RU2840025C2 - Methods of using cyclic amide derivatives for treating sigma receptor mediated disorders - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: group of inventions refers to pharmaceutical industry, namely to methods of treating schizoaffective disorder. Method of treating schizoaffective disorder, as well as a method of treating or relieving at least one symptom of schizoaffective disorder in a subject, in need thereof, comprising administering to a subject one to four times day from 1 mg to 64 mg of a compound of formula (II)

or a pharmaceutically acceptable salt, hydrate or solvate thereof. Method of treating schizoaffective disorder, as well as a method of treating or relieving at least one symptom of schizoaffective disorder in a subject, in need thereof, comprising administering to a subject twice day 32 mg of a compound of formula (II) or a pharmaceutically acceptable salt, hydrate or solvate thereof.

EFFECT: use of the group of inventions provides the treatment of schizoaffective disorder, namely the immediate improvement of negative symptoms, which lasts throughout the course of treatment, improvement of positive symptoms after four weeks of treatment, effective reduction of negative and positive symptoms for more than twelve weeks, as well as improved memory, anxiety and sleep with minimal side effects.

15 cl, 2 ex

Description

State of the art

Sigma receptors are found throughout the body and play a number of different roles as pharmacological targets. For example, sigma receptor/binding sites in the brain are important targets for the development of antipsychotic drugs that do not have the side effects of traditional antipsychotic drugs that exhibit dopamine D2 receptor antagonist activity (See, e.g., J. M. Walker et al., Pharmacological Reviews, 42:355-402, 1990).

The sigma receptor exists in two subtypes, sigma-1 and sigma-2. The sigma-1 binding site is characterized by having high affinity for haloperidol, di-o-tolylguanidine (DTG), and (+)-benzomorphans such as (+)-pentazocine. The sigma-2 binding site is characterized by having high affinity for haloperidol and DTG, but low affinity for (+)-benzomorphan.

Sigma-1 ligands can act on the gastrointestinal tract. The sigma-1 site can mediate the suppression of the muscarinic-like acetylcholine receptor/phosphoinositide cycle reaction by sigma ligands. The sigma-1 binding site is present not only in the brain but also on spleen cells (Y. Lin et al., J. Neuroimmunol., 58:143-154, 1995), and such sigma ligands can suppress the immune system (H. H Garza et al., J. Immunol., 151:4672-4680, 1993).

The sigma-2-binding site is abundant in the liver (AE Brunce et al., Neurosci. Abstr., 16:370, 1990), kidney (W.D. Bowen et al., Soc. Neurosci. Abstr., 18:456), and heart (M. Dumont, S. Lemaire, Eur. J. Pharmacol., 209:245, 248, 1991). The sigma-2-binding site in the brain is located in the hypothalamus, cerebellum, pons, and medulla oblongata. In the hippocampus, frontal lobe, and occipital lobe of the rat cerebrum, it is more abundant than the sigma-1-binding site. In guinea pig hippocampal synaptosomes there is a sigma-2-binding site that is selectively labeled with [ ³ H]BIMU (DW Bonhaus et al., J. Pharmacol. Exp. Ther., 267:961-970, 1993). The dependence between the sigma-2-binding site and the cerebral cortex and limbic system supports the utility of compounds used to treat psychiatric disorders (DC Mash, CP Zabetain, Synapse, 12:195-205, 1992). The sigma-2-binding site has been suggested to be involved in motor functions, particularly dystonia, but no evidence has been found to demonstrate such an effect in primate experimental models of functional disorders of the extrapyramidal tract (LT Meltzer et al., Neuropharmacology, 31:961-967, 1992).

Sigma-2 receptor agonists can induce changes in cell morphology and apoptosis in a variety of cell types (W.D. Bomen, 74:211-218, 2000). Activation of the sigma-2 receptor produces both transient and sustained increases in [Ca++]i arising from a variety of intracellular events. Changes in [Ca++]i and also cytotoxic effects are mediated by intracellular sigma-2 receptors. In addition, sigma-2 agonists have been shown to induce apoptosis in drug-resistant cancer cells, enhance the efficacy of DNA-damaging agents, and down-regulate p-glycoprotein mRNA expression (including some sigma-2 receptor agonists that are useful in the treatment of drug-resistant cancers). Prior art work suggests that sigma-2 antagonists could prevent the irreversible motor side effects of typical antipsychotics and that some sigma-2 receptors may serve as a novel signaling pathway for apoptosis involved in regulating cell proliferation and/or survival.

