BACKGROUND OF THE INVENTION

[0001] The present invention relates to a method of treating depression, anxiety or psychosis in a mammal, including a human, by administering to the mammal a dopamine D4 receptor antagonist (D4 receptor antagonist) in combination with an antidepressant or an anxiolytic agent. It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier, a D4 receptor antagonist and an antidepressant or an anxiolytic agent.

SUMMARY OF THE INVENTION

[0002] The present invention relates to a pharmaceutical composition for the treatment of depression, anxiety or psychosis in a mammal, comprising: (a) a compound that exhibits activity as an antidepressant or an antianxiety (i.e., anxiolytic) agent, or a pharmaceutically acceptable salt thereof; (b) a D4 receptor antagonist (i.e., dopamine D4 receptor antagonist) or pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier; wherein the active agents “a” and “b” above are present in amounts that render the composition effective in treating, respectively, depression, anxiety or psychosis.

[0003] This invention also relates to a method of treating depression, anxiety or psychosis in a mammal, comprising administering to said mammal, respectively, an antidepressant, anxiolytic or antipsychotic effective amount of a pharmaceutical composition comprising: (a) a compound that exhibits activity as, respectively, an antidepressant or an anxiolytic agent, or a pharmaceutically acceptable salt thereof; (b) a D4 receptor antagonist or pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier; wherein the active agents “a” and “b” above are present in amounts that render the composition effective in treating, respectively, depression, anxiety or psychosis.

[0004] This invention also relates to a method of treating depression, anxiety or psychosis in a mammal, comprising administering to said mammal: (a) a compound that exhibits activity as, respectively, an antidepressant or an anxiolytic agent, or a pharmaceutically acceptable salt thereof; and (b) a D4 receptor antagonist or pharmaceutically acceptable salt thereof; wherein the active agents “a” and “b” above are present in amounts that render the combination of the two agents effective in treating, respectively, depression, anxiety or psychosis.

[0005] It will be appreciated that when using a combination method of the present invention, referred to immediately above, both the D4 receptor antagonist and the antidepressant or antianxiety agent will be administered to a patient within a reasonable period of time. The compounds may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms that are taken simultaneously. The term combination, as used above, also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, the antidepressant or anxiolytic agent may be administered as a tablet and then, within a reasonable period of time, the D4 receptor antagonist may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form. By a “fast dissolving oral formulation” is meant an oral delivery form which, when placed on the tongue of a patient, dissolves within about seconds.

[0006] The compositions of the present invention that contain a D4 receptor antagonist and an antidepressant are useful for the treatment of depression. As used herein, the term “depression” includes depressive disorders, for example, single episodic or recurrent major depressive disorders, dysthymic disorders, cyclothymic disorder, depressive neurosis, and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and early morning waking, and psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, anxiety and phobias. The term “depression,” as used herein, also includes the mood disorders such as mood disorders associated with premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD), seasonal affective disorder and bipolar disorders or manic depression, for example, bipolar I disorder and bipolar II disorder.

[0007] Major depression is characterized by feelings of intense sadness and despair, mental slowing and loss of concentration, pessimistic worry, agitation, and self-deprecation. Physical changes also occur, especially in severe or “melancholic” depression. These include insomnia or hypersomnia, anorexia and weight loss (or sometimes overeating), decreased energy and libido, and disruption of normal circadian rhythms of activity, body temperature, and many endocrine functions.

[0008] Treatment regimens commonly include the use of tricyclic antidepressants, monoamine oxidase inhibitors, some psychotropic drugs, lithium carbonate, and electroconvulsive therapy (ECT) (see R. J. Baldessarini in Goodman & Gilman's The Pharmacological Basis of Therapeutics , 9th Edition, Chapter 19, McGraw-Hill, 1996 for a review). More recently, new classes of antidepressant drugs have been or are being developed including selective serotonin reuptake inhibitors (SSRIs), specific monoamine reuptake inhibitors and 5-HT _IA/ID receptor agonists, antagonists and partial agonists.

[0009] Other mood disorders encompassed within the term “depression” include dysthymic disorder with early or late onset and with or without atypical features; dementia of the Alzheimer's type, with early or late onset, with depressed mood; vascular dementia with depressed mood; mood disorders induced by alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances; schizoaffective disorder of the depressed type; and adjustment disorder with depressed mood.

[0010] The compositions of the present invention that contain a D4 receptor antagonist and an anxiolytic agent are useful for the treatment of anxiety. As used herein, the term “anxiety” includes anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalized anxiety disorders.

[0011] Anxiety disorders are generally treated using benzodiazepine sedative-antianxiety agents. Potent benzodiazepines are effective in panic disorder as well as in generalized anxiety disorder, however, the risks associated with drug dependency may limit their long-term use. 5-HT _IA receptor partial agonists also have useful anxiolytic and other psychotropic activity, and less likelihood of sedation and dependence (see R. J. Baldessarini in Goodman & Gilman's The Pharmacological Basis of Therapeutics , 9th Edition, Chapter 18, McGraw-Hill, 1996 for a review).

[0012] “Generalized anxiety” is typically defined as an extended period (e.g., at least six months) of excessive anxiety or worry with symptoms on most days of that period. The anxiety and worry is difficult to control and may be accompanied by restlessness, being easily fatigued, difficulty concentrating, irritability, muscle tension, and disturbed sleep.

[0013] “Panic disorder” is defined as the presence of recurrent panic attacks followed by at least one month of persistent concern about having another panic attack. A “panic attack” is a discrete period in which there is a sudden onset of intense apprehension, fearfulness or terror. During a panic attack, the individual may experience a variety of symptoms including palpitations, sweating, trembling, shortness of breath, chest pain, nausea and dizziness. Panic disorder may occur with or without agoraphobia.

[0014] “Phobias” includes agoraphobia, specific phobias and social phobias. “Agoraphobia” is characterized by an anxiety about being in places or situations from which escape might be difficult or embarrassing or in which help may not be available in the event of a panic attack. Agoraphobia may occur without history of a panic attack. A “specific phobia” is characterized by clinically significant anxiety provoked by a feared object or situation. Specific phobias include the following subtypes: animal type, cued by animals or insects; natural environment type, cued by objects in the natural environment, for example storms, heights or water; blood-injection-injury type, cued by the sight of blood or an injury or by seeing or receiving an injection or other invasive medical procedure; situational type, cued by a specific situation such as public transportation, tunnels, bridges, elevators, flying, driving or enclosed spaces; and other type where fear is cued by other stimuli. Specific phobias may also be referred to as simple phobias. A “social phobia” is characterized by clinically significant anxiety provoked by exposure to certain types of social or performance circumstances. Social phobia may also be referred to as social anxiety disorder.

[0015] Other anxiety disorders encompassed within the term “anxiety” include anxiety disorders induced by alcohol, amphetamines, caffeine, cannabis, cocaine, hallucinogens, inhalants, phencyclidine, sedatives, hypnotics, anxiolytics and other substances, and adjustment disorders with anxiety or with mixed anxiety and depression.

[0016] Anxiety may be present with or without other disorders such as depression in mixed anxiety and depressive disorders. The compositions of the present invention are therefore useful in the treatment of anxiety with or without accompanying depression.

[0017] The compositions of the present invention that contain a D4 receptor antagonist and an antidepressant or anxiolytic agent are useful for the treatment of psychosis. As used herein, the term “psychosis” includes all the specific disorders, including types and subtypes, listed in the DSM-IV™ under the category of schizophrenia and other psychotic disorders. These include schizophrenia, for example, of the paranoid, disorganized, catatonic, undifferentiated, or residual type, schizophreniform disorder, schizoaffective disorder, for example, of the bipolar or depressive type, delusional disorder, for example, of the erotomanic, grandiose, jealous, persecutory, somatic, mixed or unspecified type, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, for example, of the type with delusions or of the type with hallucinations, substance-induced psychotic disorder, for example, of the type with delusions or of the type with hallucinations, and psychotic disorder not otherwise specified. The meanings attributed to the different types and subtypes of schizophrenia and other psychotic disorders are as stated in the DSM-IV™. (See Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition, (DSM-IV™), American Psychiatric Association, 1994, p. 273-315).

