EA015566B1 - Lacosamide for add-on therapy - Google Patents

Abstract

The present invention is directed to the use of a class of peptide compounds for the prevention, alleviation or/and treatment of a disease that is treated with antipsychotics, in particular psychosis, more particular schizophrenia, in an add-on therapy to at least one antipsychotic.

Description

The invention relates to the use of a class of peptide compounds for the prevention, relief and / or treatment of diseases that are treated with antipsychotic drugs, in particular psychosis, more specifically schizophrenia, in adjunctive therapy for at least one antipsychotic.

Especially the present invention relates to the use of a class of peptide compounds for the prevention, relief and / or treatment of schizophrenia, bipolar disorder, autism, attention deficit disorder, hyperactive disorder, psychosis, psychosis associated with schizophrenia, bipolar disorder, autism, Alzheimer's disease, attention deficit disorder and hyperactivity disorder alcohol or drug abuse, emotional disorders, dyskinesia and related disorders, dementia (dementia), mental retardation, poly ipsiey / hyponatraemia, severe personality disorder, acute cases of mania, obsessive compulsive disorder, intractable chronic insomnia, Huntington's disease, Tourette's syndrome, Parkinson's disease, preferably wherein the psychosis associated with schizophrenia, in adjunctive therapy with at least one neuroleptic.

Background of the Related Art

It is known that some peptides are active against the central nervous system (CNS) and are used in the treatment of epilepsy and other disorders of the central nervous system. Such peptides, which are described in US patent No. 5378729, have the formula (1A):

I

К ——- ΝН — С —— С N And -...... * *] n — С .......— K1 in which

I am hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclyl, heterocyclyl lower alkyl, lower alkyl heterocyclyl, lower cycloalkyl, lower cycloalkyl lower alkyl, and I am unsubstituted or substituted by at least one electron-withdrawing group or an electron donating group;

H1 is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclyl lower alkyl, heterocyclyl, lower cycloalkyl, lower cycloalkyl lower alkyl, each of which is unsubstituted or substituted by an electron-donor group or electron-withdrawing group; and

H2 and H3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclyl, heterocyclyl lower alkyl, lower alkyl heterocyclyl, lower cycloalkyl, lower cycloalkyl lower alkyl or Ζ-Υ, where I ₂ and I ₃ may be unsubstituted or substituted by at least one electron-withdrawing group or electron-donating group;

Ζ is О, 8, 8 (О) _а , МЯ ₄ , РЯ ₄ or a chemical bond;

Υ is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halogen, heterocyclyl, heterocyclyl lower alkyl, and Υ may be unsubstituted or substituted by an electron donor group or electron withdrawing group, provided that when Υ is halogen, Ζ is a chemical bond, or ΖΥ taken together are ΝΡ ₄ ΝΡ ₅ Ρ-. № Я ₄ ОЯ ₅ , ΟΝΡ.-Я-. Armature _4, I _5, OC RP _{4 5 4} I 8YYA ₇ Yaya 8th _{4 7 4} I 8RYA ₅ or OC _{4 7} 8th, 1 <H ₄ OC ₅ I _b or OC MN _{4 5 7} I,

IKlS-Nz, ZSNz, YSChS-OKb, 8C-ORE;

X L

I ₄ , I ₅ and Yab are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl or lower alkynyl, where I ₄ , I ₅ and I ₆ may be unsubstituted or substituted by an electron withdrawing group or electron donor group; and

I ₇ is Yab or SOYA ₈ or SOYA ₈ ;

H8 is hydrogen or lower alkyl, or aryl lower alkyl, and the aryl or alkyl group may be unsubstituted or substituted with an electron withdrawing group or electron donating group; and η is 1-4; and a is 1-3.

US patent No. 5773475 also discloses additional compounds suitable for the treatment of CNS disorders. These compounds are Y-benzyl-2-amino-3-methoxy-propionamide having the formula (11a):

- 1 015566

H HH ί I I Ar-CH ^ -H-C-C-H-C-E,

I I I

About SNG about

I KZ

Formula (11a) in which

Ar is aryl which is unsubstituted or substituted by halogen;

K ₃ is lower alkoxy and

TO! is methyl.

However, neither US patent No. 5378729 nor US patent No. 5773475 describes the use of these compounds for the treatment of psychosis, in particular for the treatment of psychosis associated with schizophrenia, in adjunctive therapy to at least one antipsychotic agent.

νθ 02/074297 relates to the use of a compound according to formula (11a), in which Ar is phenyl which can be substituted with at least one halogen, K ₃ is lower alkoxy containing 1-3 carbon atoms, and Κι is methyl for pharmaceutical compositions suitable for the treatment of allodynia associated with peripheral neuropathic pain.

νθ 02/074784 relates to the use of a compound having the formula (1a) or / and the formula (11a) showing antinociceptive properties for treating various types and symptoms of acute and chronic pain, especially non-neuropathic inflammatory pain, for example, pain in rheumatoid arthritis or / and secondary inflammatory osteoarthritis pain.

Psychosis, especially schizophrenia, is a state of mental impairment, characterized by the following symptoms.

Distorted perception of reality.

People with psychosis can have a perception of reality that is strikingly different from how others see and perceive reality.

Hallucinations and illusions.

Hallucinations are perceptions that occur without communication with the appropriate source. Hallucinations can occur in any sensory form - auditory (sound), visual (visual), tactile (tactile), taste (taste) and olfactory (smell). Auditory hallucinations, especially the case of hearing voices that other people don’t hear, are a common and well-known symptom of psychosis.

Crazy ideas.

Nonsense - wrong individual ideas that are not amenable to reason or contradictory evidence and are not explainable from the point of view of ordinary cultural ideas of the individual.

Confused consciousness.

Often, psychosis affects a person’s ability to think directly. Thoughts come and go quickly; a person may be unable to concentrate on one thought for a long time and can be easily distracted (taken away), unable to concentrate. Confused thinking is largely characterized by the effect on speech and writing (the writing process).

It is believed that psychosis is a symptom of a severe mental illness, and not a diagnosis in itself. Although it is not exclusively associated with any particular psychological or physical condition, it is especially associated with schizophrenia, bipolar disorder, and severe clinical depression. There are also some physical circumstances that may include psychotic status, including electrolyte disorder, urinary tract infections in the elderly, pain syndromes, drug toxicity, and substance (drug) withdrawal syndrome (especially alcohol, barbiturates, and sometimes benzodiazepines), as well as infections or brain damage (such psychoses are currently usually referred to as organic mental disorders).

It is also known that chronic psychological stress causes a psychotic state, although the exact mechanism is not defined. Short-term psychoses initiated by stress are known as short reactive psychoses.

There are also non-psychiatric conditions, especially those associated with psychosis, which may include a brain tumor, dementia (dementia) with Levy bodies, hypoglycemia, intoxication, multiple sclerosis, systemic lupus erythematosus and / or sarcoidosis.

Psychosis is a common condition in schizophrenia with the typical symptoms mentioned above. In addition, people with schizophrenia often show a dull or flat emotional response. This refers to a severe decrease in emotional expressiveness (strength).

Schizophrenia is a chronic, severe and disabling brain disease found around the world. Approximately 1% of the population develops schizophrenia over a lifetime. The severity of symptoms and the prolonged chronic schizophrenia pattern often cause

- 2 015566 have a high degree of disability (helplessness). People with schizophrenia have a higher suicide rate than the whole population. About 10% of people with schizophrenia (especially younger adult males) commit suicide. The first signs of schizophrenia often appear as embarrassing (confusing) or even stunning (terrifying) changes in behavior. This sudden attack of severe psychotic symptoms is considered an acute phase of schizophrenia.

Some people have only one such psychotic episode; others have many cases during the life span, but lead a relatively normal life during interim periods. However, an individual with chronic schizophrenia, or the persistent or recurring nature of the disease, often does not restore full functioning and usually needs long-term treatment, usually including treatment to control the symptoms.

There is no known cause of schizophrenia. Many diseases, such as, for example, heart disease, are the result of the interaction of genetic, behavioral and other factors; with the same success, this could be the case with schizophrenia. It has long been known that schizophrenia is common in families. Scientists are studying genetic factors in schizophrenia. It seems likely that numerous genes are involved in creating a predisposition to the disorder. In addition, factors such as prenatal difficulties like intrauterine starvation or viral infections, perinatal complications and various non-specific stressors seem to influence schizophrenia. However, it is not yet clear how the genetic predisposition is transmitted and it cannot yet be accurately predicted whether the disorder will develop in a given person.

Basic knowledge of brain chemistry and its relationship with schizophrenia is expanding rapidly. It is likely, although not yet definitively, that the disorder is associated with some imbalance in the complex, interconnected chemical systems of the brain, possibly involving neurotransmitters dopamine and glutamate.

