HK1118712A

HK1118712A - Multimediator dopamine transport inhibitors, and uses related thereto

Info

Publication number: HK1118712A
Application number: HK08110303.3A
Authority: HK
Inventors: James R. Hauske
Original assignee: Prexa Pharmaceuticals, Inc.
Priority date: 2005-02-23
Filing date: 2006-02-21
Publication date: 2009-02-20

Description

Multimediator dopamine transport inhibitors, and uses related thereto

Background

Major depression is characterized by a feeling of intense sadness and despair, mental retardation and loss of attention, pessimistic distress, agitation and self-deprecation. Physical changes also exist, particularly in major or "melancholic" depression. These include insomnia or hypersomnia, anorexia and weight loss (or sometimes overeating), reduced energy and libido, and disruption of the normal circadian rhythms of activity, body temperature and various endocrine functions.

The therapeutic regimen generally involves the use of tricyclic antidepressants, monoamine oxidase inhibitors, certain psychotherapeutic agents, lithium, and electroconvulsive therapy(ECT) (see: R.J. Baldessoini in Goodman&Reviews in Gilman's The pharmaceutical Basis of Therapeutics, 9 th edition, Chapter 19, McGraw-Hill, 1996). In recent years, new classes of antidepressants are being investigated, including selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), specific monoamine reuptake inhibitors and 5-HT_1AAgonists, antagonists and partial agonists.

Anxiety is an emotional symptom characterized by sensations such as anxiety and fear, often accompanied by physical symptoms such as tachycardia, increased respiration, perspiration, and tremor. This is a normal mood, but becomes pathological when it is severe and incapacitating.

Anxiety disorders are commonly treated with benzodiazepine * sedative anxiolytics. The potent benzodiazepines * are effective in panic and general anxiety disorders, however the risks associated with drug dependence limit their long-term use. 5-HT_1APartial receptor agonists also have useful anxiolytic and other psychiatric effects and are less likely to be sedating and dependent (see r.j. baldesarini in Goodman&Reviews in Gilman's The pharmaceutical basic of therapeutics, 9 th edition, Chapter 18, McGraw-Hill, 1996).

Bipolar disorder is a psychosis that is prevalent in different cultures and age groups. The lifetime incidence of bipolar disorder can be as high as 1.6%. DSM-IV, page 353 (American psychiatric Association, Washington, D.C. 1997). Bipolar disorder is a periodic condition characterized by one or more manic episodes occurring immediately before or after a major depressive episode, or may be characterized by a major depressive episode with at least one hypomanic episode. In sum, the symptoms necessarily result in clinically significant distress, or impairment in social, occupational, or other important functional areas.

In some cases hypomanic episodes do not themselves produce lesions; however, such injuries may result from major depressive episodes, or from long-term patterns of acute episodes of unpredictable mood, as well as fluctuating unreliable interpersonal and occupational activities. The symptoms of bipolar disorder are more attributed to psychotic conditions, or due to direct physiological effects of drugs, other physical treatment of depression, drug abuse or exposure to poisons.

Bipolar disorder is associated with a significant risk of suicide. In addition, patients with bipolar disorder may also suffer from absenteeism, retrospect, occupational failure, or divorce.

Bipolar disorder is thus a serious, rather prevalent psychological disorder, which is clearly different from psychoses such as schizophrenia. DSM-IV, page 353 (American psychiatric Association, Washington, D.C. 1994). DSM-IV, p 353 (American psychiatric Association, Washington, D.C. 1994).

There remains a need to provide treatments that have a favorable safety profile and that are effective in providing relaxation to patients suffering from anxiety, depression or psychosis.

Summary of The Invention

The present invention relates to compounds, packaged pharmaceuticals, and methods of treating patients suffering from anxiety, depression, or psychiatric disorders. The invention particularly relates to compounds having dopamine transport (DAT) inhibitory activity and 5HT_2aReceptor antagonistic activity and/or 5HT_2cA compound having receptor antagonistic activity. The invention also relates to the use of said compounds in the manufacture of pharmaceutical compositions, methods of conducting pharmaceutical commerce, and methods of conducting medical assistance compensation programs.

The present invention DAT-5HT₂The antagonist is represented by formula I, or a pharmaceutically acceptable salt, solvate, metabolite, or prodrug thereof:

wherein under the conditions of valency and stability:

ar, for each occurrence, independently represents a substituted or unsubstituted aryl or heteroaryl ring;

hc represents a substituted or unsubstituted nitrogen-containing heteroaryl ring;

x represents H OR OR;

y and Z independently represent-O-, -S-, -C (-R)₂-or-N (-R) -;

r represents independently for each occurrence H or lower alkyl;

R₁represents one or more substituents independently selected from the group consisting of: halogen, amino, amido, amidino, cyano, nitro, azido, ether, thioether, sulfoxido (sulfoxido), -J-R₈-J-OH, -J-lower alkyl, -J-lower alkenyl, -J-SH, -J-BH₂Or substituted or unsubstituted lower alkyl, lower alkenyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl, or protected forms thereof;

R₈independently at each occurrence, represents H or a substituted or unsubstituted lower alkyl, cycloalkyl, heterocyclyl, aralkyl, heteroaralkyl, aryl, or heteroaryl group;

j independently at each occurrence represents a number of atoms having from 0 to 8 members selected from the group consisting of-C (-R)₂A chain of units of-N (-R) -, -O-and-S-;

m is an integer of 0 to 2;

n is an integer of 0 to 2;

p is 0 or 1; and is

q is an integer from 0 to 2, preferably 1;

and-Z-J-Hc together represent a substituted or unsubstituted nitrogen-containing heterocyclic or heteroaryl ring.

In another embodiment, the present invention provides a packaged pharmaceutical comprising an amount of the DAT-5HT2 antagonist of the present invention sufficient to treat anxiety, depression, or a psychiatric disorder and formulated in a pharmaceutically acceptable carrier; and instructions (text and/or pictures) describing the use of the formulation to treat a patient. The packaged pharmaceutical may be provided as a once daily formulation. The packaged medicament may be formulated for oral administration or in the form of a transdermal patch. The packaged medicament may be provided in an enhanced dose that results in an enhanced serum concentration of the DAT-5HT2 antagonist for a period of at least 4 hours.

In another embodiment, the present invention provides a packaged pharmaceutical comprising (i) a mood stabilizing formulation of a DAT-5HT2 antagonist of the invention; (ii) selected from 5-hydroxytryptamine reuptake inhibitor, 5HT₆Receptor antagonists, anticonvulsants, norepinephrine reuptake inhibitors, alpha-adrenoceptor antagonists, NK-3 antagonists, NK-1 receptor antagonists, PDE4 inhibitors, neuropeptide Y5 receptor antagonists, D4 receptor antagonists, 5HT_1AReceptor antagonists, 5HT_1DA second agent of a receptor antagonist, a CRF antagonist, a monoamine oxidase inhibitor and a sedative hypnotic agent; (iii) use label indicating a packaged medicament for treating a patient suffering from anxiety, depression and psychiatric disorders. In certain embodiments, the DAT-5HT2 antagonist formulation and the second agent are combined in a single dosage form.

In another embodiment, the invention provides the use of a DAT-5HT2 antagonist of the invention in the manufacture of a pharmaceutical composition for the prevention or treatment of a patient susceptible to or suffering from a movement disorder.

In yet another embodiment, the invention provides a method of treating anxiety, depression, and psychiatric disorders comprising administering to a patient a DAT-5HT2 antagonist composition of the invention. The method is useful for treating a patient diagnosed with depression. The method can be used to treat depression selected from the group consisting of: paroxysmal or recurrent major depressive disorder, dysthymic disorder, depressive neuropathy, and neurotic depression; depression in hypochondriac patients includes anorexia, weight loss, insomnia and early morning awakening, and psychomotor depression; atypical depression (or reactive depression) includes appetite increase, hypersomnia, psychomotor excitation or sensitization, seasonal affective disorder, or bipolar or manic depression.

The method may be used for the treatment of a patient diagnosed with bipolar disorder, bipolar depression or unipolar depression, or for the treatment of a patient diagnosed with anxiety. Anxiety disorders may be selected from obsessive compulsive disorder, panic disorder, substance-induced anxiety disorder, post-traumatic stress disorder, generalized anxiety disorder, anxiety disorder NOS, organ anxiety disorder, phobias, or substance-induced anxiety. Substance-induced anxiety may be selected from the group consisting of alcohol, amphetamine, caffeine, cannabis, cocaine, hallucinogens, inhalants, phencycedine, sedatives, hypnotics, anxiolytics or other substances, and accommodation disorders with anxiety or a mixture of anxiety and depression.

The method is also useful for the treatment of a patient diagnosed with a psychiatric disorder selected from the group consisting of schizophrenia, schizophreniform disorder, acute mania, schizoaffective disorder, and depression with psychotic features.

In another embodiment, the present invention provides a packaged pharmaceutical comprising: a DAT-5HT2 antagonist of the invention formulated in a pharmaceutically acceptable carrier in an amount sufficient to treat attention deficit disorder or attention deficit hyperactivity disorder; and instructions (text and/or pictures) describing the use of the formulation for treating a patient.

In another embodiment, the invention provides the use of a DAT-5HT2 antagonist of the invention in the manufacture of a pharmaceutical composition for the treatment or prevention of a patient susceptible to or suffering from attention deficit disorder or attention deficit hyperactivity disorder.

In another embodiment, the invention provides a method of treating attention deficit disorder or attention deficit hyperactivity disorder comprising administering to a patient a composition of a DAT-5HT2 antagonist of the invention.

In another embodiment, the present invention provides a method of conducting pharmaceutical commerce comprising: (a) manufacturing the packaged medicament of the invention; and (b) marketing the benefits of using the package or formulation of the present invention to a health care provider for treating patients suffering from anxiety, depression or psychiatric disorders, or attention deficit disorder or attention deficit hyperactivity disorder.

In another embodiment, the present invention provides a method of conducting pharmaceutical commerce comprising: (a) providing a sales network for selling the packaged pharmaceuticals of the present invention; and (b) providing instructions to the patient or physician for using the package or formulation in the treatment of a patient suffering from anxiety, depression or psychiatric disorders, or attention deficit disorder or attention deficit hyperactivity disorder.

In another embodiment, the present invention provides a method of conducting pharmaceutical commerce comprising: (a) determining an appropriate dosage of the DAT-5HT2 antagonist of the invention to enhance functional performance in a patient suffering from anxiety, depression or psychiatric disorders, or attention deficit disorder or attention deficit hyperactivity disorder; (b) performing a treatment curve determination of the one or more formulations of the DAT-5HT2 antagonist determined in step (a) in order to understand efficacy and toxicity in the animal; and (c) providing a sales network for selling the formulation determined in step (b) with an acceptable treatment profile. The method may further comprise the further step of providing a sales team providing the formulation to a health care provider.

In another embodiment, the invention provides a method of performing a medical aid compensation program, comprising: (a) providing a compensation program capable of at least partially compensating a health care provider or patient, or paying a drug dealer, for a prescription for the treatment of anxiety, depression or psychiatric disorders, or attention deficit disorders or attention deficit hyperactivity disorder; (b) (ii) processing one or more requirements for the prescription of a DAT-5HT2 antagonist for the treatment of anxiety, depression or psychotic disorders, or attention deficit disorder or attention deficit hyperactivity disorder; and (c) compensating the healthcare provider or patient, or paying the drug dealer the cost of at least part of the prescription.

Brief description of the drawings

FIG. 1 shows two illustrative DAT-5HT2 antagonists: CNS-30, 100 and CNS31, 100.

FIG. 2 shows two illustrative DAT-5HT2 antagonists: in vitro distribution of CNS-30, 100 and CNS31, 100.

Detailed description of the invention

I.Overview

The present invention relates to novel compounds useful in the treatment of anxiety, depression or psychosis. These diseases or conditions include, but are not limited to, single or recurrent major depressive disorder, dysthymic disorder, depressive neurosis, neurotic depression, melancholic depression, atypical depression, anxiety and phobias, seasonal affective disorder, bipolar disorder, manic depression, unipolar depression, schizophrenia, schizophreniform disorder, acute mania, schizoaffective disorder, and depression with psychotic features.

The methods and formulations of the present invention may also be used to treat attention deficit hyperactivity disorder.

II.Definition of

The term "administering" refers to prescribing or providing a drug in a dosage form and dosage amount.