[0018] Psychosis is characterized by major alterations in mental function, severe disturbances in cognitive and perceptual processes (e.g., hallucinations, delusions), inability to distinguish reality from fantasy, impaired reality testing and disturbances of feeling and behavior. Psychoses may be acute or chronic and functional or organic. They can occur in children, adolescents, adults and the elderly. (See Ayd, Jr., Frank J., Lexicon of Psychiatry, Neurology and the Neurosciences , Williams & Wilkins, Baltimore, 1995, p. 543).

[0019] Psychotic disorders are generally treated using miscellaneous antipsychotic agents, including Clorazil™, Haldol®, Loxitane®, Moban®, Navane®, Orap®, Risperdal®, Seoquel™ and Zyprex, and phenothiazines and combinations. (See Physicians' Desk Reference (PDR®), 53 ^rd Edition, Medical Economics Company, Inc., 1999, p. 215).

[0020] The compositions of the present invention are especially useful for the treatment of depression, anxiety or psychosis, where the use of an antidepressant, anxiolytic agent or antipsychotic agent, respectively, is generally prescribed. By the use of a combination of a D4 receptor antagonist and an antidepressant or anxiolytic agent in accordance with the present invention, it is possible to treat depression and/or anxiety and/or psychosis in patients for whom conventional antidepressant, antianxiety or antipsychotic therapy might not be wholly successful or where dependence upon the antidepressant or antianxiety therapy is prevalent.

[0021] Examples of classes of antidepressant agents that may be used in the present invention include norepinephrine reuptake inhibitors, serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, α-adrenoreceptor antagonists, dopamine reuptake inhibitors, NK1 receptor antagonists, 5-HT _1A/1D receptor agonists or antagonists and atypical antidepressants.

[0022] Another class of antidepressant agents that may be used in the present invention are noradrenergic and specific serotonergic antidepressants (NaSSAs). An example of a NaSSA is mirtazapine.

[0023] Examples of norepinephrine reuptake inhibitors that may be used in the present invention include tertiary amine tricyclics and secondary amine tricyclics. Examples of tertiary amine tricyclics include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine, and pharmaceutically acceptable salts thereof. Examples of secondary amine tricyclics include: amoxapine, desipramine, maprotiline, nortriptyline and protriptyline, and pharmaceutically acceptable salts thereof.

[0024] Another norepinephrine reuptake inhibitor that may be used in the present invention is reboxetine.

[0025] Examples of selective serotonin reuptake inhibitors that may be used in the present invention include: fluoxetine, fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptable salts thereof.

[0026] Examples of monoamine oxidase inhibitors that may be used in the present invention include: isocarboxazid, phenelzine, tranylcypromine and selegiline, and pharmaceutically acceptable salts thereof.

[0027] Examples of reversible inhibitors of monoamine oxidase that may be used in the present invention include: moclobemide, and pharmaceutically acceptable salts thereof.

[0028] Examples of serotonin and noradrenaline reuptake inhibitors that may be used in the present invention include: venlafaxine, and pharmaceutically acceptable salts thereof.

[0029] Examples of CRF antagonists that may be used in the present invention include those compounds described in International Patent Application Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677.

[0030] Examples of dopamine reuptake inhibitors that may be used in the present invention include: methylphenidate, destroamphetamine, bupropion, pemoline, amphetamine, methamphetamine and Adderall®, and pharmaceutically acceptable salts thereof.

[0031] Examples of NK1 receptor antagonists that may be used in the methods and pharmaceutical compositions of this invention include the following compounds, and their pharmaceutically acceptable salts, the activity and synthesis of which is referred to in U.S. Pat. No. 2,114,848, issued Oct. 7, 1998 and International Patent Application No. WO 93/00331, published Jan. 7, 1993, and U.S. Pat. No. 5,744,480, issued Apr. 28, 1998, U.S. patent application Ser. No. 09/007,268, filed Jan. 14, 1998 and U.S. patent application Ser. No. 09/293,374, filed Apr. 16, 1999, all of which are incorporated herein by reference in their entirety:

[0032] (2S,3S)-3-(5-tert-butyl-2-methoxybenzyl)amino-2-(3-trifluoro methoxyphenyl)piperidine;

[0033] (2S,3S)-3-(2-isopropoxy-5-trifluoromethoxybenzyl)amino-2-phe nyl-piperidine;

[0034] (2S,3S)-3-(2-ethoxy-5-trifluoromethoxybenzyl)amino-2-phenyl- piperidine;

[0035] (2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)-amino-2-pheny lpiperidine;

[0036] (2S,3S)-3(-5-tert-butyl-2-trifluoromethoxybenzyl)amino-2-phe nylpiperidine;

[0037] 2-(diphenylmethyl)-N-(2-methoxy-5-trifluoromethoxy-phenyl)me thyl-1-azabicyclo[2.2.2]octan-3-amine;

[0038] (2S,3S)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)-benzyl]amino-2 -phenylpiperidine;

[0039] (2S,3S)-3-(5-tert-butyl-2-trifluoromethoxybenzyl)amino-2-phe nylpiperidine;

[0040] (2S,3S)-3-(2-isopropoxy-5-trifluoromethoxybenzyl)amino-2-phe nylpiperidine;

[0041] (2S,3S)-3-(2-difluoromethoxy-5-trifluoromethoxybenzyl)-amino -2-phenylpiperidine;

[0042] (2S,3S)-2-phenyl-3-[2-(2,2,2-trifluoroethoxybenzyl)-aminopip eridine; and

[0043] (2S,3S)-2-phenyl-3-(2-trifluoromethoxybenzyl)]aminopiperidin e.

[0044] Other examples of NK1 receptor antagonists that may be used in the methods and pharmaceutical compositions of this invention include compounds of the formula A, and their pharmaceutically acceptable salts, the activity and synthesis of which is referred to in U.S. Provisional Patent Application No. 60/195,922, filed Apr. 10, 2000 and U.S. Provisional Patent Application No. 60/212,922, filed Jun. 20, 2000, all of which are incorporated herein by reference in their entirety: 1

[0045] wherein Q is C═NH, C═CH ₂ , C═S, C═O, SO or SO ₂ ;

[0046] A is CH, CH ₂ , C(C ₁ -C ₆ )alkyl, CH(C ₁ -C ₆ )alkyl, C(CF ₃ ) or CH(CF ₃ ), with the proviso that when B is present, A must be either CH, C(C ₁ -C ₆ )alkyl or C(CF ₃ );

[0047] B is absent or is methylene or ethylene;

[0048] each of Y and Z is N or CH, with the proviso that Y and Z can not both be N;

[0049] G is NH(CH ₂ ) _q , S(CH ₂ ) _q or O(CH ₂ ) _q , wherein q is zero or one;

[0050] W is a one carbon linking group (i.e., methylene) or a saturated or unsaturated two or three carbon linking group, wherein each of the foregoing W groups can optionally be substituted with one substituent R ⁷ or two substituents R ⁷ and R ⁶ , or W is a one carbon linking group that forms, together with a 2, 3, 4 or 5 carbon chain, a 3, 4, 5 or 6 membered spiro ring, respectively;

[0051] or W is a saturated two carbon chain linking group that forms, together with a separate 1, 2 or 3 carbon chain, a fused 3, 4 or 5 membered ring, respectively;

[0052] or W is a saturated two carbon chain linking group, wherein one of the two carbons in the chain forms, together with a separate 2, 3, 4 or 5 carbon chain, a 3, 4, 5 or 6 membered spiro ring, respectively;

[0053] p is zero, one or two;

[0054] R ³ is selected from hydrogen, COR ⁹ , CO ₂ R ⁹ , optionally substituted phenyl, optionally substituted heterocyclic rings, and optionally substituted (C ₁ -C ₈ )alkyl wherein one of the CH ₂ groups of said (C ₁ -C ₈ ) alkyl may optionally be replaced with a sulfur, oxygen or carbonyl group and wherein said (C ₁ -C ₈ )alkyl can optionally be substituted with from one to three substituents, preferably with zero substituents or one substituent, independently selected from hydroxy, oxo, phenyl-(C ₁ -C ₃ )alkoxy, phenyl, cyano, halo, optionally substituted heterocyclic rings, NR ⁹ COR ¹⁰ , NR ⁹ CO ₂ R ¹⁰ , CONR ⁹ R ¹⁰ , COR ⁹ , CO ₂ R ⁹ , NR ⁹ R ¹⁰ , and (C ₁ -C ₆ )alkoxy optionally substituted with from one to seven fluorine atoms, preferably with from zero to three fluorine atoms;

