methylcellulose phthalate and porous olefins. Methods for producing low dose pills and mini doublets are known in the art (see, eg, US Pat. Nos. 4,434,153; 4,721,613; 4,853,229; 2,996,431; 3,139,383 and 4,752,470, respectively). The low dose pills and mini doublets may further comprise a fusion of particles, which may contain particles of different sizes and / or release characteristics, wherein the particles are in hard or non-gelatin capsules or soft gelatin capsules. May be contained.

  In yet another embodiment of the invention, the drug release liquid matrix is a (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof. Can be used to formulate therapeutic compositions and dosage forms containing certain salts. In one exemplary embodiment, solid particulates of the active compound are prepared from liquids such as glyceryl behenate and / or glyceryl as described in Farah et al., US Pat. No. 6,375,987 and Joachim et al, US Pat. No. 6,379,700. Coated with a thin controlled release layer of palmitostearate). The liquid coating particles may be compressed as desired to form tablets. Another controlled release lipid-based matrix material suitable for use in the sustained release compositions and dosage forms of the present invention includes, for example, the polyglycol type glycerides described in Roussin et al., US Pat. No. 6,171,615.

  In another embodiment of the invention, the drug release wax comprises (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof. Can be used to produce sustained release compositions and dosage forms, including. Examples of suitable sustained drug release waxes include, but are not limited to, carnauba wax, candelilla wax, esparto wax, ouricury wax, hydrogenated vegetable oil, beeswax, paraffin, ozokerite, castor wax, and their Mixtures can be mentioned (see, eg, Cain et al, US Pat. No. 3,402,240; Shtohryn et al. US Pat. No. 4,820,523; and Walters, US Pat. No. 4,421,736).

  In yet another embodiment, the osmotic delivery system comprises (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof. Used for sustained release delivery (see, for example, Verma et al, Drug Dev. Ind. Pharm .. 2000, 26: 695-708, cited herein). In one exemplary embodiment, the osmotic delivery system is an OROS® system (Alza Corporation, Mountain View, Calif.) And is suitable for oral sustained release delivery of drugs (eg, US Pat. 3,845,770; and U.S. Pat. No. 3,916,899).

  In another embodiment of the invention the dosage form comprises (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof. An osmotic dosage form comprising a semi-permeable wall surrounding the containing therapeutic composition. For use in a patient, an osmotic dosage form comprising a homogeneous composition absorbs fluid through the semipermeable wall in the dosage form in response to the concentration difference of the semipermeable wall. The therapeutic composition in the dosage form takes a long time of up to 24 hours (or in some cases up to 30 hours) to control release and sustained release of the prodrug from the dosage form. Develop osmotic energy to flow out and administer. These delivery platforms can provide a substantially zero order delivery profile as opposed to the spike profile of immediate release formulations.