The term "depression" as used herein includes depressive disorders, such as single or recurrent major depressive disorder, as well as dysthymic disorder, depressive neurosis, and dysthymia; depression in hypochondriac patients includes anorexia, weight loss, insomnia and early morning awakening, and psychomotor depression; atypical depression (or reactive depression) includes increased appetite, hypersomnia, psychomotor stimulation or hypersensitivity, seasonal affective disorder, or bipolar or manic depression, such as bipolar I disorder, bipolar II disorder, and cyclothymic disorder.

Other mood disorders encompassed within the term "depression" include dysthymic disorder with early or late onset and with or without atypical features; late or early onset dementia of the alzheimer type with depressed mood; vascular dementia with depressed mood, conditions caused by alcohol, amphetamine, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics, and others; schizoaffective disorder of the depressive type; and accommodation disorder with depressed mood.

"unipolar depression" or "major depression" refers to the clinical history characterized by one or more major depressive episodes in individuals without a history of episodes of mania, mixed or hypomania. If manic, mixed or hypomanic episodes occur during depression; if the depression is due to a direct physiological effect of the substance; if the depression is due to a direct physiological effect of a general medical condition; if the depression is due to detachment or other significant loss ("reactive depression"); or if the onset is more largely due to schizoaffective disorder and is not superimposed on schizophrenia, schizophreniform disease, delusional disorder or psychotic disorder, then a diagnosis of unipolar depression is not made. If manic, mixed or hypomanic episodes occur, the diagnosis is changed to bipolar disorder. Depression may be associated with chronic general medical conditions (e.g. diabetes, myocardial infarction, cancer, stroke). Unipolar depression is usually more severe than dysthymia.

The term "anxiety disorders" includes, but is not limited to, obsessive compulsive disorder, substance-induced anxiety disorder, post-traumatic stress disorder, generalized anxiety disorder, anxiety disorder NOS, and organ anxiety disorder. Anxiety disorders include panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, such as specific animal phobias, social phobias, obsessive-compulsive disorders, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalized anxiety disorder. "general anxiety" is generally defined as excessive anxiety or annoyance during this period with a duration of symptoms for most days (e.g., at least 6 months). This anxiety or annoyance is difficult to control and may be accompanied by restlessness, fatigue, difficulty concentrating, allergies, muscle tension and disturbed sleep. "panic disorder" is defined as the presence of a panic attack that reoccurs after at least one month of continued fear of another panic attack. A "panic attack" is a discrete stage where there is a strong apprehension, fear, or phobia. During a panic attack, an individual may experience a variety of symptoms including palpitations, sweating, trembling, shortness of breath, chest pain, nausea, and dizziness. Panic disorder may or may not occur with agoraphobia.

"phobias" include agoraphobia, specific phobias, and social phobias. "agoraphobia" is characterized by anxiety in places or situations where escape is difficult or disconcerting or where it is not effectively aided at the time of a panic attack. Agoraphobia may occur without a history of panic attacks. "specific phobia" is characterized by clinically significant anxiety caused by a dreaded object or condition. Specific phobias include the following subtypes: animal type, initiated by animals or insects; natural environment type, induced by objects in the natural environment, such as storms, altitudes or water; blood-injection-trauma type, initiated by seeing the blood or seeing or receiving an injection or other invasive medical procedure; location type, initiated by a specific location such as public transportation, tunnel, bridge, elevator, airplane, mobile or enclosed place; and fear of other types triggered by other stimuli. Specific phobias are also known as simple phobias. "social phobia" is characterized by clinically significant anxiety induced by exposure to a particular type of social or behavioral environment. Social phobia is also known as social anxiety disorder.

Other anxiety disorders encompassed within the term "anxiety" include those caused by alcohol, amphetamines, caffeine, cannabis, cocaine, hallucinogens, inhalants, phencycedine, sedatives, hypnotics, anxiolytics and others, and accommodation disorders with anxiety or mixed anxiety and depression.

Anxiety may or may not exist with other conditions such as depression in mixed anxiety and depression. The compositions of the present invention are thus useful for treating anxiety with or without concomitant depression.

The term "psychotic disorder" includes, for example, schizophrenia, schizophreniform disorder, acute mania, schizoaffective disorder, and depression with psychotic features. The subject matter given for these disorders is indicative of multiple disease states. The following list illustrates a number of these disease states, many of which are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4 th edition, published by the American Psychiatric Association (DSM). When available, for the convenience of the reader, the DSM numbers for these disease states are provided as follows: 295.30 for paranoid schizophrenia; disorganized schizophrenia 295.10; catatonic schizophrenia 295.20; undifferentiated schizophrenia 295.90; residual schizophrenia 295.60; schizophreniform disease 295.40; schizoaffective disorder 295.70; depressive schizoaffective disorder; and major depressive disorder with psychotic features 296.24, 296.34.

"attention deficit hyperactivity disorder" or "ADHD" refers to a behavioral disorder characterized by: the persistent and frequent patterns of inappropriate development (involuntary inattention), impulsivity and hyperactivity. Indications for ADHD include lack of motor coordination, perceptual-motor dysfunction, EEG abnormalities, mood swings, antagonism, anxiety, aggressiveness, low frustration tolerance, poor social skills and peer relationships, sleep disorders, pathologic dysthymia and mood swings ("Attention defect Disorder," The merck manual of Diagnosis and Therapy (17 th edition), editors m.h. beers and r.berkow, eds., 1999, Whitehouse Station, NJ).

The term "treatment" refers to the medical treatment of a patient with the purpose of obtaining a treatment, amelioration, or prevention of a disease, pathological condition, or disorder. The term includes active therapy, that is, treatment aimed specifically at ameliorating a disease, pathological condition, or disorder; also included are causal therapies, that is, treatments aimed at removing the cause of a disease, pathological condition, or disorder. The term also includes palliative therapy, that is, treatment aimed at alleviating symptoms rather than curing a disease, pathological condition, or disorder; prophylactic therapy, that is, treatment aimed at preventing a disease, pathological condition, or disorder; and supportive therapy, that is, treatment using the treatment to supplement another specific treatment aimed at ameliorating the disease, pathological condition, or disorder. The term "treatment" also includes symptomatic treatment, that is, treatment of systemic symptoms directed to a disease, pathological condition, or disorder.

The term "agonist" refers to a compound that mimics the action of a natural transmitter when the natural transmitter is unknown to cause a change in a receptor complex in the absence of other receptor ligands.

The term "antagonist" refers to a compound that binds to a receptor site but does not produce any physiological change unless other receptor ligands are present.

The term "ligand" refers to a compound that binds at a receptor site.

III.Exemplary formulations

The DAT-5HT2 antagonists of the invention are represented by formula I, or a pharmaceutically acceptable salt, solvate, metabolite or prodrug thereof:

wherein under the conditions of valency and stability:

x represents H OR OR;

y and Z independently represent-O-, -S-, -C (-R)₂-or-N (-R) -;

r represents independently for each occurrence H or lower alkyl;

R₁represents one or more substituents independently selected from the group consisting of: halogen, amino, acylamino, amidino, cyano, nitro, azido, ether, thioether, sulfoxido, -J-R₈-J-OH, -J-lower alkyl, -J-lower alkenyl, -J-SH, -J-NH₂Or substituted or unsubstituted lower alkyl, lower alkenyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl, or protected forms thereof;

m is an integer of 0 to 2;

n is an integer of 0 to 2;

p is 0 or 1; and is

q is an integer from 0 to 2, preferably 1;

In certain embodiments, Hc is a substituted or unsubstituted five-membered ring, such as pyrrole, imidazole, triazole, or pyridine.

Suitable substituents for Hc and ArIncluding halogen, cyano, alkyl (including perfluoroalkyl), alkenyl, alkynyl, aryl, hydroxy, alkoxy, siloxy, amino, nitro, thiol, amino, imino, amido, phosphoryl, phosphonate, carboxyl, carboxamide, silyl, thioether, alkylsulfonyl, arylsulfonyl, sulfoxide, selenide, ketone, aldehyde, ester, or- (CH)₂)_mR₈Wherein m is an integer of 0 to 4. In certain embodiments, the non-hydrogen substituent is selected from the group consisting of halogen, cyano, alkyl (including perfluoroalkyl), hydroxy, alkoxy, alkenyl, alkynyl, aryl, nitro, thiol, imino, amido, carboxy, thioether, alkylsulfonyl, arylsulfonyl, ketone, aldehyde, and ester. In certain embodiments, the non-hydrogen substituent is selected from the group consisting of halogen, cyano, alkyl (including perfluoroalkyl), alkenyl, alkynyl, nitro, amido, carboxyl, alkylsulfonyl, ketone, aldehyde, and ester. Of course Ar may be a bicyclic ring system, for example comprising two or more interconnected rings and wherein at least one ring is aromatic.

In certain embodiments, J, at each occurrence, independently represents a number of 0-4 (more preferably 0-2) members selected from-C (-R)₂A chain of units of-N (-R) -, -O-and-S-. In certain preferred embodiments, J represents a substituted or unsubstituted methylene or ethylene unit.

In certain embodiments, Y adjacent to Ar represents-O-or-S-, and preferably-O-. In certain embodiments, Z represents-N (-R) -, preferably-N (H) -or-N (-CH)₂) -, or together with J and Hc, represents a heterocyclic ring attached to the core via a nitrogen atom. In embodiments where Z-J-Hc together represent a heterocyclic ring, the heterocyclic ring may be, for example, a substituted or unsubstituted piperidine, piperazine or pyrrolidine ring. For example, Z-J-Hc may represent a piperazine ring attached to the core via one nitrogen atom with an aralkyl, aryl, heteroaralkyl or heteroaryl substituent attached to the second nitrogen atom.

Certain exemplary illustrative DAT-5HT2 antagonists are shown in FIG. 1, and include CNS-30, 100 and CNS-31, 100.

Combinations comprising DAT-5HT2 agents

In certain embodiments, the methods comprise co-administering the formulations of the present invention with other agents intended for the treatment or prevention of anxiety, depression, or psychiatric disorders of interest. The agent co-administered with the agent DAT-5HT2 of the invention can be formulated with the agent DAT-5HT2 as a single pharmaceutical formulation, e.g., a pill or other agent containing both agents, or can be administered as separate pharmaceutical formulations.

Exemplary combinations having the DAT-5HT2 agents of the invention include other agents selected from the group consisting of: 5-hydroxytryptamine reuptake inhibitors, 5HT₆Receptor antagonists, anticonvulsants, norepinephrine reuptake inhibitors, alpha-adrenoceptor antagonists, NK-3 antagonists, NK-1 receptor antagonists, PDE4 inhibitors, neuropeptide Y5 receptor antagonists, D4 receptor antagonists, 5HT_1AReceptor antagonists, 5HT_1DReceptor antagonists, CRF antagonists, monoamine oxidase inhibitors and sedative-hypnotics.

Antidepressant drug

(i)5-hydroxytryptamine reuptake inhibitors (SRI).

The determination of compound activity as an SSRI is now a standard pharmacological test. Wong, et al, Neuropsychopharmacology 8, 337-344 (1993). Many compounds, including those described above, have this activity and will certainly be more determinable in the future. In the practice of the present invention, reuptake inhibitors that exhibit an effective concentration of about 1000nM or less than 50% in the protocol described by Wong above are intended to be included. 5-hydroxytryptamine reuptake inhibitors include, but are not limited to:

fluoxetine, N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine, is sold as the hydrochloride salt and as a racemic mixture of the two enantiomers. U.S. Pat. No. 4,314,081 is an early reference to this compound. Robertson et al, j.med.chem.31, 1412(1988) teach the separation of the R and S enantiomers of fluoxetine and show that they have similar activity to each other as inhibitors of 5-hydroxytryptamine uptake. In this document, the term "fluoxetine" is used to denote any acid addition salt or the free base, and includes racemic mixtures or any of the R and S enantiomers;

duloxetine, N-methyl-3- (1-naphthyloxy) -3- (2-thienyl) propylamine, is usually administered as its hydrochloride salt and as the (+) enantiomer. It was first taught in U.S. Pat. No. 4,956,388, in which high efficacy was shown. The term "duloxetine" as used herein shall mean any acid addition salt or free base of the molecule;

venlafaxine is known in the literature and its synthesis and its activity as an inhibitor of 5-hydroxytryptamine and norepinephrine uptake is taught in US4,761,501. Venlafaxine is identified in this patent as compound a;

milnacipran (N, N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide) is taught by U.S. patent No. 4,478,836 and is prepared in example 4 thereof. The patent discloses the compounds as antidepressants. Moret et al, Neuropharmacology24, 1211-19(1985) disclose its pharmacological activity as an inhibitor of 5-hydroxytryptamine and norepinephrine reuptake;

citalopram, 1- [3- (dimethylamino) propyl ] -1- (4-fluorophenyl) -1, 3-dihydro-5-isobenzofurancarbonitrile, is disclosed as a 5-hydroxytryptamine reuptake inhibitor in U.S. Pat. No. 4,136,193. Its pharmacology is disclosed by Christensen et al in eur.j. pharmacol.41, 153(1977), and its report of clinical efficacy in depression is found in Dufour et al, int.clin.psychopharmacol.2, 225(1987) and Timmerman et al, supra, 239;

fluvoxamine, 5-methoxy-1- [4- (trifluoromethyl) -phenyl ] -1-pentanone O- (2-aminoethyl) oxime, is taught in US patent US4,085,225. Scientific papers on this drug have been published, classen et al, brit.j. pharmacol.60, 505 (1977); and De Wilde et al, J.Affective disorder.4, 249 (1982); and Benfield et al, Drugs 32, 313 (1986);

paroxetine, trans- (-) -3- [ (1, 3-benzodioxol) -5-yloxy) methyl ] -4- (4-fluorophenyl) piperidine can be found in U.S. Pat. Nos. 3,912,743 and 4,007,196. Pharmaceutical activity is reported in Lassen, eur.j.pharmacol.47, 351 (1978); hassan et al, brit.j.clin.pharmacol.19, 705 (1985); laursen et al, Acta psychiat. Scand.71, 249 (1985); and Battegay et al, Neuropsychobiology 13, 31 (1985);

sertraline, (1S-cis) -4- (3, 4-dichlorophenyl) -1, 2, 3, 4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride is a 5-hydroxytryptamine reuptake inhibitor, which is marketed as an antidepressant. Which is disclosed in US4,536,518.