Numerous studies of people with schizophrenia have found abnormalities in the brain structure (e.g., an increase in fluid-filled cavities, the so-called ventricles, in the inside of the brain, and a reduced size of certain areas of the brain) or functions (e.g., decreased metabolic activity in certain areas of the brain). It should be emphasized that these deviations are quite elusive and are not a characteristic of all people with schizophrenia, and do not appear only in individuals with this disease. Microscopic studies of brain tissue after death have also shown slight changes in the distribution or number of brain cells in people with schizophrenia. It seems that many (but probably not all) of these changes exist before the individual becomes sick (before the individual development of the disease), and schizophrenia may partially be a disorder in brain development.

Available treatment can relieve many symptoms, most people with schizophrenia continue to experience some symptoms throughout their lives; it is estimated that no more than one in five people can be completely cured. Medications and other treatments for schizophrenia can help reduce and control the distressing (depleting) symptoms of the disease. However, affordable treatment does not help much to some people, and they may interrupt treatment prematurely due to unpleasant side effects. Since schizophrenia can be caused by more than one cause, and the causes that cause it are not yet known, modern treatment methods are based on both clinical research and (life) experience. These approaches are selected based on their ability to reduce the symptoms of schizophrenia and to reduce the changes in which the symptoms return.

Antipsychotic medications have been available since the mid-1950s, but they do not treat underlying illnesses such as schizophrenia, or do not guarantee that there will be no further psychotic episodes. Clinically effective antipsychotic drugs (antipsychotics) include tricyclic phenothiazines, thioxanthenes and dibenzepines, as well as butyrophenones and related compounds, other heterocyclic compounds and benzamides. Virtually all of these drugs block E ₂ dopamine receptors and reduce dopamine neurotransmission in the forebrain; some of these drugs, in particular atypical antipsychotics, also interact with Ό ₁ - and E ₄ -dopaminergic, 5-HT _2A - and 5-HT _2C- serotonergic and alpha-adrenergic receptors (Ooobtap &Oyshap'b, THe Ryagtasohelpida Ba818 , 10 ⁴ bbp, McCleaf-HN, 2001: 8thtagu £ с ар 1 1 20 20 (p. 485)). The antagonism of dopamine-mediated synaptic neurotransmission is an important action of antipsychotic drugs (same documents, p. 493, left column, ^2nd paragraph).

Since 1990, a number of new antipsychotic drugs (the so-called atypical antipsychotic drugs) have been introduced. The first of these, clozapine, has been shown to be more effective than other antipsychotics, although the likelihood of severe side effects in particular, a condition called agranulocytosis (loss of white blood cells that fight infection) requires that patients be monitored for analysis blood every one to two weeks. Even the latest antipsychotic drugs, such as risperidone and olanzapine, are more reliable than the older ones or clozapine, and can also be better tolerated. However, like clozapine, they may or may not cure the disease.

Antipsychotic medications are often more effective in treating certain symptoms.

- 3 015566 ptoms of schizophrenia, especially hallucinations and mania; Unfortunately, medications may not be useful for other symptoms, such as decreased motivation (motivation) and emotional expressiveness.

Current limitations of antipsychotic medication treatment for psychosis, especially psychosis associated with schizophrenia, include limited effectiveness, side effects, and delayed onset of action. Valproate has been shown to increase the onset of action of olanzapine or risperidone (Saksu s1 a1., No. In addition, another clinical trial, controlled by a closed placebo (double-placebo blind), showed that lamotrigine, when added to clozapine, is beneficial in the treatment of drug-resistant schizophrenia (Tyuyep s1 a1., Vyu1 Rkusyay. 54: 124111, 2003). It was determined that up to 50% of hospitalized patients with schizophrenia received additional therapy with antiepileptic drugs (Sytote L., RkusNorNagtasodu Vi11 37 (82): p7411, 2003) especially to enhance the onset of action, to control positive symptoms, for example, hallucinations, emotional symptoms, such as depression, as well as cognitive symptoms, such as attention deficit.

However, as described by Sytote L., RkusNorNagtasodu Vi11 37 (82): p7411, 2003, data on the use of anticonvulsants for adjunctive (additional, adjunct) therapy with antipsychotics are contradictory. As shown, valproate and lamotrigine predominantly reduce the positive symptoms of schizophrenia (same document, p. 86, last paragraph). As said, a possible locus of action of valproate is direct effects on the electrical voltage of the sodium inlet channels (same document, p. 78, ^2nd paragraph). However, the use of the anticonvulsant drug carbamazepine as an adjunct to the antipsychotic halogen peridol was associated with a worse clinical outcome compared to antipsychotic monotherapy (same document, p. 80, first paragraph). In another study on carbamazepine use, failure was observed in detecting a significant improvement in ASCI (brief psychiatric rating scale). The additional use of lamotrigine in addition to clozapine led to an improvement in positive rather than negative symptoms of schizophrenia (same document, p. 85, ^1st pass). Reports on the use of other anticonvulsants for schizophrenia describe a major worsening of psychosis with gabapentin or a worsening of the positive and negative symptoms of schizophrenia with topiramate (same document, p. 85, ^2nd paragraph).

The reported differences in the effectiveness of anticonvulsants as adjunctive therapy with antipsychotic drugs may be associated with their various modes of action. In contrast to antipsychotics, which have a general antagonistic effect on dopamine receptors, modern anticonvulsants are thought to work through a different mechanism of action. Such mechanisms of action are, for example, a change in the propagation of a nerve impulse through interaction with the voltage (at the input) of the sodium, calcium and potassium channels or the effect on neural transmission or the strengthening of inhibitory systems of SAVL or the inhibition of excitatory glutamate systems.

In contrast to modern anticonvulsants, lacosamide potentially has a unique, but not yet known, molecular mechanism of action. Lacosamide does not directly interact with most known subtypes of the CABA receptor, or with most known subtypes of glutamate receptors. In particular, lacosamide does not inhibit voltage-dependent sodium or calcium channels and does not enhance potassium fluxes.

In article 1app M \\ ^; , RyattasoIetaru 2004; 24 (12): 1759-1783, which deals with the cognitive symptoms of schizophrenia, describes additional therapy with antipsychotics with some other active drugs, but no reference is made to additional therapy with antipsychotic drugs for anticonvulsants.

The use of compounds of formula (IH) for the treatment of psychosis, especially schizophrenia and / or psychosis associated with schizophrenia, in the form of adjunctive (additional) therapy to at least one dopamine antagonist has not been reported. Thus, the present invention relates to the use of said compound (s) of formula (GHI) for the preparation of a pharmaceutical composition for preventing, alleviating and / or treating a disease in the treatment of an antipsychotic agent, in particular psychosis, more specifically during schizophrenia, in adjunctive therapy, at least to one dopamine antagonist.

The use of lacosamide alone (an international non-proprietary name, also formerly called charcoseride or 8PM 927) has no significant effect on prepulse inhibition in mice, which is a predictive test model for psychosis, especially for cognitive symptoms. Unexpectedly, compounds (GH), especially (K.) - 2-acetamide-L-benzyl-3-methoxypropionamide (lacosamide) caused an increase in pre-pulse inhibition by an antipsychotic drug, clozapine, when used together.

Pre-pulse inhibition in mice is a predictive value model for psychosis associated with, for example, schizophrenia, bipolar disorder, autism, Alzheimer's disease, attention deficit hyperactivity disorder, alcohol or drug abuse, emotional

- 4 015566 disorders, dyskinesia and related disorders, dementia (dementia), mental retardation, polydipsia / hyponatremia, severe personality disorders, acute cases of mania, obsessive manic disorder, intractable chronic insomnia, Huntington's disease, or Parietin's syndrome, or Turin’s syndrome dopaminergic therapy of Parkinson's disease.

Considering the previous level, as described above, in particular the many modes of action of anticonvulsants, conflicting results in adjunctive therapy of anticonvulsants and antipsychotic drugs, differences in the mode of action of valproate, only anticonvulsant with established utility in adjunctive therapy with antipsychotics compared to lacosamide, and lack of mention in the article on complementary therapy of cognitive symptoms of schizophrenia (1api Μ \ ν, see above), specialist in yes hydrochloric art should not expect lacosamide usefulness in psychotic treatment therapy as an additive at least one of neuroleptics.