  In another embodiment of the invention, the dosage form is a semi-permeable polymeric material that is permeable to the walls covering the compartments, the passage of fluid and substantially impervious to the passage of active compounds present in the compartments. Wall containing composition, drug-containing layer composition in compartment, from dosage form to (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or pharmaceutically A hydrogel push layer composition in a compartment containing an osmotic formulation for absorbing fluid to stretch in an size to extrude an acceptable salt composition layer, and in a wall to release the drug composition Another osmotic dosage form comprising at least one passage. The osmotic system delivers active compounds by absorbing fluid through the semipermeable wall at a fluid absorption rate determined by the permeability of the semipermeable wall and the osmotic pressure of the semipermeable wall extending the push layer. As a result, the active compound is delivered to the patient through the outflow passage over an extended period of time (up to 24 hours or 30 hours). The hydrogel layer composition is 10 mg to 1000 mg of hydrogel, for example, 1,000,000 weight average molecular weight polyethylene oxide, 2,000,000 molecular weight polyethylene oxide, 4,000,000 molecular weight polyethylene oxide, 5,000,000, 1,000,000 to 8,000, selected from the group consisting of polyethylene oxide of 000 molecular weight, polyethylene oxide of 7,000,000 molecular weight and polypropylene oxide of 1,000,000 to 8,000,000 weight average molecular weight A member selected from the group consisting of 1,000 polyalkylene oxides; or 10 mg to 1000 mg of 10,000 to 6,000,000 weight average molecular weight alkali carboxymethyl cellulose, such as carboxymethyl cellulose nato It may include um or carboxymethylcellulose potassium. Hydrogel swelling layer is composed of 7,500-4,500,00 weight molecular weight hydroxyalkyl cellulose (eg, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose or hydroxypentylcellulose), sodium chloride, potassium chloride, acidic phosphorus Potassium acid, tartaric acid, citric acid, raffinose, magnesium sulfate, magnesium chloride, urea, inositol, sucrose, glycol and sorbitol, or other substances such as hydroxypropyl alkylcellulose of 9,000 to 225,000 average molecular weight (e.g. Hydroxypropylethylcellulose, hydroxypropylpentylcellulose, hydroxypropylmethylcellulose, or hydroxypropyl Osmagent, iron oxide, antioxidant (eg ascorbic acid, butylated hydroxyanisole, butylated hydroxyquinoline, butylhydroxyanisole, hydroxycomarin, butylated hydroxy selected from pyruvylcellulose) Toluene, cephalm, ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propyl hydroxybenzoate, trihydroxybutylrophenone, dimethylphenol, dibutylphenol, vitamin E, lecithin and ethanolamine ) And / or lubricants (eg, calcium stearate, magnesium stearate, zinc stearate, magnesium oleate, calcium palmitate, suberin) Sodium acid, potassium laureate, fatty acid salt, alicyclic acid salt, aromatic acid salt, stearic acid, oleic acid, palmitic acid, fatty acid, alicyclic acid, or aromatic acid salt And fatty acids, cycloaliphatic acids, or aromatic acids).

  In the osmotic dosage form, the semipermeable wall is permeable to the passage of fluid and is a (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or its Compositions that are impermeable to passage of pharmaceutically acceptable salts are included. The wall is non-toxic and comprises a polymer selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate and cellulose triacetate. The wall typically comprises 75 wt% (weight percent) to 100 wt% cellulosic wall forming polymer; or the wall is further 0.01 wt% to 80 wt% polyethylene glycol, or 1 wt% to 25 wt% % Cellulose ether (eg, hydroxypropylcellulose or hydroxypropylalkylcellulose, eg, hydroxypropylmethylcellulose). The total weight percent of all components including the wall is equal to 100 wt%. The inner compartment contains the drug-containing composition alone or with the expandable hydrogel composition in the layer portion. The expandable hydrogel composition in the compartment increases in volume by absorbing fluid through the semipermeable wall so that the hydrogel swells and occupies the space in the compartment so that the drug composition Extruded from the dosage form. The treatment layer and the swelling layer work together during delivery of the dosage form for release of the drug to the patient over time. The dosage form includes a wall passage connecting the exterior and interior compartments of the dosage form. The osmotic powder dosage form provides (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane from the dosage form to the patient with a zero order release rate over a maximum of about 24 hours. Deliver the compound or a pharmaceutically acceptable salt thereof. As used herein, the expression “passage” refers to the (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound from the compartment of the osmotic dosage form or its Means and methods suitable for metered release of pharmaceutically acceptable salts are included. The outlet means comprises at least one passage comprising an orifice, bore, opening, pore, porous element, hollow fiber, capillary, channel, porous overlay, or porous element that provides osmotic controlled release of the active compound including. The passageway includes a material that erodes or is eluted from the wall in a fluid use environment to provide a passageway of at least one controlled release dimension. Representative materials suitable for the formation of passages or multiple passages are leachable poly (glycolic acid) or poly (lactic acid) polymers in the walls, gel filaments, poly (vinyl alcohol), leachable polysaccharides, Includes circles and oxides. The pore passage, or one or more pore passages, can be formed by eluting a compound that can leach from the wall, such as sorbitol. The passageway has controlled release dimensions, such as circular, triangular, square, elliptical, for metered release of the prodrug from the dosage form. The dosage form can be constructed with one or more passages in the relationship of a gap on a single surface of the wall or on one or more surfaces. The expression “fluid environment” means an aqueous or biological fluid, such as a human patient, including the gastrointestinal tract. The passages and devices for forming the passages are described in U.S. Patent Nos. 3,845,770; 3,916,899; 4,063,064; 4,088,864; 4,816,263; 4,200,098;

