WO2009067607A2

WO2009067607A2 - Combinations of pde4 inhibitors and antipsychotics for the treatment of psychotic disorders

Info

Publication number: WO2009067607A2
Application number: PCT/US2008/084207
Authority: WO
Inventors: David A. Lowe
Original assignee: Memory Pharmaceuticals Corporation
Priority date: 2007-11-20
Filing date: 2008-11-20
Publication date: 2009-05-28
Also published as: WO2009067607A3; IL205680A0

Abstract

The invention relates to methods and compositions for treating a psychotic disorder or condition, associated with cognitive impairment. The pharmaceutical composition comprises: (a) an amount of an antipsychotic agent and (b) an amount of a PDE4 inhibitor compound, wherein the amounts of (a) and (b) are together effective in treating the cognitive impairment or psychotic disorder such as schizophrenia. The method of treatment comprises administering to a patient (a) an amount of a antipsychotic agent and (b) an amount of a PDE4 inhibitor compound, wherein the amounts of (a) and (b) are together effective in treating the psychotic disorder such as schizophrenia.

Description

COMBINATIONS OF PDE4 INHIBITORS AND

ANTIPSYCHOTICS FOR THE TREATMENT OF

PSYCHOTIC DISORDERS

FIELD OF THE INVENTION

The present invention relates generally to the field of phosphodiesterase 4 (PDE4) enzyme inhibitors and the field of antipsychotic drugs. More specifically this invention relates to the combined use of PDE4 inhibitors and antipsychotic agents for the treatment of psychotic disorders such as schizophrenia, as well as compositions containing such agents.

BACKGROUND OF THE INVENTION

The cyclic nucleotide specific phosphodiesterases (PDEs) represent a family of enzymes that catalyze the hydrolysis of various cyclic nucleoside monophosphates (including cAMP and cGMP). These cyclic nucleotides act as second messengers within cells, and as messengers, carry impulses from cell surface receptors having bound various hormones and neurotransmitters. PDEs act to regulate the level of cyclic nucleotides within cells and maintain cyclic nucleotide homeostasis by degrading such cyclic mononucleotides resulting in termination of their messenger role.

PDE enzymes can be grouped into eleven families according to their specificity toward hydrolysis of cAMP or cGMP, their sensitivity to regulation by calcium, calmodulin or cGMP, and their selective inhibition by various compounds. For example, PDEl is stimulated by Ca²⁺/calmodulin. PDE2 is cGMP-dependent, and is found in the heart and adrenals. PDE3 is cGMP-inhibited, and inhibition of this enzyme creates positive inotropic activity. PDE4 is cAMP specific, and its inhibition causes airway relaxation, anti-inflammatory and antidepressant activity. PDE5 appears to be important in regulating cGMP content in vascular smooth muscle, and therefore PDE5 inhibitors may have cardiovascular activity. Since the PDEs possess distinct biochemical properties, it is likely that they are subject to a variety of different forms of regulation. PDE4 is distinguished by various kinetic properties including low Michaelis constant for cAMP and sensitivity to certain drugs. The PDE4 enzyme family consists of four genes, which produce 4 isoforms of the PDE4 enzyme designated PDE4A, PDE4B, PDE4C, and PDE4D [Wang et al., Expression, Purification, and Characterization of Human cAMP-Specific Phosphodiesterase (PDE4) Subtypes A, B, C, and D, Biochem. Biophys. Res. Comm., 234, 320-324 (1997)]. In addition, various splice variants of each PDE4 isoform have been identified.

PDE4 isoenzymes are localized in the cytosol of cells and are unassociated with any known membranous structures. PDE4 isoenzymes specifically inactivate cAMP by catalyzing its hydrolysis to adenosine 5 '-monophosphate (AMP). Regulation of cAMP activity is important in many biological processes, including inflammation and memory. Inhibitors of PDE4 isoenzymes such as rolipram, piclamilast, CDP- 840 and ariflo are powerful anti-inflammatory agents and therefore may be useful in treating diseases where inflammation is problematic such as asthma or arthritis. Further, rolipram improves the cognitive performance of rats and mice in learning paradigms.

rolipram piclamilast

In addition to such compounds as rolipram, xanthine derivatives such as pentoxifylline, denbufylline, and theophylline inhibit PDE4 and have received attention of late for their cognition enhancing effects. cAMP and cGMP are second messengers that mediate cellular responses to many different hormones and neurotransmitters. Thus, therapeutically significant effects may result from PDE inhibition and the resulting increase in intracellular cAMP or cGMP in key cells, such as those located in the nervous system and elsewhere in the body. Psychotic disorders such as schizophrenia (meaning "split mind" in Greek) and related disorders are complex diseases having uncertain etiology. Schizophrenia itself is a severe mental disease that afflicts approximately one percent of the world's population. Symptoms of schizophrenia are varied including but not limited to: bizarre behavior, disorganized thinking, disorganized speech, decreased emotional expressiveness, diminished or loss of contact with reality, diminished to total social withdrawal.

Schizophrenia is characterized by positive, negative, and cognitive symptoms. The positive symptoms included things such as disorganized speech, bizarre behavior or grossly disorganized behavior, hallucinations (such as the hearing of voices), and/or delusions. Negative symptoms include the absence of any adjustive behavior in the important areas of life, chronic maladaptiveness, flatness of affect, absence of developed interpersonal relationships (social skills), alogia (speechlessness caused by mental confusion), avolition (lack of motivation to pursue a goal), and/or anhedonia (inability to experience pleasure). Cognitive symptoms include impairments of working memory, attention, verbal reproduction, and executive function. See also DSM-IV Diagnostic and Statistical Manual of Mental Disorders, 4th edition, American Psychiatric Assoc, Washington, D.C., 2000.

The condition of schizophrenia includes various subtypes, i.e., paranoid subtype, disorganized subtype (Hebephrenic), catatonic subtype, undifferentiated subtypes, and residual subtype. The paranoid subtype is characterized by a preoccupation of bizarre delusion(s) of being persecuted or harassed including auditory hallucinations related to the delusions' theme. The disorganized subtype involves disorganized behavior, disorganized speech, and flat affect. Symptoms of the catatonic subtype include catatonic behavior (such as disconnect from the environment or encounters with other people), bizarre motor activity, stupor, immobility, hyperactivity with no apparent purpose and not influenced by external stimuli, excessive purposeless movements, mutism, marked negativism, and bizarre posturing. The undifferentiated subtype is a form of schizophrenia that is characterized by a number of schizophrenic symptoms but does not meet the criteria for any other type of schizophrenia. The residual subtype is a form of schizophrenia wherein the patient was previous diagnosed with schizophrenia, but no longer exhibits such prominent psychotic symptoms as catatonic behavior, delusions, hallucinations or disorganized speech or behavior. However, the patient still exhibits some remaining symptoms of the disorder however, such as flattened affect, disorganized speech eccentric behavior, emotional blunting, illogical thinking, and social withdrawal.

Psychotic disorders related to schizophrenia include brief psychotic disorder delusional disorder, psychotic disorder due to a general medical condition, schizoeffective disorder, schizophreniform disorder, and substance-induced psychotic disorder.

Antipsychotic drugs that have been used for the treatment of schizophrenia and other psychotic disorders include clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®).

In general, schizophrenia is generally treated by the administration antipsychotic drugs, including both typical antipsychotics and atypical antipsychotics. Typical antipsychotic drugs include chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, and droperidol. Atypical antipsychotic drugs include clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole. Due to the complexity of psychotic diseases, side effects associated with the use of known antipsychotic agents (side effects such as diabetes, agranulocytosis, extrapyramidal side effects like Tardive Dyskinesia, and Neuroleptic Malignant Syndrome) and problems with patient compliance, there continues to be a need for new forms f treatment for schizophrenia and other psychotic disorders.

SUMMARY OF THE INVENTION

According to an aspect of the invention, there is provided a method for treating a patient (e.g., a human) suffering from a psychotic disorder comprising administering to the patient a PDE4 inhibitor and an antipsychotic agent. The PDE4 inhibitor and antipsychotic agent can be administered separately or in a combined formulation. When administered separately, the PDE4 inhibitor and the antipsychotic agent can be administered simultaneously or sequentially. The psychotic disorder to be treated can be, for example, schizophrenia, bipolar disorder, manic depression, brief psychotic disorder delusional disorder, psychotic disorder due to a general medical condition, schizoeffective disorder, schizophreniform disorder, and substance-induced psychotic disorder. Preferably, the psychotic disorder is schizopherenia, including the various subtypes such as paranoid subtype, disorganized subtype (Hebephrenic), catatonic subtype, undifferentiated subtypes, and residual subtype.

According to a further aspect of the invention, there is provided a composition suitable for treating a patient suffering from a psychotic disorder, the composition comprising a PDE4 inhibitor and an antipsychotic agent.

In the context of the invention, the antipsychotic agent is selected from 5-HT_1A agnostics, dopamine modulators, sodium channel blockers, 5-HT uptake inhibitors, D3 antagonists, D2 antagonists, Dl antagonists, Dl agonists, secretin agonist, phospholipase A2 inhibitors, 5-HT2 antagonists, 5HT6 antagonists, COX 2 inhibitors, 5-HT₂A antagonists, 5HT₂c modulators, NK3 antagonists, alpha 1 adrenoreceptor antagonists, alpha 2 adrenoreceptor antagonists, AMPA modulators and NK 3 antagonists. According to a further aspect of the invention, the antipsychotic agent is selected from clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®,), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan®, Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®).

According to a further aspect of the invention, the antipsychotic agent is selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole.

According to a further aspect of the invention, the antipsychotic agent is selected from risperidone (Risperdal®), aripiprazole (Abilify®), clozapine (Clozaril®), olanzapine (Zyprexa®), perphenazine (Trilafon ®), and haloperidol (Haldol®).

The above-listed antipsychotic agents can optionally be in form of the pharmaceutically acceptable salts, hydrates and/or solvates, and, in the case of optically active compounds, the agents can optionally be in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates thereof.

Further examples of antipsychotic drugs include Perospirone, Zotepine, Nemonapride, Sertindole, Levosulpiride, Tandospirone, Bifeprunox, Asenapine, Paliperidone, Mifepristone, Lamotrigine, ϋoperidone, Blonanserin, DU- 125530, Lurasidone, ACP-103, Idazoxan, Org-24448, CX-516, Aplindore, SLV-313, SLV- 310, Ocaperidone, PNU-170413, POL-255, ABT-089 Talnetant, NE- 100, LAX-101, LAX-111, RG-1068 (Secretin), Dexefraoxan, Dihydrexidine, SM-13496, D-Serine, Osanetant, EMR-62218, SB-399885, TC-1698, SR-147778, SLV-319, SSR-181507, AVE-5997, PNU- 177864, Abaperidone, SSR- 146977, Neboglamine, Lamictal XT, N- Desmethylclozapine, Topiramate and cycloserine.

In the context of the invention, the PDE4 inhibitors for use in the method and composition according to the invention are the PDE4 inhibitors disclosed in US 6,669,890, US Patent Application Serial No. 10/067,996, US Patent Application Serial No. 10/270,724, US Patent Application Serial No. 10/622,833, US Patent Application Serial No. 10/622,117, US Patent Application Serial No. 10/636,979, US Patent Application Serial No. 10/636,996, US Patent Application Serial No. 10/715,819, US Patent Application Serial No. 10/825,610, US Patent Application Serial No. 10/825,611, US Patent Application Serial No. 11/008,775, US Patent Application Serial No. 11/249,769, US Patent Application Serial No. 11/253,812, US Patent Application Serial No. 11/449,868, and US Patent Application Serial No. 11/785,741.

US 6,669,890 discloses a genus of PDE4 compounds defined by the following Formula, hereinafter referred to as Formula A:

wherein R¹ is alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen (e.g., CH₃, CHF₂, CF₃, etc.);

R is alkyl having 1 to 12, preferably 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, Ci-₄-alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH₂CH₂- groups is replaced in each case by -CH=CH- or -C≡C- (e.g., CH₃, CHF₂, CF₃, methoxyethyl, etc.),

cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof (e.g., cyclopentyl),

cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, Cr₄- alkyl, Cr₄-alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.),

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF_3> OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof

(e.g., methylphenyl, methoxyphenyl, chlorophenyl, etc.),

arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, which the arylalkyl radical is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF_3> OCF₃, alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more - CH₂CH₂- groups are each optionally replaced by -CH=CH- or -C≡C-, and one or more -CH₂- groups are each optionally replaced by -O- or - NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., phenylethyl, phenylpropyl, phenylbutyl, methoxyphenylethyl, methoxyphenylpropyl, chlorophenylethyl, chlorophenylpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, chlorophenoxyethyl, chlorophenylaminoethyl, etc.),

a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof (e.g., cyclohexenyl, cyclohexadienyl, indanyl, tetrahydronaphthenyl, etc.),

a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof (e.g., 3-thienyl, 3- tetrahydrofuranyl, 3-pyrrolyl, etc.), or

a heterocycle- alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and the alkyl portion is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, OCF₃, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, wherein in the alkyl portion one or more -CH₂CH₂- groups are each optionally replaced by -CH=CH- or -C≡C-, and one or more -

CH₂- groups are each optionally replaced by -O- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., pyridylethyl, pydridylpropyl, methylpiperazinylethyl, etc.); is H,

alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, cyano, Ci-₄-alkoxy, or combinations thereof (e.g., methyl, ethyl, propyl, etc.),

a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion which is branched or unbranched has 1 to 5 carbon atoms, and which is unsubstituted or substituted in the carbocyclic portion one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, and the alkyl portion is optionally substituted by halogen, Cr₄- alkoxy, cyano or combinations thereof (e.g., cyclohexenylmethyl, etc.),

arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF₃O, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trfluoromethyl, benzyl, methylenedioxobenzyl, etc.), or

heteroarylalkyl group, wherein the heteroaryl portion may be partially or fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heteroarylalkyl group is unsubstituted or substituted one or more times in the heteroaryl portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF₃O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof (e.g., pyridylmethyl, pyridylpropyl, methylpyridylmethyl, chloropyridylmethyl, dichloropyridylmethyl, thienylmethyl, thiazolylmethyl, quinolinylmethyl, isoquinolinylmethyl, piperidinylmethyl, furanylmethyl, imidazolylmethyl, methylimidazolylmethyl, pyrrolylmethyl, etc.);

is H,

aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF₃, amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl (e.g., 2-(2-tetrahydropyranyl)tetrazole-5- yl), hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert- butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg. tert- butyldimethylsilyloxy), R⁵-L-, or combinations thereof (e.g., substituted or unsubstituted phenyl, naphthyl, and biphenyl, such as phenyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.), or

heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg. te/t-butyldimethylsilyloxy), R⁵-L-, or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.);

is H,

alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times with halogen, Cr₄- alkyl, Cr₄-alkoxy, oxo, or combinations thereof (e.g., methyl, ethyl, propyl, etc.),

alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8, preferably 1 to 4 carbon atoms (e.g., dimethylamino, etc.),

a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion has 1 to 5 carbon atoms, which is unsubstituted or substituted, preferably in the carbocyclic portion, one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof (e.g., cyclohexenylmethyl, etc.),

cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof (e.g., cyclopentyl),

cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, alkyl, alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.),

aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, (e.g., substituted or unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.),

arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF₃O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trfluoromethyl, benzyl, methylenedioxobenzyl, etc.),

a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.), or

a heterocycle-alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and the alkyl portion which is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF₃O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof (e.g., pyridylmethyl, pyridylpropyl, methylpridylmethyl, etc.);

L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH₂- groups are each optionally replaced by -O-, -S-, -NR⁶-, -SO₂NH-, -NHSO₂-, -CO-, -NR⁶CO-, -CONR⁶-, - NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or - NHCSNH- (e.g.,-0-, CH₂-, -CO-, -CO-O-, -O-CO-, -CO-NH-, -NH- CO-, -CH₂CH₂CH₂-NH-CO-, -CH₂-CH₂-O-, -SO₂-NH-CH₂CH₂-O-, - 0-CH₂CH₂-O-, -CH₂-NH-CO-, -CO-NH-CH₂-, -SO₂-NH-, -CH₂-NH-

SO₂-, -CH₂CH₂CH₂-SO₂-NH-, etc.); and

R⁶ is H,

alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, Ci-₄-alkyl, Ci-₄-alkoxy, oxo, or combinations thereof (e.g., methyl, ethyl, propyl, etc.);

wherein at least one of R³ and R⁴ is other than H; and pharmaceutically acceptable salts thereof.

Thus, according to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formula A and pharmaceutically acceptable salts thereof.

According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formula A, and pharmaceutically acceptable salts thereof, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole.

US 6,669,890 also specifically discloses, among others, the following PDE4 inhibitor compounds (hereinafter referred to as Group I):

3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine;

N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid;

3-cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine ; iV-3,4-bis(difluoromethoxy)phenyl)-iV-(3-pyridylmethyl)-3-aminobenzoic acid;

3-[3-(4-Chlorophenyl)prop-l-yloxy]-4-methoxy-iV-(3-pyridylmethyl)diphenylamine;

4-Methoxy-3- [3-(4-methoxyphenyl)prop- 1 -yl] oxy-N-(3- pyridylmethyl)diphenylamine ;

3-[2-(4-Chlorophenoxy)ethoxy)-4-methoxy-iV-(3-pyridylmethyl)diphenylamine; 3 -Indanyloxy-4-methoxy-./V- (3 -pyridylmethyl)diphenylamine ;

4-Methoxy-3-(2-methoxyethoxy)-iV-(3-pyridylmethyl)diphenylamine;

3-Cyclopropylmethoxy-4-methoxy-iV-(3-pyridylmethyl)diphenylamine;

3-[2-(4-Chlorophenyl)ethenyloxy]-4-methoxy-iV-(3-pyridylmethyl)diphenylamine;

4-Methoxy-3-(2-phenoxyethoxy)-iV-(3-pyridylmethyl)diphenylamine; 3 -Cyclopropylmethoxy-4-difluoromethoxy-iV- (3 -pyridylmethyl)diphenylamine ;

3'-Chloro-4-methoxy-3-(2-methoxyethoxy)-iV-(3-pyridylmethyl)diphenylamine;

3-Cyclopropylmethoxy-4'-hydroxy-4-methoxy-iV-(3-pyridylmethyl)diphenylamine;

3,4-Bis(difluoromethoxy)-iV-(3-pyridylmethyl)diphenylamine; iV-3,4-Bis(difluoromethoxy)phenyl)-iV-(3-pyridylmethyl)-3-aminobenzoic acid;

N- (3 -Cyclopropylmethoxy-4-methoxyphenyl) -N- (3 -pyridylmethyl) -4- aminobenzoic acid;

N- (3 -Cyclopropylmethoxy-4-difluoromethoxyphenyl) -N- (3 -pyridylmethyl) -3 - aminobenzoic acid; iV-[3-(4-Chlorophenyl)prop-l-yloxy-4-methoxyphenyl]-iV-(3-pyridylmethyl)-3- aminobenzoic acid;

N- (3 -Cyclopropylmethoxy-4-methoxyphenyl) -N- (3 -pyridylmethyl) -3 - aminobenzoic acid; iV-[3-(2-Indanyloxy)-4-methoxyphenyl]-iV-(3-pyridylmethyl)-3-aminobenzoic acid; iV-[3-(2-Methoxyethoxy)-4-methoxyphenyl]-iV-(3-pyridylmethyl)-3-aminobenzoic acid;

3 -Cyclopropylmethyloxy-4-difluoromethoxy-iV- (3 -pyridylmethyl) -4 ' - (2H-tetrazol- 5 - yl)diphenylamine ;

3 -Cyclopropylmethyloxy-4-methoxy-iV- (3 -pyridylmethyl) -4 ' - (2H-tetrazol- 5 - yl)diphenylamine;

3 -Cyclopropylmethyloxy-4-difluoromethoxy-iV- (3 -pyridylmethyl) -3 ' - (2H-tetrazol- 5 - yl)diphenylamine ;

Bis-3,4-difluoromethoxy-iV-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine

3-Cyclopropylmethoxy-3 ' -ethanesulfonylamino-4-methoxy-iV-(3- pyridylmethyl)diphenylamine; and pharmaceutically acceptable salts thereof.

Thus, according to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from Group I. According to further aspect of the invention, the PDE4 inhibitor compounds are selected from Group I, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole.

Patent Application Serial No. 10/067,996 discloses a genus of PDE4 compounds defined by the following Formula, hereinafter referred to as Formula B:

wherein, R¹ is H,

alkyl having 1 to 5 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, or combinations thereof, and wherein a -

CH₂- group can be optionally replaced by -O-, -S-, or -NH-,

cycloalkyl having 3 to 6 carbon atoms, or cycloalkylalkyl having 4 to 7 C atoms;

R² is alkyl having 1 to 12 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano or combinations thereof, wherein one or more -CH₂- groups is each independently optionally replaced by -O-, - S-, or -NH-, and wherein optionally one or more -CH₂CH₂- groups is replaced in each case by -CH=CH- or -C≡C-,

alkyl ether having 3 to 12 carbon atoms,

cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted or substituted one or more times by halogen, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-4 alkoxy, cyano or combinations thereof,

cycloalkylalkyl having 4 to 12 C atoms, which is unsubstituted or substituted one or more times by C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-4 alkoxy, cyano, halogen, or combinations thereof,

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1-4- alkoxy, halogenated C_1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1-4 alkylamino, di-Ci-₄-alkylamino, Ci_₄-hydroxyalkyl, C_1-4- hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C_2-4- acyl, C₂_₄-alkoxycarbonyl, C_1-4-alkyrthio, C_1-4-alkylsulphinyl, C_1-4- alkylsulphonyl, phenoxy, or combinations thereof,

arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted one or more times by halogen, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1- ₄-alkoxy, halogenated C_1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1-4 alkylamino, di-C_1-4-alkylamino, C_1-4- hydroxyalkyl, C_1-4-hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C₂_₄-acyl, C₂_₄-alkoxycarbonyl, C_1-4-alkylthio, C_1-4- alkylsulphinyl, C_1-4-alkylsulphonyl, phenoxy, or combinations thereof, heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, Ci-₄-alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C₁.

₄-alkylamino, di-C^-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, Ci-₄-alkylthio, Ci-₄-alkylsulphinyl, C_1- ₄-alkylsulphonyl,or combinations thereof,

heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and the alkyl portion has 1 to 3 carbon atoms, the heteroaryl portion is unsubstituted or is substituted one or more times in by halogen, aryl, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, Ci_₄-alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, Ci-₄-alkylamino, di-Ci_₄- alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, Ci_₄-alkylthio, C^-alkylsulphinyl, C₁_₄-alkylsulphonyl,or combinations thereof,

heterocycle having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or is substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C^-alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1-4- alkylamino, di-Ci-₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof (e.g., piperidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, piperazinyl, and indolinyl),

heterocycle-alkyl wherein the heterocycle portion has 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and the alkyl portion has 1 to 3 carbon atoms, the heterocycle portion is nonaromatic and is unsubstituted or is substituted one or more times in the by halogen, aryl, C_1-4 alkyl, halogenated Ci_₄ alkyl, hydroxy, C^-alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C₁_₄-alkylamino, di-C₁_₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof (e.g., piperidinyl-ethyl and pyrrolinyl-methyl), or

carbocycle which is nonaromatic, monocyclic or bicyclic, group having 5 to 14 carbon atoms, which is unsubstituted or is substituted one or more times in the by halogen, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1- ₄-alkoxy, halogenated C_1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1-4 alkylamino, di-C_1-4-alkylamino, C_1-4- hydroxyalkyl, Ci-₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C_2-4-acyl, C_2-4-alkoxycarbonyl, C_1-4-alkylthio, C_1-4- alkylsulphinyl, C_1-4-alkylsulphonyl, phenoxy, or combinations thereof;

and pharmaceutically acceptable salts thereof,

with the provisos that:

(a) when R¹ is methyl, then R² is not arylalkyl, heteroarylalkyl, 2- (l,2,3,4-tetrahydro)quinolinyl-methyl, methyl or 2-butyl;

(b) when R¹ is cyclopropyl, R² is not 4-methylbenzyl;

(c) when R¹ is ethyl, then R² is not ethyl, 3-aminobenzyl, 2- thienylmethyl, 3-thienylmethyl, or 2-pyridylmethyl;

(d) when R¹ is cyclopropyl, then R² is not cyclopropylmethyl;

(e) when R¹ is H, then R² is not methyl, ethyl, benzyl, 4-methylbenzyl, or substituted tetrahydrofuranyl;

(f) when R¹ is methoxyethyl, then R² is not benzyl, 3- dimethylaminobenzyl, or 3-thienylmethyl;

(g) when R¹ is iso-butyl, then R² is not benzyl; and (h) when R¹ is n-butyl, then R² is not n-butyl. Patent Application Serial No. 10/067,996 also discloses, among others, the following compounds (hereinafter referred to as Group II): 6-Cyclopropylamino-9-(2-fluorobenzyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(4-fluorobenzyl)-2-trifluoromethylpurine

6-Cyclopropylamino-9-(2, 6-difluorobenzyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(2, 3-difluorobenzyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-propyl-2-trifluoromethylpurine 6-Cyclopropylamino-9-cyclopentyl-2-trifluoromethylpurine 6-Cyclopropylamino-9-(3, 4-dimethoxybenzyl)-2-trifluoromethylpurine

6-Cyclopropylamino-9-(3,4-methylenedioxybenzyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(3-thiophenemethyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-cycloheptyl-2-trifluoromethylpurine 6-Methylamino-9-cyclopentyl-2-trifluoromethylpurine 6-Cyclopropylamino-9-cyclohexyl-2-trifluoromethylpurine 6-Methylamino-9-cycloheptyl-2-trifluoromethylpurine 6-Cyclopropylamino-9-cyclopentylmethyl-2-trifluoromethylpurine 6-Cyclopropylamino-9-phenyl-2-trifluoromethylpurine 6-Cyclopropylamino-9-(2-fluorophenyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-cyclobutyl-2-trifluoromethylpurine

6-Cyclopropylamino-9-(2-norboranane)-2-trifluoromethylpurine 6-Cyclopropylamino-9-( 1 -indanyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(4-fluorophenyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(4-chlorophenyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(3-thienyl)-2-trifluoromethylpurine

6-Cyclopropylamino-9-(3-cyclopentyloxy-4-methoxybenzyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(3, 4-dimethoxyphenyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(2, 6-dichloro-4-pyridylmethyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(4-methoxybenzyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(3-cyanophenyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(2, 4-dimethoxyphenyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(3-nitrobenzyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(6-methoxy-3-pyridyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(4-pyridyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(3-pyridyl)-2-trifluoromethylpurine

6-Cyclopropylamino-9-(4-dimethylaminophenyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(3-aminophenyl)-2-trifluoromethylpurine 6-Methylamino-9-(2, 4-dimethoxy-5-pyrimidyl)-2-trifluoromethylpurine 6-Methylamino-9-(2-methoxyphenyl)-2-trifluoromethylpurine 6-Methylamino-9-(4-methoxyphenyl)-2-trifluoromethylpurine 6-Methylamino-9-(3-acetylphenyl)-2-trifluoromethylpurine 6-Methylamino-9-(3-methoxyphenyl)-2-trifluoromethylpurine 6-Methylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(3-furanyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(4-ethoxyphenyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(2-ethoxyphenyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(3, 4-methylenedioxyphenyl)-2-trifluoromethylpurine 6-Cyclopropylamino-9-(3-ethoxyphenyl)-2-trifluoromethylpurine 6-Methylamino-9-(3,4-dimethoxyphenyl)-2-trifluoromethylpurine; and pharmaceutically acceptable salts thereof.

