JP2008528532A - SPM927 for add-on treatment of schizophrenia - Google Patents

Abstract

  The present invention involves the use of a class of peptide compounds to prevent, reduce and / or treat diseases treated with antipsychotics, in particular psychosis, especially schizophrenia, in add-on therapy to at least one antipsychotic. set to target.

Description

  The present invention involves the use of a class of peptide compounds to prevent, reduce and / or treat diseases treated with antipsychotics, in particular psychosis, especially schizophrenia, in add-on therapy to at least one antipsychotic. set to target.

  In particular, the present invention relates to schizophrenia, bipolar disorder, autism, attention deficit / hyperactivity disorder, psychosis, particularly psychosis associated with: schizophrenia, in an add-on treatment to at least one antipsychotic drug. Bipolar disorder, autism, Alzheimer's disease, attention deficit / hyperactivity disorder, drug abuse and / or alcoholism, affective disorder, dyskinesia and related diseases, dementia, mental retardation, hypertension / hyponatremia, Treatment of severe personality disorder, acute mania, obsessive compulsive disorder, refractory chronic insomnia, Huntington's disease, Tourette syndrome, Parkinson's disease and / or dopaminergic Parkinson's disease, preferably psychosis is associated with schizophrenia To the use of a peptide compound class for preventing, reducing and / or treating said illness.

  Certain peptides are known to exhibit central nervous system (CNS) activity and are useful in the treatment of epilepsy and other CNS diseases. These peptides described in US Pat. No. 5,378,729 have the following formula (Ia)

[式中、
− Rは、水素、低級アルキル、低級アルケニル、低級アルキニル、アリール、アリール低級アルキル、複素環、複素環低級アルキル、低級アルキル複素環、低級シクロアルキル、低級シクロアルキル低級アルキルであって、Rは非置換、又は少なくとも1つの電子求引基若しくは電気供与基で置換されており；
− R₁は、水素又は低級アルキル、低級アルケニル、低級アルキニル、アリール低級アルキル、アリール、複素環低級アルキル、複素環、低級シクロアルキル、低級シクロアルキル低級アルキルであって、それぞれ、非置換であるか、又は電子供与基若しくは電子求引基で置換されており；
− R₂及びR₃は、独立して、水素、低級アルキル、低級アルケニル、低級アルキニル、アリール低級アルキル、アリール、複素環、複素環低級アルキル、低級アルキル複素環、低級シクロアルキル、低級シクロアルキル低級アルキル、又はZ−Yであり、ここで、R₂及びR₃は、非置換であっても、又は少なくとも1つの電子求引基若しくは電子供与基で置換されていてもよく；
− Zは、O、S、S（O）_a、NR₄、PR₄、又は化学結合であり；
− Yは、水素、低級アルキル、アリール、アリール低級アルキル、低級アルケニル、低級アルキニル、ハロ、複素環、複素環低級アルキルであって、Yは、非置換であっても、又は電子供与基若しくは電子求引基で置換されていてもよいが、ただしYがハロである場合にはZは化学結合であるという条件であり、あるいは
− ZYは一緒になって、NR₄NR₅R₇、NR₄OR₅、ONR₄R₇、OPR₄R₅、PR₄OR₅、SNR₄R₇、NR₄SR₇、SPR₄R₅又はPR₄SR₇、NR₄PR₅R₆又はPR₄NR₅R₇、

[Where
-R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocycle, heterocycle lower alkyl, lower alkyl heterocycle, lower cycloalkyl, lower cycloalkyl lower alkyl, and R is non- Substituted or substituted with at least one electron withdrawing group or electricity donating group;
-R ₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, each of which is unsubstituted Or substituted with an electron donating group or an electron withdrawing group;
R ₂ and R ₃ are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic ring, heterocyclic lower alkyl, lower alkyl heterocyclic ring, lower cycloalkyl, lower cycloalkyl lower Alkyl, or Z—Y, wherein R ₂ and R ₃ may be unsubstituted or substituted with at least one electron withdrawing group or electron donating group;
-Z is O, S, S (O) _a , NR ₄ , PR ₄ , or a chemical bond;
-Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocycle, heterocycle lower alkyl, Y may be unsubstituted or an electron donating group or electron Optionally substituted with an attractive group, provided that when Y is halo, Z is a chemical bond, or -ZY is taken together to form NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ , OPR ₄ R ₅ , PR ₄ OR ₅ , SNR ₄ R ₇ , NR ₄ SR ₇ , SPR ₄ R ₅ or PR ₄ SR ₇ , NR ₄ PR ₅ R ₆ or PR ₄ NR ₅ R ₇ ,

であり；
− R₄、R₅、及びR₆は、独立して、水素、低級アルキル、アリール、アリール低級アルキル、低級アルケニル、又は低級アルキニルであって、ここで、R₄、R₅、及びR₆は、非置換であっても、又は電子求引基若しくは電子供与基で置換されていてもよく；かつ
− R₇は、R₆又はCOOR₈又はCOR₈であり；
− R₈は、水素又は低級アルキル、又はアリール低級アルキルであって、ここで、前記アリール又はアルキル基は、非置換であっても、又は電子求引基若しくは電子供与基で置換されていてもよく；かつ
− nは1〜4であり；かつ
− aは1〜3である]
を有する。

Is;
R ₄ , R ₅ , and R ₆ are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R ₄ , R ₅ , and R ₆ are May be unsubstituted, substituted, or substituted with an electron withdrawing or electron donating group; and-R ₇ is R ₆ or COOR ₈ or COR ₈ ;
R ₈ is hydrogen or lower alkyl, or aryl lower alkyl, wherein the aryl or alkyl group may be unsubstituted or substituted with an electron withdrawing group or electron donating group Well; and -n is 1 to 4; and -a is 1 to 3]
Have

  US Pat. No. 5,773,475 also discloses additional compounds useful for the treatment of CNS diseases. These compounds have the following formula (IIa):

[式中、
− Arは、非置換又はハロで置換されているアリールであり；
− R₃は低級アルコキシであり；かつ
− R₁はメチルである]
を有する、N−ベンジル−2−アミノ−3−メトキシ−プロピオンアミドである。

[Where
-Ar is aryl which is unsubstituted or substituted with halo;
- R ₃ is lower alkoxy; and - R ₁ is methyl
N-benzyl-2-amino-3-methoxy-propionamide having

  However, both U.S. Pat. Nos. 5,378,729 and 5,773,475 disclose these compounds for treating psychosis, particularly for treating psychosis associated with schizophrenia, in an add-on treatment to at least one antipsychotic drug. The use of is not described.

WO 02/074297 provides a compound of formula (IIa) for preparing a pharmaceutical composition useful for the treatment of allodynia associated with peripheral neuropathic pain, wherein Ar is at least one Is phenyl optionally substituted with halo, R ₃ is lower alkoxy containing 1 to 3 carbon atoms, and R ₁ is methyl.

  WO 02/074784 deals with different types and symptoms of acute and chronic pain, in particular non-neuropathic inflammatory pain, such as rheumatoid arthritis pain and / or secondary inflammatory osteoarthritis pain It relates to the use of a compound having formula (Ia) and / or formula (IIa) exhibiting antinociceptive properties for the treatment.

Psychosis, particularly schizophrenia, is a mental defect state characterized by the following symptoms:
Realistic distorted recognition:
People with psychosis may have a perception of reality that is significantly different from the reality that others around them see and share;
-Hallucinations and illusions:
Hallucinations are perceptions that do not relate to appropriate sources. Hallucinations can occur in any sensory form-auditory (sound), visual (sight), tactile (contact), taste (taste), and smell (odor). Hearing, especially the experience of hearing sounds that cannot be heard by others, is a common and frequent distinguishing feature of psychosis;
・ Delusion:
Delusions are false personal beliefs that are unfounded or contradictory, and are not explained by the individual's normal cultural concepts;
・ Thinking disorder:
Psychosis often affects an individual's ability to “think reasonably”. Thoughts can change rapidly; people may not be able to concentrate on one idea for a very long time, and may be easily distracted and unable to concentrate. Thought disorders are broadly classified by their effects on speech and writing.

  Psychosis is a symptom of a serious mental disorder and is not considered a diagnosis in itself. Psychosis is not necessarily associated with any particular psychological or physical condition, but is particularly associated with schizophrenia, bipolar disorder, and severe clinical depression. Electrolyte disorders, elderly urinary tract infections, pain syndromes, drug addiction, and drug withdrawal (especially alcohol, barbiturate hypnotics, and sometimes benzodiazepines), and brain infections or brain injuries (these psychosis are There are also several physical environments that can induce psychotic conditions, including more commonly referred to as organic mental disorders.

  Chronic mental stress is also known to cause psychotic conditions, but the exact mechanism is unknown. Temporary psychosis induced by stress is known as short-term reactive psychosis.

  There are also some non-mental conditions that are particularly associated with psychosis, which may include brain tumors, Lewy body dementia, hypoglycemia, addiction, multiple sclerosis, systemic lupus erythematosus, and / or sarcoidosis .

  Psychosis is a common condition in schizophrenia, typically characterized by the symptoms described above. In addition, people with schizophrenia often exhibit “feeling blunt” or “feeling flattening”. This is referred to as a severe decline in emotional expression.

  Schizophrenia is a chronic, severely disabled brain disease that is found worldwide. The lifetime incidence of schizophrenia is approximately 1% of the population. The severity of symptoms and the long-term chronic tendency of schizophrenia often cause a high degree of disability. People with schizophrenia have a higher rate of suicide than the general population. Approximately 10% of people with schizophrenia (especially young adult men) commit suicide. The first sign of schizophrenia often manifests as disrupted behavioral changes or even shocking behavioral changes. This sudden onset of severe psychotic symptoms is referred to as the “acute” phase of schizophrenia.

  Some people have only one such psychotic episode; others have many episodes over their lifetime, but have a relatively normal life for some time. However, individuals with a tendency for “chronic” schizophrenia or continuous or recurrent illness often do not fully restore normal functioning, and are Typically requires long-term treatment.

  There is no known single cause of schizophrenia. Many illnesses, such as heart disease, result from the interaction of genetic factors, behavioral factors, and other factors; this may also be the case for schizophrenia. Schizophrenia has long been known to be a family-onset. Scientists are studying genetic factors in schizophrenia. Perhaps multiple genes are involved in creating a predisposition and appear to develop disease. In addition, factors such as prenatal problems such as intrauterine starvation or viral infection, perinatal complications, and various non-specific stress factors appear to affect the onset of schizophrenia. However, it is not yet understood how the genetic predisposition is transmitted, and it is still not possible to accurately predict whether a given person will develop the disease.

  Basic knowledge about chemical components in the brain and its association with schizophrenia is rapidly expanding. Although still uncertain, the disease appears to be associated with several imbalances in the complex that correlate with the brain chemistry, possibly involving the neurotransmitters dopamine and glutamate.

  Many studies of people with schizophrenia are related to brain structure (eg, enlargement of cavities filled with body fluids called ventricles inside the brain, and reduction in the size of certain brain regions) or brain function (Eg, decreased metabolic activity in specific brain regions) has been discovered. It should be emphasized that these abnormalities are quite subtle and are not a feature of all people with schizophrenia, nor are they only occurring in individuals with this disease. Microscopic studies of postmortem brain tissue also show small changes in the distribution or number of brain cells in people with schizophrenia. Many (but perhaps not all) of these changes exist before an individual becomes ill, and schizophrenia can be, in part, a disease of brain development.

  Available treatments can relieve many symptoms, but most people with schizophrenia continue to suffer from some symptoms throughout their lives; only one-fifth or less individuals will fully recover Estimated. Medications and other treatments for schizophrenia can help to reduce and control the symptoms associated with illness. However, some people may not be able to help greatly with available treatments or may discontinue treatment prematurely due to unpleasant side effects. Because schizophrenia cannot be a single condition and its cause is not yet known, current treatment methods are based on both clinical research and experience. These approaches are selected based on their ability to reduce the symptoms of schizophrenia and reduce the chances of the symptoms recurring.