To illustrate, the SRI may be venlafaxine or a derivative thereof. For example, the SRI can be a compound of the formula:

wherein

R₁Is hydrogen or alkyl of 1 to 6 carbon atoms;

R₂is alkyl of 1 to 6 carbon atoms;

R₃is hydrogen or alkyl of 1 to 6 carbon atoms;

R₄is hydrogen, alkyl of 1 to 6 carbon atoms, formyl, or alkanoyl of 2 to 7 carbon atoms;

R₅and R₆Independently hydrogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 7 carbon atoms, cyano, nitro, alkylmercapto of 1 to 6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms, dialkylamino, wherein each alkyl is 1 to 6 carbon atoms, alkanoylamino of 2 to 7 carbon atoms, halogen, trifluoromethyl, or when taken together, methylenedioxy;

n is an integer of one of 0, 1, 2, 3 or 4.

The non-tricyclic compound venlafaxine, chemically designated (±) -1- [2- (dimethylamino) -1- (4-methoxyphenyl) ethyl ] -cyclohexanol, is an antidepressant that has been extensively studied and is disclosed, for example, in US4,761,501 and Pento, j.t. drugs of the Future13 (9): 839 (1988).

Venlafaxine includes active derivatives of venlafaxine. The term "derivative" includes metabolites. Venlafaxine derivatives include O-desmethylvenlafaxine and single enantiomers of both compounds.

In certain preferred embodiments, the venlafaxine compound is provided in optically pure form, e.g., optically pure (-) -N-desmethylvenlafaxine, chemical name (-) -1- [2- (methylamino) -1- (4-methoxyphenyl) ethyl ] cyclohexanol; optically pure (-) -N, N-didemethyl venlafaxine, with the chemical name (-) -1- [2- (amino) -1- (4-methoxyphenyl) ethyl ] cyclohexanol; optically pure (-) -O-desmethylvenlafaxine with the chemical name (-) -1- [2- (dimethylamino) -1- (4-phenol) ethyl ] cyclohexanol; optically pure (-) -N, O-didemethyl venlafaxine with the chemical name of (-) -1- [2- (methylamino) -1- (4-phenol) ethyl ] cyclohexanol; and optically pure (-) -O-desmethyl-N, N-didemethyl venlafaxine, having the chemical name (-) -1- [2- (amino) -1- (4-phenol) ethyl ] cyclohexanol.

In other embodiments, the SRI compound is an optically pure derivative of (+) -venlafaxine, e.g., (+) -O-desmethylvenlafaxine. Other examples of (+) -venlafaxine derivatives are provided in us patent 6197828.

In a preferred embodiment, the SRI is a selective 5-hydroxytryptamine reuptake inhibitor (SSRI). SSRIs include fluoxetinids, sertraline (ZOLOFT), Citalopram (CELEXA), Paroxetine (PAXIL), and fluvoxamine (LUVOX), cilchloramine, fexocetin, efoxetine, cyanotipin, and ritoxetine. Terms such as "sertraline", "citalopram", "paroxetine" and "fluvoxamine" include active derivatives and metabolites such as the demethyl metabolite norfluoxetine, norsertraline and norcitalopram.

Preferred SSRIs are fluoroxetinids and citalopram (and derivatives thereof). A more preferred SSRI is fluoroxetinids.

Fluoxetines useful in the methods and compositions of the present invention include compounds that inhibit 5-hydroxytryptamine reuptake and have the formula:

wherein under the conditions of valency and stability:

R₁independently at each occurrence, represents H or lower alkyl, preferably H or methyl;

R₂、R₃and R₄Each independently represents H, methyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl, such that R₂、R₃And R₄Exactly one of which is a substituted or unsubstituted phenyl group or a substituted or unsubstituted benzyl group;

y represents O, S or-S (O)₂-, preferably O;

q represents a substituted or unsubstituted aryl or heteroaryl ring, including polycyclic ring systems.

In certain embodiments, at least one occurrence of R₁Represents hydrogen.

In certain embodiments, R₂And R₃Selected from H and methyl, preferably H, and R₄Represents a substituted or unsubstituted benzene ring.

In certain embodiments, Q is a substituted or unsubstituted phenyl ring.

Examples of compounds belonging to the above formula are disclosed in U.S. Pat. nos. 4,902,710, 4,824,868, 4,692,469, 4,626,549, 4,584,404 and 4,314,081.

In certain embodiments, the fluoroxetinoid has the following formula:

wherein under the conditions of valency and stability:

R₅independently at each occurrence, represents H or methyl;

R₆represents a substituted or unsubstituted benzene ring, preferably unsubstituted;

y represents O, S or-S (O)₂-, preferably O; and

R₇represents a group selected from halogen, lower alkyl, lower alkenyl, lower alkoxy, substituted or unsubstituted phenyl and CF₃1 to 5 substituents in (1).

In certain embodiments, at least one occurrence of R bound to N₅Is H.

In certain embodiments, R₆Represents an unsubstituted phenyl group.

In certain embodiments, R₇Represents a halogen atom selected from halogen and CF₃1 to 2 substituents of (1).

Fluoxetine is metabolized very slowly, the main metabolic derivative being norfluoxetine, which is similar to fluoxetine in selectivity and effect. Any combination of these compounds, racemic or enriched for any of the enantiomers, and pharmaceutically acceptable salts thereof, may be used in the methods and compositions described herein, and as the term is used herein, any of these compounds may be included in the term "fluoroxetinoid".

In certain embodiments, the SSRI is sertraline or a derivative thereof. For example, the SSRI can be a compound represented by the formula:

wherein

R₈Selected from hydrogen and n-alkyl of 1 to 3 carbon atoms;

R′₈is an n-alkyl group of 1 to 3 carbon atoms;

R₉selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl and alkoxy of 1 to 3 carbon atoms;

R₁₀is composed of

R₁₁And R₁₂Each independently selected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, alkoxy of 1 to 3 carbon atoms and cyano, at least one R₁₁And R₁₂Is a group other than hydrogen; and is

U.S. Pat. Nos. 4,536,518, 4,940,731, 4,962,128, and 5,130,338 disclose sertraline and various derivatives and formulations thereof, which may be used in the formulations and methods of the present invention. The sertraline derivatives include N-demethylsertraline.

In certain preferred embodiments, the compound may optionally be a cis isomeric host of the above formula. The term "cis-isomer" refers to the N (R 'on the cyclohexene ring'₈)R₈And R₁₀The relative orientation of the parts (i.e. they are all on the same side of the ring). Due to the unbalanced substitution of the 1-and 4-carbons of formula, each cis compound has two optically active enantiomeric forms (according to the 1-carbon) represented as the cis- (1R) and cis- (1S) enantiomers. A preferred embodiment is the (1S) enantiomer, such as cis- (1S) -N-methyl-4- (3, 4-dichlorophenyl) -1, 2, 3, 4-tetrahydro-1-naphthylamine, and pharmaceutically acceptable salts thereofAcid addition salts of (a).

In certain embodiments, the SSRI is paroxetine or a derivative thereof. For example, the SSRI can be a compound represented by the formula:

wherein

R₁₃Represents hydrogen or an alkyl group having 1 to 4 carbon atoms, and

R₁₄represents hydrogen, an alkyl group having 1 to 4 carbon atoms, C_1-6Alkoxy radical, C_1-6Trifluoroalkyl (preferably trifluoromethyl), hydroxy, halogen, methylthio or C_1-6Aryl radical (C)_1-6) Alkoxy (e.g. phenyl (C)_1-6) Alkoxy and benzyl (C)_1-6) Alkoxy) and

R₁₅represents alkyl or alkynyl having 1-4 carbon atoms, or optionally substituted by C_1-4Alkyl radical, C_1-6Alkylthio radical, C_1-6Alkoxy, halogen, nitro, acylamino, methanesulfonyl or methylenedioxy substituted phenyl, or represents tetrahydronaphthyl.

In certain embodiments, the SSRI is a compound represented by the formula:

wherein R is₁₃Represents hydrogen or an alkyl group having 1 to 4 carbon atoms, and R₁₄Represents halogen. In certain preferred embodiments R₁₃Is fluorine. Particularly therapeutically effective are (-) forms of the compound of formula I wherein R¹Is hydrogen and fluorine is para.

The synthesis of paroxetine and its acid addition salts is specifically disclosed in U.S. patent No. 4,007,196 to Christensen et al and U.S. patent No. 4,721,723 to Barnes et al. Derivatives of paroxetine are also disclosed in WO 035910.

In yet other embodiments, the SSRI is citalopram or a derivative thereof. For example, the SSRI can be a compound represented by the formula:

wherein R16 and R17 each independently represent halogen, trifluoromethyl, cyano or-C (═ O) -R₁₈，

Wherein R is₁₈Alkyl groups having 1 to 4 carbon atoms (including head to tail).

Citalopram was first disclosed in DE 2,657,271 corresponding to US4,136,193. This patent document discloses the preparation of citalopram by one process and discloses another process which may be used for the preparation of citalopram. A process for the preparation of individual enantiomers of citalopram is disclosed in U.S. Pat. No. 4,943,590, e.g. (+) -1- (3-dimethylaminopropyl) -1- (4' -fluorophenyl) -1, 3-dihydroisobenzofuran-5-carbonitrile. Citalopram derivatives include desmethylcitalopram and didermethylcitalopram, as well as single enantiomers of all three compounds.

In yet another embodiment, the SSRI is fluvoxamine or a derivative thereof. For example, the SSRI can be a compound represented by the formula:

wherein R is₁₉Represents cyano, cyanomethyl, methoxymethyl or ethoxymethyl. Fluvoxamine orOther oxime ethers are disclosed in U.S. patent No. US4,085,225.

(ii)5-HT₆Receptor antagonists

The DAT-5HT2 antagonists of the invention can be reacted with 5-HT₆Combinations of receptor antagonists, such as bicyclic piperazinyl benzenesulfonamides, substituted N-phenyl-4-methoxy-3-piperazin-1-yl benzenesulfonamides, and conformationally constrained analogs thereof. Exemplary 5-HT₆Receptor antagonists include:

● (4-piperazin-1-ylquinolin-6-yl) arylsulfonamides, such as those disclosed in Bromidge et al, Bioorg Med Chem Lett.2001 Nov 5; 11(21): 2843-6;

● 5-chloro-N- (4-methoxy-3-piperazin-1-yl-phenyl) -3-methyl-2-benzothiophenesulfonamide (SB-271046)

● N- (2, 5-dibromo-3-fluorophenyl) -4-methoxy-3-piperazin-1-ylbenzenesulfonamide (SB-357134)

● 4-amino-N- (2, 6-bis-methylamino-pyrimidin-4-yl) -benzenesulfonamide (Ro04-6790)

(iii)Others

Suitable norepinephrine reuptake inhibitors for use with the present invention include tertiary amine tricyclics and secondary amine tricyclics. Suitable examples of tertiary amine tricycles include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine, and pharmaceutically acceptable salts thereof. Suitable examples of secondary amine tricyclics include: amoxapine, desipramine, meprotiline, nortriptyline and protriptyline, and pharmaceutically acceptable salts thereof. Another norepinephrine reuptake inhibitor for use with the present invention is reboxetine.