  In more detailed embodiments, the compounds described herein can be used in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or macroemulsions, e.g., coacervation. They can be encapsulated for delivery in microcapsules, microparticles, or microspheres, eg, hydroxymethylcellulose or gelatin-microcapsules and poly (methyl methacrylate) microcapsules, prepared by methods or by interfacial polymerization.

  For (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compounds or pharmaceutically acceptable salts thereof to provide sustained or delayed release of the active compound Various methods are known, which can be encapsulated in the form of microparticles, for example by encapsulating the active compound in a biocompatible biodegradable wall-forming material (eg a polymer). In these methods, the active compound is typically dissolved, dispersed, or emulsified in a solution containing the wall forming material. The solvent is then removed from the finished microparticles to form a microparticle product. These references include (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compounds or pharmaceuticals thereof in the sustained release formulations described in the present invention. Discloses a method by which it is possible to easily prepare fine particles containing an acceptable salt. For example, as described in US Pat. No. 5,650,173, a microparticulate formulation can be produced by appropriate selection of the polymeric material, and the resulting microparticles are both diffuse and biodegradable. The characteristics of With respect to the mechanism of diffusion release, the active agent is released from the microparticles prior to substantial degradation of the polymer. The bioactive agent is also released from the microparticles as the limeric excipient erodes. In addition, US Pat. No. 6,596,316 discloses a method for preparing microparticles having a selected release profile to fine tune the release profile of the active agent from the microparticles.

  In another embodiment of the invention, the enteric preparation can be used for oral sustained release administration. Preferred coating materials include polymers with pH dependent solubility (ie pH controlled release), polymers with low or pH dependent swelling rate, dissolution rate or erosion rate (ie time controlled release), enzymatically degraded Included are (ie, enzyme controlled release) polymers and polymers that form film layers that are broken by pressure increase (ie, pressure controlled release). The enteric coating may be between layers of a multilayer solid dosage form (see below) and / or on one or more outer surfaces of one or more layers of the multilayer solid dosage form (eg, substantially cylindrical (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3 .1.0] can function as a means for modulating the sustained release of a hexane compound or a pharmaceutically acceptable salt thereof. The barrier layer is, for example, substantially or completely impermeable to water or an aqueous medium, or gradually erodes in water or an aqueous medium or biological fluid, and / or contacts with water or an aqueous medium It can consist of a polymer that expands. Suitable polymers for use as the barrier layer include acrylates, methacrylates, copolymers of acrylic acid, cellulose and its derivatives such as ethyl cellulose, cellulose acetate propionate, polyethylene and polyvinyl alcohol. A barrier layer comprising a polymer that swells in contact with water or an aqueous medium can swell until the swelled layer forms a relatively large amount of swelling, a size that delays immediate release from the stomach to the small intestine. The barrier layer can itself contain an active substance content, for example, the barrier layer can be a slow release or delayed release layer. The barrier layers typically each have a thickness of 10 microns to 2 mm. Suitable polymers of the barrier layer that are relatively impermeable to water include Methocel ™ species polymers and Ethocel ™ polymers used alone or in combination. The polymer may suitably be used in combination with a plasticizer, such as hydrogenated castor oil. The barrier layer may also include conventional binders, fillers, lubricants, compression acids such as Polyvidon K30 ™, magnesium stearate, and silicon dioxide.