Broadly, the term antipsychotic substance or antipsychotic agent refers to any compound known in the art for the prevention, alleviation, or treatment of psychosis, including but not limited to: (-) - isofloxitepine, (+ -) - idazoxane monohydrochloride, (+) - isofloxitepine , 1,2-benzisoxazole-3-methanesulfonamide, monosodium salt, 1H-isoindole, 3 (2H) -dione, 2- [4- [4- (1,2-benzisothiazole-3-yl) -1-piperazinyl] drilled ] hexahydro-, monohydrochloride, (3aK, 7a8) -rel-, 2 (1H) -quinolinone, 1- [3- [4- (chlorophenyl) -1-piperazinyl] propyl] -3,4-dihydro-5-methoxy (ODP 14 523), 2-propen-1-one, 1- (2-fluorophenyl) -3- (4-hydrophenyl) -O- [2- (dimethylamino) ethyl] oxime, (1Ζ2Ε) -, (2E) -2-bougenodioate ( 2: 1), 9H-xanthene-9-propanoic acid, a-amino-a - [(18.28] -2carboxycyclopropyl] -m (a8) (LU 341495), abaperidone, acetophenazine, aminosultopride, amisulpride, ampalex, aplindora fumarate, aripiprazole, asenapine maleate, benperidol, benzinamide, beta-uridine, bromperidol, buramate, butaperazine, carbadipimidine, carbamazepine, carfenazine, carpipramine, carpipramine dihydrochloride, chloropentinazinpromin, chloropinazinpropinolum, chloropinazinprominol, chloropinazinpropinazole, chloropinazinpropinazole -klopentiksol, cis-tramadol hydrochloride, citalopram hydrobromide, klorapramin, klorapramina dihydrochloride klomakran, klopentiksol, klospirazin, clotiapine, clozapine, tsiamemazin, devazepin, divalproex Sodium, diksirazin, droperidol, duloxetine hydrochloride, etilloflazepat, farampator, fluanizon, fluoxetine hydrochloride, flyupentiksol , flupenazine, flupenazine decanoate, flupenazine enanthate, flupenazine hydrochloride, fluspirylene, flutoprazepam, fluvoxamine, fluvoxamine maleate, halogenperidol, halogenperidol and halogenperidol decanoate, iloperidone, isofloxitepine, lamotrigine, loxapine succinate, lurasidone hydrochloride, melperon, meperon hydrochloride, mepazin, mesoridazine, mesoridazine besilate, methoxypromazine, metophenazate, mifinolidminolindminolindminolindminolindolindin , nemonapride, okaperidone, octoclotepine, olanzapine, opipramol, paroxetine, penfluuridol, perazin, peritsiazin, perimetazin, perospiron, perphenazine, phenothiazines, pimozide, piperacitazine, pipotiazine, pipotia ina palmeate, pipothiazine, pramipexole, prochlorperazine, promazine, protipendil, quetiapine, quetiapine fumarate, racemic idazoxane, remoxypride, risperidone, subcommeline, secretin, sertraline hydrochloride, spiperone, sulforididazinitropinazidetrazidazinitrazidazinitrazidazinitrazidazinitrazidazinitrazidazinitrazidazinotripidazinitrapinaziditropintrazidazinitropinaziditrapintrazidazinitropinaziditropintrazidazinitropinaziditropinaziditropinaziditrapin , thioridazine, thioridazine hydrochloride, thiotixen, thiotixen hydrochloride, thioxanthenes, thimeperon, topiramate, trifluopreazine, trifluoperazin hydrochloride, trifluperidol, triflupromazine, zaprazidone, zaprazidone hydrochloride, zonides , zotepine, zuclopentixol acetate, zuclopentixol decanoate, enantiomers, racemates, pharmaceutically acceptable salts, esters, amides, prodrugs and their metabolites.

More specifically, the term antipsychotic or antipsychotic, as used herein, includes classical or so-called typical antipsychotic drugs, also called classical or typical antipsychotics, as well as atypical antipsychotic drugs, also called atypical antipsychotics. Examples of classic antipsychotics are acetophenazine, Benperidol, benzquinamide, biriperon, bromoperidol, butaperazin, butyrophenones, karfenazin, tsentbutindol, chlorpromazine, chlorpromazine hydrochloride, chlorprothixene, klomakran, klopentiksol, clotiapine, tsiamemazin, CR gas, digidroindolony, diksirazin, droperidol, flyuanizon, flyupentiksol , flufenazine, flufenazine decanoate, flufenazine enanthate, flufenazine hydrochloride, halogenperidol, halogenperidol decanoate, isofloxitepine, levomepromazine, loxapine su ccinate, melperone, melperone hydrochloride, mepazine, mesoridazine, mesoridazine bezilate, metotrimeprazine, methoxypromazine, metophenazate, molindone, molindone hydrochloride, moperon, neboglamine, nemonapride, perinopinazinazinazinazinazinazinazin, perinazinazinazinazinazinazinazinazin palmitate, prochlorperazine, promazin, protipendil, spiperone, sulforidazine, sultopride, talnetant, thiapride, thiopropazate, thioproperazine, thioridazine, thioridazine hydrochloride, thiotixene, thiotixene hydrochloride, thioxanthene, three fluoperazine, trifluoperazine hydrochloride, trifluperidol, triflupromazine, zuclopentixol acetate, zuclopentixol decanoate and enantiomers, racemates, pharmaceutically acceptable salts and derivatives thereof, especially esters, amides, prodrugs and their metabolites. Examples of atypical antipsi

- 5 015566 topical drugs are abaperidone, aminosultoprid, amisulpride, ampalex, aripiprazole, asenapine maleate, clozapine, fluspirylene, iloperidone, mozapramine, mozapramine dihydrochloride, okaperidinperinpiperitonepperitoneperinone, peperipinperitonepiperone, pereperinone, pereperinone, pereperinone, pereperinone, pereperinone, pereperinone , sertindole, sulpiride, ziprasidone, ziprosidone hydrochloride, zotepine, and enantiomers, racemates, pharmaceutically acceptable salts and derivatives, especially esters, amides, drugs and their metabolites. The term antipsychotic then includes dopamine antagonists, preferably Ό ₂ antagonists.

The term antipsychotic or antipsychotic when used here preferably does not include substances that are not antipsychotic as defined above, although they can also be used in the treatment of psychosis, such as, for example, anticonvulsants (such as carbamazepine, valproate, lamotrigine), antidepressants, such as tri- and tetracyclic antidepressants (e.g. amitriptyline, clomipramine, doxepin, imipramine, trimipramine, nortriptyline, desipramine, maprotiline, trazodone), selective re inhibitors absorption (reverse absorption) of serotonin (e.g. citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), selective norepinephrine reuptake inhibitors (e.g. reboxetine), serotonin norepinephrine reuptake inhibitors (e.g. venlafaxine, duloxetine), serotoninderenine, mirtazapine) or monoamine oxidase inhibitors (e.g. tranylcypromine, moclobemide), lithium salts or benzodiazepines (e.g. alprazolam, lorazepam, diazepam).

Doses of typical dopamine antagonists that can be used in this invention are:

Compounds used in psychosis [CA8 KeG.] Mechanism of action Approximate dose Link Amisulpride [71675- 85-91] Dopamine antagonist ϋ2 / ϋ3 200-1200 mg / day 11HP: //ep.myk1re41a.og§/ tk1 / Apizi1rp <1е Aripiprazole [129722-12-9] Partial Dopamine Antagonist Ό2 Recommended Initial and the target dose is 10 or 15 mg / day, administered by scheduled once a day without taking attention to food. Y1p: // \ ut ™ .11ea1111ur1ase.sop1 / Sottipytez / Ptoschfy ΟίΐοηΙίΤϊ.ΑϋΙιίζο / ιη еЛсаИ op s / at1р1раго1.азр £ ЕОО8 АСЕ Biriperone 142021-34-11 Dopamine antagonist 3-4.5 mg / day po

Compounds used for psychosis [SAZ Kek] Mechanism of action Approximate dose Link Bromperidol [10457- 90-6] Dopamine antagonist G) 2 3-18 mg / day 1i1r: /. 'S11gst. 111Sh1z.s (ac.) P / ΒΝΝΟ / ϋΚυΟϋΑΤΑ / 46Gotregk1o1.111t1 Carpipramine [5942-95-0; 7075-03- 81 Dopamine antagonist 02 Clocapramia [28058- 62-0; 47739-98-0] Serotonin antagonist; aimed at dopamine Ό2 receptor 30-150 mg / day Lp: //s11gop1LiNp8,1i1.as.] P / ΠΚΝΟ / ΟΚΟΟΟΑίΑ · '57c1osartattte.N1t1 Clorothepine [13448-22-1] Dopamine antagonist Clozapine [5786-21-0] Dopamine antagonist Reaches the target dose of 300-450 mg / day by the end of 2 weeks. Adults - Initially, 12.5 mg once or daa once a day. However, the dose is usually is not more than 900 mg per day. People's Republic of China: // \ ™ msgh1181. sogp / s £ 1 / 2spsg1s3 / s1o7.ar1ps1 <1k. 111t 1Wr: / 'Ulta.p! T. ηίΐι. §Ον / teiiper1iv / <1g§t1o / i8rb1 / 2O2157.Yt1 Isofpoxitepine [106819-39-0; 106819- Dopamine antagonist 5 mg / kg orally P5us1yur11appasoduod (Vep.) 1982; 76 (4): 381-4.