Thus, according to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formula B and pharmaceutically acceptable salts thereof. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formula B, and pharmaceutically acceptable salts thereof, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine

(Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole.

According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from Group II. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from Group II, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole. US Patent No. 7,235,579 discloses a genus of PDE4 compounds defined by the following Formula, hereinafter referred to as Formula C:

wherein

X is O;

R is alkyl having 1 to 8 carbon atoms wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups,

alkyl having 1 to 8 carbon atoms which is substituted one or more times by halogen, oxo or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or - C≡C- groups,

cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl having 1 to 4 carbon atoms or combinations thereof,

a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom (e.g., 3-thienyl, 2-thienyl, 3-tetrahydrofuran), which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof,

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF₃ OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

arylalkyl having 8 to 16 carbon atoms, which is unsubstituted or substituted preferably in the aryl portion, one or more times by halogen, CF_3, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, (e.g., cyclohexenyl, cyclohexadienyl, indanyl, and tetrahydronaphthenyl), which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof ,

arylalkenyl having 8 to 16 carbon atoms, wherein the alkenyl portion has up to 5 carbon atoms, which is unsubstituted or substituted preferably in the aryl portion, one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof;

a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof, or

cycloalkylalkyl having 4 to 16 carbon atoms (e.g., cyclopentylethyl and cyclopropylmethyl), which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof,

R² is alkyl having 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times by halogen;

R³ is H,

alkyl having 1 to 8 carbon atoms wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups,

alkyl having 1 to 8 carbon atoms which is substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or - C≡C- groups,

cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl, or combinations thereof,

arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted preferably in the aryl portion, one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, and acyloxy (e.g., acetoxy), or combinations thereof, heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof,

alkoxyalkyl having 3 to 8 carbon atoms,

-C(O)R⁴, or

-CH₂CONHR⁵;

is alkyl having 1 to 12 carbon atoms wherein optionally one or more

-CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups,

alkyl having 1 to 12 carbon atoms which is substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or - C≡C- groups,

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF₃, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

arylalkyl having 8 to 16 carbon atoms, which is unsubstituted or substituted preferably in the aryl portion, one or more times by halogen, CF₃, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a

N, O or S atom (e.g., 3-thienyl, 2-thienyl, 3-tetrahydrofuran), which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof, or

a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; and

is H,

alkyl having 1 to 12 carbon atoms wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups, alkyl having 1 to 12 carbon atoms which is substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or - C≡C- groups,

a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom (e.g., 3-thienyl, 2-thienyl, 3-tetrahydrofuran), which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, alkoxycarbonyl, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof, or

a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; with the proviso that:

(a) when X is O, R² is CH₃ and R³ is H, then R¹ is not methyl, ethyl, n-propyl, isopropyl, sec -butyl, n- butyl, isobutyl, neopentyl, n-pentyl, 2-methylbutyl, isopentyl, n-hexyl, phenyl , cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, methylcyclopentyl, cyclopropylmethyl, cyclopentylmethyl, 2-propenyl, 2-propynyl, 3- methyl-2-butenyl, N-substituted 2-piperazinylethyl, norbornyl, 3-tetrahydrofuryl, 2-tetrahydrofuryl, 3- tetrahydrothienyl, 2-oxacyclopropyl, 2- oxacyclopenyl, 3-oxacyclopentyl, 2-chloroethyl, 2- bromoethyl, 2,2,2-trifluoroethyl, 3-bromopropyl, 3- chloropropyl, or 4-bromobutyl;

(b) when X is O, R¹ is cyclopentyl, and R² is methyl, then R³ is not H, acetyl, benzyl, 4-hydroxybenzyl, 4-acetoxybenzyl, 4-bromobenzyl, 3,4- dimethoxybenzyl, 4-methylthiobenzyl, 4- cyanobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4- aminobenzyl, 4-dimethylaminobenzyl, 2,4- diaminobenzyl, 4-amino-3,5-dimethoxybenzyl, 3- carboxybenzyl, 3-methoxycarbonylbenzyl, 4- methoxycarbonylbenzyl, 4-methylsulfinylbenzyl, 4- methylsufonylbenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2,4-dinitrobenzyl, 2-nitro-4- aminobenzyl, 2-amino-4-nitrobenzyl, morpholinoethyl, 2-pyridylmethyl, 3- pyridylmethyl, 4-pyridylmethyl, 4-(6- fluoroquinolyl)methyl, 2-(7-chloroquinolyl)methyl,

2-imidazoylmethyl, or substituted imidazoylmethyl.

(c) when X is O, R¹ is CH₃, and R³ is H, then R² is not methyl, ethyl, or butyl. (d) when X is O and R³ is H, then R¹ and R² are not both ethyl or isobutyl. (e) When X is O, and R¹ and R² are both difluoromethyl, then R³ is not 4-aminobenzyl, or 4- amino-3,5-dimethoxybenzyl.

US Patent No. 7,235,579 also disclose, among others, the following specific compounds (hereinafter referred to as Group III):

4(S)-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-l-(N-(2-(6-methylpyridyl))- aminocarbonylmethyl)-2-pyrrolidone, l-(N-(2,3-Difluorophenyl)-aminocarbonylmethyl)-4(S)-(4-methoxy-3-(3(R)-tetra hydrofuryloxy)phenyl)-2-pyrrolidone,

4(S)-(4-Methoxy-3-(3(R)-tetrahydrofuryloxy)phenyl)-l-(N-(2-methylphenyl)- aminocarbonylmethyl)-2-pyrrolidone,

4(S)-(4-Methoxy-3-(3(R)-tetrahydrofuryloxy)phenyl)-l-(N-(2-(6-methylpyridinyl))- aminocarbonylmethyl)-2-pyrrolidone,

(4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(N-(2,6-dimethylphenyl)- aminocarbonylmethyl)-2-pyrrolidone,

(4i?)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(N-(2,6-dimethylphenyl)- aminocarbonylmethyl)-2-pyrrolidone, 4-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(N-(2-methylphenyl)- aminocarbonylmethyl)-2-pyrrolidone,

(4R)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(N-(2-methylphenyl)- aminocarbonylmethyl)-2-pyrrolidone, (4S)-4-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(N-(2-methylphenyl)- aminocarbonylmethyl)-2-pyrrolidone,

4-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(N-(2,3-difluorophenyl)- aminocarbonylmethyl)-2-pyrrolidone, 4-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(N-(3-chlorophenyl)- aminocarbonylmethyl)-

2-pyrrolidone,

4-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(N-(4-pyridyl)-aminocarbonylmethyl)-2- pyrrolidone, 4-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(N-(4-methoxyphenyl)- aminocarbonylmethyl)-2-pyrrolidone,

4-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(N-(4-chloro-2-fluorophenyl)- aminocarbonylmethyl)-2-pyrrolidone,

4-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(N-(3-methylphenyl)- aminocarbonylmethyl)-2-pyrrolidone,

4-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(N-(4-methylphenyl)- aminocarbonylmethyl)-2-pyrrolidone,

4-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(N-(4-nitrophenyl)-aminocarbonylmethyl)-

2-pyrrolidone, 4-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-l-(N-(2,3-difluorophenyl)-amino carbonylmethyl)-2-pyrrolidone,

4(S)-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-l-(N-(2-(6-methylpyridyl))- aminocarbonylmethyl)-2-pyrrolidone,

4(S)-(4-Methoxy-3-(3(R)-tetrahydrofuryloxy)phenyl)-l-(N-(2-(6-methylpyridyl))- aminocarbonylmethyl)-2-pyrrolidone, l-(N-(2,3-Difluorophenyl)-aminocarbonylmethyl)-4(S)-(4-methoxy-3-(3(R)-tetra hydrofuryloxy)phenyl)-2-pyrrolidone, l-(N-(2-(6-Aminopyridyl))-aminocarbonylmethyl)-4(S)-(3-cyclopentyloxy-4- methoxyphenyl)-2-pyrrolidone, 4(S)-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(N-(2-(6-ethylpyridyl))- aminocarbonylmethyl)-2-pyrrolidone,

4(S)-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(N-(2-(4,6-dimethylpyridyl))- aminocarbonylmethyl)-2-pyrrolidone, l-(N-(2-(6-Bromopyridyl))-aminocarbonylmethyl)-4(S)-(3-cyclopentyloxy-4- methoxyphenyl)-2-pyrrolidone, l-(N-(2-(6-Bromopyridyl))-aminocarbonylmethyl)-4(S)-(4-methoxy-3-(3(R)- tetrahydrofuryloxy)phenyl)-2-pyrrolidone, 4(S)-(4-Methoxy-3-(3(R)-tetrahydrofuryloxy)phenyl)-l-(N-(2-methylphenyl)- aminocarbonylmethyl)-2-pyrrolidone,

4(S)-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(N-(3-(2-methoxypyridyl))- aminocarbonylmethyl)-2-pyrrolidone, l-(N-(6-(3-Bromo-2-methylpyridyl))-aminocarbonylmethyl)-4(S)-(3-cyclopentyloxy- 4-methoxyphenyl)-2-pyrrolidone,

4(S)-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(N-(3-(4-methoxycarbonyl)-pyridyl)- aminocarbonylmethyl)-2-pyrrolidone,

4(S)-(3-Cyclopentyloxy-4-methoxyphenyl)-l-(N-(2-(6-methylpyridyl))- aminocarbonylmethyl)-2-pyrrolidone, l-(N-(3-(2-Cyanopyridyl))-aminocarbonylmethyl)-4(S)-(3-cyclopentyloxy-4- methoxyphenyl)-2-pyrrolidone,

4(S)-(4-Methoxy-3-(3(R)-tetrahydrofuryloxy)phenyl)-l-(N-(2-(6-methylpyridinyl))- aminocarbonylmethyl)-2-pyrrolidone, and pharmaceutically acceptable salts thereof.

Thus, according to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formula C and pharmaceutically acceptable salts thereof. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formula C, and pharmaceutically acceptable salts thereof, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole.

According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from Group in. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from Group in, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole. US Patent Application Serial No. 10/622,833 discloses a genus of PDE4 compounds defined by the following Formula, hereinafter referred to as Formula D:

wherein R¹ is H or alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen (e.g., CH₃, CHF₂, CF₃, etc.); in one preferred embodiment, R¹ is H; R² is alkyl having 1 to 12, preferably 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, Ci-₄-alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH₂CH₂- groups is replaced in each case by -CH=CH- or -C≡C- (e.g., CH₃, CHF₂, CF₃, methoxyethyl, etc.), cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof (e.g., cyclopentyl), cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, Cr₄- alkyl, Ci-₄-alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.), aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF₃ OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof (e.g., methylphenyl, methoxyphenyl, chlorophenyl, etc.), arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, which the arylalkyl radical is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF_3> OCF₃, alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more - CH₂CH₂- groups are each optionally replaced by -CH=CH- or -C≡C-, and one or more -CH₂- groups are each optionally replaced by -O- or - NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., phenylethyl, phenylpropyl, phenylbutyl, methoxyphenylethyl, methoxyphenylpropyl, chlorophenylethyl, chlorophenylpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, chlorophenoxyethyl, chlorophenylaminoethyl, etc.), a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof (e.g., cyclohexenyl, cyclohexadienyl, indanyl, tetrahydronaphthenyl, etc.), a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof (e.g., 3-thienyl, 3- tetrahydrofuranyl, 3-pyrrolyl, etc.), or a heterocycle- alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and the alkyl portion is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, OCF₃, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, wherein in the alkyl portion one or more -CH₂CH₂- groups are each optionally replaced by -CH=CH- or -C≡C-, and one or more -

CH₂- groups are each optionally replaced by -O- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., pyridylethyl, pydridylpropyl, methylpiperazinylethyl, etc.); is H, alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, cyano, Ci-₄-alkoxy, or combinations thereof (e.g., methyl, ethyl, propyl, etc.), a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion which is branched or unbranched has 1 to 5 carbon atoms, and which is unsubstituted or substituted in the carbocyclic portion one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, and the alkyl portion is optionally substituted by halogen, Cr₄- alkoxy, cyano or combinations thereof (e.g., cyclohexenylmethyl, etc.), arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF₃O, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trfluoromethyl, benzyl, methylenedioxobenzyl, etc.), or heteroarylalkyl group, wherein the heteroaryl portion may be partially or fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heteroarylalkyl group is unsubstituted or substituted one or more times in the heteroaryl portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF₃O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof (e.g., pyridylmethyl, pyridylpropyl, methylpyridylmethyl, chloropyridylmethyl, dichloropyridylmethyl, thienylmethyl, thiazolylmethyl, quinolinylmethyl, isoquinolinylmethyl, piperidinylmethyl, furanylmethyl, imidazolylmethyl, methylimidazolylmethyl, pyrrolylmethyl, etc.); R⁴ is H, cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof (e.g., cyclopentyl), aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF₃, amino, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, pyrrolyl, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl (e.g., 2-(2- tetrahydropyranyl)tetrazole-5-yl), hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg. te/t-butyldimethylsilyloxy), R⁵-L-, or combinations thereof (e.g., substituted or unsubstituted phenyl, naphthyl, and biphenyl, such as phenyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.), or heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg. te/t-butyldimethylsilyloxy), R -L-, or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.); R⁵ is H, alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times with halogen, Cr₄- alkyl, Ci-₄-alkoxy, oxo, or combinations thereof (e.g., methyl, ethyl, propyl, etc.), alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8, preferably 1 to 4 carbon atoms (e.g., dimethylamino, etc.), a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion has 1 to 5 carbon atoms, which is unsubstituted or substituted, preferably in the carbocyclic portion, one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof (e.g., cyclohexenylmethyl, etc.), cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof (e.g., cyclopentyl), cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, alkyl, alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.), aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, cycloalkyl, aryl, heteroaryl or combinations thereof (e.g., substituted or unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.), arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF₃O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trfluoromethyl, benzyl, methylenedioxobenzyl, etc.), a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, cycloalkyl, aryl, heteroaryl or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.), or a heterocycle- alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and the alkyl portion which is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle- alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF₃O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof (e.g., pyridylmethyl, pyridylpropyl, methylpridylmethyl, etc.); is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH₂- groups are each optionally replaced by -O-, -S-, -SO-, -SO₂-,

-NR⁶-, -SO₂NH-, -NHSO₂-, -SO₂NR⁶-, -NR⁶SO₂-, -CO-, -NR⁶CO-, - CONR⁶-, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH- (e.g., -0-, CH₂-, -CO-, -CO-O-, -0-C0-, -CO-NH-, -NH- CO-, -CH₂CH₂CH₂-NH-CO-, -CH₂-CH₂-O-, -SO₂-NH-CH₂CH₂-O-, - 0-CH₂CH₂-O-, -CH₂-NH-CO-, -CO-NH-CH₂-, -SO₂-NH-, -CH₂-NH- SO₂-, -CH₂CH₂CH₂-SO₂-NH-, -SO₂-, -CONHSO₂-, etc.); and R⁶ is H, alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, Ci-₄-alkyl, Ci-₄-alkoxy, oxo, or combinations thereof (e.g., methyl, ethyl, propyl, etc.); arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF₃O, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trfluoromethyl, benzyl, methylenedioxobenzyl, etc.); aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, (e.g., substituted or unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.), wherein at least one of R³ and R⁴ is other than H; and pharmaceutically acceptable salts thereof.

US Patent Application Serial No. 10/622,833 further discloses, among others, the following specific compounds (hereinafter referred to as Group IV): 3-Cyclopentyloxy-4-methoxy-N-(3-?err-butyloxycarbonylphenyl)-N-(3- pyridylmethyl))-aniline, N-(3,4-Bis-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4- aminobenzoic acid,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(5-fluoro-3-pyridylmethyl)-4- aminobenzoic acid,

N-(3-Cyclobutyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid,

N-(3,4-Dimethoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid ,

N-(3-Ethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid ,

N-(3-Isopropoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid , N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoic acid,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(5-chloro-3-pyridylmethyl)-3- aminobenzoic acid,

N-(3,4-Dimethoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid, 3-Cyclopentyloxy-4-methoxy-N-(4-(N,N-bis(2,4-dimethoxy)benzyl)- aminosulfonylphenyl)-N-(3-pyridylmethyl)aniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(4-(3,5- dichloropyridyl)methyl)-4-(5-(2H)-tetrazolyl)aniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4- methanesulfonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-(4- piperidinyl)sulfonylaniline,

N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-methylsulfonyl- aminocarbonylaniline, N- (3 -Cyclopentyloxy-4-methoxyphenyl) -N- (3 -pyridylmethyl)- 3 - (2-methylphenyl) - sulfonylaminocarbonylaniline,

N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-phenylsulfonyl- aminocarbonylaniline,

N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-phenylsulfonyl- aminocarbonylaniline,

N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-methylsulfonyl- aminocarbonylaniline, N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-(4- fluorophenyl)sulfonylaminocarbonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(4-(3,5- dichloropyridylmethyl)-4-phenylsulfonylaminocarbonylaniline, N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(4-(3,5- dichloropyridylmethyl)-4-methylsulfonylaminocarbonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4- ethylsulfonylaminocarbonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-(2- fluorophenyl) sulf onylaminocarbonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-(4- methoxyphenyl)sulfonylaminocarbonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-(3- chlorophenyl)sulfonylaminocarbonylaniline, N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4- methylsulfonylaminocarbonylaniline,

N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4- phenylsulfonylaminocarbonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4- phenylsulfonylaminocarbonylaniline,

N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(5-fluoro-3-pyridylmethyl)-3-(4- fluorophenyl)sulfonylaminocarbonylaniline,

N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-3- methylsulfonylaminocarbonylaniline, N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-3- phenylsulfonylaminocarbonylaniline,

N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-

(3-chlorophenyl)sulfonylaminocarbonylaniline,

N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4- (2-fluorophenyl)sulfonylaminocarbonylaniline,

N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-

(2,4-difluorophenyl)sulfonylaminocarbonylaniline,

N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-

(3,4-difluorophenyl)sulfonylaminocarbonylaniline, N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-

(1,1 -dimethylethyl) sulf onylaminocarbonylaniline,

N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-

(5-chloro-2-thienyl)sulfonylaminocarbonylaniline, N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-

(3-thienyl)sulfonylaminocarbonylaniline,

N-(3,4-Bisdifluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3- pyridylmethyl)-4-(4-fluorophenyl)sulfonylaminocarbonylaniline,

N-(3,4-Bisdifluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3- pyridylmethyl)-4-(3-fluorophenyl)sulfonylaminocarbonylaniline,

N-(3,4-Bisdifluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3- pyridylmethyl)-4-(3-chlorophenyl)sulfonylaminocarbonylaniline,

N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-

(3-cyanophenyl)sulfonylaminocarbonylaniline, N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-

(4-fluorophenyl)sulfonylaminocarbonylaniline,

N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-

(2-thienyl)sulfonylaminocarbonylaniline,

N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4- (3-fluorophenyl)sulfonylaminocarbonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-(3- cyanophenyl)sulfonylaminocarbonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(2,6-difluorobenzyl)-4-(4- fluorophenyl)sulfonylaminocarbonylaniline, N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-(3- fluorophenyl)sulfonylaminocarbonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-(2,4- difluorophenyl)sulfonylaminocarbonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-(3,4- difluorophenyl)sulfonylaminocarbonylaniline,

N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-(3- chlorophenyl)sulfonylaminocarbonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-fluorobenzyl)-4-(4- fluorophenyl)sulfonylaminocarbonylaniline, N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-(4- fluorophenyl)sulfonylaminocarbonylaniline,

N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-(3- fluorophenyl)sulfonylaminocarbonylaniline, N-(4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4- ethylsulfonylaminocarbonylaniline,

N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-4-(3- cyanophenyl)sulfonylaminocarbonylaniline,

N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-4-(4- fluorophenyl) sulf onylaminocarbonylaniline,

N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-4-(3- fluorophenyl)sulfonylaminocarbonylaniline,

N-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-4-(3- chlorophenyl)sulfonylaminocarbonylaniline, N-(3-Ethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-(2,4- difluorophenyl)sulfonylaminocarbonylaniline,

N-(3,4-Bisdifluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3- pyridylmethyl)-4-methylsulfonylaminocarbonylaniline,

N-(3-Cyclopropylmethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4- ethylsulfonylaminocarbonylaniline,

N-(3-Ethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-(4- fluorophenyl)sulfonylaminocarbonylaniline,

N-(3-Ethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-(3- chlorophenyl)sulfonylaminocarbonylaniline, N-(3-Ethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-(3,4- difluorophenyl)sulfonylaminocarbonylaniline,

N-(3-Ethoxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-(2- thienyl)sulfonylaminocarbonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4- cyclopentylmethylcarbonylaminosulfonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-(4- fluorophenyl)carbonylaminosulfonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-(l-ethyl-

5-methylpyrazol-4-yl)carbonylaminosulfonylaniline, N- (3 -Cyclopentyloxy-4-methoxyphenyl) -N- (3 -pyridylmethyl)- 3 - (4-methylpiperazin-

1 -yl)sulfonylaniline,

N- (3 -Cyclopentyloxy-4-methoxyphenyl) -N- (3 -pyridylmethyl)- 3 - (4- morpholinyl)sulfonylaniline, N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-(4-methylpiperazin-

1 -yl)sulfonylaniline,

N-(3-Cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-4-(4- morpholinyl)sulfonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-3-(4- methylpiperazin- 1 -yl)sulfonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-(4- methylpiperazin- 1 -yl)sulfonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-(4- morpholinyl)sulfonylaniline, N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-3-(4- morpholinyl)sulfonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-(4- ethylpiperazin- 1 -yl)sulfonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-(4- cyclohexylpiperazin- 1 -yl)sulfonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-(3,5- dimethylpiperazin- 1 -yl)sulfonylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-(4-(2- pyridyl)piperazin- 1 -yl) sulf onylaniline, N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-(4-(4- fluorophenyl)piperazin- 1 -yl) sulf onylaniline,

N-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-N-(3-pyridylmethyl)-4-(2,5- dimethylpyrrol- 1 -yl) sulf onylaniline, and pharmaceutically acceptable salts thereof.

Thus, according to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to

Formula D and pharmaceutically acceptable salts thereof. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formula D, and pharmaceutically acceptable salts thereof, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine

According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from Group IV. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from Group IV, and the antipsychotic agent is selected from: the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine

(Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, trifhipromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole.

US Patent Application Serial No. 10/622, 117 discloses a genus of PDE4 compounds defined by the following Formulas, hereinafter referred to as Formulas El and E2:

wherein

R¹ is H,

alkyl having 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen,

cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof, or

a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof,

R² is H, or

alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, cyano, and/or C₁- 4-alkoxy, and where one or more -CH₂CH₂- groups are optionally replaced in each case by -CH=CH- or -C≡C-,

R³ is H,

alkyl having 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, cyano, Cr₄- alkoxy, or combinations thereof,

a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion which is branched or unbranched has 1 to 5 carbon atoms, and which is unsubstituted or substituted in the carbocyclic portion one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, and the alkyl portion is optionally substituted by halogen, Cr₄-alkoxy, cyano or combinations thereof,

arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF₃O, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl, or

heterocycle-alkyl group, wherein the heterocyclic portion may be aromatic, or partially or fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF₃O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof;

R⁴ is H,

aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF₃, amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy, R⁵-L-, or combinations thereof, or

heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy, R⁵-L-, or combinations thereof;

R⁵ is H,

alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times with halogen, Ci-₄-alkyl, Ci-₄-alkoxy, oxo, or combinations thereof,

alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8 carbon atoms,

a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion has 1 to 5 carbon atoms, which is unsubstituted or substituted, preferably in the carbocyclic portion, one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof,

cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof,

cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, alkyl, alkoxy or combinations thereof,

aryl having 6 to 14 carbon atoms which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or combinations thereof,

arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF₃O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino, or combinations thereof, and/or substituted in the alkyl portion by halogen, cyano, θf methyl, or combinations thereof,

a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof, or a heterocycle-alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and the alkyl portion which is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF₃O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof;

L is a single bond or a divalent aliphatic radical having up to 8 carbon atoms wherein one or more -CH₂- groups are each optionally replaced by -O-, -S-, -

SO₂-, -SO-, -NR⁶-, -SO₂NH-, -NHSO₂-, -CO-, -NR⁶CO-, -CONR⁶-, - NHCONH-, -OCONH-, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH-; and

R⁶ is H,

alkyl having 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, Ci-₄-alkyl, C₁-

₄-alkoxy, oxo, or combinations thereof;

R⁷ is alkoxy or alkylthio, in each case having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen;

R⁸ is -C0-Ci_₄-alkyl which is branched or unbranched and where the alkyl is unsubstituted or substituted one or more times by halogen, or is

V R⁹ <^Y X> or

R⁹ is H or alkyl having 1 to 4 carbon atoms, which is branched or unbranched, and which is unsubstituted or substituted one or more times by halogen;

R¹⁰ is alkyl having 1 to 6 carbon atoms, which is branched or unbranched, and which is unsubstituted or substituted one or more times by halogen;

R¹¹ is alkyl having 1 to 6 carbon atoms, which is branched or unbranched, and which is unsubstituted or substituted one or more times by halogen;

X and Y are each independently O or S; and

A is alkylene having 2 to 7 carbon atoms which is unsubstituted or substituted one or more times by halogen; wherein in Formula EI both of R³ and R⁴ are other than H and in Formula E2 I at least one of R³ and R⁴ is other than H; or a pharmaceutically acceptable salt thereof; wherein an optically active compound can be in the form of one of its separate enantiomers or mixtures thereof, including racemic mixtures.