Suitable monoamine oxidase inhibitors for use with the present invention include: isocarboxazid, phenelzine, tranylcypromine and selegiline, and pharmaceutically acceptable salts thereof. Suitable reversible inhibitors of monoamine oxidase for use with the present invention include: moclobemide, and pharmaceutically acceptable salts thereof.

Suitable CRF antagonists for use with the present invention include those disclosed in international patent specifications WO94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677.

Other antidepressants for use with the present invention include: adezolam, alapropyl ester, anetholide, amitriptyline/chlorine nitrogen * combination, altemezole, azamianserin, piperazinopram, benfuralathin, diphenylmelen, binodaline, biperanol, bromofamine, bupropion, caroxazone, cilliramine, cyanamide, simoxanone, citalopram, clomeprol, clovoxamine, nitrogen * denier, deanol, demetireline, diphenylazepine, dulthiopine, droxidopa, efletoxin, estazolam, etoperazone, femoxetine, fexofenadine, fexogabine, fexozolamide, flutricine, idazoxan, indaparine, lolizine, iprindole, levalbutinine, ritoxetine, lofepramine, metiramine, metirarine, milnacipran, mirtazapine, oxazepinine, oxazepindol, oxazepinine, doxepinasil, pheniramine, doxepinasil, valprozil, doxylamine, valprozil, valdecoxidone, valdecoxi, Pinacidin, pirlindone, pilindidine, ritanserin, sercloremene, sertraline, sibutramine, sulbutiamine, sulpiride, tenisazine, tozaninone, thymolberin, tianeptine, tiflorbine, tofacicine, toffexopam, toloxatone, tomoxetine, vilapride, zimetidine and zometapine, and pharmaceutically acceptable salts thereof, and malus lutescens (st. john's worb) or hypericum perforatum (hypericum perforatum), or extracts thereof.

Other anxiolytics for use with the present invention include the benzodiazepines * class. Suitable benzodiazepines * for use with the present invention include: alprazolam, clonazepam *, clonazepam, dipotassium clonazepam *, diazepam, halazepam, lorazepam, oxazepam and pramazepam, and pharmaceutically acceptable salts thereof.

In addition to benzodiazepines *, other suitable anxiolytics are non-benzodiazepines * class sedative hypnotics, such as zolpidem; mood stabilising drugs such as clobazam, gabapentin, lamotrigine, clothianidin, oxcarbazepine, setoplane and vigabatrin; and barbiturates.

Suitable 5-HT for use with the present invention_1AReceptor agonists or antagonists include in particular 5-HT_1AThe receptor partial agonists buspirone, fluccinolone, gepirone and ixabepilone, and pharmaceutically acceptable salts thereof. Having a 5-HT_1AAn example of a compound with receptor agonist/partial agonist activity is pindolol.

Another class of anxiolytics for use with the present invention are compounds having muscarinic cholinergic activity. Suitable compounds within this class include muscarinic cholinergic receptor agonists such as those described in european patent specifications 0709093, 0709094 and 0773021 and PCT publication WO 96/12711.

Another class of anxiolytics for use with the present invention are compounds that act on ion channels. Suitable compounds in this class of compounds are carbamazepine, lamotrigine and valproate, as well as pharmaceutically acceptable salts thereof.

Anticonvulsant/antiepileptic

Anticonvulsants and antiepileptics contemplated as the second component include, but are not limited to, phenytoin (phenytoin, mephenytoin, and ethphenytoin), barbiturates (phenobarbital, mefenofibrate, and primidone), iminostilbene (carbamazepine), succinimide (ethosuximide), valproic acid, oxazolidinedione (trimethazone), and other antiepileptics (gabapentin, lamotrigine, acetazolamide, felbamate, and γ -vinyl GABA).

● carbamazepine, 5H-dibenzo [ b, f ] azepine * -5-carboxamide is an anticonvulsant and an analgesic for the sale of trigeminal neuralgia; US 2,948,718 (incorporated herein by reference in its entirety) discloses carbamazepine.

● valproic acid, 2-valproic acid or diisopropylacetic acid are known antiepileptic drugs which dissociate in the gastrointestinal tract into valproate ions; various pharmaceutically acceptable salts are disclosed in US4,699,927.

● lamotrigine, 6- (2, 3-dichlorophenyl) -1, 2, 4-triazine-3, 5-diamine is an antiepileptic drug required in adjuvant therapy for the treatment of partial seizures in adult epileptic patients. Lamotrigine is disclosed in US4,486,354.

● gabapentin, 1- (aminomethyl) cyclohexaneacetic acid, is an antiepileptic drug required as an adjunct therapy in the treatment of partial seizures with or without secondary generalizations in adult epileptic patients. Gabapentin is disclosed in US4,024,175 and 4,087,544.

● topiramate, 2, 3: 4, 5-di-O- (1-propyllidine) -3-D-fructopyranosylsulfamate is an antiepileptic drug and is disclosed in US4,513,006.

Atypical antipsychotics

Another aspect of the present invention relates to combination therapies for treating depression, anxiety or psychosis using one or more DAT-5HT2 antagonists of the invention and an atypical antipsychotic.

Compared to typical antipsychotics, such as haloperidol, the basic treatment-related characteristics of atypical antipsychotics are less drastic extrapyramidal symptoms, especially dystonia. While conventional antipsychotics are primarily characterized by D2 dopamine receptor blockade, atypical antipsychotics exhibit antagonism at multiple receptors including 5HT2a and 5HT2c, and varying degrees of receptor affinity. See Meltzer inNeuropsychopharmacology：The Fifth Generation of Progress2002, page 819. sup. 831; and Baldesessini and Tarazi inGoodman &Gilman′s The Pharmacological Basis of Therapeutics 10th Edition2001, page 485. Atypical antipsychotics, also commonly referred to as 5-hydroxytryptamine/dopamine antagonists, reflect the hypothesis of influence: the greater affinity of the 5HT2 receptor than the D2 receptor is known as the basis for an "atypical" antipsychotic effect or "second generation antipsychotic" drug.

The original atypical antipsychotic, clozapine, differs from typical antipsychotics in the following characteristics: (1) greater efficacy in the overall psychopathological treatment of patients with schizophrenia, unresponsive to typical antipsychotics; (2) greater efficacy in the treatment of negative symptoms of schizophrenia; and (3) a less frequent and less quantitative increase in plasma prolactin concentration associated with treatment (Beasley et al, Neuropsychopharmacology, 14 (2)), 111-.

Atypical antipsychotics include, but are not limited to:

● olanzapine, 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2, 3-b ] [1-, 5] benzodiazepine * are known compounds and are disclosed in U.S. Pat. No. 5,229,382;

● clozapine, 8-chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo [ b, e ] [1, 4- ] diazepine *, disclosed in U.S. Pat. No. 3,539,573;

● risperidone, 3- [2- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidino ] ethyl ] -2-methyl-6, 7, 8, 9-tetrahydro-4H-pyrido- [1, 2-a ] pyrimidin-4-one, and its use in the treatment of psychosis is disclosed in US4,804,663;

● Sertindole, 1- [2- [4- [ 5-chloro-1- (4-fluorophenyl) -1H-indol-3-yl ] -1-piperidinyl ] ethyl ] imidazolidin-2-one is disclosed in U.S. Pat. No. 3,4,710,500. Its use in the treatment of schizophrenia is disclosed in US5,112,838 and 5,238,945;

● Quetiapine, 5- [2- (4-dibenzo [ b, f ] [1, 4] thiazepin * -11-yl-1-piperazinyl) -ethoxy ] ethanol, and its activity in tests demonstrating efficacy in the treatment of schizophrenia is disclosed in U.S. Pat. No. 4,879,288. In certain preferred embodiments, quetiapine is provided as its (E) -2-butenedioate (2: 1) salt; and

● ziprasidone, 5- [2- [4- (1, 2-benzisothiazol-3-yl) -1-piperazinyl ] ethyl- ] -6-chloro-1, 3-dihydro-2H-indol-2-one, and in particular its hydrochloride monohydrate. Such compounds are disclosed in US4,831,031 and 5,312,925.

E. Preparation

In another aspect, the invention provides a pharmaceutical formulation comprising a DAT-5HT2 antagonist of the invention. For administration, the DAT-5HT2 antagonist used in the methods of the invention can be conveniently formulated using biologically acceptable, pyrogen-free and/or sterile media, such as water, buffered saline, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), or suitable mixtures thereof. The optimum concentration of the active ingredient in the chosen medium can be determined empirically according to methods known to behavioral scientists. The term "biologically acceptable medium" as used herein includes any and all solvents, dispersion media and the like suitable for the desired route of administration of the pharmaceutical formulation. The use of such media for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the DAT-5HT2 antagonist activity, its use in the pharmaceutical formulations of the invention is contemplated. Suitable excipients and formulations thereof containing other proteins are disclosed, for example, in Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences. Mack publishing Company, Easton, Pa., USA 1985). These excipients include injectable "depot formulations".

The method of introduction may also be provided by a rechargeable or biodegradable device. In recent years, various sustained release polymeric devices have been developed and tested in vivo for controlled release of drugs. A variety of biocompatible polymers (including hydrogels), including biodegradable or non-degradable polymers, can be used to form implants for sustained release of the DAT-5HT2 antagonist at a particular target. In accordance with the practice of the present invention, it has been found that it is possible to provide a dosage form and method for administering a DAT-5HT2 antagonist in a regimen that substantially reduces or completely compensates for tolerance in a patient. The tolerability defined by Brill in Pharmacology in Medicine, p.227(1965), McGraw-Hill, is characterized by a reduction in efficacy following administration of the drug. When tolerance develops in a very short time after a single dose or several doses, it is called acute tolerance. When a drug exhibits significant tolerability after being administered for an extended period of time, it is referred to as chronic tolerability. The exemplified medical literature, The Pharmacological Bases of therapeutics, Goodman and Gilman, 8 th edition, page 72 (1990) Pergamon Press, reports that The effects of various drugs can be tolerated and that tolerance is classified as acute and chronic based on The time of their attainment. That is, acute tolerance develops over a single dosing period or over a day, while chronic tolerance results from chronic administration, typically over weeks, months, and years.

In certain embodiments, particularly where the selected DAT-5HT2 antagonist is one that can produce tolerance, e.g., acute tolerance, in a patient, it may be desirable to formulate the drug in variable doses, preferably in a dosing regimen with escalating doses. In a preferred embodiment, the DAT-5HT2 antagonist of the invention is formulated to provide a sustained and increased dose, for example, for at least 4 hours, more preferably at least 8 hours or even 16 hours.

In certain embodiments, a typical dosage form comprises a hydrogel matrix containing a plurality of mini-pills. The hydrogel matrix contains hydrophilic polymers such as polysaccharides, agar, agarose, natural gums, alkali metal alginates including sodium alginate, carrageenan, fucoidan, danish agar, laminarin, hypnea (hypnea), acacia, ghatti gum, karaya gum, tragacanth gum, locust bean gum, pectin, pullulan, gelatin, and hydrocolloids. The hydrogel matrix contains a plurality of micro-pills (e.g., 4 to 50) in doses that each contain an increasing population of doses from 100 ng upwards, e.g., 0.5 mg, 1 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, etc. The pellets contain release rate controlling walls with a thickness of 0.0 mm to 10 mm in preparation for prolonged drug release. Typical wall-forming materials include triglycerides selected from: glyceryl tristearate, glyceryl monostearate, glyceryl dipalmitate, glyceryl laurate, glyceryl didecenoate, and glyceryl tridecenoate. Other wall-forming materials include polyvinyl acetate phthalate, methyl cellulose phthalate, and porous vinyl olefins. Methods for making pellets are disclosed in U.S. patents US4,434,153, 4,721,613, 4,853,229, 2,996,431, 3,139,383 and 4,752,470, which are incorporated herein by reference.