Halopyridol, a clinically effective dopaminergic antipsychotic, exhibits high affinity for both sigma subtypes, 1 and 2. However, the reduced metabolite of halopyridol, which acts on the central nervous system, has higher affinity and selectivity for the sigma-2 receptor than dopamine D2, compared with halopyridol (J.C. Jaen et al., J. Med. Chem., 36:3929-3936, 1993).

U.S. Patent No. 7,166,617, incorporated herein by reference in its entirety, discloses cyclic amide derivatives having high affinity for the sigma-2 binding site. Certain compounds disclosed in this patent have high affinity for the (sigma ligand) binding site and a low inhibition constant _Ki for sigma-1 and/or sigma-2, as well as selective binding profiles that are completely different from the selective binding profiles of conventional known compounds. Such compounds may be useful for the treatment of diseases that can be therapeutically and/or prophylactically treated due to the nervous system regulatory function of sigma ligands. However, the properties and characteristics of specific derivatives are not disclosed in U.S. Patent No. 7,166,617.

Detailed description of the invention

The present invention provides compounds of formula I and methods of using such compounds for the treatment of sigma receptor-mediated disorders, and in particular sigma-2 receptor-mediated disorders.

Definitions

The term "modulate" as used herein includes, but is not limited to, stabilizing, stimulating, enhancing, inhibiting, or disrupting protein-protein interactions (e.g., homophilic and/or heterophilic). As used herein, the term "modulate" also refers to influencing the interaction between non-protein molecules and receptor molecules.

As used here, the term schizophrenia encompasses the full spectrum of schizophrenic disorders known to those skilled in the art. These include, but are not limited to, the following disorders: catatonic, hebephrenic, paranoid, residual, and undifferentiated schizophrenia; schizophreniform disorder; and schizoaffective disorder.

The term "receptor" used here means the membrane-bound type of receptor as well as other binding sites. For example, the existence of at least two subtypes of sigma receptors, i.e., sigma-1 and sigma-2, and the classification of sigma-binding sites are proposed by R. Quirion et al., TiPS, 13:85-86, 1992.

The definition of "subject" refers to any animal organism, including mammals such as, but not limited to, humans, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates.

The term "treatment" (and the corresponding terms "treat" and "therapy") includes palliative, restorative, and preventive (prophylactic) treatment of a subject. The term "palliative treatment" refers to a therapy that alleviates or reduces the effect or intensity of a patient's condition without treating the condition itself. The term "preventive treatment" (and the corresponding term "prophylactic treatment") refers to a therapy that prevents an episode of a condition in a patient. The term "restorative treatment" ("curative") refers to a therapy that arrests the progression, reduces the pathological manifestations, or completely eliminates a condition in a patient. Treatment may be performed with a therapeutically effective amount of a compound, salt, or composition that elicits a biological or medical response in a tissue, system, or patient, as determined by a specialist such as a researcher, physician, veterinarian, or clinician.

"PANSS" stands for Positive and Negative Syndrome Scale;

"BACS" stands for Brief Assessment of Cognition in Schizophrenia test;

"HAMD" stands for Hamilton Depression Rating Scale;

"HAMA" stands for Hamilton Anxiety Scale;

"ADAS COG" stands for Alzheimer's Disease Assessment Scale Cognitive Subscale and Test.

"MADRS" stands for Montgomery-Asberg Depression Rating Scale;

"PSQI" stands for Pittsburgh Sleep Quality Index.

The invention provides compositions and methods for treating disorders or conditions associated with sigma-2 receptors. It will be understood by one of skill in the art that any condition that mediates a sigma-2 receptor or depends on a sigma-2 receptor can be impaired by a compound that regulates a sigma receptor. The compound and method of the invention can be used to modify or interfere with a condition, disorder, disease or process that mediates a sigma-2 receptor or depends on a sigma-2 receptor. In one aspect, the condition is a neurological condition. In an embodiment of the invention, the condition is selected from the group including, but not limited to, schizoaffective disorder, behavioral and cognitive components of Alzheimer's disease, dementia with Lewy bodies, bipolar disorders, attention deficit disorder, attention deficit hyperactivity disorder, dementia associated with acquired immunodeficiency syndrome, depression, hypomania and addiction.

In one embodiment, the compounds of formula I are shown to be useful for the treatment of schizophrenia.