  Additional enteric materials that mediate sustained release of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compounds or pharmaceutically acceptable salts include Included are coating agents in the form of polymeric membranes, which can be permeable membranes, porous membranes, or asymmetric membranes. These and other types of coatings used in the present invention may also include, for example, at least one delivery port in the coating formed by laser piercing a water-soluble material plug or erosion of the plug, or Can contain pores. Other useful coating agents of the invention include coating agents that are destroyed in the environment of use (eg, gastrointestinal compartment) to form a release site or delivery port. Specific coating agents in these and other embodiments of the present invention include poly (acrylic) acid and ester; poly (methacrylic) acid and ester; poly (acrylic) acid and poly (methacrylic) acid and ester copolymer Cellulose ester; cellulose ether; and cellulose ester / ether.

  Building a solid dosage form for mediating sustained release of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compounds or pharmaceutically acceptable salts thereof Additional coating materials used for polyethylene glycol, polypropylene glycol, copolymers of polyethylene glycol and polypropylene glycol, poly (vinyl pyrrolidone), ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl ethyl cellulose, starch, dextran, Dextrin, chitosan, collagen, gelatin, bromethaine, cellulose acetate, unplasticized cellulose acetate, plasticized cellulose acetate, reinforced cellulose acetate, phthalate acetate cell , Cellulose trimellitic acetate, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate acetate, hydroxypropylmethylcellulose trimellitic acetate, cellulose nitrate, cellulose diacetate, cellulose triacetate, agar acetate, amylose triacetate , Β-glucan acetate, β-glucan triacetate, acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose Cellulose acetate dimethaminoacetate, cellulose acetate ethyl carbonate (cellulose acetate et hyl carbonate), cellulose acetate chloroacetate, cellulose acetate ethyl oxalate, cellulose acetate methyl sulfonate, cellulose acetate butyl sulfonate, propionate acetate Cellulose acid, cellulose acetate p-toluene sulfonate, locust bean gum triacetate, cellulose acetate with acetylated hydroxyethyl cellulose, ethylene vinyl acetate, cellulose acetate butyrate, polyalkene, polyether, Polysulfone, polyethersulfone, polystyrene, halogenated polyvinyl, polyvinyl ester and ether, natural wax and synthetic wax It is not limited to these.

  In a further embodiment of the invention, the sustained release of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof is multilayered. It is provided by formulating the active compound in dosage forms including tablets or other multilayer or multi-component dosage forms. In a specific embodiment, the active compound is formulated in a layered tablet, for example having a first layer that is an immediate release layer and a second layer that is a sustained release layer. Other multilayer dosage forms of the present invention comprise a plurality of layers of compressed active ingredients having variable (ie selectable) release characteristics selected from immediate release, sustained release and / or delayed release mechanisms. May be included. Useful for producing sustained release dosage forms of ((+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compounds or pharmaceutically acceptable salts thereof. The multilayer tablet technique is described, for example, in International Publications WO95 / 20946; WO94 / 06416; and WO98 / 05305. (+)-1- (3,4-Dichlorophenyl) -3-azabicyclo [3.1.0 Other multi-component dosage forms for providing sustained release of hexane compounds or pharmaceutically acceptable salts thereof are coated with a release retardant and an outer coating layer (optionally containing an active compound) A tablet formulation having a core containing the active compound, which is covered by an enteric coating agent so that the contents of the outer core are released immediately, and then the core The first from the core to delay until reaching the intestines In addition, WO 96/04908 describes a tablet formulation comprising an active substance in a matrix for immediate release and a granule in a delayed release form comprising the active substance. Is coated with an enteric coating, so the release is delayed until the granule reaches the intestine.WO 96/04908 describes a granule with a core containing an active substance covered by a layer containing the active substance. Describes the delayed release or sustained release formulations that are formed.