[0055] and wherein the heterocyclic rings of R ³ and the heterocyclic ring substituents on the alkyl groups of R ³ are selected, independently, from 3 to 7 membered saturated or unsaturated monocyclic rings containing from 1 to 4 ring heteroatoms, and 8 to 12 membered saturated or unsaturated bicyclic rings containing from 1 to 4 ring heteroatoms, wherein said heteroatoms are selected, independently, from oxygen, nitrogen and sulfur, with the proviso that there can not be two adjacent ring oxygen atoms or two adjacent ring sulfur atoms in either the monocyclic or bicyclic heterocyclic rings, and with the proviso that heterocyclic rings formed from NR ⁹ R ¹⁰ or CONR ⁹ R ¹⁰ must contain at least one nitrogen atom;

[0056] and wherein the heterocyclic rings of R ³ and the heterocyclic ring substituents on the alkyl groups of R ³ can optionally be substituted with one or more substituents, preferably with zero, one or two substituents, independently selected from oxo, hydroxy, thioxo, halo, cyano, phenyl, (CH ₂ ) _m NR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , (CH ₂ ) _m OR ⁹ , wherein m is zero, one or two, and (C ₁ -C ₆ )alkyl optionally substituted with one or more substituents, preferably with from zero to two substituents, independently selected from halo, CF ₃ , methoxy and phenyl;

[0057] and wherein the phenyl groups of R ³ and the phenyl substituents in the alkyl groups of R ³ can optionally be substituted with one or more substitutents, preferably with from zero to two substituents, independently selected from the group consisting of halo, cyano, nitro, CF ₃ , (CH ₂ ) _m NR ⁹ R ¹⁰ , wherein m is zero, one or two, NR ⁹ COR ¹⁰ , NR ⁹ CO ₂ R ¹⁰ , CONR ⁹ R ¹⁰ , CO ₂ NR ⁹ R ¹⁰ , COR ⁹ , CO ₂ R ⁹ , (C ₁ -C ₆ )alkyl optionally substituted with from one to seven fluorine atoms, preferably with from zero to three fluorine atoms, (C ₁ -C ₆ )alkoxy optionally substituted with from one to seven fluorine atoms, preferably with from zero to three fluorine atoms, and (C ₂ -C ₆ )alkenyl optionally substituted with from one to seven fluorine atoms, preferably with from zero to three fluorine atoms;

[0058] each of R ¹ , R ² , R ¹¹ , R ¹² and R ¹³ are selected, independently, from hydrogen and (C ₁ -C ₆ )alkyl optionally substituted with one or more substituents, preferably with zero, one or two substituents, that are selected, independently, from hydroxy, oxo, (C ₁ -C ₆ )alkoxy and cyano;

[0059] or R ¹ and R ² , together with the carbon atoms to which they are attached, or R ² and R ³ , together with the carbon and nitrogen to which they are attached, respectively, form a 5 or 6 membered saturated heterocyclic ring containing one or two heteroatoms that are selected, independently, from nitrogen, oxygen and sulfur, with the proviso that said ring can not contain two adjacent oxygen atoms or two adjacent sulfur atoms; or R ¹ and R ² , together with the carbons to which they are attached, form a 5 or 6 membered, saturated or unsaturated carbocyclic ring, and wherein said heterocyclic and carbocyclic rings formed by R ¹ and R ² or by R ² and R ³ can be substituted with one or more substituents, preferably with zero substituents or one substituent, independently selected from halo, oxo, NR ⁹ R ¹⁰ , (C ₁ -C ₆ )alkyl optionally substituted with from one to seven fluorine atoms, preferably with from zero to three fluorine atoms, and (C ₁ -C ₆ )alkoxy optionally substituted with from one to seven fluorine atoms, preferably with from zero to three fluorine atoms;

[0060] or R ¹² and R ¹³ , together with the carbon atoms to which they are attached, form a 5 or 6 membered saturated heterocyclic ring containing one or two heteroatoms that are selected, independently, from nitrogen, oxygen and sulfur, with the proviso that said ring can not contain two adjacent oxygen atoms or two adjacent sulfur atoms, or R ¹² and R ¹³ , together with the carbons to which they are attached, form a 5 or 6 membered, saturated or unsaturated carbocyclic ring, and wherein said heterocyclic and carbocyclic rings formed by R ¹² and R ¹³ can be substituted with one or more substituents, preferably with zero substituents or one substituent, independently selected from NR ⁹ R ¹⁰ , halo, phenyl-S—, phenyl-SO—, phenyl-SO ₂ —, oxo, (C ₁ -C ₆ )alkoxy optionally substituted with from one to seven fluorine atoms, preferably with from zero to three fluorine atoms, and (C ₁ -C ₆ )alkyl optionally substituted with from one to seven fluorine atoms, preferably with from zero to three fluorine atoms:

[0061] with the proviso that no more than one of R ¹ and R ² , R ² and R ³ , and R ¹² and R ¹³ can form a ring;

[0062] R ⁴ is selected from phenyl, 2-, 3- or 4-pyridyl, 2- or 3-thienyl, and pyrimidyl, wherein R ⁴ can be optionally substituted with one or more substituents, preferably with zero or one substituent, selected, independently, from halo, (C ₁ -C ₆ )alkyl optionally substituted with from one to seven fluorine atoms, preferably with from zero to three fluorine atoms, (C ₁ -C ₆ )alkoxy optionally substituted with from one to seven fluorine atoms, preferably with from zero to three fluorine atoms, and (C ₂ -C ₆ ) alkenyl optionally substituted with from one to seven fluorine atoms, preferably with from zero to three fluorine atoms;

[0063] R ⁵ and R ⁸ are selected, independently, from hydrogen, —SO(C ₁ -C ₆ )alkyl, —SO ₂ —(C ₁ -C ₆ )alkyl, —SO-aryl, —SO ₂ -aryl, CF ₃ , halo, phenyl, phenyl-(C ₁ -C ₂ )alkyl, hydroxy, aryloxy, heteroaryloxy, pyridyl, tetrazolyl, oxazolyl, thiazolyl, (C ₁ -C ₆ )alkoxy optionally substituted with from one to seven fluorine atoms, preferably with from zero to three fluorine atoms, (C ₁ -C ₆ )alkyl optionally substituted with from one to seven fluorine atoms, preferably with from zero to three fluorine atoms, and (C ₁ -C ₆ )alkyl substituted with one or more substituents, preferably with from zero to two substituents selected, independently, from hydroxy, oxo, (C ₁ -C ₆ )alkoxy, phenyl-(C ₁ -C ₃ )alkoxy, phenyl, cyano, chloro, bromo, iodo, NR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ CO ₂ R ¹⁰ , CONR ⁹ R ¹⁰ , COR ⁹ and CO ₂ R ⁹ ;

[0064] R ⁶ and R ⁷ are selected, independently, from —SO(C ₁ -C ₆ )alkyl, —SO ₂ —(C ₁ -C ₆ )alkyl, —SO-aryl, —SO ₂ -aryl, CF ₃ , halo, phenyl, phenyl-(C ₁ -C ₂ )alkyl, hydroxy, aryloxy, heteroaryloxy, pyridyl, tetrazolyl, oxazolyl, thiazolyl, (C ₁ -C ₆ )alkoxy optionally substituted with from one to seven fluorine atoms, preferably with from zero to three fluorine atoms, (C ₁ -C ₆ )alkyl optionally substituted with from one to seven fluorine atoms, preferably with from zero to three fluorine atoms, and (C ₁ -C ₆ )alkyl substituted with one or more substituents, preferably with from zero to two substituents selected, independently, from hydroxy, oxo, (C ₁ -C ₆ )alkoxy, phenyl-(C ₁ -C ₃ )alkoxy, phenyl, cyano, chloro, bromo, iodo, NR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , NR ⁹ CO ₂ R ¹⁰ , CONR ⁹ R ¹⁰ , COR ⁹ and CO ₂ R ⁹ ;

[0065] each R ⁹ and each R ¹⁰ is selected, independently, from hydrogen, (C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkyl, phenyl and CF ₃ ;

[0066] or R ⁹ and R ¹⁰ , when R ³ is NR ⁹ R ¹⁰ or CONR ⁹ R ¹⁰ , can form, together with the nitrogen to which they are attached, an optionally substituted heterocyclic ring that contains at least one nitrogen atom;