- 6 015566

41-4; 70931-18-91 Melperon [1622-79-3; 3575-80- 2] Dopamine antagonist ϋ2 300 mg / day Squeeze: SsGorkorkesh KeesagesI 62 (2): 65 Mozapramine [89419-40-9; 98043- 60-8] Dopamine antagonist Ό2 6.25-25 mg / day Nemonapride [75272-39-8] Dopamine antagonist 1) 2/1) 3 9-36 mg / day Olanzapine [132539-06-11 Dopamine antagonist Ό2 10 mg / day Bpr'lal ’. t / <1g £ / p30-o02.11PT | 1 Penfluridol [26864-56-2] Dopamine antagonist (1) 1 and 02) 60-80 mg once a day a week 1. SKP. Paganto!., Arp1 1.1977: 17 (4): 252-258. Perospiron [129273- 38-7; 150915-41-6] Dopamine antagonist Ό2 8-48 mg / day Pimozide [2062-78-4] Dopamine antagonist 02 The average maintenance dose is 6 mg daily with the usual limit of 2 to 12 mg per day. LKr: / Lute.t1kot.sot/ pbatzapzzep / ogar-syrp!

Compounds used in psychosis (CA8 B. e £] Mechanism of action Approximate dose Link Pipothiazine palmitate [37517-26-3; 39860- 99-6] Dopamine antagonist; aimed at dopamine receptor ϋ2 It should be administered ONLY by intramuscular injection; it is often possible to achieve adequate control at a dose between 75 and 150 mg administered every 4 weeks Yyr: / L ¥ \ chlu.tep1aSheaSh1.so t / ygid / pZO-ROS.b (t1 # NeaF8 Quetiapine Fumarate [111974-69-7; 11197472-2] Dopamine antagonist Ό2 varies υηϊϊегзз ίίί1Ьег111 \ \ \ \Ь11апапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапапап; ;апапапапапапап;;;;; ;апапапап; Ιιίίρ 7 / λνννΛν.Γχ 1181.sot / s§1 / aepeps2 / die11ar 1yz b1t # О Risperidone [106266- 06-2] Dopamine antagonist Ό2 6 mg / day Lir. 7 / a] p. Oh y / ss / herppu! 5ΊΠΙΧ 178 ~ a Rlzregba! Sozz (a: 25-75 mg / day intramuscularly K1zreg <1a1 1pzgazo1u: average modal dose 4.1 mg / day People's Republic of China: // Chiu \ ¥. Гх1181. hundred / s§1 / §Epeps / pzrep <1 Wed 1111t # CP

- 7 015566

(Sulpiride [15676-16-1] Dopamine antagonist Ώ2 600-800 mg / day intramuscularly; or 200-3200 mg / day in 2 or 3 separate doses, orally 11Hp. 7Al \ l ^ -. Tstag11ea1 (! 1.so ηι / άιυ§ / ρ30-506.1ιίηι! Sulopride [53583-79-21 Dopamine P2 antagonist Tiapride [51012-32-9] Dopamine antagonist ϋ2 The usual final dose is 200-300 mg / day, for 1 to 2 months 11 Ex 7 / t ™. Sp1v <1ep1o.sot / KX / KHO15r1au.azrh? ϋ = KX22030204 & dz8es6op = 5 Timiperon [57648-21-2] Dopamine antagonist 02 4-8 mg / day Ziprasidone [122883- 93-6; 146939-27-71 Dopamine antagonist Ό2 varies Lyr: / L ™ \ ¥. £ ео (1op.sot / ysryot.azr Zotepin [26615-21-41 Dopamine antagonist 75-300 mg / day ΗΐΙρ: // \ ν \ ν \ ν.ιιΚΚηη.ιιΙΐ3Λ6 </ ΝβΛνΜηίβΐ'ί a1 / Yt 1 / s1osa / ζοίερϊηβ.ράΓ Zuclopentixol [53772-83-1; 982-241] Dopamine antagonist Ό2 The usual therapeutic interval is 20-60 mg / day. Bir: /L*tome.ep1a111ea1y1.so t / UgikrZO-g03.1yt1 # Neas1 8 Zuclopentixol Acetate [85721-05-7] Dopamine antagonist 02 50-150 mg intramuscularly, repeating with need every 2 to 3 days; maximum cumulative dose should not exceed 400 mg and the number of injections should not exceed 4 6Ηρ: / Λν \ ν «·· .ν6ρ1ιηητΐ5ΐτ. sot / ROTM / Mopoagarks / ζυε1ορβηΰιίχο1% 20ase! а (е.11! т

Compounds used in psychosis [SAZ Ke! '. | Mechanism of action Approximate dose Link Zuclopentixol Decanoate [64053-00-5] Dopamine antagonist ϋ2 The minimum effective dose of zuclopentixol was 200 mg / 2 weeks (range 60-400), with a serum concentration of 22 nmol / L (7.1-69.7). Riaptasorsus gaogu 1994 Mau; 27 (3): 119-123

In a particularly preferred embodiment, the present invention relates to a specific combination of lacosamide with at least one dopamine antagonist, which may be at least one Ό ₂ antagonist, even more specifically with at least one atypical antipsychotic, such as at least one antipsychotic an agent as defined above, most preferably clozapine, risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, sulpiride, amisulpiride and / or zotepine.

The adjunctive therapy of the present invention for preventing, alleviating and / or treating a disease that is treated with an antipsychotic agent, in particular psychosis, more specifically schizophrenia and / or psychosis associated with schizophrenia, is the joint administration of at least one compound of formula (11b) of at least with one dopamine antagonist suitable for preventing, alleviating and / or treating psychosis, especially schizophrenia, to increase effectiveness, reduce side effects and / or increase the onset of action antipsychotic treatment, for example.

The term co-administration refers to numerous agents that, when administered to a subject, together or separately, are co-active in providing therapeutic benefit

- 8 015566 Threat to the subject. Such co-administration also refers to the terms combination therapy, co-therapy, adjuvant therapy or adjunctive therapy. For example, one agent can potentiate or enhance the therapeutic effect of another, or reduce the adverse side effect of another, or one or more agents can be effectively used at a lower dose than when it is used alone, or can provide greater therapeutic benefits than when using one , or may further focus on various aspects, symptoms or etiological factors of the disease or condition.

Co-administration includes the administration of an amount in an amount sufficient to achieve or / and maintain a therapeutically effective concentration, i.e. plasma concentrations in a subject in need of this. Co-administration includes simultaneous or sequential administration. Simultaneous administration includes the administration of an agent as one or different compositions (see below) at the same time within the treatment period. Sequential administration includes the introduction of funds at intervals throughout the treatment period.

Administration at the same time includes the administration of at least one dopamine antagonist suitable for the prevention, relief, and / or treatment of psychosis, and the compound (s) of formula (11b) literally at the same time, but also includes the use of directly one after another.

Interval administration includes administering at least one dopamine antagonist suitable for preventing, alleviating, and / or treating psychosis, and the compound (s) of formula (11b) with a longest interval of 1 hour, preferably a longest interval of 6 hours, more preferably with the largest interval of 12 hours and most preferably with the largest interval of 1 month.

At least one dopamine antagonist suitable for the prevention, amelioration, and / or treatment of psychosis, and at least one compound of formula (11b) can be formulated into one pharmaceutical preparation (unit dosage form) for administration at the same time, or may be formulated in two separate formulations (separate dosage form) for administration at the same time or at intervals, as described in the preferred embodiment below for example. Two different drugs in separate dosage forms can be administered in the same way or in different ways.

Separate dosage forms may optionally be jointly packaged, for example, in a single container or in multiple containers with a single outer packaging, or jointly provided in separate packages (general provision). As an example of co-packaging or co-provision, a kit is provided comprising in different containers at least one dopamine antagonist and at least one compound of formula (11b). In another example, at least one dopamine antagonist and at least one compound of formula (11b) are separately packaged and may be sold separately from one another, but are co-marketed or advertised together for use according to the invention. Separate dosage forms may also be provided to a subject separately and independently for use in accordance with the invention.

Depending on the dosage forms, which may be identical or different, for example, fast-release dosage forms, controlled-release dosage forms and / or depot forms of at least one dopamine antagonist suitable for the prevention, relief or treatment of psychosis, and the compound (i ) formulas (11b) can be applied at the same time or in different modes based on a schedule (schedule) for a day, week or month. Therefore, the range of use of at least one dopamine antagonist suitable for preventing, alleviating, or treating psychosis and the compound (s) of formula (11b) may depend on the modes of administration or dosage forms.

In a preferred embodiment, the compounds of formula (11b) are suitable for the preparation of a pharmaceutical composition comprising (a) at least one dopamine antagonist suitable for preventing, alleviating or treating psychosis; and (b) at least one compound of formula (11b).

In the application of the present invention, at least one dopamine antagonist suitable for preventing, alleviating or treating psychosis may preferably be a Ό ₂ antagonist, more preferably an atypical antipsychotic agent, even more preferably an atypical antipsychotic agent, as described above, and most preferably the drug is clozapine, risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, sulpiride, amisulpiride and / or zotepine.