  (+)-1- (3,4-Dichlorophenyl) -3-azabicyclo [3.1.0] another useful multi-component for the sustained release of hexane compounds or pharmaceutically acceptable salts thereof A layered tablet) dosage form is described in US Pat. No. 6,878,386. That is, the bilayer tablet includes an immediate release layer and a sustained release layer, which may optionally have a coating layer. An immediate release layer can be, for example, a layer that has a composition similar to known tablets that degrade immediately or rapidly and that break down immediately or rapidly. Another type of immediate release layer is a swellable composition that incorporates a polymeric material that swells immediately and extensively in contact with water or an aqueous medium to form a water permeable but relatively large swollen mass. It can be a layer. The active substance content can be leached out of the mass immediately. The sustained release layer comprises (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof, a release-retarding vehicle, a matrix, It may have a composition that includes a binder, a coating agent, or an excipient that allows sustained release of the active compound. Suitable release retarding excipients include pH selective polymers, such as polymers with methacrylic acid copolymers, which can be used alone or in conjunction with plasticizers; high swellability in contact with water or aqueous media such as stomach contents A release-retarding polymer having; a polymeric material that forms a gel in contact with water or an aqueous medium; and a polymeric material that has both swellable and gelling properties in contact with water or an aqueous medium. Highly expansible release retarding polymers include, among others, crosslinked sodium carboxymethylcellulose, crosslinked hydroxypropylcellulose, high molecular weight hydroxypropylmethylcellulose, carboxymethylamide, potassium methacrylate-divinylbenzene copolymer, polymethylmethacrylate, crosslinked polyvinylpyrrolidone, high Molecular weight polyvinyl alcohol and the like are included. Release delayed gel polymers include methyl cellulose, carboxymethyl cellulose, low molecular weight hydroxypropyl methyl cellulose, low molecular weight polyvinyl alcohol, polyoxyethylene glycol, non-crosslinked polyvinyl pyrrolidone, xanthan gum and the like. Release-retarding polymers having both swellable and gelling properties include intermediate viscosity hydroxypropyl methylcellulose and intermediate viscosity polyvinyl alcohol. Specific release retarding polymers are xanthan gum, in particular fine grade xanthan gum, preferably pharmaceutical grade xanthan gum, 200 mesh, for example the product Xantal 75 (also known as eltrol CR ™, Monsanto, 800 N Lindbergh Blvd). , St Louis, Mo. 63167, USA). Xanthan gum is a polysaccharide that forms a sticky gel layer around tablets that needs to be hydrated to diffuse the active substance. It has been shown that the smaller the particle size, the slower the release rate. Furthermore, the release rate of the active compound depends on the amount of xanthan gum used and can be adjusted to obtain the desired profile. Examples of other polymers that can be used in these aspects of the invention include Methocel 4M ™, Methocel E5 ™, Methocel E50 ™, Methocel E4M ™, Methocel K15M ™ and Methocel K100M ( Trademark). This is to provide a sustained release composition or dosage form of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof. Other known release-retarding polymers that can be incorporated into these and other embodiments of the invention include hydrocolloids such as natural or synthetic rubbers, other cellulose derivatives, carbohydrate-based materials such as acacia, tragacanth gum, locust Bean gum, guar gum, agar, pectin, carrageenan, soluble and insoluble alginate, carboxypolymethylene, casein, zein, and the like, and proteins such as gelatin.

Within other embodiments of the invention, a sustained release delivery device or system is placed in the subject near the target of the active compound, so only a portion of the systemic dose is needed (eg, Goodson , In "Medical Applications of Controlled Release", supra, vol. 2, pp. 115-138, 1984; and Langer, 1990, Science 249: 1527-1533, each of which is hereby incorporated by reference). In other embodiments, oral sustained release pumps can be used (eg, Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14: 201; and Saudek et al., 1989, N. Engl). J. Med. 321: 574, each incorporated herein by reference).

  The pharmaceutical compositions and dosage forms used in the present invention are typically administered in a form that is sterile or easily sterilizable, biologically inert, and easily administered.