[0067] and wherein the phenyl groups in the definition of R ⁵ , R ⁶ , R ⁷ and R ⁸ and the phenyl moiety of phenyl (C ₁ -C ₂ )alkyl in the definition of R ⁵ , R ⁶ , R ⁷ and R ⁸ can optionally be substituted with one or more substituents, preferably with from zero to two substituents, that are selected, independently, from halo, hydroxy, (C ₁ -C ₆ )alkoxy optionally substituted with from one to seven fluorine atoms, preferably with from zero to three fluorine atoms, and (C ₁ -C ₆ )alkyl optionally substituted with from one to seven fluorine atoms, preferably with from zero to three fluorine atoms;

[0068] with the proviso that: (a) R ⁸ can not be halo, hydroxy, cyano, aryloxy, heteroaryloxy, substituted or unsubstituted (C ₁ -C ₆ )alkoxy or methyl substituted with from 1-3 fluorine atoms; and (b) when Q is C═O or C═S, and Y and Z are both carbon, and W is a methylene, ethylene or propylene group that is optionally substituted with (C ₁ -C ₆ )alkyl or fluoro substituted (C ₁ -C ₆ )alkyl, and all of R ¹ , R ² , R ¹¹ , R ¹² and R ¹³ are hydrogen, and R ⁵ , R ⁶ , R ⁷ , and R ⁸ are selected from hydrogen, halo, (C ₁ -C ₆ ) alkyl optionally substituted with from 1 to 7 fluorine atoms, (C ₁ -C ₆ ) alkoxy optionally substituted with from 1 to 7 fluorine atoms, then R ³ can not be hydrogen.

[0069] Examples of compounds of the formula A that are preferred for use in the methods and pharmaceutical compositions of this invention are the following compounds and their pharmaceutically acceptable salts:

[0070] 7-[(1-Dimethylaminoacetyl-2-phenyl-piperidin-3-ylamino)-meth yl]-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one;

[0071] 6-Methoxy-1-methyl-7-{[2-phenyl-1-(pyridin-2-yl-acetyl)-pipe ridin-3-ylamino]-methyl}-3,4-dihydro-1H-quinolin-2-one;

[0072] 6-Methoxy-1-methyl-7-{[2-phenyl-1-(pyridin-3-yl-acetyl)-pipe ridin-3-ylamino]-methyl}-3,4-dihydro-1H-quinolin-2-one;

[0073] 6-Methoxy-1-methyl-7-{[2-phenyl-1-(pyridin-4-yl-acetyl)-pipe ridin-3-ylamino]-methyl}-3,4-dihydro-1H-quinolin-2-one;

[0074] 6-Cyclopropoxy-1-methyl-7-[(2-phenyl-piperidin-3-ylamino)-me thyl]-3,4-dihydro-1H-quinolin-2-one;

[0075] (5-Chloro-2-methoxy-benzyl)-(2-phenyl-octahydro-cyclopenta[b ]pyrrol-3-yl)-amine;

[0076] 6-Methoxy-1-methyl-7-[(1-[1,2,4]oxadiazol-3-ylmethyl-2-pheny l-piperidin-3-ylamino)-methyl]-3,4-dihydro-1H-quinolin-2-one ;

[0077] 7-{[1-(Imidazol-1-yl-acetyl)-2-phenyl-piperidin-3-ylamino]-m ethyl}-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one;

[0078] 1-[3-(2-Methoxy-5-trifluoromethoxy-benzylamino)-2-phenyl-pip eridin-1-yl]-2-pyridin-2-yl-ethanone;

[0079] 1-[3-(2-Methoxy-5-trifluoromethoxy-benzylamino)-2-phenyl-pip eridin-1-yl]-2-pyridin-3-yl-ethanone;

[0080] 1-[3-(2-Methoxy-5-trifluoromethoxy-benzylamino)-2-phenyl-pip eridin-1-yl]-2-pyridin-4-yl-ethanone;

[0081] 2-Imidazol-1-yl-1-[3-(2-methoxy-5-trifluoromethoxy-benzylami no)-2-phenyl-piperidin-1-yl]-ethanone;

[0082] 2-Dimethylamino-1-[3-(2-methoxy-5-trifluoromethoxy-benzylami no)-2-phenyl-piperidin-1-yl]-ethanone

[0083] 3-(2-Benzyloxy-5-trifluoromethoxy-phenyl)-6-phenyl-1-oxa-7-a za-spiro[4.5]decane;

[0084] 1-[3-(2-Methoxy-5-trifluoromethoxy-benzylamino)-2-phenyl-pip eridin-1-yl]-2-pyrrolidin-1-yl-ethanone;

[0085] (2-Methoxy-5-trifluoromethoxy-benzyl)-(1-[1,2,4]oxadiazol-3- ylmethyl-2-phenyl-piperidin-3-yl)-amine;

[0086] 7-{[2-(4-Fluoro-phenyl)-piperidin-3-ylamino]-methyl}-6-metho xy-1-methyl-3,4-dihydro-1H-quinolin-2-one;

[0087] [1-(2-Imidazol-1-yl-ethyl)-2-phenyl-piperidin-3-yl]-(2-metho xy-5-trifluoromethoxy-benzyl)-amine;

[0088] 7-{[1-(2-Dimethylamino-ethyl)-2-phenyl-piperidin-3-ylamino]- methyl}-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one;

[0089] (5-Chloro-2-ethoxy-pyridin-3-ylmethyl)-(2-phenyl-piperidin-3 -yl)-amine;

[0090] (5-Chloro-2-methoxy-pyridin-3-ylmethyl)-(2-phenyl-piperidin- 3-yl)-amine;

[0091] Dibenzofuran-2-ylmethyl-(2-phenyl-piperidin-3-yl)-amine;

[0092] [3-(Indan-2-yloxy)-4-methoxy-benzyl]-(2-phenyl-piperidin-3-y l)-amine;

[0093] 6-[(2-Phenyl-piperidin-3-ylamino)-methyl]-chroman-4-one;

[0094] (5-Methyl-benzo[b]thiophen-3-ylmethyl)-(2-phenyl-piperidin-3 -yl)-amine;

[0095] (2,2-Dimethyl-chroman-6-ylmethyl)-(2-phenyl-piperidin-3-yl)- amine;

[0096] (1H-Benzoimidazol-5-ylmethyl)-(2-phenyl-piperidin-3-yl)-amin e;

[0097] 1-{2-[(2-Phenyl-piperidin-3-ylamino)-methyl]-phenyl}-pyrroli din-2-one;

[0098] (2-Phenyl-piperidin-3-yl)-[3-(pyridin-2-yloxy)-benzyl]-amine ;

[0099] [3-(4-Methoxy-phenoxy)-benzyl]-(2-phenyl-piperidin-3-yl)-ami ne;

[0100] (4-Phenoxy-benzyl)-(2-phenyl-piperidin-3-yl)-amine;

[0101] (2-Phenyl-piperidin-3-yl)-thiophen-2-ylmethyl-amine;

[0102] Furan-2-ylmethyl-(2-phenyl-piperidin-3-yl)-amine;

[0103] (5-Methyl-furan-2-ylmethyl)-(2-phenyl-piperidin-3-yl)-amine;

[0104] (3-Methyl-thiophen-2-ylmethyl)-(2-phenyl-piperidin-3-yl)-ami ne;

[0105] (2-Phenyl-piperidin-3-yl)-thiophen-3-ylmethyl-amine;

[0106] (3-Methyl-benzo[b]thiophen-2-ylmethyl)-(2-phenyl-piperidin-3 -yl)-amine;

[0107] Benzofuran-2-ylmethyl-(2-phenyl-piperidin-3-yl)-amine;

[0108] (5-Ethyl-furan-2-ylmethyl)-(2-phenyl-piperidin-3-yl)-amine;

[0109] (5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-ylmethyl)-(2-phenyl -piperidin-3-yl)-amine;

[0110] 6-Methoxy-7-{[1-(2-methoxy-ethyl)-2-phenyl-piperidin-3-ylami no]-methyl}-1-methyl-3,4-dihydro-1H-quinolin-2-one;

[0111] (5-Methyl-3-phenyl-isoxazol-4-ylmethyl)-(2-phenyl-piperidin- 3-yl)-amine;

[0112] (3-Phenoxy-benzyl)-(2-phenyl-piperidin-3-yl)-amine;