In another preferred embodiment, the compounds of formula (11b) are used to prepare a pharmaceutical composition comprising a single dosage form containing at least one compound according to formula (11b) and at least one dopamine antagonist suitable for preventing, alleviating and / or treatment of psychosis, in a single composition.

In another preferred embodiment, the compounds of formula (11b) are used to prepare

- 9 015566 pharmaceutical composition, which in separate dosage forms includes (ί) the first composition containing at least one dopamine antagonist, suitable for the prevention, relief or / and treatment of psychosis, and (ίί) the second composition containing at least at least one compound of formula (Pb).

In yet another preferred embodiment of the present invention, a commercially available dopamine antagonist composition suitable for preventing, alleviating, and / or treating psychosis can be administered to a subject in need thereof. Therefore, in this preferred embodiment, the compounds of formula (PI) are suitable for the preparation of a pharmaceutical composition containing at least one compound according to formula (PI) and not containing a dopamine antagonist suitable for preventing, alleviating, and / or treating psychosis.

Use according to the present invention may include the preparation of a pharmaceutical composition for the administration of at least one compound of formula (PI) and at least one dopamine antagonist suitable for preventing, alleviating and / or treating psychosis at the same time or at intervals as defined above.

The compound according to the invention has the general formula (PI)

N NN

I I I

Ag-SNg-M-S-O-N-S-K!

Ιί I II about

Formula (Hb) in which

Ag is phenyl which is unsubstituted or substituted by at least one halogen group;

B ₃ is CH _; -R. where β is alkoxy containing 1-6 carbon atoms; and

IN! is alkyl containing 1-6 carbon atoms.

In particular, B ₁ is methyl.

The present invention also relates to a pharmaceutical composition comprising at least one compound according to formula (11b), suitable for preventing, alleviating and / or treating a disease that can be treated with a dopamine antagonist, in particular psychosis, in adjunctive therapy for at least one antagonist dopamine.

In a preferred embodiment, the pharmaceutical composition comprises (a) at least one dopamine antagonist suitable for the prevention, amelioration and / or treatment of psychosis, and (b) at least one compound of formula (11b).

In the pharmaceutical composition of the present invention, at least one dopamine antagonist suitable for preventing, alleviating or treating psychosis can be preferably a Ό ₂ antagonist, more preferably an atypical antipsychotic agent, even more preferably an atypical antipsychotic agent as described above, and most preferably the agent is clozapine, risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, sulpiride, amisulpiride and / or zotepine,

In another preferred embodiment, the pharmaceutical composition of the present invention contains a single dosage form comprising at least one compound according to formula (PI) and at least one dopamine antagonist suitable for the prevention, amelioration and / or treatment of psychosis, in a single composition.

In another preferred embodiment, the pharmaceutical composition of the present invention comprises separate dosage forms comprising (ί) a first composition containing at least one dopamine antagonist suitable for preventing, alleviating, and / or treating psychosis, and (s) a second composition containing at least one compound of the formula (11b).

In yet another preferred embodiment of the present invention, a commercially available dopamine antagonist composition suitable for preventing, alleviating, and / or treating psychosis can be administered to a subject in need thereof. Therefore, in a preferred embodiment, the pharmaceutical composition of the present invention contains at least one compound according to formula (PI) and does not contain a dopamine antagonist suitable for the prevention, amelioration and / or treatment of psychosis.

The pharmaceutical composition of the present invention can be prepared for the administration of at least one compound of formula (PI) and at least one dopamine antagonist suitable for preventing, alleviating and / or treating psychosis at the same time or at intervals as defined above.

The term alkyl (alone or in combination with another term (s)) means a saturated carbohydrate

- 10 015566 native substituent with a straight chain or branched chain, preferably containing from 1 to about 20 carbon atoms, more preferably from 1 to about 8 carbon atoms and even more preferably from 1 to about 6 carbon atoms.

Most preferably, alkyl is lower alkyl, as defined below.

Lower alkyl groups when used alone or in combination with other groups are lower alkyls containing from 1 to 6 carbon atoms, especially from 1 to 3 carbon atoms, and may be branched or unbranched. 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 a substituent alkyl ether, i.e. -O-alkyl.

Lower alkoxy groups are lower alkoxy containing from 1 to 6 carbon atoms, especially from 1 to 3 carbon atoms, and may be branched or unbranched. These groups include methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy and the like.

The term halogen includes fluoro, chloro, bromo and iodo.

The most preferred compounds used are compounds of formula (PI):

wherein

Ag is phenyl which is unsubstituted or substituted by at least one halogen group,

Κι is alkyl, especially containing 1-3 carbon atoms; and

K ₃ is CH ₂ -f, in which O is alkoxy, for example lower alkoxy, especially containing 1-3 carbon atoms.

Most preferably, Κι is CH ₃ . Most preferably, K ₃ is CH ₂ -f, in which O is methoxy.

The most preferred halogen is fluorine.

Most preferred compounds include (K) -2-acetamido-Y-benzyl-3-methoxypropionamide; (K) -2-acetamido-l-benzyl-3-ethoxypropionamide;

O-methyl-Y-acetyl-E-serine-m-fluorobenzylamide; O-methyl-Y-acetyl-E-serine-p-fluorobenzylamide.

It should be understood that the various combinations and permutations of the Markush groups Ag, Κι and K ₃ described herein are considered within the scope of the present invention. In addition, the present invention also encompasses compounds and compositions that contain one or more elements of each Markush group in Ag, Κι and K _3, and various combinations thereof. Thus, for example, the present invention contemplates that K ₁ may be one or more of the substituents listed above, in combination with any or all of the substituents Ar and K ₃ .

The compounds used in the present invention may contain one or more asymmetric carbons and may exist in racemic and optically active form. The configuration around each asymmetric carbon can be either Ό or L shape. It is well known in the art that the configuration around a chiral carbon atom can also be described as K or 8 in the Kahn-Prelog-Ingold nomenclature system. All of the various configurations around each asymmetric carbon, including various enantiomers and diastereomers, as well as racemic mixtures and mixtures of enantiomers, diastereomers, or both, are contemplated by the present invention.

Asymmetry exists in the main chain at the carbon atom, to which the K ₃ and N groups are attached.

As used herein, the term “configuration” will refer to a configuration around a carbon atom to which K ₃ and H are attached, even though there are other chiral centers that may be present in the molecule. Therefore, referring to a separate configuration, such as Ό or b, it should be understood that this means the Ό or b stereoisomer at the carbon atom to which K ₃ and H are attached. However, this also includes all possible enantiomers and diastereomers at other chiral centers present in conjunction, if any.

The compounds of the present invention are directed to all optical isomers, i.e., the compounds of the present invention are either the L-stereoisomer or the L-stereoisomer (at the carbon atom to which K ₃ and H are attached). These stereoisomers can be created in a mixture of b and Ό stereoisomers, for example, a racemic mixture. The preferred is the. Stereoisomer. Lacosamide Ό Stereo

- 11 015566 the isomer corresponds to the K enantiomer in accordance with K, 8 terminology.

Compounds of formula (11b), in particular lacosamide, can be substantially enantiomerically pure. As used herein, the term “substantially enantiomeric” means an enantiomeric purity of at least 88%, more preferably at least 90%, most preferably at least 95, 96, 97, 98, or 99%.

Depending on the substituents, the present compounds may also form additional salts. All of these forms are contemplated within the scope of this invention, including mixtures of stereoisomeric forms.

The manufacture of the compounds used is described in US patent No. 5378729 and 5773475, the contents of which are incorporated by reference.

The compounds used in the present invention are suitable as such as depicted in formula (11b) or can be used as salts due to their basic nature from the presence of a free amino group. Thus, the compounds of formula (11b) form salts with a wide variety of acids, inorganic and organic, including pharmaceutically acceptable acids. Salts with pharmaceutically acceptable acids are, of course, suitable for the preparation of formulas in which increased aqueous solubility is most advantageous.

These pharmaceutically acceptable salts also have therapeutic efficacy. These salts include salts of inorganic acids, such as hydrochloric, iodide, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric, as well as organic acids, such as tartaric, acetic, citric, malic, benzoic, perchloric, glycolic, gluconic, succinic, aryls (e.g. p-toluenesulfonic acid, benzenesulfonic acid), phosphoric, malonic and the like.

The present invention further relates to a method for preventing, alleviating and / or treating a disease that is treated with an antipsychotic agent, especially psychosis, more particularly schizophrenia, in adjunctive therapy to at least one dopamine antagonist by administering at least one compound of formula (11b) to a subject, in need of it.

In a preferred embodiment, the method of the present invention comprises (a) administering at least one dopamine antagonist suitable for preventing, alleviating, and / or treating psychosis, and (b) administering at least one compound of formula (11b) in adjunctive therapy in addition to at least at least one dopamine antagonist (a), a subject in need thereof.