US Patent Application Serial No. 10/622,117 also discloses, among others, the following specific compounds (hereinafter referred to as Group V):

7-Methoxy-2-(2-methyl-(l,3-dioxolane-2-yl))-4-[_V-(4- pyridylmethyl)] aminobenzofuran, 7-Methoxy-2-(2-methyl-(l,3-dioxolane-2-yl))-4-[N-(3- pyridylmethyl)] aminobenzofuran,

7-Methoxy-2-(2-me%l-(l,3-dioxolane-2-yl))-4-[iV-phenyl-iV-(4- pyridylmethyl)] aminobenzofuran,

7-Methoxy-2-(2-methyl-(l,3-dioxolane-2-yl))-4-[iV-(3-cyanophenyl)-iV-(3- pyridylmethyl)] aminobenzofuran,

7-Methoxy-2-(2-methyl-(l,3-dioxolane-2-yl))-4-[iV-phenyl-iV-(3- pyridylmethyl)] aminobenzofuran,

7-Methoxy-2-(2-methyl-(l,3-dioxolane-2-yl))-4-[iV-(3-cyanophenyl)-iV-(4- pyridylmethyl)] aminobenzofuran, 7-Methoxy-2-(2-methyl-(l,3-dioxolane-2-yl))-4-[iV-(4-acetylphenyl)-iV-(3- pyridylmethyl)] aminobenzofuran, 7-Methoxy-2-(2-methyl-(l,3-dioxolane-2-yl))-4-[N-(4-carboxyphenyl)-N-(3- pyridylmethyl)] aminobenzofuran,

7-Methoxy-2-(2-methyl-(l,3-dioxolane-2-yl))-4-[N-(4-(2H-tetrazol-5-yl)phenyl)-N-

(3-pyridylmethyl]aminobenzofuran, 7-Methoxy-2-(2-methyl-(l,3-dioxolane-2-yl))-4-[iV-(4-carboxy-3-chlorophenyl)-iV-(3- pyridylmethyl)] aminobenzofuran,

7-Methoxy-2-(2-methyl-(l,3-dioxolane-2-yl))-4-[iV-(3-carboxy-5-fluorophenyl)-iV-(3- pyridylmethyl)] aminobenzofuran,

2-Acetyl-7-methoxy-4-(N-(4-cyanophenyl)-N-(3-pyridylmethyl))aminobenzofuran, 2-Acetyl-7-methoxy-4-(N-phenyl-N-(4-pyridylmethyl))aminobenzofuran,

2-Acetyl-7-methoxy-4-(N-(3-carboxyphenyl)-N-(3-pyridylmethyl))aminobenzofuran,

7-Methoxy-2-(2-methyl-(l,3-dioxolane-2-yl))-4-(N-(4-cyanophenyl)-N-(3- pyridylmethyl))-aminobenzofuran,

2-Acetyl-7-methoxy-4-(N-(3-cyanophenyl)-N-(3-pyridylmethyl))aminobenzofuran, 2-Acetyl-7-methoxy-4-(N-phenyl-N-(3-pyridylmethyl))aminobenzofuran,

2-Acetyl-7-methoxy-4-(N-(3-cyanophenyl)-N-(4-pyridylmethyl))aminobenzofuran,

2-Acetyl-7-methoxy-4-(N-(4-acetylphenyl)-N-(3-pyridylmethyl))aminobenzofuran,

2-Acetyl-7-methoxy-4-[iV-(4-carboxyphenyl)-iV-(3-pyridylmethyl)]aminobenzofuran,

2-Acetyl-7-methoxy-4-[iV-(4-(2H-tetrazol-5-yl)phenyl)-iV-(3- pyridylmethyl] aminobenzofuran,

2-Acetyl-7-methoxy-4-[7V-(4-carboxy-3-chlorophenyl)-./V-(3- pyridylmethyl)] aminobenzofuran,

2-Acetyl-7-methoxy-4-[iV-(3-carboxy-5-fluorophenyl)-iV-(3- pyridylmethyl)] aminobenzofuran, 2-Acetyl-7-methoxy-iV-(4-phenylsulfonylaminocarbonylphenyl)-iV-(3-pyridylmethyl]-

4-aminobenzofuran, and pharmaceutically acceptable salts thereof.

According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formula El and E2, and pharmaceutically acceptable salts thereof, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole.

According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from Group V. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from Group V, and pharmaceutically acceptable salts thereof, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine

(Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®,

Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole.

US Patent Application Serial No. 10/636,979 discloses a genus of PDE4 compounds defined by the following Formula, hereinafter referred to as Formula F:

wherein, R¹ is H,

alkyl having 1 to 5 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, or combinations thereof, and wherein a - CH₂- group can be optionally replaced by -O-, -S-, or -NH-,

cycloalkyl having 3 to 6 carbon atoms, or

cycloalkylalkyl having 4 to 7 C atoms;

alkyl ether having 3 to 12 carbon atoms, cycloalkyl having 3 to 12 carbon atoms, which is unsubstituted or substituted one or more times by halogen, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-4 alkoxy, cyano or combinations thereof,

aryl having 6 to 14 carbon atoms (e.g., phenyl), which is unsubstituted or substituted one or more times by halogen, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, Ci_₄-alkoxy, halogenated C_1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1-4 alkylamino, di-Ci_₄-alkylamino, C_1-4- hydroxyalkyl, C_1-4-hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C₂_₄-acyl, C₂_₄-alkoxycarbonyl, Ci_₄-alkylthio, C_1-4- alkylsulphinyl, C_1-4-alkylsulphonyl, phenoxy, benzyloxy, -NR³R⁴, -

CO-NH-SO₂-R⁵, -SO₂-NH-CO-R⁵ or combinations thereof,

arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted one or more times by halogen, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1- ₄-alkoxy, halogenated C_1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1-4 alkylamino, di-Ci_₄-alkylamino, C_1-4-hydroxyalkyl, C_1-4- hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C₂_₄-acyl, C₂. 4-alkoxycarbonyl, C_1-4-alkylthio, C_1-4-alkylsulphinyl, C_1-4-alkylsulphonyl, phenoxy, benzyloxy, -NR³R⁴, -CO-NH-SO₂-R⁵, -SO₂-NH-CO-R⁵ or combinations thereof,

heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom (e.g., pyrimidinyl), which is unsubstituted or substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1-4- alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino,

C_1-4-alkylamino, di-C_1-4-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, C_1-4-alkylthio, C_1-4-alkylsulphinyl, C_1-4-alkylsulphonyl, morpholinyl, piperazinyl, -NR³R⁴, -CO-NH-SO₂-R⁵, -SO₂-NH-CO-R⁵ or combinations thereof,

heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and the alkyl portion has 1 to 3 carbon atoms, the heteroaryl portion is unsubstituted or is substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1-4- alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C₁_₄-alkylamino, di-C₁_₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, Ci_₄-alkylthio, C_1-4-alkylsulphinyl, C_1-4-alkylsulphonyl, morpholinyl, piperazinyl, -NR³R⁴, -CO-NH-SO₂-R⁵, -SO₂-NH-CO-R⁵ or combinations thereof,

heterocycle having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or is substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, Ci-₄-alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1-4- alkylamino, di-C₁_₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof (e.g., piperidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, piperazinyl, and indolinyl),

heterocycle-alkyl wherein the heterocycle portion has 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and the alkyl portion has 1 to 3 carbon atoms, the heterocycle portion is nonaromatic and is unsubstituted or is substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1-4-alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, Ci-₄-alkylamino, di-Ci-₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof (e.g., piperidinyl-ethyl and pyrrolinyl-methyl), or

carbocycle which is nonaromatic, monocyclic or bicyclic, group having 5 to 14 carbon atoms, which is unsubstituted or is substituted one or more times by halogen, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1-4- alkoxy, halogenated Ci_₄-alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1-4 alkylamino, di-Ci-₄-alkylamino, C_1-4- hydroxyalkyl, Ci_₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C_2-4-acyl, C₂_₄-alkoxycarbonyl, Ci_₄-alkylthio, C_1-4- alkylsulphinyl, Ci-₄-alkylsulphonyl, phenoxy, -CO-NH-SO₂-R⁵, -SO₂- NH-CO-R⁵ or combinations thereof;

R³ is cycloalkyl having 3 to 8 carbon atoms (e.g., cyclopropyl), which is unsubstituted or substituted one or more times by halogen, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-4 alkoxy, cyano or combinations thereof,

aryl having 6 to 14 carbon atoms (e.g., phenyl), which is unsubstituted or substituted one or more times by halogen, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, Ci_₄-alkoxy, halogenated C_1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1-4 alkylamino, di-Ci-₄-alkylamino, C_1-4- hydroxyalkyl, C_1-4-hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C₂_₄-acyl, C₂_₄-alkoxycarbonyl, C_1-4-alkyrthio, C_1-4- alkylsulphinyl, C_1-4-alkylsulphonyl, phenoxy, benzyloxy, or combinations thereof,

heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom (e.g., pyridinyl), which is unsubstituted or substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1-4- alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1-4-alkylamino, di-C_1-4-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, C_1-4-alkylthio, C_1-4-alkylsulphinyl, C_1-4-alkylsulphonyl, morpholinyl, piperazinyl, or combinations thereof, C₁_₄-alkylsulphonyl, or

Ci-4-alkyl-CO-O- Ci-4-alkylene;

R⁴ is H or alkyl having 1 to 4 carbon atoms which is straight chain or branched, and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano or combinations thereof; and

R⁵ is alkyl having 1 to 12 carbon atoms (e.g., methyl, ethyl), which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano or combinations thereof, wherein one or more -CH₂- groups is each independently optionally replaced by -O-, -S-, or -NH-, and wherein optionally one or more -CH₂CH₂- groups is replaced in each case by - CH=CH- or -C≡C-,

cycloalkyl having 3 to 8 carbon atoms (e.g., cyclopropyl), which is unsubstituted or substituted one or more times by halogen, C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-4 alkoxy, cyano or combinations thereof,

aryl having 6 to 14 carbon atoms (e.g., phenyl), which is unsubstituted or substituted one or more times by halogen, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, Ci_₄-alkoxy, halogenated C_1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1-4 alkylamino, di-Ci-₄-alkylamino, C_1-4- hydroxyalkyl, Ci-₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C₂_₄-acyl, C₂_₄-alkoxycarbonyl, C^-alkylthio, C_1-4- alkylsulphinyl, C^-alkylsulphonyl, phenoxy, benzyloxy, or combinations thereof (e.g., phenyl, fluorophenyl, difluorophenyl, chlorophenyl), arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted one or more times by halogen, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C₁. ₄-alkoxy, halogenated C_1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1-4 alkylamino, di-Ci-₄-alkylamino, Ci_₄-hydroxyalkyl, C_1-4- hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C₂_₄-acyl, C₂.

₄-alkoxycarbonyl, Ci_₄-alkylthio, Ci_₄-alkylsulphinyl, Ci_₄-alkylsulphonyl, phenoxy, benzyloxy, -NR³R⁴, or combinations thereof,

heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom (e.g., pyridinyl), which is unsubstituted or substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1-4- alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, Ci_₄-alkylamino, di-Ci_₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, C_1-4-alkylthio, C_1-4-alkylsulphinyl, C_1-4-alkylsulphonyl, morpholinyl, piperazinyl, or combinations thereof (e.g., thienyl, chlorothienyl, benzothienyl, chloromethylbenzothienyl, benzothiazolyl, ethoxybenzothiazolyl, pyridyl, methylpyridyl, chloropyridyl),

heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and the alkyl portion has 1 to 3 carbon atoms, the heteroaryl portion is unsubstituted or is substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1-4- alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, Ci-₄-alkylamino, di-Ci-₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, C_1-4-alkylthio, C_1-4-alkylsulphinyl, C_1-4-alkylsulphonyl, morpholinyl, piperazinyl, -NR³R⁴,or combinations thereof, heterocycle having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or is substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, Ci-₄-alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1-4- alkylamino, di-C₁_₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof (e.g., piperidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, piperazinyl, and indolinyl), or

heterocycle-alkyl wherein the heterocycle portion has 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and the alkyl portion has 1 to 3 carbon atoms, the heterocycle portion is nonaromatic and is unsubstituted or is substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, Ci_₄-alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1-4-alkylamino, di- Ci-₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof

(e.g., piperidinyl-ethyl and pyrrolinyl-methyl);

and pharmaceutically acceptable salts thereof, with the provisos that: (a) when R¹ is methyl, then R² is not arylalkyl, heteroarylalkyl, 2-

(l,2,3,4-tetrahydro)quinolinyl-methyl, methyl or 2-butyl;

(b) when R¹ is cyclopropyl, R² is not 4-methylbenzyl;

(c) when R¹ is ethyl, then R² is not ethyl, 3-aminobenzyl, 2- thienylmethyl, 3-thienylmethyl, or 2-pyridylmethyl; (d) when R¹ is cyclopropyl, then R² is not cyclopropylmethyl;

(f) when R¹ is methoxyethyl, then R² is not benzyl, 3- dimethylaminobenzyl, or 3-thienylmethyl; (g) when R¹ is iso-butyl, then R² is not benzyl; and

(h) when R¹ is n-butyl, then R² is not n-butyl. US Patent Application Serial No. 10/636,979 also discloses, among others, the following specific compounds (hereinafter referred to as Group VI): 6-Cyclopropylamino-9-(2,6-dimethoxypyrimidin-4-yl)-2-trifluoromethylpurine, 6-Cyclopropylamino-9-(4,6-dimethoxypyrimidin-2-yl)-2-trifluoromethylpurine, 6-Cyclopropylamino-9-(2-methylsulfonylpyrimidin-4-yl)-2-trifluoromethyl-purine, 6-Cyclopropylamino-9-(2-methoxypyrimidin-4-yl)-2-trifluoromethylpurine, 6-Methylamino-9-(3-methoxycarbonylphenyl)-2-trifluoromethylpurine [or 9-(3- Methoxycarbonylphenyl)-6-methylamino-2-trifluoromethylpurine], 6-Cyclopropylamino-9-(3-carboxyphenyl)-2-trifluoromethylpurine [or 9-(3- Carboxyphenyl)-6-cyclopropylamino-2-trifluoromethylpurine] ,

6-Cyclopropylamino-9-(3-methoxycarbonylphenyl)-2-trifluoromethylpurine, 6-Methylamino-9-(2-methylthiopyrimidin-4-yl)-2-trifluoromethylpurine, 6-Methylamino-9-(2-methoxypyrimidin-4-yl)-2-trifluoromethylpurine, 6-Ethylamino-9-(2-chloropyrimidin-4-yl)-2-trifluoromethylpurine [or 9-(2- Chloropyrimidin-4-yl)-6-ethylamino-2-trifluoromethylpurine] ,

6-Methylamino-9-(2-N,N-dimethylaminopyrimidin-4-yl)-2-trifluoromethylpurine [or -9-(2-N,N-Dimethylaminopyrimidin-4-yl)- 6-methylamino 2-trifluoromethylpurine, 6-Methylamino-9-(2-aminopyrimidin-4-yl)-2-trifluoromethylpurine [or 9-(2- Aminopyrimidin-4-yl)-6-methylamino-2-trifluoromethylpurine], 6-Methylamino-9-(2-N-methylaminopyrimidin-4-yl)-2-trifluoromethylpurine,

6-Methylamino-9-(2-N-ethylaminopyrimidin-4-yl)-2-trifluoromethylpurine [or 9- (2- N-Ethylaminopyrimidin-4-yl)-6-methylamino-2-trifluoromethylpurine], 6-Methylamino-9-(2-N-phenylaminopyrimidin-4-yl)-2-trifluoromethylpurine, 6-Cyclopropylamino-9-(2-N-(4-pyridylamino)pyrimidin-4-yl)-2- trifluoromethylpurine,

6-Cyclopropylamino-9-(2-N,N-dimethylaminopyrimidin-4-yl)-2- trifluoromethylpurine,

6-Cyclopropylamino-9-(2-methylpyrimidin-4-yl)-2-trifluoromethylpurine, 6-Cyclopropylamino-9-(2-N-methylaminopyrimidin-4-yl)-2-trifluoromethylpurine, 6-Cyclopropylamino-9-(2-N-ethylaminopyrimidin-4-yl)-2-trifluoromethylpurine, 6-Cyclopropylamino-9-(2-N-cyclopropylaminopyrimidin-4-yl)-2- trifluoromethylpurine, 6-Methylamino-9-(2-N-methylaminopyrimidin-4-yl)-2-trifluoromethylpurine, 6-Methylamino-9-(2-N-cyclopropylaminopyrimidin-4-yl)-2-trifluoromethylpurine [or 9-(2-N-Cyclopropylaminopyrimidin-4-yl)- 6-methylamino-2-trifluoromethylpurine], 6-Cyclopropylamino-9-(2-N-methoxycarbonylmethylaminopyrimidin-4-yl)-2- trifluoromethylpurine, 6-Cyclopropylamino-9-(2-N-methoxycarbonylethylaminopyrimidin-4-yl)-2- trifluoromethylpurine,

6-Cyclopropylamino-9-(2-(4-morpholinyl)pyrimidin-4-yl)-2-trifluoromethylpurine, 6-Cyclopropylamino-9-(2-N-hydroxyethylaminopyrimidin-4-yl)-2- trifluoromethylpurine, 6-Cyclopropylamino-9-(2-( 1 -piperazinyl)pyrimidin-4-yl)-2-trifluoromethylpurine, 6-Methylamino-9-(2-benzyloxyphenyl)-2-trifluoromethylpurine [or 9-(2- Benzyloxyphenyl)-6-methylamino-2-trifluoromethylpurine], 6-Methylamino-9-(3-benzyloxyphenyl)-2-trifluoromethylpurine [or 9-(3- Benzyloxyphenyl)-6-methylamino-2-trifluoromethylpurine], 6-Methylamino-9-(3-iodophenyl)-2-trifluoromethylpurine [or 9-(3-Iodophenyl)- 6- methylamino-2-trifluoromethylpurine],

6-Methylamino-9-(2-methylsulfinylpyrimidin-4-yl)-2-trifluoromethylpurine, 6-Methylamino-9-(3-hydroxyphenyl)-2-trifluoromethylpurine [or 9-(3- Hydroxyphenyl)-6-methylamino-2-trifluoromethylpurine], 6-Methylamino-9-(2-hydroxyphenyl)-2-trifluoromethylpurine [or 9-(2- Hydroxyphenyl)-6-methylamino-2-trifluoromethylpurine], 6-Methylamino-9-(2-methylsulfonylpyrimidin-4-yl)-2-trifluoromethylpurine, 6-Cyclopropylamino-9-(3-benzyloxyphenyl)-2-trifluoromethylpurine [or 9-(3- Benzyloxyphenyl)-6-cyclopropylamino-2-trifluoromethylpurine], 6-Cyclopropylamino-9-(4-benzyloxyphenyl)-2-trifluoromethylpurine [or 9-(4- Benzyloxyphenyl)-6-cyclopropylamino-2-trifluoromethylpurine], 6-Methylamino-9-(2-fluoro-3-methoxyphenyl)-2-trifluoromethylpurine [or 9-(2- Fluoro-3-methoxyphenyl)-6-methylamino-2-trifluoromethylpurine], 6-Methylamino-9-(3-nitrophenyl)-2-trifluoromethylpurine, 6-Methylamino-9-(3-trifluoromethoxyphenyl)-2-trifluoromethylpurine,

6-Methylamino-9-(3-methylsulfonylaminophenyl)-2-trifluoromethylpurine, 6-Cyclopropylamino-9-(2-hydroxyphenyl)-2-trifluoromethylpurine, 6-Methylamino-9-(2-nitrophenyl)-2-trifluoromethylpurine, 6-Methylamino-9-(3-methylthiophenyl)-2-trifluoromethylpurine, 6-Methylamino-9-(2-methoxycarbonylphenyl)-2-trifluoromethylpurine [or 9-(2- Methoxycarbonylphenyl)-6-methylamino-2-trifluoromethylpurine], 6-Methylamino-9-(8-quinolinyl)-2-trifluoromethylpurine,

6-Methylamino-9-(3-aminophenyl)-2-trifluoromethylpurine [or 9-(3-Aminophenyl)-6- methylamino-2-trifluoromethylpurine] ,

6-Methylamino-9-(3-N,N-dimethylaminophenyl)-2-trifluoromethylpurine [or 9-(3- N,N-Dimethylaminophenyl)-6-methylamino-2-trifluoromethylpurine], 6-Cyclopropylamino-9-(3-hydroxyphenyl)-2-trifluoromethylpurine, 6-Cyclopropylamino-9-(4-hydroxyphenyl)-2-trifluoromethylpurine, 6-Methylamino-9-(3-methylaminophenyl)-2-trifluoromethylpurine,

6-Methylamino-9-(2-trifluoromethoxyphenyl)-2-trifluoromethylpurine, 6-Methylamino-9-(2-methylsulfinylphenyl)-2-trifluoromethylpurine, 6-Methylamino-9-(3-methylsulfonylphenyl)-2-trifluoromethylpurine, 6-Methylamino-9-(2-methylsulfonylaminophenyl)-2-trifluoromethylpurine, 9-(3-Chloro-4-pyridyl)-6-cyclopropylamino-2-trifluoromethylpurine, 6-Cyclopropylamino-9-(2-methyl-4-pyridyl)-2-trifluoromethylpurine, 6-Cyclopropylamino-9-(3-methyl-4-pyridyl)-2-trifluoromethylpurine, 9-(3-Ethylsulfonylphenyl)-6-methylamino-2-trifluoromethylpurine, 6-Cyclopropylamino-9-(3-ethylsulfonylphenyl)-2-trifluoromethylpurine, 6-Cyclopropylamino-9-(3-trifluoromethoxylphenyl)-2-trifluoromethylpurine, 6-Cyclopropylamino-9-(2-trifluoromethyl-5-pyridyl)-2-trifluoromethyl-purine, 9-(2-Chloro-4-pyridyl)-6-cyclopropylamino-2-trifluoromethylpurine, 9-(5-Chloro-3-pyridyl)-6-cyclopropylamino-2-trifluoromethylpurine, 6-Cyclopropylamino-9-(2-methoxycarbonylphenyl)-2-trifluoromethylpurine, 6-Cyclopropylamino-9-(4-methoxycarbonylphenyl)-2-trifluoromethylpurine, 9-(3-Methoxycarbonylphenyl)-6-methylamino-2-trifluoromethylpurine, 9-(4-Methoxycarbonylphenyl)-6-methylamino-2-trifluoromethylpurine, 6-Cyclopropylamino-9-(3-methylsulfonylphenyl)-2-trifluoromethylpurine, 6-Methylamino-9-(2-methylsulfinylpyrimidin-4-yl)-2-trifluoromethylpurine, 6-Methylamino-9-(2-methylsulfonylpyrimidin-4-yl)-2-trifluoromethylpurine, 6-Methylamino-9-(2-methylsulfinylphenyl)-2-trifluoromethylpurine, 6-Methylamino-9-(3-methylsulfonylphenyl)-2-trifluoromethylpurine, 9-(4-Carboxyphenyl)-6-cyclopropylamino-2-trifluoromethylpurine, 9-(2-Carboxyphenyl)-6-cyclopropylamino-2-trifluoromethylpurine, 9-(3-Carboxyphenyl)-6-methylamino-2-trifluoromethylpurine,

9-(4-Carboxyphenyl)-6-methylamino-2-trifluoromethylpurine,

6-Cyclopropylamino-9-(3-methylsulfonylaminocarbonylphenyl)-2- trifluoromethylpurine, 6-Cyclopropylamino-9-(3-methylsulfonylaminocarbonylphenyl)-2- trifluoromethylpurine,

6-Methylamino-9-(3-methylsulfonylaminocarbonylphenyl)-2-trifluoromethylpurine,

6-Methylamino-9-(4-methylsulfonylaminocarbonylphenyl)-2-trifluoromethylpurine,

6-Cyclopropylamino-9-(4-methylsulfonylaminocarbonylphenyl)-2- trifluoromethylpurine,

6-Cyclopropylamino-9-(3-ethylsulfonylaminocarbonylphenyl)-2- trifluoromethylpurine,

6-Cyclopropylamino-9-[3-(4-fluorophenyl)sulfonylaminocarbonylphenyl]-2- trifluoromethylpurine, 6-Cyclopropylamino-9-(4-ethylsulfonylaminocarbonylphenyl)-2- trifluoromethylpurine,

6-Cyclopropylamino-9-(3-phenylsulfonylaminocarbonylphenyl)-2- trifluoromethylpurine,

6-Cyclopropylamino-9-[4-(4-fluorophenyl)sulfonylaminocarbonylphenyl]-2- trifluoromethylpurine,

6-Cyclopropylamino-9-(4-phenylsulfonylaminocarbonylphenyl)-2- trifluoromethylpurine,

9-[3-(3-Chlorophenyl)sulfonylaminocarbonylphenyl]-6-cyclopropylamino-2- trifluoromethylpurine, 6-Cyclopropylamino-9-[3-(2,6-difluorophenyl)sulfonylamino-carbonylphenyl]-2- trifluoromethylpurine,

6-Cyclopropylamino-9-[3-(2,4-difluorophenyl)sulfonylamino-carbonylphenyl]-2- trifluoromethylpurine,

6-Cyclopropylamino-9-[3-(2-thienyl)sulfonylaminocarbonylphenyl]-2- trifluoromethylpurine,

9-[3-(5-Chloro-2-thienyl)sulfonylaminocarbonylphenyl]-6-cyclopropylamino-2- trifluoromethylpurine,

9-[3-(5-Chloro-3-methylbenzothien-2-yl)sulfonylaminocarbonylphenyl]-6- cyclopropylamino-2-trifluoromethylpurine, 6-Cyclopropylamino-9-[3-(6-ethoxy-2-benzothiazolyl)sulfonylamino- carbonylphenyl]-2-trifluoromethylpurine,

6-Cyclopropylamino-9-[3-(5-methyl-2-pyridyl)sulfonylamino-carbonylphenyl]-2- trifluoromethylpurine, 9-[3-(4-Chloro-3-pyridyl)sulfonylaminocarbonylphenyl]-2-trifluoromethylpurine, and, 6-Methylamino-9-(2-methylaminopyrimidin-4-yl)-2-trifluoromethylpurine,

and pharmaceutically acceptable salts thereof.