Although antipsychotic drugs have been available since the mid 1950s, they do not “treat” underlying illnesses such as schizophrenia or do not guarantee that there are no more psychotic episodes. Clinically effective antipsychotics include tricyclic phenothiazine, thioxanthene, and dibenzepine, butyrophenone and congeners, other heterocycles, and experimental benzamides. Virtually all of these drugs block D ₂ -dopamine receptors and reduce dopamine neurotransmission in the forebrain; some of these drugs, especially atypical antipsychotics, are also D ₁ -and D ₄ - dopamine receptor, 5-HT _2A - and 5-HT _2C - serotonin receptor, as well as alpha - both adrenergic receptor interacts (Goodman &Gilman's, the Pharmacological Basis of Therapeutics, 10 th edition, McGraw-Hill, 2001: Summary of chapter 20 (p. 485)). Antagonism of synaptic neurotransmission via dopamine is an important action of antipsychotic drugs (identical literature, p. 493, left column, second paragraph).

  A number of new antipsychotics (so-called “atypical antipsychotics”) have been introduced since 1990. The first of these is clozapine, which shows that it is more effective than other antipsychotics, but has serious side effects, especially a condition called agranulocytosis (loss of white blood cells that fights infection) Because of this possibility, patients need to be monitored by blood tests every 1 or 2 weeks. Newer antipsychotics such as risperidone and olanzapine are safer than older drugs or clozapine and may be more resistant. However, like clozapine, they are not sure if they can treat the disease.

  Antipsychotic drugs are often very effective in treating certain symptoms of schizophrenia, particularly hallucinations and delusions; unfortunately, the drugs are useful for other symptoms such as reduced motivation and It cannot be useful for expressing emotions.

  Current limitations of antipsychotic treatment of psychosis, particularly psychosis associated with schizophrenia, include limited efficacy, side effects, and delayed action. Valproate has been shown to enhance the onset of action of olanzapine or risperidone (Casey et al., Neuropsychopharmacology 28: 182 ff, 2003). In addition, other double-blind, placebo-controlled clinical trials have demonstrated that lamotrigine is beneficial for the treatment of refractory schizophrenia when added to clozapine (Tihohen et al., Biol Psychiatr. 54: 1241 ff, 2003). Up to 50% of schizophrenic patients currently hospitalized, especially to increase the effects, adjust positive symptoms such as hallucinations, adjust emotional symptoms such as depression, and attention deficits In order to regulate cognitive symptoms, he is receiving adjuvant therapy with antidepressants (Citrome L., Psychopharmacology Bull 37 (S2): p74ff, 2003).

  However, as described in Citrome L., Psychopharmacology Bull 37 (S2): p74ff, 2003, data on the use of anticonvulsants for add-on therapy to antipsychotics are inconsistent. Valproate and lamotrigine have been shown to preferentially reduce positive symptoms of schizophrenia (identical literature, p. 86, last paragraph). The likely location for valproate action is thought to be a direct effect on voltage-gated sodium channels (identical literature, p. 78, second paragraph). However, the use of the anticonvulsant carbamazepine as an add-on to the antipsychotic haloperidol was associated with poor clinical outcome compared to antipsychotic monotherapy (identical literature, p. 80, first paragraph). Other studies on carbamazepine use failed to detect significant improvements in overall BPRS (Simple Psychiatric Rating Scale). Adjunct use of lamotrigine in addition to clozapine resulted in an improvement in positive symptoms rather than negative symptoms in schizophrenia (identical literature, p. 85, first paragraph). Reports on the use of other anticonvulsants in schizophrenia reported general worsening with gabapentin or worsening in both positive and negative symptoms of schizophrenia with topiramate. (Same literature, p. 85, second paragraph).

  The reported differences in the effectiveness of anticonvulsants as add-on treatments to antipsychotics may be attributed to their different mechanisms of action. In contrast to antipsychotics that share a common antagonism to dopamine receptors, current anticonvulsants are thought to work through a variety of mechanisms of action. These mechanisms of action are, for example, alterations in neuronal impulse propagation through interactions with voltage-gated sodium-, calcium-, or potassium channels, or by enhancement of inhibitory GABA systems, or excitability It is an effect on neurotransmission either by inhibition of the glutamate system.

In contrast to current anticonvulsants, lacosamide has a potentially unique but unknown molecular mechanism of action. Lacosamide does not interact directly with various known GABA receptor subtypes, nor does it interact directly with various known glutamate receptor subtypes. In particular, lacosamide does not inhibit voltage-gated sodium or calcium channels and does not enhance potassium current.
US Pat. No. 5,378,729 US Pat. No. 5,773,475

  The literature by Jann MW, Pharmacotherapy 2004; 24 (12): 1759-1783, which targets cognitive symptoms of schizophrenia, describes add-on treatment of antipsychotics to several other active agents, There is no mention of antipsychotic add-on treatments to anticonvulsants.

  Use of a compound of formula (Ib) and / or formula (IIb) to treat psychosis, in particular schizophrenia and / or psychosis associated with schizophrenia, in an add-on treatment to at least one antipsychotic drug Not reported. Accordingly, the present invention provides a pharmaceutical composition for preventing, reducing and / or treating a disease treated with an antipsychotic agent, particularly a psychosis, particularly schizophrenia, in an add-on treatment to at least one antipsychotic agent. It relates to the use of said compound (s) of formula (Ib) and / or formula (IIb) for the preparation of a product.

  The application of lacosamide (an international non-trade name, formally also called harkoseride or SPM 927) alone is a predictive validity model for psychosis, especially for cognitive symptoms, in mice It has no significant effect on prepulse suppression. Surprisingly, compounds (Ib) and / or (IIb), in particular (R) -2-acetamido-N-benzyl-3-methoxypropionamide (lacosamide), when administered together with the antipsychotic clozapine Increased the increase in prepulse inhibition of clozapine.

  Prepulse inhibition in mice includes, for example, schizophrenia, bipolar disorder, autism, Alzheimer's disease, attention deficit / hyperactivity disorder, drug abuse and / or alcoholism, affective disorder, dyskinesia and related diseases, dementia, Associated with treatment for mental retardation, polytrophic / hyponatremia, severe personality disorder, onset of acute mania, obsessive compulsive disorder, refractory chronic insomnia, Huntington's disease, Tourette syndrome, Parkinson's disease, and / or dopaminergic Parkinson's disease It is a predictive value model for psychosis.

  Prior art as outlined above, in particular, numerous mechanisms of action of anticonvulsants, contradictory results in add-on treatments of anticonvulsants and antipsychotics, demonstrated in add-on treatments with antipsychotics compared to lacosamide Anticonvulsants in the literature (Jann MW, see above) for differences in the mechanism of action of valproate, the only anticonvulsant with limited efficacy, and add-on treatment of cognitive symptoms of schizophrenia Given the lack of drug reference, even those skilled in the art cannot predict the effectiveness of lacosamide in the treatment of psychosis in add-on therapy to at least one antipsychotic drug.

  In a broad sense, the term “antipsychotic agent” or “anti-psychotic” means any compound known in the art for preventing, reducing or treating psychosis, including but not limited to Contains: (−)-Isofuroxepin, (+-)-Idoxoxane monohydrochloride, (+)-Isofuroxepin, 1,2-benzisoxazole-3-methanesulfonamide, monosodium Salt, 1H-isoindole-a, 3 (2H) -dione, 2- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] bryl] -hexahydro-, monohydro Chloride, (3aR, 7aS) -rel-, 2 (1H) -quinolinone, 1- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -3,4-dihydro-5-methoxy- ( OPC 14523), 2-propen-1-one, 1- (2 -Fluorophenyl) -3- (4-hydroxyphenyl) -O- [2- (dimethylamino) -ethyl] oxime, (1Z, 2E)-, (2E) -2-butenedioate (2: 1), 9H-xanthene-9-propanoic acid, a-amino-a-[(1S, 2S) -2-carboxycyclopropyl] -m (aS) (LY 341495), avaperidone, acetophenazine, aminosulprid, amisulpride, am Parex, Aprido Fumarate, Aripiprazole, Asenapine Maleate, Benperidol, Benzquinamide, Beta-Uridine, Bromoperidol, Bramate, Butaperazine, Carbazipymidine, Carbamazepine, Carphenazine, Carpipramine, Carpipramine Dihydrochloride, Saint Butindole, Chlor Pentixol, chlorpromazine, chlorpromazine hydrochloride Lolide, chlorprothixene, cis-clopentixol, cis-tramadol, cis-tramadol hydrochloride, citalopram hydrobromide, clocapramine, clocapramine dihydrochloride, chromamacran, clopentixol, crospyrazine, clothiapine, clozapine, Cyamemazine, devazepide, divalprox sodium, dixylazine, droperidol, duloxetine hydrochloride, ethyl iofurazepart, frampatol, fluanizone, flubuperone, fluoxetine hydrochloride, flupentixol, fluphenazine, fluphenazine decanoate, fluphenazine enanthate , Fluphenazine hydrochloride, flupirylene, fltoprazepam, fluvoxamine, fluvoxamine maleate, halo Ridol, haloperidol and haloperidol decanoate, iloperidone, isofluxicepin, lamotrigine, loxapine succinate, lurasidone hydrochloride, melperone, melperone hydrochloride, mepazine, mesoridazine, mesoridazine besylate, methoxypromazine, methofenazete , Mifepristone, minaprine, minaprine hydrochloride, moclobemide, morindon, morindon hydrochloride, moperon, mosapramine, mosapramine dihydrochloride, nevogramin, nemonapride, ocaperidone, octoclocepine, olanzapine, opipramol, paroxetine, penfluridol , Perazine, pericazine, permethazine, perospirone, perphenazine, phenothiazine, pimozide, piperacetazi , Pipothiazine, pipothiazine palmitate, pipothiazine, pramipexole, prochlorperazine, promazine, protipendil, quetiapine, quetiapine fumarate, racemic idoxane, remoxiprid, risperidone, subcomerin, secretin, sertraline hydrochloride, spiperone, sulpholide , Sultopride, talnetrant, tetrabenazine, thiopride, thiopropazate, thioproperazine, thioridazine, thioridazine hydrochloride, thiothixene, thiothixene hydrochloride, thioxanthene, thimeperone, topiramate, trifluoperazine, trifluoroperazine hydrochloride, trifluperidol, Triflupromazine, zapracidone, ziprasidone hydrochloride, zonisa Mido, zotepine, zuclopentixol acetate, zuclopentixol decanoate, their enantiomers, racemates, pharmaceutically acceptable salts, esters, amides, prodrugs, and metabolites.

In particular, as used herein, the term “antipsychotic” refers to what are referred to as classical or so-called typical antipsychotics, or classical or typical neuroleptics, and atypical antipsychotics or atypicals. It is intended to include what are termed neuroleptics. Examples of classic antipsychotics are acetophenazine, benperidol, benzquinamide, biliperone, bromoperidol, butaperazine, butyrophenone, carphenazine, centbutindole, chlorpromazine, chlorpromazine hydrochloride, chlorprothixene, clomaclan, clopentixol , Clothiapine, ciamemazine, dibenzoxazepine, dihydroindolone, dixylazine, droperidol, fluanizone, flupentixol, fluphenazine, fluphenazine decanoate, fluphenazine enanthate, fluphenazine hydrochloride, haloperidol, haloperidol decano Ate, isofuroxepin, levomepromazine, loxapine succinate, melperone, melperone hydrochloride, mepazine, mesoridazi , Mesoridazine besylate, methotremeprazine, methoxypromazine, metofenazeate, molindone, molindone hydrochloride, moperone, nevogramin, nemonapride, octoclocepine, penfluridol, pericazine, permethazine, perphenazine, phenothiazine, pimozide, Pipamperone, pipetiazine, pipetiazine palmitate, prochlorperazine, promazine, protipendyl, spiperone, sulforidazine, sultopride, talnetant, thiopride, thiopropazate, thioproperazine, thioridazine, thioridazine hydrochloride, thiothixene hydrochloride, thiothixene hydrochloride Xanthene, trifluoperazine, trifluoperazine hydrochloride, trifluperidol, triflupromazine Zuclopenthixol acetate, zuclopenthixol decanoate as well as their enantiomers, racemates, pharmaceutically acceptable salts, and derivatives, in particular esters, amides, prodrugs, and metabolites. Examples of atypical antipsychotics are avaperidone, aminosulprid, amisulpride, amparex, aripiprazole, asenapine maleate, clozapine, fluspirylene, iloperidone, mosapramine, mosapramine dihydrochloride, ocaperidone, olanzapine, oxypertin, perospirone , Piperacetazine, quetiapine, quetiapine fumarate, remoxiprid, risperidone, sertindole, sulpiride, ziprasidone, ziprasidone hydrochloride, zotepine, and their enantiomers, racemates, pharmaceutically acceptable salts, and derivatives, especially esters, amides, pros Drugs and metabolites. The term “antipsychotic” further includes dopamine antagonists, preferably D ₂ antagonists.