In the method of the present invention, at least one dopamine antagonist suitable for preventing, alleviating, and / or treating psychosis can be preferably a Ό ₂ antagonist, more preferably an atypical antipsychotic agent, even more preferably an atypical antipsychotic agent, as described above, and most preferably the agent is clozapine, risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone, sulpiride, amisulpiride and / or zotepine.

It is further preferred that at least one compound of formula (11b) and at least one dopamine antagonist suitable for preventing, alleviating, and / or treating psychosis are administered in a single composition (unit dosage form).

In another preferred embodiment, the method of the present invention comprises administering separate dosage forms comprising (ί) a first composition containing at least one dopamine antagonist suitable for preventing, alleviating, and / or treating psychosis, and (ίί) a second composition comprising at least one compound of formula (11b), to a subject in need thereof.

In yet another preferred embodiment of the present invention, a commercially available dopamine antagonist composition suitable for preventing, alleviating, and / or treating psychosis can be administered to a subject in need thereof. Therefore, in this preferred embodiment, the method of the present invention for preventing, alleviating, and / or treating a disease treated with a dopamine antagonist, especially psychosis, comprises administering a pharmaceutical composition comprising at least one compound according to formula (11b) and not containing a dopamine antagonist, suitable for preventing, alleviating and / or treating psychosis, a subject receiving a commercially available composition comprising a dopamine antagonist for preventing, alleviating, and / or treating psychosis for.

Compounds of formula (PI) may also be useful in adjunctive treatment of disorders and / or diseases other than schizophrenia that are treated with dopamine antagonists. Therefore, another subject of the present invention is adjunctive therapy for the prevention, alleviation and / or treatment of bipolar disorders, autism, psychosis in diseases other than schizophrenia, for example, in Alzheimer's disease and / or attention deficit hyperactivity disorder, by administering the pharmaceutical composition of the present invention. The compounds of formula (11b) can also be used to prepare a pharmaceutical composition suitable for prevention, easier

- 12 015566 treatment and / or treatment in the additional treatment of disorders and / or diseases other than schizophrenia, which can be treated with dopamine antagonists, such as bipolar disorders, autism, psychosis in other diseases other than schizophrenia, for example, with Alzheimer's disease and / and attention deficit hyperactivity disorder. The pharmaceutical composition of the present invention, as described above, for the treatment of schizophrenia can also be used to prevent, alleviate and / or treat, in adjunctive therapy, disorders and / or diseases other than schizophrenia that can be treated with dopamine antagonists such as bipolar disorder, autism, psychosis in diseases other than schizophrenia, for example, with Alzheimer's disease and / or attention deficit hyperactivity disorder.

Compounds of formula (IH) may also be useful in adjunctive therapy to at least one dopamine antagonist for the treatment of psychosis other than psychosis in schizophrenia. Therefore, another subject of the present invention is adjunctive therapy to at least one dopamine antagonist to prevent, alleviate and / or treat psychosis associated with, for example, bipolar disorder, autism, Alzheimer's disease, attention deficit hyperactivity disorder, alcohol or drug abuse, emotional disorders, dyskinesia and related disorders, dementia (dementia), mental retardation, polydipsia / hyponatremia, severe personality disorders, acute common cases of mania, obsessive manic disorder, intractable chronic insomnia, Huntington's disease, Tourette’s syndrome, Parkinson’s disease, the introduction of the pharmaceutical composition of the present invention. The compounds of formula (11b) can also be used to prepare a pharmaceutical composition suitable for the prevention, amelioration and / or treatment in adjunctive therapy with at least one dopamine antagonist for the treatment of psychosis associated, for example, with bipolar disorder, autism, Alzheimer's disease, attention deficit hyperactivity disorder, alcohol or drug abuse, emotional disorders, dyskinesia and related disorders, dementia (dementia), mental retardation, polydip with / hyponatremia, severe personality disorders, acute cases of mania, obsessive manic disorder, intractable chronic insomnia, Huntington's disease, Tourette’s syndrome, Parkinson’s disease and / or dopaminergic therapy for Parkinson’s disease.

The pharmaceutical composition of the present invention, as described above, can also be used to prevent, alleviate, and / or treat adjunctive psychosis associated with, for example, bipolar disorder, autism, Alzheimer's disease, attention deficit hyperactivity disorder, alcohol or drug abuse, emotional disorders, dyskinesia and related disorders, dementia (dementia), mental retardation, polydipsia / hyponatremia, severe personality disorders, acute cases and mania, obsessive manic disorder, intractable chronic insomnia, Huntington's disease, Tourette’s syndrome, Parkinson’s disease and / or dopaminergic therapy for Parkinson’s disease.

Preferably, the compounds used in the present invention are used in pharmaceutically effective amounts.

The most appropriate and varying dose of these therapeutic agents will be determined by the doctor, depending on the type of application and the particular drug chosen, and in addition, the dose will vary depending on the patient being treated, the age of the patient, the type of disorder being treated. As a rule, the doctor prefers to start treatment with small doses significantly lower than the optimal dose of the compound, and increase the dose with small increases (increments) until the optimal result is achieved under the given circumstances. When the composition is administered orally, a larger amount of active agent will be required to obtain the same effect as when applying a smaller amount administered parenterally. The compounds are used in the same manner as similar therapeutic agents, and dose levels are of the same order of magnitude as other commonly used therapeutic agents.

Typical doses of dopamine antagonists administered to a subject in need of them in adjunctive therapy to at least one dopamine antagonist according to the present invention are doses of dopamine antagonists, as given above, or the following doses: 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, amisulpiride 50-1200 mg / day, zotepine 75-450 mg / day. Such doses may also be included in the pharmaceutical composition of the present invention and / or can be used to prepare the pharmaceutical composition of the present invention.

The method of administration of at least one agent for the prevention, relief, and / or treatment of psychosis is determined by the doctor, the method may be the same or different from the method of administration of at least one compound of the present invention of formula (11b). Typical routes of administration of at least one dopamine antagonist suitable for the prevention, relief, and / or treatment of psychosis are via the oral, intravenous, intramuscular, intrathecal, or subcutaneous routes. Oral and / or intravenous is preferred.

- 13 015566

In a preferred embodiment, the compounds of formula (11b) of the present invention are administered in an amount ranging from about 1 mg to about 10 mg per kilogram of body weight per day. To ensure an optimal therapeutic response, this dose regimen can be set by a doctor. Patients in need thereof may be treated with doses of a compound of the present invention of 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, and most preferably at least 400 mg / day. In most cases, a patient in need of this can be treated with doses of a maximum of 6 g / day, more preferably a maximum of 1 g / day, and most preferably a maximum of 600 mg / day. In some cases, however, higher or lower doses may be necessary.

In another preferred embodiment, the daily doses are increased until a predetermined daily dose is reached, which is maintained for further treatment.

In another preferred embodiment, several divided doses may be administered daily. For example, you can enter three doses per day, preferably two doses per day. More preferred is a single dose per day.

In another preferred embodiment, the amount of the compounds of the present invention can be administered, which will result in a plasma concentration of from 0.1 to 15 μg / ml (minimum) and from 5 to 18.5 μg / ml (maximum (peak)), calculated as the average of many processed subjects.

The compounds of Formula (11b) can be administered in a suitable manner, such as, for example, orally, intravenously (when soluble in water), intramuscularly, intrathecally or subcutaneously. Oral and / or intravenous administration is preferred.

The pharmaceutical composition of the present invention can be prepared for treatment regimens, as described above, especially for doses, as described above, to obtain plasma concentrations as described above, for periods of administration and / or routes of administration, as precisely defined (prescribed) in implementations of the present invention as described above.

The pharmaceutical compositions of the present invention, containing at least one dopamine antagonist for the prevention, relief, and / or treatment of psychosis, especially schizophrenia, are formulated with conventional carriers, diluents, and / or excipients known to those skilled in the art. In the case of separate dosage forms, the first composition containing at least one dopamine antagonist suitable for the prevention, alleviation and / or treatment of psychosis, and the second composition containing at least one compound of formula (11b) may contain carriers, diluents and / or excipients that are independent of each other, identical or different in the first composition containing at least one dopamine antagonist, suitable for the prevention, alleviation and / or treatment of psychosis, and in the WTO a swarm composition containing at least one compound of formula (11b).

The compounds of Formula (11b) may be administered orally, for example, with an inert diluent or with an assimilable, edible carrier, or they may be enclosed in hard or soft gelatin capsules, or they may be compressed into tablets, or they may be administered directly in food or diet. For oral therapeutic use, the active compound of formula (11b) can be mixed with an excipient and used in the form of absorbable tablets, buccal tablets, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions and preparations should contain at least 1% of the active compound of formula (11b). The percentage of compositions and preparations may, of course, vary and may suitably be from about 5 to about 80% of the unit weight. The amount of active compound of formula (11b) in such therapeutically useful compositions is such that appropriate doses are obtained.

Preferably, the compositions or preparations of the present invention contain about 10 mg to 6 g of the active compound of formula (11b).