  In another embodiment, the present invention provides a pharmaceutical kit for reducing symptoms in a human subject suffering from a disorder affected by monoamine neurotransmitters, including depression. The kit comprises an effective amount of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof, and a cooperative to said subject Container means for containing (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof for administration (eg, Container, split bottle, or split foil pack). The container means can include a package with a label or fold that provides instructions for treating the disorder and using multiple kit contents to reduce a subject's symptoms. In a more detailed embodiment, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof is a single combination It is mixed or formulated into a form, for example a liquid or solid oral dosage form. In another embodiment, ((+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane compound or a pharmaceutically acceptable salt thereof is for coordinated administration. Examples of such kits are so-called blister packs, which are well known in the packaging industry for packaging pharmaceutical dosage forms (tablets, capsules, etc.). Widely used.

  Throughout the specification and claims, the terms `` comprise '', `` comprising '', etc. shall have an exclusive or exhaustive meaning, unless the context clearly dictates otherwise. Should be construed in a comprehensive sense, in other words, in the sense of "including but not limited to". Terms using the singular or plural number also include the plural or singular number respectively. Furthermore, the terms “herein”, “above”, “below” and like terms when used in this application refer to the entire application, It does not mean a specific part of. When the claim uses the term “or” in a list of two or more matters, the term encompasses all of the following term interpretations: any of the items in the list, all of the items in the list And any combination of items in the list.

  It should be understood that the invention is not limited to such formulations, process steps, and materials, as the specific formulations, process steps, and materials described herein may vary somewhat. is there. Since the scope of the present invention is limited only by the appended claims and their equivalents, the terminology used herein is used to describe only specific embodiments, and It should also be understood that it is not intended to be limiting.

  The following examples illustrate certain embodiments of the present invention, but are not intended to limit the scope of the invention in any way.

Example I
Effect of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane on ethanol consumption by alcohol-preferred rats (+)-1- ( The efficacy of 3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane was evaluated in genetically selected alcohol preference (P) rats, an animal model for human alcohol abuse. The effect of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane on P rats was tested in a bindioperant reaction experiment.

  P-rats were obtained from the Alcohol Research Center of Indiana University School of Medicine. Male P rats were used in all experiments, were about 4-5 months of age, and had a starting body weight of 420-580 g. The animals were individually housed in a facility at room temperature of 21 ° C. with a standard 12 hour light / dark cycle. All rats had free access to food and water except during training in the operant self-administration study where the rats were not hydrated for 23 hours daily for the first 5 days of the training phase. These animals then had free food and water retention. All training and experimental periods for all subjects took place between 9 am and 5 pm.

  P rats were orally administered (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane in deionized water at a dose of 1 ml / kg using a feeding tube (PO )did. Deionized water was administered as a control injection.

  Behavioral experiments were conducted in a standard operant chamber (Coulbourn Instruments, Allentown, PA) with two removable levers and two zipper fluid delivery systems surrounded by the aforementioned soundproof room (Cook et al., 2004). ). All zipper displays provided 1.5 seconds of access to a 0.1 ml zipper followed by a 3 second timeout period. When each lever was raised, there were three types of stimulation light (red, green and yellow), and stimulation transmission / enhancement was indicated by illumination of medium (green) stimulation light. Responses and enhancements were recorded and managed using the 4.0 Coulbour L2T2 operant software package. The operant period was 90 seconds.

  Rats were trained to push the lever with EtOH (10% v / v), using a modification of the sucrose reduction technique described above (Foster et al., 2004). Briefly, for all training protocols, animals were not given water for the first 5 days of training using a 23 hour fluid loss schedule to facilitate lever push-up. Initially, rats pushed the lever up with sucrose (3% w / v) under a fixed rate enhancement 1 (FR1) schedule for about 5-7 days. Rats were then classified into sucrose and alcohol enriched groups. Rats belonging to the sucrose group were trained and then stabilized on both the right and left lever constant rate enhancement (FR) 4 schedules. Rats belonging to the alcohol group were subjected to a sucrose reduction method, which then reacted under an FR4 schedule of both right and left lever EtOH (10% v / v). Stabilization of both sucrose and alcohol fortification was defined as having a daily response within ± 20% of the average response for 5 consecutive days.