In certain embodiments, the drug delivery pellet is characterized by the following dissolution profile: wherein 0-20% of the beads dissolve and release the drug within 0-2 hours, 20-40% of the beads dissolve and release the drug within 2-4 hours, 40-60% exhibit dissolution and release within 4-6 hours, 60-80% exhibit dissolution and release within 6-8 hours, and 80-100% exhibit dissolution and release within 8-10 hours. The drug-releasing pellet may include a central composition or core containing the drug and pharmaceutically acceptable composition-forming components, including lubricants, antioxidants, and buffers. The pellets contain an increasing amount of drug, e.g., 1 mg, 2 mg, 5 mg, etc., up to a high dose, and in certain preferred embodiments, up to a high dose of 15 to 100 mg. The pellets are coated with a release rate controlling polymer, which can be selected using the dissolution profile disclosed above. The pellets can be prepared using the following method: liu et al, (1994) inter.j.of pharm., 112: 105-116; liu et al, (1994) inter.j.of pharm., 112: 117-124; pharm. scl, Remington, 14 th edition, page 1626-1628 (1970); fincher et al, (1968) j.pharm.scl, 57: 1825-1835; and US patent US4,083,949.

Another exemplary dosage form provided by the present invention comprises from 1 mg to 15-600 mg of the DAT-5HT2 antagonist coated on a polymeric substrate from a lower, anterior dose to a higher, posterior dose. The polymer may be an erodible or a non-erodible polymer. The coated substrate rolls on itself from a higher dose behind the center of the dosage form to a lower dose in front of the exposed outer ends of the substrate. The coated substrate is rolled from a high dose to a low dose to provide release from a low dose to a high dose as the substrate unfolds or erodes. For example, 1 mg to 600 mg amphetamine is coated on an erodible polymer such as polypeptide, collagen, gelatin or polyvinyl alcohol and the substrate is rolled concentrically from a high dose on the surface and inside to accommodate a central location and then out to a low dose to form an outer location. In operation, the dosage form erodes to disperse the ascending dose of amphetamine released over time.

The present invention provides another dosage form comprising multiple layers, wherein each layer is characterized by an elevated dose of a drug. The term "multilayer" means 2-6 layers of a contact stack. The layers are arranged in series, that is, each layer is arranged sequentially one after the other, the first layer being the exposed layer, the sixth layer being in contact with the fifth layer and the exposed surface of which is coated with a drug impermeable polymer. The sixth layer is coated with a drug impermeable polymer to ensure release of the DAT-5HT2 antagonist from the first layer to the sixth layer. For example, the first layer contains 1-50 mg of drug and each adjacent layer contains an additional 1-50 mg of drug. The biodegradable polymer undergoes chemical decomposition to form soluble monomer or soluble polymer units. Biodegradation of polymers typically involves chemical or enzymatic hydrolysis. Typical biodegradable polymers are suitable for increasing the drug loading of each layer by 5-50% by weight over the first layer and successive layers, wherein the first layer contains 100 nanograms. Typical biodegradable polymers include biodegradable poly (amides), poly (amino acids), poly (esters), poly (lactic acid), poly (glycolic acid), poly (orthoesters), poly (anhydrides), biodegradable poly (dehydropyrans), and poly (dioxinones). Polymers are well known in the art, Controlled Release of Drugs, Rosoff, Chapter 2, pages 53-95 (1989); and US3,811,444, 3,962,414, 4,066,747, 4,070,347, 4,079,038 and 4,093,709.

In other embodiments, the invention uses dosage forms containing polymers that release drug by diffusion, flow through pores, or by rupture of a polymeric matrix. The drug releasing polymer system contains a concentration gradient, wherein the gradient is a gradient from a starting or initial concentration to a final or higher concentration. The dosage form contains an exposed surface for the initial dose and a spaced, non-contacting surface for the final dose. The non-contact surface is made of a pharmaceutically acceptable drug impermeable material.

The dosage form configuration provides an increase in drug release from the start to the final delivered dose. The drug matrix may be prepared by methods known in the polymer art. In one preparation, 3-5 or more cast compositions are prepared independently, wherein each cast composition comprises an increased dosage of drug, wherein each composition covers from a lower to a higher dosage. This provides a series of layers that are joined together to provide a unitary polymer matrix with a concentration gradient. In another preparation, the higher dose is cast first, followed by layering of the lower dose layers to provide a polymer matrix with a drug concentration gradient. One example of providing a dosage form includes mixing a pharmaceutically acceptable carrier, such as polyethylene glycol, with a known dose of the DAT-5HT2 antagonist and adding it to a silicone rubber medical grade elastomer with a cross-linking agent, such as stannous octoate, and then casting in a mold. This step is repeated for each adjacent layer. The system allows setting for example 1 hour to provide a dosage form. Typical polymers from which the dosage form is made include olefin and ethylene polymers, condensation polymers, carbohydrate polymers and silicon polymers, expressed as: poly (ethylene), poly (propylene), poly (vinyl acetate), poly (methyl acrylate), poly (isobutyl methacrylate), poly (alginate), poly (amide), and poly (silicone). Polymers and manufacturing processes are known in the following documents: polymers, Coleman et al, Vol.31, pp.1187-1230 (1990); drug Carrier Systems, Roerdink et al, Vol.9, pp.57-109 (1989); drug Delivery Rev., Leong et al, Vol.1, pp.199-233 (1987); handbook of Commonpolymers, Roff et al, (1971), CRC Press publication; and US patent US3,992,518.

In other embodiments, the formulations of the invention may be a mixture of different prodrug forms of one or more different DAT-5HT2 antagonists, each prodrug form having a different rate of hydrolysis and thus a different rate of activation, to provide increased plasma concentrations of the active DAT-5HT2 antagonist.

In other embodiments, the formulations of the invention may be a mixture of different DAT-5HT2 antagonists, each compound having a different adsorption rate (e.g., along the gut and epithelium) and/or plasma half-life.

The escalating dose therapy of the invention can be used to compensate for the loss of therapeutic efficacy of the DAT-5HT2 antagonist, if any, by providing a method of delivery to continually compensate for the development of acute tolerance by considering the clinical effect (E) of the drug over time (t) as a function of the drug concentration (C) according to equation 1:

effect f (t, C)

Furthermore, the drug delivery rate (a) in mg/hr is inversely proportional to the concentration time for drug clearance. Since the effect is inversely proportional to time and function, then according to the invention, (a) can be adjusted to ensure that the therapeutic effect is maintained at a clinical value. If the effect of the drug is found to decrease over time clinically, this decrease can be linear as shown in equation 2:

effect (t) — effect (ini) -k · effect · t

Wherein the effect (int) represents a clinical effect observed at the start of drug administration and the effect (t) represents an effect observed at time (t) hour, and the k-effect is a proportional constant obtained by measuring the clinical effect (E1) at time (t1) hour and the clinical effect (E2) at time (t2) hour while maintaining a constant plasma concentration and then dividing (E1) - (E2) by (t1) - (t 2). In order to maintain a constant effect, (a) must be adjusted using the same function according to equation 3.

A (t) ═ a (ini) + k effect t

Where A (ini) is the initial drug input in milligrams per hour at the start of treatment and A (t) is the drug input over time (t) hours, and the k-effect is the above-mentioned proportional constant. If the effect is found to decrease exponentially over time, this relationship is expressed by the following equation:

effect (t) ═ effect (ini) × exp (-k effect × t)

Wherein the effects (ini) and (t) are as defined above, the k-effect is the rate constant (h-1) in reciprocal hours, determined by measuring the clinical effect (E1) at time (t1) hours and the clinical effect (E2) at time (t2) hours while maintaining a constant plasma concentration and then dividing the natural logarithm of (E1) - (E2) by (t1) - (t 2). To maintain a constant effect, (a) must be adjusted according to equation 5:

a (t) ═ a (ini) × exp (k effect × t)

Where A (ini) and A (t) are defined as described above, and the k effect is the rate constant (h-1) given above. These equations appear in Holford et al, (1982) pharmac, ther, 16: 143, 166.

The formulations of the present invention may be administered orally, parenterally, topically or rectally. Of course, can be administered in a form suitable for each route of administration. For example, the administration may be in the form of tablets or capsules, or by injection, infusion, inhalation, rectal suppository or controlled release patch. Oral or controlled release patch administration is preferred.

In certain preferred embodiments, the treatment of the present invention is performed by a transdermal patch. The patch is typically a flat, hollow device having a permeable membrane on one side and some form of adhesive to place the patch on the skin of the patient, and a membrane in contact with the skin to allow the drug to permeate out of the patch reservoir into the skin. The outer side of the patch is formed of a water impermeable material and the membrane side and the outer side are joined along the perimeter of the patch forming the drug reservoir and the carrier between the two layers.

Patch technology enables a permanent contact of the active ingredient with the epidermis. Over a considerable period of time, the drug molecules that remain in this state will eventually enter the blood. The patch technology thus relies on the ability of the human body to access the drug molecules through the skin. Transdermal drug delivery using patch technology has recently been used to assist smokers in nicotine delivery when quitting smoking, to deliver nitroglycerin to patients with angina, to deliver replacement hormones to postmenopausal women, and the like. These conventional drug delivery systems include a patch having an active component, such as a drug incorporated therein, and an adhesive for attachment to the skin to place the active component in proximity to the skin. Exemplary patch technologies are available from Ciba-Geigy and Alza. Such transdermal delivery devices are also readily adaptable for use with the DAT-5HT2 antagonists of the present invention.

The passage of the compound of interest along the skin can also be modulated by altering (a) the resistance (diffusion coefficient) or (b) the driving force (solubility of the drug in the stratum corneum and thus the diffusion gradient). Various methods may be used to enhance skin penetration of the target compound, including penetration enhancers, use of prodrug forms, excess excipients, iontophoresis, sonophoresis, and thermomigration. Various enhancer compositions have been developed to alter one or both factors. See, for example, US4,006,218, 3,551,154, and 3,472,931, which disclose the use of dimethyl sulfoxide (DMSO), Dimethylformamide (DMF), and N, N-Dimethylacetamide (DMA), respectively, to enhance the absorption of topically applied drugs through the stratum corneum. Enhancer combinations consisting of diethylene glycol monoethyl ether or monomethyl ether and propylene glycol monolaurate and methyl laurate have been disclosed in U.S. Pat. No. 4,973,468. Dual enhancers consisting of glycerol monolaurate and ethanol for transdermal drug delivery have been disclosed in U.S. patent No. 4,820,720. Many enhancers for transdermal drug delivery are listed in US5,006,342, including fatty acid esters or fatty alcohol ethers of C2-C4 alkylene glycols, wherein each fatty acid/alcohol moiety of the ester/ether is from about 8 to 22 carbon atoms. US4,863,970 discloses a permeation enhancing composition for topical administration, comprising an active osmotic body contained in a permeation enhancing excipient, containing a specific amount of one or more cell-coating disordering compounds, such as oleic acid, oleyl alcohol and glycerol esters of oleic acid; c2 or C3 alkanol; and an inert diluent such as water. Other examples include the teaching of US4,933,184, which discloses the use of menthol as a penetration enhancer; US5,229,130, which discloses the use of vegetable oils (soy and/or coconut oil) as penetration enhancers; and US4,440,777, which discloses the use of eucalyptol as a penetration enhancer.

The terms "parenteral administration" and "administered parenterally" as used herein refer to modes of administration other than enteral and topical administration, typically by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

The terms "systemic administration," "systemic administration," and "peripheral administration" as used herein refer to the administration of a compound, drug, or other substance other than directly into the central nervous system, whereby it enters the patient's body and is thus metabolized, as well as other like processes, e.g., subcutaneously.

The compounds may be administered to humans or other animals for therapeutic purposes by any suitable route of administration, including oral, nasal (e.g., by spray), rectal, vaginal, parenteral, intracisternal, and topical (e.g., by powder, paste, or drops, including buccal and sublingual administration).

Regardless of the route of administration chosen, the compounds of the invention (which may be used in a suitable hydrated form) and/or the pharmaceutical compositions of the invention are formulated, for example, in pharmaceutically acceptable dosage forms as described below or by other conventional methods well known to those skilled in the art.

The actual dosage level of the active ingredient in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, and the composition and mode of administration are non-toxic to the patient.

The selected dosage level will depend upon a variety of factors including the activity of the particular compound or ester thereof, salt thereof or amide thereof used in the present invention, the route of administration, the time of administration, the rate of excretion of the particular compound used, the period of treatment, other drugs, compounds and/or substances used in combination with the particular DAT-5HT2 antagonist used, the age, sex, body weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start administration of a pharmaceutical composition of a compound of the present invention at a level lower than that required to achieve the desired therapeutic effect and then gradually increase the dosage until the desired effect is achieved.

Generally, a suitable daily dose of a compound of the invention is the lowest effective dose of the compound that produces a therapeutic effect. Such effective dosages will depend upon the factors described above. Typically, intravenous, intracerebroventricular, and subcutaneous doses of the compounds of the invention will be in the range of about 0.0001 to about 100 mg/kg of body weight/day of the patient.

If desired, effective daily dosages of the active compound may be administered in two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms.