[0113] Furan-3-ylmethyl-(2-phenyl-piperidin-3-yl)-amine;

[0114] (3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl)-(2-phenyl-pipe ridin-3-yl)-amine;

[0115] (5,7-Dimethoxy-1H-indol-4-ylmethyl)-(2-phenyl-piperidin-3-yl )-amine;

[0116] (5-Methoxy-1H-indol-3-ylmethyl)-(2-phenyl-piperidin-3-yl)-am ine;

[0117] (4-Oxy-quinoxalin-2-ylmethyl)-(2-phenyl-piperidin-3-yl)-amin e;

[0118] (2-Phenyl-piperidin-3-yl)-quinoxalin-2-ylmethyl-amine;

[0119] 7-{[1-(2,3-Dihydroxy-propyl)-2-phenyl-piperidin-3-ylamino]-m ethyl}-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one;

[0120] (2-Methoxy-5-trifluoromethoxy-benzyl)-[2-phenyl-1-(2-pyrroli din-1-yl-ethyl)-piperidin-3-yl]-amine;

[0121] 6-Ethoxy-1-methyl-7-[(2-phenyl-piperidin-3-ylamino)-methyl]- 3,4-dihydro-1H-quinolin-2-one;

[0122] [1-(2-Dimethylamino-ethyl)-2-phenyl-piperidin-3-yl]-(2-metho xy-5-trifluoromethoxy-benzyl)-amine;

[0123] 3-(2-Cyclopropoxy-5-trifluoromethoxy-phenyl)-6-phenyl-1-oxa- 7-aza-spiro[4.5]decane;

[0124] [1-(2-Methoxy-ethyl)-2-phenyl-piperidin-3-yl]-(2-methoxy-5-t rifluoromethoxy-benzyl)-amine;

[0125] 6-Hydroxy-1-methyl-7-[(2-phenyl-piperidin-3-ylamino)-methyl] -3,4-dihydro-1H-quinolin-2-one;

[0126] 6-Methoxy-1-methyl-7-[(2-phenyl-octahydro-cyclopenta[b]pyrro l-3-ylamino)-methyl]-3,4-dihydro-1H-quinolin-2-one;

[0127] 7-{[2-(4-Fluoro-phenyl)-piperidin-3-ylamino]-methyl}-6-metho xy-3,4-dihydro-1H-quinolin-2-one;

[0128] 6-Methoxy-1-methyl-7-(6-phenyl-1-oxa-7-aza-spiro[4.5]dec-3-y l)-3,4-dihydro-1H-quinolin-2-one;

[0129] 6-Methoxy-1,3,3-trimethyl-5-[(2-phenyl-octahydro-cyclopenta[ b]pyrrol-3-ylamino)-methyl]-1,3-dihydro-indol-2-one;

[0130] [3-Chloro-2-(4-fluoro-phenoxy)-pyridin-4-ylmethyl]-(2-phenyl -piperidin-3-yl)-amine;

[0131] 6-Ethoxy-1,3,3-trimethyl-5-[(2-phenyl-piperidin-3-ylamino)-m ethyl]-1,3-dihydro-indol-2-one;

[0132] 6-Ethoxy-1,3,3-trimethyl-5-[(2-phenyl-octahydro-cyclopenta[b ]pyrrol-3-ylamino)-methyl]-1,3-dihydro-indol-2-one;

[0133] 6-Isopropoxy-1,3,3-trimethyl-5-[(2-phenyl-piperidin-3-ylamin o)-methyl]-1,3-dihydro-indol-2-one;

[0134] 6-Isopropoxy-1,3,3-trimethyl-5-[(2-phenyl-octahydro-cyclopen ta[b]pyrrol-3-ylamino)-methyl]-1,3-dihydro-indol-2-one;

[0135] 6-Ethoxy-1,3,3-trimethyl-5-[(2-phenyl-octahydro-cyclopenta[b ]pyrrol-3-ylamino)-methyl]-1,3-dihydro-indol-2-one;

[0136] 6-Isopropoxy-1,3,3-trimethyl-5-[(2-phenyl-octahydro-cyclopen ta[b]pyrrol-3-ylamino)-methyl]-1,3-dihydro-indol-2-one;

[0137] 7-Isopropoxy-1-methyl-6-[(2-phenyl-piperidin-3-ylamino)-meth yl]-3,4-dihydro-1H-quinolin-2-one;

[0138] 6-Methoxy-1-methyl-7-[(6-methyl-2-phenyl-piperidin-3-ylamino )-methyl]-3,4-dihydro-1H-quinolin-2-one;

[0139] 6-Methoxy-1,3,3-trimethyl-7-[(2-phenyl-piperidin-3-ylamino)- methyl]-3,4-dihydro-1H-quinolin-2-one;

[0140] 6-Methoxy-1,3-dimethyl-7-[(2-phenyl-piperidin-3-ylamino)-met hyl]-3,4-dihydro-1H-quinolin-2-one;

[0141] 6-Methoxy-1,3-dimethyl-5-[(2-phenyl-piperidin-3-ylamino)-met hyl]-1,3-dihydro-indol-2-one;

[0142] 6-Methoxy-1-methyl-5-[(2-phenyl-piperidin-3-ylamino)-methyl] -1,3-dihydro-indol-2-one;

[0143] 5-[(1-Isopropyl-2-phenyl-piperidin-3-ylamino)-methyl]-6-meth oxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one;

[0144] 6-Methoxy-1-methyl-7-[(2-phenyl-1-propyl-piperidin-3-ylamino )-methyl]-3,4-dihydro-1H-quinolin-2-one;

[0145] 6-Methoxy-1-methyl-7-{[1-(5-methyl-3H-imidazol-4-ylmethyl)-2 -phenyl-piperidin-3-ylamino]-methyl}-3,4-dihydro-1H-quinolin -2-one;

[0146] 7-{[1-(1H-Imidazol-4-ylmethyl)-2-phenyl-piperidin-3-ylamino] -methyl}-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one;

[0147] 7-[(1-Isopropyl-2-phenyl-piperidin-3-ylamino)-methyl]-6-meth oxy-1-methyl-3,4-dihydro-1H-quinolin-2-one;

[0148] 6-Methoxy-1,3-dimethyl-7-[(1-methyl-2-phenyl-piperidin-3-yla mino)-methyl]-3,4-dihydro-1H-quinolin-2-one;

[0149] 5-[(1-Isopropyl-2-phenyl-piperidin-3-ylamino)-methyl]-6-meth oxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one

[0150] 6-Methoxy-1-methyl-7-{[1-(5-oxo-2,5-dihydro-1H-[1,2,4]triazo l-3-ylmethyl)-2-phenyl-piperidin-3-ylamino]-methyl}-3,4-dihy dro-1H-quinolin-2-one;

[0151] 6-Methoxy-7-[(2-phenyl-piperidin-3-ylamino)-methyl]-3,4-dihy dro-1H-quinolin-2-one;

[0152] 1-Ethyl-6-methoxy-7-[(2-phenyl-piperidin-3-ylamino)-methyl]- 3,4-dihydro-1H-quinolin-2-one;

[0153] 1-Methanesulfonyl-6-methoxy-7-[(2-phenyl-piperidin-3-ylamino )-methyl]-3,4-dihydro-1H-quinolin-2-one;

[0154] 6-Methoxy-1,4,4-trimethyl-7-[(2-phenyl-piperidin-3-ylamino)- methyl]-3,4-dihydro-1H-quinolin-2-one;

[0155] 8-Fluoro-6-methoxy-1,4,4-trimethyl-7-[(2-phenyl-piperidin-3- ylamino)-methyl]-3,4-dihydro-1H-quinolin-2-one;

[0156] 6-Methoxy-1-methyl-7-[(2-phenyl-piperidin-3-ylamino)-methyl] -3,4-dihydro-1H-quinolin-2-one;

[0157] 6-Methoxy-1,4-dimethyl-7-[(2-phenyl-piperidin-3-ylamino)-met hyl]-3,4-dihydro-1H-quinolin-2-one;

[0158] 6-Methoxy-2-methyl-7-[(2-phenyl-piperidin-3-ylamino)-methyl] -3,4-dihydro-2H-isoquinolin-1-one;

[0159] 6-Methoxy-3-methyl-5-[(2-phenyl-piperidin-3-ylamino)-methyl] -1,1a,3,7b-tetrahydro-3-aza-cyclopropa[a]naphthalen-2-one;