Tablets, beads, pills, capsules and the like may also contain the following: a binder, such as tragacanth gum, gum arabic, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant (lubricant) such as magnesium stearate; and a sweetener such as sucrose, lactose or saccharin can be added or a flavoring agent such as peppermint (peppermint oil), gaulteria oil or cherry flavor. If the unit dosage form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier.

Various other materials may be present as coating or also modifying the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain an active compound, sucrose as a sweetener, methyl and propyl parabens as preservatives, a colorant and a flavoring agent (flavoring) such as cherry or orange. Of course, any material used in the preparation of any kind of dosage unit should be pharmaceutically pure and substantially non-toxic in the amounts used. In addition, the asset

The 14015566 compound may be included in the sustained release formulations and formulas (recipes). For example, sustained release dosage forms are contemplated in which the active ingredient is bound to an ion exchange resin, which optionally may be coated with a diffusion inhibiting layer in order to modify the release properties of the resin.

The active compound can also be administered parenterally or intraperitoneally (intraperitoneally). Dispersions in glycerol, liquid (water), polyethylene glycol and mixtures thereof and in oil can also be prepared. Under normal conditions of storage and use, the data may contain preservatives to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions (if water soluble) or dispersions and sterile powders for the preparation of injectable solutions or dispersions for immediate use. In all cases, the forms must be sterile and liquid in the sense that they are easy to administer. They must be stable under conditions of production and storage and protected from contamination by microorganisms such as bacteria and fungi. The carrier must be solvent or dispersion medium, for example, water, ethanol, high molecular weight alcohol (for example, glycerin, propylene glycol and liquid propylene glycol, and the like), suitable mixtures thereof and vegetable oils. The proper liquid state (fluidity) can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersion, and by using surfactants (surfactants). Prevention of the action of microorganisms can be provided by various antibacterial and antifungal drugs, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of injectable (injectable) compositions can be achieved by the use of absorption delaying agents, for example aluminum monostearate and gelatin, in the composition.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount into a suitable solvent with various other ingredients listed above, as required, followed by sterilization by filtration. Typically, dispersions are prepared by incorporating various sterile active ingredients into a sterile carrier that contains a basic dispersion medium and other necessary ingredients from those mentioned above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is vacuum drying by lyophilization plus any additional necessary ingredient from a previously sterile filtered solution thereof.

As used herein, a pharmaceutically acceptable carrier includes any and all solvents, dispersion medium, coatings, antibacterial and antifungal agents, isotonic and absorption-delaying agents for pharmaceutically active substances also well known in the art. Except that any conventional medium or substance is incompatible with the active ingredient, then its use in the therapeutic composition is considered. Additional active ingredients may also be included in the composition.

It is especially favorable (useful) to create parenteral compositions in the form of dosage units to facilitate administration and uniformity of dosage. Dosage unit forms when used herein refer to physically separate units suitable as unit dosages for a mammalian subject to be treated; each unit containing a predetermined amount of the active substance to obtain the desired therapeutic effect in combination with the necessary pharmaceutical carrier. The features for the new dosage unit forms of the invention are dictated and directly depend on (a) the unique characteristics of the active substance to achieve a particular therapeutic effect, and (b) the limitations inherent in a component (component of a mixture), such as an active substance for treating a disease in a living subject, located in a disease in which physical health is impaired, as detailed above.

The main active ingredient is mixed (combine) for convenient and effective use in effective amounts with a suitable pharmaceutically acceptable carrier in a dosage unit form, as described above. A unit dosage form may, for example, contain the main active compound in amounts of from about 10 mg to about 6 g. Expressed in quantitative proportions, the active compound is usually in the carrier in an amount of from about 1 to about 750 mg / ml carrier. In the case of compositions containing additional active ingredients, the dosages are determined by the ratio to (proportionally) the usual dose and the route of administration of these ingredients.

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

The term treat refers to the prevention, treatment or alleviation of a disease or condition.

- 15 015566 patients.

The compounds of the present invention are administered to a patient suffering from the aforementioned type of disorder in an effective amount. These amounts are equivalent to the therapeutically effective amounts described above.

The following examples show the properties of lacosamide, formerly called Harcoseride (Nagkokepbe), or 8PM 927, which enhances pre-pulse inhibition with the antipsychotic clozapine in mice when co-administered.

Used lacosamide. According to the standard chemical nomenclature - (K) -2-acetamide-N-benzyl-3methoxypropionamide.

Example

Effects of lacosamide alone or in combination with clozapine on animal schizophrenia models.

Some anticonvulsants have proven preclinical and / or clinical efficacy as adjunctive therapy for antipsychotic agents for schizophrenia. Lacosamide was tested on simple animal models with predictive validity for psychosis, such as schizophrenia (i.e., pre-pulse inhibition (PP1) of the sound scare reflex).

Lacosamine has been tested alone and in combination with the atypical antipsychotic drug clozapine.

It should be noted that pre-pulse inhibition is the main model of psychosis and therefore indicates psychosis associated with other diseases or conditions, such as psychosis associated with schizophrenia, bipolar disorder, autism, Alzheimer's disease, attention deficit hyperactive disorder, alcohol abuse and / or medicine , emotional disorders, dyskinesia and related disorders, dementia (dementia), mental retardation, polydipsia / hyponatremia, severe disorders chnosti, cases of acute mania, obsessive manic disorders, intractable chronic insomnia, Huntington's disease, Tourette's syndrome, Parkinson's disease and / or dopaminergic therapy of Parkinson's disease.

Sound (acoustic) fright is an unconditioned reflex response to external sound stimulation. PP1 relates to reducing the fright response caused by the presentation of a low-intensity sound stimulus to an irritant causing fright. The PP1 module is the object of choice in the study of schizophrenia and antipsychotic effects due to the similarity between the results of studies in humans and rodents. Antipsychotics such as clozapine lead to a dose-dependent increase in PP1 in mice. Thus, an increase in PP1 in a normal mouse may indicate antipsychotic efficacy.

The C57BB / 61 mice from the Jackson Laboratory, Wag Nagog, Maine, were obtained at the age of 6 weeks, and were assigned separate identification numbers (tail marking). Animals were placed four per cage in polycarbonate cages with filter caps and acclimatized for 7 days. All animals were examined, taken with their hands and weighed before the start of the study to assess adequate (sufficient) health and suitability and to minimize nonspecific stress associated with manipulation.

During the course of the study, 12/12 day / night cycles and room temperature from 20 to 23 ° C with a relative humidity of about 50% were established. Food and water were provided freely during the continuation of the study. Each mouse was randomly assigned to the experimental groups and distributed according to cell numbers. The test was performed during the light phase of the animal cycle. In each experimental group, twelve animals were used.

Lacosamide was dissolved in physiological saline (0.9% No. 1C1 in sterile H ₂ O). Clozapine was dissolved in 1% Tween 80 in sterile H ₂ O at a final pH of 6.0. All compounds were administered intraperitoneally (WB) (injection volume: 10 ml / kg). Lacosamide was administered at doses of 1, 10 and 30 mg / kg and clozapine at a dose of 3 mg / kg. Doses are expressed as mg of salt. Control mice were injected with saline (solvent 1, UEN 1) or 1% Tween 80 (solvent 2, UEN 2) at pH 6.0. Treatment with the drug was distributed over days and animals were used only once. All tests were performed blindly. All compounds were administered 30 minutes prior to testing.

The animals were placed in a PP1 chamber (Meb A55OS1a1e5) for implantation during a 5-minute session of white noise (70 dB). After a period of acclimatization, an experimental session was automatically started. The session began with an addiction block of 6 presentations of one irritant causing fright, followed by 10 PP1 blocks from 6 different types of tests. Test types: zero (no stimulus), startle (120 dB), startle plus prepulse (4, 8 and 12 dB above the main noise, i.e. 74, 78 or 82 dB) and only one prepulse (82 dB). Test types were randomly offered within each block. Each test began with a 50 ms zero period during which the main movements were recorded. Over the next 20 ms period, a prepulse stimulus was presented and responses to it were measured. After a further 100 ms, fright stimuli were presented within 40 ms and responses were recorded within 100 ms from the start of the fright.

Responses were recorded every millisecond. The interval between tests averaged

- 16 015566 s (in the range from 10 to 20 s). In tests of a single startle, the main sound startle was measured, and in tests under the influence of a prepulse plus startle, the inhibition of the normal startle was determined and expressed as a percentage of the main response to the stimulus causing the startle (from tests of one startle), excluding the response to the startle at the first block of addiction. Eight animals were tested simultaneously.

Twelve animals were tested in each group. A total of 108 mice were tested using the following scheme:

VEN1 / VEN2 lacosamide [3 mg / kg] / VEN2 lacosamide [10 mg / kg] / VEN2 lacosamide [30 mg / kg] / VEN2

UEN1 / 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]

A two-factor ΑΝΟνΑ (analysis of variance) was performed with the types of treatments as an independent factor and the intensity of the prepulse as a dependent factor (i.e., repeated measurement). Where shown, this was followed by the Newman-Keuls posterior test. Considered significant p <0.05. The Newman-Keuls test compares two independent samples.