In another embodiment, the compounds of formula I are shown to be useful for treating one or more symptoms of schizophrenia. In one aspect, the symptoms are negative symptoms. In another aspect, the symptoms are positive symptoms. In yet another aspect, the symptoms are general symptoms. In one embodiment, the invention provides methods and compositions for treating schizophrenia and symptoms of schizophrenia, as more fully described below.

The invention also provides compositions and methods for treating symptoms of other sigma-2-related disorders or conditions. A skilled artisan will understand how to define, characterize and quantify symptoms of sigma-2-related disorders or conditions. In one aspect, the symptoms are one or more symptoms of the conditions specified elsewhere in this description. In another aspect, the symptoms are one or more symptoms selected from, but not limited to, the following symptoms: confused thinking, problems performing tasks, problems remembering, impulsive behavior, hallucinations, gambling, alcoholism, anxiety, dysthymia, akathisia resulting from treatment with atypical antipsychotics, extrapyramidal symptoms resulting from treatment with atypical antipsychotics, and obesity.

In the present invention, the compounds of formula I are useful for treating one or more negative symptoms of schizophrenia. In one aspect, the compounds of formula I are useful for treating one or more negative symptoms of schizophrenia, while not affecting one or more positive symptoms of schizophrenia. In another aspect, the compounds of formula I are useful for treating one or more negative symptoms of schizophrenia, while also treating one or more positive symptoms of schizophrenia. In another aspect, the compounds of formula I are useful for treating one or more negative symptoms of schizophrenia, while also treating one or more general symptoms of schizophrenia. In yet another aspect, the compounds of formula I are useful for treating one or more positive symptoms of schizophrenia. In another aspect, the compounds of formula I are useful for enhancing therapy for schizophrenia in a patient currently receiving one or more compounds for the treatment of schizophrenia.

In an embodiment of the invention, the compound of formula I is a compound represented by formula II, also referred to herein as CYR-101:

2-[[1-[2-(4-Fluorophenyl)-2-oxoethyl]piperidin-4-yl]methyl]isoindolin-1-one.

In another embodiment, the compound of formula I is a compound represented by formula III:

In one embodiment of the invention, the compound of formula III has properties and activity similar to the properties and activity of the compound of formula II.

The compounds of formula I disclosed herein have a receptor binding profile demonstrating preferential binding for sigma-2 receptors, 5-HT _2A receptors, and α ₁ adrenergic receptors. However, it will be appreciated that some compounds of formula I may not have preferential binding for a certain list of receptors, and in some cases may exhibit preferential binding for one or more different receptors, including less than all of the sigma-2, 5-HT _2A , and α ₁ adrenergic receptors. In another aspect, the compounds disclosed herein have little or no affinity for dopaminergic, muscarinic, cholinergic, or histaminergic receptors, and may have varying affinities for any combination of such receptors. In one embodiment, the compound of formula II has little or no affinity for dopaminergic, muscarinic, cholinergic, or histaminergic receptors.

In an embodiment of the invention there is provided a method of treating sigma-2-related disorders or conditions (e.g. schizophrenia in a patient) or for treating at least one symptom of sigma-2-related disorders or conditions, the method comprising administering to a patient in need of treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein X is an alkyl group, a cycloalkyl-substituted alkyl group, an aryl-substituted alkyl group, an aryl-substituted alkenyl group, an aryl-substituted alkynyl group, a monocyclic or polycyclic cycloalkyl group which may be substituted with an alkyl group, an aryl group, a heterocyclic group or a substituted or unsubstituted amino group; Q represents a group represented by -CO-, -O-, -S-, -CH(OR ₇ )-, -C(=CH ₂ )- or -C(=NR ₈ )-, wherein R ₇ represents a hydrogen atom, an alkyl group, a hydroxyalkyl group or an acyl group, and R ₈ represents a hydroxyl group, an alkoxyl group, an aralkyloxy group, an acyloxy group, an acylamino group or an alkoxycarbonylamino group; n represents an integer from 0 to 5; R ₁ and R ₂ each independently of one another represent a hydrogen atom or an alkyl group.

The remainder B is represented by the following groups:

where R ₃ , R ₄ , R ₅ and R ₆ each independently of one another represent a substituent selected from the group consisting of a hydrogen atom, a halogen atom, a nitro group, an alkyl group, a halogenated alkyl group, a hydroxyl group, an alkoxyl group, a halogenated alkoxyl group and a cyano group; and m is 1 or 2.

Dosage forms and quantities

For therapeutic administration according to the present invention, the compound of formula I may be used in the form of its base, but is preferably used in the form of a pharmaceutically acceptable salt, typically in the form of a hydrochloride.