[0160] 6-Methoxy-1-methyl-,3,3-cyclopropyl-5-[(2-phenyl-piperidin-3 -ylamino)-methyl]-1,3-dihydro-indol-2-one;

[0161] 5-Methoxy-1-methyl-,3,3-cyclopropyl-6-[(2-phenyl-piperidin-3 -ylamino)-methyl]-1,3-dihydro-indol-2-one;

[0162] 6-Methoxy-1-methyl-(6-phenyl-1,7-diaza-spiro[4.5]dec-3-yl)-3 ,4-dihydro-1H-quinolin-2-one;

[0163] 6-Methoxy-1-methyl-7-phenyl-1,7-diaza-spiro[4.5]dec-3-yl)-3, 4-dihydro-1H-quinolin-2-one;

[0164] 6-Methoxy-3-methyl-5-[(1-phenyl-8-aza-bicyclo[3.2.1]oct-2-yl amino)-methyl]-1,1a,3,7b-tetrahydro-3-aza-cyclopropa[a]napht halen-2-one;

[0165] (6-Methoxy-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2-thiobenzo [c[1,2]thiazin-7-yl-methyl)-(2-phenyl-piperidin-3-yl)-amine;

[0166] 6-Methoxy-3-methyl-5-[(6-methyl-2-phenyl-piperidin-3-ylamino )-methyl]-1,1a,3,7b-tetrahydro-3-aza-cyclopropa[a]naphthalen -2-one;

[0167] 6-Methoxy-1-methyl-7-(6-phenyl-1,7-diaza-spiro[4.5]dec-3-yl) -3,4-dihydro-1H-quinolin-2-one;

[0168] 6-Methoxy-1,3,3-trimethyl-5-[(2-phenyl-piperidin-3-ylamino)- methyl]-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one;

[0169] 5-Methoxy-1,3,3-trimethyl-6-[(2-phenyl-piperidin-3-ylamino)- methyl]-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one;

[0170] 6-Methoxy-1-methyl-7-[(2-phenyl-piperidin-3-ylamino)-methyl] -3,4-dihydro-1H-[1,5]naphthyridin-2-one;

[0171] 7-[(6-Ethyl-2-phenyl-piperidin-3-ylamino)-methyl]-6-methoxy- 1-methyl-3,4-dihydro-1H-quinolin-2-one;

[0172] 5-[(6-Ethyl-2-phenyl-piperidin-3-ylamino)-methyl]-6-methoxy- 1,3,3-trimethyl-1,3,-dihydro-indol-2-one;

[0173] 6-Methoxy-1,3,3-trimethyl-5-[(2-phenyl-piperidin-3-ylamino)- methyl]-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one;

[0174] 5-Methoxy-1,3,3-trimethyl-6-[(2-phenyl-piperidin-3-ylamino)- methyl]-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one;

[0175] 6-Methoxy-1-methyl-7-[(2-phenyl-piperidin-3-ylamino)-methyl] -3,4-dihydro-1H-[1,5]naphthyridin-2-one;

[0176] 6-Methoxy-3-methyl-5-[(6-methyl-2-phenyl-piperidin-3-ylamino )-methyl]-1,1a,3,7b-tetrahydro-3-aza-cyclopropa[a]naphthalen -2-one; and

[0177] 6-Methoxy-1-methyl-7-(6-phenyl-1,7-diaza-spiro[4.5]dec-3-yl) -3,4-dihydro-1H-quinolin-2-one.

[0178] Other examples of NK1 receptor antagonists that may be used in the methods and pharmaceutical compositions of this invention include the compounds disclosed in U.S. Provisional Patent Application No. 60/236375, filed Sep. 28, 2000, and their pharmaceutically acceptable salts, the activity and synthesis of which is referred to in the aforementioned patent application, which application is incorporated herein by reference in its entirety.

[0179] Examples of atypical antidepressants that may be used in the present invention include: bupropion, lithium, nefazodone, trazodone and viloxazine, and pharmaceutically acceptable salts thereof. Another suitable atypical antidepressant is sibutramine.

[0180] Other antidepressants that may be used in the present invention include adinazolam, alaproclate, amineptine, amitriptyline/chlordiazepoxide combination, atipamezole, azamianserin, bazinaprine, befuraline, bifemelane, binodaline, bipenamol, brofaromine bupropion, caroxazone, cericlamine, cianopramine, cimoxatone, citalopram, clemeprol, clovoxamine, dazepinil, deanol, demexiptiline, dibenzepin, dothiepin, droxidopa, enefexine, estazolam, etoperidone, femoxetine, fengabine, fezolamine, fluotracen, idazoxan, indalpine, indeloxazine, iprindole, levoprotiline, litoxetine, lofepramine, medifoxamine, metapramine, metralindole, mianserin, milnacipran, minaprine, mirtazapine, montirelin, nebracetam, nefopam, nialamide, nomifensine, norfluoxetine, orotirelin, oxaflozane, pinazepam, pirlindone, pizotyline, ritanserin, rolipram, sercloremine, setiptiline, sibutramine, sulbutiamine, sulpiride, teniloxazine, thozalinone, thymoliberin, tianeptine, tiflucarbine, tofenacin, tofisopam, toloxatone, tomoxetine, veralipride, viqualine, zimelidine and zometrapine, and pharmaceutically acceptable salts thereof, and St. John's wort herb, or Hypericuin perforatum , or extracts thereof.

[0181] Examples of classes of antianxiety agents that may be used in the present invention include benzodiazepines and 5-HT _IA/1D agonists or antagonists, especially 5-HT _IA partial agonists and 5-HT _1D antagonists, corticotropin releasing factor (CRF) antagonists, serotonin reuptake inhibitors (SRIs) and GABA receptor agonists. In addition to benzodiazepines, other suitable classes of antianxiety agents are nonbenzodiazepine sedative-hypnotic drugs such as zolpidem; mood-stabilizing drugs such as clobazam, gabapentin, lamotrigine, loreclezole, oxcarbamazepine, stiripentol and vigabatrin; and barbiturates.

[0182] Examples of benzodiazepines that may be used in the present invention include: alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam, and pharmaceutically acceptable salts thereof.

[0183] Examples of 5-HT _1A receptor agonists or antagonists that may be used in the present invention include, in particular, the 5-HT _IA receptor partial agonists buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof. An example of a compound with 5-HT _IA receptor antagonist/partial agonist activity is pindolol.

[0184] Examples of CRF antagonists that may be used in the present invention include those compounds described in International Patent Application Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677.

[0185] Another class of antianxiety agents that may be used in the present invention are compounds having muscarinic cholinergic activity. Examples of compounds in this class include m1 muscarinic cholinergic receptor agonists such as those compounds described in European Patent Application Nos. 0 709 093, 0 709 094 and 0 773 021, and International Patent Application No. WO 96/12711.

[0186] Another class of antianxiety agents that may be used in the present invention are compounds acting on ion channels. Examples of compounds in this class include carbamazepine, lamotrigine and valproate, and pharmaceutically acceptable salts thereof.

[0187] Other antidepressants and antianxiety agents that may be used in the present invention include gabapentin, and pharmaceutically acceptable salts thereof.