Thus, according to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formula F and pharmaceutically acceptable salts thereof. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formula F, and pharmaceutically acceptable salts thereof, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from Group VI. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from Group VI, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole.

US Patent Application Serial No. 10/636,996 discloses a genus of PDE4 compounds defined by the following Formula, hereinafter referred to as Formula G:

wherein, R¹ is halogen (e.g., chloro), dimethylamino,

alkyl having 1 to 6 carbon atoms (e.g., ethyl), which is unsubstituted or substituted one or more times by halogen, hydroxy, or combinations thereof, and wherein a -CH₂- group can be optionally replaced by -O-, -S-, or -NCH₃-, and/or one or more - CH₂-CH₂- groups can each be replaced by -CH=CH- or - C≡C-,

cycloalkyl having 3 to 6 carbon atoms (e.g., cyclopropyl),

cycloalkylalkyl having 4 to 7 C atoms (e.g., cyclopropylmethyl),

methoxy, or

pyrrolidinyl;

is alkyl having 1 to 12 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano or combinations thereof, wherein one or more -CH₂- groups is each independently optionally replaced by -O-, -

S-, or -NH-, and wherein optionally one or more -CH₂CH₂- groups is replaced in each case by -CH=CH- or -C≡C-,

alkyl ether having 3 to 12 carbon atoms,

cycloalkylalkyl having 4 to 12 C atoms, which is unsubstituted or substituted one or more times by C_1-4 alkyl, halogenated C_1-4 alkyl, C_1-4 alkoxy, cyano, halogen, or combinations thereof, aryl having 6 to 14 carbon atoms (e.g., phenyl), which is unsubstituted or substituted one or more times by halogen, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1-4 -alkoxy, halogenated C_1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C 1-4 alkylamino, di-Cl-4-alkylamino, C 1-4- hydroxyalkyl, C_1-4 -hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C₂_₄-acyl, C₂_₄-alkoxycarbonyl, C_1-4 -alkylthio, C_1-4 - alkylsulphinyl, C_1-4 -alkylsulphonyl, phenoxy, benzyloxy, -NR³R⁴ , -CO-NH- SO₂-R⁵, -SO₂-NH-CO-R⁵ or combinations thereof,

arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted one or more times by halogen, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1- ₄-alkoxy, halogenated C_1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1-4 alkylamino, di-Ci_₄-alkylamino, C_1-4-hydroxyalkyl, C_1-4- hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C₂_₄-acyl, C₂. ₄-alkoxycarbonyl, C_1-4-alkylthio, C_1-4-alkylsulphinyl, C_1-4-alkylsulphonyl, phenoxy, benzyloxy, -NR³R⁴ , -CO-NH-SO₂-R⁵, -SO₂-NH-CO-R⁵ or combinations thereof,

heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom (e.g., pyrimidinyl), which is unsubstituted or substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1-4- alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C₁. ₄-alkylamino, di-Ci-₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, C_1-4-alkylthio, C_1-4-alkylsulphinyl, C_1-4-alkylsulphonyl, morpholinyl, piperazinyl, -NR³R⁴ , -CO-NH-SO₂-R⁵, -SO₂-NH-CO-R⁵ or combinations thereof,

heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and the alkyl portion has 1 to 3 carbon atoms, the heteroaryl portion is unsubstituted or is substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1-4- alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C₁_₄-alkylamino, di-C₁_₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, Ci_₄-alkylthio, C^-alkylsulphinyl, Ci-₄-alkylsulphonyl, morpholinyl, piperazinyl, -NR³R⁴ , -CO-NH-SO₂-R⁵, -SO₂-NH-CO-R⁵ or combinations thereof,

heterocycle having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or is substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, Ci-₄-alkoxy, halogenated Ci_₄ alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1-4- alkylamino, di-C₁_₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof (e.g., piperidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, piperazinyl, and indolinyl),

heterocycle-alkyl wherein the heterocycle portion has 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and the alkyl portion has 1 to 3 carbon atoms, the heterocycle portion is nonaromatic and is unsubstituted or is substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated Ci_₄ alkyl, hydroxy, C^-alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, Ci-₄-alkylamino, di-Ci-₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof (e.g., piperidinyl-ethyl and pyrrolinyl-methyl), or

carbocycle which is nonaromatic, monocyclic or bicyclic, group having 5 to 14 carbon atoms, which is unsubstituted or is substituted one or more times by halogen, C_1-4 alkyl, halogenated Ci_₄ alkyl, hydroxy, C^-alkoxy, halogenated

Ci_₄ alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1-4 alkylamino, di- Ci-₄-alkylamino, Ci-₄-hydroxyalkyl, Ci-₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C₂_₄-acyl, C₂_₄-alkoxycarbonyl, Ci-₄-alkylthio, C₁_₄4-alkylsulphinyl, C^-alkylsulphonyl, phenoxy, benzyloxy, -NR³R⁴ , -CO- NH-SO₂-R⁵, -SO₂-NH-CO-R⁵ or combinations thereof;

is cycloalkyl having 3 to 8 carbon atoms (e.g., cyclopropyl), which is unsubstituted or substituted one or more times by halogen, Ci_₄ alkyl, halogenated C_1-4 alkyl, C_1-4 alkoxy, cyano or combinations thereof,

cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, Ci-₄-alkyl, Ci-₄-alkoxy, halogenated C_1-4 alkyl, halogenated C_1-4 alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.),

aryl having 6 to 14 carbon atoms (e.g., phenyl), which is unsubstituted or substituted one or more times by halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy, Ci_₄-alkoxy, halogenated C_1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1-4 alkylamino, di- Ci_₄-alkylamino, C_1-4- hydroxyalkyl, C_1-4-hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C_2-4-acyl, C₂_₄-alkoxycarbonyl, Ci_₄-alkylthio, C_1-4- alkylsulphinyl, C_1-4-alkylsulphonyl, phenoxy, benzyloxy, or combinations thereof,

heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom (e.g., pyridinyl), which is unsubstituted or substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1-4- alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, Ci-₄-alkylamino, di-Ci-₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, C_1-4-alkylthio, C_1-4-alkylsulphinyl, C_1-4-alkylsulphonyl, morpholinyl, piperazinyl, or combinations thereof,

C_1-4-alkylsulphonyl, or

Ci-4-alkyl-CO-O- Ci-4-alkylene;

is H or alkyl having 1 to 4 carbon atoms which is straight chain or branched, and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano or combinations thereof; is alkyl having 1 to 12 carbon atoms (e.g., methyl, ethyl), which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano or combinations thereof, wherein one or more -CH₂- groups is each independently optionally replaced by -O-, -S-, or NH-, and wherein optionally one or more -CH₂CH₂- groups is replaced in each case by -CH=CH- or -C≡C-

cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, Ci-₄-alkyl, Cr₄-alkoxy, halogenated C_1-4 alkyl, halogenated C_1-4 alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.),

aryl having 6 to 14 carbon atoms (e.g., phenyl), which is unsubstituted or substituted one or more times by halogen, C_1-4alkyl, halogenated C_1-4 alkyl, hydroxy, Ci_₄-alkoxy, halogenated Cl-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1-4 alkylamino, di- Ci_₄-alkylamino, C_1-4-hydroxyalkyl, Ci_₄-hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C_2-4- acyl, C₂_₄-alkoxycarbonyl, C_1-4-alkylthio, C_1-4-alkylsulphinyl, C_1-4- alkylsulphonyl, phenoxy, benzyloxy, -NR³R⁴ or combinations thereof (e.g., phenyl, fluorophenyl, difluorophenyl, chlorophenyl),

arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted one or more times by halogen, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C₁. ₄-alkoxy, halogenated C_1-4 alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, C_1-4 alkylamino, di-Ci-₄-alkylamino, C_1-4-hydroxyalkyl, C_1-4- hydroxyalkoxy, carboxy, cyano, hydroxamic acid, carboxamide, C₂_₄-acyl, C₂- ₄-alkoxycarbonyl, Ci_₄-alkylthio, C₁_₄-alkylsulphinyl, C^-alkylsulphonyl, phenoxy, benzyloxy, -NR³R⁴ , or combinations thereof,

heterocycle having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or is substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated Ci_₄ alkyl, hydroxy, C^-alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C_1-4- alkylamino, di-Ci-₄-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof (e.g., piperidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, morpholinyl, piperazinyl, and indolinyl),

heterocycle-alkyl wherein the heterocycle portion has 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and the alkyl portion has 1 to 3 carbon atoms, the heterocycle portion is nonaromatic and is unsubstituted or is substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, Ci-₄-alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C₁_₄-alkylamino, di- C_1-4-alkylamino, carboxy, alkoxycarbonyl, or combinations thereof (e.g., piperidinyl-ethyl and pyrrolinyl-methyl),

heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom (e.g., pyridinyl), which is unsubstituted or substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1-4- alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, C₁_₄-alkylamino, di-C₁_₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, C₁_₄-alkylthio, C_1-4-alkylsulphinyl, C_1-4-alkylsulphonyl, morpholinyl, piperazinyl, or combinations thereof (thienyl, chlorothienyl, benzothienyl, chloromethylthienyl, benzothiazolyl, ethoxybenzothiazolyl, pyridyl, methylpyridyl, chloropyridyl);

heteroarylalkyl wherein the heteroaryl portion has 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and the alkyl portion has 1 to 3 carbon atoms, the heteroaryl portion is unsubstituted or is substituted one or more times by halogen, aryl, C_1-4 alkyl, halogenated C_1-4 alkyl, hydroxy, C_1-4- alkoxy, halogenated C_1-4 alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, Ci-₄-alkylamino, di-Ci-₄-alkylamino, carboxy, alkoxycarbonyl, hydroxamic acid, carboxamide, C^-alkylthio, Ci_₄-alkylsulphinyl, Ci_₄-alkylsulphonyl, morpholinyl, piperazinyl, -NR³R⁴ , ⁵ or combinations thereof; and

and

pharmaceutically acceptable salts thereof,

with the provisos that:

(a) when R¹ is methoxy, R² is cycloalkyl (e.g., cyclopentyl) or pyrimidinyl substituted by dialkylamino (e.g., dimethylamino); and (b) when R¹ is pyrrolidinyl, R² is cycloalkyl (e.g., cyclopentyl) or arylalkyl (e.g., fluorine substituted benzyl).

US Patent Application Serial No. 10/636,996 also discloses, among others, the following specific compounds (hereinafter referred to as Group VII):

6-Chloro-9-(2-fluorobenzyl)-2-trifluoromethylpurine, 6-Chloro-9-cyclopentyl-2-trifluoromethylpurine,

9-Cyclopentyl-6-methoxy-2-trifluoromethylpurine,

9-(4-(2-N,N-Dimethylamino)pyrimidinyl)-6-methoxy-2- trifluoromethylpurine,

9-Cyclopentyl-6-(l-pyrrolidinyl)-2-trifluoromethylpurine, 9-(2-Fluorobenzyl)-6-(l-pyrrolidinyl)-2-trifluoromethylpurine,

9-Cyclopentyl-6-methyl-2-trifluoromethylpurine,

9-(2-Fluorobenzyl)-6-methyl-2-trifluoromethylpurine,

9-Cyclopentyl-6-ethyl-2-trifluoromethylpurine,

6-Ethyl-9-(2-fluorobenzyl)-2-trifluoromethylpurine, 6-Ethyl-9-Phenyl-2-trifluoromethylpurine,

6-Ethyl-9-(3-methoxyphenyl)-2-trifluoromethylpurine, 6-Ethyl-9-(2-methoxyphenyl)-2-trifluoromethylpurine,

9-Cyclopentyl-6-(2-propyl)-2-trifluoromethylpurine,

6-Ethyl-9-(3-methylsulfonylphenyl)-2-trifluoromethylpurine,

6-Ethyl-9-(3-methylsulfinylphenyl)-2-trifluoromethylpurine, 6-( 1 -Butyl)-9-cyclopentyl-2-trifluoromethylpurine_i

9-Cyclopentyl-6-(l-propyl)-2-trifluoromethylpurine,

9-(2,3-Difluorobenzyl)-6-ethyl-2-trifluoromethylpurine,

6-Ethyl-9-(3-methylbenzyl)-2-trifluoromethylpurine,

6-Ethyl-9-(3-methoxybenzyl)-2-trifluoromethylpurine, 9-(2,4-Difluorobenzyl)-6-ethyl-2-trifluoromethylpurine,

9-(3-Cyanophenyl)-6-ethyl-2-trifluoromethylpurine,

9-(2,3-Dichlorophenyl)-6-ethyl-2-trifluoromethylpurine,

9-(4-Chlorophenyl)-6-ethyl-2-trifluoromethylpurine,

6-Ethyl-9-(2-fluorophenyl)-2-trifluoromethylpurine, 6-Ethyl-9-(3-fluorophenyl)-2-trifluoromethylpurine,

9-(4-Benzyloxyphenyl)-6-ethyl-2-trifluoromethylpurine,

6-Ethyl-9-(3-methylthiophenyl)-2-trifluoromethylpurine,

6-Ethyl-9-(3-methylphenyl)-2-trifluoromethylpurine,

6-Ethyl-9-(4-methylphenyl)-2-trifluoromethylpurine, 6-Ethyl-9-(4-fluorophenyl)-2-trifluoromethylpurine,

9-(2-Chlorophenyl)-6-ethyl-2-trifluoromethylpurine,

6-Ethyl-9-(4-pyridyl)-2-trifluoromethylpurine,

6-Ethyl-9-(4-methoxyphenyl)-2-trifluoromethylpurine,

9-(3-Chlorophenyl)-6-ethyl-2-trifluoromethylpurine, 9-(3-Chloro-4-pyridyl)-6-ethyl-2-trifluoromethylpurine,

6-Ethyl-9-(2-methyl-4-pyridyl)-2-trifluoromethylpurine,

6-Ethyl-9-(3-methyl-4-pyridyl)-2-trifluoromethylpurine,

6-Ethyl-9-(3-methoxy-4-pyridyl)-2-trifluoromethylpurine,

6-Ethyl-9-(3-ethylsulfonylphenyl)-2-trifluoromethylpurine, 6-Ethyl-9-(3-trifluoromethoxyphenyl)-2-trifluoromethylpurine,

6-Ethyl-9-(3-methoxycarbonylphenyl)-2-trifluoromethylpurine_i

6-Ethyl-9-(4-methoxycarbonylphenyl)-2-trifluoromethylpurine_i

6-Ethyl-9-(4-hydroxyphenyl)-2-trifluoromethylpurine,

9-(3-Aminomethylphenyl)-6-ethyl-2-trifluoromethylpurine, 9-(3-Carboxyphenyl)-6-ethyl-2-trifluoromethylpurine, 9-(4-Carboxyphenyl)-6-ethyl-2-trifluoromethylpurine, 6-Ethyl-9-(3-methylsulfonylaminocarbonylphenyl)-2-trifluoromethylpurine; and pharaiaceutically acceptable salts thereof.

Thus, according to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formula G and pharmaceutically acceptable salts thereof. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formula G, and pharmaceutically acceptable salts thereof, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine

According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from Group VII. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from Group VII, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole.

US Patent Application Serial No. 10/715,819 discloses a genus of PDE4 compounds defined by the following Formulas, hereinafter referred to as Formulas Hl, H2, and H3:

wherein one of A, B and D is N-O and the others are CR (preferably, B is N-O) R¹ is alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen (e.g., CH₃, CHF₂, CF₃, etc.);

(e.g., methylphenyl, methoxyphenyl, chlorophenyl, etc.),

arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, wherein the arylalkyl radical is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF_3> OCF₃, alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more - CH₂CH₂- groups are each optionally replaced by -CH=CH- or -C≡C-, and/or one or more -CH₂- groups are each optionally replaced by -O- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., phenylethyl, phenylpropyl, phenylbutyl, methoxyphenylethyl, methoxyphenylpropyl, chlorophenylethyl, chlorophenylpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, chlorophenoxyethyl, chlorophenylaminoethyl, etc.),

a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, wherein the heterocyclic group is unsubstituted or substituted one or more times by halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof (e.g., 3- thienyl, 3-tetrahydrofuranyl, 3-pyrrolyl, etc.), or

a heterocycle- alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, and the alkyl portion is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, OCF₃, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, wherein in the alkyl portion one or more -CH₂CH₂- groups are each optionally replaced by -CH=CH- or -C≡C-, and/or one or more -

aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF₃, amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid, pyrrolyl, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl (e.g., 2-(2- tetrahydropyranyl)tetrazole-5-yl), hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (e.g. te/t-butyldimethylsilyloxy), R⁴-L-, or combinations thereof (e.g., substituted or unsubstituted phenyl, naphthyl, and biphenyl, such as phenyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.),

heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom (preferably N, S or O), which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (e.g. te/t-butyldimethylsilyloxy), R⁴-L-, or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.), or

a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times by halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof (e.g., 3-thienyl, 3- tetrahydrofuranyl, 3-pyrrolyl, etc.);

is H,

alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times by halogen, Ci-₄-alkyl, Ci-₄-alkoxy, oxo, or combinations thereof (e.g., methyl, ethyl, propyl, etc.),

aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, cycloalkyl, aryl (e.g., phenyl, naphthyl, and biphenyl), heteroaryl, or combinations thereof (e.g., substituted or unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.),

arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, wherein the arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF₃O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino, or combinations thereof, and/or substituted in the alkyl portion by halogen, cyano, methyl, or combinations thereof, wherein in the alkyl portion one or more -CH₂CH₂- groups are each optionally replaced by -CH=CH- or -C≡C-, and/or one or more - CH₂- groups are each optionally replaced by -O- or -NH- (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trfluoromethyl, benzyl, methylenedioxobenzyl, etc.),

a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.), or

L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH₂- groups are each optionally replaced by -O-, -S-, -SO-, -SO₂-, -NR⁵-, -SO₂NH-, -NHSO₂-, -SO₂NR⁵-, - NR⁵SO₂-, -CO-, -NR⁵CO-, -CONR⁵-, -NHCONH-, -OCONH, -

NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH- (e.g.,-0-, CH₂-, -CO-, -CO-O-, -0-C0-, -CO-NH-, -NH-CO-, -CH₂CH₂CH₂-NH-CO-, -CH₂- CH₂-O-, -SO₂-NH-CH₂CH₂-O-, -0-CH₂CH₂-O-, -CH₂-NH-CO-, -CO- NH-CH₂-, -SO₂-NH-, -CH₂-NH-SO₂-, -CH₂CH₂CH₂-SO₂-NH-, -CO- NH-SO₂-, -SO₂-, -SO₂NHCO-, etc.);

R³ is H, alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, Ci-₄-alkyl, Ci-₄-alkoxy, oxo, or combinations thereof (e.g., methyl, ethyl, propyl, etc.),

aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, (e.g., substituted or unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.), or

arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, wherein the arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF₃O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino, or combinations thereof, and/or substituted in the alkyl portion by halogen, cyano, methyl, or combinations thereof, wherein in the alkyl portion one or more -CH₂CH₂- groups are each optionally replaced by -CH=CH- or -C≡C-, and/or one or more - CH₂- groups are each optionally replaced by -O- or -NH- (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trfluoromethyl, benzyl, methylenedioxobenzyl, etc.);

is H, halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, CN, or hydroxyl; is H,

alkyl having 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, cyano, hydroxy, Ci-₄-alkoxy, or combinations thereof

cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, Cr₄- alkyl, Ci-₄-alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.),

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF_3, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof

(e.g., methylphenyl, methoxyphenyl, chlorophenyl, etc.),

arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, wherein the arylalkyl radical is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF₃ OCF₃, alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more - CH₂CH₂- groups are each optionally replaced by -CH=CH- or -C≡C-, and/or one or more -CH₂- groups are each optionally replaced by -O- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., phenylethyl, phenylpropyl, phenylbutyl, methoxyphenylethyl, methoxyphenylpropyl, chlorophenylethyl, chlorophenylpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, chlorophenoxyethyl, chlorophenylaminoethyl, etc.),

a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof (e.g., tetrahydrofuranyl, pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.), or

CH₂- groups are each optionally replaced by -O- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., pyridylethyl, pydridylpropyl, methylpiperazinylethyl, etc.);

is H, or

alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, cyano, and/or Ci-₄-alkoxy (e.g., CH₃, C₂H₅, CHF₂, CF₃, etc.), and one or more -CH₂CH₂- groups can be replaced in each case by -CH=CH- or -C≡C-;

R⁹ is alkoxy or alkylthio, in each case having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen (e.g., OCH₃, OCHF₂, OCF₃, etc.);

R¹⁰ is -C0-Ci_₄-alkyl which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen (e.g., CH₃,

CHF₂, CF₃, etc.), or is Υ.

< > :G

X or

R¹¹ is H or alkyl having 1 to 4 carbon atoms, which is branched or unbranched, and which is unsubstituted or substituted one or more times by halogen (e.g., CH₃, CHF₂, CF₃, etc.);

R¹² is alkyl having 1 to 6 carbon atoms, which is branched or unbranched, and which is unsubstituted or substituted one or more times by halogen (e.g., CH₃, CHF₂, CF₃, etc.);

R¹³ is alkyl having 1 to 6 carbon atoms, which is branched or unbranched, and which is unsubstituted or substituted one or more times by halogen (e.g., CH₃, CHF₂, CF₃, etc.);

X and Y are each independently O or S; and G is alkylene having 2 to 7 carbon atoms which is unsubstituted or substituted one or more times by halogen; and

pharmaceutically acceptable salts thereof; wherein optically active compounds can be in the form of one of their separate enantiomers or in the form of mixtures thereof, including racemic mixtures.

Thus, according to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formulas Hl, H2, and H3 and pharmaceutically acceptable salts thereof. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formulas Hl, H2, and H3, and pharmaceutically acceptable salts thereof, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole.

US Patent Application Serial No. 10/825,610 discloses a genus of PDE4 compounds defined by the following Formula, hereinafter referred to as Formula J:

wherein

R¹ is alkyl having 1 to 8 carbon atoms wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups,

alkyl having 1 to 8 carbon atoms which is substituted one or more times by halogen, oxo or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -

C≡C- groups,

a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom (e.g., 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl), which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof,

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF₃ OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof, arylalkyl having 8 to 16 carbon atoms, which is unsubstituted or substituted preferably in the aryl portion, one or more times by halogen, CF_3, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

a partially unsaturated carbocyclic group having 5 to 14 carbon atoms,

(e.g., cyclohexenyl, cyclohexadienyl, indanyl, and tetrahydronaphthenyl), which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof ,

a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof, or cycloalkylalkyl having 4 to 16 carbon atoms (e.g., cyclopentylethyl and cyclopropylmethyl), which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof,

R^J is H,

alkyl having 1 to 8 carbon atoms wherein optionally one or more

-CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups,

arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted preferably in the aryl portion, one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenyl, phenoxy, and acyloxy (e.g., acetoxy), or combinations thereof,

heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof,

alkoxyalkyl having 3 to 8 carbon atoms,

-C(O)R⁴, -(CH₂)_nC(O)R⁴, -(CH₂)_nOR⁵, -(CH₂)_nSR⁵, -(CH₂)_nSO₂R⁴, - (CH₂)_nNR⁵R⁶, -CH₂CO₂R⁵, -CH₂CONR⁶R⁵, -CH₂CONHR⁵, - (CH₂)_nNR⁶SO₂R⁴, -(CH₂)_nNR⁶COR⁴, or -CH₂CONHSO₂R⁴;

is alkyl having 1 to 12 carbon atoms which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups,

alkoxyalkyl having 3 to 8 carbon atoms which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups,

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF₃, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonamido (e.g., CH₃SO₂NH-, C₂H₅SO₂NH-), arylsulphonamido (e.g., C_OH_SSO₂NH-), halogenated arylsulphonamido (e.g., 4-F-C_OH_SSO₂NH-), phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

arylalkyl having 8 to 16 carbon atoms, which is unsubstituted or substituted preferably in the aryl portion, one or more times by halogen, CF₃, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, aminosulphonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

N, O or S atom (e.g., 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl, 1,3,4- thiadiazolyl), which is unsubstituted or substituted one or more times by halogen, aryl (e.g., phenyl, methylphenyl), alkyl, cycloalkyl (e.g., cyclopropyl), cycloalkylalkyl (e.g., cyclopropylmethyl), alkoxy, alkoxyalkyl (e.g., methoxymethyl), cyano, halogenated alkyl (e.g., trifluoromethyl), halogenated alkoxy (e.g., trifluoromethoxy), nitro, oxo, amino, alkylamino, dialkylamino, aminosulphonyl, heterocycle (e.g., pyridyl, piperidinyl, thienyl, tetrahydrofuranyl, pyrazinyl), heterocyclic-alkyl (e.g., thienylmethyl, piperidinylcarbonylmethyl), or combinations thereof, or

a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; and is H,

alkyl having 1 to 12 carbon atoms wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups,

alkyl having 1 to 12 carbon atoms which is substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -

C≡C- groups,

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF₃, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonamido (e.g., CH₃SO₂NH-, C₂H₅SO₂NH-), arylsulphonamido (e.g., C_OH_SSO₂NH-), halogenated arylsulphonamido (e.g., 4-F-C_όH₅SO₂NH-),phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof, arylalkyl having 8 to 16 carbon atoms, which is unsubstituted or substituted preferably in the aryl portion, one or more times by halogen, CF₃, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, aminosulphonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom (e.g., 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl, 1,3,4- thiadiazolyl), which is unsubstituted or substituted one or more times by halogen, aryl (e.g., phenyl, methylphenyl), alkyl, cycloalkyl (e.g., cyclopropyl), cycloalkylalkyl (e.g., cyclopropylmethyl), alkoxy, alkoxyalkyl (e.g., methoxymethyl), cyano, halogenated alkyl (e.g., trifluoromethyl), halogenated alkoxy (e.g., trifluoromethoxy), nitro, oxo, amino, alkylamino, dialkylamino, aminosulphonyl, heterocycle (e.g., pyridyl, piperidinyl, thienyl, tetrahydrofuranyl, pyrazinyl), heterocyclic-alkyl (e.g., thienylmethyl, piperidinylcarbonylmethyl), or combinations thereof, or

a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof;

is H, alkyl having 1 to 12 carbon atoms wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups,

cycloalkylalkyl having 4 to 16 carbon atoms (e.g., cyclopentylethyl and cyclopropylmethyl), which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof, aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF₃, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

arylalkyl having 8 to 16 carbon atoms, which is unsubstituted or substituted preferably in the aryl portion, one or more times by halogen, CF₃, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof;