  For alcohol and sucrose maintenance reaction tests, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane [3.1, 6.3, 12.5, 25, or 50 mg / kg] was orally administered 25 minutes before each P rat was placed in the operant chamber to allow optimal absorption and CNS distribution. The rats were then observed for 90 minutes in the operant chamber. Seven to ten rats were evaluated at each concentration of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane [3.1-50 mg / kg].

  The results of the bindioperant reaction experiment are shown in FIG. Alcohol-maintained rats had a pharmacologically relevant blood alcohol concentration (BAC) of 158 ± mg% / dL. The graph of FIG. 1A demonstrates the dose response of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane in P rats. The graph in FIG. 1B shows the lack of effect of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane on P rats that maintained sucrose water. These results indicate that the effect of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane on P rat alcohol consumption is due to loss of pleasure or nonspecific effects. Prove that it was not.

Example II
Effect of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane on ethanol consumption by hyperalcoholic mice (+)-1 for reducing alcohol consumption The efficacy of-(3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane is observed in genetically selected, high alcohol addictive (HAP) mice, an animal model for human alcohol abuse. It was evaluated. The effect of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane on HAP mice was tested in a vindioperant reaction experiment using standard protocols.

  HAP mice were obtained from the Alcohol Research Center of the Indiana University School of Medicine. The animals were individually housed in a facility at room temperature of 21 ° C. with a standard 12 hour light / dark cycle. All mice had free access to food and water except during training in the operant self-administration study where the rats were not watered for 23 hours daily for the first 5 days of the training phase. These animals then had free food and water retention.

  HAP mice were injected intraperitoneally with (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane in saline solution. Saline was administered as a control injection.

  Behavioral experiments were conducted in a standard operant chamber (Coulbourn Instruments, Allentown, PA) with two removable levers and two zipper fluid delivery systems surrounded by the aforementioned soundproof room (Cook et al., 2004). ). All zipper displays provided 1.5 seconds of access to a 0.1 ml zipper followed by a 3 second timeout period. When each lever was raised, there were three types of stimulation light (red, green and yellow), and stimulation transmission / enhancement was indicated by illumination of medium (green) stimulation light. Responses and enhancements were recorded and managed using the 4.0 Coulbour L2T2 operant software package. The operant period was 90 seconds.

  HAP mice were trained to push the lever with EtOH (10% v / v) using the previously described improved sucrose reduction technique (Foster et al., 2004). Briefly, for all training protocols, animals were not given water for the first 5 days of training using a 23 hour fluid loss schedule to facilitate lever push-up. Initially, mice pushed the lever up with sucrose (3% w / v) under a fixed rate enhancement 1 (FR1) schedule for about 5-7 days. The mice were then classified into sucrose and alcohol enriched groups. HAP mice belonging to the sucrose group were trained and then stabilized on both the right and left lever constant rate enhancement (FR) 4 schedules. HAP mice belonging to the alcohol group were subjected to sucrose reduction, and then they reacted under both the right and left lever EtOH (10% v / v) FR4 schedule. Stabilization of both sucrose and alcohol fortification was defined as having a daily response within ± 20% of the average response for 5 consecutive days.

  For the alcohol and sucrose maintenance reaction test, (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane [25, 50, or 75 mg / kg] was given to each HAP mouse. Infused and then immediately placed in the operant chamber. The mice were then observed in the operant chamber for 90 minutes. Six HAP mice were evaluated with (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane [25, 50, or 75 mg / kg] at each concentration.

  The results of the bindioperant reaction experiment are shown in FIG. The ethanol response graph in FIG. 2 demonstrates the dose response of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane in HAP mice. The control sucrose response graph of FIG. 2 shows the lack of effect of (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane on HAP mice maintained with sucrose water. These results indicated that (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane had a specific effect on alcohol consumption in HAP mice. Indicates.