[0188] Other antidepressants and antianxiety agents that may be used in the methods and pharmaceutical compositions of this invention include compounds of the formula B, which compounds act as 5-HT _1A/1D agonists and antagonists, and their pharmaceutically acceptable salts, the activity and synthesis of which is referred to in U.S. patent application Ser. No. 09/254,999, filed Sep. 8, 1997 and International Patent Application No. WO 98/14433, published Apr. 9, 1998, all of which are incorporated herein by reference in their entirety: 2

[0189] wherein R ¹ is a group of the formula G ¹ , G ² , G ³ , G ⁴ , G ⁵ , G ⁶ or G ⁷ depicted below, 3

[0190] a is zero to eight;

[0191] each R ¹³ is, independently, (C ₁ -C ₄ )alkyl or a (C ₁ -C ₄ )methylene bridge from one of the ring carbons of the piperazine or piperidine ring of G ¹ or G ² , respectively, to the same or another ring carbon or a ring nitrogen of the piperazine or piperidine ring of G ¹ or G ² , respectively, having an available bonding site, or to a ring carbon of R ⁶ having an available bonding site;

[0192] E is oxygen, sulfur, SO or SO ₂ ;

[0193] X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C ₁ -C ₆ )alkyl, hydroxy, trifluoromethyl, (C ₁ -C ₆ )alkoxy, —SO _t (C ₁ -C ₆ )alkyl wherein t is zero, one or two, —CO ₂ R ¹⁰ or —CONR ¹¹ R ¹² ;

[0194] Y is an optionally substituted (C ₁ -C ₄ ) heteroalkyl bridge that, together with the atoms to which it is attached, forms a five to seven membered heterocycle containing two to four heteroatoms selected from the group consisting of 1,3-oxazolidin-4-on-5-yl, 1,3-oxazolidin-2,4-dion-5-yl, 4,5-dihydro-1,2-oxazolidin-3-on-4-yl, 1,3-thiazolidin-4-on-5-yl, 1,3-thiazolidin-2,4-dion-5-yl, 1,3-pyrazolidin-4-on-5-yl, 1,3-imidazolidin-2,4-dion-5-yl, 1,2-pyrazolidin-3-on-4-yl, 1,2-thiazolidin-1,1,3-trion-4-yl, 1,2-thiazolidin-3-on-4-yl, tetrahydro-1,2-oxazin-3-on-4-yl, tetrahydro-1,3-oxazin-4-on-5-yl, tetrahydro-1,3-oxazin-2,4-dion-5-yl, morpholin-3-on-2-yl, morpholin-3,5-dion-2-yl, 2,3-dihydro-1,4-oxazin-3-on-2-yl, tetrahydro-1,3-thiazin-4-on-5-yl, tetrahydro-1,3-thiazin-2,4-dion-5-yl, tetrahydro-1,2-thiazin-3-on-4-yl, thiomorpholin-3-on-2-yl, thiomorpholin-3,5-dion-2-yl, 2,3-dihydro-1,4-thiazin-3-on-2-yl, hexahydro-1,2-diazin-3-on-4-yl, 4,5dihydro-2H-pyridazin-3-on-4-yl, hexahydro-1,3-diazin-4-on-5-yl, hexahydro-1,3-diazin-2,4-dion-5-yl, piperazin-2-on-3-yl, piperazin-2,6-dion-3-yl, tetrahydro-1,3,4-thiadiazin-5-on-6-yl, 5,6-dihydro-1,3,4-thiadiazin-5-on-6-yl, 1,3,4-oxadiazin-5-on-6-yl, 5,6-dihydro-1,2,4-oxadiazin-5-on-6-yl, tetrahydro-1,2,4-oxadiazin-5-on-6-yl, 1,2,4-triazin-5-on-6-yl, tetrahydro-1,2,4-oxadiazin-5-on-6-yl, 5,6-dihydro-1-2,4-oxadiazin-5-on-6-yl, 1,2,4-oxadiazin-3,5-dion-6-yl, 1,2,4-trazin-6-on-5-yl, hexahydro-1,2-oxazepin-3-on-2-yl, hexahydro-1,3-oxazepin-4-on-5-yl, hexahydro-1,4-oxazepin-3-on-2-yl, hexahydro-1,4-oxazepin-3,5-dion-2-yl, hexahydro-1,4-oxazepin-3,5-dion-6-yl, 2,3,5,6-tetrahydro-1-4-oxazepin-5,7-dion-6-yl, hexahydro-1,4-oxazepin-5-on-6-yl, hexahydro-1,3-oxazepin-2,4-dion-5-yl, hexahydro-1,2-thiazepin-3-on-4-yl, hexahydro-1,4-thiazepin-3-on-2-yl, 2,3,4,5-tetrahydro-1,4-thiazepin-3-on-2-yl, hexahydro-1,4-thiazepin-3,5-dion-2-yl, hexahydro-1,4-thiazepin-3,5-dion-6-yl, 2,3,6,7-tetrahydro-1,4-thiazepin-5-on-6-yl, 6,7-dihydro-1,4-thiazepin-5-on-6-yl, hexahydro-1,3-thiazepin-2,4-dion-5-yl, hexahydro-1,2-diazepin-3-on-4-yl, hexahydro-1,3-diazepin-2,4-dion-5-yl, hexahydro-1,4-diazepin-2-on-3-yl, hexahydro-1,4-diazepin-5-on-6-yl, hexahydro-1,4-diazepin-5,7-dion-6-yl, hexahydro-1,3,5-thiadiazepin-3-on-7-yl, 4,5,6,7-tetrahydro-1-3,5-thiadiazepin-6-on-7-yl, and 2,3,5,6-tetrahydro-1,2,4-triazepin-3,5-dion-7-yl; wherein the substituents on any of the carbon atoms capable of supporting an additional bond, of said (C ₁ -C ₄ ) heteroalkyl bridge, are chloro, fluoro, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, trifluoromethyl or cyano; wherein the substituents on any of the nitrogen atoms capable of supporting an additional bond, of said (C ₁ -C ₄ ) heteroalkyl bridge, are (C ₁ -C ₆ )alkyl or trifluoromethyl;

[0195] R ² is hydrogen, (C ₁ -C ₄ )alkyl, phenyl or naphthyl, wherein said phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, trifluoromethyl, cyano and —SO _k (C ₁ -C ₆ )alkyl wherein k is zero, one or two;

[0196] R ³ is —(CH ₂ ) _m B, wherein m is zero, one, two or three and B is hydrogen, phenyl, naphthyl or a 5 or 6 membered heteroaryl group containing from one to four heteroatoms in the ring, and wherein each of the foregoing phenyl, naphthyl and heteroaryl groups may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ ) alkoxy-(C ₁ -C ₆ )alkyl-, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, —COOH and —SO _n (C ₁ -C ₆ )alkyl wherein n is zero, one or two;

[0197] R ⁶ is selected from the group consisting of hydrogen, (C ₁ -C ₆ )alkyl optionally substituted with (C ₁ -C ₆ )alkoxy or one to three fluorine atoms, or [(C ₁ -C ₄ )alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH ₂ ) _q —, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and q is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, trifluoromethyl, cyano and —SO _g (C ₁ -C ₆ )alkyl, wherein g is zero, one or two;

[0198] R ⁷ is selected from the group consisting of hydrogen, (C ₁ -C ₆ )alkyl, [(C ₁ -C ₄ )alkyl]aryl wherein the aryl moiety is phenyl, naphthyl, or heteroaryl-(CH ₂ ) _r —, wherein the heteroaryl moiety is selected from the group consisting of pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and r is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties may optionally be substituted with one or more substituents independently selected from the group consisting of chloro, fluoro, bromo, iodo, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, trifluoromethyl, —C(═O)—(C ₁ -C ₆ )alkyl, cyano and —SO _j (C ₁ -C ₆ )alkyl, wherein j is zero, one or two;

[0199] or R ⁶ and R ⁷ taken together form a 2 to 4 carbon chain;

[0200] R ⁸ is hydrogen or (C ₁ -C ₃ )alkyl;

[0201] R ⁹ is hydrogen or (C ₁ -C ₆ )alkyl;

[0202] or R ⁶ and R ⁹ , together with the nitrogen atom to which they are attached, form a 5 to 7 membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen;

[0203] and p is one, two, or three;

[0204] each of R ¹⁰ , R ¹¹ and R ¹² is selected, independently, from the radicals set forth in the definition of R ² ; or R ¹¹ and R ¹² , together with the nitrogen to which they are attached, form a 5 to 7 membered heteroalkyl ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; and

[0205] the broken lines indicate optional double bonds, with the proviso that when the broken line in G ² is a double bond that R ⁸ is absent.