N, O or S atom (e.g., 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl), which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, alkoxycarbonyl, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof, or

n is 0 to 4 (e.g., 1 to 4 or 2 to 4); and

pharmaceutically acceptable salts thereof;

with the proviso that:

(f) when R² is CH₃ and R³ is H, then R¹ is not methyl, ethyl, n-propyl, isopropyl, sec-butyl, n-butyl, isobutyl, neopentyl, n-pentyl, 2-methylbutyl, isopentyl, n-hexyl, phenyl , cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, methylcyclopentyl, cyclopropylmethyl, cyclopentylmethyl, 2-propenyl, 2-propynyl, 3- methyl-2-butenyl, N-substituted 2-piperazinylethyl, norbornyl, 3-tetrahydrofuryl, 2-tetrahydrofuryl, 3- tetrahydrothienyl, 2-oxacyclopropyl, 2- oxacyclopenyl, 3-oxacyclopentyl, 2-chloroethyl, 2- bromoethyl, 2,2,2-trifluoroethyl, 3-bromopropyl, 3- 5 chloropropyl, or 4-bromobutyl;

(g) when R¹ is cyclopentyl, and R² is methyl, then R³ is not H, acetyl, benzyl, 4-hydroxybenzyl, 4- acetoxybenzyl, 4-bromobenzyl, 3,4-

10 dimethoxybenzyl, 4-methylthiobenzyl, 4- cyanobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4- aminobenzyl, 4-dimethylaminobenzyl, 2,4- diaminobenzyl, 4-amino-3,5-dimethoxybenzyl, 3- carboxybenzyl, 3-methoxycarbonylbenzyl, 4-

15 methoxycarbonylbenzyl, 4-methylsulfinylbenzyl, 4- methylsufonylbenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2,4-dinitrobenzyl, 2-nitro-4- aminobenzyl, 2-amino-4-nitrobenzyl, morpholinoethyl, 2-pyridylmethyl, 3-

20 pyridylmethyl, 4-pyridylmethyl, 4-(6- fluoroquinolyl)methyl, 2-(7-chloroquinolyl)methyl, 2-imidazoylmethyl, or substituted imidazoylmethyl;

(h) when R¹ is CH₃, and R³ is H, then R² is not methyl, 25 ethyl, or butyl;

(i) when R³ is H, then R¹ and R² are not both ethyl or isobutyl; and

30 Q) When R¹ and R² are both difluoromethyl, then R³ is not 4-aminobenzyl, or 4-amino-3,5- dimethoxybenzyl. Additionally, also discloses, among others, the following specific compounds

(hereinafter referred to as Group VIII):

(4S)-4-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-2-pyrrolidone-l-acetic acid,

(4S)-4-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-l-[N-(2-methylphenyl-(N- methyl)aminocarbonylmethyl)] -2-pyrrolidone,

(4S)-4-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-l-[N-(2-(6-methylpyridyl)-

(N-methyl)aminocarbonylmethyl)]-2-pyrrolidone,

(4S)-l-[N-(2,3-Difluorophenyl-(N-methyl)aminocarbonylmethyl)]-4-(4-methoxy-3-

(3R)-tetrahydrofuranyloxyphenyl)-2-pyrrolidone, (4S)-l-[N-(4,5-Dimethylthiazol)-2-yl)aminocarbonylmethyl]-4-(4-methoxy-3-(3R)- tetrahydrofuranyloxyphenyl)-2-pyrrolidone,

(4S)-4-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-l-(N- phensulfonylaminocarbonylmethyl)-2-pyrrolidone,

(4S)-l-[N-(2,3-Difluorophenyl-(N-ethyl)aminocarbonylmethyl)]-4-(4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl)-2-pyrrolidone,

(4S)-l-[N-(2,3-Difluorophenyl-(N-isopropyl)aminocarbonylmethyl)]-4-(4-methoxy-

3-(3R)-tetrahydrofuranyloxyphenyl)-2-pyrrolidone,

(4S)-l-[N-(2,3-Difluorophenyl-(N-cyclopropylmethyl)aminocarbonylmethyl)]-4-(4- methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-2-pyrrolidone, (4S)-4-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-l-[N-(2- thiazolyl)aminocarbonylmethyl]-2-pyrrolidone,

(4S)-4-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-l-[N-(2- phenylsulfonylethyl)]-2-pyrrolidone,

(4S)-4-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-l-[N-(2- methylphenyl)sulfonylaminocarbonylmethyl] -2-pyrrolidone,

(4S)-4-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-l-[N-(2-(4- methoxyphenyl)oxyethyl)]-2-pyrrolidone,

(4S)-l-[2-(3-Chlorophenoxy)ethyl]-4-[4-methoxy-3-(3R)- tetrahydrofuranyloxyphenyl]-2-pyrrolidone, (4S)-l-[2-(4-Isopropylphenoxy)ethyl]-4-[4-methoxy-3-(3R)- tetrahydrofuranyloxyphenyl]-2-pyrrolidone,

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-methylthiazol-2- yl)aminocarbonylmethyl]-2-pyrrolidone, (4S)-l-[N-(4-tert-Butylthiazol-2-yl)aminocarbonylmethyl]-4-[4-methoxy-3-(3R)- tetrahydrofuranyloxyphenyl]-2-pyrrolidone,

(4S)-l-[2-(4-Isopropylphenylthio)ethyl]-4-[4-methoxy-3-(3R)- tetrahydrofuranyloxyphenyl]-2-pyrrolidone, (4S)-l-[2-(3-Chlorophenylthio)ethyl]-4-[4-methoxy-3-(3R)- tetrahydrofuranyloxyphenyl]-2-pyrrolidone,

(4S)-l-[2-(2,3-Difluorophenoxy)ethyl]-4-[4-methoxy-3-(3R)- tetrahydrofuranyloxyphenyl]-2-pyrrolidone,

(4S)-l-[N-(2,3-Difluorophenyl)-N-(2-methylpropyl)aminocarbonylmethyl]-4-[4- methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-2-pyrrolidone,

(4S)-l-[N-(6-Fluorobenzothiazol-2-yl)-N-(methyl)aminocarbonylmethyl]-4-[4- methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-2-pyrrolidone,

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-N-[2-(2-oxopyrrolidin-l- yl)ethyl] -4-phenoxybenzamide, (4S)-l-[N-(3-Fluorophenyl)-N-(methyl)aminocarbonylmethyl]-4-[4-methoxy-3-(3R)- tetrahydrofuranyloxyphenyl]-2-pyrrolidone,

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(4-methoxyphenyl)-N-

(methyl)aminocarbonylmethyl]-2-pyrrolidone,

(4S)-l-[N-(4-Isopropylphenyl)-N-(methyl)aminocarbonylmethyl]-4-[4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl] -2-pyrrolidone,

(4S)-l-[N-(3,4-Methylenedioxyphenyl)-N-(methyl)aminocarbonylmethyl]-4-[4- methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-2-pyrrolidone,

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(4-methylthiazol-2- yl)aminocarbonylmethyl]-2-pyrrolidone, (4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-methyl-N-(thiazol-2- yl)aminocarbonylmethyl]-2-pyrrolidone,

(4S)-l-[N-(5-Chlorothiazol-2-yl)aminocarbonylmethyl]-4-[4-methoxy-3-(3R)- tetrahydrofuranyloxyphenyl]-2-pyrrolidone,

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(4-phenylthiazol-2- yl)aminocarbonylmethyl] -2-pyrrolidone,

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-N-[2-(2-oxopyrrolidin-l- yl)ethyl]benzamide,

(4S)-2,3-Difluoro-4-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-N-[2-(2- oxopyrrolidin- 1 -yl)ethyl] -benzamide, (4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-N-[2-(2-oxopyrrolidin-l- yl)ethyl] -4-methoxybenzamide,

(4S)-4-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[2-(4- trifluoromethylphenoxy)ethyl]-2-pyrrolidone, (4S)-l-[N-(5-Cyclopropyl-l,3,4-thiadiazol-2-yl)aminocarbonylmethyl]-4-[4-methoxy-

3-(3R)-tetrahydrofuranyloxyphenyl]-2-pyrrolidone,

(4S)- 1 - [N-(4-Ethoxycarbonylthiazol-2-yl)aminocarbonylmethyl] -4- [4-methoxy-3-

(3R)-tetrahydrofuranyloxyphenyl]-2-pyrrolidone,

(4S)-l-[N-(5-tert-Butyl-l,3,4-thiadiazol-2-yl)aminocarbonylmethyl]-4-[4-methoxy-3- (3R)-tetrahydrofuranyloxyphenyl] -2-pyrrolidone,

(4S)-l-[N-Cyclopropylmethyl-N-(6-fluorobenzothiazol-2-yl)aminocarbonylmethyl]-

4-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-2-pyrrolidone,

(4S)-l-[N-(3,4-(Difluoromethylene)dioxyphenyl)-N-methylaminocarbonylmethyl]-4-

[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-2-pyrrolidone, (4S)-l-[N-(4-(4-Fluorophenyl)thiazol-2-yl)aminocarbonylmethyl]-4-[4-methoxy-3-

(3R)-tetrahydrofuranyloxyphenyl]-2-pyrrolidone,

(4S)-l-[N-(4-Carboxythiazol-2-yl)aminocarbonylmethyl]-4-[4-methoxy-3-(3R)- tetrahydrofuranyloxyphenyl]-2-pyrrolidone,

(4S)-l-[2-(2-Flurorophenylthio)ethyl]-4-[4-methoxy-3-(3R)- tetrahydrofuranyloxyphenyl] -2-pyrrolidone,

(4S)-l-[2-(3-Flurorophenylthio)ethyl]-4-[4-methoxy-3-(3R)- tetrahydrofuranyloxyphenyl]-2-pyrrolidone,

(4S)-4-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[2-(4- methoxyphenylthio)ethyl]-2-pyrrolidone, (4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-trifluoromethyl- l,3,4-thiadiazol-2-yl)aminocarbonylmethyl]-2-pyrrolidone,

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-(4-pyridyl)-l,3,4- thiadiazol-2-yl)aminocarbonylmethyl]-2-pyrrolidone,

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(4-(3-pyridyl)thiazol-2- yl)aminocarbonylmethyl] -2-pyrrolidone,

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(4-(2-pyridyl)thiazol-2- yl)aminocarbonylmethyl]-2-pyrrolidone,

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(4-(4-pyridyl)thiazol-2- yl)aminocarbonylmethyl]-2-pyrrolidone, (4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-(4-pyridyl)-l,3,4- thiadiazol-2-yl)aminocarbonylmethyl]-2-pyrrolidone

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-ethoxycarbonyl- l,3,4-thiadiazol-2-yl)aminocarbonylmethyl]-2-pyrrolidone (4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-methoxycarbonyl- l,3,4-thiadiazol-2-yl)aminocarbonylmethyl]-2-pyrrolidone

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-(3,4- methylenedioxyphenyl)-l,3,4-thiadiazol-2-yl)aminocarbonylmethyl]-2-pyrrolidone

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-(2-thienyl)-l,3,4- thiadiazol-2-yl)aminocarbonylmethyl] -2-pyrrolidone

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-(2-thienylmethyl)- l,3,4-thiadiazol-2-yl)aminocarbonylmethyl]-2-pyrrolidone

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-(2-propyl)-l,3,4- thiadiazol-2-yl)aminocarbonylmethyl]-2-pyrrolidone (4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-(2-pyrazinyl)-l,3,4- thiadiazol-2-yl)aminocarbonylmethyl]-2-pyrrolidone

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-methoxymethyl- l,3,4-thiadiazol-2-yl)aminocarbonylmethyl]-2-pyrrolidone

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-(2- tetrahydrofuranyl)-l,3,4-thiadiazol-2-yl)aminocarbonylmethyl]-2-pyrrolidone

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-aminosulfonyl- l,3,4-thiadiazol-2-yl)aminocarbonylmethyl]-2-pyrrolidone

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-(4-methoxyphenyl)- l,3,4-thiadiazol-2-yl)aminocarbonylmethyl]-2-pyrrolidone (4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-(4- methoxyphenyloxymethyl)-l,3,4-thiadiazol-2-yl)aminocarbonylmethyl]-2- pyrrolidone

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-(4- morpholinylcarbonylmethyl)-l,3,4-thiadiazol-2-yl)aminocarbonylmethyl]-2- pyrrolidone

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-(l- piperidinylcarbonylmethyl)-l,3,4-thiadiazol-2-yl)aminocarbonylmethyl]-2- pyrrolidone (4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-(l- pyrrolidinylcarbonylmethyl)-l,3,4-thiadiazol-2-yl)aminocarbonylmethyl]-2- pyrrolidone

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-(4-piperidinyl)- l,3,4-thiadiazol-2-yl)aminocarbonylmethyl]-2-pyrrolidone

(4S)-4-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-l-[N-(5-(4-(N-tert- butyloxycarbonyl)piperidinyl)-l,3,4-thiadiazol-2-yl)aminocarbonylmethyl]-2- pyrrolidone, and pharaiaceutically acceptable salts thereof.

Thus, according to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formula J and pharmaceutically acceptable salts thereof. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formula J, and pharmaceutically acceptable salts thereof, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected Group VIIL According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected Group Vπi, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone

(Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole.

US Patent Application Serial No. 10/825,611 discloses a genus of PDE4 compounds defined by the following Formulas, hereinafter referred to as Formulas Kl, K2, K3, K4, K5, K6, K7, and K8:

π πi

IV V VI

vπ vπi

wherein

X is CH or N;

is a single bond; C₁-C₆ straight chain or branched alkylene, wherein a CH₂ group is optionally replaced by O, NH, NR¹, or S, which is unsubstituted or substituted one or more times by oxo, halogen (preferably F), hydroxy, cyano or combinations thereof; (CH₂)_nCONH; (CH₂)nCON(C₁.6-alkyl); (CH₂)_nNHCO; (CH₂)nCONHSO₂; (CH₂)_nSO₂NH; (CH₂)nSO₂; or (CH₂)_nCO₂ (e.g., a bond, CH₂CONH, SO₂, CH₂CO₂, CH₂CO);

is O to 3; R¹ is alkyl having 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times by halogen (e.g., CH₃, CHF₂);

R² is H,

alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups (e.g., CH₃, CHF₂),

cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl having 1 to 4 carbon atoms or combinations thereof (e.g., cyclopentyl),

a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom (e.g., 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl), which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof

(e.g., tetrahydrofuranyl),

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF_3> OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, CF₃ OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof (e.g., benzyl, difluorobenzyl),

a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, (e.g., cyclohexenyl, cyclohexadienyl, indanyl, and tetrahydronaphthenyl), which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof,

arylalkenyl having 8 to 16 carbon atoms, wherein the alkenyl portion has up to 5 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof, or

cycloalkylalkyl having 4 to 16 carbon atoms (e.g., cyclopentylethyl and cyclopropylmethyl), which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof;

is H, alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups (e.g., C₂H₅, CH(CH₃)₂, n-propyl, n-butyl, t. -butyl),

cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl, or combinations thereof (e.g., cyclopentyl, cyclohexyl),

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, halogenated alkoxy (e.g., OCF₃), nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy (e.g., acetoxy), acylamido (e.g., acetamido), imidazolyl, pyridinyl, morpholinyl, piperadinyl, piperazinyl, tetrazolyl, alkylsulphonimide (e.g., CH₃SO₂-NHCO-), arylsulphonimide (e.g., C_OH_SSO₂-NHCO-) or combinations thereof (e.g., phenyl, bromophenyl, cyanophenyl, nitrophenyl, fluorophenyl, difluorophenyl, trifluoromethoxyphenyl, methylphenyl, dimethylphenyl, methoxyphenyl),

heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl (e.g., trifluoromethyl), halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy, tetrazolyl, alkylsulphonimide, arylsulphonimide, aryl, oxo, acylamido (e.g., acetamido), or combinations thereof (e.g., pyridyl, methylpyridyl, benzothiazolyl),

arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl (e.g. CF₃₎, halogenated alkoxy (e.g. OCF₃), nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy (e.g., acetoxy), acylamido (e.g., acetamido), tetrazolyl, alkylsulphonimide, arylsulphonimide, or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof (e.g., benzyl, methylbenzyl, t.-butylbenzyl, methoxybenzyl, dimethoxybenzyl, fluorobenzyl, difluorobenzyl, trifluoromethylbenzyl, trifluoromethoxybenzyl, chlorobenzyl, aminobenzyl, nitrobenzyl, methoxycarbonylbenzyl, methylsulfonylbenzyl, phenethyl, phenpropyl),

a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl (e.g., trifluoromethyl), halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, arylsulphinyl, arylsulphonyl, phenyl, halogenated phenyl, phenoxy, acyloxy, tetrazolyl, alkylsulphonimide, arylsulphonimide, aryl, oxo, or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof (e.g., pyridylmethyl), cycloalkylalkyl having 4 to 16 carbon atoms (e.g., cyclopentylethyl and cyclopropylmethyl), which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof, or

alkoxyalkyl having 3 to 8 carbon atoms;

R >4 is alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups (e.g., CH₃);

R^s is H,

alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups (e.g., CH₃, C₂H₅);

R⁶ is H,

alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups,

cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl, or combinations thereof (e.g., cyclopentyl),

arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, CF₃, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom (e.g., 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl), which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, alkoxycarbonyl, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof, or

a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; R⁷ is H, halogen, or alkyl having 1 to 6 carbon atoms wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen;

R⁸ is H, halogen, alkyl having 1 to 6 carbon atoms wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen or hydroxyl (e.g., CH₃, C₂Hs, CF₃, hydroxymethyl, 2-(2-hydroxy)propyl, hydroxymethyl), carboxy, alkoxycarbonyl having 2 to 6 carbon atoms (e.g., ethoxycarbonyl), - CO-alkyl having 2 to 6 carbon atoms (e.g., CH₃CO), or phenyl; and

R⁹ is halogen (e.g., F);

and pharmaceutically acceptable salts thereof.

Thus, according to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formulas Kl, K2, K3, K4, K5, K6, K7, and K8 and pharmaceutically acceptable salts thereof. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formulas Kl, K2, K3, K4, K5, K6, K7, and K8, and pharmaceutically acceptable salts thereof, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, trifrupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole.

US Patent Application Serial No. 11/008,775 discloses a genus of PDE4 compounds defined by the following Formula, hereinafter referred to as Formula L:

wherein

A, B and D are each N or CR⁵ wherein at least one of A, B and D is N;

R¹ is halogen, alkyl having 1 to 4 carbon atoms (e.g., methyl, ethyl), halogenated alkyl having 1 to 4 carbon atoms (e.g., CH₂F, CHF₂, CF₃), OR⁶, COR⁶, CONR⁶, or NR⁶COR¹⁰;

R² is halogen, alkyl having 1 to 4 carbon atoms (e.g., methyl, ethyl), halogenated alkyl having 1 to 4 carbon atoms (e.g., CH₂F, CHF₂, CF₃), OR⁷, COR⁶, CONR⁶, or NR⁶COR¹⁰;

R³ is a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion which is branched or unbranched has 1 to 5 carbon atoms, and which is unsubstituted, substituted in the carbocyclic portion one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, and/or substituted in the alkyl portion one or more times by halogen, Ci-₄-alkoxy, cyano or combinations thereof (e.g., cyclohexenylmethyl, etc.),

arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, wherein the arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF₃O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino, or combinations thereof, and/or substituted in the alkyl portion by halogen, cyano, alkyl having 1 to 4 carbon atoms (e.g., methyl), or combinations thereof, wherein in the alkyl portion one or more -CH₂CH₂- groups are each optionally replaced by - CH=CH- or -C≡C-, and/or one or more -CH₂- groups are each optionally replaced by -O- or -NH- (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trifluoromethyl, benzyl, methylenedioxobenzyl, etc.), or

heteroarylalkyl group, wherein the heteroaryl portion may be partially or fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is an N, N-O (that is N-oxide), O or S, the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heteroarylalkyl group is unsubstituted, substituted one or more times in the heteroaryl portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF₃O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion one or more times by halogen, cyano, alkyl having 1 to 4 carbon atoms (e.g., methyl), or combinations thereof (e.g., pyridylmethyl, pyridylpropyl, methylpyridylmethyl, chloropyridylmethyl, dichloropyridylmethyl, thienylmethyl, thiazolylmethyl, quinolinylmethyl, isoquinolinylmethyl, piperidinylmethyl, furanylmethyl, imidazolylmethyl, methylimidazolylmethyl, pyrrolylmethyl, etc.);

is cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, OXO, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof (e.g., cyclopentyl),

aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF₃, amino, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid, pyrrolyl, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl (e.g., 2-(2- tetrahydropyranyl)tetrazole-5-yl), hydroxyalkoxy, carboxy, carboxyalkyl, alkoxycarbonyl (e.g., te/t-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (e.g. te/t-butyldimethylsilyloxy), R⁸-L-, or combinations thereof (e.g., substituted or unsubstituted phenyl, naphthyl, and biphenyl, such as phenyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.),

heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom (e.g., N, S or O), which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, carboxyalkyl, alkoxycarbonyl (e.g., te/t-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (e.g. te/t-butyldimethylsilyloxy), R⁸-L-, or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.),

a heterocyclic group, which is saturated or partially saturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, oxo, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF₃,amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., te/t-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl (e.g., optionally substituted acetyl or optionally substituted benzoyl), alkylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, phenoxy, cycloalkyl, aryl, heteroaryl or combinations thereof (e.g., piperidinyl, pyrrolydinyl, amidazolidinyl, pyrrolinyl, etc.),

a heterocycle- alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, and the alkyl portion is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted, substituted one or more times in the heterocyclic portion by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, oxo, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF₃, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., te/t-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl alkylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, phenoxy, cycloalkyl, aryl, heteroaryl or combinations thereof, and/or substituted in the alkyl portion one or more times by halogen, oxo, hydroxy, cyano, or combinations thereof, and wherein in the alkyl portion one or more -CH₂CH₂- groups are each optionally replaced by -CH=CH- or - C≡C-, and one or more -CH₂- groups are each optionally replaced by - O- or -NH- (e.g., pyridylethyl, pydridylpropyl, methylpiperazinylethyl, piperidinylmethyl, pyrrolydinylmethyl, amidazolidinylmethyl, pyrrolinylmethyl, etc.); R⁵ is H, halogen, alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or halogenated alkoxy having 1 to 4 carbon atoms;

R⁶ is H or alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen (e.g., CH₃, CHF₂, CF₃, etc.);

R⁷ is H or alkyl having 1 to 12, preferably 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, Ci-₄-alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH₂CH₂- groups is replaced in each case by -CH=CH- or -C≡C- (e.g., CH₃, CHF₂, CF₃, methoxyethyl, etc.),

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF_3> OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof (e.g., methylphenyl, methoxyphenyl, chlorophenyl, etc.),

arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, wherein the arylalkyl radical is unsubstituted, substituted in the aryl portion one or more times by halogen, CF₃ OCF₃, alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and/or substituted in the alkyl portion one or more times by halogen, oxo, hydroxy, cyano, or combinations thereof, and wherein in the alkyl portion one or more -CH₂CH₂- groups are each optionally replaced by -CH=CH- or -C≡C-, and one or more -CH₂- groups are each optionally replaced by -O- or -NH- (e.g., phenylethyl, phenylpropyl, phenylbutyl, methoxyphenylethyl, methoxyphenylpropyl, chlorophenylethyl, chlorophenylpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, chlorophenoxyethyl, chlorophenylaminoethyl, etc.),

a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof

(e.g., cyclohexenyl, cyclohexadienyl, indanyl, tetrahydronaphthenyl, etc.),

a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times by halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof (e.g., 3-thienyl, 3- tetrahydrofuranyl, 3-pyrrolyl, etc.), or

a heterocycle- alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, and the alkyl portion is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted, substituted one or more times in the heterocyclic portion by halogen, OCF₃, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, and/or substituted in the alkyl portion one or more times by halogen, oxo, hydroxy, cyano, or combinations thereof, and wherein in the alkyl portion one or more -CH₂CH₂- groups are each optionally replaced by -CH=CH- or -C≡C-, and one or more -CH₂- groups are each optionally replaced by -O- or -NH- (e.g., pyridylethyl, pydridylpropyl, methylpiperazinylethyl, etc.);

is H,

a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion has 1 to 5 carbon atoms, and which is unsubstituted or substituted, preferably in the carbocyclic portion, one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof (e.g., cyclohexenylmethyl, etc.),

cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, alkyl, alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.), aryl having 6 to 14 carbon atoms which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., te/t-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, cycloalkyl, aryl (e.g., phenyl, naphthyl, biphenyl), heteroaryl or combinations thereof (e.g., substituted or unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.),

arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, wherein the arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF₃O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino, or combinations thereof, and/or substituted in the alkyl portion by halogen, cyano, alkyl having 1 to 4 carbon atoms (e.g., methyl), or combinations thereof, wherein in the alkyl portion one or more -CH₂CH₂- groups are each optionally replaced by - CH=CH- or -C≡C-, and/or one or more -CH2- groups are each optionally replaced by -O- or -NH- (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trifluoromethyl, benzyl, methylenedioxobenzyl, etc.),

a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., te/t-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, cycloalkyl, aryl, heteroaryl or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.), or

a heterocycle-alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted, substituted one or more times in the heterocyclic portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF₃O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted one or more times in the alkyl portion by halogen, cyano, alkyl having 1 to 4 carbon atoms (e.g., methyl), or combinations thereof (e.g., pyridylmethyl, pyridylpropyl, methylpridylmethyl, etc.);

L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH₂- groups are each optionally replaced by -O-, -S-, -SO-, -SO₂-, -NR⁹-, -SO₂NR⁹-, -NR⁹SO₂-, -CO-, -CO₂-, - NR⁹CO-, -CONR⁹-, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, - SCSNH-, -NHCSNH-, -CONHSO₂- or -SO₂NHCO- (e.g., -0-, CH₂-, - CO-, -CO-O-, -0-C0-, -CO-NH-, -NH-CO-, -CH₂CH₂CH₂-NH-CO-, -

CH₂-CH₂-O-, -SO₂-NH-CH₂CH₂-O-, -0-CH₂CH₂-O-, -CH₂-NH-CO-, - CO-NH-CH₂-, -SO₂-NH-, -CH₂-NH-SO₂-, -CH₂CH₂CH₂-SO₂-NH-, - SO₂-, -CONHSO₂-, -SO₂NHCO-, etc.); and

R⁹ is H,

alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, Ci-₄-alkyl, Ci-₄-alkoxy, oxo, or combinations thereof (e.g., methyl, ethyl, propyl, etc.),

aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., te/t-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or combinations thereof (e.g., substituted or unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.); and

is H or alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen (e.g., CH₃, CHF₂, CF₃, etc.); and pharmaceutically acceptable salts thereof;

wherein said compound is not 5-chloro-N-(3-chlorophenyl)-4,6-difluoro-N-(4- methoxybenzyl)pyrimidin-2-amine.