Other salts of the compound of formula I with pharmaceutically acceptable acids may also be used in therapeutic administration; for example, salts derived from the functional free base and acids including, but not limited to, palmitic acid, hydrobromic acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, salicylic acid, citric acid, oxalic acid, lactic acid, malic acid, methanesulfonic acid, and p-toluenesulfonic acid.

All solvates and all alternative physical forms of the compound of formula I or its pharmaceutically acceptable derivatives described herein, including, but not limited to, alternative crystalline forms, amorphous forms and polymorphs, are also within the scope of the present invention; and all references to a compound of formula I include all pharmaceutically acceptable salts and all solvates and alternative physical forms thereof.

For therapeutic administration, a compound of formula I or a pharmaceutically acceptable salt thereof, such as a compound of formula II, may be administered in pure form, but will preferably be formulated into any suitable pharmaceutically acceptable and effective composition that provides effective levels of the active ingredient in the body.

Preferred forms include, but are not limited to, depot formulations (e.g., crystalline structure, emulsion), depot formulations suitable for intramuscular or subcutaneous injection, controlled release forms including controlled release tablets, transdermal systems (e.g., patch), buccal forms (e.g., film, tablet), effervescent tablets, and subdermal lozenge. In one embodiment, the depot formulation comprises palmitate (salt) of the compound of formula I.

Treatment of a sigma-2-related disorder or condition (e.g., treatment of schizophrenia in a patient) or treatment of at least one symptom of a sigma-2-related disorder or condition may comprise administering a compound of formula I or a pharmaceutically acceptable salt thereof at a dose of 10 mcg to 200 mg, 15 mcg to 190 mg, 25 mcg to 180 mg, 50 mcg to 170 mg, 75 mcg to 160 mg, 100 mcg to 150 mg, 250 mcg to 140 mg, 400 mcg to 130 mg, 500 mcg to 128 mg, 600 mcg to 100 mg, 750 mcg to 75 mg, 900 mcg to 50 mg, or at doses of 1 to 64 mg. In one aspect, treatment may comprise administering a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of <200 mg, <150 mg, <100 mg, <50 mg, <40 mg, <30 mg, <20 mg, <10 mg, <9 mg, <8 mg, <7 mg, <6 mg, <5 mg, <4 mg, <3 mg, <2 mg, <1 mg, <0.5 mg, <0.25 mg, <0.1 mg, <0.05, or <0.01 mg.

In an embodiment of the invention, the treatment of schizophrenia may comprise administering a compound of formula I or a pharmaceutically acceptable salt thereof at a dose of 10 mcg to 200 mg, 100 mcg to 150 mg, 500 mcg to 128 mg, or 1 to 64 mg. The dose may be administered as a single daily dose, twice daily, three times daily, or four times daily. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dose of 8 to 32 mg twice daily.

Co-administration of compounds

In an embodiment of the invention, the compound of formula I or a pharmaceutically acceptable salt thereof is administered independently of any other medicament. In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in combination with one or more other medicaments.

In an embodiment of the invention, a sigma-2 receptor-mediated disorder or condition is treated by administering a compound of formula I in combination with at least one additional compound. One skilled in the art will understand that the at least one additional compound will be selected based on the disorder or condition being treated. As a non-limiting example, treating anxiety may involve treating a patient in need thereof with a compound of formula II in combination with at least one antianxiolytic compound. Similarly, one skilled in the art will understand how to establish a therapeutically effective dose of the additional compound based on the patient, the condition, the compound, and information known regarding the properties and activity of the additional compound.

In another embodiment, at least one symptom of a sigma-2 receptor-mediated disorder or condition is treated by administering a compound of formula I in combination with at least one additional compound. Again, one skilled in the art will appreciate that the at least one additional compound will be selected based on the disorder or condition being treated or, where appropriate, based on the particular symptom or symptoms being treated.

As another non-limiting example, a compound represented by formula II, or a pharmaceutically acceptable salt thereof, can be advantageously administered in combination with at least one neuroleptic agent (e.g., a typical or atypical antipsychotic agent) to provide improved treatment of any combination of negative symptoms of schizophrenia, positive symptoms of schizophrenia, general symptoms of schizophrenia, or therapy for schizophrenia itself. The combinations, uses, and methods of therapy of the present invention can provide advantages in the treatment of patients who do not adequately respond to or who are resistant to other known therapies.