  As used herein, the term “antipsychotic” may also be used for the treatment of psychosis, but preferably does not include a non-antipsychotic agent as defined above, examples of such agents include: , Anticonvulsants (eg, carbamazepine, valproate, lamotrigine), antiepileptics, eg, tri and tetracyclic antidepressants (eg, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, nortriptyline, desipramine, maprotiline, trazodone), Selective serotonin reuptake inhibitors (eg citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), selective noradrenaline reuptake inhibitors (eg reboxetine), serotonin-noradrenaline-reuptake inhibitors -(Eg, venlafaxine, duloxetine), serotonin-noradrenaline-specific antidepressants (eg, mianserin, mirtazapine) or monoamine oxidase inhibitors (eg, tranylcypromine, moclobemide), lithium salts or benzodiazepines (eg, alprazolam, Lorazepam, diazepam).

  Exemplary dopamine antagonist doses that may be used in the present invention are as follows.

  In a particularly preferred embodiment, the present invention relates to lacosamide and at least one antipsychotic agent as indicated above, in particular at least one dopamine antagonist, which may be at least one D2 antagonist, more particularly as defined above. It relates to specific combinations with at least one atypical antipsychotic such as at least one atypical antipsychotic, most particularly clozapine, risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, sulpiride, amisulpride, and / or zotepine.

  The add-on treatment of the present invention for the prevention, reduction and / or treatment of diseases treated with antipsychotics, in particular psychosis, in particular schizophrenia and / or psychosis associated with schizophrenia, comprises formula (Ib) and Integration with at least one of the compounds of (IIb) and psychosis, in particular integration, for example to increase the effectiveness of antipsychotic administration, to reduce its side effects and / or to enhance its action Co-administration with at least one antipsychotic agent useful for preventing, reducing and / or treating ataxia.

  The term “co-administration” refers to a plurality of agents that are co-active, when administered together or separately to a subject, that provides a therapeutic benefit to the subject. Such co-administration is also referred to as “combination therapy”, “co-therapy”, “adjuvant therapy”, or “add-on therapy”. For example, one drug can increase or enhance the therapeutic effect of another, or it can reduce the side effects of another, or it can be effective at a lower dose than when one or more drugs are used alone Or can provide superior therapeutic utility when used alone, or can complement different aspects, symptoms, or etiological factors of a disease or condition in a complementary manner.

  Co-administration includes administering the agent in an amount sufficient to achieve and / or maintain a therapeutically effective concentration, eg, plasma concentration, in a subject in need thereof. Co-administration includes simultaneous and / or sequential administration. Co-administration includes administering the agents “simultaneously” within the treatment period, either alone or as different compositions (see below). Continuous administration includes administration of the agent “at intervals” within the treatment period.

  “Simultaneous” administration literally includes at least one antipsychotic agent useful for preventing, reducing and / or treating psychosis and the compound (s) of formula (Ib) and / or (IIb) Administration "simultaneously" is included, but also includes administration one after the other. “Interval” administration includes at least one antipsychotic agent useful for preventing, reducing and / or treating psychosis and a compound (one or more) of formula (Ib) and / or (IIb) At an interval of up to 1 hour, preferably up to 6 hours, more preferably up to 12 hours, even more preferably up to 1 day, most preferably up to 1 month. .

  At least one antipsychotic drug useful for preventing, reducing and / or treating psychosis and at least one compound of formula (Ib) and / or (IIb), one pharmaceutical preparation for simultaneous administration Product (single dose form) or may be formulated in two separate preparations (separated dose form) for simultaneous or spaced administration, for example As described in the embodiments. Two separate preparations in separate dosage forms may be administered by the same route or by different routes.

  Separate dosage forms can optionally be co-packaged, for example, in a single container or multiple containers within a single sheath, or can be co-presented in separate packaging ("common presentation" "). As an example of co-packaging or co-presentation, a kit comprising at least one antipsychotic drug and at least one compound of formula (Ib) and / or (IIb) in separate containers is contemplated. In another example, the at least one antipsychotic and the at least one compound of formula (Ib) and / or (IIb) are packaged separately and are commercially available independently of each other, For co-marketing or co-promotion. Separate dosage forms may also be presented to the subject separately and independently for use in the present invention.

  Depending on the dosage form, which may be the same or different, for example, a rapid release dosage form, a controlled release dosage form, and / or a depot form, at least one anticancer drug useful for preventing, reducing and / or treating psychosis The psychotic drug and the compound (s) of formula (Ib) and / or (IIb) may be administered on the same or different schedules on a daily, weekly, or monthly basis. Thus, the administration interval between at least one antipsychotic drug useful for preventing, reducing and / or treating psychosis and the compound (one or more) of formula (Ib) and / or (IIb) is the administration schedule. And / or may depend on the dosage form.

In a preferred embodiment, the compound of formula (Ib) and / or (IIb) is
(A) at least one antipsychotic agent useful for preventing, reducing and / or treating psychosis, and (b) at least one compound of formula (Ib) and / or (IIb),
For the preparation of a pharmaceutical composition comprising

In use of the present invention, preventing psychosis, mitigation, and / or treatment of at least one antipsychotic agent useful for the dopamine antagonist, preferably D ₂ antagonist, more preferably an atypical antipsychotic, even more preferably May be an atypical antipsychotic as defined above, and the most preferred agents are clozapine, risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, sulpiride, amisulpride, and / or zotepine.

  In a further preferred embodiment, the compound of formula (Ib) and / or (IIb) is combined with at least one compound of formula (Ib) and / or (IIb) to prevent, reduce and / or treat psychosis It is used for the preparation of a pharmaceutical composition comprising a single dose form comprising at least one antipsychotic useful in the form of one composition.

In another preferred embodiment, the compound of formula (Ib) and / or (IIb) is
(I) a first composition comprising at least one antipsychotic agent useful for preventing, reducing and / or treating psychosis, and (ii) at least one compound of formula (Ib) and / or (IIb) A second composition comprising,
Is used to prepare a pharmaceutical composition that is in a separate dosage form.

  In yet another preferred embodiment of the invention, a commercially available antipsychotic composition useful for preventing, reducing and / or treating psychosis may be administered to a subject in need thereof. Thus, in this preferred embodiment, the compound of formula (Ib) and / or (IIb) comprises at least one compound of formula (Ib) and / or formula (IIb), but prevents, reduces, and / or Alternatively, it is used to prepare a pharmaceutical composition free of antipsychotics useful for treatment.

  The use of the present invention includes, as defined above, at least one compound of formula (Ib) and / or (IIb) and at least one antipsychotic useful for preventing, reducing and / or treating psychosis Preparation of a pharmaceutical composition for administration of the drug simultaneously or at intervals may be included.

  The compound of the present invention has the following general formula (Ib):

［式中、
− Rは、水素、アルキル、アルケニル、アルキニル、アリール、アリールアルキル、複素環、複素環アルキル、アルキル複素環、シクロアルキル、又はシクロアルキルアルキルであって、Rは、非置換であるか、あるいは少なくとも1つの電子求引基及び／又は少なくとも1つの電子供与基で置換されており；
− R₁は、水素又はアルキル、アルケニル、アルキニル、アリールアルキル、アリール、複素環アルキル、アルキル複素環、複素環、シクロアルキル、シクロアルキルアルキルであって、それぞれ、非置換あるいは少なくとも1つの電子供与基及び／又は少なくとも1つの電子求引基で置換されており；かつ
− R₂及びR₃は、独立して、水素、アルキル、アルケニル、アルキニル、アリールアルキル、アリール、ハロ、複素環、複素環アルキル、アルキル複素環、シクロアルキル、シクロアルキルアルキル、又はZ−Yであり、ここで、R₂及びR₃は、非置換であっても、あるいは少なくとも1つの電子求引基及び／又は少なくとも1つの電子供与基で置換されていてもよく；
− Zは、O、S、S（O）_a、NR₄、NR'₆、PR₄、又は化学結合であり；
− Yは、水素、アルキル、アリール、アリールアルキル、アルケニル、アルキニル、ハロ、複素環、複素環アルキル、アルキル複素環であって、Yは、非置換であっても、あるいは少なくとも1つの電子供与基及び／又は少なくとも1つの電子求引基で置換されていてもよいが、ただし、Yがハロである場合にはZは化学結合であるという条件であり、あるいは
− ZYは一緒になって、NR₄NR₅R₇、NR₄OR₅、ONR₄R₇、OPR₄R₅、PR₄OR₅、SNR₄R₇、NR₄SR₇、SPR₄R₅、PR₄SR₇、NR₄PR₅R₆、PR₄NR₅R₇、又はN^＋R₅R₆R₇、

[Where:
-R is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, alkylheterocycle, cycloalkyl, or cycloalkylalkyl, R is unsubstituted or at least Substituted with one electron withdrawing group and / or at least one electron donating group;
R ₁ is hydrogen or alkyl, alkenyl, alkynyl, arylalkyl, aryl, heterocyclic alkyl, alkylheterocyclic, heterocyclic, cycloalkyl, cycloalkylalkyl, each unsubstituted or at least one electron donating group And / or is substituted with at least one electron withdrawing group; and -R ₂ and R ₃ are independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, aryl, halo, heterocycle, heterocyclealkyl , Alkyl heterocycle, cycloalkyl, cycloalkylalkyl, or ZY, wherein R ₂ and R ₃ may be unsubstituted or at least one electron withdrawing group and / or at least one Optionally substituted with an electron donating group;
- Z is, O, S, S (O ) a, NR 4, NR '6, PR 4, or a chemical bond;
-Y is hydrogen, alkyl, aryl, arylalkyl, alkenyl, alkynyl, halo, heterocycle, heterocyclealkyl, alkylheterocycle, wherein Y is unsubstituted or at least one electron donating group And / or may be substituted with at least one electron withdrawing group, provided that if Y is halo, then Z is a chemical bond, or ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ , OPR ₄ R ₅ , PR ₄ OR ₅ , SNR ₄ R ₇ , NR ₄ SR ₇ , SPR ₄ R ₅ , PR ₄ SR ₇ , NR ₄ PR ₅ R ₆ , PR ₄ NR ₅ R ₇ , or N ⁺ R ₅ R ₆ R ₇ ,