Thus, according to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formula L and pharmaceutically acceptable salts thereof. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formula L, and pharmaceutically acceptable salts thereof, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole.

US Patent Application Serial No. 11/249,769 discloses a genus of PDE4 compounds defined by the following Formulas, hereinafter referred to as Formulas Ml, M2, M3, M4, M5, M6, M7, M8, and M9:

R π πi

IV V VI

VII viπ IX

X wherein X is CH or N;

L is a single bond; C₁-C₆ straight chain or branched alkylene, wherein a CH₂ group is optionally replaced by O, NH, NR¹, or S, which is unsubstituted or substituted one or more times by oxo, halogen (preferably F), hydroxy, cyano or combinations thereof; (CH₂)_nCONH;

(CH₂)_nOCONH; (CH₂)_nCON(Ci_₆-alkyl); (CH₂)_nNHCO; (CH₂)nCONHSO_2; (CH₂)_nSO₂NH; (CH₂)_nSO_2; or (CH₂)_nCO₂ (e.g., a bond, CH₂CONH, SO₂, CH₂CO₂, CH₂CO);

n is O to 3;

R¹ is alkyl having 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times by halogen (e.g., CH₃, CHF₂);

R² is H,

alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by

-CH=CH- or -C≡C- groups (e.g., CH₃, CHF₂),

(e.g., tetrahydrofuranyl),

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF_3> OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, CF_3, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof (e.g., benzyl, difluorobenzyl),

arylalkenyl having 8 to 16 carbon atoms, wherein the alkenyl portion has up to 5 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

is H,

alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups (e.g., C₂H₅, CH(CH₃)₂, n-propyl, n-butyl, t.-butyl),

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, halogenated alkoxy (e.g., OCF₃), nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, -CO-N(R¹⁰)₂, -SO₂- N(R¹⁰)₂, hydroxyalkyl, hydroxyalkoxy (e.g., -OCH₂HC₂OH), alkoxyalkoxy (e.g., methoxyethoxy (CH₃OCH₂CH₂O-), alkoxyalkoxyalkyl (e.g., CH₃OCH₂CH₂OCH₂-), carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, phenyl, halogenated phenyl, phenoxy, benzyloxy, acyloxy (e.g., acetoxy), acylamido (e.g., acetamido), furanyl which is unsubstituted or substituted by halogen, Ci_₄-alkyl, C₁.

₄-alkoxy, C₂_₈-alkoxycarbonyl, and/or benzyl, pyrrolyl which is unsubstituted or substituted by halogen, Ci-₄-alkyl, Ci-₄-alkoxy, C₂_s- alkoxycarbonyl, and/or benzyl, pyrazolyl which is unsubstituted or substituted by halogen, Ci_₄-alkyl, C^-alkoxy, C₂_₈-alkoxycarbonyl, and/or benzyl, isoxazolyl which is unsubstituted or substituted by halogen, Ci-₄-alkyl, Ci-₄-alkoxy, C₂_₈-alkoxycarbonyl, and/or benzyl, imidazolyl which is unsubstituted or substituted by halogen, C_1-4-alkyl, Ci_₄-alkoxy, C₂-₈-alkoxycarbonyl, and/or benzyl, pyridinyl which is unsubstituted or substituted by halogen, Ci-₄-alkyl, Ci-₄-alkoxy, C₂-s- alkoxycarbonyl, and/or benzyl, pyrimidinyl which is unsubstituted or substituted by halogen, Ci_₄-alkyl, C^-alkoxy, C₂-₈-alkoxycarbonyl, and/or benzyl, morpholinyl which is unsubstituted or substituted by C₁. ₄-alkyl, C₂-₈-alkoxycarbonyl, and/or benzyl, piperadinyl which is unsubstituted or substituted by Ci-₄-alkyl, C₂-₈-alkoxycarbonyl, and/or benzyl, piperazinyl which is unsubstituted or substituted by C_1-4-alkyl, C₂-₈-alkoxycarbonyl, and/or benzyl, tetrazolyl which is unsubstituted or substituted by Ci-₄-alkyl, C₂-₈-alkoxycarbonyl, and/or benzyl, alkylsulphonimide (e.g., CH₃SO₂-NHCO-), arylsulphonimide (e.g., C₆H₅SO₂-NHCO-) wherein the aryl portion is optionally substituted by halogen, Ci_₄-alkyl, Ci_₄-alkoxy, or combinations thereof (e.g., phenyl, bromophenyl, cyanophenyl, nitrophenyl, fluorophenyl, difluorophenyl, trifluoromethoxyphenyl, methylphenyl, dimethylphenyl, methoxyphenyl, biphenyl substituted by -CONH₂, and phenyl substituted by biphenyl or -CONH₂),

heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl (e.g., trifluoromethyl), halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, phenyl, halogenated phenyl, phenoxy, acyloxy, tetrazolyl, alkylsulphonimide, arylsulphonimide, aryl, oxo, acylamido (e.g., acetamido), or combinations thereof (e.g., pyridyl, methylpyridyl, benzothiazolyl),

arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl (e.g. CF₃), halogenated alkoxy (e.g. OCF₃), nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, phenyl, halogenated phenyl, phenoxy, acyloxy (e.g., acetoxy), acylamido (e.g., acetamido), tetrazolyl, alkylsulphonimide, arylsulphonimide, or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof (e.g., benzyl, methylbenzyl, t.-butylbenzyl, methoxybenzyl, dimethoxybenzyl, fluorobenzyl, difluorobenzyl, trifluoromethylbenzyl, trifluoromethoxybenzyl, chlorobenzyl, aminobenzyl, nitrobenzyl, methoxycarbonylbenzyl, methylsulfonylbenzyl, phenethyl, phenpropyl),

a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl (e.g., trifluoromethyl), halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, phenyl, halogenated phenyl, phenoxy, acyloxy, tetrazolyl, alkylsulphonimide, arylsulphonimide, aryl, oxo, or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof (e.g., pyridylmethyl),

cycloalkylalkyl having 4 to 16 carbon atoms (e.g., cyclopentylethyl and cyclopropylmethyl), which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof, or

alkoxyalkyl having 3 to 8 carbon atoms;

is alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups (e.g., CH₃);

R⁵ is H, or

alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen wherein optionally one or more -

CH₂CH₂- groups are replaced in each case by -CH=CH- or -C=C- groups (e.g., CH₃, C₂H₅);

R⁶ is H,

alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, hydroxy or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups,

alkoxyalkyl having 2 to 6 carbon atoms (e.g., methoxyethyl (CH₂CH₂OCH₃), ethoxymethyl (CH₂OCH₂CH₃)), which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof;

alkoxycarbonyl (-C(=O)O-alkyl) having 2 to 6 carbon atoms (e.g., -C(=O)OCH(CH₃)₂);

-CO-NR⁵R¹²;

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF₃, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, CF₃, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom (e.g., 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl, 2- pyrimidinyl, 4-tetrahydropyranyl), which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, alkoxycarbonyl, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof, or

is H, halogen, or alkyl having 1 to 6 carbon atoms wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen; R⁸ is H, halogen, alkyl having 1 to 6 carbon atoms wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen or hydroxyl (e.g., CH₃, C₂H₅, CF₃, hydroxymethyl, 2-(2-hydroxy)propyl, hydroxymethyl), carboxy, alkoxycarbonyl having 2 to 6 carbon atoms (e.g., ethoxycarbonyl), - CO-alkyl having 2 to 6 carbon atoms (e.g., CH₃CO), or phenyl;

R⁹ is halogen (e.g., F); and

R¹⁰ is H,

alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups (e.g., CH₃, CHF₂), or

alkoxy having 2 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen;

R¹¹ is H,

alkyl having 1 to 6 carbon atoms (e.g., methyl, ethylpropyl), which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups (e.g.,

CH₃, C₂H₅), or

a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof (e.g., tetrahydro-2H-pyranylmethyl, pyrrolidinylethyl ;

R¹² is H,

alkyl having 1 to 6 carbon atoms (e.g., methyl, ethylpropyl), which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups (e.g., CH₃, C₂H₅),

cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl, or combinations thereof (e.g., cyclopentyl), or

a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof (e.g., furylmethyl);

and pharmaceutically acceptable salts or solvates (e.g., hydrates) thereof, or solvates of pharmaceutically acceptable salts thereof.

US Patent Application Serial No. 11/249,769 also discloses, among others, the following specific compounds (hereinafter referred to as Group IX):

4-[5-(3-ethyl-2-methyl-2H-indazol-6-yl)- lH-pyrazol- l-yl]benzoic acid, l,3-diethyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-lH-indazole, l-(cyclopropylmethyl)-3-ethyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol- 5-yl}-lH-indazole,

3-ethyl-l-isopropyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-lH- indazole, 3-ethyl-l-(2-methoxyethyl)-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5- yl}-lH-indazole,

1 -(ethoxymethyl)-3-ethyl-6- { 1 - [4-(methylsulfonyl)phenyl] - lH-pyrazol-5-yl } - lH-indazole, 3-ethyl-l-(l-ethylpropyl)-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}- lH-indazole,

3-ethyl-2-(l-ethylpropyl)-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}- 2H-indazole,

3-ethyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-l-(tetrahydro-2H- pyran-2-ylmethyl)-lH-indazole,

3-ethyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-2-(tetrahydro-2H- pyran-2-ylmethyl)-2H-indazole,

3-ethyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-2-(2-pyrrolidin-l- ylethyl)-2H-indazole, Isopropyl 3-ethyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-lH- indazole- 1 -carboxylate,

3-ethyl-6- { 1 - [4- (methylsulf onyl)phenyl] - 1 H-pyrazol-5-yl } - 1 -(2-pyrrolidin- 1 - ylethyl)- lH-indazole,

N-(sec-butyl)-3-ethyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-lH- indazole- 1 -carboxamide,

3-ethyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-l-pyridin-3-yl-lH- indazole,

N-cyclopentyl-3-ethyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-lH- indazole- 1 -carboxamide, N,3-diethyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-lH-indazole-

1 -carboxamide,

3-ethyl-N-(2-furylmethyl)-6- { 1 - [4-(methylsulfonyl)phenyl] - 1 H-pyrazol-5-yl } - lH-indazole-1 -carboxamide,

3-ethyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-l-pyrimidin-2-yl- lH-indazole,

3-ethyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-l-pyrimidin-5-yl- lH-indazole,

1 -cyclopropyl-S-ethyl-β- { 1 - [4-(methylsulfonyl)phenyl] - 1 H-pyrazol-5-yl } - IH- indazole, l-(3-ethyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-lH-indazol-l- yl)-2-methylpropan-2-ol,

3-ethyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-l-(tetrahydro-2H- pyran-4-yl)-lH-indazole, l-(difluoromethyl)-3-ethyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5- yl}-lH-indazole,

3-ethyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-l-pyridin-2-yl-lH- indazole, l-(5-cyclopropyl-l,3,4-thiadiazol-2-yl)-3-ethyl-6-{ l-[4- (methylsulfonyl)phenyl]- lH-pyrazol-5-yl}- lH-indazole,

3-ethyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-l-(tetrahydrofuran- 3-yl)- lH-indazole,

Tert-butyl 3-(3-ethyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-lH- indazol- 1 -yl)pyrrolidine- 1 -carboxylate, l-cyclopropyl-3-ethyl-6-(l-isopropyl-lH-pyrazol-5-yl)-lH-indazole, l-cyclopropyl-3-ethyl-6-(l-methyl-lH-pyrazol-5-yl)-lH-indazole, l-cyclopropyl-3-ethyl-6-(lH-pyrazol-5-yl)-lH-indazole, l-cyclopropyl-3-ethyl-6-(l-ethyl-lH-pyrazol-5-yl)-lH-indazole, l-cyclopropyl-3-ethyl-6-(l-pyridin-4-yl-lH-pyrazol-5-yl)-lH-indazole, 2-[5-(l-cyclopropyl-3-ethyl-lH-indazol-6-yl)-lH-pyrazol-l-yl]quinoxaline,

{4-[5-(l-cyclopropyl-3-ethyl-lH-indazol-6-yl)-lH-pyrazol-l- yl]phenyl}methanol,

2-{4-[5-(l-cyclopropyl-3-ethyl-lH-indazol-6-yl)-lH-pyrazol-l- yl]phenyl}propan-2-ol, l-{4-[5-(l-cyclopropyl-3-ethyl-lH-indazol-6-yl)-lH-pyrazol-l-yl]phenyl}-N- methylmethanesulfonamide, l-cyclopropyl-3-ethyl-6-[l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl]-lH- indazole, l-cyclopropyl-3-ethyl-6-[l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-3-yl]-lH- indazole, l-cyclopropyl-6-[l-(l,l-dioxidotetrahydro-3-thienyl)-lH-pyrazol-5-yl]-3- ethyl- lH-indazole,

6-(l-cyclopentyl-lH-pyrazol-5-yl)-l-cyclopropyl-3-ethyl-lH-indazole, l-cyclopropyl-3-ethyl-6-[l-(2,2,6,6-tetramethylpiperidin-4-yl)-lH-pyrazol-5- yl]-lH-indazole,

6- { 1 - [3-(benzyloxy)phenyl] - lH-pyrazol-5-yl } - 1 -cyclopropyl-S-ethyl- IH- indazole, 3-[5-(l-cyclopropyl-3-ethyl-lH-indazol-6-yl)-lH-pyrazol-l-yl]phenol,

3-ethyl-l-isopropyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-lH- pyrazolo [3 ,4-b]pyridine,

2-{3-[5-(l-cyclopropyl-3-ethyl-lH-indazol-6-yl)-lH-pyrazol-l- yl] phenoxy } ethanol, 6- { 1 - [4-(benzyloxy)phenyl] - lH-pyrazol-5-yl } - 1 -cyclopropyl-3-ethyl- IH- indazole,

3-ethyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-l-(tetrahydro-2H- pyran-4-yl)-lH-pyrazolo[3,4-b]pyridine,

4-[5-(l-cyclopropyl-3-ethyl-lH-indazol-6-yl)-lH-pyrazol-l-yl]phenol, (4-{5-[3-ethyl-l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazolo[3,4-b]pyridin-6-yl]- lH-pyrazol-l-yl}phenyl)methanol,

2-(4-{5-[3-ethyl-l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazolo[3,4-b]pyridin-6- yl]-lH-pyrazol-l-yl}phenyl)propan-2-ol, l-cyclopropyl-3-ethyl-6-{ l-[3-(2-methoxyethoxy)phenyl]-lH-pyrazol-5-yl}- lH-indazole, l-cyclopropyl-3-ethyl-6-[l-(3-methoxyphenyl)-lH-pyrazol-5-yl]-lH-indazole,

1 -cyclopropyl-S-ethyl-β- { 1 - [4-(2-methoxyethoxy)phenyl] - 1 H-pyrazol-5-yl } - lH-indazole, l-cyclopropyl-3-ethyl-6-[l-(4-methoxyphenyl)-lH-pyrazol-5-yl]-lH-indazole, l-cyclopropyl-3-ethyl-6-(l-pyrimidin-2-yl-lH-pyrazol-5-yl)-lH-indazole,

3-ethyl-l-(2-methoxypyridin-4-yl)-6-(l-pyrimidin-2-yl-lH-pyrazol-5-yl)-lH- indazole,

4-[5-(3-ethyl-l-methyl-lH-indazol-6-yl)-lH-pyrazol-l-yl]benzoic acid 4-[5-(3-ethyl-l-methyl-lH-indazol-6-yl)-lH-pyrazol-l-yl]benzenesulfonamide 3-ethyl-l-methyl-6-{ l-[4-(methylsulfonyl)phenyl]-lH-pyrazol-5-yl}-lH- indazole

4-[5-(3-ethyl-l-methyl-lH-indazol-6-yl)-lH-pyrazol-l-yl]benzonitrile 4-[5-(3-ethyl-2-methyl-2H-indazol-6-yl)-lH-pyrazol-l-yl]benzenesulfonamide 3-ethyl-2-methyl-6- { 1 - [4-(methylsulfonyl)phenyl] - lH-pyrazol-5-yl } -2H- indazole

4-[5-(3-ethyl-2-methyl-2H-indazol-6-yl)-lH-pyrazol-l-yl]benzonitrile

6- { 1 - [4-(difluoromethoxy)phenyl] - lH-pyrazol-5-yl } -3-ethyl- 1 -(tetrahydro- 2H-pyran-4-yl)- lH-pyrazolo[3,4-b]pyridine

3-ethyl-6- [ 1 -(4-fluorophenyl)- lH-pyrazol-5-yl] - 1 -(tetrahydro-2H-pyran-4-yl)- 1 H-pyrazolo [3 ,4-b]pyridine

3-ethyl-6-(l-pyridin-4-yl-lH-pyrazol-5-yl)-l-(tetrahydro-2H-pyran-4-yl)-lH- pyrazolo [3 ,4-b]pyridine 3-ethyl-6-(l-phenyl-lH-pyrazol-5-yl)-l-(tetrahydro-2H-pyran-4-yl)-lH- pyrazolo [3 ,4-b]pyridine

3-ethyl-6-(l-pyrimidin-2-yl-lH-pyrazol-5-yl)-l-(tetrahydro-2H-pyran-4-yl)- 1 H-pyrazolo [3 ,4-b]pyridine

3-ethyl-6-[l-(3-fluorophenyl)-lH-pyrazol-5-yl]-l-(tetrahydro-2H-pyran-4-yl)- lH-pyrazolo[3,4-b]pyridine

3-ethyl-6- [ 1 -(4-methoxyphenyl)- lH-pyrazol-5-yl] - 1 -(tetrahydro-2H-pyran-4- yl)-lH-pyrazolo[3,4-b]pyridine

3-ethyl-6-[l-(3-methoxyphenyl)-lH-pyrazol-5-yl]-l-(tetrahydro-2H-pyran-4- yl)-lH-pyrazolo[3,4-b]pyridine 6-{ l-[4-(benzyloxy)phenyl]-lH-pyrazol-5-yl}-3-ethyl-l-(tetrahydro-2H- pyran-4-yl)-lH-pyrazolo[3,4-b]pyridine

6-{ l-[3-(benzyloxy)phenyl]-lH-pyrazol-5-yl}-3-ethyl-l-(tetrahydro-2H- pyran-4-yl)-lH-pyrazolo[3,4-b]pyridine

4-{5-[3-ethyl-l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazolo[3,4-b]pyridin-6-yl]- lH-pyrazol-l-yl}phenol

3-{5-[3-ethyl-l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazolo[3,4-b]pyridin-6-yl]- 1 H-pyrazol- 1 -yl Jphenol and physiologically acceptable salts thereof.

Thus, according to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formulas Ml, M2, M3, M4, M5, M6, M7, M8, and M9 and pharmaceutically acceptable salts thereof. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formulas Ml, M2, M3, M4, M5, M6, M7, M8, and M9, and pharmaceutically acceptable salts thereof, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole.

According to a further method and composition aspect of the invention, the

PDE4 inhibitor compounds are selected from Group IX. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from Group IX, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fhiphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, trifhipromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole.

US Patent Application Serial No. 11/253,812 discloses a genus of PDE4 compounds defined by the following Formula, hereinafter referred to as Formula N:

wherein

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF_3, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

arylalkyl having 7 to 16 carbon atoms (e.g., 8 to 16 carbon atoms), which is unsubstituted or substituted preferably in the aryl portion, one or more times by halogen, CF_3> OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

R³ is H,

arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted preferably in the aryl portion, one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenyl, phenoxy, and acyloxy (e.g., acetoxy), or combinations thereof, heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof,

alkoxyalkyl having 3 to 8 carbon atoms,

-C(O)R⁴, -(CH₂)_nC(O)R⁴, -(CH₂)_nOR⁵, -(CH₂)_nSR⁵, -(CH₂)_nSO₂R⁴,

-(CH₂)_nNR⁵R⁶, -CH₂CO₂R⁵, -CH₂CONR⁶R⁵, -CH₂CONHR⁵, -CHR⁷CONR⁶R⁵, -CHR⁷CONHR⁵, -(CH₂)_nNR⁶SO₂R⁴, - (CH₂)_nNR⁶COR⁴, or -CH₂CONHSO₂R⁴;

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF₃, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonamido (e.g., CH₃SO₂NH-, C₂H₅SO₂NH-), arylsulphonamido (e.g., C_OH_SSO₂NH-), halogenated arylsulphonamido

(e.g., 4-F-C_OH_SSO₂NH-), phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; and

is H,

a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom (e.g., 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl, 1,3,4- thiadiazolyl, 1,2,4-thiadiazolyl, isoxazolyl, pyrazolyl, pyrazinyl, isothiazolyl, 1,3-thiazolyl, pyridyl, benzothiazolyl), which is unsubstituted or substituted one or more times by halogen, alkyl (e.g., methyl, ethyl, isopropyl), cycloalkyl (e.g., cyclopropyl), cycloalkylalkyl (e.g., cyclopropylmethyl), alkoxy, alkoxyalkyl (e.g., methoxymethyl), cyano, halogenated alkyl (e.g., trifluoromethyl), halogenated alkoxy (e.g., trifluoromethoxy), nitro, oxo, amino, alkylamino, dialkylamino, carboxamide, aminosulphonyl, aryl which is optionally substituted by alkyl or alkoxy (e.g., phenyl, methylphenyl, methoxyphenyl), arylalkyl which is optionally substituted by alkyl or alkoxy (e.g., benzyl), aryloxyalkyl wherein the aryl portion is optionally substituted by alkyl or alkoxy, arylsulfonyl (e.g., benzenesulfonyl), anilino, heterocycle (e.g., furyl, pyridyl, piperidinyl, thienyl, tetrahydrofuranyl, pyrazinyl), heterocyclic-alkyl wherein the alkyl portion is optionally substituted by oxo (e.g., thienylmethyl, piperidinylethyl, 2-oxo-2-piperidinyl-l-ylethyl or piperidinylcarbonylmethyl, 2-morpholin-4-yl-2-oxoethyl, 2-oxo-2- pyrrolidinyl-1-ylethyl), or combinations thereof, or

is H,

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF₃, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof, arylalkyl having 8 to 16 carbon atoms, which is unsubstituted or substituted preferably in the aryl portion, one or more times by halogen, CF₃, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof;

a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom (e.g., 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl), which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, alkoxycarbonyl, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof, or

is alkyl having 1 to 8 carbon atoms (e.g., 1 to 4 carbon atoms) wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups (e.g., CH₃),

alkyl having 1 to 8 carbon atoms which is substituted one or more times by halogen, oxo or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or - C≡C- groups, cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, alkyl having 1 to 4 carbon atoms or combinations thereof, or

cycloalkylalkyl having 4 to 16 carbon atoms (e.g., cyclopropylmethyl), which is unsubstituted or substituted one or more times by halogen, oxo, alkyl or combinations thereof,

n is 0 to 4 (e.g., 1 to 4 or 2 to 4);

and pharmaceutically acceptable salts or solvates (e.g., hydrates) thereof, or solvates of pharmaceutically acceptable salts thereof;

with the proviso that:

(k) when R² is CH₃ and R³ is H, then R¹ is not methyl, ethyl, n- propyl, isopropyl, sec -butyl, n-butyl, isobutyl, neopentyl, n- pentyl, 2-methylbutyl, isopentyl, n-hexyl, phenyl , cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, methylcyclopentyl, cyclopropylmethyl, cyclopentylmethyl, 2-propenyl, 2-propynyl, 3-methyl-2-butenyl, N-substituted 2-piperazinylethyl, norbornyl, 3-tetrahydrofuryl, 2-tetrahydrofuryl, 3- tetrahydrothienyl, 2-oxacyclopropyl, 2-oxacyclopenyl, 3- oxacyclopentyl, 2-chloroethyl, 2-bromoethyl, 2,2,2- trifluoroethyl, 3-bromopropyl, 3-chloropropyl, or A- bromobutyl;

(1) when R¹ is cyclopentyl, and R² is methyl, then R³ is not H, acetyl, benzyl, 4-hydroxybenzyl, 4-acetoxybenzyl, A- bromobenzyl, 3,4-dimethoxybenzyl, 4-methylthiobenzyl, A- cyanobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 4-dimethylaminobenzyl, 2,4-diaminobenzyl, 4-amino-3,5- dimethoxybenzyl, 3-carboxybenzyl, 3-methoxycarbonylbenzyl, 4-methoxycarbonylbenzyl, 4-methylsulfinylbenzyl, A- methylsufonylbenzyl, 2-nitrobenzyl, 3-nitrobenzyl, A- nitrobenzyl, 2,4-dinitrobenzyl, 2-nitro-4-aminobenzyl, 2- amino-4-nitrobenzyl, morpholinoethyl, 2-pyridylmethyl, 3- pyridylmethyl, 4-pyridylmethyl, 4-(6-fluoroquinolyl)methyl, 2- (7-chloroquinolyl)methyl, 2-imidazoylmethyl, or substituted imidazoylmethyl;

(m) when R¹ is CH₃, and R³ is H, then R² is not methyl, ethyl, or butyl;

(n) when R³ is H, then R¹ and R² are not both ethyl or isobutyl; and

(o) when R¹ and R² are both difluoromethyl, then R³ is not A- aminobenzyl, or 4-amino-3,5-dimethoxybenzyl.