The term "treatment" also includes prophylaxis, therapy and cure.

The subject receiving the treatment is any animal in need of such treatment, including primates, particularly humans, and other mammals such as horses, cattle, pigs and sheep; and poultry and pets in general.

The compounds of the present invention may be administered as such or in admixture with a pharmaceutically acceptable carrier, and may also be administered together with other drugs, such as dopamine precursors, dopaminergic and anticholinergic agents, dopamine agonists, MAO-B (monoamine oxidase B) inhibitors, COMT (catechol-O-methyltransferase) inhibitors, muscle relaxants, sedatives, anticonvulsants, dopamine reuptake inhibitors, dopamine blockers, beta-blockers, carbonic anhydrase inhibitors, anesthetics, gabapentinizing agents or alpha antagonists. Combination therapy thus involves the administration of the active compounds sequentially, simultaneously or separately in a manner such that the therapeutic effect of the first administration is not completely lacking when administered subsequently.

Although the compound of the present invention may be administered alone, it is preferable that the compound is administered as a pharmaceutical preparation (composition). For administration, the DAT-5HT2 antagonists according to the invention can be administered by any method convenient for human or veterinary use.

Thus according to a further aspect of the invention there is provided a pharmaceutically acceptable composition comprising a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. As described below, the pharmaceutical compositions of the present invention may be formulated for administration as a solid or liquid, including the following: (1) oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets, pellets, powders, granules, or pastes applied to the tongue; (2) parenteral administration, for example by subcutaneous, intramuscular or intravenous injection, for example in the form of sterile solutions or suspensions; (3) topical application, e.g., as a cream, ointment or spray applied to the skin; or (4) intravaginally or intrarectally, for example in the form of pessary cream or foam. In certain embodiments, however, the subject compound may simply be dissolved or suspended in sterile water.

The term "pharmaceutically acceptable carrier" as used herein refers to a pharmaceutically acceptable material. Compositions or excipients, such as liquid or solid filters, diluents, excipients, solvents, or encapsulating materials that transport or transfer the modulator of interest from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Examples of certain materials that can be used as pharmaceutically acceptable carriers include (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible materials that can be used in pharmaceutical formulations.

As mentioned above, the DAT-5HT2 antagonists of the invention can contain a basic functional group, such as amino or alkylamino, and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term "pharmaceutically acceptable salts" in this regard refers to the relatively non-toxic, inorganic and organic acid addition salts of the compounds of the present invention. These salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or alternatively the salts formed may be formed and isolated by reacting the purified compounds of the invention in free base form with a suitable organic or inorganic acid. Typical salts include, but are not limited to: 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, acetate, adipate, alginate, aminostilbene sulfonate (amsonate), aspartate, benzenesulfonate, benzoate, benzenesulfonate (besylate), bicarbonate, bisulfate, borate, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, citrate, clavulanate (clavulanate), cyclopentanepropionate, digluconate, dodecylsulfate, edetate, edisylate (edisylate), estolate, ethanesulfonate, fumarate, glucoheptonate, gluceptate, gluconate, glutamate, glycerophosphate, p-hydroxyacetaminophenylarsonate (glycolisanilate), Hemisulfate, heptanoate, hexafluorophosphate, hexanoate, hexylbenzenedisulfonate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, laurylsulfonate, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, naphthenate, naphthalenesulfonate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoate, pantothenate, pectate, persulfate, phosphate/diphosphate, picrate, pivalate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, hydrabamine, hydrobromide, hydrochloride, methanesulfonate, methyl nitrate, methylsulfate, mucate, cinnamate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoate, pantothenate, pectate, Succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, theachlorate, thiocyanate, tosylate, triiodonium, undecanoate, and valerate, and the like (see, e.g., Berge et al, (1977) "Pharmaceutical Salts," J.pharm. Sci.66: 1-19)).

In certain embodiments, pharmaceutically acceptable salts of the subject compounds include conventional non-toxic salts of the compounds, e.g., salts derived from non-toxic organic or inorganic acids. Particularly suitable are salts of weak acids. For example, these non-toxic salts include those derived from the following inorganic acids: such as hydrochloric acid, hydrobromic acid, hydroiodic acid, cinnamic acid, gluconic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and those prepared from the following organic acids: such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, maleic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, and the like.

In other cases, the compounds of the present invention may contain one or more acidic functional groups and are thus capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of the compounds of the present invention. These salts can likewise be prepared in situ during the final isolation or purification of the compound, or by reacting the purified compound in its free acid form with a suitable base, such as a pharmaceutically acceptable hydroxide, carbonate or bicarbonate of a metal cation, or with ammonia or with a pharmaceutically acceptable primary, secondary or tertiary organic amine alone. Representative alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, e.g., Berge et al, supra).

Wetting agents, emulsifying agents, and lubricating agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, sequestering agents, coating agents, sweetening, flavoring and perfuming agents, preserving agents, and antioxidants can also be present in the composition.

Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants such as ascorbyl palmitate, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

The formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that is combined with the carrier materials to produce a single dosage form will depend upon the particular patient being treated and the particular mode of administration. The amount of active ingredient combined with a carrier material to produce a single dosage form is generally that amount of the compound which produces a therapeutic effect. Typically, the amount will be from about 1% to about 99%, preferably from about 5% to about 70%, most preferably from about 10% to about 30% of the active ingredient by weight.

The method of making the formulation or composition includes the step of mixing the compound of the invention with a carrier and optionally one or more formulations. Generally, the formulations are prepared by uniformly and intimately admixing the compounds of the invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the resulting mixture.

Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), and/or as mouthwashes and the like, each containing a predetermined amount of a compound of the invention as an active ingredient. The compounds of the invention may also be administered as a bolus, electuary or paste.

In the solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and/or any of the following: (1) fillers or extenders, for example starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrants, for example agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as waxes; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) adsorbents such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and (10) a colorant. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using sugars such as lactose or milk, as well as high molecular weight polyethylene glycols and the like as excipients.

Tablets may be prepared by compression or molding, optionally together with one or more accessory ingredients. Compressed tablets may be prepared using binders (for example, gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrating agents (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), or surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared for coating and outer shells, such as enteric coatings as well as other coatings well known in the pharmaceutical formulating art. They may also be formulated to provide slow or controlled release of the active ingredient using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymers, liposomes and/or microspheres. For example, they may be sterilized by filtration through a filter containing the bacteria immediately prior to use, or by addition of a bactericide in the form of a sterile solid composition which is soluble in sterile water, or some other sterile injectable medium. These compositions may optionally also contain opacifying agents and may be of a type that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate with one or more of the abovementioned excipients.

Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, seed, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

In addition to inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, as well as sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations of the pharmaceutical compositions of the present invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository paraffin or salicylate, and which is solid at room temperature but liquid at body temperature and, therefore, will melt in the rectum and vaginal cavity and release the active DAT-5HT2 antagonist.

Formulations of the invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, with any preservatives, buffers, or propellants which may be required.

In addition to the active compounds according to the invention, ointments, pastes, emulsions and gels may contain excipients, such as animal and vegetable fats, oils, paraffins, white wax, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.

Powders and sprays can contain, in addition to a compound of the invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powders or mixtures of these substances. Sprays can also contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

In certain embodiments, the compound of interest is formulated as part of a transdermal patch. Transdermal patches have the additional advantage of providing controlled release of the compounds of the present invention to the body. Such dosage forms may be prepared by dissolving or dispersing the DAT-5HT2 antagonist in a suitable medium. Absorption enhancers may also be used to increase the passage of the DAT-5HT2 antagonist along the skin. The rate of passage can be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

The "free base form" of a compound of the invention refers to a form of the compound that is not complexed with an acid, e.g., is not an ammonium salt. This form may be incorporated into a patch. It will be appreciated that the DAT-5HT2 antagonist can be complexed, for example, with an element of the patch matrix that retains the drug, and thus the DAT-5HT2 antagonist need not be in the form of a free base when actually retained by the patch.

The patch preferably contains a drug impermeable backing layer. Suitable examples of drug impermeable backing layers that may be used in transdermal or medicated patches include polyolefins, polyesters, polyurethanes, polyvinyl alcohols, polyvinyl chlorides, polyvinylidene chlorides, polyamides, ethylene-vinyl acetate copolymers (EVA), ethylene-ethyl acrylate copolymers (EEA), vinyl acetate-vinyl chloride copolymers, cellulose acetates, ethyl cellulose films or sheets, metal vapor deposited films or sheets thereof, rubber sheets or films, expanded synthetic resin sheets or films, nonwovens, fabrics, knits, papers, and foils. Preferred drug impermeable resilient backing materials are selected from the group consisting of polyethylene terephthalate (PET), polyurethane, Ethylene Vinyl Acetate (EVA), plasticized polyvinyl chloride, and woven and non-woven fabrics. Particularly preferred is non-woven polyethylene terephthalate (PET). Other liners will be apparent to those skilled in the art.

The term "block copolymer" in the preferred adhesives of the invention refers to a macromolecule consisting of two or more chemically distinct polymer structures joined together at the end (Block copolymers: Overview and clinical surface, Noshay and McGrath, 1977)). These different polymer structures, segments and portions represent "blocks" of the block polymer. The blocks may be generally arranged in an A-B structure, an A-B-A structure, or a multiblock- (A-B) n-system, where A and B are chemically distinct polymer segments of a block copolymer.

Block copolymers of the A-B-A structure are generally preferred, especially those in which one of A and B is an acrylic polymeric unit. It will be appreciated that the present invention also suitably uses block copolymers having three or more different blocks, for example a-B-C block copolymers. However for convenience the following references to block copolymers will assume the presence of only a and B subunits, however unless otherwise stated it will be understood that these references also include block copolymers having more than two subunits.

It will be appreciated that the properties of the block copolymer are determined largely by the properties of the a and B blocks. Block copolymers typically have "hard" and "soft" segments. A "hard" segment is a polymer having a glass transition temperature (Tg) and/or a dissolution temperature (Tm) above room temperature, whereas a "soft" segment refers to a polymer having a Tg (and possibly a Tm) below room temperature. Different segments will be thought of as imparting different properties to the block copolymer. Without being bound by theory, it is believed that the association of the rigid segments of the individual block copolymer units results in actual crosslinking within the block polymer, thereby promoting the adhesive properties of the block copolymer. It is particularly preferred that the rigid segments of the block copolymer form these physical occlusive associations.

The block copolymer useful in the present invention is preferably an acrylic block copolymer. In the acrylic block copolymer, at least one block of the block copolymer is an acrylic polymer or a polymer of an acrylic derivative. The polymer may consist of exactly one repeating monomer. It will be appreciated, however, that mixtures of monomer species may be used to form each block, whereby the block itself may be substantially a copolymer. The use of different monomer combinations may affect various properties of the resulting block copolymer. In particular, the ratio or the nature of the monomers used is varied such that properties such as adhesion, tackiness and cohesion are adjusted, whereby it is generally advantageous that the soft segments of the block copolymers consist of more than one monomer species.

Preferably, the alkyl acrylates and alkyl methacrylates are polymerized to form the soft portion of the block copolymer. Alkyl acrylates and methacrylates are believed to provide both tack and adhesive properties. Suitable alkyl acrylates and methacrylates include n-butyl acrylate, n-butyl methacrylate, hexyl acrylate, 2-ethylbutyl acrylate, isooctyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, and tridecyl methacrylate, while other suitable acrylates and methacrylates will be apparent to those skilled in the art. Preferably, the acrylic block copolymer contains at least 50% by weight of an alkyl acrylate or alkyl methacrylate (co) polymer.

The change in the composition of the soft segment affects the overall properties of the block copolymer, but the essential feature remains the crosslinking of the soft segment. For example, soft segments consisting essentially of diacetone acrylamide and butyl acrylate and/or 2-ethylhexyl acrylate in approximately equal proportions are very useful, and a weight ratio of about 3: 4 provides good results. It is preferred that diacetone acrylamide or other polar monomers such as hydroxyethyl methacrylate or vinyl acetate be present in an amount not exceeding 50% w/w of the soft segment monomer mixture, as this may result in, for example, reduced adhesion. The acrylate component is generally more freely variable, with good results being observed with 2-ethylhexyl acrylate and butyl acrylate, either simultaneously or separately.

As mentioned above, it is generally preferred that the proportions of the various monomers are approximately equal. For adhesives, it is preferred to use polar components that constitute 50% or less of the soft segment, and non-polar components up to about 85% weight/weight, preferably about 50% to 70% weight/weight. In the above embodiment, it is about 72% (4+4) polarity to about 18% (3) polarity.