であり；
− R'₆は、水素、アルキル、アルケニル、又はアルキニルであって、非置換であっても、あるいは少なくとも1つの電子求引基及び／又は少なくとも1つの電子供与基で置換されていてもよく；
− R₄、R₅、及びR₆は、独立して、水素、アルキル、アリール、アリールアルキル、アルケニル、又はアルキニルであって、ここで、R₄、R₅、及びR₆は、独立して、非置換であっても、あるいは少なくとも1つの電子求引基及び／又は少なくとも1つの電子供与基で置換されていてもよく；
− R₇は、R₆又はCOOR₈又はCOR₈であって、ここで、R₇は、非置換であっても、あるいは少なくとも1つの電子求引基及び／又は少なくとも1つの電子供与基で置換されていてもよく；
− R₈は、水素又はアルキル、又はアリールアルキルであって、ここで、前記アリール又はアルキル基は、非置換であっても、あるいは少なくとも1つの電子求引基及び／又は少なくとも1つの電子供与基で置換されていてもよく；かつ
− nは1〜4であり；かつ
− aは1〜3である]
を有する。

Is;
- R _'6 is hydrogen, alkyl, alkenyl, or a alkynyl may be unsubstituted or may be substituted with at least one electron withdrawing group and / or at least one electron donating group;
R ₄ , R ₅ , and R ₆ are independently hydrogen, alkyl, aryl, arylalkyl, alkenyl, or alkynyl, wherein R ₄ , R ₅ , and R ₆ are independently May be unsubstituted, substituted with at least one electron withdrawing group and / or at least one electron donating group;
R ₇ is R ₆ or COOR ₈ or COR ₈ , wherein R ₇ is unsubstituted or substituted with at least one electron withdrawing group and / or at least one electron donating group May be;
R ₈ is hydrogen or alkyl, or arylalkyl, wherein the aryl or alkyl group may be unsubstituted or at least one electron withdrawing group and / or at least one electron donating group And -n is 1 to 4; and -a is 1 to 3]
Have

  Preferably, the compound of the present invention has the following general formula (IIb):

[式中、
− Arは、アリール、特にフェニルであって、非置換、又は水素、ハロ、アルキル、アルケニル、アルキニル、ニトロ、カルボキシ、ホルミル、カルボキシアミド、アリール、第四級アンモニウム、ハロアルキル、アリールアルカノイル、ヒドロキシ、アルコキシ、アミノ、アルキルアミノ、ジアルキルアミノ、アリールオキシ、メルカプト、アルキルチオ、アルキルメルカプト、及びジスルフィドからなる群から独立して選択される少なくとも1つの置換基で置換されており；
− R₃は、水素、アルキル、アルコキシ、アルコキシアルキル、アリール、N−アルコキシ−N−アルキルアミノ、及びN−アルコキシアミノからなる群から選択され；かつ
− R₁は、アルキルである]
を有する。

[Where
Ar is aryl, especially phenyl, unsubstituted or hydrogen, halo, alkyl, alkenyl, alkynyl, nitro, carboxy, formyl, carboxyamide, aryl, quaternary ammonium, haloalkyl, arylalkanoyl, hydroxy, alkoxy Substituted with at least one substituent independently selected from the group consisting of:, amino, alkylamino, dialkylamino, aryloxy, mercapto, alkylthio, alkylmercapto, and disulfide;
- R ₃ is hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, N- alkoxy -N- alkylamino, and from the group consisting of N- alkoxy amino; and - R ₁ is an alkyl
Have

In particular, Ar is aryl, in particular phenyl, unsubstituted or substituted with at least one halo; R ₃ is —CH ₂ —Q, wherein Q is lower alkoxy; and R ₁ is lower alkyl, especially methyl.

  The present invention also provides formula (Ib) and / or useful in the add-on treatment to at least one antipsychotic agent, which is useful for preventing, reducing and / or treating diseases that can be treated with antipsychotic agents, particularly psychosis. Also contemplated are pharmaceutical compositions comprising at least one compound of formula (IIb).

In a preferred embodiment, the pharmaceutical composition comprises
(A) at least one antipsychotic agent useful for preventing, reducing and / or treating psychosis, and (b) at least one compound of formula (Ib) and / or (IIb),
including.

In the pharmaceutical compositions of the present invention, preventing psychosis, reducing, or treating at least one antipsychotic agent useful for the dopamine antagonist, preferably D ₂ antagonist, more preferably an atypical antipsychotic, even more preferably May be an atypical antipsychotic as defined above, and the most preferred agents are clozapine, risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, sulpiride, amisulpride, and / or zotepine.

  In a further preferred embodiment, the pharmaceutical composition according to the invention comprises at least one compound of formula (Ib) and / or (IIb) and at least one anti-cancer useful for preventing, reducing and / or treating psychosis. It includes a single dose form comprising a psychotic drug in the form of one composition.

In another preferred embodiment, the pharmaceutical composition of the present invention comprises
(I) a first composition comprising at least one antipsychotic agent useful for preventing, reducing and / or treating psychosis, and (ii) at least one compound of formula (Ib) and / or (IIb) A second composition comprising,
A separate dosage form comprising

  In yet another preferred embodiment of the invention, a commercially available antipsychotic composition useful for preventing, reducing and / or treating psychosis may be administered to a subject in need thereof. Thus, in this preferred embodiment, the pharmaceutical composition of the invention comprises at least one compound of formula (Ib) and / or formula (IIb), but is useful for preventing, reducing and / or treating psychosis Contains no antipsychotics.

  The pharmaceutical composition of the invention comprises, as defined above, at least one compound of formula (Ib) and / or (IIb) and at least one anti-cancer useful for preventing, reducing and / or treating psychosis. Psychiatric drugs may be prepared for administration at the same time or at intervals.

  The term “alkyl” (alone or in combination with another term (s)) preferably has from 1 to about 20 carbon atoms, more preferably from 1 to about 8 carbon atoms, even more preferably from 1 to about 6 carbon atoms. By straight chain or branched chain saturated hydrocarbon substituent containing carbon atoms. Most preferably, alkyl is lower alkyl as defined below.

  A “lower alkyl” group, when used alone or in combination with other groups, is a lower alkyl containing 1 to 6 carbon atoms, especially 1 to 3 carbon atoms, straight or branched It can be a chain. These groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and pentyl isomers, hexyl and hexyl isomers, and the like.

  The term “alkoxy” (alone or in combination with another term (s)) means an alkyl ether substituent, ie —O-alkyl.

  A “lower alkoxy” group is a lower alkoxy containing 1 to 6 carbon atoms, especially 1 to 3 carbon atoms, and may be straight or branched. These groups include methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy and the like.

  “Arylalkyl” or “aryl lower alkyl” groups include, for example, benzyl, phenylethyl, phenylpropyl, phenylisopropyl, phenylbutyl, diphenylmethyl, 1,1-diphenylethyl, 1,2-diphenylethyl, and the like. .

  When used alone or in combination, the term “aryl” refers to an aromatic group containing from 6 to up to 18 ring carbon atoms and up to a total of up to 25 carbon atoms, including polynuclear aromatics. Means. These aryl groups may be monocyclic, bicyclic, tricyclic or polycyclic and are fused rings. As used herein, polynuclear aromatics include bicyclic and tricyclic fused aromatic ring systems containing 10-18 ring carbon atoms and up to a total of 25 carbon atoms. Is intended. Aryl groups include phenyl and polynuclear aromatics such as naphthyl, anthracenyl, phenanthrenyl, azulenyl and the like. Aryl groups also include groups such as ferrocenyl. The aryl group may be unsubstituted or mono- or polysubstituted with an electron withdrawing group and / or electron donating group as described below.

  The term “alkenyl” (alone or in combination with another term (s)) contains one or more double bonds, preferably 2 to about 20 carbon atoms, more preferably 2 to about 8 carbon atoms, Even more preferably, it refers to a straight or branched chain hydrocarbon substituent containing from 2 to about 6 carbon atoms. An alkenyl group can have a cis or trans configuration if it is asymmetric. Most preferably, alkenyl is lower alkenyl as defined below.

  A “lower alkenyl” is an alkenyl group containing 2 to 6 carbon atoms and at least one double bond. These groups may be linear or branched and may be Z or E type. Such groups include vinyl, propenyl, 1-butenyl, isobutenyl, 2-butenyl, 1-pentenyl, (Z) -2-pentenyl, (E) -2-pentenyl, (Z) -4-methyl-2 -Pentenyl, (E) -4-methyl-2-pentenyl, pentadienyl, such as 1,3- or 2,4-pentadienyl and the like.

  The term “alkynyl” (alone or in combination with another term (s)) contains one or more triple bonds, preferably 2 to about 20 carbon atoms, more preferably 2 to about 8 carbon atoms, More preferably, it means a straight or branched chain hydrocarbon substituent containing 2 to about 6 carbon atoms. Most preferably, alkynyl is lower alkynyl as defined below.

  The term “lower alkynyl” is an alkynyl group containing 2 to 6 carbon atoms, which may be straight and branched. Such groups include ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl Etc. are included.

  The term “lower cycloalkyl” or “cycloalkyl” when used alone or in combination is a cycloalkyl group containing from 3 to 18 ring carbon atoms and up to a total of 25 carbon atoms. Cycloalkyl groups can be monocyclic, bicyclic, tricyclic, or polycyclic, and the rings are fused. Cycloalkyls can be fully saturated or partially saturated. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctenyl, cycloheptenyl, decalinyl, hydroindanyl, indanyl, fenkyl, pinenyl , Adamantyl and the like. Cycloalkyl includes the cis or trans forms. Cycloalkyl groups can be unsubstituted or mono- or polysubstituted with electron withdrawing groups and / or electron donating groups as described below. Further, the substituent may be either endo or exo in the bridged bicyclic system.

  The terms “electron withdrawing” and “electron donating” refer to the ability of a substituent to withdraw or donate electrons relative to that of hydrogen, respectively, when the hydrogen atom occupies the same position in the molecule. . These terms are well understood by those skilled in the art and are described in Advanced Organic Chemistry, by J. March, John Wiley and Sons, New York, NY, pp. 16-18 (1985), incorporated herein by reference. Are listed. Electron withdrawing groups include halo, including bromo, fluoro, chloro, iodo and the like; haloalkyls such as nitro, carboxy, alkenyl, alkynyl, formyl, carboxyamide, aryl, quaternary ammonium, trifluoromethyl, arylalkanoyl, carbalkoxy Etc. are included. Electron donating groups include alkoxy, including hydroxy, methoxy and ethoxy; alkyl, such as methyl and ethyl; aryloxy such as amino, alkylamino, di (alkyl) amino, phenoxy, mercapto, alkylthio, alkylmercapto, disulfide Groups such as (alkyldithio) are included. One skilled in the art will appreciate that some of the above substituents may be considered electron donating or electron withdrawing under different chemical conditions. Furthermore, the present invention contemplates any combination of substituents selected from the groups identified above.

  “Carbaloxy” means —CO—O-alkyl where alkyl may be lower alkyl as defined above.

  The term “halo” includes fluoro, chloro, bromo, and iodo.

  When used alone or in combination with another term, “alkanoyl” preferably refers to 1 to about 20 carbon atoms, more preferably 1 to about 8 carbon atoms, even more preferably 1 to about Means a straight-chain or branched alkanoyl substituent containing 6 carbon atoms.

  The term “acyl” includes lower alkanoyl containing 1 to 6 carbon atoms and may be straight or molecular chain. These groups include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, tertiary butyryl, pentanoyl and pentanoyl isomers, and hexanoyl and hexanoyl isomers.

  As used herein, a heterocyclic group contains at least one sulfur ring atom, nitrogen ring atom, or oxygen ring atom, but may contain several such atoms in the ring. Heterocyclic groups contemplated by the present invention include heterocyclic aromatic compounds and saturated and partially saturated heterocyclic compounds. These heterocycles may be monocyclic, bicyclic, tricyclic or polycyclic, for example fused rings. These may preferably contain up to 18 ring atoms, up to a total of 17 ring carbon atoms, and up to a total of 25 carbon atoms. Heterocycles are also intended to include so-called benzoheterocyclic. Representative heterocycles include furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl , Benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl, pyrazolinedinyl, imidazolinyl, imidazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridinyl, oxettanyl, oxettanyl Nitrogen-containing heterocyclic N-oxides such as pyridyl, pyrazinyl, and pyrimi N- oxides of sulfonyl and the like.