US Patent Application Serial No. 11/253,812 also discloses, among others, the following specific compounds (hereinafter referred to as Group X):

2-[4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(3- fluorophenyl)acetamide,

2-[4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(3-methyl-lH-pyrazol-5- yl)acetamide,

2-[4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(5-methylisoxazol-3- yl)acetamide, 2-[4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(4-methyl-l,3-thiazol-2- yl)acetamide,

2-[4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(3-methylisothiazol-5- yl)acetamide,

2-[4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(6-methylpyridin-2- yl)acetamide,

2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(3- fluorophenyl)acetamide,

2-[(4R)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(3- fluorophenyl)acetamide, 2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-methyl-N-(4-methyl- 1 ,3-thiazol-2-yl)acetamide,

2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(3-isopropyl- 1,2,4- thiadiazol-5-yl)-N-methylacetamide,

N-(5-cyclopropyl-l,3,4-thiadiazol-2-yl)-2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2- oxopyrrolidin- 1 -yl] -N-methylacetamide, N-(cyclopropylmethyl)-2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]- N-(3-isopropyl- 1 ,2,4-thiadiazol-5-yl)acetamide,

2-[(4R)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(3-isopropyl- 1,2,4- thiadiazol-5-yl)-N-methylacetamide, N-(cyclopropylmethyl)-N-(3-isopropyl- 1 ,2,4-thiadiazol-5-yl)-2-((4S)-4- { 4-methoxy- 3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-2-oxopyrrolidin-l-yl)acetamide,

N-(cyclopropylmethyl)-2-[(4R)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l- yl]-N-(3-isopropyl-l,2,4-thiadiazol-5-yl)acetamide,

2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(3-methylisothiazol- 5-yl)acetamide,

2-[(4R)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(3-methylisothiazol- 5-yl)acetamide,

2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(3-isopropyl- 1,2,4- thiadiazol-5-yl)acetamide, N-(5-cyclopropyl-l,3,4-thiadiazol-2-yl)-2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2- oxopyrrolidin- 1 -yl] acetamide,

N-(4-cyclopropyl-l,3-thiazol-2-yl)-2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2- oxopyrrolidin- 1 -yl] acetamide,

2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(5-pyridin-4-yl- 1 ,3,4-thiadiazol-2-yl)acetamide,

2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(4-methyl-l,3- benzothiazol-2-yl)acetamide,

2-[(4S)-4-(3-isopropoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(3-isopropyl- l,2,4-thiadiazol-5-yl)-N-methylacetamide, N-(5-cyclopropyl-l,3,4-thiadiazol-2-yl)-2-[(4S)-4-(3-isopropoxy-4-methoxyphenyl)- 2-oxopyrrolidin- 1 -yl] -N-methylacetamide,

N-(5-cyclopropyl- 1,3,4- thiadiazol-2-yl)-2-[(4S)-4-(3-isopropoxy-4-methoxyphenyl)- 2-oxopyrrolidin- 1 -yl] acetamide,

N-(3-fluorophenyl)-2-[(4S)-4-(3-isopropoxy-4-methoxyphenyl)-2-oxopyrrolidin-l- yl] -N-methylacetamide,

2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(3-methyl-lH- pyrazol-5-yl)acetamide,

2-[(4S)-4-(3-isopropoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(3-isopropyl- l,2,4-thiadiazol-5-yl)acetamide, 2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(3-fluorophenyl)-N- methylacetamide,

2-{(4S)-4-[4-(difluoromethoxy)-3-ethoxyphenyl]-2-oxopyrrolidin-l-yl}-N-(3- isopropyl- 1 ,2,4-thiadiazol-5-yl)acetamide,

2-{(4S)-4-[4-(difluoromethoxy)-3-ethoxyphenyl]-2-oxopyrrolidin-l-yl}-N-(3- isopropyl- 1 ,2,4-thiadiazol-5-yl)-N-methylacetamide, N-(5-cyclopropyl-l,3,4-thiadiazol-2-yl)-2-{(4S)-4-[4-(difluoromethoxy)-3- ethoxyphenyl] -2-oxopyrrolidin- 1 -yl } acetamide,

N-(5-cyclopropyl-l,3,4-thiadiazol-2-yl)-2-{(4S)-4-[4-(difluoromethoxy)-3- ethoxyphenyl] -2-oxopyrrolidin- 1 -yl } -N-methylacetamide, 2-{ (4S)-4-[4-(difluoromethoxy)-3-ethoxyphenyl]-2-oxopyrrolidin- l-yl}-N-(3- fluorophenyl)acetamide,

2-{(4S)-4-[4-(difluoromethoxy)-3-ethoxyphenyl]-2-oxopyrrolidin-l-yl}-N-(3- fluorophenyl)-N-methylacetamide,

N-(4-cyclopropyl-l,3-thiazol-2-yl)-2-{(4S)-4-[4-(difluoromethoxy)-3-ethoxyphenyl]- 2-oxopyrrolidin- 1 -yl } acetamide,

2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-[4-(trifluoromethyl)- l,3-thiazol-2-yl] acetamide,

2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(4-methoxy-l,3- benzothiazol-2-yl)acetamide, 2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(4-methyl-l,3- thiazol-2-yl)acetamide,

2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-methyl-N-(3- methylisothiazol-5-yl)acetamide,

2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(5-methylisoxazol-3- yl)acetamide,

(2S)-2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(3-isopropyl- l,2,4-thiadiazol-5-yl)propanamide,

(2R)-2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(3-isopropyl- l,2,4-thiadiazol-5-yl)propanamide, (2S)-2-[(4R)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(3-isopropyl- l,2,4-thiadiazol-5-yl)propanamide,

(2R)-2-[(4R)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(3-isopropyl- l,2,4-thiadiazol-5-yl)propanamide,

(2R)-2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(4-methyl-l,3- thiazol-2-yl)propanamide,

(2S)-2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2-oxopyrrolidin-l-yl]-N-(4-methyl-l,3- thiazol-2-yl)propanamide,

N-(4-cyclopropyl-l,3-thiazol-2-yl)-2-[(4S)-4-(3-isopropoxy-4-methoxyphenyl)-2- oxopyrrolidin- 1 -yl] acetamide, N-(3-fluorophenyl)-2-[(4S)-4-(3-isopropoxy-4-methoxyphenyl)-2-oxopyrrolidin-l- yl] acetamide,

N-(4-cyclopropyl-l,3-thiazol-2-yl)-2-[(4S)-4-(3-isopropoxy-4-methoxyphenyl)-2- oxopyrrolidin- 1 -yl] -N-methylacetamide,

N-(4-cyclopropyl-l,3-thiazol-2-yl)-2-[(4S)-4-(3-ethoxy-4-methoxyphenyl)-2- oxopyrrolidin- 1 -yl] -N-methylacetamide, 2-{(4S)-4-[4-(difluoromethoxy)-3-isopropoxyphenyl]-2-oxopyrrolidin-l-yl}-N-(3- fluorophenyl)acetamide,

2-{(4S)-4-[4-(difluoromethoxy)-3-isopropoxyphenyl]-2-oxopyrrolidin-l-yl}-N-(3- isopropyl- 1 ,2,4-thiadiazol-5-yl)acetamide, 2-{(4S)-4-[4-(difluoromethoxy)-3-isopropoxyphenyl]-2-oxopyrrolidin-l-yl}-N-(3- isopropyl- 1 ,2,4-thiadiazol-5-yl)-N-methylacetamide,

N-(4-cyclopropyl-l,3-thiazol-2-yl)-2-{(4S)-4-[4-(difluoromethoxy)-3- isopropoxyphenyl] -2-oxopyrrolidin- 1 -yl } acetamide,

N-(4-cyclopropyl-l,3-thiazol-2-yl)-2-{(4S)-4-[4-(difluoromethoxy)-3- isopropoxyphenyl] -2-oxopyrrolidin- 1 -yl } -N-methylacetamide,

2-{(4S)-4-[4-(difluoromethoxy)-3-isopropoxyphenyl]-2-oxopyrrolidin-l-yl}-N-(3- fluorophenyl)-N-methylacetamide,

N-(4-cyclopropyl-l,3-thiazol-2-yl)-2-{(4S)-4-[4-(difluoromethoxy)-3-ethoxyphenyl]- 2-oxopyrrolidin- 1 -yl } -N-methylacetamide, N-(5-cyclopropyl-l,3,4-thiadiazol-2-yl)-2-{(4S)-4-[4-(difluoromethoxy)-3- isopropoxyphenyl] -2-oxopyrrolidin- 1 -yl } acetamide,

N-(5-cyclopropyl-l,3,4-thiadiazol-2-yl)-2-{(4S)-4-[4-(difluoromethoxy)-3- isopropoxyphenyl] -2-oxopyrrolidin- 1 -yl } -N-methylacetamide, and 2-{ (4S)-4-[4-(difluoromethoxy)-3-ethoxyphenyl]-2-oxopyrrolidin- l-yl}-N-(3- methylis othiazol- 5 -yl)acetamide

and pharmaceutically acceptable salts thereof,

Thus, according to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formula N and pharmaceutically acceptable salts thereof. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formula N, and pharmaceutically acceptable salts thereof, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole.

According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from Group X. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from Group X, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole. US Patent Application Serial No. 11/449,868 discloses a genus of PDE4 compounds defined by the following Formula, hereinafter referred to as Formula O:

wherein

A, B and D are each, independently, N or CR⁵ wherein at least one of A, B and D is N;

R¹ is halogen, alkyl having 1 to 4 carbon atoms (e.g., methyl, ethyl), halogenated alkyl having 1 to 4 carbon atoms (e.g., CH₂F, CHF₂, CF₃), OR⁶, COR⁶, CONR⁶R¹⁰, or NR⁶COR¹⁰;

R is halogen, alkyl having 1 to 4 carbon atoms (e.g., methyl, ethyl), halogenated alkyl having 1 to 4 carbon atoms (e.g., CH₂F, CHF₂, CF₃), OR⁷, COR⁶, CONR⁶R¹⁰, or NR⁶COR¹⁰;

R³ is a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion which is branched or unbranched has 1 to 5 carbon atoms, wherein the partially unsaturated carbocycle-group is unsubstituted, substituted in the carbocyclic portion one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, and/or substituted in the alkyl portion one or more times by halogen, Ci-₄-alkoxy, cyano or combinations thereof (e.g., cyclohexenylmethyl, etc.),

arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, wherein the arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF₃O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino, or combinations thereof, and/or substituted in the alkyl portion by halogen, cyano, alkyl having 1 to 4 carbon atoms (e.g., methyl), or combinations thereof, wherein in the alkyl portion one or more -CH₂CH₂- groups are each optionally replaced by - CH=CH- or -C≡C-, and/or one or more -CH₂- groups are each optionally replaced by -O- or -NH- (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trifluoromethylbenzyl, methylenedioxobenzyl, etc.), or

a heterocycle- alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated (e.g., heteroaryl), and has 5 to 10 ring atoms in which at least 1 ring atom is an N, N-O (that is N- oxide), O or S, the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heterocycle- alkyl group is unsubstituted, substituted one or more times in the heterocyclic portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF₃O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion one or more times by halogen, cyano, alkyl having 1 to 4 carbon atoms (e.g., methyl), or combinations thereof (e.g., pyridylmethyl, pyridylpropyl, methylpyridylmethyl, chloropyridylmethyl, dichloropyridylmethyl, thienylmethyl, thiazolylmethyl, quinolinylmethyl, isoquinolinylmethyl, piperidinylmethyl, furanylmethyl, imidazolylmethyl, methylimidazolylmethyl, pyrrolylmethyl, etc.);

aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF₃, amino, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid (- C(O)-NHOH), pyrrolyl, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl (e.g., 2-(2-tetrahydropyranyl)tetrazole-5-yl), hydroxyalkoxy, carboxy, carboxyalkyl, alkoxycarbonyl (e.g., te/t-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (e.g. te/t-butyldimethylsilyloxy), R⁸-L-, or combinations thereof (e.g., substituted or unsubstituted phenyl, naphthyl, and biphenyl, such as phenyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.),

heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom (e.g., N, S or O), which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid (-C(O)-NHOH), tetrazole-5-yl, hydroxyalkoxy, carboxy, carboxyalkyl, alkoxycarbonyl (e.g., tert- butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (e.g. tert- butyldimethylsilyloxy), R⁸-L-, or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.),

a heterocyclic group, which is saturated or partially saturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, oxo, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF₃,amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid (-C(O)-NHOH), tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., te/t-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl (e.g., optionally substituted acetyl or optionally substituted benzoyl), alkylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, phenoxy, cycloalkyl, aryl, heteroaryl or combinations thereof (e.g., piperidinyl, pyrrolydinyl, amidazolidinyl, pyrrolinyl, etc.),

a heterocycle-alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated (e.g., heteroaryl), and has 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, and the alkyl portion is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted, substituted one or more times in the heterocyclic portion by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, oxo, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF₃, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid (-C(O)-NHOH), tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., te/t-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl alkylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, phenoxy, cycloalkyl, aryl, heteroaryl or combinations thereof, and/or substituted in the alkyl portion one or more times by halogen, oxo, hydroxy, cyano, or combinations thereof, and wherein in the alkyl portion one or more -CH₂CH₂- groups are each optionally replaced by -CH=CH- or -C≡C-, and one or more -CH₂- groups are each optionally replaced by -O- or -NH- (e.g., pyridylethyl, pydridylpropyl, methylpiperazinylethyl, piperidinylmethyl, pyrrolydinylmethyl, amidazolidinylmethyl, pyrrolinylmethyl, etc.);

R⁵ is H, halogen, alkyl having 1 to 4 carbon atoms, halogenated alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or halogenated alkoxy having 1 to 4 carbon atoms;

arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, wherein the arylalkyl radical is unsubstituted, substituted in the aryl portion one or more times by halogen, CF₃ OCF₃, alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and/or substituted in the alkyl portion one or more times by halogen, oxo, hydroxy, cyano, or combinations thereof, and wherein in the alkyl portion one or more -CH₂CH₂- groups are each optionally replaced by -CH=CH- or -C≡C-, and one or more -CH₂- groups are each optionally replaced by -O- or -NH- (e.g., phenylethyl, phenylpropyl, phenylbutyl, methoxyphenylethyl, methoxyphenylpropyl, chlorophenylethyl, chlorophenylpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, chlorophenoxyethyl, chlorophenylaminoethyl, etc.), a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof (e.g., cyclohexenyl, cyclohexadienyl, indanyl, tetrahydronaphthenyl, etc.),

a heterocyclic group, which is saturated, partially saturated or unsaturated (e.g., heteroaryl), having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times by halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof (e.g., 3- thienyl, 3-tetrahydrofuranyl, 3-pyrrolyl, etc.), or

a heterocycle- alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated (e.g., heteroaryl), and has 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, and the alkyl portion is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted, substituted one or more times in the heterocyclic portion by halogen, OCF₃, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, and/or substituted in the alkyl portion one or more times by halogen, oxo, hydroxy, cyano, or combinations thereof, and wherein in the alkyl portion one or more -CH₂CH₂- groups are each optionally replaced by -CH=CH- or -C≡C-, and one or more -CH₂- groups are each optionally replaced by -O- or -NH- (e.g., pyridylethyl, pydridylpropyl, methylpiperazinylethyl, etc.);

is H,

alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times by halogen, Ci-₄-alkyl, Ci-₄-alkoxy, oxo, or combinations thereof (e.g., methyl, ethyl, propyl, etc.), alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8, preferably 1 to 4 carbon atoms (e.g., dimethylamino, etc.),

aryl having 6 to 14 carbon atoms which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid (-C(O)-NHOH), tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., te/t-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, cycloalkyl, aryl (e.g., phenyl, naphthyl, biphenyl), heteroaryl or combinations thereof (e.g., substituted or unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.), arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, wherein the arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF₃O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino, or combinations thereof, and/or substituted in the alkyl portion by halogen, cyano, alkyl having 1 to 4 carbon atoms (e.g., methyl), or combinations thereof, wherein in the alkyl portion one or more -CH₂CH₂- groups are each optionally replaced by - CH=CH- or -C≡C-, and/or one or more -CH₂- groups are each optionally replaced by -O- or -NH- (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trifluoromethyl, benzyl, methylenedioxobenzyl, etc.),

a heterocyclic group, which is saturated, partially saturated or unsaturated (e.g., heteroaryl), having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy, dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid (-C(O)-NHOH), tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert- butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, cycloalkyl, aryl, heteroaryl or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.), or

a heterocycle- alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated (e.g., heteroaryl), and has 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heterocycle- alkyl group is unsubstituted, substituted one or more times in the heterocyclic portion by halogen, alkyl, alkoxy, cyano, trifluoromethyl, CF₃O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted one or more times in the alkyl portion by halogen, cyano, alkyl having 1 to 4 carbon atoms (e.g., methyl), or combinations thereof (e.g., pyridylmethyl, pyridylpropyl, methylpyridylmethyl, etc.);

L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH₂- groups are each optionally replaced by -O-, -S-, -SO-, -SO₂-, -NR⁹-, -SO₂NR⁹-, -NR⁹SO₂-, -CO-, -CO₂-, - NR⁹CO-, -CONR⁹-, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, - SCSNH-, -NHCSNH-, -CONHSO₂- or -SO₂NHCO- (e.g., -0-, -CH₂-, - CO-, -CO-O-, -0-C0-, -CO-NH-, -NH-CO-, -CH₂CH₂CH₂-NH-CO-, -

R⁹ is H,

arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, wherein the arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifluoromethyl, CF₃O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino, or combinations thereof, and/or substituted in the alkyl portion by halogen, cyano, alkyl having 1 to 4 carbon atoms (e.g., methyl), or combinations thereof, wherein in the alkyl portion one or more -CH₂CH₂- groups are each optionally replaced by - CH=CH- or -C≡C-, and/or one or more -CH₂- groups are each optionally replaced by -O- or -NH- (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trifluoromethyl, benzyl, methylenedioxobenzyl, etc.), or aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (e.g., hydroxymethyl), hydroxamic acid (-C(O)-NHOH), tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., te/t-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or combinations thereof (e.g., substituted or unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.); and

R¹⁰ is H or alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen (e.g., CH₃, CHF₂, CF₃, etc.);

wherein if the compound exhibits chirality it can be in the form of a mixture of enantiomers such as a racemate or a mixture of diastereomers, or can be in the form of a single enantiomer or a single diastereomer;

with the proviso that when R³ is pyridinylmethyl, R⁴ is other than substituted or unsubstituted piperidinyl, substituted or unsubstituted phenyl, or cyclohexyl,

and wherein said compound is not:

4-[[[5-methoxy-6-[[tetrahydro-3-furanyl]oxy]-2-pyridinyl](3- pyridinylmethyl)amino] methyl] -1-piperidinecarboxylic acid, 1,2-dimethylethyl ester,

N-[5-methoxy-6- [[tetrahydro-3-furanyl] oxy] -2-pyridinyl] -N-(4- piperidinylmethyl)-3-pyridinemethanamine, 4-[[[3,5-bis(trifluoromethyl)phenyl]methyl][5-bromo-4(phenylmethoxy)-2- pyrimidinyl] amino] ^-ethyl-S^-dihydro-β-methoxy- 1 ,5-naphthydrine- 1 (2H)- carboxylic acid ethyl ester,

5-chloro-N-(3-chlorophenyl)-4,6-difluoro-N-(4-methoxybenzyl)pyrimidin-2- amine,

or a pharmaceutically acceptable salt thereof, or solvate thereof, or solvate of a pharmaceutically acceptable salt thereof.

Formula O and pharmaceutically acceptable salts thereof. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formula O, and pharmaceutically acceptable salts thereof, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole. US Patent Application Serial No. 11/785,741 discloses a genus of PDE4 compounds defined by the following Formulas, hereinafter referred to as Formulas Pl, P2, P3, P4, P5, P6, P7, P8, P9 and PlO:

π πi

IV V VI

VII viπ IX

X

wherein

X is CH or N;

L is a single bond; C₁-C₆ straight chain or branched alkylene, wherein a CH₂ group is optionally replaced by O, NH, NR¹, or S, which is unsubstituted or substituted one or more times by oxo, halogen (preferably F), hydroxy, cyano or combinations thereof; (CH₂)_nCONH; (CH₂)_nOCONH; (CH₂)_nCON(C₁.₆-alkyl); (CH₂)_nNHCO; (CH₂)nCONHSO₂; (CH₂)_nSO₂NH; (CH₂)nSO₂; or (CH₂)_nCO₂ (e.g., a bond, CH₂CONH, SO₂, CH₂CO₂, CH₂CO);

n is O to 3;

R² is H,

a heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom (e.g., 3-thienyl, 2-thienyl, 3-tetrahydrofuranyl), which is unsubstituted or substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof (e.g., tetrahydrofuranyl),

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF₃ OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, CF₃ OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof (e.g., benzyl, difluorobenzyl),

a partially unsaturated carbocyclic group having 5 to 14 carbon atoms,

(e.g., cyclohexenyl, cyclohexadienyl, indanyl, and tetrahydronaphthenyl), which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof,

is H,

alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups (e.g., C₂H₅, CH(CH₃)₂, n-propyl, n-butyl, t. -butyl),

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, halogenated alkoxy (e.g., OCF₃), nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, -CO-N(R¹⁰)₂, -SO₂- N(R¹⁰)₂, hydroxyalkyl, hydroxyalkoxy (e.g., -OCH₂HC₂OH), alkoxyalkoxy (e.g., methoxyethoxy (CH₃OCH₂CH₂O-), alkoxyalkoxyalkyl (e.g., CH₃OCH₂CH₂OCH₂-), carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, phenyl, halogenated phenyl, phenoxy, benzyloxy, acyloxy (e.g., acetoxy), acylamido (e.g., acetamido), furanyl which is unsubstituted or substituted by halogen, Ci_₄-alkyl, C_1- ₄-alkoxy, C₂_₈-alkoxycarbonyl, and/or benzyl, pyrrolyl which is unsubstituted or substituted by halogen, C^-alkyl, Ci_₄-alkoxy, C₂_s- alkoxycarbonyl, and/or benzyl, pyrazolyl which is unsubstituted or substituted by halogen, Ci-₄-alkyl, Ci_₄-alkoxy, C₂_₈-alkoxycarbonyl, and/or benzyl, isoxazolyl which is unsubstituted or substituted by halogen, C^-alkyl, Ci_₄-alkoxy, C₂_₈-alkoxycarbonyl, and/or benzyl, imidazolyl which is unsubstituted or substituted by halogen, C^-alkyl,

Ci-₄-alkoxy, C₂_₈-alkoxycarbonyl, and/or benzyl, pyridinyl which is unsubstituted or substituted by halogen, Ci-₄-alkyl, Ci-₄-alkoxy, C₂_s- alkoxycarbonyl, and/or benzyl, pyrimidinyl which is unsubstituted or substituted by halogen, Ci_₄-alkyl, Ci_₄-alkoxy, C₂_₈-alkoxycarbonyl, and/or benzyl, morpholinyl which is unsubstituted or substituted by Ci-

₄-alkyl, C₂_₈-alkoxycarbonyl, and/or benzyl, piperadinyl which is unsubstituted or substituted by Ci_₄-alkyl, C₂_s-alkoxycarbonyl, and/or benzyl, piperazinyl which is unsubstituted or substituted by Ci_₄-alkyl, C₂_₈-alkoxycarbonyl, and/or benzyl, tetrazolyl which is unsubstituted or substituted by Ci-₄-alkyl, C₂_₈-alkoxycarbonyl, and/or benzyl, pyrrolidinyl which is unsubstituted or substituted by halogen, Ci_₄- alkyl, Ci_₄-alkoxy, C₂_s-alkoxycarbonyl, and/or benzyl, alkylsulphonimide (e.g., CH₃SO₂-NHCO-), arylsulphonimide (e.g., C_OH_SSO₂-NHCO-) wherein the aryl portion is optionally substituted by halogen, Ci_₄-alkyl, Ci_₄-alkoxy, or combinations thereof (e.g., phenyl, bromophenyl, cyanophenyl, nitrophenyl, fluorophenyl, difluorophenyl, trifluoromethoxyphenyl, methylphenyl, dimethylphenyl, methoxyphenyl, biphenyl substituted by -CONH₂, and phenyl substituted by biphenyl or -CONH₂),

heterocyclic group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, halogenated alkyl (e.g., trifluoromethyl), halogenated alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, phenyl, halogenated phenyl, phenoxy, acyloxy, tetrazolyl which is unsubstituted or substituted by Ci_₄-alkyl, C₂-₈-alkoxycarbonyl, and/or benzyl, furanyl which is unsubstituted or substituted by halogen, C_1-4- alkyl, Ci_₄-alkoxy, C₂-₈-alkoxycarbonyl, and/or benzyl, pyrrolyl which is unsubstituted or substituted by halogen, C^-alkyl, Ci_₄-alkoxy, C₂-s- alkoxycarbonyl, and/or benzyl, pyrazolyl which is unsubstituted or substituted by halogen, Ci-₄-alkyl, Ci-₄-alkoxy, C₂-₈-alkoxycarbonyl, and/or benzyl, isoxazolyl which is unsubstituted or substituted by halogen, C^-alkyl, Ci_₄-alkoxy, C₂-₈-alkoxycarbonyl, and/or benzyl, imidazolyl which is unsubstituted or substituted by halogen, C^-alkyl, Ci-₄-alkoxy, C₂-₈-alkoxycarbonyl, and/or benzyl, pyridinyl which is unsubstituted or substituted by halogen, Ci-₄-alkyl, Ci-₄-alkoxy, C₂-s- alkoxycarbonyl, and/or benzyl, pyrimidinyl which is unsubstituted or substituted by halogen, Ci_₄-alkyl, Ci_₄-alkoxy, C₂-₈-alkoxycarbonyl, and/or benzyl, morpholinyl which is unsubstituted or substituted by C_1- ₄-alkyl, C₂-₈-alkoxycarbonyl, and/or benzyl, piperadinyl which is unsubstituted or substituted by Ci_₄-alkyl, C₂-₈-alkoxycarbonyl, and/or benzyl, piperazinyl which is unsubstituted or substituted by Ci_₄-alkyl, C₂-₈-alkoxycarbonyl, and/or benzyl, pyrrolidinyl which is unsubstituted or substituted by halogen, Ci-₄-alkyl, Ci-₄-alkoxy, C₂-₈-alkoxycarbonyl, and/or benzyl, alkylsulphonimide, arylsulphonimide, aryl, oxo, acylamido (e.g., acetamido), or combinations thereof (e.g., pyridyl, fluoropyridyl, methylpyridyl, benzothiazolyl, pyrimidinyl, bromopyrimidinyl, morpholinopyrimidinyl),

alkoxyalkyl having 3 to 8 carbon atoms;

R⁴ is alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups (e.g., CH₃);

R is H, or alkyl having 1 to 6 carbon atoms, which is unsubstituted or substituted one or more times by halogen wherein optionally one or more - CH₂CH₂- groups are replaced in each case by -CH=CH- or -C=C- groups (e.g., CH₃, C₂H₅);

is H,

alkoxyalkyl having 2 to 6 carbon atoms (e.g., methoxyethyl

(CH₂CH₂OCH₃), ethoxymethyl (CH₂OCH₂CH₃)), which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof;

-CO-NR⁵R¹²;

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF₃, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof, arylalkyl having 7 to 16 carbon atoms, which is unsubstituted or substituted, preferably in the aryl portion, one or more times by halogen, CF₃, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, acylamido (e.g., acetamido), and acyloxy (e.g., acetoxy), or combinations thereof,

R⁷ is H, halogen, or alkyl having 1 to 6 carbon atoms wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen;

R⁸ is H, halogen, alkyl having 1 to 6 carbon atoms wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups and wherein the alkyl is unsubstituted or substituted one or more times by halogen or hydroxyl (e.g., CH₃, C₂H₅, CF₃, hydroxymethyl, 2-(2-hydroxy)propyl, hydroxymethyl), carboxy, alkoxycarbonyl having 2 to 6 carbon atoms (e.g., ethoxycarbonyl), - CO-alkyl having 2 to 6 carbon atoms (e.g., CH₃CO), or phenyl;

R⁹ is halogen (e.g., F); and

R¹⁰ is H,

R¹¹ is H,

CH₃, C₂H₅), or

a heterocyclic-alkyl group, which is saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or S atom, which is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g., trifluoromethyl), nitro, oxo, amino, alkylamino, dialkylamino, carboxy or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof (e.g., tetrahydro-2H-pyranylmethyl, pyrrolidinylethyl);

R¹² is H,

alkyl having 1 to 6 carbon atoms (e.g., methyl, ethylpropyl), which is unsubstituted or substituted one or more times by halogen, oxo, or combinations thereof wherein optionally one or more -CH₂CH₂- groups are replaced in each case by -CH=CH- or -C≡C- groups (e.g., CH₃, C₂Hs),

Thus, according to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to Formulas Pl, P2, P3, P4, P5, P6, P7, P8, P9 and PlO and pharmaceutically acceptable salts thereof. According to a further method and composition aspect of the invention, the PDE4 inhibitor compounds are selected from the compounds according to f Formulas Pl, P2, P3, P4, P5, P6, P7, P8, P9 and PlO, and pharmaceutically acceptable salts thereof, and the antipsychotic agent is selected from: clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan® Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®), preferably selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, trifrupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole.