It is generally particularly preferred to use any non-polar monomer which does not impart acidity to the adhesive. The adhesives of the present invention are preferably substantially neutral, preventing any unwanted degradation of the DAT-5HT2 antagonist.

Reactive functional groups, particularly those having active hydrogens, are generally preferred to allow for widespread use of any resulting adhesive formulation, regardless of how it may chemically interact with its surroundings. Chemically inert binders are therefore generally preferred, without the opposite requirement.

As noted above, polymers suitable for use in the rigid portion of the block copolymer have a glass transition temperature above room temperature. Suitable monomers for forming the hard segment polymer include styrene, X-methylstyrene, methyl methacrylate, and vinyl pyrrolidone, although other suitable monomers will be apparent to those skilled in the art. Styrene and polymethylmethacrylate have been found to be suitable for the formation of the rigid segments of the block copolymers. The rigid portion of the block copolymer preferably constitutes from 3 to 30% w/w, particularly preferably from 5 to 15% w/w, of the total block copolymer.

The block copolymer is further characterized in that the flexible portion contains a degree of chemical crosslinking. Such crosslinking may be achieved by any suitable crosslinking agent. It is particularly preferred that the crosslinking agent is in the form of a monomer suitable for incorporation into the soft segment during polymerization. Preferably, the crosslinking agent has two or more basic polymerizable groups, such as vinyl groups, in each monomer molecule, at least one of which tends to remain unchanged during the initial polymerization reaction, thereby allowing crosslinking of the resulting block copolymer.

Suitable cross-linking agents for use in the present invention include divinylbenzene, methylenebisacrylamide, ethylene glycol di (meth) acrylate, ethylene glycol tetra (meth) acrylate, propylene glycol di (meth) acrylate, butylene glycol di (meth) acrylate, or trimethylolpropane tri (meth) acrylate, although other suitable cross-linking agents will be apparent to those skilled in the art. A preferred cross-linking agent is tetraethylene glycol dimethacrylate. Preferably, the crosslinking agent comprises about 0.01 to 0.6 weight percent, and particularly preferably 0.1 to 0.4 weight percent of the block copolymer.

Methods for forming block copolymers from monomeric components are well known. The Block copolymer portion of the present invention may be produced by any suitable method, such as step growth, anionic, cationic and radical methods (Block Copolymers, supra). Since solvents and monomers do not have to be purified, free radical processes are generally preferred over other processes such as anionic polymerization.

Polymerization suitable initiators include polyperoxides having more than one peroxide moiety per molecule. Once a suitable initiator has been selected, the appropriate choice of reaction conditions is within the purview of one skilled in the art.

The initiator is preferably used in an amount of 0.005 to 0.1% by weight, particularly preferably 0.01 to 0.05% by weight, of the block copolymer, although it will be understood that the choice of this amount is within the scope of the person skilled in the art. It is particularly preferred that the amount is not so high as to cause instantaneous gelation of the mixture, nor so low as to slow down the polymerization reaction so as to leave residual monomer. The preferred concentration of residual monomers is less than 2000 ppm.

It will also be appreciated that the amount of initiator will depend essentially on considerations of the nature of the initiator itself and the monomer.

The block polymer is an adhesive, preferably a pressure sensitive adhesive. The pressure sensitive adhesive can be applied to a surface by hand pressure and does not require activation by heat, water or solvent. It is therefore particularly suitable for use in the present invention.

The block copolymer can be used without using a tackifier, and is thus particularly advantageous. It will be appreciated, however, that the block copolymer may also be used in combination with an adhesive to improve tack. Suitable tackifiers are well known and will be apparent to those skilled in the art.

Without being bound by theory, it is believed that chemical crosslinking between the soft segments of the copolymer, often in combination with hydrophobic interactions, or physical crosslinking between the hard segments, results in a "matrix-like" structure. Copolymers having only rigid segments physically crosslinked are rarely capable of forming such matrices. It is believed that the combination of both cross-linked forms of the block copolymer provides good internal strength (cohesion) as well as high drug storage capacity.

More particularly, it is believed that the rigid segments associate to form "islands" or nodes from which and between which the flexible segments stretch.

There is a defined physical structure of the "sea" between these islands, in which the soft segments are cross-linked, thus eliminating the need for extensive doping of the soft segments. This results in greater cohesion of the entire block copolymer, but at the same time results in shorter flexible segment lengths and still has large or greater distances between islands, thereby allowing good drug storage capacity.

The block copolymer is preferably crosslinked in a solvent-removing manner, whereby crosslinking can be timed to occur after coating, which is a preferred method.

Thus, not only is the block copolymer easily coated on the surface, but the entire solution can also be stored for a certain time before coating. Thus, during the manufacture of the patch, the method preferably comprises polymerizing the monomer components of each soft segment in solution, then adding the hard segment components to each resulting solution and polymerizing the resulting mixture, and then crosslinking by removing (e.g., by evaporation) all of the solvent or solvent system. If the solution needs to be stored for any period of time, it may be desirable to prevent the polymer from settling out, which may be accomplished by known means such as suspending agents or vibration. It is also desirable to select the polymer type so that substantially no crosslinking occurs before the solvent evaporates.

It is generally preferred that the adhesive have a minimum amount of functional groups with active hydrogens to avoid undesirable reactions/interactions, such as with any drug that is desired to be added to the adhesive. It will be appreciated that this is only a preferred limitation and that any adhesive may be tailored by one skilled in the art to suit individual needs.

Suitable monomers for forming the rigid segment include styrene, a-methylstyrene, methyl methacrylate and vinylpyrrolidone, with the preferred proportion of the rigid segment being from 5 to 15% w/w. In particular, the use of the compounds of WO99/02141 is advantageous since it is possible to incorporate more than 30% of the drug into such a system.

Thus, in the patch of the present invention, it is generally desirable to calculate the amount of drug required based on the patient's body weight and determine the appropriate patch size for a given drug load, which can be readily calculated by one skilled in the art.

In certain embodiments, a small amount of plasticizer, such as isopropyl myristate (IPM), is added. This helps solubilize the DAT-5HT2 antagonist and makes the adhesive less harsh on the skin. Concentrations of 2 to 25% by weight are generally used, more preferably 3 to 20% by weight, particularly preferably 5 to 15% by weight, most preferably about 10%. Other plasticizers may also be used, and suitable plasticizers will be apparent to those skilled in the art.

Plasticizers are generally in the form of oily substances incorporated into the adhesive polymer. The effect of this oily substance addition is to soften the physical structure of the adhesive and at the same time act as a contact surface between the adhesive and the skin, thereby contributing to a somewhat reduced adhesion and reduced flaking.

The free base oil can be obtained by basifying the salt of the target compound or any other suitable salt with a suitable base in the presence of a hydrophilic solvent (especially water) and an organic solvent. For example, water and ethyl acetate in approximately equal proportions are suitable, with ammonia as the alkalizing agent. The water can then be removed and the formulation washed with additional water or other aqueous formulation, and then after the ethyl acetate has been removed, the formulation can be extracted with ether as appropriate. Especially after completion, the formulation is preferably kept under an inert atmosphere.

It will also be appreciated that the patch of the present invention may be removed from the patient at any time once it is desired to terminate the administration, which may have the disadvantage of creating a potential opportunity for abuse of the drug by partially removing the patch. Abuse of the target compound is highly undesirable.

In certain embodiments, it may be advantageous to use a patch that is adjusted to deliver about 8 hours after application, with most of the target compound being able to be delivered within a 24 hour period, whereby the patch may be left in place and the drug concentration still substantially diminished. Advantageously, the drug delivery profile has first order kinetics such that most of the drug is delivered during the major part of the day and even if the patient forgets to remove the patch, the amount of drug has been depleted at the end of the day and the amount of drug drops rapidly.

It is understood that the patch of the present invention may be constructed in any manner known in the art for use in the manufacture of transdermal patches. The patch may simply contain an adhesive, drug, and liner, or may be other composite, such as having flaps to prevent drug leakage from the sides of the patch. The patch may also be multi-layered.

Ophthalmic formulations, eye ointments, powders, solutions, and the like are also within the scope of the invention.

Pharmaceutical compositions of the invention suitable for parenteral administration may contain one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Suitable aqueous and nonaqueous carriers for use in the pharmaceutical compositions of the invention include, for example, water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. For the dispersing agent, appropriate fluidity can be maintained, for example, by using a membrane material such as lecithin to maintain a desired particle size and using a surfactant.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. The preservative action of the microorganisms can be ensured by doping with different antibacterial or antifungal agents, for example parabens (parabens), chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption by injectable pharmaceutical forms can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

In some cases, it may be desirable to delay absorption of the drug for prolonged action, either subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. The rate of absorption of a drug depends on its rate of dissolution, which in turn depends on crystal size and crystal form. Alternatively, dissolving or suspending a drug in an oily vehicle may also delay absorption of the parenterally administered drug.

Injectable storage forms can be made by forming microencapsulated particles of the compounds of the present invention in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Long acting injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

When the compounds of the present invention are administered as medicaments to humans and animals, they may be administered alone or in the form of a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of an active ingredient and a pharmaceutically acceptable carrier.

Example

Having now generally described the invention, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.

Example 1: in vitro curves of two illustrative DAT-5HT2 antagonists

In vitro inhibition curves for two illustrative DAT-5HT2 antagonists CNS-30, 100 and CNS-31, 100 were measured for their respective IC's using standard assays₅₀And (4) determining.

IC at measurement DAT₅₀In a typical absorption test of (1), test is carried out at room temperature with the addition of 0.1% D-glucose, 1mM ascorbic acid, 1mM tropolone [ catechol-O-methyltransferase (EC2.1.1.6) -inhibitor]And 10 μ M of Bajilin (monoamine oxidase-B inhibitor) in Krebs-Ringer's HEPES (KRH) buffer (125mM NaCl, 4.8mM KCl, 1.2mM MgSO4, 1.2mM KH2PO4, 1.3mM CaCl2 and 25mM HEPES, pH 7.4). Prior to the assay, DAT expressing cells were washed once with KRH and equilibrated for 5 min. Cells can be tested in 24-well plates and incubated for 2-5 minutes with tritiated amine. The non-transport inhibitor was incubated for 5 minutes beforehand and the substrate was used together with the tritiated substrate. The absorption assay was terminated using two ice-cold KRH washes, and the accumulated radioactivity was recovered by lysing the cells in 0.2% SDS and 0.1N NaOH and counted on a liquid scintillation analyzer 1900 TR (Packard, Meriden, CT). Nonspecific uptake can be determined in the presence of 10 μ M GBR12909 (for hDAT).

The assays to determine the ionic requirement for DAT-mediated absorption were performed in KRH buffer using LiCl or choline chloride instead of NaCl (sodium dependent), or D-gluconate instead of NaCl and KCl, and calcium nitrate instead of calcium chloride (chloride dependent). Prior to the assay, cells were washed twice with KRH without sodium or chloride (at least 5 minutes per wash step). In all transport experiments, the culture period and substrate concentration were chosen such that absorption followed first order kinetics.

The Vmax values for amine uptake in stably transfected DAT cells were determined in parallel experiments with at least two amines in each experiment and are expressed as relative values.

Similarly, the IC of the 5-HT-2A/C receptor₅₀Can be measured by standard absorption assays using the label 5-HT. See Rudolph et al, j.pharmacol. exp.ther.287 (1): 389-94, 1998. Briefly, the time course of 5-HT uptake can be determined by adding 2 ml of RBS without Ca⁺⁺By culturing each cell/tissue at 30 ℃ using the receptor, to which was added³H]5HT (38 nM). In order to evaluate the kinetic parameter of 5-HT absorption, several kinds of [2 ], [³H]5HT concentrations, e.g., in the range of 25-240nM, using a 30 minute incubation period. In the absence of Na⁺The medium of (2) was cultured accordingly to correct for non-specific adsorption. Radioactivity not introduced by tissue/cells was washed away by incubation in 100 ml RBS for an additional 10 min. After the culture was completed, the tissue/cells were homogenized in 2 ml of 10% perchloric acid. The resulting suspension was centrifuged at 600 Xg for 5 minutes and 0.1 ml of the supernatant was analyzed for radioactivity.

Figure 2 shows typical results in tabular form. In particular, IC of CNS-30, 100 pairs of DAT (SLC6A3)₅₀At 20nM, however, its IC for the 5-HT-2A/2C receptor₅₀About 35-60 nM.

Similarly, the results for CNS-31, 100 are also provided, where IC for DAT₅₀About 75nM, however, its IC for the 5-HT-2A/2C receptor₅₀About 25-75 nM.