Animals that were injected with clozapine (3 mg / kg) showed a significant improvement in pre-pulse inhibition compared with animals treated with a solvent (p <0.05, Table 1). Lacosamide, when administered alone, did not have any significant effect on pre-pulse inhibition at any tested dose compared to the solvent.

Administration of lacosamide (at 30 mg / kg, rather than 3 or 10 mg / kg) in combination with clozapine, however, enhanced the effect of clozapine alone on pre-pulse inhibition, i.e. pre-pulse inhibition was significantly higher than the effect of clozapine alone (p <0.05).

The findings provide a basis for clinical trials in humans using lacosamide as adjunctive therapy for the treatment of psychosis, especially schizophrenia or psychosis associated with schizophrenia and / or other disease or conditions.

Table 1. Effects of lacosamide alone or in combination with clozapine on pre-pulse inhibition of response to sonic fright (RRG)

Treatment

ΡΡΙ value

UEN1 / UEN229 ± 3

UESH / CHF [3 mg / kg] 45 ± 2 * lacosamide [3 mg / kg] / UEN 229 ± 3 lacosamide [10 mg / kg] / UEN 234 ± 3 lacosamide [30 mg / kg] / UEN 227 ± 2 lacosamide [3 mg / kg] / € ΕΟΖ [3 mg / kg] 43 ± 2 * lacosamide [10 mg / kg] / CbO2 [3 mg / kg] 45 ± 2 * lacosamide [30 mg / kg] / € ΧΟΖ [3 mg / kg] 57 ± 5 *. # * p <0.05 compared with the νΕΗ / νΕΗ group # p <0.05 compared with the νΕΗ / ΕΗ.ΕΟΖ group

Claims (39)

CLAIM 1. The use of compounds having the formula (GG) H NN I I I Ar — CHg ~ E1 — C — C — C — C — C — GB Ιί I II o o o Formula in which Ar is phenyl, which is unsubstituted or substituted by at least one halogen group; P ₃ is CH ₂ -p, where O is alkoxy containing 1-6 carbon atoms, and Κι is alkyl containing 1-6 carbon atoms, or its pharmaceutically acceptable salt for preparing a pharmaceutical composition for preventing, alleviating or / or treating a disease treated with a dopamine antagonist, in addition - 17 015566 therapy to at least one dopamine antagonist. 2. The use according to claim 1, in which Ar is unsubstituted phenyl. 3. The use according to claim 1, in which the halogen is fluorine. 4. The use according to any one of claims 1 to ₃ , in which K ₃ is CH ₂ -O. where O is alkoxy containing 1-3 carbon atoms. 5. The use according to claim 1, where the compound is in the K-configuration and has the formula (III) H _g o I Η II I-IN-S-DAY-S-K! II I Oh Kz to Formula (III) in which K is benzyl, which is unsubstituted or substituted by at least one halogen group; K ₂ is hydrogen, K ₃ is CH ₂ -O, where O is alkoxy, containing 1-6 carbon atoms, and Κι is alkyl, containing 1-6 carbon atoms. 6. The use according to claim 5, wherein the compound is at least 88% enantiomerically pure. 7. The use according to claim 5 or 6, where K is unsubstituted benzyl. 8. The use according to any one of claims 5-6, where the halogen is fluorine. 9. The use according to any one of claims 5 to 8, wherein K ₃ is CH ₂ -O, wherein O is alkoxy containing 1 to 3 carbon atoms. 10. The use according to claim 1, wherein the compound of formula (11b) is selected from (K) -2-acetamido-N-benzyl-3methoxypropionamide, (K) -2-acetamido-N-benzyl-3-ethoxypropionamide, O-methyl- N-acetyl-O-serine-mfluorobenzylamide, O-methyl-N-acetyl-E-serine-p-fluorobenzylamide, and their pharmaceutically acceptable salts. 11. The use of claim 10, where the compound is at least 88% enantiomerically pure. 12. The use according to any one of the preceding claims, wherein the disease that is treated with a dopamine antagonist is schizophrenia, bipolar disorder, autism, attention deficit hyperactivity disorder, psychosis, psychosis associated with schizophrenia, bipolar disorder, autism, Alzheimer's disease or / and / or Iz and / or /) and / or / and / or schizophrenia, bipolar disorder, autism, Alzheimer's disease, and / or attention deficit and hyperactivity disorder, drug and / or alcohol abuse, emotional disorders, dyskinesias and related disorders, dementia, mental retardation, polydipsia / hyponatry severe personality disorders, acute cases of mania, obsessive manic disorder, intractable chronic insomnia, Huntington's disease, Tourette syndrome, Parkinson's disease, and / or dopaminergic therapy of Parkinson's disease. 13. The use according to any one of the preceding claims, wherein the disease that is being treated with a dopamine antagonist is schizophrenia, and the compound of formula (11b) is (K) -2-acetamido-N-benzyl-3methoxypropionamide. 14. The use according to any one of claims 1 to 12, wherein the disease treated by the dopamine antagonist is a bipolar disorder and the compound of the formula (11b) is (K) -2-acetamido-N-benzyl-3methoxypropionamide. 15. The use according to any one of the preceding claims, wherein the pharmaceutical composition is prepared for treatment with doses of a compound of at least 100 mg / day. 16. The use according to any one of the preceding claims, wherein the pharmaceutical composition is prepared for treatment with doses of a compound of a maximum of 1 g / day. 17. The use according to any one of the preceding claims, wherein the pharmaceutical composition is prepared for treatment with daily increasing doses of the compound until a predetermined daily dose is reached, which is maintained for further treatment. 18. The use according to any one of the preceding claims, wherein the pharmaceutical composition is prepared for treatment with 3 doses per day. 19. The use according to any one of claims 1 to 17, where the pharmaceutical composition is prepared for treatment with two doses per day. 20. The use according to any one of claims 1-17, where the pharmaceutical composition is prepared for the treatment of a single dose per day. 21. The use according to any preceding claims, wherein the pharmaceutical composition is prepared for administration, resulting in a plasma concentration of from 0.1 to 15 μg / ml (minimum) and from 5 to 18.5 μg / ml (peak), calculated as the average for multiple treated subjects. 22. The use according to any one of the preceding claims, wherein the pharmaceutical composition is prepared for oral or intravenous administration. 23. The use according to any one of the preceding claims, wherein the pharmaceutical composition for - 18 015566 preventing, alleviating or / or treating a disease that is being treated with a dopamine antagonist, contains: (a) at least one dopamine antagonist; and (b) at least one compound as defined in any one of claims 1 to 11. 24. The use according to any one of the preceding claims, wherein the pharmaceutical composition comprises a single dosage form. 25. The use according to any one of claims 1 to 23, where the pharmaceutical composition contains a separate dosage form, and the specified separate dosage form contains: (a) a first composition containing at least one dopamine antagonist, and (b) a second composition containing at least one compound, as defined in any one of claims 1 to 11. 26. The use according to any one of claims 24 or 25, wherein at least one dopamine antagonist is a Ό ₂ dopamine antagonist. 27. The use according to any one of claims 23 to 26, wherein the dopamine antagonist is olanzapine, used at a dose of 5-20 mg / day. 28. Use according to any one of claims 23 to 26, wherein the dopamine antagonist is clozapine at a dose of 100,900 mg / day. 29. The use according to any one of claims 23 to 26, wherein the dopamine antagonist is quetiapine at a dose of 100,800 mg / day. 30. The use according to any one of claims 23 to 26, wherein the dopamine antagonist is risperidone at a dose of 116 mg / day. 31. The use according to any one of p-26, where the dopamine antagonist is aripiprazole at a dose of 330 mg / day. 32. The use according to any one of p-26, where the dopamine antagonist is ziprasidone at a dose of 40160 mg / day. 33. The use according to any one of paragraphs.23-26, where the dopamine antagonist is sulpiride at a dose of 3001600 mg / day. 34. The use according to any one of p-26, where the dopamine antagonist is amisulpride at a dose of 50-1200 mg / day. 35. The use according to any one of claims 23 to 26, wherein the dopamine antagonist is zotepin at a dose of 75-450 mg / day. 36. A pharmaceutical composition comprising: (a) at least one dopamine antagonist; and (b) at least one compound as defined in any one of claims 1 to 11. 37. The pharmaceutical composition according p, which contains a single dosage form. 38. The pharmaceutical composition according p, which contains a separate dosage form, and the specified separate dosage form contains: (a) a first composition containing at least one dopamine antagonist, and (b) a second composition containing at least one compound, as defined in any one of claims 1 to 11. 39. The pharmaceutical composition according to any one of claims 36 to 38, in which at least one dopamine antagonist is a Ό ₂ dopamine antagonist.