[0206] Other antidepressants and antianxiety agents that may be used in the methods and pharmaceutical compositions of this invention include compounds of the formula C, which compounds act as monoamine reuptake inhibitors, and their pharmaceutically acceptable salts, the activity and synthesis of which is referred to in U.S. patent application Ser. No. 09/529,207, filed Feb. 2, 2000 and International Patent Application No. WO 00/50380, published Aug. 31, 2000, all of which are incorporated herein by reference in their entirety: 4

[0207] wherein phenyl ring A and phenyl ring B can each, independently, be replaced by a naphthyl group, and wherein when phenyl ring A is replaced by a naphthyl group, the ethereal oxygen of structure I and the carbon to which R ³ , R ⁴ and NR ¹ R ² are attached, are attached to adjacent ring carbon atoms of the naphthyl group and neither of said adjacent ring carbon atoms is also adjacent to a fused ring carbon atom of said naphthyl group;

[0208] n and m are, selected, independently, from one, two and three;

[0209] R ¹ and R ² are selected, independently, from hydrogen (C ₁ -C ₄ )alkyl, (C ₂ -C ₄ )alkenyl, and (C ₂ -C ₄ )alkynyl, or R ¹ and R ² , together with the nitrogen to which they are attached, form a four to eight membered saturated ring containing one or two heteroatoms, including the nitrogen to which R ¹ and R ² are attached, wherein the second heteroatom, when present, is selected from oxygen, nitrogen and sulfur, and wherein said ring may optionally be substituted at available binding sites with from one to three substituents selected, independently, from hydroxy and (C ₁ -C ₆ )alkyl;

[0210] R ³ and R ⁴ are selected, independently, from hydrogen and (C ₁ -C ₄ ) alkyl optionally substituted with from one to three fluorine atoms, or R ³ and R ⁴ , together with the carbon to which they are attached, form a four to eight membered saturated carbocyclic ring, and wherein said ring may optionally be substituted at available binding sites with from one to three substituents selected, independently, from hydroxy and (C ₁ -C ₆ )alkyl;

[0211] or R ² and R ³ , together with the nitrogen to which R is attached and the carbon to which R ³ is attached, form a four to eight membered saturated ring containing one or two heteroatoms, including the nitrogen to which R ² is attached, wherein the second heteroatom, when present, is selected from oxygen, nitrogen and sulfur, and wherein said ring may optionally be substituted at available binding sites with from one to three substituents selected, independently, from hydroxy and (C ₁ -C ₆ )alkyl; and

[0212] each X and each Y is selected, independently, from hydrogen, halo (i.e., chloro, fluoro, bromo or iodo), (C ₁ -C ₄ )alkyl optionally substituted with from one to three fluorine atoms, (C ₁ -C ₄ )alkoxy optionally substituted with from one to three fluorine atoms, cyano, nitro, amino, (C ₁ -C ₄ )alkylamino, di-[(C ₁ -C ₄ )alkyl]amino, NR ⁵ (C═O)(C ₁ -C ₄ )alkyl wherein R ⁵ is hydrogen or (C ₁ -C ₆ )alkyl, and SO _p (C ₁ -C ₆ )alkyl wherein p is zero, one or two;

[0213] with the proviso that: (a) no more than one of NR ¹ R ² , CR ³ R ⁴ and R ² NCR ³ can form a ring; and (b) at least one X must be other than hydrogen when (i) R ³ and R ⁴ are both hydrogen, (ii) R ¹ and R ² are selected, independently, from hydrogen and (C ₁ -C ₄ )alkyl, and (iii) ring B is mono- or disubstituted with, respectively, one or two halo groups.

[0214] Examples of D4 receptor antagonists that may be used in the methods and pharmaceutical compositions of this invention are compounds of the formula 5

[0215] and their pharmaceutically acceptable salts, wherein Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl, quinolyl, furyl, benzofuryl, thienyl, benzothienyl, oxazolyl or benzoxazolyl;

[0216] Ar ¹ is phenyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl;

[0217] A is O, S, SO, SO ₂ , C═O, CHOH or —(CR ³ R ⁴ )—;

[0218] n is 0, 1 or 2;

[0219] each of Ar and Ar ¹ may be independently and optionally substituted with one to four substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, thiocyano, —SR, —SOR, —SO ₂ R, —NHSO ₂ R, —(C ₁ -C ₆ )alkoxy, —NR ¹ R ² , —NRCOR ¹ , —CONR ¹ R ² , phenyl, —COR, —COOR, —(C ₁ -C ₆ )alkyl, —(C ₁ -C ₆ )alkyl substituted with one to six halogens independently selected from fluoro, chloro, bromo and iodo, —(C ₃ -C ₆ )cycloalkyl and trifluoromethoxy;

[0220] each and every R, R ¹ , and R ² is independently selected from the group consisting of hydrogen, —(C ₁ -C ₆ )alkyl, —(C ₁ -C ₆ )alkyl substituted with one to thirteen halogens independently selected from fluoro, chloro, bromo and iodo, phenyl, benzyl, —(C ₂ -C ₆ )alkenyl, —(C ₃ -C ₆ )cycloalkyl and —(C ₁ -C ₆ )alkoxy; and

[0221] each and every R ³ and R ⁴ is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl and i-propyl.

[0222] In certain embodiments, this invention relates to the above pharmaceutical compositions for the treatment of depression, anxiety or psychosis, and the above methods of treating depression, anxiety or psychosis, wherein the D4 receptor antagonist, or pharmaceutically acceptable salt thereof, is a compound of the formula I, wherein Ar is phenyl, naphthyl, benzoxazolonyl, indolyl, indolonyl, benzimidazolyl or quinolyl; A is O, S, SO ₂ , C═O, CHOH or CH ₂ ; n is 0 or 1; wherein Ar and Ar ¹ may be independently substituted with up to three substituents independently selected from the group consisting of fluoro, chloro, cyano, —NR ¹ R ² , —(C ₁ -C ₆ )alkoxy, —COOR, —CONR ¹ R ² and —(C ₁ -C ₆ )alkyl; and the pharmaceutically acceptable salts thereof.

[0223] In other embodiments, this invention relates to the above pharmaceutical compositions for the treatment of depression, anxiety or psychosis, and the above methods of treating depression, anxiety or psychosis, wherein the D4 receptor antagonist, or pharmaceutically acceptable salt thereof, is a compound of the formula I, wherein A is O or S; n is 1; Ar is phenyl or substituted phenyl; and the pharmaceutically acceptable salts thereof; or A is CH ₂ ; n is 0; Ar is benzoxazolonyl or substituted benzoxazolonyl; and the pharmaceutically acceptable salts thereof; or wherein A is CH ₂ ; n is 0; Ar is indolyl or substituted indolyl; and the pharmaceutically acceptable salts thereof; or wherein A is C═O or CHOH; n is 0 or 1; Ar is phenyl or substituted phenyl; and the pharmaceutically acceptable salts thereof; or wherein A is O; Ar is fluorophenyl, difluorophenyl or cyanophenyl; Ar ¹ is chloropyridinyl; and the pharmaceutically acceptable salts thereof; or wherein A is O; Ar is fluorophenyl, difluorophenyl or cyanophenyl; Ar ¹ is fluoropyrimidinyl; and the pharmaceutically acceptable salts thereof; or wherein A is O; Ar is fluorophenyl, difluorophenyl or cyanophenyl; Ar ¹ is fluorophenyl; and the pharmaceutically acceptable salts thereof; or wherein Ar ¹ is 5-chloro-pyridin-2-yl; and the pharmaceutically acceptable salts thereof; or wherein Ar ¹ is 5-fluoro-pyrimidin-2-yl; and the pharmaceutically acceptable salts thereof.

[0224] In a preferred aspect of the invention, A is O.

[0225] In another aspect, A is S, SO, or SO ₂ .

[0226] In another aspect, A is C═O or CHOH.

[0227] In another preferred aspect, A is CH ₂ .

[0228] In another preferred aspect, Ar is phenyl or substituted phenyl.

[0229] In another preferred aspect, Ar is naphthyl or substituted naphthyl.

[0230] In another preferred aspect, Ar is benzoxazolonyl or substituted benzoxazolonyl.

[0231] In another preferred aspect, Ar is indolyl or substituted indolyl.

[0232] In another preferred aspect, Ar is indolonyl or substituted indolonyl.

[0233] In another preferred aspect, Ar is benzimidazolyl or substituted benzimidazolyl.

[0234] In another preferred aspect, Ar is quinolyl or substituted quinolyl.

[0235] In another preferred aspect, Ar ¹ is phenyl or substituted phenyl.

[0236] In another preferred aspect, Ar ¹ is pyridinyl or substituted pyridinyl.

[0237] In another preferred aspect, Ar ¹ is pyridazinyl or substituted pyridazinyl.

[0238] In another preferred aspect, Ar ¹ is pyrimidinyl or substituted pyrimidinyl.

[0239] In another preferred aspect, Ar ¹ is pyrazinyl or substituted pyrazinyl.

[0240] Preferred embodiments of this invention relate to the above pharmaceutical compositions for the treatment of depression, anxiety or psychosis, and the above methods of