  Heterocyclic groups may be unsubstituted or mono- or polysubstituted with electron withdrawing and / or electron donating groups.

  Preferred heterocycles are thienyl, furyl, pyrrolyl, benzofuryl, benzothienyl, indolyl, methylpyrrolyl, morpholinyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl, or pyridazinyl. Preferred heterocycles are 5 or 6 membered heterocyclic compounds. Particularly preferred heterocycles are furyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl, or pyridazinyl. The most preferred heterocycles are furyl and pyridyl.

  Preferred compounds are those where n is 1, but di (n = 2), tri (n = 3), and tetrapeptides (n = 4) are also intended to be within the scope of the present invention. .

  Preferred values for R are aryl lower alkyl, especially benzyl, especially the phenyl ring itself, which is unsubstituted or substituted with an electron donating group and / or an electron withdrawing group such as halo (eg F). It is what.

Preferred R ₁ is H or lower alkyl. The most preferred R ₁ group is methyl.

Preferred electron donating and / or electron withdrawing substituents are halo, nitro, alkanoyl, formyl, arylalkanoyl, aryloyl, carboxyl, carbalkoxy, carboxamide, cyano, sulfonyl, sulfoxide, heterocycle, guanidine, quaternary. Secondary ammonium, alkenyl, alkynyl, sulfonium salt, hydroxy, alkoxy, alkyl, amino, alkylamino, di (alkyl) amino, aminoalkyl, mercapto, mercaptoalkyl, alkylthio, and alkyldithio. The term “sulfide” includes mercapto, mercaptoalkyl, and alkylthio, while the term disulfide includes alkyldithio. Particularly preferred electron donating groups and / or electron withdrawing groups are halo or alkoxy, such as lower alkoxy, with fluoro or methoxy being most preferred. These preferred substituents may be present on one of any groups in formulas (Ib) and / or (IIb), for example R, R ₁ , R _{2 as} defined herein. , R ₃ , R ₄ , R ₅ , R ₆ , R ′ ₆ , R ₇ , R ₈ , and / or R _50, etc.

ZY groups representing R ₂ and R ₃ include hydroxy, alkoxy such as methoxy, ethoxy, aryloxy such as phenoxy; thioalkoxy such as thiomethoxy, thioethoxy and the like; thioaryloxy such as thiophenoxy and the like; Alkylamino, such as methylamino, ethylamino, etc .; arylamino, such as anilino; lower dialkylamino, such as dimethylamino; trialkylammonium salts, hydrazino; alkylhydrazino and arylhydrazino, such as N-methylhydra Dino, N-phenylhydrazino, carbalkoxyhydrazino, aralkoxycarbonylhydrazino, aryloxycarbonylhydrazino, hydroxylamino, eg N-hydroxylamino (—NH—OH) Etc., alkoxy amino [(NHOR _18), wherein, R ₁₈ is alkyl], N-alkyl hydroxylamino [(NR ₁₈₎ OH, wherein, R ₁₈ is alkyl], N-alkyl--O- Alkylhydroxyamino, ie [N (R ₁₈ ) OR ₁₉ , wherein R ₁₈ and R ₁₉ are independently alkyl], and O-hydroxylamino (—O—NH ₂ ); alkylamide, Examples include acetamide and the like; trifluoroacetamide; alkoxyamino (eg NH (OCH ₃ )); and heterocyclic amino such as pyrazoylamino and the like.

Preferred heterocyclic groups representing R ₂ and R ₃ have the following formula:

の単環式5員又は6員複素環部分であるか、又はこれらの対応する、部分若しくは完全飽和型であり、式中、
− nは、0又は1であり；かつ
− R₅₀は、H又は電子求引基若しくは電子供与基であり；
− A、E、L、J、及びGは、独立して、CH、又はN、O、及びSからなる群から選択されるヘテロ原子であるが；
− nが0の場合には、Gは、CH、又はNH、O、及びSからなる群から選択されるヘテロ原子であり、ただし、A、E、L、J、及びGのうち多くて2つはヘテロ原子である。

A monocyclic 5-membered or 6-membered heterocyclic moiety, or a corresponding, partially or fully saturated form thereof, wherein
-N is 0 or 1; and-R ₅₀ is H or an electron withdrawing group or electron donating group;
-A, E, L, J and G are independently a heteroatom selected from the group consisting of CH or N, O and S;
-When n is 0, G is CH or a heteroatom selected from the group consisting of NH, O and S, provided that at most 2 of A, E, L, J and G One is a heteroatom.

  When n is 0, the above heteroaromatic moiety is a 5-membered ring, while when n is 1, the heterocyclic moiety is a 6-membered monocyclic heterocyclic moiety. Preferred heterocycle moieties are those described above that are monocyclic.

  Where the ring represented above contains a nitrogen ring atom, the N-oxide form is also intended to be within the scope of the invention.

When R ₂ or R ₃ is a heterocyclic ring of the above formula, it may be bonded to the main chain by a ring carbon atom. When n is 0, R ₂ or R ₃ may be further bonded to the main chain by a nitrogen ring atom.

Other preferred moieties for R ₂ and R ₃ are hydrogen, aryl, such as phenyl, arylalkyl, such as benzyl, and alkyl.

It should be understood that preferred groups for R ₂ and R ₃ can be unsubstituted or mono- or polysubstituted with electron donating and / or electron withdrawing groups. Preferably, R ₂ and R ₃ are independently hydrogen, alkyl and are either unsubstituted or substituted with an electron withdrawing group and / or an electron donating group, for example , Alkoxy (such as methoxy and ethoxy), N-hydroxylamino, N-alkylhydroxyamino, N-alkyl-O-alkyl, alkylhydroxyamino and the like.

One of R ₂ and R ₃ is preferably hydrogen.

  n is preferably 1.

More preferably, n = 1 and one of R ₂ and R ₃ is hydrogen. Particularly preferably, in this embodiment, R ₂ is hydrogen and R ₃ is lower alkyl or ZY;
Z is O, NR ₄ , or PR ₄ ; Y is hydrogen or alkyl, such as lower alkyl; ZY is NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ ,

である。

It is.

In another particularly preferred embodiment, n = 1, R ₂ is hydrogen, and R ₃ is alkyl, which may be unsubstituted or substituted with an electron donating or electron withdrawing group, For example, lower alkyl, NR ₄ OR ₅ , or ONR ₄ R ₇ .

In yet another particularly preferred embodiment, n = 1, R ₂ is hydrogen, and R ₃ is alkyl, unsubstituted or substituted with hydroxy or lower alkoxy, such as lower alkyl, NR ₄ OR ₅ , Or ONR ₄ R ₇ , wherein R ₄ , R ₅ , and R ₇ are independently hydrogen or alkyl, R is arylalkyl, wherein the aryl group is unsubstituted Or may be substituted with an electron withdrawing group and R ₁ is alkyl, eg, lower alkyl. In this embodiment, it is most preferred that aryl is phenyl which is unsubstituted or substituted with halo.

Preferably R ₂ is hydrogen and R ₃ is hydrogen, an unsubstituted or alkyl group substituted with at least one electron donating or electron withdrawing group, or ZY. In this preferred embodiment, more preferably R ₃ is hydrogen, an alkyl group such as methyl, unsubstituted or substituted with an electron donating group, or NR ₄ OR ₅ , or ONR ₄ R ₇ , wherein , R ₄ , R ₅ , and R ₇ are independently hydrogen or lower alkyl. It is preferred that the electron donating group is alkoxy, such as lower alkoxy, especially methoxy or ethoxy.

Preferably,
-R ₂ and R ₃ are independently hydrogen, alkyl, such as lower alkyl, or ZY;
-Z is O, NR ₄ or PR ₄ ;
-Y is hydrogen or alkyl, such as lower alkyl; or -ZY is

である。

It is.

  It is also preferred that R is arylalkyl, such as aryl lower alkyl. The most preferred aryl for R is phenyl. The most preferred R group is benzyl. In preferred embodiments, the aryl group can be unsubstituted or substituted with an electron donating or electron withdrawing group. When the aryl ring in R is substituted, it is most preferred that it is substituted with an electron withdrawing group, particularly on the aryl ring. The most preferred electron withdrawing group for R is halo, especially fluoro.

Preferred R ₁ is lower alkyl, especially methyl.

More preferably, R is aryl lower alkyl and R ₁ is lower alkyl.

Further preferred compounds are those of the formula (Ib) in which n is 1; R ₂ is hydrogen; R ₃ is hydrogen, an alkyl group such as a lower alkyl group, in particular an electron donating group or Methyl substituted with an electron withdrawing group, or ZY; R is arylalkyl, for example aryl lower alkyl, for example benzyl, wherein the aryl group is unsubstituted or electron donating or electron withdrawing. Substituted with a pulling group; and R ₁ is alkyl, eg, lower alkyl. In this embodiment, R ₃ is hydrogen; an alkyl group optionally substituted with an electron-donating group such as alkoxy; for example, lower alkoxy (eg, methoxy and ethoxy), such as a lower alkyl group, particularly methyl; NR ₄ OR ₅ ; or ONR ₄ R ₇ , where these groups are defined above.

  The most preferred compound used is the following formula (IIb):

[式中、
− Arは、アリール、特にフェニルであって、非置換又は少なくとも1つの電子供与基若しくは電子求引基、特にハロで置換されており；
− R₁は、アルキル、特に1〜3個の炭素原子を含むものであり；かつ
− R₃は、先に定義したとおりであるが、特に、水素、非置換又は少なくとも1つの電子供与基若しくは電子求引基で置換されているアルキル、例えば低級アルキル、あるいはZYである]
のものである。さらにより好ましくは、この実施態様において、R₃は、水素、非置換若しくは電子供与基で置換されているアルキル基、NR₄OR₅、又はONR₄R₇である。最も好ましくは、R₃は、CH₂−Q（式中、Qは、アルコキシ、例えば低級アルコキシ、特に1〜3個の炭素原子を含むものである）；NR₄OR₅、又はONR₄R₇であって、式中、R₄は、水素又は1〜3個の炭素原子を含むアルキルであり、R₅は、水素、又は1〜3個の炭素原子を含むアルキルであり、かつR₇は、水素、又は1〜3個の炭素原子を含むアルキルである。

[Where
Ar is aryl, especially phenyl, unsubstituted or substituted with at least one electron donating or electron withdrawing group, especially halo;
-R ₁ is alkyl, in particular containing 1 to 3 carbon atoms; and-R ₃ is as defined above, but in particular hydrogen, unsubstituted or at least one electron donating group or Alkyl substituted with electron withdrawing groups, such as lower alkyl, or ZY]
belongs to. Even more preferably, in this embodiment, R ₃ is hydrogen, an alkyl group unsubstituted or substituted with an electron donating group, NR ₄ OR ₅ , or ONR ₄ R ₇ . Most preferably, R ₃ is CH ₂ -Q where Q is alkoxy, such as lower alkoxy, especially one containing 1-3 carbon atoms; NR ₄ OR ₅ , or ONR ₄ R ₇ Wherein R ₄ is hydrogen or alkyl containing 1 to 3 carbon atoms, R ₅ is hydrogen or alkyl containing 1 to 3 carbon atoms, and R ₇ is hydrogen. Or alkyl containing 1 to 3 carbon atoms.

Most preferred R ₁ is CH ₃ . Most preferred R ₃ is CH ₂ -Q, where Q is methoxy.

  The most preferred aryl is phenyl. The most preferred halo is fluoro.

The most preferred compounds include:
(R) -2-acetamido-N-benzyl-3-methoxy-propionamide;
(R) -2-acetamido-N-benzyl-3-ethoxy-propionamide;
O-methyl-N-acetyl-D-serine-m-fluorobenzyl-amide;
O-methyl-N-acetyl-D-serine-p-fluorobenzyl-amide;
N-acetyl-D-phenylglycine benzylamide;
D-1,2- (N, O-dimethylhydroxylamino) -2-acetamidoacetic acid benzylamide;
D-1,2- (O-methylhydroxylamino) -2-acetamidoacetic acid benzylamide.