One of ordinary skill in the art will recognize that some of the compounds of PDE4 inhibitor compounds of the present invention can exist in different geometrical isomeric forms. In addition, some of the PDE4 inhibitor compounds of the present invention possess one or more asymmetric atoms and are thus capable of existing in the form of optical isomers, as well as in the form of racemic or nonracemic mixtures thereof, and in the form of diastereomers and diastereomeric mixtures inter alia. All of these compounds, including cis isomers, trans isomers, diastereomic mixtures, racemates, nonracemic mixtures of enantiomers, substantially pure, and pure enantiomers, are within the scope of the present invention. Substantially pure enantiomers contain no more than 5% w/w of the corresponding opposite enantiomer, preferably no more than 2%, most preferably no more than 1%.

The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereomeric salts using an optically active acid or base or formation of covalent diastereomers.

Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. The optically active bases or acids are then liberated from the separated diastereomeric salts.

A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivation, optimally chosen to maximize the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivitization, are also useful. The optically active compounds of Formulas A, B, C, D, El, E2, F, G, Hl, H2, H3, J, Kl, K2, K3, K4, K5, K6, K7, K8, L, Ml, M2, M3, M4, M5, M6, M7, M8, M9, N, O, Pl, P2, P3, P4, P5, P6, P7, P8, P9 and PlOcan likewise be obtained by utilizing optically active starting materials in chiral syntheses processes under reaction conditions which do not cause racemization.

The present invention also relates to useful forms of the compounds as disclosed herein, both PDE4 inhibitor compounds and the antipsychotic agents, such as pharmaceutically acceptable salts or prodrugs of all the compounds of the present invention for which salts or prodrugs can be prepared. Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid. Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and choline salts. Those skilled in the art will further recognize that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.

The following are further examples of acid salts that can be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopentanepropionates, dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides, hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, succinates, tartrates, thiocyanates, tosylates, mesylates and undecanoates.

For example, the pharmaceutically acceptable salt can be a hydrochloride, a hydroformate, hydrobromide, or a maleate.

One of ordinary skill in the art will also recognize that some of the compounds of the present invention may exist in different polymorphic forms. As known in the art, polymorphism is an ability of a compound to crystallize as more than one distinct crystalline or "polymorphic" species. A polymorph is a solid crystalline phase of a compound with at least two different arrangements or polymorphic forms of that compound molecule in the solid state. Polymorphic forms of any given compound are defined by the same chemical formula or composition and are as distinct in chemical structure as crystalline structures of two different chemical compounds.

One of ordinary skill in the art will further recognize that compounds of the present invention can exist in different solvate forms. Solvates of the compounds of the invention may also form when solvent molecules are incorporated into the crystalline lattice structure of the compound molecule during the crystallization process. For example, suitable solvates include hydrates, e.g., monohydrates, dihydrates, sesquihydrates, and hemihydrates.

Numerous standard references are available that describe procedures for preparing various formulations suitable for administering the compounds according to the invention. Examples of potential formulations and preparations are contained, for example, in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition). Administration may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion) by inhalation, rectally, vaginally, topically and by ocular administration. Various solid oral dosage forms can be used for administering compounds of the invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders. The compounds of the present invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and excipients known in the art, including but not limited to suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like. Time release capsules, tablets and gels are also advantageous in administering the compounds of the present invention.

Various liquid oral dosage forms can also be used for administering compounds of the inventions, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms can also contain suitable inert diluents known in the art such as water and suitable excipients known in the art such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention. The compounds of the present invention may be injected, for example, intravenously, in the form of an isotonic sterile solution. Other preparations are also possible.

Suppositories for rectal administration of the compounds of the present invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols. Formulations for vaginal administration can be in the form of a pessary, tampon, cream, gel, paste, foam, or spray formula containing, in addition to the active ingredient, such suitable carriers as are known in the art.

For topical administration, the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose. Topical administration may also involve transdermal administration via means such as transdermal patches.

Aerosol formulations suitable for administering via inhalation also can be made. For example, for treatment of disorders of the respiratory tract, the compounds according to the invention can be administered by inhalation in the form of a powder (e.g., micronized) or in the form of atomized solutions or suspensions. The aerosol formulation can be placed into a pressurized acceptable propellant.

The dosages of the compounds of the present invention, both the PDE4 inhibitors and the antipsychotic agents, depend upon a variety of factors including the particular syndrome to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the particular compound utilized, the efficacy, toxicology profile, pharmacokinetic profile of the compound, and the presence of any deleterious side-effects, among other considerations. Each active ingredient can be administered either in accordance with their usual dosage range or a dose below their usual dosage range.

The PDE4 inhibitor compounds of the invention are typically administered at dosage levels and in a manner customary for PDE4 inhibitors such as those known compounds mentioned above. For example, the compounds can be administered, in single or multiple doses, by oral administration at a dosage level of generally 0.001- 100 mg/kg/day, for example, 0.01-100 mg/kg/day, preferably 0.1-70 mg/kg/day, especially 0.5-10 mg/kg/day. Unit dosage forms can contain generally 0.01-1000 mg of active compound, for example, 0.1-50 mg of active compound. For intraveneously or intramuscular administration, the compounds can be administered, in single or multiple dosages, at a dosage level of, for example, 0.001-50 mg/kg/day, preferably 0.001-10 mg/kg/day, especially 0.01-1 mg/kg/day. Unit dosage forms can contain, for example, 0.1-10 mg of active compound.

Typical daily dosages for antipsychotic compounds mentioned above, administered orally, are as follows: 100-1000 mg chlorpromazine (Thorazine ®); 1-40 mg fluphenazine (Permitil ®, Prolixin ®); 12-64 mg perphenazine (Trilafon ®); 30- 150 mg prochlorperazine (Compazine ®); 150-800 mg thioridazine (Mellaril®); 4-40 mg trifluoperazine (Stelazine ®); 40-1000 mg promazine (Sparine ®), 50-1000 mg levomepromazine (a.k.a. methotrimeprazine); 30-200 mg chlorprothixene (Taractan ®); 3-12 mg flupenthixol (Fluanxol ®); 5-60 mg thiothixene (Navane ®); 10-75 mg zuclopenthixol (Clopixol®); 1-100 mg haloperidol (Haldol®); 12.5-900 mg clozapine (Clozaril ®); 5-20 mg olanzapine (Zyprexa ®); 2-8 mg risperidone (Risperdal ®); 50-800 mg quetiapine (Seroquel ®); 40-160 mg ziprasidone (Geodon ®); 50-1200 mg amisulpride (Solian ®); 3-12 mg paliperidone (Invega®); and 10-30 mg aripiprazole (Abilify ®).

Triflupromazine and droperidol are administered by injection. Typical daily doses are as follows: 60-150 mg of triflupromazine (Vesprin ®), and 1-10 mg of droperidol (Inapsine ®) by injection.

Thus, according to a further aspect of the invention there is provided a method of treating a patient suffering from a psychotic disorder, particularly schizophrenia, comprising administering orally to the patient, on a daily basis:

0.001-100 mg/kg/day, for example, 0.01-100 mg/kg/day, preferably 0.1-70 mg/kg/day, especially 0.5-10 mg/kg of a compound according to anyone of Formulas A, B, C, D, El, E2, F, G, Hl, H2, H3, J, Kl, K2, K3, K4, K5, K6, K7, K8, L, Ml, M2, M3, M4, M5, M6, M7, M8, M9, N, O, Pl, P2, P3, P4, P5, P6, P7, P8, P9 and PlO; and

100-1000 mg chlorpromazine, 1-40 mg fluphenazine, 12-64 mg perphenazine, 30-150 mg prochlorperazine, 150-800 mg thioridazine, 4-40 mg trifluoperazine, 40- 1000 mg promazine, 50-1000 mg levomepromazine, 30-200 mg chlorprothixene, 3-12 mg flupenthixol, 5-60 mg thiothixene, 10-75 mg zuclopenthixol, 1-100 mg haloperidol, 12.5-900 mg clozapine, 5-20 mg olanzapine, 2-8 mg risperidone, 50-800 mg quetiapine, 40-160 mg ziprasidone, 50-1200 mg amisulpride, 3-12 mg paliperidone, or 10-30 mg aripiprazole, wherein the active ingredients are administered in combined or separate formulations, preferably separate.

According to a further aspect of the invention there is provided a method of treating a patient suffering from a psychotic disorder, particularly schizophrenia, comprising intraveneously or intramuscularly administering to the patient, on a daily basis:

0.001-50 mg/kg, preferably 0.001-10 mg/kg, especially 0.01-1 mg/kg of a compound according to anyone of Formulas A, B, C, D, El, E2, F, G, Hl, H2, H3, J, Kl, K2, K3, K4, K5, K6, K7, K8, L, Ml, M2, M3, M4, M5, M6, M7, M8, M9, N, O, Pl, P2, P3, P4, P5, P6, P7, P8, P9 and PlO; and 60-150 mg of triflupromazine or 1-10 mg of droperidol.

0.001-100 mg/kg/day, for example, 0.01-100 mg/kg/day, preferably 0.1-70 mg/kg/day, especially 0.5-10 mg/kg of a compound selected from any one of Groups I-X; and

0.001-50 mg/kg, preferably 0.001-10 mg/kg, especially 0.01-1 mg/kg of a compound according to selected from any one of Groups I-X; and 60-150 mg of triflupromazine or 1-10 mg of droperidol.

According to a further aspect of the invention there is provided a pharmaceutical composition suitable for treating a patient suffering from a psychotic disorder, particularly schizophrenia, comprising: administering orally to the patient, on a daily basis:

0.01-1000 mg of active compound, for example, 0.1-50 mg of a compound according to anyone of Formulas A, B, C, D, El, E2, F, G, Hl, H2, H3, J, Kl, K2, K3, K4, K5, K6, K7, K8, L, Ml, M2, M3, M4, M5, M6, M7, M8, M9, N, O, Pl, P2, P3, P4, P5, P6, P7, P8, P9 and PlO; and 100-1000 mg chlorpromazine, 1-40 mg fluphenazine, 12-64 mg perphenazine, 30-150 mg prochlorperazine, 150-800 mg thioridazine, 4-40 mg trifluoperazine, 40- 1000 mg promazine, 50-1000 mg levomepromazine, 30-200 mg chlorprothixene, 3-12 mg flupenthixol, 5-60 mg thiothixene, 10-75 mg zuclopenthixol, 1-100 mg haloperidol, 12.5-900 mg clozapine, 5-20 mg olanzapine, 2-8 mg risperidone, 50-800 mg quetiapine, 40-160 mg ziprasidone, 50-1200 mg amisulpride, 3-12 mg paliperidone, or 10-30 mg aripiprazole.

0.01-1000 mg of active compound, for example, 0.1-50 mg of a compound selected from Groups I-X; and 100-1000 mg chlorpromazine, 1-40 mg fluphenazine, 12-64 mg perphenazine,

30-150 mg prochlorperazine, 150-800 mg thioridazine, 4-40 mg trifluoperazine, 40- 1000 mg promazine, 50-1000 mg levomepromazine, 30-200 mg chlorprothixene, 3-12 mg flupenthixol, 5-60 mg thiothixene, 10-75 mg zuclopenthixol, 1-100 mg haloperidol, 12.5-900 mg clozapine, 5-20 mg olanzapine, 2-8 mg risperidone, 50-800 mg quetiapine, 40-160 mg ziprasidone, 50-1200 mg amisulpride, 3-12 mg paliperidone, or 10-30 mg aripiprazole.

The present invention will now be further described by way of the following non-limiting examples. In applying the disclosure of these examples, it should be kept clearly in mind that other and different embodiments of the methods disclosed according to the present invention will no doubt suggest themselves to those of skill in the relevant art.

The entire disclosures of all applications, patents and publications, cited above and below, are hereby incorporated by reference in their entirety. EXAMPLES

Protocol for Conditioned Avoidance Responding in Rats

Conditioned avoidance responding (CAR) occurs when an animal subject learns that a tone and light predict the onset of a mild foot shock. The subject learns that when the light and tone conditioned stimulus (CS) are presented it must leave one side of the chamber and enter the other, safe, area. All known antipsychotic drugs reduce this avoidance response at doses which do not cause escape failures.

Examining the ability of test compounds to suppress the conditioned avoidance has been used for many years to help predict which compounds may be useful antipsychotic drugs.

In conditioned avoidance responding (CAR) an animal is placed in a two- chambered shuttle box and presented with a neutral conditioned stimulus (CS) consisting of a light and tone, followed by an aversive unconditioned stimulus (US), consisting of a mild foot shock through a floor grid in the shuttle box chamber. The animal is free to escape the US by moving from one chamber to the other, where the grid is not electrified. After several presentations of the CS-US pair, the animal typically learns to leave the chamber during the presentation of the CS and avoid the US altogether. Animals treated with clinically-relevant doses of antipsychotic drugs have a suppression of their rate of avoidances in the presence of the CS even though their escape response to the shock itself is unaffected. It is a hallmark of all known antipsychotic drugs that they can selectively suppress the animal's avoidance responses in CAR. As such, suppression of CAR has been widely used by pharmaceutical companies for close to fifty years to screen for new antipsychotic drugs that may have clinical efficacy.

Conditioned avoidance training is conducted using a shuttle box (Med

Associates, St. Albans, VT). The shuttle box is divided into 2 equal compartments, each of which contains a light source, a speaker that emits an 85 dB tone when activated and an electrified grid that can deliver a scrambled foot shock. Sessions consist of 20 trials per day (intertrial interval of 25-40 sec) during which a 10 sec illumination and a concurrent 10 sec tone signals the subsequent delivery of a 0.5 rnA shock applied for a maximum of 10 sec. Active avoidance, defined as the crossing into the opposite compartment during the 10 sec conditioning stimuli (light and tone) prevents the delivery of the shock. Crossing over to the other compartment after the delivery of the shock terminates shock delivery and is recorded as an escape response. If an animal does not leave the conditioning chamber during the delivery of the shock it is recorded as an escape failure. Training will be continued daily until the avoidance of 16 or more shocks out of 20 trials (80% avoidance) on 2 consecutive days is achieved. After this criterion is reached the rats are given one day of pharmacological testing. On test day, rats are randomly assigned to experimental groups, weighed and injected either intraperitoneally i.p. (1 cc tuberculin syringe, 26 3/8 gauge needle) or p. o.(18 gauge feeding needle) with either control or compound solutions. Compounds are injected at 1.0ml/kg for i.p. and from 2 ml/kg to 10 ml/kg for p.o. administration. Compounds may be administered either acutely or chronically. For testing, each rat is placed in the shuttle box, and given 20 trials with the same parameters as described above for training trials. The number of avoidances, escapes, and escape failures are recorded.

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

While the invention has been illustrated with respect to the production and of particular compounds, it is apparent that variations and modifications of the invention can be made without departing from the spirit or scope of the invention. Upon further study of the specification, further aspects, objects and advantages of this invention will become apparent to those skilled in the art.

Claims

We claim:

1. A pharmaceutical composition for treating cognitive impairment or a psychotic disorder in a patient comprising: (a) an amount of an antipsychotic agent and (b) an amount of a PDE4 inhibitor compound, wherein the amounts of (a) and (b) are together effective in treating the cognitive impairment or psychotic disorder such as schizophrenia.

2. A pharmaceutical composition according to claim 1, wherein the antipsychotic agent is selected from 5-HT_1A agnostics, dopamine modulators, sodium channel blockers, 5-HT uptake inhibitors, D3 antagonists, D2 antagonists, Dl antagonists, Dl agonists, secretin agonist, phospholipase A2 inhibitors, 5-HT2 antagonists, 5HT6 antagonists, COX 2 inhibitors, 5-HT_2A antagonists, 5HT_2C modulators, NK3 antagonists, alpha 1 adrenoreceptor antagonists, alpha 2 adrenoreceptor antagonists, AMPA modulators and NK 3 antagonists.

3. A pharmaceutical composition according to claim 1, wherein the antipsychotic agent is selected from clozapine (Clozaril ®), prochlorperazine (Compazine ®), etrafon ® (a combination of perphenazine and amitriptyline, Tiavil ®), haloperidol (Haldol®)), haloperidol decanoate, droperidol (Inapsine ®), molindone (Lidone ®, Moban ®), loxapine (Loxitane ®), thioridazine (Mellaril®), thiothixene (Navane ®), pimozide (Orap ®), fluphenazine (Permitil ®, Prolixin ®), fluphenazine decanoate, fluphenazine enanthate, risperidone (Risperdal ®,), mesoridazine besylate (Serentil ®), promazine (Sparine ®), trifluoperazine (Stelazine ®), chlorprothixene (Taractan ®), chlorpromazine (Thorazine ®), acetophenazine (Tindal ® ), perphenazine (Trilafon ®), triflupromazine (Vesprin ®), aripiprazole (Abilify ®), ziprasidone (Geodon ®), olanzapine (Zyprexa ®), quetiapine (Seroquel ®), levomepromazine (a.k.a. methotrimeprazine) (Nosinan®, Nozinan®, Levoprome®), flupenthixol (Fluanxol ®), amisulpride (Solian ®), paliperidone (Invega®), and zuclopenthixol (Clopixol®).

4. A pharmaceutical composition according to claim 1, wherein the antipsychotic agent is selected from chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, promazine, triflupromazine, levomepromazine (methotrimeprazine), chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone, and aripiprazole.

5. A pharmaceutical composition according to claim 1, wherein the antipsychotic agent is selected from risperidone (Risperdal®), aripiprazole (Abilify®), clozapine (Clozaril®), olanzapine (Zyprexa®), perphenazine (Trilafon ®), and haloperidol (Haldol®).

6. A pharmaceutical composition according to any one of claims 1 to 5, wherein the PDE4 inhibitor compound is selected from Formula A:

wherein

R¹ is alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen (e.g., CH₃, CHF₂, CF₃, etc.);

R² is alkyl having 1 to 12, preferably 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, Ci-₄-alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH₂CH₂- groups is replaced in each case by -CH=CH- or -C≡C- (e.g., CH₃, CHF₂, CF₃, methoxyethyl, etc.),

cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof (e.g., cyclopentyl), cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, Cr₄- alkyl, Cr₄-alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.),

aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF₃ OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof

(e.g., methylphenyl, methoxyphenyl, chlorophenyl, etc.),

arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, which the arylalkyl radical is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF_3> OCF₃, alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more - CH₂CH₂- groups are each optionally replaced by -CH=CH- or -C≡C-, and one or more -CH₂- groups are each optionally replaced by -O- or -

NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., phenylethyl, phenylpropyl, phenylbutyl, methoxyphenylethyl, methoxyphenylpropyl, chlorophenylethyl, chlorophenylpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, chlorophenoxyethyl, chlorophenylaminoethyl, etc.),

(e.g., cyclohexenyl, cyclohexadienyl, indanyl, tetrahydronaphthenyl, etc.), a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof (e.g., 3-thienyl, 3- tetrahydrofuranyl, 3-pyrrolyl, etc.), or

a heterocycle- alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and the alkyl portion is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, OCF₃, hydroxy, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, or combinations thereof, wherein in the alkyl portion one or more -CH₂CH₂- groups are each optionally replaced by -CH=CH- or -C≡C-, and one or more - CH₂- groups are each optionally replaced by -O- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., pyridylethyl, pydridylpropyl, methylpiperazinylethyl, etc.);

is H,

aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, OCF₃, amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole- 5-yl (e.g., 2- (2- tetrahydropyranyl)tetrazole- 5 - yl), hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert- butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg. tert- butyldimethylsilyloxy), R⁵-L-, or combinations thereof (e.g., substituted or unsubstituted phenyl, naphthyl, and biphenyl, such as phenyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.), or

heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy

(eg. te/t-butyldimethylsilyloxy), R -L-, or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.);

is H,

alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8, preferably 1 to 4 carbon atoms (e.g., dimethylamino, etc.), a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion has 1 to 5 carbon atoms, which is unsubstituted or substituted, preferably in the carbocyclic portion, one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof (e.g., cyclohexenylmethyl, etc.),

aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifluoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg., hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkylthio, alkylsulfinyl, alkylsulfonyl,

(e.g., substituted or unsubstituted phenyl and naphthyl, methylphenyl, chlorophenyl, fluorophenyl, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.),

is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH₂- groups are each optionally replaced by -O-, -S-, -NR⁶-, -SO₂NH-, -NHSO₂-, -CO-, -NR⁶CO-, -CONR⁶-, - NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or - NHCSNH- (e.g.,-0-, CH₂-, -CO-, -CO-O-, -0-C0-, -CO-NH-, -NH- CO-, -CH₂CH₂CH₂-NH-CO-, -CH₂-CH₂-O-, -SO₂-NH-CH₂CH₂-O-, - 0-CH₂CH₂-O-, -CH₂-NH-CO-, -CO-NH-CH₂-, -SO₂-NH-, -CH₂-NH- SO₂-, -CH₂CH₂CH₂-SO₂-NH-, etc.); and

R⁶ is H,

7. A pharmaceutical composition according to any one of claims 1 to 5, wherein the PDE4 inhibitor compound is selected from Group I:

3-cyclopentyloxy-4-methoxy-N-(3-pyridylmethyl)diphenylamine;

N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-3-aminobenzoic acid;

3-cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-N-(3- pyridylmethyl)diphenylamine; iV-3,4-bis(difluoromethoxy)phenyl)-iV-(3-pyridylmethyl)-3-aminobenzoic acid;

3-[3-(4-Chlorophenyl)prop-l-yloxy]-4-methoxy-iV-(3-pyridylmethyl)diphenylamine;

4-Methoxy-3-[3-(4-methoxyphenyl)prop-l-yl]oxy-iV-(3- pyridylmethyl)diphenylamine ; 3-[2-(4-Chlorophenoxy)ethoxy)-4-methoxy-iV-(3-pyridylmethyl)diphenylamine;

3 -Indanyloxy-4-methoxy-./V- (3 -pyridylmethyl)diphenylamine ;

4-Methoxy-3-(2-methoxyethoxy)-iV-(3-pyridylmethyl)diphenylamine;

3-Cyclopropylmethoxy-4-methoxy-iV-(3-pyridylmethyl)diphenylamine;

3-[2-(4-Chlorophenyl)ethenyloxy]-4-methoxy-iV-(3-pyridylmethyl)diphenylamine; 4-Methoxy-3 - (2-phenoxyethoxy)-iV- (3 -pyridylmethyl)diphenylamine ;

3-Cyclopropylmethoxy-4-difluoromethoxy-iV-(3-pyridylmethyl)diphenylamine;

3'-Chloro-4-methoxy-3-(2-methoxyethoxy)-iV-(3-pyridylmethyl)diphenylamine;

3-Cyclopropylmethoxy-4'-hydroxy-4-methoxy-iV-(3-pyridylmethyl)diphenylamine;

3 -Cyclopropylmethyloxy-4-difluoromethoxy-iV- (3 -pyridylmethyl) -4 ' - (2H-tetrazol- 5 - yl)diphenylamine ; 3 -Cyclopropylmethyloxy-4-methoxy-iV- (3 -pyridylmethyl) -4 ' - (2H-tetrazol- 5 - yl)diphenylamine ;

Bis -3 ,4-difluoromethoxy-iV- (3 -pyridylmethyl) -4 ' - (2H-tetrazol- 5 -yl)diphenylamine 3-Cyclopropylmethoxy-3 ' -ethanesulfonylamino-4-methoxy-iV-(3- pyridylmethyl)diphenylamine; and pharmaceutically acceptable salts thereof.

8. A pharmaceutical composition according to any one of claims 1 to 5, wherein the PDE4 inhibitor compound is selected from Formulas B, C, D, El, E2, F,

G, Hl, H2, H3, J, Kl, K2, K3, K4, K5, K6, K7, K8, L, Ml, M2, M3, M4, M5, M6, M7, M8, M9, N, O, Pl, P2, P3, P4, P5, P6, P7, P8, P9 and PlO.

9. A pharmaceutical composition according to any one of claims 1 to 5, wherein the PDE4 inhibitor compound is selected from Groups H-X.

10. A method for treating a psychotic disorder or condition in a patient in need thereof comprising administering to said patient (a) an amount of a antipsychotic agent and (b) an amount of a PDE4 inhibitor compound, wherein the amounts of (a) and (b) are together effective in treating a psychotic disorder such as schizophrenia.

11. A method for treating a psychotic disorder or condition in a patient in need thereof comprising administering to said patient a composition according to any one of claims 1 to 9.

12. Use of an antipsychotic agent and a PDE4 inhibitor compound for the treating a psychotic disorder such as schizophrenia, wherein the amounts of (a) and (b) are together effective for treating the psychotic disorder.