These data indicate that the DAT-5HT2 antagonists of the invention inhibit both predetermined targets of DAT and 5HT2 receptors.

Example 2: in vivo efficacy of several illustrative DAT-5HT2 antagonists

The in vivo effect of the DAT-5HT2 antagonists of the invention can be performed using rats using a standard forced swim test model.

A typical forced swimming test is disclosed in Porsolt et al, Nature 266: 730, 732, 1977; and Porsolt et al, Psychopharmacology, Olivier, Mos, and Slangen (eds) Birkhauser Verlag, Basel, pp.137-159, 1991. Briefly, when mice (or rats) are forced to swim in a cylinder where there is no escape possibility, they tend to adopt a motionless posture and do not attempt to escape except for a small amount of motion needed to keep floating. This inactivity reflects, at least in part, a "depressed mood" (Porsolt et al, Nature 266: 730-. The inactivity caused by this approach is influenced by a number of antidepressants (Porsolt et al, psychopharmacography, Olivier, Mos, and Slangen (eds.) Birkhauser Verlag, Basel, pp.137-159, 1991) and has a good expected effect, in which point antidepressants have been found to have different mechanisms of action (TCAs, SSRIs, MAOIs and other atypical forms). This test is sensitive to muscle relaxant (phenylenediamine) and sedative (neuroleptic) effects, resulting in increased inactivity (Porsolt et al, psychopharmacography, Olivier, Mos, and Slangen (eds.) Birkhauser Verlag, Basel, pp.137-159, 1991).

In a typical experiment, rats were individually placed in cylinders (46X 30 cm) containing fresh water at 23 ℃ for 6 minutes. The observer measures the activity (or inactivity) of the animal in minutes.

To measure the in vivo inhibitory effect of the DAT and 5-HT-2A/2C receptors in rats using the DAT-5HT2 antagonists of the invention, a test inhibitor (CNS-30, 100 or CNS-31, 100) was injected intraperitoneally into animals at different doses (e.g., 7.5 and 15 mg/kg). Sibutramine, bupropion and imipramine were performed as the control group. It is expected that the DAT-5HT2 antagonist will have the same effect, if not better than the commercial drugs sibutramine, bupropion and imipramine.

Other routes of administration may also be used in this assay.

Example 3: illustrative DAT-5HT2 antagonist toxicology profiles

To study the toxicology profile of the DAT-5HT2 antagonists of the invention, different DAT-5HT2 antagonists (e.g., 30, 90, 120 and 200 mg/kg) were administered at different doses to the test rats in a panel (e.g., 5/group), and the toxicological effects observed were recorded.

It is expected that rats can tolerate less than 90-120 mg/kg of the DAT-5HT2 antagonist of the invention with no significant symptoms observed with drug administration. At higher symptoms, e.g., 200 mg/kg, the animals show reduced grip and/or mild depression.

Equivalents of

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

All patents, publications, and other references cited above are hereby incorporated by reference in their entirety.

Claims

1. DAT-5HT as shown in formula I₂An antagonist, or a pharmaceutically acceptable salt, solvate, metabolite or prodrug thereof:

wherein under the conditions of valency and stability:

x represents H OR OR;

y and Z independently represent-O-, -S-, -C (-R)₂-or-N (-R) -;

r represents independently for each occurrence H or lower alkyl;

R₁represents one or more substituents independently selected from the group consisting of: halogen, amino, acylamino, amidino, cyano, nitro, azido, ether, thioether, sulfoxido, -J-R₈-J-OH, -J-lower alkyl, -J-lower alkenyl, -J-SH, -J-BH₂Or substituted or unsubstituted lower alkyl, lower alkenyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl, or protected forms thereof;

m is an integer of 0 to 2;

n is an integer of 0 to 2;

p is 0 or 1; and is

q is an integer from 0 to 2, preferably 1;

and-Z-J-Hc together represent a substituted or unsubstituted nitrogen-containing heterocyclic or heteroaryl ring,

wherein the DAT-5HT2 antagonist has dopamine transport (DAT) inhibitory effect and 5HT2_2aReceptor antagonism and/or 5HT_2cReceptor antagonism.

2. The DAT — 5HT2 antagonist of claim 1, wherein Hc is a substituted or unsubstituted five-membered ring.

3. The DAT — 5HT2 antagonist of claim 2, wherein Hc represents a substituted or unsubstituted pyrrole, imidazole, triazole or pyridine.

4. The DAT — 5HT2 antagonist of claim 1, wherein Ar represents a bicyclic ring system in which at least one ring is aromatic.

5. The DAT — 5HT2 antagonist of any of claims 1-4, wherein Hc and Ar, if substituted, are substituted with one or more substituents selected from the group consisting of: halogen, cyano, alkyl, alkenyl, alkynyl, aryl, hydroxy, alkoxy, siloxy, amino, nitro, thiol, amino, imino, amido, phosphoryl, phosphonate, carboxyl, carboxamide, silyl, thioether, alkylsulfonyl, arylsulfonyl, sulfoxide, selenide, ketone, aldehyde, ester, or- (CH)₂)_mR₈Wherein m is an integer of 0 to 4.

6. The DAT — 5HT2 antagonist of claim 1, wherein J, independently for each occurrence, represents a compound having 0-4 members selected from-C (-R)₂A chain of units of-N (-R) -, -O-and-S-.

7. The DAT — 5HT2 antagonist of claim 6, wherein J, at each occurrence, independently represents a substituted or unsubstituted methylene or ethylene group.

8. The DAT — 5HT2 antagonist of claim 1, wherein Y adjacent to Ar represents-O-or-S-and preferably-O-.

9. The DAT — 5HT2 antagonist of claim 1, wherein Z represents-N (-R) -.

10. The DAT — 5HT2 antagonist of claim 9, wherein Z represents-N (h) -or-N (-CH)₂)-。

11. The DAT — 5HT2 antagonist of claim 1, wherein Z, together with J and Hc, represents a heterocyclic ring attached to the core via a nitrogen atom.

12. The DAT — 5HT2 antagonist of claim 1, wherein the heterocyclic ring is a substituted or unsubstituted piperidine, piperazine, or pyrrolidine ring.

13. A packaged pharmaceutical comprising: a DAT-5HT2 antagonist of any of claims 1-12 in an amount sufficient to treat anxiety, depression, or a psychotic disorder, and formulated in a pharmaceutically acceptable carrier; and instructions (text and/or pictures) describing the use of the formulation for treating a patient.

14. The packaged pharmaceutical of claim 13, wherein the DAT-5HT2 antagonist is provided in a once-a-day formulation.

15. The packaged pharmaceutical of claim 13, formulated for oral administration.

16. The packaged pharmaceutical of claim 13, wherein the DAT-5HT2 antagonist is formulated as a transdermal patch.

17. The packaged pharmaceutical of claim 13, wherein said DAT-5HT2 antagonist is provided in a escalating dose that results in a escalating serum concentration of said DAT-5HT2 antagonist over a period of at least 4 hours.

18. A packaged pharmaceutical comprising:

(i) a mood stabilizing formulation of the DAT — 5HT2 antagonist of any of claims 1-12;

(ii) selected from 5-hydroxytryptamine reuptake inhibitor, 5HT₆Receptor antagonists, anticonvulsants, norepinephrine reuptake inhibitors, alpha-adrenoceptor antagonists, NK-3 antagonists, NK-1 receptor antagonists, PDE4 inhibitors, neuropeptide Y5 receptor antagonists, D4 receptor antagonists, 5HT_1AReceptor antagonists, 5HT_1DReceptor antagonists, CRF antagonists, monoamine oxidase inhibitionA second drug of an agent and a sedative hypnotic;

(iii) label indicating that a packaged drug is for use in treating a patient suffering from anxiety, depression or a psychotic disorder.

19. The packaged pharmaceutical of claim 18, wherein the DAT-5HT2 antagonist formulation and the second pharmaceutical agent are combined in a single dosage form.

20. Use of the DAT — 5HT2 antagonist of any of claims 1-12 for the manufacture of a pharmaceutical composition for the prevention or treatment of a patient susceptible to or suffering from dyskinesia.

21. A method of treating anxiety, depression, or psychotic disorders comprising administering to a patient a DAT-5HT2 antagonist composition of any of claims 1-12.

22. The method of claim 21 for the treatment of a patient diagnosed with depression.

23. The method of claim 21, wherein the depression disorder treated is selected from the group consisting of: paroxysmal or recurrent major depressive disorder, dysthymic disorder, depressive neurosis, and dysthymia; depression in hypochondriac patients includes anorexia, weight loss, insomnia and early morning awakening, and psychomotor depression; atypical depression (or reactive depression) includes appetite increase, hypersomnia, psychomotor excitation or sensitization, seasonal affective disorder, or bipolar or manic depression.

24. The method of claim 21 for the treatment of a patient diagnosed with bipolar disorder, bipolar depression, or unipolar depression.

25. The method of claim 21 for the treatment of a patient diagnosed with anxiety.

26. The method of claim 25, wherein the anxiety disorder is selected from the group consisting of: obsessive compulsive disorder, panic disorder, anxiety disorder caused by psychoactive substances, post-traumatic stress disorder, generalized anxiety disorder, anxiety disorder NOS, organ anxiety disorder.

27. The method of claim 25 wherein the anxiety disorder is phobia.

28. The method of claim 25, wherein the anxiety disorder is substance-induced anxiety.

29. The method of claim 28 wherein the substance-induced anxiety is selected from the group consisting of alcohol, amphetamine, caffeine, cannabis, cocaine, hallucinogens, inhalants, phencycedine, sedatives, hypnotics, anxiolytics or other substances, and accommodation disorders with anxiety or a mixture of anxiety and depression.

30. The method of claim 21 for the treatment of a patient diagnosed with a psychiatric disorder.

31. The method of claim 30 wherein the psychotic disorder is selected from schizophrenia, schizophreniform disorder, acute mania, schizoaffective disorder and depression with psychotic features.

32. A packaged pharmaceutical comprising: the DAT-5HT2 antagonist of any of claims 1-12 formulated in a pharmaceutically acceptable carrier in an amount sufficient to treat attention deficit disorder or attention deficit hyperactivity disorder; and instructions (text and/or pictures) describing the use of the formulation for treating a patient.

33. Use of the DAT — 5HT2 antagonist of any of claims 1-12 in the manufacture of a pharmaceutical composition for the treatment or prevention of a patient susceptible to or suffering from attention deficit disorder or attention deficit hyperactivity disorder.

34. A method of treating attention deficit disorder or attention deficit hyperactivity disorder comprising administering to a patient a combination of the DAT-5HT2 antagonists of any of claims 1-12.

35. A method of conducting pharmaceutical commerce, comprising:

a. manufacturing a packaged pharmaceutical of any one of claims 13-19; and

b. marketing to a health care provider the benefit of using the package or formulation to treat patients suffering from anxiety, depression or psychotic disorders, or patients suffering from attention deficit disorders or attention deficit hyperactivity disorder.

36. A method of conducting pharmaceutical commerce, comprising:

a. providing a sales network for selling the packaged pharmaceutical of any of claims 13-19; and

b. the patient or physician is provided with instructional material for using the package or formulation to treat a patient suffering from anxiety, depression, or psychiatric disorder, or from attention deficit disorder or attention deficit hyperactivity disorder.

37. A method of conducting pharmaceutical commerce, comprising:

a. determining an appropriate dose of the DAT — 5HT2 antagonist of any of claims 1-12 to enhance functional performance in a patient suffering from anxiety, depression or psychotic disorders, or a class of patients suffering from attention deficit disorder or attention deficit hyperactivity disorder;

b. performing a treatment curve assay of the one or more formulations of the DAT-5HT2 antagonist identified in step (a) to determine its efficacy and toxicity in the animal.

c. Providing a sales network for selling the formulation determined in step (b) having an acceptable treatment profile.

38. The method according to claim 37, comprising the further step of providing a sales team selling the preparation to a health care provider.

39. A method of performing a medical aid compensation program, comprising:

a. the prescription of the DAT-5HT2 antagonist of any of claims 1-12 for the treatment of anxiety, depression or psychotic disorders, or attention deficit disorder or attention deficit hyperactivity disorder, provides a compensation program that enables at least partial compensation to a health care provider or patient, or payment to a drug dealer;

b. (ii) processing one or more requirements for the prescription of a DAT-5HT2 antagonist for the treatment of anxiety, depression or psychotic disorders, or attention deficit disorder or attention deficit hyperactivity disorder; and

c. compensating the healthcare provider or patient, or paying the drug dealer at least part of the cost of the prescription.