In an embodiment of the invention, a compound of formula I may be administered to a patient already undergoing treatment with at least one neuroleptic agent (e.g., a typical or atypical antipsychotic agent) to provide improved treatment of any combination of negative symptoms of schizophrenia, positive symptoms of schizophrenia, general symptoms of schizophrenia, or therapy for schizophrenia itself.

Experimental examples

Example 1: CYR-101 Clinical Study

The study is being conducted using a compound of formula II to evaluate the efficacy in schizophrenia and the treatment of schizophrenia symptoms. The study is a multicenter, inpatient and outpatient, phase 2, double-blind, randomized, placebo-controlled study of a compound of formula II in patients with DSM-IV schizophrenia. Twenty-one centers in three different countries participated in the study.

The study is designed to test the therapeutic efficacy of the compound of formula II on all features of schizophrenia (e.g., positive, negative, general symptoms, cognition, sleep, mood, and anxiety). The study also evaluates the safety of the administered dose of the compound of formula II (also referred to herein as CYR-101), including cardiac repolarization (i.e., QT interval), weight change, adverse events, prolactin, and extrapyramidal symptoms.

The study was conducted over a three-month period, a sufficient period of time to allow the compound to demonstrate its full therapeutic potential, particularly in terms of cognitive parameters.

The objectives of the study include the following tasks:

1. To determine the efficacy of CYR-101 compared with placebo according to the PANSS total score and scale items after one month (28 days ± 2 days) of therapy 2. To test whether the administered dose of CYR-101 would show significantly higher efficacy, as assessed by the PANSS total score and scale items, after three months (84 days ± 2 days) of therapy 3. To determine the efficacy of CYR-101 compared with placebo, as assessed by the Clinical Global Impression-Score (CGI-S), after one and three months of therapy 4. To determine the subjective efficacy of CYR-101 in patients compared with placebo, as assessed using the Drug Attitudes Inventory 10 (DAI-10), after one and three months of therapy 5. To determine subjective sleep quality, as assessed by the Pittsburgh Sleep Quality Index (PSQI), after three months of therapy 6. To investigate the efficacy of CYR-101 versus placebo on cognitive function, as measured by the Brief Assessment of Cognitive Function in Schizophrenia (BACS), after one and three months of treatment 7. To determine the efficacy compared with placebo of CYR-101 on depressive symptoms, as measured by the full-scale Montgomery-Asberg Depression Rating Scale (MADRS), after one month of treatment 8. To determine the efficacy compared with placebo of CYR-101 on anxiety, as measured by the full scale of the Hamilton Anxiety Rating Scale (HAMA), after one month of treatment 9. To evaluate the cardiovascular safety (especially ventricular repolarization as assessed by QT/QTc interval measurements) of CYR-101 compared with placebo 10. To assess the overall safety and tolerability of CYR-101 compared with placebo 11. To determine the pharmacokinetics of CYR-101 in schizophrenic patients

In one aspect of the study, the dose of the compound was increased to 32 mg twice daily.

The data obtained were analyzed in three ways: 1) the safety analysis set; 2) the full analysis set, with each patient having at least one post-treatment PANSS score included in the efficacy assessment. The LOCF method was used; and 3) the per-protocol set, where in some analyses all patients who completed three months of treatment were included. Analysis of covariance was ANCOVA, followed by analysis of differences at each time point, and in some cases the nonparametric Wilcoxon test was used.

The results show no significant difference between the CYR-101 and placebo groups in the occurrence or worsening of extrapyramidal symptoms. There are three statistically significant adverse reactions (SAEs), two of which are in the placebo group. One of the SAEs in the active component group does not appear to be related to CYR-101 based on clinical history.

Improvement in negative symptoms is immediate and lasts for the entire course of treatment. This effect of the compound is unexpected. Positive symptoms do not improve until the first four weeks of treatment. Moreover, the improvement in both positive symptoms and negative symptoms lasts for more than twelve weeks. This is also unexpected, since other antipsychotics typically show improvement for only six weeks.

In addition, CYR-101 has been shown to have a positive effect on cognition in schizophrenic patients. Cognition has been shown to improve rapidly when patients are started on CYR-101. Cognitive performance assessed by the BACS shown on the FAS shows no difference between the placebo and CYR-101 groups, with the exception of the token task. On the RMS at D84, descriptive data show minor differences in favor of the CYR-101 group compared to the placebo group for the token task, learning list and verbal fluency, and for information processing speed. These differences are not statistically significant. However, in comparison, it should be noted that most other antipsychotic treatments have a significant negative effect on cognition.