It should be understood that various combinations and permutations of the R ₁ , R ₂ , R ₃ , R, and n Markush groups described herein are intended to be within the scope of the present invention. It is. Furthermore, the present invention also encompasses compounds and compositions comprising one or more elements of each R ₁ , R ₂ , R ₃ , n, and R Markush groupings, and various combinations thereof. Thus, for example, R ₁ may be one or more of the substituents listed above in combination with any and all substituents of R ₂ , R ₃ , and R for each value of n. The present invention is intended.

  The compounds used in the present invention may contain one or more asymmetric carbons and may exist in racemic and optically active forms. The configuration around each asymmetric carbon can be either D-type or L-type. It is known to those skilled in the art that the configuration around a chiral carbon atom can also be described as R or S in the Cahn-Prelog-Ingold naming convention. All of the various configurations around each asymmetric carbon are contemplated by the present invention, including various enantiomers and diastereomers, and racemic mixtures and enantiomers, diastereomers, or a mixture of both.

In the main chain, asymmetry exists at the carbon atom to which the R ₂ and R ₃ groups are bonded. When n is 1, the compound of the present invention has the following formula:

[式中、R、R₁、R₂、R₃、R₄、R₅、R₆、R'₆、R₇、R₈、R₅₀、Z、及びYは先に定義したとおりである]
のものである。

[Wherein R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ′ ₆ , R ₇ , R ₈ , R ₅₀ , Z, and Y are as defined above]
belongs to.

As used herein, the term configuration shall mean the configuration around the carbon atom to which R ₂ and R ₃ are attached, even though other chiral centers may be present in the molecule. Thus, when referring to a particular configuration such as D or L, it should be understood to mean the D or L stereoisomer at the carbon atom to which R ₂ and R ₃ are attached. However, all possible enantiomers and diastereomers at other chiral centers, if present in the compound, are also included.

The compounds of the present invention are directed to all optical isomers, ie the compounds of the present invention are either L-stereoisomers or D-stereoisomers (at the carbon atom to which R ₂ and R ₃ are attached). It is. These stereoisomers can be found in mixtures of L and D stereoisomers, such as racemic mixtures. The D stereoisomer is preferred. In lacosamide, the D stereoisomer corresponds to the R enantiomer according to the R, S terminology.

  The compounds of formula (Ib) and / or (IIb), in particular lacosamide, may be substantially enantiopure. As used herein, the term “substantially enantiopure” preferably has an enantiomeric purity of at least 88%, more preferably at least 90%, and most preferably at least 95, 96, 97, 98, or 99%. means.

  Depending on the substituents, the compounds of the invention may further form addition salts. All of these forms are intended to be within the scope of the present invention, including mixtures of stereoisomeric forms.

  The methods for preparing the compounds used are described in US Pat. Nos. 5,378,729 and 5,773,475, the contents of both of which are incorporated herein by reference.

  The compounds used in the present invention are useful as those represented by the formula (Ib) and / or (IIb), or those that can be used in the form of a salt in consideration of their basic properties due to the presence of a free amino group. . Accordingly, compounds of formula (Ib) and / or (IIb) form salts with a wide variety of acids, inorganic acids and organic acids, including pharmaceutically acceptable acids. The salts with therapeutically acceptable acids are of course useful in the preparation of formulations where enhanced water solubility is most advantageous.

  These pharmaceutically acceptable salts also have a therapeutic effect. These salts include inorganic acids such as hydrochloric acid, hydroiodic acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid, and organic acids such as tartaric acid, acetic acid, citric acid, Examples include salts such as malic acid, benzoic acid, perchloric acid, glycolic acid, gluconic acid, succinic acid, arylsulfonic acid (eg, p-toluenesulfonic acid, benzenesulfonic acid), phosphoric acid, and malonic acid.

  The invention further provides treatment with an antipsychotic in an add-on treatment to at least one antipsychotic by administering at least one compound of formula (Ib) and / or (IIb) to a subject in need thereof Also contemplated are methods for the prevention, reduction and / or treatment of certain illnesses, particularly psychosis, particularly schizophrenia.

In a preferred embodiment, the method of the present invention applies to a subject in need thereof:
(A) administering at least one antipsychotic agent useful for preventing, reducing and / or treating psychosis, and (b) an add-on treatment in addition to at least one agent of (a) above. Administering at least one compound of (Ib) and / or (IIb);
including.

In the method of the present invention, preventing psychosis, reduction or treatment of at least one antipsychotic agent useful for the dopamine antagonist, preferably D ₂ antagonist, more preferably an atypical antipsychotic, even more preferably above An atypical antipsychotic as defined in, and the most preferred agents are clozapine, risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, sulpiride, amisulpride, and / or zotepine.

  At least one compound of formula (Ib) and / or (IIb) and at least one antipsychotic drug useful for preventing, reducing and / or treating psychosis are in the form of a single composition (single More preferably, it is administered in a dosage form.

In another preferred embodiment, the method of the invention comprises:
(I) a first composition comprising at least one antipsychotic agent useful for preventing, reducing and / or treating psychosis, and (ii) at least one compound of formula (Ib) and / or (IIb) A second composition comprising,
Administering an isolated dosage form comprising: to a subject in need thereof.

  In yet another preferred embodiment of the invention, a commercially available antipsychotic composition useful for preventing, reducing and / or treating psychosis may be administered to a subject in need thereof. Thus, in this preferred embodiment, the method of the present invention for preventing, reducing and / or treating a disease, particularly psychosis, treated with an antipsychotic agent comprises at least one of formula (Ib) and / or formula (IIb): A pharmaceutical composition comprising one compound but not containing an antipsychotic useful for preventing, reducing and / or treating psychosis, and an antipsychotic for preventing, reducing and / or treating psychosis Administering to a subject being given a commercially available composition comprising.

  Compounds of formula (Ib) and / or (IIb) may also be useful in add-on treatments for diseases and / or conditions other than schizophrenia that are treated with antipsychotic drugs. Accordingly, still another subject of the present invention is a psychosis in diseases other than bipolar disorder, autism, schizophrenia, such as psychosis in Alzheimer's disease, and / or by administration of the pharmaceutical composition of the present invention. An add-on treatment to prevent, reduce and / or treat attention deficit hyperactivity disorder. Compounds of formula (Ib) and / or (IIb) can also be treated with antipsychotics, diseases and / or illnesses other than schizophrenia, eg diseases other than bipolar disorder, autism, schizophrenia Used in the preparation of pharmaceutical compositions useful for the prevention, reduction and / or treatment in add-on therapy for psychosis, such as psychosis in Alzheimer's disease and / or attention deficit hyperactivity disorder Good. The pharmaceutical compositions of the invention described herein for treating schizophrenia can also be treated with antipsychotic drugs and / or diseases other than schizophrenia, such as bipolar disorder, autism May be used to prevent, alleviate, and / or treat in add-on treatments for psychosis in diseases other than schizophrenia, such as psychosis in Alzheimer's disease, and / or attention deficit hyperactivity disorder.

  The compounds of formula (Ib) and / or (IIb) may also be useful in add-on therapy to at least one antipsychotic to treat psychoses other than psychosis in schizophrenia. Accordingly, still another subject of the present invention is, for example, bipolar disorder, autism, Alzheimer's disease, attention deficit hyperactivity disorder, drug abuse and / or alcohol dependence by administering the pharmaceutical composition of the present invention. Disorder, affective disorder, dyskinesia and related diseases, dementia, mental retardation, polyptysia / hyponatremia, severe personality disorder, acute mania, obsessive-compulsive disorder, refractory chronic insomnia, Huntington's disease, Tourette syndrome, Parkinson's disease And / or an add-on treatment to at least one antipsychotic to prevent, reduce and / or treat psychosis associated with treatment of dopaminergic Parkinson's disease. Compounds of formula (Ib) and / or (IIb) may also be used, for example, for bipolar disorder, autism, Alzheimer's disease, attention deficit hyperactivity disorder, drug abuse and / or alcoholism, affective disorder, dyskinesia and related Disease, Dementia, Mental Retardation, Pulmonary / Hypernatremia, Severe Personality Disorder, Acute Manic Development, Obsessive Compulsive Disorder, Intractable Chronic Insomnia, Huntington's Disease, Tourette Syndrome, Parkinson's Disease, and / or Dopaminergic Parkinson In add-on therapy to at least one antipsychotic agent for treating psychosis associated with disease treatment, it may be used to prepare a pharmaceutical composition useful for prevention, alleviation, and / or treatment. The pharmaceutical compositions of the invention described herein are also, for example, bipolar disorder, autism, Alzheimer's disease, attention deficit hyperactivity disorder, drug abuse and / or alcoholism, affective disorder, dyskinesia and related Disease, Dementia, Mental Retardation, Pulmonary / Hypernatremia, Severe Personality Disorder, Acute Manic Development, Obsessive Compulsive Disorder, Intractable Chronic Insomnia, Huntington's Disease, Tourette Syndrome, Parkinson's Disease, and / or Dopaminergic Parkinson It may be used to prevent, reduce, and / or treat in add-on treatments for treating psychosis associated with disease treatment.

  The compound used in the present invention is preferably used in a therapeutically effective amount.

  The physician will determine the dose of the therapeutic agent of the invention that will be most suitable, which will vary depending on the mode of administration and the particular compound selected, as well as the patient being treated, the age of the patient and being treated It will vary depending on the type of illness. In general, it may be desirable to begin treatment at a lower dose that is substantially less than the optimum dose of the compound, and increase the dose in small increments until the optimum effect under the conditions is achieved. If the composition is administered orally, a larger amount of active agent will be required to achieve the same effect as a smaller amount administered parenterally. The compounds are useful in the same way as comparable therapeutic agents, and the dosage levels are on the order of magnitude as commonly practiced with these other therapeutic agents.

  In add-on therapy to at least one antipsychotic of the present invention, the usual dose of antipsychotic administered to a subject in need thereof is a dopamine antagonist dose as indicated above or the following dose: Olanzapine 5 -20 mg / day, clozapine 100-900 mg / day, quetiapine 100-800 mg / day, risperidone 1-16 mg / day, aripiprazole 3-30 mg / day, ziprasidone 40-160 mg / day, sulpiride 300-1600 mg / day, amisulpride 50-1200 mg / day, zotepine 75-450 mg / day. Such doses can also be included in the pharmaceutical composition of the present invention and / or used to prepare the pharmaceutical composition of the present invention.

  The physician is at least one useful for preventing, reducing and / or treating psychosis, which may be the same or different from the route of administration of at least one compound of the invention of formula (Ib) and / or (IIb) The route of administration of the drug can be determined. The usual routes of administration of at least one antipsychotic useful for preventing, reducing and / or treating psychosis are oral, intravenous, intramuscular, intrathecal, or subcutaneous routes. Oral and / or intravenous administration is preferred.

  In a preferred embodiment, the compounds of formula (Ib) and / or (IIb) of the invention are administered in an amount ranging from about 1 mg to about 10 mg per kg body weight per day. This usage may be adjusted by the physician to provide the optimal therapeutic response. Patients in need thereof are at least 50 mg / day, preferably at least 100 mg / day, more preferably at least 200 mg / day, even more preferably at least 300 mg / day, most preferably at least 400 mg / day It may be treated with a compound dose of the invention. In general, patients in need thereof may be treated at doses up to 6 g / day, more preferably up to 1 g / day, most preferably up to 600 mg / day. However, in some cases higher or lower doses may be required.

  In another preferred embodiment, the daily dose is increased until a predetermined daily dose is reached that is maintained during further treatment.

  In yet another preferred embodiment, several divided doses may be administered daily. For example, 3 doses per day may be administered, preferably 2 doses per day. More preferably, a single dose is administered per day.