All publications and patents are cited herein, for example, to describe and disclose the materials and methods described in the publications and can be used in connection with the present invention. The publications listed above and throughout this specification are provided solely for their disclosure prior to the filing date of the present application. Nothing in this specification should be construed as an admission that the inventors are not entitled to an earlier disclosure based on the prior invention.
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Claims (23)

  A method of treating or preventing an alcohol-related disorder or addictive disorder, said patient being in need of said treatment or prevention in an effective amount, each substantially free of its corresponding (-)-enantiomer, (+)- A method comprising administering 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 contains the corresponding (−)-enantiomer from about 2% by weight. The method of claim 1, wherein   (+)-1- (3,4-Dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof comprises the corresponding (−)-enantiomer from about 1% by weight. The method of claim 1, wherein   (+)-1- (3,4-dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof is (+)-1- (3,4-dichlorophenyl) The method of claim 1, wherein the method is effective in reducing alcohol consumption in a patient compared to a control who does not receive -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof.   Alcohol-related disorders include delusional alcohol-induced psychotic disorder; alcohol abuse; alcohol intoxication; alcohol withdrawal; alcohol intoxication delirium; alcohol withdrawal delirium; alcohol-induced persistent dementia; alcohol-induced persistent amnesia; alcohol dependence Alcohol-induced psychotic disorder with hallucinations; Alcohol-induced mood disorder; Alcohol-induced anxiety disorder; Alcohol-induced sexual dysfunction; Alcohol-induced sleep disorder; Unspecified alcohol-related disorder (NOS); and alcohol 2. The method of claim 1, wherein the method is selected from the group consisting of addiction.   The addictive disorder is selected from the group consisting of eating disorders, impulse control disorders, nicotine related disorders, amphetamine related disorders, cannabis related disorders, cocaine related disorders, hallucinogen use disorders, inhalant related disorders, and opioid related disorders. The method of claim 1.   The method of claim 1, further comprising administering another therapeutic agent.   8. The method of claim 7, wherein the other therapeutic agent is an anti-alcohol agent.   The anti-alcohol consists of disulfuram, naltrexone, acamprosate, ondansetron, sertraline, galantamine, nalmefene, naloxone, desoxypeganine, benzodiazepines, neuroleptics, risperidone, rimonabant, trazodone, topiramate, and aripiprazole The method of claim 8, wherein the method is selected from the group.   8. The method of claim 7, wherein the other therapeutic agent is an antinicotine agent.   8. The method of claim 7, wherein the other therapeutic agent is an anti-opiate agent.   8. The method of claim 7, wherein the other therapeutic agent is an anticocaine agent.   8. The method of claim 7, wherein the other therapeutic agent is an antidepressant.   8. The method of claim 7, wherein the other therapeutic agent is an antipsychotic agent.   8. The method of claim 7, wherein the other therapeutic agent is an anxiolytic agent.   8. The method of claim 7, wherein the other therapeutic agent is an anti-alcohol agent.   A method of treating or preventing ethanol consumption, wherein a patient in need of said treatment or prevention is substantially free of each corresponding (-)-enantiomer, (+)-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 contains the corresponding (−)-enantiomer from about 2% by weight. 18. The method of claim 17, wherein   (+)-1- (3,4-Dichlorophenyl) -3-azabicyclo [3.1.0] hexane or a pharmaceutically acceptable salt thereof comprises the corresponding (−)-enantiomer from about 1% by weight. 18. The method of claim 17, wherein   20. The method of claim 17, further comprising administering another therapeutic agent.   21. The method of claim 20, wherein the other therapeutic agent is an anti-alcohol agent.   The anti-alcohol consists of disulfuram, naltrexone, acamprosate, ondansetron, sertraline, galantamine, nalmefene, naloxone, desoxypeganine, benzodiazepines, neuroleptics, risperidone, rimonabant, trazodone, topiramate, and aripiprazole 24. The method of claim 21, wherein the method is selected from the group.   A method of treating or preventing an alcohol-related disorder or addictive disorder, wherein the inhibitory rate of serotonin-norepinephrine-dopamine reuptake in an amount effective for a patient in need of the treatment or prevention is about 1-2: 1-3: 4. Administering a triple reuptake inhibitor in the range of -12.

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