Prolongation of the QT interval has been observed following administration of CYR-101 at doses up to 32 mg twice daily. However, the observed prolongation remains stable over time and does not exceed clinically acceptable limits (e.g., 10-15 milliseconds or less).

Overall, CYR-101 induces a surprising and unexpected immediate and persistent effect on negative symptoms and some cognitive functions impaired in schizophrenic patients. CYR-101 also has some effect on positive symptoms, but longer-term treatment is needed to see differentiation from placebo. All the above effects are accompanied by some improvements in memory, anxiety and sleep, providing CYR-101 with a desirable basis for therapy to treat schizophrenia and schizophrenic symptoms with minimal side effects and a beneficial, immediate and beneficial effect on negative symptoms and cognition.

Example 2: Receptor binding profile of CYR-101

U.S. Patent No. 7,166,617, incorporated herein by reference in its entirety, illustrates the preferential binding of CYR-101 to the sigma-2 receptor site. The test compound of Example 1 of U.S. Patent No. 7,166,617 is CYR-101. As shown in Table 1 of U.S. Patent No. 7,166,617, CYR-101 has an affinity for the sigma-2 receptor of 13 nM. These data indicate that CYR-101 exhibits selective sigma-2 receptor binding. Moreover, CYR-101 is known to be a dual 5-HT2A/sigma-2 antagonist and lacks dopamine binding properties.

The invention has been described herein with the aid of certain preferred embodiments. However, since obvious variations thereof will be apparent to those skilled in the art, the invention should not be considered as limited thereto. All patents, patent applications and references cited in the specification are incorporated by reference in their entirety.

Claims (23)

1. A method for treating schizoaffective disorder in a subject in need thereof, comprising administering to the subject one to four times daily from 1 mg to 64 mg of a compound of formula (II) or a pharmaceutically acceptable salt, hydrate or solvate thereof. 2. A method for treating or alleviating at least one symptom of schizoaffective disorder in a subject in need thereof, comprising administering to the subject one to four times daily from 1 mg to 64 mg of a compound of formula (II) or a pharmaceutically acceptable salt, hydrate or solvate thereof. 3. The method of claim 2, wherein at least one symptom of schizoaffective disorder is selected from the group consisting of confused thinking, problems with task performance, problems with memory, impulsive behavior, hallucinations, gambling addiction, alcoholism, anxiety, dysthymia, akathisia arising from treatment with atypical antipsychotics, extrapyramidal symptoms arising from treatment with atypical antipsychotics, and obesity. 4. The method according to claim 3, wherein at least two schizoaffective symptoms are treated. 5. The method according to any one of claims 1-4, wherein the subject is administered from 8 mg to 32 mg of the compound of formula (II) or a pharmaceutically acceptable salt, hydrate or solvate thereof. 6. The method according to any one of claims 1-4, wherein the subject is administered 32 mg of the compound of formula (II) or a pharmaceutically acceptable salt, hydrate or solvate thereof. 7. The method according to any one of claims 1-6, wherein the compound of formula (II) or a pharmaceutically acceptable salt, hydrate or solvate thereof is administered to the subject twice a day. 8. The method according to any one of claims 1-6, wherein the subject is administered a compound of formula (II) or a pharmaceutically acceptable salt, hydrate or solvate thereof once a day. 9. A method for treating schizoaffective disorder in a subject in need thereof, comprising administering to the subject twice daily 32 mg of a compound of formula (II) or a pharmaceutically acceptable salt, hydrate or solvate thereof. 10. A method for treating or alleviating at least one symptom of schizoaffective disorder in a subject in need thereof, comprising administering to the subject twice daily 32 mg of a compound of formula (II) or a pharmaceutically acceptable salt, hydrate or solvate thereof. 11. The method of claim 10, wherein at least one symptom of schizoaffective disorder is selected from the group consisting of confused thinking, problems with task performance, problems with memory, impulsive behavior, hallucinations, gambling addiction, alcoholism, anxiety, dysthymia, akathisia arising from treatment with atypical antipsychotics, extrapyramidal symptoms arising from treatment with atypical antipsychotics, and obesity. 12. The method according to claim 11, wherein at least two schizoaffective symptoms are treated. 13. The method according to any one of paragraphs 1-12, further comprising administering to the subject a typical or atypical antipsychotic. 14. The method according to any one of claims 1 to 13, wherein the compound of formula (II) is a hydrochloride salt. 15. The method according to any one of claims 1-14, wherein the compound of formula (II) is a hydrate.