  In yet another preferred embodiment, the amount of the compound of the invention results in plasma concentrations of 0.1-15 μg / mL (trough) and 5-18.5 μg / mL (peak), calculated as an average across multiple subjects. May be administered.

  The compounds of formula (Ib) and / or (IIb) are administered in a convenient manner, for example by oral, intravenous (in this case water-soluble), intramuscular, intrathecal, or subcutaneous route. It's okay. Oral and / or i.v. administration is preferred.

  The pharmaceutical composition of the present invention provides a treatment regime as described above to produce a plasma concentration as described above, with a period of administration and / or route of administration as specified in embodiments of the present invention as described above, In particular, it may be prepared for treatment at a dose as described above.

  The pharmaceutical composition of the present invention comprising at least one antipsychotic agent for preventing, reducing and / or treating psychosis, particularly schizophrenia, is a common carrier, diluent and / or known to those skilled in the art. Formulated with adjuvants. In the case of an isolated dosage form, a first composition comprising at least one antipsychotic agent useful for preventing, reducing and / or treating psychosis, and at least one of formulas (Ib) and / or (IIb) The second composition comprising one compound includes the first composition comprising at least one antipsychotic agent useful for preventing, reducing and / or treating psychosis, and the formula (Ib) and / or (IIb) In the second composition comprising at least one compound of), carriers, diluents and / or adjuvants which are the same or different independently of one another may be included.

  The compound of formula (Ib) and / or (IIb) may be administered orally together with, for example, an inert diluent or an absorbable edible carrier, or may be enclosed in a hard or soft shell gelatin capsule, or It may be compressed into tablets or incorporated directly into food or diet. For oral administration for therapeutic purposes, the active compounds of formula (Ib) and / or (IIb) may be incorporated with excipients and ingestible tablets, buccal tablets, troches, capsules, elixirs , Suspensions, syrups, wafers and the like. Such compositions and preparations should contain at least 1% of active compound of formula (Ib) and / or (IIb). The percentages of the compositions and preparations can of course vary and can conveniently be from about 5% to about 80% by weight of the unit. The amount of active compound of formula (Ib) and / or (IIb) in such therapeutically useful compositions is such that a suitable dosage is obtained. Preferred compositions or preparations according to the invention contain from about 10 mg to 6 g of active compound of formula (Ib) and / or (IIb).

  Tablets, troches, pills, capsules and the like may also include the following: binders such as gum tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as Corn starch, potato starch, alginic acid, etc .; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose or saccharin may be added or flavoring agents such as peppermint, Wintergreen oil or cherry flavor may be added. Where the dosage unit form is a capsule, a liquid carrier may be included in addition to the types of materials described above.

  Various other materials may be present as coatings, or alternatively, the physical form of the dosing unit may be altered. For instance, tablets, pills, or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and formulations. For example, sustained release dosage forms are intended to bind the active ingredient to an ion exchange resin, which can optionally be coated with a diffusion barrier coating to alter the release characteristics of the resin. .

  The active compound may also be administered parenterally or intraperitoneally. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

  Pharmaceutical forms suitable for injectable use include sterile aqueous solutions (in this case water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. The form must be stable under the conditions of manufacture and storage and must be stored against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, vegetable oils, and the like. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of microbial action can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of injectable compositions can be brought about by use in compositions that delay absorption, for example, aluminum monostearate and gelatin.

  Sterile injectable solutions are prepared by incorporating the required amount of the active compound in a suitable solvent having the various other ingredients listed above, followed by filter sterilization, if necessary. In general, dispersions are prepared by incorporating various sterilized active ingredients in a sterile vehicle that contains a basic dispersion medium and the other required ingredients from those listed above. The In the case of sterile powders for preparing sterile injectable solutions, the preferred method of preparation is a vacuum drying, lyophilization technique with any additional desired components from the solution pre-sterilized by filtration.

  As used herein, “pharmaceutically acceptable carrier” refers to any and all solvents, dispersion media, coatings, antibacterials and antimicrobials known in the art for pharmaceutically active substances. Fungal agents, isotonic agents, and absorption delaying agents are included. Except insofar as any conventional vehicle or drug is incompatible with the active ingredient, its use in a therapeutic composition is contemplated. Additional active ingredients can also be incorporated into the compositions.

  It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. As used herein, dosage unit form means a physically separate unit suitable as a single dose for the mammalian subject to be treated; each unit is combined with the required pharmaceutical carrier. A predetermined amount of active substance calculated to produce the desired therapeutic effect. Specificity for the novel dosage unit form of the present invention is: (a) the unique properties of the active substance and the specific therapeutic effect to be achieved; and (b) details on the body as disclosed in detail herein. It is dictated and directly dependent on the inherent limitations in the field of formulating active substances and the like to treat biological diseases with pathological conditions that are compromised in their health.

  The major active ingredients are formulated for convenient and effective administration in an effective amount in a dosage unit form, as described above, with a suitable pharmaceutically acceptable carrier. For example, a unit dosage form can contain the principal active compound in amounts ranging from about 10 mg to about 6 g. Expressed in proportions, the active compound is usually present in the carrier at about 1 to about 750 mg / mL of the carrier. In the case of compositions containing additional active ingredients, the dosage is determined by reference to the usual dosage and manner of administration of the ingredients.

  As used herein, the term “patient” or “subject” refers to warm-blooded animals, preferably mammals, such as primates, including cats, dogs, horses, cows, pigs, mice, rats, and humans. means. A preferred patient is a human.

  The term “treatment” means to prevent, cure or alleviate a patient's illness or condition.

  The compounds of the present invention are administered in effective amounts to patients suffering from the types of diseases described above. These amounts correspond to therapeutically effective amounts as described above.

  The following examples demonstrate the properties of lacosamide, formally referred to as harcoceride or SPM 927, that enhances prepulse inhibition of clozapine in mice when administered with the antipsychotic drug clozapine.

  The material used was lacosamide. The standard chemical nomenclature is (R) -2-acetamido-N-benzyl-3-methoxypropionamide.

[Example]
(Effects of lacosamide alone and in combination with clozapine in animal models for schizophrenia)
As an add-on treatment to antipsychotics for schizophrenia, several anticonvulsants have demonstrated preclinical and / or clinical efficacy. Lacosamide was tested in a simple animal model with predictive validity for psychosis such as schizophrenia (ie, prepulse inhibition (PPI) of the auditory startle reflex). Lacosamide was tested alone and in combination with the atypical antipsychotic drug clozapine.

  Prepulse inhibition is a common model of psychosis and is therefore a psychosis associated with other illnesses or conditions, such as schizophrenia, bipolar disorder, autism, Alzheimer's disease, attention deficit hyperactivity disorder, drug abuse And / or alcoholism, affective disorder, dyskinesia and related diseases, dementia, mental retardation, polydeficiency / hyponatremia, severe personality disorder, acute mania, obsessive compulsive disorder, refractory chronic insomnia, Huntington's disease, It should be noted that it is an indicator of Tourette syndrome, Parkinson's disease, and / or psychosis associated with dopaminergic Parkinson's treatment.

  Auditory startle is an unconditional reflex that responds to external auditory stimuli. PPI refers to the reduction in startle response that results from presenting low intensity auditory stimuli prior to startle stimuli. The PPI paradigm is an option to study schizophrenia and antipsychotic effects due to the similarities between human and rodent study results. Antipsychotics such as clozapine result in a dose-dependent increase in PPI in mice. Thus, an increase in PPI in normal mice can be an indicator of antipsychotic efficacy.

  C57BL / 6J mice obtained from Jackson Laboratory, Bar Harbor, Maine were received at 6 weeks of age and assigned a unique identification number (marked on the tail). Four animals per cage were housed in a polycarbonate cage with a filter top and allowed to acclimate for 7 days. Prior to the start of the study, all animals were examined, processed and weighed to ensure proper health and fitness and to minimize non-specific stress associated with manipulation.

  During the study period, a 12/12 light / dark cycle and a room temperature of 20-23 ° C. were maintained at a relative humidity maintained at about 50%. During the study period, food and water were provided ad libitum as appropriate. Each mouse was randomly assigned across treatment groups and balanced by cage number. Testing was performed during the animal light cycle phase. Twelve animals were used in each treatment group.

Lacosamide was dissolved in saline (0.9% NaCl in sterile H ₂ O). Clozapine was dissolved in 1% Tween 80 in sterile H ₂ O at a final pH = 6.0. All compounds were administered intraperitoneally (ip) (injection volume: 10 mL / kg). Lacosamide was administered at doses of 1, 10, and 30 mg / kg, and clozapine was administered at a dose of 3 mg / kg. The dose is expressed as mg of salt. Control mice were administered saline (vehicle 1, VEH 1) or 1% Tween 80 (vehicle 2, VEH 2) at pH = 6.0. Drug treatment was balanced over the day and used only once for animals. All trials were performed blind. All compounds were administered 30 minutes before the test.

  Animals were placed in a PPI chamber (Med Associates) during a 5 minute session of white noise (70 dB) acclimatization. After the acclimation period, the test session was automatically started. The session began with six presentation habituation blocks of startle stimuli alone, followed by 10 PPI blocks of 6 different types of trials. The test types are: zero (no stimulation), startle (120 dB), startle and prepulse (4, 8, and 12 dB above background noise, ie 74, 78, or 82 db), and Prepulse alone (82 dB). The test type was presented randomly within each block. Each test started with a 50 ms null period, during which time baseline shifts were recorded. Subsequently, prepulse stimulation was presented for a period of 20 ms, and the response to the prepulse was measured. After another 100 ms, a startle stimulus was presented for 40 ms, and a reaction was recorded for 100 ms from the start of startle.

  The reaction was sampled every ms. The interval between tests was variable with an average of 15 s (range 10-20 s). The startle alone test measures basic auditory startle, the prepulse and startle test measures the amount of normal startle suppression, and excluding the startle response of the first habituation block, the basic startle response (startle alone) Expressed as a percentage). Eight animals were tested at a time.

In each group, 12 animals were tested. A total of 108 mice were tested using the following design:
・ VEH 1 / VEH 2
・ Lacosamide [3 mg / kg] / VEH 2
・ Lacosamide [10 mg / kg] / VEH 2
・ Lacosamide [30 mg / kg] / VEH 2
・ VEH 1 / clozapine [3 mg / kg]
・ Lacosamide [3 mg / kg] / Clozapine [3 mg / kg]
・ Lacosamide [10 mg / kg] / clozapine [3 mg / kg]
・ Lacosamide [30 mg / kg] / Clozapine [3 mg / kg]

  Two-way ANOVA (Analysis of Variance) using treatment as an independent factor and prepulse intensity as a dependent factor (ie, repeated measurements) was performed. This was followed by the post-hoc Newman Keuls test shown here. p <0.05 was considered significant. Newman Keuls test allows comparison of two independent samples.

  Animals injected with clozapine (3 mg / kg) showed a significant improvement in prepulse inhibition compared to animals that received vehicle (p <0.05, Table 1). When lacosamide was administered alone, at any test dose, lacosamide had no significant effect on prepulse inhibition compared to vehicle. However, administration of lacosamide in combination with clozapine (at 30 mg / kg rather than 3 or 10 mg / kg) greatly enhances the effect of clozapine alone on prepulse inhibition, ie prepulse inhibition is the effect of clozapine alone Significantly higher (p <0.05).

  The resulting data provides the basis for clinical trials in humans using lacosamide as an add-on treatment to treat psychosis, particularly schizophrenia, or psychosis associated with schizophrenia and / or other illnesses or conditions To do.

(table 1)
Effect of lacosamide alone and in combination with clozapine on prepulse inhibition (PPI) of auditory startle response

Claims (36)

The following general formula (Ib) for preparing a pharmaceutical composition for preventing, reducing and / or treating a disease treated with an antipsychotic in an add-on treatment to at least one antipsychotic:

[Where:
-R is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, alkylheterocycle, cycloalkyl, or cycloalkylalkyl, and R is unsubstituted or at least Substituted with one electron withdrawing group and / or at least one electron donating group;
R ₁ is hydrogen or alkyl, alkenyl, alkynyl, arylalkyl, aryl, heterocyclic alkyl, alkylheterocyclic, heterocyclic, cycloalkyl, cycloalkylalkyl, each unsubstituted or at least one electron donating group And / or is substituted with at least one electron withdrawing group;
R ₂ and R ₃ are independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, aryl, halo, heterocycle, heterocyclealkyl, alkylheterocycle, cycloalkyl, cycloalkylalkyl, or ZY Wherein R ₂ and R ₃ may be unsubstituted or substituted with at least one electron withdrawing group and / or at least one electron donating group; and R ₂ and The heterocycle in R ₃ is furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, Benzoxazolyl, tetrahydroph , Pyranyl, indazolyl, purinyl, indolinyl, pyrazolinedinyl, imidazolinyl, imidazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, oxetanyl, azetidinyl, or N The N-oxide if present in the heterocycle;
- Z is, O, S, S (O ) a, NR 4, NR '6, or PR _4, or a chemical bond;
-Y is hydrogen, alkyl, aryl, arylalkyl, alkenyl, alkynyl, halo, heterocycle, heterocyclealkyl, alkylheterocycle, wherein Y is unsubstituted or at least one electron donating group And / or optionally substituted with at least one electron withdrawing group, wherein heterocycle has the same meaning as R ₂ and R ₃ except that Z is a chemical when Y is halo. Or ZY together is NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ , OPR ₄ R ₅ , PR ₄ OR ₅ , SNR ₄ R ₇ , NR ₄ SR ₇ , SPR ₄ R ₅ , PR ₄ SR ₇ , NR ₄ PR ₅ R ₆ , PR ₄ NR ₅ R ₇ , or N ⁺ R ₅ R ₆ R ₇ ,

Is;
- R _'6 is hydrogen, alkyl, alkenyl, or a alkynyl may be unsubstituted or may be substituted with at least one electron withdrawing group and / or at least one electron donating group;
R ₄ , R ₅ , and R ₆ are independently hydrogen, alkyl, aryl, arylalkyl, alkenyl, or alkynyl, wherein R ₄ , R ₅ , and R ₆ are independently May be unsubstituted, substituted or substituted with at least one electron withdrawing group and / or at least one electron donating group; and-R ₇ is R ₆ or COOR ₈ or COR ₈ Where R ₇ may be unsubstituted or substituted with at least one electron withdrawing group and / or at least one electron donating group;
R ₈ is hydrogen or alkyl, or arylalkyl, wherein the aryl or alkyl group may be unsubstituted or at least one electron withdrawing group and / or at least one electron donating group And -n is 1-4; and -a is 1-3]
Use of at least one compound having the formula: or a pharmaceutically acceptable salt thereof.   Said illness treated with antipsychotics is schizophrenia, bipolar disorder, autism, attention deficit hyperactivity disorder and / or psychosis, in particular psychosis associated with: schizophrenia, bipolar disorder, Autism, Alzheimer's disease, and / or attention deficit / hyperactivity disorder, drug abuse and / or alcoholism, affective disorder, dyskinesia and related disorders, dementia, mental retardation, polydulnia / hyponatremia, severe Treatment of personality disorder, acute mania, obsessive compulsive disorder, refractory chronic insomnia, Huntington's disease, Tourette syndrome, Parkinson's disease and / or dopaminergic Parkinson's disease, preferably psychosis is associated with schizophrenia The use according to claim 1. Use according to claim 1 or 2, wherein one of R ₂ and R ₃ is hydrogen.   4. Use according to any one of claims 1 to 3, wherein n is 1. Use according to any one of claims 1 to 4, wherein one of R ₂ and R ₃ is hydrogen and n is 1. R is aryl lower alkyl, and R ₁ is lower alkyl, the use of any one of claims 1 to 5. -R ₂ and R ₃ are independently hydrogen, lower alkyl, or ZY;
-Z is O, NR ₄ or PR ₄ ;
-Y is hydrogen or lower alkyl; or-ZY is

The use according to any one of claims 1 to 6, wherein -R ₂ is hydrogen and R ₃ is lower alkyl or ZY;
-Z is O, NR ₄ or PR ₄ ;
-Y is hydrogen or lower alkyl; or-ZY is

8. Use according to claim 7, wherein Lower alkyl, NR ₄ OR ₅ , wherein R ₂ is hydrogen and R ₃ is unsubstituted or optionally substituted with at least one electron donating group and / or at least one electron withdrawing group, or ONR is ₄ R _7, use according to any one of claims 1 to 8. R ₃ is lower or unsubstituted alkyl substituted with hydroxy or lower alkoxy, NR ₄ OR ₅ , or ONR ₄ R ₇ , wherein R ₄ , R ₅ , and R ₇ are independently , Hydrogen or lower alkyl, R is aryl lower alkyl, wherein the aryl group may be unsubstituted or substituted with at least one electron withdrawing group and R ₁ is 10. Use according to any one of claims 1 to 9, which is lower alkyl.   11. Use according to any one of claims 1 to 10, wherein aryl is phenyl and is unsubstituted or substituted with halo. The compound is
(R) -2-acetamido-N-benzyl-3-methoxy-propionamide;
(R) -2-acetamido-N-benzyl-3-ethoxy-propionamide;
O-methyl-N-acetyl-D-serine-m-fluorobenzylamide;
O-methyl-N-acetyl-D-serine-p-fluorobenzylamide;
N-acetyl-D-phenylglycine benzylamide;
D-1,2- (N, O-dimethylhydroxylamino) -2-acetamidoacetic acid benzylamide; or D-1,2- (O-methylhydroxylamino) -2-acetamidoacetic acid benzylamide,
12. Use according to any one of claims 1 to 11, wherein The compound is represented by the following formula (IIb):

[Where
Ar is phenyl which is unsubstituted or substituted, for example with at least one halo group;
- R ₃ is a CH ₂ -Q, wherein, Q is a lower alkoxy containing 1 to 3 carbon atoms; and - R ₁ is a lower alkyl containing 1 to 3 carbon atoms ]
Or a pharmaceutically acceptable salt thereof.   14. Use according to claim 13, wherein Ar is unsubstituted phenyl.   15. Use according to claim 13 or 14, wherein halo is fluoro. A R ₃ is CH ₂ -Q, wherein, Q is an alkoxy containing 1 to 3 carbon atoms, and Ar is an unsubstituted phenyl, any of claims 13 to 15 Use of. The compound is in the R configuration and has the following formula:

[Where
-R is benzyl which is unsubstituted or substituted with at least one halo group;
- R ₃ is a CH ₂ -Q, wherein, Q is a lower alkoxy containing 1 to 3 carbon atoms; and - R ₁ is methyl
The use according to any one of claims 1 to 11 or 13 to 16, which has a pharmaceutically acceptable salt thereof.   18. Use according to claim 17, which is at least 88% enantiopure.   19. Use according to claim 17 or 18, wherein R is unsubstituted benzyl.   20. Use according to any one of claims 17 to 19, wherein halo is fluoro. A R ₃ is CH ₂ -Q, wherein, Q is an alkoxy containing 1 to 3 carbon atoms, and R is unsubstituted benzyl, any one of claims 17 to 20 Use of.   The use according to claim 1, wherein the compound of formula (Ib) is (R) -2-acetamido-N-benzyl-3-methoxypropionamide or a pharmaceutically acceptable salt thereof.   23. Use according to claim 22, wherein the compound is at least 88% enantiopure.   Said pharmaceutical composition is prepared for treatment at a dose of said compound of at least 100 mg / day, preferably at least 200 mg / day, more preferably at least 300 mg / day, most preferably at least 400 mg / day 24. Use according to any one of claims 1 to 23.   The pharmaceutical composition is prepared for treatment at a compound dose of up to 6 g / day, more preferably up to 1 g / day, most preferably up to 600 mg / day. 24. Use according to any one of 24.   26. Use according to any one of claims 1 to 25, wherein the pharmaceutical composition is prepared for treatment with increasing daily doses until a predetermined daily dose is maintained which is maintained during further treatment.   27. The pharmaceutical composition according to any one of claims 1 to 26, wherein the pharmaceutical composition is prepared for treatment with 3 doses per day, preferably 2 doses per day, more preferably 1 dose per day. use.   The pharmaceutical composition is prepared for administration resulting in plasma concentrations of 0.1-15 μg / mL (trough) and 5-18.5 μg / mL (peak), calculated as an average across multiple subjects. 28. Use according to any one of 1 to 27.   29. Use according to any one of claims 1 to 28, wherein the pharmaceutical composition is prepared for oral or i.v. administration. Said pharmaceutical composition for preventing, reducing and / or treating diseases treated with antipsychotics, in particular psychoses,
(A) at least one antipsychotic agent useful for preventing, reducing and / or treating psychosis, and (b) at least one compound as defined in any one of claims 1 to 23,
30. Use according to any one of claims 1 to 29, comprising: The pharmaceutical composition comprises a single dosage form or comprises a separate dosage form, wherein the separated dosage form comprises
(A) a first composition comprising at least one antipsychotic agent useful for preventing, reducing and / or treating psychosis, and (b) as defined in any one of claims 1 to 23. A second composition comprising at least one compound of
31. Use according to any one of claims 1 to 30, comprising: Wherein the at least one antipsychotic, dopamine antagonists, preferably D ₂ antagonist, more preferably an atypical antipsychotic, even more preferably Abaperidon, amino Surt pre-de, amisulpride, Amuparekkusu, aripiprazole, asenapine maleate, clozapine , Fluspirylene, iloperidone, mosapramine, mosapramine dihydrochloride, ocaperidone, olanzapine, oxypertin, perazine, perospirone, piperacetazine, quetiapine, quetiapine fumarate, remoxiprid, risperidone, sertindol, sulpiride, ziprasidone, ziprasidone, ziprasidone Zotepine, most preferably clozapine, risperidone, aripiprazole, quetiapine, olanzapine, zipura 32. Use according to claim 31 which is cydon, sulpiride, amisulpride and / or zotepine.   Olanzapine at a dose of 5-20 mg / day, Clozapine at a dose of 100-900 mg / day, Quetiapine at a dose of 100-800 mg / day, Risperidone at a dose of 1-16 mg / day, and Aripiprazole At doses of 3-30 mg / day, ziprasidone at doses of 40-160 mg / day, sulpiride at doses of 300-1600 mg / day, amisulpride at doses of 50-1200 mg / day, and / or zotepine 33. Use according to claim 31 or 32, wherein is applied at a dose of 75-450 mg / day. (A) at least one antipsychotic agent useful for preventing, reducing and / or treating psychosis, and (b) at least one compound as defined in any one of claims 1 to 22,
A pharmaceutical composition comprising: Comprising a single dosage form or comprising a separate dosage form, wherein the separate dosage form comprises:
(A) a first composition comprising at least one antipsychotic agent useful for preventing, reducing and / or treating psychosis, and (b) as defined in any one of claims 1 to 22. A second composition comprising at least one compound of
35. A pharmaceutical composition according to claim 34, comprising: Wherein the at least one antipsychotic, dopamine antagonists, preferably D ₂ antagonist, more preferably an atypical antipsychotic, even more preferably Abaperidon, amino Surt pre-de, amisulpride, Amuparekkusu, aripiprazole, asenapine maleate, clozapine , Fluspirylene, iloperidone, mosapramine, mosapramine dihydrochloride, ocaperidone, olanzapine, oxypertin, perazine, perospirone, piperacetazine, quetiapine, quetiapine fumarate, remoxiprid, risperidone, sertindol, sulpiride, ziprasidone, ziprasidone, ziprasidone Zotepine, most preferably clozapine, risperidone, aripiprazole, quetiapine, olanzapine, zipura 36. The pharmaceutical composition according to claim 34 or 35, which is sidon, sulpiride, amisulpride, and / or zotepine.